9781118016022 · 2013-10-07 · 1.2.1.2 examples of enamine–enamine and enamine–enamine...
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CatalytiC CasCade ReaCtions
CatalytiC CasCade ReaCtions
Edited by
Peng-Fei XuState Key Laboratory of Applied Organic ChemistryCollege of Chemistry and Chemical EngineeringLanzhou UniversityLanzhou PR China
Wei WangDepartment of Chemistry and Chemical BiologyUniversity of New MexicoAlbuquerque New Mexico
Copyright copy 2014 by John Wiley amp Sons Inc All rights reserved
Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data
Catalytic cascade reactions edited by Dr Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Dr Wei Wang Department of Chemistry and Chemical Biology University of New Mexico pages cm Includes bibliographical references and index ISBN 978-1-118-01602-2 (hardback) 1 Organic reaction mechanisms 2 Catalysis 3 Chemical reactions 4 Organic compoundsndashSynthesis I Xu Peng-Fei 1964ndash editor of compilation II Wang Wei (Associate professor of chemistry) editor of compilation QD5025C38 2013 547prime215ndashdc23
2013011112
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
v
Contents
Contributors xi
Preface xiii
1 amine-Catalyzed Cascade Reactions 1Aiguo Song and Wei Wang
11 Introduction 212 Enamine-Activated Cascade Reactions 3
121 EnaminendashEnamine Cascades 31211 Design of EnaminendashEnamine Cascades 31212 Examples of EnaminendashEnamine and EnaminendashEnamine
Cyclization Cascades 31213 EnaminendashEnamine in Three-Component Cascades 61214 Enamine-Activated Double α-Functionalization 71215 Robinson Annulations 7
122 EnaminendashIminium Cascades 81221 Design of EnaminendashIminium Cascades 81222 Examples of [4 + 2] Reactions with Enamine-Activated
Dienes 81223 Inverse-Electron-Demand [4 + 2] Reactions with
Enamine-Activated Dienophiles 131224 EnaminendashIminiumndashEnamine Cascades 16
123 Enamine Catalysis Cyclization 191231 Design of Enamine-Cyclization Cascade Reactions 191232 Enamine-Intermolecular Addition Cascades 19
vi CONTENTS
1233 Enamine-Intramolecular Addition Cascades 201234 Enamine-Intramolecular Aldol Cascades 21
13 Iminium-Initiated Cascade Reactions 21131 Design of IminiumndashEnamine Cascade Reactions 21132 Iminium-Activated DielsndashAlder Reactions 22133 Iminium-Activated Sequential [4 + 2] Reactions 24134 Iminium-Activated [3 + 2] Reactions 25135 Iminium-Activated Sequential [3 + 2] Reactions 27136 Iminium-Activated [2 + 1] Reactions 30
1361 Iminium-Activated Cyclopropanations 301362 Iminium-Activated Epoxidations 321363 Iminium-Activated Aziridinations 34
137 Iminium-Activated Multicomponent Reactions 35138 Iminium-Activated [3 + 3] Reactions 37
1381 Iminium-Activated All-Carbon-Centered [3 + 3] Reactions 37
1382 Iminium-Activated Hetero-[3 + 3] Reactions 40139 Other Iminium-Activated Cascade Reactions 42
14 Cycle-Specific Catalysis Cascades 4215 Other Strategies 4516 Summary and Outlook 46References 46
2 Broslashnsted acidndashCatalyzed Cascade Reactions 53Jun Jiang and Liu-Zhu Gong
21 Introduction 5422 Protonic AcidndashCatalyzed Cascade Reactions 55
221 Mannich Reaction 55222 PictectndashSpengler Reaction 56223 Biginelli Reaction 58224 Povarov Reaction 59225 Reduction Reaction 60226 13-Dipolar Cycloaddition 61227 Darzen Reaction 65228 Acyclic Aminal and Hemiaminal Synthesis 66229 Rearrangement Reaction 672210 αb-Unsaturated Imine-Involved Cyclization Reaction 692211 Alkylation Reaction 692212 Desymmetrization Reaction 702213 Halocyclization 712214 Redox Reaction 722215 Isocyanide-Involved Multicomponent Reaction 732216 Other Protonic AcidndashCatalyzed Cascade
Reactions 7523 Chiral Thiourea (Urea)ndashCatalyzed Cascade Reactions 75
231 Neutral Activation 76
CONTENTS vii
2311 Halolactonization 762312 Mannich Reaction 772313 MichaelndashAldol Reaction 782314 Michael-Alkylation Reaction 792315 Cyano-Involved Michael-Cyclization Reaction 822316 Michael-Hemiketalization (Hemiacetalization)
Reaction 842317 MichaelndashHenry Reaction 872318 MichaelndashMichael Reaction 902319 Petasis Reaction 9423110 Sulfur YlidendashInvolved Michael-Cyclization Reaction 9523111 α-Isothiocyanato ImidendashInvolved Cascade Reaction 9623112 α-IsocyanidendashInvolved Cascade Reaction 98
232 Anion-Binding Catalysis 992321 PictetndashSpengler Reaction 992322 Other Iminium IonndashInvolved Cascade Reaction 1012323 Oxocarbenium IonndashInvolved Cascade Reaction 103
24 Broslashnsted Acid and Transition Metal Cooperatively Catalyzed Cascade Reactions 104241 Dual Catalysis 105242 Cascade Catalysis 108
2421 Pd(0)Broslashnsted Acid System 1092422 RutheniumBroslashnsted Acid System 1092423 Au(I)Broslashnsted Acid System 1132424 Other Binary Catalytic Systems 114
25 Conclusions 116References 117
3 application of organocatalytic Cascade Reactions in natural Product synthesis and drug discovery 123Yao Wang and Peng-Fei Xu
31 Introduction 12332 Amine-Catalyzed Cascade Reactions in Natural Product Synthesis 125
321 Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis 125
322 Cycle-Specific Cascade Catalysis in Natural Product Synthesis 1293221 IminiumndashEnamine Cycle-Specific Cascade Catalysis 1303222 Enamine (Dienamine)ndashIminium Cycle-Specific
Cascade Catalysis 1323223 More Complex Cycle-Specific Cascade Catalysis 134
33 Broslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 137
34 Bifunctional BaseBroslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 139
35 Summary and Outlook 140References 142
viii CONTENTS
4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang
41 Introduction 14542 Cascade Reactions of Alkynes 147
421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154
422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165
43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174
5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu
51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219
6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang
61 Introduction 22662 Cascade Reactions Involving Alkenes 226
621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234
63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
CatalytiC CasCade ReaCtions
CatalytiC CasCade ReaCtions
Edited by
