organicreactions€¦ · catalytic methods. notably, the chapter outlines the scope and...

Organic Reactions

ADVISORY BOARD

John E. Baldwin Steven V. LeyPeter Beak James A. MarshallDale L. Boger Michael J. MartinelliAndré B. Charette Stuart W. McCombieEngelbert Ciganek Scott J. MillerDennis Curran John MontgomerySamuel Danishefsky Larry E. OvermanHuw M. L. Davies T. V. RajanBabuScott E. Denmark Hans J. ReichJohn Fried James H. RigbyJacquelyn Gervay-Hague William R. RoushHeinz W. Gschwend Tomislav RovisStephen Hanessian Scott D. RychnovskyLouis Hegedus Martin SemmelhackPaul J. Hergenrother Charles SihJeffrey S. Johnson Amos B. Smith, IIIRobert C. Kelly Barry M. TrostLaura Kiessling James D. WhiteMarisa C. Kozlowski Peter Wipf

FORMER MEMBERS OF THE BOARDNOW DECEASED

Roger Adams Herbert O. HouseHomer Adkins John R. JohnsonWerner E. Bachmann Robert M. JoyceA. H. Blatt Andrew S. KendeRobert Bittman Willy LeimgruberVirgil Boekelheide Frank C. McGrewGeorge A. Boswell, Jr. Blaine C. McKusickTheodore L. Cairns Jerrold MeinwaldArthur C. Cope Carl NiemannDonald J. Cram Leo A. PaquetteDavid Y. Curtin Gary H. PosnerWilliam G. Dauben Harold R. SnyderRichard F. Heck Milán UskokovicLouis F. Fieser Boris WeinsteinRalph F. Hirschmann

Organic ReactionsV O L U M E 101

EDITORIAL BOARD

P. Andrew Evans, Editor-in-Chief

Steven M. Weinreb, Executive Editor

Jeffrey Aubé Gary A. MolanderDavid B. Berkowitz Albert PadwaPaul R. Blakemore Jennifer M. SchomakerDennis G. Hall Kevin H. ShaughnessyDonna M. Huryn Christopher D. VanderwalJeffrey B. Johnson

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Danielle Soenen, Editorial Coordinator

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Landy K. Blasdel, Processing Editor

Debra Dolliver, Processing Editor

Engelbert Ciganek, Editorial Advisor

ASSOCIATE EDITORS

Robert DhalGilles Dujardin

Catherine GaulonMathieu Yves Laurent

Arnaud Martel

Copyright © 2020 by Organic Reactions, Inc. All rights reserved.

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PREFACE TO VOLUME 101

Your fair discourse hath been as sugar,

Making the hard way sweet and delectable.

William ShakespeareRichard II, act 2, sc. 3, l. 6-7

Cycloadditions can hardly be described as sweet and delectable; however, theimpact of these transformations often circumvents protracted and time-consumingalternatives for the de novo construction of carbocycles and heterocycles. Thefollowing single-volume chapter by Arnaud Martel, Robert Dhal, Catherine Gaulon,Mathieu Yves Laurent, and Gilles Dujardin describes the inverse-electron-demandoxa-Diels–Alder (IODA) reactions of α,β-unsaturated carbonyl compounds withelectron-rich dienophiles to prepare 3,4-dihydro-2H-pyrans. The history of dihy-dropyrans can be traced back to the late 1800s when Perkin first described theirpreparation through a simple dehydration reaction; however, their importance maybe more significantly connected to the pioneering work of Emil Fischer, who firstgenerated glycals (dihydropyrans derived from sugars) in 1913. It is therefore withsome irony that the very same dihydropyrans would later feature so prominently inthe synthesis of complex sugars, and that their construction can be achieved by asimple adaptation of the conventional Diels-Alder reaction. Indeed, the importanceof the classical Diels-Alder process was elegantly delineated by Corey in 2002.

