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Florencio Zaragoza Dorwald

Side Reactions in OrganicSynthesis II

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Florencio Zaragoza Dorwald

Side Reactions in Organic Synthesis II

Aromatic Substitutions

The Author

Dr. Florencio Zaragoza DorwaldLonza AGRottenstrasse 63930 VispSwitzerland

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V

Contents

Preface IXGlossary and Abbreviations XIJournal Abbreviation List XIII

1 Electrophilic Alkylation of Arenes 11.1 General Aspects 11.1.1 Catalysis by Transition-Metal Complexes 21.1.2 Typical Side Reactions 51.2 Problematic Arenes 71.2.1 Electron-Deficient Arenes 71.2.2 Phenols 91.2.3 Anilines 131.2.4 Azoles 191.3 Problematic Electrophiles 191.3.1 Methylations 191.3.2 Olefins 201.3.3 Allylic Electrophiles 211.3.4 Epoxides 231.3.5 α-Haloketones and Related Electrophiles 251.3.6 Nitroalkanes 261.3.7 Ketones 271.3.8 Alcohols 32

References 34

2 Electrophilic Olefination of Arenes 452.1 General Aspects 452.2 Olefinations with Leaving-Group-Substituted Olefins 452.3 Olefinations with Unsubstituted Olefins 462.4 Olefinations with Alkynes 52

References 57

3 Electrophilic Arylation of Arenes 613.1 General Aspects 613.2 Arylations with Aryl Halides 61

VI Contents

3.2.1 Via Cationic Intermediates 613.2.2 Via Radicals 633.2.3 Via Transition-Metal Chelates 653.2.4 By Transition-Metal Catalysis 673.3 Arylations with Diazonium Salts 693.4 Arylations with Other Functionalized Arenes 733.5 Arylations with Unsubstituted Arenes 78

References 79

4 Electrophilic Acylation of Arenes 854.1 General Aspects 854.2 Problematic Arenes 884.2.1 Dealkylation/Isomerization of Arenes 884.2.2 Styrenes 884.2.3 Anilines, Phenols, and Thiophenols 904.2.4 Electron-Deficient Arenes 924.2.5 Azoles 934.3 Problematic Electrophiles 954.3.1 Problematic Acyl Halides 954.3.2 Carboxylic Esters and Lactones 984.3.3 Carbonic Acid Derivatives 1014.3.4 Formic Acid Derivatives 1064.3.5 Mixed Carboxylic Anhydrides and Other Polyelectrophiles 110

References 112

5 Electrophilic Halogenation of Arenes 1215.1 General Aspects 1215.2 Typical Side Reactions 1215.3 Regioselectivity 1255.4 Catalysis 1285.5 Fluorinations 1295.6 Electron-Deficient Arenes 1325.6.1 Pyridines 1335.6.2 Benzoic Acid Derivatives 1345.7 Electron-Rich Arenes 1375.7.1 Phenols and Arylethers 1385.7.2 Anilines 1385.7.3 Azoles 1445.8 Sensitive Functional Groups 1475.8.1 Alkenes 1485.8.2 Amines 1485.8.3 Ethers 1495.8.4 Thiols and Thioethers 149

Contents VII

5.8.5 Aldehydes, Ketones, and Other C–H Acidic Compounds 1515.8.6 Amides 152

References 152

6 Electrophilic Formation of Aromatic C–N Bonds 1616.1 Nitration of Arenes 1616.1.1 Mechanisms 1616.1.2 Regioselectivity 1646.1.3 Catalysis 1676.1.4 Electron-Deficient Arenes 1676.1.5 Electron-Rich Arenes 1696.1.5.1 Anilines 1716.1.5.2 Indoles 1736.1.5.3 Phenols 1736.2 Electrophilic Aromatic Aminations 1756.2.1 Typical Side Reactions 1776.3 Electrophilic Aromatic Amidations 1776.3.1 Typical Side Reactions 177

References 184

7 Electrophilic Formation of Aromatic C–S Bonds 1917.1 Sulfonylation 1917.1.1 General Aspects 1917.1.2 Typical Side Reactions 1937.2 Sulfinylation 1957.2.1 General Aspects 1957.2.2 Typical Side Reactions 1957.3 Sulfenylation 1997.3.1 General Aspects 1997.3.2 Typical Side Reactions 200