Peng-Fei XuState Key Laboratory of Applied Organic ChemistryCollege of Chemistry and Chemical EngineeringLanzhou UniversityLanzhou PR China
Wei WangDepartment of Chemistry and Chemical BiologyUniversity of New MexicoAlbuquerque New Mexico
Copyright copy 2014 by John Wiley amp Sons Inc All rights reserved
Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada
No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording scanning or otherwise except as permitted under Section 107 or 108 of the 1976 United States Copyright Act without either the prior written permission of the Publisher or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center Inc 222 Rosewood Drive Danvers MA 01923 (978) 750-8400 fax (978) 750-4470 or on the web at wwwcopyrightcom Requests to the Publisher for permission should be addressed to the Permissions Department John Wiley amp Sons Inc 111 River Street Hoboken NJ 07030 (201) 748-6011 fax (201) 748-6008 or online at httpwwwwileycomgopermission
Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages including but not limited to special incidental consequential or other damages
For general information on our other products and services or for technical support please contact our Customer Care Department within the United States at (800) 762-2974 outside the United States at (317) 572-3993 or fax (317) 572-4002
Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products visit our web site at wwwwileycom
Library of Congress Cataloging-in-Publication Data
Catalytic cascade reactions edited by Dr Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Dr Wei Wang Department of Chemistry and Chemical Biology University of New Mexico pages cm Includes bibliographical references and index ISBN 978-1-118-01602-2 (hardback) 1 Organic reaction mechanisms 2 Catalysis 3 Chemical reactions 4 Organic compoundsndashSynthesis I Xu Peng-Fei 1964ndash editor of compilation II Wang Wei (Associate professor of chemistry) editor of compilation QD5025C38 2013 547prime215ndashdc23
2013011112
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
v
Contents
Contributors xi
Preface xiii
1 amine-Catalyzed Cascade Reactions 1Aiguo Song and Wei Wang
11 Introduction 212 Enamine-Activated Cascade Reactions 3
121 EnaminendashEnamine Cascades 31211 Design of EnaminendashEnamine Cascades 31212 Examples of EnaminendashEnamine and EnaminendashEnamine
Cyclization Cascades 31213 EnaminendashEnamine in Three-Component Cascades 61214 Enamine-Activated Double α-Functionalization 71215 Robinson Annulations 7
122 EnaminendashIminium Cascades 81221 Design of EnaminendashIminium Cascades 81222 Examples of [4 + 2] Reactions with Enamine-Activated
Dienes 81223 Inverse-Electron-Demand [4 + 2] Reactions with
Enamine-Activated Dienophiles 131224 EnaminendashIminiumndashEnamine Cascades 16
123 Enamine Catalysis Cyclization 191231 Design of Enamine-Cyclization Cascade Reactions 191232 Enamine-Intermolecular Addition Cascades 19
vi CONTENTS
1233 Enamine-Intramolecular Addition Cascades 201234 Enamine-Intramolecular Aldol Cascades 21
13 Iminium-Initiated Cascade Reactions 21131 Design of IminiumndashEnamine Cascade Reactions 21132 Iminium-Activated DielsndashAlder Reactions 22133 Iminium-Activated Sequential [4 + 2] Reactions 24134 Iminium-Activated [3 + 2] Reactions 25135 Iminium-Activated Sequential [3 + 2] Reactions 27136 Iminium-Activated [2 + 1] Reactions 30
1361 Iminium-Activated Cyclopropanations 301362 Iminium-Activated Epoxidations 321363 Iminium-Activated Aziridinations 34
137 Iminium-Activated Multicomponent Reactions 35138 Iminium-Activated [3 + 3] Reactions 37
1381 Iminium-Activated All-Carbon-Centered [3 + 3] Reactions 37
1382 Iminium-Activated Hetero-[3 + 3] Reactions 40139 Other Iminium-Activated Cascade Reactions 42
14 Cycle-Specific Catalysis Cascades 4215 Other Strategies 4516 Summary and Outlook 46References 46
2 Broslashnsted acidndashCatalyzed Cascade Reactions 53Jun Jiang and Liu-Zhu Gong
21 Introduction 5422 Protonic AcidndashCatalyzed Cascade Reactions 55
221 Mannich Reaction 55222 PictectndashSpengler Reaction 56223 Biginelli Reaction 58224 Povarov Reaction 59225 Reduction Reaction 60226 13-Dipolar Cycloaddition 61227 Darzen Reaction 65228 Acyclic Aminal and Hemiaminal Synthesis 66229 Rearrangement Reaction 672210 αb-Unsaturated Imine-Involved Cyclization Reaction 692211 Alkylation Reaction 692212 Desymmetrization Reaction 702213 Halocyclization 712214 Redox Reaction 722215 Isocyanide-Involved Multicomponent Reaction 732216 Other Protonic AcidndashCatalyzed Cascade
Reactions 7523 Chiral Thiourea (Urea)ndashCatalyzed Cascade Reactions 75
231 Neutral Activation 76
CONTENTS vii
2311 Halolactonization 762312 Mannich Reaction 772313 MichaelndashAldol Reaction 782314 Michael-Alkylation Reaction 792315 Cyano-Involved Michael-Cyclization Reaction 822316 Michael-Hemiketalization (Hemiacetalization)
Reaction 842317 MichaelndashHenry Reaction 872318 MichaelndashMichael Reaction 902319 Petasis Reaction 9423110 Sulfur YlidendashInvolved Michael-Cyclization Reaction 9523111 α-Isothiocyanato ImidendashInvolved Cascade Reaction 9623112 α-IsocyanidendashInvolved Cascade Reaction 98
232 Anion-Binding Catalysis 992321 PictetndashSpengler Reaction 992322 Other Iminium IonndashInvolved Cascade Reaction 1012323 Oxocarbenium IonndashInvolved Cascade Reaction 103
24 Broslashnsted Acid and Transition Metal Cooperatively Catalyzed Cascade Reactions 104241 Dual Catalysis 105242 Cascade Catalysis 108
2421 Pd(0)Broslashnsted Acid System 1092422 RutheniumBroslashnsted Acid System 1092423 Au(I)Broslashnsted Acid System 1132424 Other Binary Catalytic Systems 114
25 Conclusions 116References 117
3 application of organocatalytic Cascade Reactions in natural Product synthesis and drug discovery 123Yao Wang and Peng-Fei Xu
31 Introduction 12332 Amine-Catalyzed Cascade Reactions in Natural Product Synthesis 125
321 Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis 125
322 Cycle-Specific Cascade Catalysis in Natural Product Synthesis 1293221 IminiumndashEnamine Cycle-Specific Cascade Catalysis 1303222 Enamine (Dienamine)ndashIminium Cycle-Specific
Cascade Catalysis 1323223 More Complex Cycle-Specific Cascade Catalysis 134
33 Broslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 137