“If one chemical reaction had to be selected from those in the repertoireof synthetic organic chemists as the most useful and powerful construc-tion, it was clear by 1970 that the Diels-Alder reaction would be thelogical choice. Its application not only leads to a strong increase inmolecular complexity (molecular size, topology, stereochemistry, func-tionality and appendages), but also can result in structures that lendthemselves to additional amplification of complexity by the use of otherpowerful synthetic reactions.”

E. J. Corey (Angew. Chem. Int. Ed. 2002, 41, 1650).

The inverse-electron-demand oxa-Diels–Alder (IODA) reaction represents animportant variant of the classical Diels-Alder process, which, as noted, providesa very powerful approach to generating molecular complexity. Nevertheless, thecritical developments in the IODA reaction followed from the foundation establishedby the more venerable counterpart, and arguably with the relevance of dihydropyransalready well established. As with the development of many reactions, the preliminarydiscovery provided dogma that delayed the full exploitation of this conceptionally

vii

viii PREFACE TO VOLUME 101

useful process. For instance, the first example of the IODA reaction by Sherlinin 1938 involved the dimerization of acrolein, which was closely followed by thedimerization of methyl vinyl ketone by Alder in 1941. Although the crossed variantwas initially restricted to highly electron-rich dienophiles, as exemplified by thethermal reactions of enamines and enol ethers, the intermolecular IODA process hasnow been extended to a variety of alkenes using a wide range of activated oxadienesthat contain an array of substituents on the 4π component. This chapter providesan historical perspective of the development of IODA reactions and delineates thevarious advances that pertain to asymmetric variants, particularly the advent ofcatalytic methods. Notably, the chapter outlines the scope and limitations, whichidentify knowledge gaps and provide the reader with a perspective of the criticalcontributions and their impact, while also highlighting the current limitationsand how these are manifested in target-directed synthesis. Furthermore, in theComparison with Other Methods section, the authors list representative alternativeapproaches that provide this important motif. The Tabular Survey is organized bythe function of the oxadiene that undergoes the IODA, which makes identificationof the optimal reaction and the associated conditions relatively easy for the reader toidentify.

I would like to take this opportunity to acknowledge Scott E. Denmark’s tenureas Editor-in-Chief and President of Organic Reactions, Inc. Remarkably, he oversawthe completion of 30 volumes that boast 69 chapters including nearly 20,000 pagesencompassing an array of modern synthetic reactions. His intrepid leadership andpursuit of excellence has elevated the Organic Reactions brand into one of the lead-ing reference texts in the chemical literature. Volume 100 was a landmark publication,featuring a who’s who list of authors using a truncated format. While OR will con-tinue to provide the most definitive reviews of specific reactions, the format has beenchanged and in the future the tables and references will no longer be comprehensive,but rather will list what the author believes are the most relevant examples to assistthe reader in their reaction selection. Additionally, we are now publishing OrganicReactions volumes quarterly, so please add this to your calendar to make sure youcan obtain the latest installment of this venerable series.

Finally, I would be remiss if I did not acknowledge the entire Organic ReactionsEditorial Board for their collective efforts in steering this chapter through the variousstages of the editorial process. I would like to particularly thank Steven Weinreb, whoserved as the Responsible Editor and worked tirelessly with the authors to ensure thecompletion of this chapter. I am also deeply indebted to Dr. Danielle Soenen for hercontinuous efforts as the Editorial Coordinator; her knowledge of Organic Reactionsis a critical component to maintaining consistency in the series. Dr. Dena Lindsay(Secretary to the Editorial Board) is thanked for coordinating the contributions of theauthors, editors and publisher. In addition, the Organic Reactions enterprise could notmaintain the quality of production without the efforts of Steven Weinreb (ExecutiveEditor), Dr. Linda S. Press (Editorial Consultant), Dr. Engelbert Ciganek (EditorialAdvisor), Dr. Landy Blasdel (Processing Editor) and Dr. Debra Dolliver (ProcessingEditor). I would also like to acknowledge Dr. Jeffery Press (Secretary-Treasurer) for

PREFACE TO VOLUME 101 ix

his constant effort to keep everyone on task and his attention to making sure that weare fiscally solvent!