References 201

8 Aromatic Nucleophilic Substitutions 2058.1 General Aspects 2058.1.1 Mechanisms 2058.1.2 Regioselectivity 2058.1.3 Acid-/Base-Catalysis 2118.1.4 Transition-Metal Catalysis 2118.2 Problematic Electrophiles 2168.2.1 Incompatible Functional Groups 2168.2.2 Non-Activated Arenes 2178.2.3 Nitroarenes 2198.2.4 Diazonium Salts 2268.2.5 Phenols 2298.2.6 Arylethers and Arylthioethers 229

VIII Contents

8.2.7 Other Phenol-Derived Electrophiles 2318.2.8 Arynes 2328.3 Problematic Nucleophiles 2338.3.1 Enolates 2338.3.2 Organomagnesium and Related Organometallic Compounds 2358.3.3 Ammonia 2418.3.4 Primary and Secondary Amines 2428.3.5 Tertiary Amines 2448.3.6 Azides 2478.3.7 Hydroxide 2488.3.8 Alcohols 2508.3.9 Thiols 2528.3.10 Halides 253

References 260

Epilogue Economics, Politics, and the Quality of Chemical Research 277Prosperity 277Slavery and Freedom 279The Quality of Chemical Research 281References 283

Index 285

IX

Preface

Our job as chemists is mainly about problem solving. Therefore, the most inter-esting aspect of chemistry is not what works, but what does not work, and why.Difficult or ‘‘impossible’’ reactions, poor selectivities, low yields, expensive cata-lysts, or excessive waste generation are nothing to shrink away from, but greatopportunities for relevant chemical research.

Ten years ago, I wrote ‘‘Side Reactions in Organic Synthesis,’’ with the aimof highlighting the competing processes and limitations of some of the mostcommon reactions used in organic synthesis. Although some readers found thetitle confusing (and, yes, there are no side reactions), I also received a lot of positivefeedback. For this reason I decided to write a second sequel.

In the first book of this series the focus had been alkylations, that is, substitu-tions at sp3 carbon. An equally important area of organic synthesis is aromaticsubstitution, the main topic of the present book. Again, I try to show the mainproblems and limitations of popular synthetic transformations, hoping to helpchemists to identify byproducts and plan better syntheses. As in my earlier titles,my main aim is to encourage bold experimentation, to inspire, challenge, andmotivate.

Because time is a precious resource, I have kept the texts short (chemists canassimilate graphical information faster than text), and included in all equationsa short code for the source. This code has the format year-journal-first page. Forinstance, 08joc4956 means J. Org. Chem. 2008, 4956. The abbreviations used forthe journals can be found in the ‘‘Journal Abbreviation List.’’ All patents can bedownloaded at worldwide.espacenet.com.

I would like to thank Paul Hanselmann and Marcel Suhartono for proofreadingand for the many instructive chemical discussions. I am also thankful for thehelp and support provided by the editors at Wiley-VCH, in particular by AnneBrennfuhrer.

Visp, Switzerland Florencio Zaragoza DorwaldMay 2014

XI

Glossary and Abbreviations

Ac Acetyl, MeCOacac Acetylacetone, pentane-2,4-dioneAda AdamantylAIBN 2,2′-Azobis(2-methylpropionitrile)aq AqueousAr Undefined aryl groupBINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthylBoc tert-Butyloxycarbonylbpy 2,2′-BipyridineCAN Ceric ammonium nitrate, (NH4)2Ce(NO3)6

cat Catalyst or catalytic amountcod 1,5-Cyclooctadienecoe cis-Cycloocteneconcd Concentratedcot 1,3,5-CyclooctatrieneCp CyclopentadienylCp* PentamethylcyclopentadienylCy Cyclohexylcym Cymene, 4-isopropyltolueneDABCO 1,4-Diazabicyclo[2.2.2]octanedba 1,5-Diphenyl-1,4-pentadien-3-oneDBU 1,8-Diazabicyclo[5.4.0]undec-5-eneDCE 1,2-DichloroethaneDDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinoneDMA N,N-DimethylacetamideDME 1,2-DimethoxyethaneDMF N,N-DimethylformamideDMI 1,3-Dimethylimidazolidin-2-oneDMPU 1,3-Dimethyltetrahydropyrimidin-2-oneDMSO Dimethyl sulfoxideDPEphos Bis[(2-diphenylphosphino)phenyl] etherdppb 1,4-Bis(diphenylphosphino)butanedppf 1,1′-Bis(diphenylphosphino)ferrocenedppp 1,3-Bis(diphenylphosphino)propane