34 Bifunctional BaseBroslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 139
35 Summary and Outlook 140References 142
viii CONTENTS
4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang
41 Introduction 14542 Cascade Reactions of Alkynes 147
421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154
422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165
43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174
5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu
51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219
6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang
61 Introduction 22662 Cascade Reactions Involving Alkenes 226
621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234
63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
CatalytiC CasCade ReaCtions
Edited by
Peng-Fei XuState Key Laboratory of Applied Organic ChemistryCollege of Chemistry and Chemical EngineeringLanzhou UniversityLanzhou PR China
Wei WangDepartment of Chemistry and Chemical BiologyUniversity of New MexicoAlbuquerque New Mexico
Copyright copy 2014 by John Wiley amp Sons Inc All rights reserved
Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data
Catalytic cascade reactions edited by Dr Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Dr Wei Wang Department of Chemistry and Chemical Biology University of New Mexico pages cm Includes bibliographical references and index ISBN 978-1-118-01602-2 (hardback) 1 Organic reaction mechanisms 2 Catalysis 3 Chemical reactions 4 Organic compoundsndashSynthesis I Xu Peng-Fei 1964ndash editor of compilation II Wang Wei (Associate professor of chemistry) editor of compilation QD5025C38 2013 547prime215ndashdc23
2013011112
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
v
Contents
Contributors xi
Preface xiii
1 amine-Catalyzed Cascade Reactions 1Aiguo Song and Wei Wang
11 Introduction 212 Enamine-Activated Cascade Reactions 3
121 EnaminendashEnamine Cascades 31211 Design of EnaminendashEnamine Cascades 31212 Examples of EnaminendashEnamine and EnaminendashEnamine
Cyclization Cascades 31213 EnaminendashEnamine in Three-Component Cascades 61214 Enamine-Activated Double α-Functionalization 71215 Robinson Annulations 7
122 EnaminendashIminium Cascades 81221 Design of EnaminendashIminium Cascades 81222 Examples of [4 + 2] Reactions with Enamine-Activated
Dienes 81223 Inverse-Electron-Demand [4 + 2] Reactions with
Enamine-Activated Dienophiles 131224 EnaminendashIminiumndashEnamine Cascades 16
123 Enamine Catalysis Cyclization 191231 Design of Enamine-Cyclization Cascade Reactions 191232 Enamine-Intermolecular Addition Cascades 19
vi CONTENTS
1233 Enamine-Intramolecular Addition Cascades 201234 Enamine-Intramolecular Aldol Cascades 21
13 Iminium-Initiated Cascade Reactions 21131 Design of IminiumndashEnamine Cascade Reactions 21132 Iminium-Activated DielsndashAlder Reactions 22133 Iminium-Activated Sequential [4 + 2] Reactions 24134 Iminium-Activated [3 + 2] Reactions 25135 Iminium-Activated Sequential [3 + 2] Reactions 27136 Iminium-Activated [2 + 1] Reactions 30
1361 Iminium-Activated Cyclopropanations 301362 Iminium-Activated Epoxidations 321363 Iminium-Activated Aziridinations 34
137 Iminium-Activated Multicomponent Reactions 35138 Iminium-Activated [3 + 3] Reactions 37
1381 Iminium-Activated All-Carbon-Centered [3 + 3] Reactions 37
1382 Iminium-Activated Hetero-[3 + 3] Reactions 40139 Other Iminium-Activated Cascade Reactions 42
14 Cycle-Specific Catalysis Cascades 4215 Other Strategies 4516 Summary and Outlook 46References 46
2 Broslashnsted acidndashCatalyzed Cascade Reactions 53Jun Jiang and Liu-Zhu Gong
21 Introduction 5422 Protonic AcidndashCatalyzed Cascade Reactions 55
221 Mannich Reaction 55222 PictectndashSpengler Reaction 56223 Biginelli Reaction 58224 Povarov Reaction 59225 Reduction Reaction 60226 13-Dipolar Cycloaddition 61227 Darzen Reaction 65228 Acyclic Aminal and Hemiaminal Synthesis 66229 Rearrangement Reaction 672210 αb-Unsaturated Imine-Involved Cyclization Reaction 692211 Alkylation Reaction 692212 Desymmetrization Reaction 702213 Halocyclization 712214 Redox Reaction 722215 Isocyanide-Involved Multicomponent Reaction 732216 Other Protonic AcidndashCatalyzed Cascade
Reactions 7523 Chiral Thiourea (Urea)ndashCatalyzed Cascade Reactions 75
231 Neutral Activation 76
CONTENTS vii
2311 Halolactonization 762312 Mannich Reaction 772313 MichaelndashAldol Reaction 782314 Michael-Alkylation Reaction 792315 Cyano-Involved Michael-Cyclization Reaction 822316 Michael-Hemiketalization (Hemiacetalization)
Reaction 842317 MichaelndashHenry Reaction 872318 MichaelndashMichael Reaction 902319 Petasis Reaction 9423110 Sulfur YlidendashInvolved Michael-Cyclization Reaction 9523111 α-Isothiocyanato ImidendashInvolved Cascade Reaction 9623112 α-IsocyanidendashInvolved Cascade Reaction 98
232 Anion-Binding Catalysis 992321 PictetndashSpengler Reaction 992322 Other Iminium IonndashInvolved Cascade Reaction 1012323 Oxocarbenium IonndashInvolved Cascade Reaction 103
24 Broslashnsted Acid and Transition Metal Cooperatively Catalyzed Cascade Reactions 104241 Dual Catalysis 105242 Cascade Catalysis 108
2421 Pd(0)Broslashnsted Acid System 1092422 RutheniumBroslashnsted Acid System 1092423 Au(I)Broslashnsted Acid System 1132424 Other Binary Catalytic Systems 114
25 Conclusions 116References 117
3 application of organocatalytic Cascade Reactions in natural Product synthesis and drug discovery 123Yao Wang and Peng-Fei Xu
31 Introduction 12332 Amine-Catalyzed Cascade Reactions in Natural Product Synthesis 125
321 Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis 125
322 Cycle-Specific Cascade Catalysis in Natural Product Synthesis 1293221 IminiumndashEnamine Cycle-Specific Cascade Catalysis 1303222 Enamine (Dienamine)ndashIminium Cycle-Specific
Cascade Catalysis 1323223 More Complex Cycle-Specific Cascade Catalysis 134
33 Broslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 137
34 Bifunctional BaseBroslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 139
35 Summary and Outlook 140References 142
viii CONTENTS
4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang
41 Introduction 14542 Cascade Reactions of Alkynes 147
421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154