In summary, I am indebted to all the people that work so hard to maintain the qual-ity of Organic Reactions. The unique format of the chapters, in conjunction with thecollated tables of examples, make this series of reviews both unique and exceptionallyuseful to the practicing synthetic organic chemist.

P. Andrew EvansKingston

Ontario, Canada

INTRODUCTION TO THE SERIESROGER ADAMS, 1942

In the course of nearly every program of research in organic chemistry, the inves-tigator finds it necessary to use several of the better-known synthetic reactions. Todiscover the optimum conditions for the application of even the most familiar one to acompound not previously subjected to the reaction often requires an extensive searchof the literature; even then a series of experiments may be necessary. When the resultsof the investigation are published, the synthesis, which may have required months ofwork, is usually described without comment. The background of knowledge andexperience gained in the literature search and experimentation is thus lost to thosewho subsequently have occasion to apply the general method. The student of prepar-ative organic chemistry faces similar difficulties. The textbooks and laboratory manu-als furnish numerous examples of the application of various syntheses, but only rarelydo they convey an accurate conception of the scope and usefulness of the processes.

For many years American organic chemists have discussed these problems. Theplan of compiling critical discussions of the more important reactions thus wasevolved. The volumes of Organic Reactions are collections of chapters each devotedto a single reaction, or a definite phase of a reaction, of wide applicability. Theauthors have had experience with the processes surveyed. The subjects are presentedfrom the preparative viewpoint, and particular attention is given to limitations,interfering influences, effects of structure, and the selection of experimental tech-niques. Each chapter includes several detailed procedures illustrating the significantmodifications of the method. Most of these procedures have been found satisfactoryby the author or one of the editors, but unlike those in Organic Syntheses, theyhave not been subjected to careful testing in two or more laboratories. Each chaptercontains tables that include all the examples of the reaction under consideration thatthe author has been able to find. It is inevitable, however, that in the search of theliterature some examples will be missed, especially when the reaction is used as onestep in an extended synthesis. Nevertheless, the investigator will be able to use thetables and their accompanying bibliographies in place of most or all of the literaturesearch so often required. Because of the systematic arrangement of the material inthe chapters and the entries in the tables, users of the books will be able to findinformation desired by reference to the table of contents of the appropriate chapter.In the interest of economy, the entries in the indices have been kept to a minimum,and, in particular, the compounds listed in the tables are not repeated in the indices.

The success of this publication, which will appear periodically, depends upon thecooperation of organic chemists and their willingness to devote time and effort tothe preparation of the chapters. They have manifested their interest already by thealmost unanimous acceptance of invitations to contribute to the work. The editors willwelcome their continued interest and their suggestions for improvements in OrganicReactions.

v

INTRODUCTION TO THE SERIESSCOTT E. DENMARK, 2008

In the intervening years since “The Chief” wrote this introduction to the second ofhis publishing creations, much in the world of chemistry has changed. In particular,the last decade has witnessed a revolution in the generation, dissemination, andavailability of the chemical literature with the advent of electronic publication andabstracting services. Although the exponential growth in the chemical literaturewas one of the motivations for the creation of Organic Reactions, Adams couldnever have anticipated the impact of electronic access to the literature. Yet, as oftenhappens with visionary advances, the value of this critical resource is now evengreater than at its inception.

From 1942 to the 1980’s the challenge that Organic Reactions successfullyaddressed was the difficulty in compiling an authoritative summary of a prepara-tively useful organic reaction from the primary literature. Practitioners interestedin executing such a reaction (or simply learning about the features, advantages,and limitations of this process) would have a valuable resource to guide theirexperimentation. As abstracting services, in particular Chemical Abstracts andlater Beilstein, entered the electronic age, the challenge for the practitioner was nolonger to locate all of the literature on the subject. However, Organic Reactionschapters are much more than a surfeit of primary references; they constitute adistillation of this avalanche of information into the knowledge needed to correctlyimplement a reaction. It is in this capacity, namely to provide focused, scholarly, andcomprehensive overviews of a given transformation, that Organic Reactions takeson even greater significance for the practice of chemical experimentation in the 21st

century.Adams’ description of the content of the intended chapters is still remarkably

relevant today. The development of new chemical reactions over the past decadeshas greatly accelerated and has embraced more sophisticated reagents derived fromelements representing all reaches of the Periodic Table. Accordingly, the successfulimplementation of these transformations requires more stringent adherence to impor-tant experimental details and conditions. The suitability of a given reaction for anunknown application is best judged from the informed vantage point provided byprecedent and guidelines offered by a knowledgeable author.