XII Glossary and Abbreviations

dtbpy 2,6-Di(tert-butyl)pyridineeq EquivalentFmoc 9-FluorenylmethyloxycarbonylGDP Gross domestic productHal Undefined halogenHFIP 1,1,1,3,3,3-Hexafluoro-2-propanolHMPA Hexamethylphosphoric triamide, (Me2N)3POL Undefined ligandLTMP Li-TMPMes Mesityl, 2,4,6-trimethylphenylMs MethanesulfonylMS Molecular sievesMW MicrowaveNBS N-BromosuccinimideNCS N-ChlorosuccinimideNIS N-IodosuccinimideNMP N-Methylpyrrolidin-2-oneNu Undefined nucleophilePEGDM Poly(ethylene glycol) dimethacrylatephen Phenanthrolinepin pinacolylPiv Pivaloyl, 2,2-dimethylpropanoylPPA Polyphosphoric acidpyr PyridineR Undefined alkyl groupSET Single electron transferSNAr Aromatic nucleophilic substitutionSN1 Monomolecular nucleophilic substitutionSN2 Bimolecular nucleophilic substitutionS-phos 2-(2′,6′-Dimethoxybiphenyl)dicyclohexylphosphinest.mat. Starting materialTBAB Tetrabutylammonium bromideTBAF Tetrabutylammonium fluorideTEMPO (2,2,6,6-Tetramethyl-piperidin-1-yl)oxylTFA Trifluoroacetic acidTFAA Trifluoroacetic acid anhydrideTfOH Triflic acid, F3CSO3HTHF TetrahydrofuranTMEDA N,N,N′,N′-Tetramethyl-1,2-ethylenediamineTMP 2,2,6,6-TetramethylpiperidineTol TolylTs Tosyl, 4-toluenesulfonylwt Weightxantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

XIII

Journal Abbreviation List

PLEASE NOTE:Included in all equations is a short code for the source. This code has the format

year-journal-first-page, for instance:

08joc4956 means J. Org. Chem. 2008, 4956.

a Arkivocac Acta Crystallographicaacr Accounts of Chemical Researchajc Australian Journal of Chemistryang Angewandte Chemie, International Edition in Englishasc Advanced Synthesis & Catalysisbcsj Bulletin of the Chemical Society of Japanbj Biochemical Journalcatc Catalysis Communicationscatl Catalysis Letterscb Chemistry & Biologycc Chemical Communicationscej Chemistry – A European Journalcjc Canadian Journal of Chemistrycl Chemistry Letterscoc Current Organic Chemistrycpb Chemical & Pharmaceutical Bulletincr Chemical Reviewsejoc European Journal of Organic Chemistryhca Helvetica Chimica Actaiec Industrial & Engineering Chemistryja Journal of the American Chemical Societyjbcs Journal of the Brazilian Chemical Societyjcat Journal of Catalysisjcs(p1) Journal of the Chemical Society, Perkin Transactions 1jmc Journal of Medicinal Chemistryjoc Journal of Organic Chemistry

XIV Journal Abbreviation List

jpc Journal fur Praktische Chemieobmc Organic & Biomolecular Chemistryol Organic Lettersoprd Organic Process Research & Developmentoscv(1) Organic Syntheses, Collective Volume 1p Pharmaziepcs Proceedings of the Chemical Societyrjoc Russian Journal of Organic Chemistrysc Synthetic Communicationssl Synlettsyn Synthesistet Tetrahedronthl Tetrahedron Letterszok Zhurnal Organicheskoi Khimii

1

1Electrophilic Alkylation of Arenes

1.1General Aspects

For large-scale industrial organic syntheses, electrophilic alkylations of arenesare essential (Scheme 1.1). Their attractive features include the absence of wastewhen alcohols or olefins are used as electrophiles, the large scope of availablestarting materials, and the high structural complexity attainable in a single step.The main issues are low regioselectivity, overalkylations, and isomerization ofthe intermediate carbocations. Important products resulting from this chemistryinclude isopropylbenzene (cumene – starting material for phenol and acetone),ethylbenzene (starting material for styrene), methylphenols, geminal diarylalkanes(monomers for polymer production), trityl chloride (from CCl4 and benzene [1]),dichlorodiphenyltrichloroethane (DDT) (from chloral and chlorobenzene), andtriarylmethane dyes.

To obtain acceptable yields, careful optimization of most reaction parameters isoften required. Because the reactivity of an arene increases upon alkylation (around2–3-fold for each new alkyl group), multiple alkylation can be a problem. Thismay be prevented by keeping the conversion low, or by modifying the reactiontemperature, the concentration, the rate of stirring, or the solvent used (e.g.,to provide for a homogeneous reaction mixture). In dedicated plants, processesare usually run at low conversion if the starting materials can be recycled. Inthe laboratory or when working with complex, high-boiling compounds, though,electrophilic alkylations of arenes can be more difficult to perform.