422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165
43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174
5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu
51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219
6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang
61 Introduction 22662 Cascade Reactions Involving Alkenes 226
621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234
63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
Copyright copy 2014 by John Wiley amp Sons Inc All rights reserved
Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada
No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording scanning or otherwise except as permitted under Section 107 or 108 of the 1976 United States Copyright Act without either the prior written permission of the Publisher or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center Inc 222 Rosewood Drive Danvers MA 01923 (978) 750-8400 fax (978) 750-4470 or on the web at wwwcopyrightcom Requests to the Publisher for permission should be addressed to the Permissions Department John Wiley amp Sons Inc 111 River Street Hoboken NJ 07030 (201) 748-6011 fax (201) 748-6008 or online at httpwwwwileycomgopermission
Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages including but not limited to special incidental consequential or other damages
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Library of Congress Cataloging-in-Publication Data
Catalytic cascade reactions edited by Dr Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Dr Wei Wang Department of Chemistry and Chemical Biology University of New Mexico pages cm Includes bibliographical references and index ISBN 978-1-118-01602-2 (hardback) 1 Organic reaction mechanisms 2 Catalysis 3 Chemical reactions 4 Organic compoundsndashSynthesis I Xu Peng-Fei 1964ndash editor of compilation II Wang Wei (Associate professor of chemistry) editor of compilation QD5025C38 2013 547prime215ndashdc23
2013011112
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
v
Contents
Contributors xi
Preface xiii
1 amine-Catalyzed Cascade Reactions 1Aiguo Song and Wei Wang
11 Introduction 212 Enamine-Activated Cascade Reactions 3
121 EnaminendashEnamine Cascades 31211 Design of EnaminendashEnamine Cascades 31212 Examples of EnaminendashEnamine and EnaminendashEnamine
Cyclization Cascades 31213 EnaminendashEnamine in Three-Component Cascades 61214 Enamine-Activated Double α-Functionalization 71215 Robinson Annulations 7
122 EnaminendashIminium Cascades 81221 Design of EnaminendashIminium Cascades 81222 Examples of [4 + 2] Reactions with Enamine-Activated
Dienes 81223 Inverse-Electron-Demand [4 + 2] Reactions with
Enamine-Activated Dienophiles 131224 EnaminendashIminiumndashEnamine Cascades 16
123 Enamine Catalysis Cyclization 191231 Design of Enamine-Cyclization Cascade Reactions 191232 Enamine-Intermolecular Addition Cascades 19
vi CONTENTS
1233 Enamine-Intramolecular Addition Cascades 201234 Enamine-Intramolecular Aldol Cascades 21
13 Iminium-Initiated Cascade Reactions 21131 Design of IminiumndashEnamine Cascade Reactions 21132 Iminium-Activated DielsndashAlder Reactions 22133 Iminium-Activated Sequential [4 + 2] Reactions 24134 Iminium-Activated [3 + 2] Reactions 25135 Iminium-Activated Sequential [3 + 2] Reactions 27136 Iminium-Activated [2 + 1] Reactions 30
1361 Iminium-Activated Cyclopropanations 301362 Iminium-Activated Epoxidations 321363 Iminium-Activated Aziridinations 34
137 Iminium-Activated Multicomponent Reactions 35138 Iminium-Activated [3 + 3] Reactions 37
1381 Iminium-Activated All-Carbon-Centered [3 + 3] Reactions 37
1382 Iminium-Activated Hetero-[3 + 3] Reactions 40139 Other Iminium-Activated Cascade Reactions 42
14 Cycle-Specific Catalysis Cascades 4215 Other Strategies 4516 Summary and Outlook 46References 46
2 Broslashnsted acidndashCatalyzed Cascade Reactions 53Jun Jiang and Liu-Zhu Gong
21 Introduction 5422 Protonic AcidndashCatalyzed Cascade Reactions 55
221 Mannich Reaction 55222 PictectndashSpengler Reaction 56223 Biginelli Reaction 58224 Povarov Reaction 59225 Reduction Reaction 60226 13-Dipolar Cycloaddition 61227 Darzen Reaction 65228 Acyclic Aminal and Hemiaminal Synthesis 66229 Rearrangement Reaction 672210 αb-Unsaturated Imine-Involved Cyclization Reaction 692211 Alkylation Reaction 692212 Desymmetrization Reaction 702213 Halocyclization 712214 Redox Reaction 722215 Isocyanide-Involved Multicomponent Reaction 732216 Other Protonic AcidndashCatalyzed Cascade
Reactions 7523 Chiral Thiourea (Urea)ndashCatalyzed Cascade Reactions 75
231 Neutral Activation 76
CONTENTS vii
2311 Halolactonization 762312 Mannich Reaction 772313 MichaelndashAldol Reaction 782314 Michael-Alkylation Reaction 792315 Cyano-Involved Michael-Cyclization Reaction 822316 Michael-Hemiketalization (Hemiacetalization)
Reaction 842317 MichaelndashHenry Reaction 872318 MichaelndashMichael Reaction 902319 Petasis Reaction 9423110 Sulfur YlidendashInvolved Michael-Cyclization Reaction 9523111 α-Isothiocyanato ImidendashInvolved Cascade Reaction 9623112 α-IsocyanidendashInvolved Cascade Reaction 98
232 Anion-Binding Catalysis 992321 PictetndashSpengler Reaction 992322 Other Iminium IonndashInvolved Cascade Reaction 1012323 Oxocarbenium IonndashInvolved Cascade Reaction 103
24 Broslashnsted Acid and Transition Metal Cooperatively Catalyzed Cascade Reactions 104241 Dual Catalysis 105242 Cascade Catalysis 108
2421 Pd(0)Broslashnsted Acid System 1092422 RutheniumBroslashnsted Acid System 1092423 Au(I)Broslashnsted Acid System 1132424 Other Binary Catalytic Systems 114
25 Conclusions 116References 117
3 application of organocatalytic Cascade Reactions in natural Product synthesis and drug discovery 123Yao Wang and Peng-Fei Xu
31 Introduction 12332 Amine-Catalyzed Cascade Reactions in Natural Product Synthesis 125
321 Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis 125
322 Cycle-Specific Cascade Catalysis in Natural Product Synthesis 1293221 IminiumndashEnamine Cycle-Specific Cascade Catalysis 1303222 Enamine (Dienamine)ndashIminium Cycle-Specific
Cascade Catalysis 1323223 More Complex Cycle-Specific Cascade Catalysis 134
33 Broslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 137