Typical electrophilic alkylating reagents for arenes include aliphatic alcohols,alkenes, halides, carboxylic and sulfonic esters, ethers, aldehydes, ketones, andimines. Examples of alkylations with carbonates [2], ureas [3], nitroalkanes [4],azides [5], diazoalkanes [6], aminoalcohols [7], cyclopropanes [8], and thioethers(Scheme 1.14) have also been reported. Amines can be used as alkylating agentseither via intermediate conversion to N-alkylpyridinium salts [9] or by transientdehydrogenation to imines [10]. Some examples of Friedel–Crafts alkylation aregiven in Scheme 1.2.

In most instances, the electrophilic alkylation of arenes proceeds viacarbocations, and complete racemization of chiral secondary halides or alcohols isusually observed. Only if neighboring groups are present and capable of forming

Side Reactions in Organic Synthesis II: Aromatic Substitutions, First Edition. Florencio Zaragoza Dorwald.c© 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.

2 1 Electrophilic Alkylation of Arenes

− H

R

OH

R

X

R

R

RR

R

O

R

N

R′RR

H

RR

R

R

Scheme 1.1 Mechanism of the Friedel–Crafts alkylation.

cyclic configurationally stable cations, arylations can occur with retention ofconfiguration [18].

Stabilized carbocations (e.g., tertiary carbocations) are easy to generate, but theyare less reactive (and more selective) than less stable cations. Thus, the trityl ortropylium (C7H7

+) cations react with anisole but not with benzene. On the otherhand, carbocations destabilized by a further positively charged group in closeproximity will show an increased reactivity [7, 19]. Highly stabilized cations mayeven be generated and arylated under almost neutral reaction conditions [20].

1.1.1Catalysis by Transition-Metal Complexes

Electrophilic alkylations of arenes by olefins or alkyl halides can be catalyzedby soft electrophilic transition metals, for example, by Pd, Rh, or Ru complexes(Scheme 1.3). Most of the reported examples proceed via aromatic metallationthrough chelate formation. With Ru-based catalysts, selective meta-alkylation canbe achieved when using sterically demanding electrophiles (fifth equation inScheme 1.3).

Reactions where carbocation formation is the slowest (rate-determining) step canbe catalyzed by any compound capable of stabilizing the intermediate carbocation(and thereby promote its formation). This form of catalysis should be mostpronounced in nonpolar solvents, in which free carbocations are only slightlystabilized by solvation. Some transition-metal complexes, for example, IrCl3 andH2[PtCl6], catalyze Friedel–Crafts alkylations with benzyl acetates, probably by

1.1 General Aspects 3

+Cl

1 eq 4 eq

1.2% AlCl345 °C, 1 h

+

65% 33%

08joc4956

(CH2O)n, ZnBr2HBr (33% in AcOH)

90 °C, 16 h

94%80−90%

BrBr

Br

10joc6416, 05syn2080

1.06 eq AlCl33.06 eq EtBr

0−20 °C, 12 h

OH+

3 eq MeSO3HMeNO2

80 °C, 6−12 hOMe

61%

N

SH2N

N

SH2N

1 eq 2 eq09ol5154

OMe

S

S OH

CN

+

OMe1 eq AlCl3

CH2Cl220 °C, 0.5 h

S

S

CN

S

S

CNOMe

OMe87%

80 : 20

+

1 eq 4 eq08joc2264

O

N3

OAc

AcO

+O

1.1 eq BF3OEt2MeCN, 20 °C, 0.5 hthen K2CO3, MeOH

O

N3

HO

O

60%

5 eq1 eq 10ja15528

OO

+Cl

F

2 eq 1 eq

1.05 eq ZnCl2H2O, 85 °C, 6 h

OO

F

OO

F

+ + O

F F70% 5% 5%

07oprd1059

Scheme 1.2 Examples of Friedel–Crafts alkylations [11–17].