34 Bifunctional BaseBroslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 139
35 Summary and Outlook 140References 142
viii CONTENTS
4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang
41 Introduction 14542 Cascade Reactions of Alkynes 147
421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154
422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165
43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174
5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu
51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219
6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang
61 Introduction 22662 Cascade Reactions Involving Alkenes 226
621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234
63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
v
Contents
Contributors xi
Preface xiii
1 amine-Catalyzed Cascade Reactions 1Aiguo Song and Wei Wang
11 Introduction 212 Enamine-Activated Cascade Reactions 3
121 EnaminendashEnamine Cascades 31211 Design of EnaminendashEnamine Cascades 31212 Examples of EnaminendashEnamine and EnaminendashEnamine
Cyclization Cascades 31213 EnaminendashEnamine in Three-Component Cascades 61214 Enamine-Activated Double α-Functionalization 71215 Robinson Annulations 7
122 EnaminendashIminium Cascades 81221 Design of EnaminendashIminium Cascades 81222 Examples of [4 + 2] Reactions with Enamine-Activated
Dienes 81223 Inverse-Electron-Demand [4 + 2] Reactions with
Enamine-Activated Dienophiles 131224 EnaminendashIminiumndashEnamine Cascades 16
123 Enamine Catalysis Cyclization 191231 Design of Enamine-Cyclization Cascade Reactions 191232 Enamine-Intermolecular Addition Cascades 19
vi CONTENTS
1233 Enamine-Intramolecular Addition Cascades 201234 Enamine-Intramolecular Aldol Cascades 21
13 Iminium-Initiated Cascade Reactions 21131 Design of IminiumndashEnamine Cascade Reactions 21132 Iminium-Activated DielsndashAlder Reactions 22133 Iminium-Activated Sequential [4 + 2] Reactions 24134 Iminium-Activated [3 + 2] Reactions 25135 Iminium-Activated Sequential [3 + 2] Reactions 27136 Iminium-Activated [2 + 1] Reactions 30
1361 Iminium-Activated Cyclopropanations 301362 Iminium-Activated Epoxidations 321363 Iminium-Activated Aziridinations 34
137 Iminium-Activated Multicomponent Reactions 35138 Iminium-Activated [3 + 3] Reactions 37
1381 Iminium-Activated All-Carbon-Centered [3 + 3] Reactions 37
1382 Iminium-Activated Hetero-[3 + 3] Reactions 40139 Other Iminium-Activated Cascade Reactions 42
14 Cycle-Specific Catalysis Cascades 4215 Other Strategies 4516 Summary and Outlook 46References 46
2 Broslashnsted acidndashCatalyzed Cascade Reactions 53Jun Jiang and Liu-Zhu Gong
21 Introduction 5422 Protonic AcidndashCatalyzed Cascade Reactions 55
221 Mannich Reaction 55222 PictectndashSpengler Reaction 56223 Biginelli Reaction 58224 Povarov Reaction 59225 Reduction Reaction 60226 13-Dipolar Cycloaddition 61227 Darzen Reaction 65228 Acyclic Aminal and Hemiaminal Synthesis 66229 Rearrangement Reaction 672210 αb-Unsaturated Imine-Involved Cyclization Reaction 692211 Alkylation Reaction 692212 Desymmetrization Reaction 702213 Halocyclization 712214 Redox Reaction 722215 Isocyanide-Involved Multicomponent Reaction 732216 Other Protonic AcidndashCatalyzed Cascade
Reactions 7523 Chiral Thiourea (Urea)ndashCatalyzed Cascade Reactions 75
231 Neutral Activation 76
CONTENTS vii
2311 Halolactonization 762312 Mannich Reaction 772313 MichaelndashAldol Reaction 782314 Michael-Alkylation Reaction 792315 Cyano-Involved Michael-Cyclization Reaction 822316 Michael-Hemiketalization (Hemiacetalization)
Reaction 842317 MichaelndashHenry Reaction 872318 MichaelndashMichael Reaction 902319 Petasis Reaction 9423110 Sulfur YlidendashInvolved Michael-Cyclization Reaction 9523111 α-Isothiocyanato ImidendashInvolved Cascade Reaction 9623112 α-IsocyanidendashInvolved Cascade Reaction 98
232 Anion-Binding Catalysis 992321 PictetndashSpengler Reaction 992322 Other Iminium IonndashInvolved Cascade Reaction 1012323 Oxocarbenium IonndashInvolved Cascade Reaction 103
24 Broslashnsted Acid and Transition Metal Cooperatively Catalyzed Cascade Reactions 104241 Dual Catalysis 105242 Cascade Catalysis 108
2421 Pd(0)Broslashnsted Acid System 1092422 RutheniumBroslashnsted Acid System 1092423 Au(I)Broslashnsted Acid System 1132424 Other Binary Catalytic Systems 114
25 Conclusions 116References 117
3 application of organocatalytic Cascade Reactions in natural Product synthesis and drug discovery 123Yao Wang and Peng-Fei Xu
31 Introduction 12332 Amine-Catalyzed Cascade Reactions in Natural Product Synthesis 125
321 Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis 125
322 Cycle-Specific Cascade Catalysis in Natural Product Synthesis 1293221 IminiumndashEnamine Cycle-Specific Cascade Catalysis 1303222 Enamine (Dienamine)ndashIminium Cycle-Specific
Cascade Catalysis 1323223 More Complex Cycle-Specific Cascade Catalysis 134
33 Broslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 137
34 Bifunctional BaseBroslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 139
35 Summary and Outlook 140References 142
viii CONTENTS
4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang
41 Introduction 14542 Cascade Reactions of Alkynes 147
421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154
422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165
43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174
5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu
51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219
6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang
61 Introduction 22662 Cascade Reactions Involving Alkenes 226
621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234
63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
vi CONTENTS
1233 Enamine-Intramolecular Addition Cascades 201234 Enamine-Intramolecular Aldol Cascades 21
13 Iminium-Initiated Cascade Reactions 21131 Design of IminiumndashEnamine Cascade Reactions 21132 Iminium-Activated DielsndashAlder Reactions 22133 Iminium-Activated Sequential [4 + 2] Reactions 24134 Iminium-Activated [3 + 2] Reactions 25135 Iminium-Activated Sequential [3 + 2] Reactions 27136 Iminium-Activated [2 + 1] Reactions 30
1361 Iminium-Activated Cyclopropanations 301362 Iminium-Activated Epoxidations 321363 Iminium-Activated Aziridinations 34