NH

5% PdCl2(MeCN)23 eq CuCl2, CO, MeOH

25 °C, 3 h

85% NH

CO2Me06cej2371

MeO

HN

O

N+ I

1 eq 3 eq

5% Pd(OAc)22 eq K2CO3

3 eq NaOTf, O2EtMe2COH 125 °C, 36 h

MeO

HN

O

N

84%11ol4850

N2.5% [RuCl2(p-cymene)]2

30% 1-AdaCO2HK2CO3, NMP, 100 °C, 20 h+

N

5%

N2.5% [RuCl2(p-cymene)]2

30% 1-AdaCO2HK2CO3, NMP, 100 °C, 20 h+

N

74%Br

09ang6045

09ang6045

N

N+

Br

5% [RuCl2(p-cymene)]230% MesCO2H

2 eq K2CO3dioxane, 100 °C, 20 h

3 eq1 eq

N

N

54%

13ja5877

NMeO

+AcO

5% [RhCl2Cp*]220% AgSbF6

2.1 eq Cu(OAc)2THF, 75 °C, 20 h

NMeO

1 eq 3 eq

46%

NMeO

RhCp*X NMeO

OAc

RhCp*X

10ol540

O

N+

HN

1.0 eq 1.2 eq

1.1 eq CH2Cl2, 10% CuCl1.2 eq DBU

MeCN, 85 °C, 12 h O

N

N87%

12asc1672

Scheme 1.3 Transitions-metal-catalyzed arene alkylations [21–26].

1.1 General Aspects 5

Excess

+AcO

10% catalyst80 °C, 20 h

Catalyst:HCl or AcOH or H2SO4

RhCl3 hydrate (50 °C)IrCl3 hydrate

PtCl2H2[PdCl4] hexahydrateH2[PtCl6] hexahydrate

Yield:0%79%99%7%99%99%

05ang238

Ph Me

X

Ph Me

Ph Me

Cat

Cat

Ph Me

Cat

Energy

+ Cat

− X

− X

Ph Me

Ar

Scheme 1.4 Catalysis of Friedel–Crafts alkylations [28].

transient formation of benzylic metal complexes (Scheme 1.4). Because racemi-zation is also observed in these instances, the intermediate complexes are likelyto undergo fast transmetallation. Ru-based catalysts have been developed thatenable the preparation of enantiomerically enriched alkylbenzenes and alkylatedheteroarenes from racemic alcohols [27] (Scheme 1.18).

1.1.2Typical Side Reactions

The rearrangement of intermediate carbocations is a common side reaction inFriedel–Crafts chemistry (Scheme 1.5). Rearrangements can sometimes be avoidedwith the aid of transition-metal-based catalysts, because the intermediate complexesare less reactive than uncomplexed carbocations.

Carbocations can also act as oxidants and abstract hydride from other molecules[31]. The newly formed carbocations may also alkylate arenes and lead to theformation of complex product mixtures (Scheme 1.6).

When using noble metal halides as catalysts, or α-haloketones, α-haloesters(Section 1.3.5), or perhaloalkanes as electrophiles, arenes may undergohalogenation instead of alkylation (Scheme 1.7). Alkyl halides with the halogen


+ F Br

BF3

0−20 °C, 2 h

89%

Br

64joc23174 eq 1 eq

+ TfO

1 eq 2 eq

5% AuCl3/3 AgOTf

120 °C, DCE, 48 h+

40% 50%

04ja13596

Scheme 1.5 Rearrangement of carbocations during Friedel–Crafts alkylations [29, 30].

+Cl

+

5 eq 1 eq 1 eq

10% AlCl322 °C, 1 h

+ H

11%

+ +

60% 10%

63joc1624

Scheme 1.6 Hydride abstraction by carbocations as side reaction during Friedel–Craftsalkylations [32].

OH

+CO2EtEtO2C

Br

OH

+ CO2EtEtO2C

Br

neat, 100 °C82%

01bcsj179

CO2Me

OH

+

O

Cl

ClCl

Cl

Cl

Cl

1.1 eq1.0 eq

DMF, CCl420 °C, 24 h

CO2Me

OH

Cl

34%

US 2011306621

TfO+

0.2 eq AuCl30.6 eq AgOTf

DCE120 °C, 1 h

35% conversion

04ja13596

+

Cl

12% 20%

Scheme 1.7 Halogenation of arenes by alkyl halides and by AuCl3 [30, 33, 34].

1.2 Problematic Arenes 7

bound to good leaving groups (positions where a carbanion would be stabilized)are electrophilic halogenating reagents.

If the concentration of alkylating reagent is too low, arenes may undergoacid-catalyzed oxidative dimerization (Scholl reaction) [35]. This reaction occursparticularly easily with electron-rich arenes, such as phenols and anilines.

1.2Problematic Arenes

1.2.1Electron-Deficient Arenes

Yields of alkylations of electron-deficient arenes by carbocations are usually low.This is mainly because the reaction is too slow, and the carbocation undergoes rear-rangement and polymerization before attacking the arene. If no alternative reactionpathways are available for the carbocation, though, high-yielding Friedel–Craftsalkylations of electron-deficient arenes can be achieved (Scheme 1.8).

O

+ OH

H2SO4

90 °C, 1.2 h

O O O

+ +

25% conversionof benzophenone

0.6% 19% 3.2%

+dialkylatedproducts

2.4%

1 eq 2 eq91joc7160

HO2C

CO2H

+O

O

O

H2SO4 (27% SO3)

135 °C, 6 h

HO2C

O

O

65%

0.85 eq1.00 eqEP 1118614

NO2

+ OCl Cl

2.4 eq 1.0 eq

H2SO4

50 °C, 1 week

35%

NO2Cl

US 2758137

Scheme 1.8 Friedel–Crafts alkylation of electron-deficient arenes [36–38].


Electron-deficient arenes can be alkylated by olefins or alkyl halides via inter-mediate arene metallation. Chelate formation is usually required and crucial forthe regioselectivity of transition-metal-catalyzed reactions (Scheme 1.9). The Ru-and Rh-catalyzed ortho-alkylation of acetophenones and acetophenone-imines byalkenes can even proceed at room temperature [39]. With sterically demanding alkylhalides, Ru complexes can mediate meta-alkylations [24]. When conducted in thepresence of oxidants, these reactions can yield styrenes instead of alkylbenzenes[40–42] (see also Section 2.3).

Cl

Oethylene (30 bar), PhMe

10% RuH2(H2)2(PCy3)2

23 °C, 24 h

Cl

O

+

Cl

O

89% 7%

01asc192

NO

+

Cl

OMe

O

2.5% [RuCl2(p-cymene)]230% 1-AdaCO2H

2 eq K2CO3

PhMe, 100 °C, 20 h

1.0 eq 1.5 eq

NOOMe

O

61%

09ol4966

N Ph

+

2% RhCl(PPh3)3

PhMe, 150 °C, 2 hthen hydrolysis

O

95%

02cej485

N

N

20% Pd(OAc)21 eq Cu(OAc)2

10 eq TFA

DCE, 110 °C, 48 h+

S

CF3BF4

1.0 eq 1.5 eq

N

N

CF353%

10ja3648

Scheme 1.9 Ru-, Rh-, and Pd-catalyzed, chelate-mediated alkylation of electron-deficientarenes [43–46].

The metals used as catalysts for this ortho-alkylation of acetophenones insertnot only into C–H bonds but also at similar rates into C–O and C–N bonds(Scheme 1.10). The selectivity can sometimes be improved by the precise choice ofthe catalyst [47]. Another potential side reaction of the alkylations described above


OMeO

+ Si(OEt)3

1 eq 2 eq

2.5% [RuCl2(p-cym)]215% PPh3

30% NaHCO3

PhMe, 140 °C, 60 h

OMeO

Si(OEt)3

+

O

20% 25%

(EtO)3Si

09ja7887

ONH

+O

BO

Ph

1.0 eq 1.2 eq

4% RuH2(CO)(PPh3)3

PhMe, 111 °C, 20 h

OPh

87%

ON

+O

BO

Ph

1.0 eq 2.0 eq

OPh

+ SiMe3

as above

99%SiMe3

2.0 eq

07ja6098

Scheme 1.10 Ru-catalyzed ortho-alkylation and -arylation of acetophenones [50, 51]. Furtherexamples: [52, 53].

is aromatic hydroxylation, which can readily occur if oxidants are present in thereaction mixture [48, 49].

Some heteroarenes, such as pyridine N-oxides, thiazoles, or imidazoles, arestrongly C–H acidic, and can be metallated catalytically even without chelateformation. In the examples in Scheme 1.11, the intermediates are, in fact, metalcarbene complexes.

Under forcing conditions, fluoro- or nitrobenzenes can also be metallated with-out chelate formation, and trapped in situ with a number of electrophiles, includingaldehydes and ketones (Scheme 1.12). Owing to the competing Cannizzaro reactionand the potential cleavage of ketones by strong nucleophiles (e.g., Haller–Bauerreaction), these reactions may require a large excess of electrophile andcareful optimization.

Electron-deficient arenes and heteroarenes, such as pyridinium salts, can reactwith carbon-centered, electron-rich radicals. These can be generated from alkanes,alkyl halides, carboxylic acids, and some diacylperoxides [58] (Scheme 1.13), orby oxidation of boranes [59]. The regioselectivity of such alkylations is, however,often poor.