137 Iminium-Activated Multicomponent Reactions 35138 Iminium-Activated [3 + 3] Reactions 37
1381 Iminium-Activated All-Carbon-Centered [3 + 3] Reactions 37
1382 Iminium-Activated Hetero-[3 + 3] Reactions 40139 Other Iminium-Activated Cascade Reactions 42
14 Cycle-Specific Catalysis Cascades 4215 Other Strategies 4516 Summary and Outlook 46References 46
2 Broslashnsted acidndashCatalyzed Cascade Reactions 53Jun Jiang and Liu-Zhu Gong
21 Introduction 5422 Protonic AcidndashCatalyzed Cascade Reactions 55
221 Mannich Reaction 55222 PictectndashSpengler Reaction 56223 Biginelli Reaction 58224 Povarov Reaction 59225 Reduction Reaction 60226 13-Dipolar Cycloaddition 61227 Darzen Reaction 65228 Acyclic Aminal and Hemiaminal Synthesis 66229 Rearrangement Reaction 672210 αb-Unsaturated Imine-Involved Cyclization Reaction 692211 Alkylation Reaction 692212 Desymmetrization Reaction 702213 Halocyclization 712214 Redox Reaction 722215 Isocyanide-Involved Multicomponent Reaction 732216 Other Protonic AcidndashCatalyzed Cascade
Reactions 7523 Chiral Thiourea (Urea)ndashCatalyzed Cascade Reactions 75
231 Neutral Activation 76
CONTENTS vii
2311 Halolactonization 762312 Mannich Reaction 772313 MichaelndashAldol Reaction 782314 Michael-Alkylation Reaction 792315 Cyano-Involved Michael-Cyclization Reaction 822316 Michael-Hemiketalization (Hemiacetalization)
Reaction 842317 MichaelndashHenry Reaction 872318 MichaelndashMichael Reaction 902319 Petasis Reaction 9423110 Sulfur YlidendashInvolved Michael-Cyclization Reaction 9523111 α-Isothiocyanato ImidendashInvolved Cascade Reaction 9623112 α-IsocyanidendashInvolved Cascade Reaction 98
232 Anion-Binding Catalysis 992321 PictetndashSpengler Reaction 992322 Other Iminium IonndashInvolved Cascade Reaction 1012323 Oxocarbenium IonndashInvolved Cascade Reaction 103
24 Broslashnsted Acid and Transition Metal Cooperatively Catalyzed Cascade Reactions 104241 Dual Catalysis 105242 Cascade Catalysis 108
2421 Pd(0)Broslashnsted Acid System 1092422 RutheniumBroslashnsted Acid System 1092423 Au(I)Broslashnsted Acid System 1132424 Other Binary Catalytic Systems 114
25 Conclusions 116References 117
3 application of organocatalytic Cascade Reactions in natural Product synthesis and drug discovery 123Yao Wang and Peng-Fei Xu
31 Introduction 12332 Amine-Catalyzed Cascade Reactions in Natural Product Synthesis 125
321 Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis 125
322 Cycle-Specific Cascade Catalysis in Natural Product Synthesis 1293221 IminiumndashEnamine Cycle-Specific Cascade Catalysis 1303222 Enamine (Dienamine)ndashIminium Cycle-Specific
Cascade Catalysis 1323223 More Complex Cycle-Specific Cascade Catalysis 134
33 Broslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 137
34 Bifunctional BaseBroslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 139
35 Summary and Outlook 140References 142
viii CONTENTS
4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang
41 Introduction 14542 Cascade Reactions of Alkynes 147
421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154
422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165
43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174
5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu
51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219
6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang
61 Introduction 22662 Cascade Reactions Involving Alkenes 226
621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234
63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
CONTENTS vii
2311 Halolactonization 762312 Mannich Reaction 772313 MichaelndashAldol Reaction 782314 Michael-Alkylation Reaction 792315 Cyano-Involved Michael-Cyclization Reaction 822316 Michael-Hemiketalization (Hemiacetalization)
Reaction 842317 MichaelndashHenry Reaction 872318 MichaelndashMichael Reaction 902319 Petasis Reaction 9423110 Sulfur YlidendashInvolved Michael-Cyclization Reaction 9523111 α-Isothiocyanato ImidendashInvolved Cascade Reaction 9623112 α-IsocyanidendashInvolved Cascade Reaction 98
232 Anion-Binding Catalysis 992321 PictetndashSpengler Reaction 992322 Other Iminium IonndashInvolved Cascade Reaction 1012323 Oxocarbenium IonndashInvolved Cascade Reaction 103
24 Broslashnsted Acid and Transition Metal Cooperatively Catalyzed Cascade Reactions 104241 Dual Catalysis 105242 Cascade Catalysis 108
2421 Pd(0)Broslashnsted Acid System 1092422 RutheniumBroslashnsted Acid System 1092423 Au(I)Broslashnsted Acid System 1132424 Other Binary Catalytic Systems 114
25 Conclusions 116References 117
3 application of organocatalytic Cascade Reactions in natural Product synthesis and drug discovery 123Yao Wang and Peng-Fei Xu
31 Introduction 12332 Amine-Catalyzed Cascade Reactions in Natural Product Synthesis 125
321 Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis 125
322 Cycle-Specific Cascade Catalysis in Natural Product Synthesis 1293221 IminiumndashEnamine Cycle-Specific Cascade Catalysis 1303222 Enamine (Dienamine)ndashIminium Cycle-Specific
Cascade Catalysis 1323223 More Complex Cycle-Specific Cascade Catalysis 134
33 Broslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 137
34 Bifunctional BaseBroslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 139
35 Summary and Outlook 140References 142
viii CONTENTS
4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang
41 Introduction 14542 Cascade Reactions of Alkynes 147
421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154
422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165
43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174
5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu
51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219
6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang
61 Introduction 22662 Cascade Reactions Involving Alkenes 226
621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234
63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
viii CONTENTS
4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang
41 Introduction 14542 Cascade Reactions of Alkynes 147
421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154
422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165