1.2.2Phenols

Phenols are inherently problematic nucleophiles in Friedel–Crafts type chemistrybecause the free hydroxyl group can deactivate Lewis acids and because phenols


N

O

+O

O

2% [Rh(cod)Cl]25% Ph2PCH2CH2PPh2

0.25 eq CsOAc, PhMe

120 °C, 24 h

1 eq 5 eq

N

O

O

O

O

O

86%

N

N+

O

O

2% [Rh(cod)Cl]25% Ph2PCH2CH2PPh2

0.25 eq CsOAc, PhMe

120 °C, 12 h

2 eq

72%

1 eq

N

N

O

O

12ang3677

12ang3677

NO

Ph

+S

O

solvent1 eq

10% PdCl2(MeCN)2

2 eq Bu4NOAc

2 eq ZnO, 2 eq NBu3

air, 120 °C, 36 h

N

Ph

75%

12asc1890

S+ Br

13% ligand

5% FeCl3TMPMgCl−LiCl

THF, 20 °C, 6 h

74% S

1.0 eq1.8 eq

ligand:

HN

NH10ol4277

Scheme 1.11 Metallation and alkylation of C–H acidic heteroarenes [54–56].

MeO

F

F

F

F

+

1 eq 3 eq

Cl

O1.5 eq t-BuOLi

DMF, 20 °C, 2 h

93%MeO

F

F

F

F

OH

Cl

SCl +

O

3 eq1 eq

1.5 eq t-BuOLi

DMF, 105 °C, 20 h

41%SCl

OH

09joc8309

09joc8309

Scheme 1.12 Metallation and alkylation of C–H acidic arenes [57].


are tautomers of enones and may themselves act as electrophiles (see below).Moreover, phenols readily dimerize to biaryls in the presence of oxidants.

Under suitable reaction conditions, though, phenols can be alkylated at carbon,without extensive O-alkylation. Stabilized carbocations are soft electrophiles, andreact preferentially with soft nucleophiles, such as arenes or olefins. PhenolO-alkylation under acidic conditions is observed only with hard alkylating reagents(diazomethane, dimethyl carbonate, methanol, methyl esters, alkoxyphosphoniumsalts (Mitsunobu reaction), or acetals). O-Alkylated phenols sometimes rearrangeto C-alkylated phenols in the presence of acids [66] (Scheme 1.14).

At high temperatures, phenols and aluminum phenolates are C-alkylated byolefins (Scheme 1.15). This reaction proceeds less readily and has a narrower scope

O

O

OH

OH

OH

HO

O

O

OH

OH

OH

HO

O

O

OH

OH

OH

HO

O

O

O

t-BuOH, 82 °C60% conversion

02tet1751

+

51% 6%

O

CO2H

+

1 eq 9 eq

10% Ru3(CO)12

5% dppb, 2 eq (t-BuO)2

air, 135 °C, 12 h

CO2H

65%

dppb: 1,4-bis(diphenylphosphino)butane

N

9 eq C6H12, 10% Ru3(CO)12

5% dppb, 2 eq (t-BuO)2

135 °C, 12 h NN+

70% 10%

11ol4977

11ol4977

N

+I

1 eq 3 eq

3 eq H2O2 (30% in H2O)

1 eq H2SO4, DMSO

0.2 eq FeSO4-7H2O

20 °C, 20 min

N84%

89joc5224

Scheme 1.13 Alkylation of arenes with radicals [59–64]. Further examples: [65].


+

N

N

CO2HHO2C

CO2H

1 eq 10 eq

0.6 eq AgNO3

10 eq NH4S2O8

excess 10% aq H2SO4

80 °C24%

N

N

N

NN

N

WO 2008048967

N

N

OH

+

KF3B

1 eq 1 eq

2.5 eq Mn(OAc)3

1 eq TFA

AcOH/H2O 1 : 1

50 °C, 18 h

59%N

N

OH

11ol1852

N

+

N

I

Boc

1 eq 2 eq

0.9 eq FeSO4

6 eq H2O2 (30% in H2O)

2 eq H2SO4, DMSO

40 °C, 3 h

50%

N

N

Boc

09joc6354

Scheme 1.13 (Continued)

than the corresponding reaction of aluminum anilides (see next section). Althoughortho-alkylation occurs first, upon prolonged reaction with an excess of olefin,2,4,6-trialkylated and higher alkylated phenols result [72, 73]. At high pressure,even Diels–Alder reactions with the olefin may occur [74]. Today, a number ofimportant alkylphenols are prepared by high-temperature alkylations with olefinsin the presence of heterogeneous catalysts [73, 75].