43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174
5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu
51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219
6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang
61 Introduction 22662 Cascade Reactions Involving Alkenes 226
621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234
63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
CONTENTS ix
632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or
Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263
64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274
65 Summary and Outlook 276Acknowledgments 277References 277
7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei
71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284
721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297
722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total
Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic
Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic
Synthesis 32276 Summary 326References 326
8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang
81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
x CONTENTS
821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343
83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356
84 Conclusions and Perspectives 359References 360
9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling
91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364
921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368
93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic
Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding
Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390
94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal
Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal
Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor
and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal
Catalysts 41395 Summary and Outlook 415References 415
index 419
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
xi
ContRiButoRs
Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China
liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China
Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China
Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Ping lu Department of Chemistry Zhejiang University Hangzhou PR China
aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico
yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China
yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California
Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
xii CONTRIBUTORS
yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China
Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China
Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China
liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
xiii
PReFaCe
The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments
The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
xiv PREFACE
cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced
The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book
Lanzhou PR China Peng-Fei Xu
Albuquerque New Mexico Wei Wang
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc
1
aMine-CatalyZed CasCade ReaCtions
Aiguo Song and Wei Wang
1
11 Introduction 2
12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3
1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine
cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7
122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with
enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16
123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21
13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
2 AMINE-CATALYZED CASCADE REACTIONS
11 intRoduCtion
Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst
sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions
(a)
H2OR
O
R1
1
R
O
X
4
NH
ndashH2O
R
N
R1
2
X Y
ndashY
R
N
R1 R1
X
3
(b)
H2OR
O
R1
1
R1
R
O
X
6
YH
R1
R
N
X
5
YNH
ndashH2O
X YR
N
R1
2
1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34
137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37
1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40
139 Other iminium-activated cascade reactions 42
14 Cycle-specific catalysis cascades 42
15 Other strategies 45
16 Summary and outlook 46
References 46
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
ENAMINE-ACTIVATED CASCADE REACTIONS 3
Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)
12 enaMine-aCtivated CasCade ReaCtions
We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here
121 enaminendashenamine Cascades
1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process
1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23
H2OR
O
7
R1 R
O
10
R1
NuNH
R
N Nu
8R1 R
N
9
Nu
R1
sCHeMe 12 Iminium catalysis
R
O
R1
X
4
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
R
O
R1
X
6
Electrophilicattacked by
enamine Nucleophilicformation of
enamine
YH
Nucleophilic
FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
4 AMINE-CATALYZED CASCADE REACTIONS
sCHeMe 13 Design of enaminendashenamine cascade catalysis
(a) Intermolecular enaminendashenamine catalysis
H2O
R1 R1
R
N
XOR
14
R1R1
R
O
XOHR
15
R
N
R1 R1
R
O
X
2 4
(b) Intermolecular enaminendashenamine catalysis and cyclization
H2O
R1R1R
OX
OHR
12
YHR1
R1
YX
HO
R
R OH
13
R1R1R
NX
OR
11
YH
R1 R1R
N
R
OX
2 6
YH
(c) Double-enamine catalysis at the same site
H2O
R1
R
O
18
E
E
R1
R
O
E
4 or 6
ndashH2O
NH
R1
R
N
E E
16
R1
R
N
17
E
E
(d) Robinson annulation
R1
R
O
1R1
R4
R5
R
O
20
O
R1
R4
R5
O
R
22
R5
R4
O
19
then H2O
R1
R4
R5
R
O
21
N
ndashH2O
NH
ndashH2ONH
R1
R
N
2
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
ENAMINE-ACTIVATED CASCADE REACTIONS 5
(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]
The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24
Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)
Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]
It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of
H
O3
DERA O
OH
OH
H
O3
L-proline
H
OOH
23
24
10 yield90 eeTHF 0 degC
5 h
sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde
H
O
+NH
O
OH
ndashH2O
N
O
OH
N
HO
HO
O
N
O
OOH24
Mannich-type condensation
sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
6 AMINE-CATALYZED CASCADE REACTIONS
similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)
To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]
1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]
L-proline
H
O
OTIPS27
H
O
OTIPS
OHOTIPS
OAc
H
Me3SiO
TiCl4 CH2 Cl2ndash40 to ndash20 degC
O
TIPSO OAcOH
OH
28
TIPSO68ndash96 yieldabout 19 1 dr
95ndash99 ee
sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis
R H
O+
H
O
R1
29
R1
R H
OOHO
OH
R1
R O H
30
L-proline(or D-proline)
DMF
D-proline(or L-proline)
propionaldehydeDMF
15ndash42 yieldsingle diastereomer
gt 99 ee
sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses
H
O3 MnO2
EtOAc rt48 h
O
OH
HO
25
O
OH
O
2653 yield
8 1 dr
L-proline
DMF 4 degC10 h
sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
ENAMINE-ACTIVATED CASCADE REACTIONS 7
1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center
Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C
2-symmetric bbprime-diaminoaldehydes
37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]
1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]
O
H
O
Me
N
N
Cbz
Cbz
+ +
31
O
NCbz
HNCbz
Me
OH
32
L-prolineCH3CNrt 72 h
80 yield56 44 antisynup to gt 99 ee
sCHeMe 19 Proline-catalyzed three-component reaction
H
O
R I NO2+
33
DMSO rt
34 PhCO2H
41ndash62 yieldup to 99 1 drup to 97 ee
NH
Ph
OTMSPh
3435
O2N
R
CHO
sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene
H
O N
RH
Boc
+
36
R R
CHO
NH HNBoc Boc
37
L-prolineCH3CN 0 degC to rt
18ndash24 h
up to 90 yieldgt99 1 drgt99 ee
sCHeMe 111 Double Mannich reactions of acetaldehyde
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
8 AMINE-CATALYZED CASCADE REACTIONS
122 enaminendashiminium Cascades
1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)
A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)
In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)
1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael
O
CHO
38
39
rt 5 d
84 yield97 ee
OH
40
NH2
O
O
39
Nn-Bu4
sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation
R
O
R1
R1
R2X
6
Nucleophilichindered
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
12-addition
R = H aliphatic or aromatic groups
O
X
41
YH
Nucleophilicattack
iminium ion
Electrophiliciminiumion for
14-addition
Nucleophilichindered
FiguRe 12 Design of enaminendashiminium cascade catalysis
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
ENAMINE-ACTIVATED CASCADE REACTIONS 9
reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions
In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones
sCHeMe 113 Design of an enaminendashiminium cascade with enones
(a) Double-addition reactions via enaminendashiminium
O
R1
X
YH
R
H2O R1
O
XR Y
42
NH
R1
N
X
YH
R
R1
N
XR Y
(b) [4 + 2] Reactions with HOMO-raising dienes
R1
O
R
H2O
O
X
R1
R Y
42
NH
R1
R1
N
R
X
Y
43
N
XR Y
sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44
(a) Double-addition reactions via enaminendashiminium cascade
R
O
R1
1
acid R1
R4
R3Z
OHR
47
NH
ndashH2O R1
R2 R3
R
N
2
Z
44
R1R2
R3
R
N
45
ZZ
NR1
R2
R3 R
46
(b) [4 + 2] Reactions with activated dienophiles
acid R1R3
R2
Z
OHR
47
Z
NR1 R3
R2
R
46
R
N
R1
R3
R2
2
Z
44
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
10 AMINE-CATALYZED CASCADE REACTIONS
was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)
On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58
O
Ph +
NO2
CHO
+
O O
O O
54 55 56
OO
OO
O
Ar
Ph
57
OO
OO
O
Ar
Ar
58
+
Ar = 4 - NO2 - Ph
(DMTC)
S
NH
CO2H
MeOHrt
88 yieldgt 100 1 dr
86 ee
sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction
R1 R1 R2R2
NO2 NO2
O O
51 52
+
NH
N
50
R2 NO2+
O
R148 49
NH
50 orL-proline
up to 87 yieldup to 8 1 dr
38 ee
R2 NO2
R1R2
NO2
N
R1
N
53
sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
ENAMINE-ACTIVATED CASCADE REACTIONS 11
The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst
The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]
Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products
O O
O O
Ar H
O
+
55
56
KnoevenagelreactionO
O
O
OAr
O
NH
RR
NRR
Ph
N
Ph
Ar
RR
OO
O
O
O
Ph
Ar
OO
O
O
DielsndashAlder 57
54
60
59
Ph
sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction
OAr
O
H
ArO
H O
OO
O
+
NH
Ar = 4-NO2C6H4
O
ArO
Ar
Ar
O
O
O
O
O
Ar
OH
O Ar
O
O
O
O
+
+ +
58
sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
12 AMINE-CATALYZED CASCADE REACTIONS
The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)
Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]
The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70
The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]
Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]
O O
H
Ph
Ph
O
HO
OO
O
+
P
Ph
Ph
Ph
61 O
Ph
Ph
O
O
O
O62
L-proline
C6H6 MeOH65 degC
99 yieldgt100 1 dr
sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction
O
ArNC
O
NC
O
Ar H
O
NH
HH+
L-proline
DMSO70ndash75 yield
99 de
Ar
Ar
CN
NC
66
63
64 65
CO2EtEtO2C
R2O2C
CO2R1
OR2
OR1
sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
ENAMINE-ACTIVATED CASCADE REACTIONS 13
1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]
NO
RO R
NH HN N
NN
74 73
73CH3CN
40 degC15 h50ndash64 yield
98ndash99 ee
O
R R
NO
71 72
+
sCHeMe 122 o-Nitroso aldolndashMichael reactions
(S)-proline
DMSO 50 degC24 h
82 yield99 ee
N
O
75 O
O NH2
H
O
H
O
+ +
sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction
L-proline
O
Ar Ar
CO2R1NC
67CO2R1
CO2R2
CO2H
Ar
NC
Ar
N
CN
69
Ar Ar
CO2R1
CO2R2
NC
NC
70
Ar Ar
CO2R1
CO2R2
NC
NC
66
CO2
Ar Ar
CO2R1
CO2R2
NC
NH
CNHndash L-proline
EtO2C
EtO2C
NHH
H
65
CO2R1
OR2CO2
Ar Ar
NC
N
CN
O
68
H
64
sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with
14 AMINE-CATALYZED CASCADE REACTIONS
The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle
OO
Ph
76
silicaON
PhO
Ph
NH
N
HO
H2O
H2O
CO2Me
CO2Et
CO2Et
77
81
78
82
79
sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction
O
i-Pr
+
CO2MeO
Ph
76 77
78
Silica
CO2EtOHO
Pri
Ph
79
PCC
62ndash93 yieldgt100 1 dr
up to 94 ee
CO2EtOO
i-Pr
Ph
NH Ar
Ar
7880
Ar = 35-(CH3)2C6H3
sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction
Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported
Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions
Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with