Some bis-electrophiles can alkylate phenols both at oxygen and at carbon. 1,3-Dienes, for instance, react with phenols in the presence of acids [78] or Rhcomplexes [79] to yield chromanes (Scheme 1.16).

Phenols are tautomers of cyclohexadienones, and may react as such. In particu-lar, 1- or 2-naphthols, 1,3-dihydroxybenzenes, and 1,3,5-trihydroxybenzenes showstrong cyclohexenone character. Phenols and arylethers react with arenes in thepresence of aluminum halides or HF/SbF5 to yield 3- or 4-arylcyclohexenones[81–83]. The precise outcome of these reactions is difficult to predict; depending onthe amount of acid used and the basicity of the phenol, either conjugate arylationof an enone or arylation of a dication can occur (Scheme 1.17). Moreover, 4,4-disubstituted cyclohexenones, which also may be formed, undergo acid-mediatedrearrangement to 3,4-disubstituted cyclohexanones. Phenols substituted with leav-ing groups (halides, hydroxyl groups) can undergo elimination after the arylationand yield 3- or 4-arylphenols.


10sl261

O

SMe

NH

NO2

+

EtOH

79 °C, 12 h

88%

O NH

NO2

HO

11tet8146HO

OH

MeO

+ HOPh

1% [PhH(PCy3)(CO)RuH]BF4

10% cyclopentene

PhMe, 100 °C, 8 h

92%

Ph

OH

MeO12ja7325

1.0 eq 1.2 eq

OH

MeO

+

OMe OMeO

OH

OH

1 eq2 eq

0.2 eq Me3SiOTf

CH2Cl225 °C, 1 h

O

OH

OHOH

OMeMeO

98%

98joc2307

HS

+

NO2

CHO3 eq1 eq

0.01 eq [Ir(cod)Cl]20.04 eq SnCl4

90 °C, 1 h

NO2

HS SH

74%

07joc3100

SH

1.1 eq

HO Ph +

0.1 eq CuBr2

0.2 eq Fe

DCE, 84 °C, 20 h

72%

SH

Ph

1.0 eq

Scheme 1.14 C-Alkylation of phenols and thiophenols under acidic conditions [67–71].

1.2.3Anilines

Regardless of being N-protonated by acids, anilines can be alkylated at carbon andat nitrogen under acidic reaction conditions. Suitable alkylating reagents includealcohols, ethers, alkenes, aldehydes, ketones, and alkyl halides.

Despite the electron-withdrawing effect of ammonium groups, Friedel–Craftsalkylations of anilines usually proceed with ortho and para selectivity, and more


OH

+

4% Al(OPh)3

320 °C, 60 bar, 10 hOH

+

OH

24% 8%

OH

+

4% Al(OPh)3

240 °C, 38 bar, 2 hOH

61%

56joc712

56joc712

OH

Ph

Al, 220 °C, 1.5 h

then cyclohexene

180 °C, 11 h

OH

PhPd/C

340 °C, 4 h

OH

Ph Ph

62%(two steps)

JP 2009269868

Scheme 1.15 Alkylation of aluminum phenolates with alkenes [76, 77].

OH

+

0.5% TfOH

DCE, 20 °C, 2 h

1.0 eq 1.5 eq

63%

O

11joc9353

OHO

+HO

HO

1.0 eq 1.2 eq

1% RuH(PhH)(PCy3)(CO)BF4

3 eq cyclopentene

PhMe, 100 °C, 12 h

43%

12ja7325

Scheme 1.16 Formation of chromanes from phenols [68, 80].

readily than Friedel–Crafts alkylations of the corresponding benzenes. Thus,although aniline hydrochloride can be para-tritylated in acetic acid (first examplein Scheme 1.18), benzene does not react with the trityl cation.

The precise outcome of the reaction of anilines with alkylating reagents canbe difficult to predict. Stoichiometric amounts of strong acids usually favor C-alkylations. At high temperatures or in the presence of acids, N-alkylanilinesmay be dealkylated and act as alkylating agents themselves [91–93]. Occasionally,mixtures of N- and C-alkylated products are obtained (Scheme 1.19).

If anilines are treated with aldehydes or ketones in the presence of acids atroom temperature, reversible aminal, imine, or enamine formation usually occurs.Upon heating, irreversible alkylation at carbon can take place. Thus, if aniline is

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