As Adams clearly understood, the ultimate success of the enterprise depends on thewillingness of organic chemists to devote their time and efforts to the preparation ofchapters. The fact that, at the dawn of the 21st century, the series continues to thrive isfitting testimony to those chemists whose contributions serve as the foundation of thisedifice. Chemists who are considering the preparation of a manuscript for submissionto Organic Reactions are urged to contact the Editor-in-Chief.

vi

CONTENTS

chapter page

1. Dihydropyrans by Cycloadditions of OxadienesArnaud Martel, Robert Dhal, Catherine Gaulon, Mathieu Yves Laurent,and Gilles Dujardin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Cumulative Chapter Titles by Volume . . . . . . . . . . . . . . . . . . . . . . 933

Author Index, Volumes 1–101 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953

Chapter and Topic Index, Volumes 1–101 . . . . . . . . . . . . . . . . . . . . . 961

xi

CHAPTER 1

DIHYDROPYRANS BY CYCLOADDITIONS OF OXADIENES

Arnaud Martel, Robert Dhal, Catherine Gaulon,Mathieu Yves Laurent, and Gilles Dujardin

IMMM-UMR 6283 CNRS, Faculté des Sciences Le Mans Université72085 Le Mans Cedex 9 France

Edited by Steven M. Weinreb

CONTENTS

Page

Acknowledgments . . . . . . . . . . . . . . . 3Introduction . . . . . . . . . . . . . . . . . 3Mechanism And Stereochemistry . . . . . . . . . . . . 4

Thermal Cycloadditions . . . . . . . . . . . . . . 4IODA Reactions Promoted by Hyperbaric Conditions . . . . . . . 8Lewis Acid Catalyzed/Promoted Cycloadditions . . . . . . . . 8Facially Controlled Cycloadditions . . . . . . . . . . . . 9

Scope And Limitations . . . . . . . . . . . . . . . 14Synthesis of Oxadienes . . . . . . . . . . . . . . 14Intermolecular Cycloadditions . . . . . . . . . . . . . 17

Unactivated Oxadienes: α, β-Unsaturated Carbonyl Compounds andDerivatives . . . . . . . . . . . . . . . . 18

Oxadienes Functionalized at C4 . . . . . . . . . . . . 28Oxadienes Activated at C3 . . . . . . . . . . . . . 32Oxadienes Activated at C2 . . . . . . . . . . . . . 49

Uncatalyzed Reactions . . . . . . . . . . . . . 50Lewis Acid Catalyzed Reactions . . . . . . . . . . . 56Chiral Lewis Acid Catalyzed and Organocatalyzed Reactions . . . . 67

Cycloadditions of Oxadienes on Solid Support . . . . . . . . 83Dimerization of Oxadienes . . . . . . . . . . . . . . 87Intramolecular IODA Reactions . . . . . . . . . . . . 88

Intramolecular IODA Reactions Involving Simple Enals . . . . . . 89Intramolecular IODA Reactions Involving Simple Enones . . . . . . 90Intramolecular IODA Reactions Involving Oxadienes Activated at C3 . . . 92Intramolecular IODA Reactions Involving Oxadienes Activated at C2 . . . 95

Domino Reactions . . . . . . . . . . . . . . . . 96Domino Reactions Involving Intermolecular IODA of Oxadienes . . . . 97Domino Reactions Involving Intramolecular IODA of Oxadienes . . . . 100

[email protected] Reactions, Vol. 101, Edited by P. Andrew Evans et al.© 2020 Organic Reactions, Inc. Published in 2020 by John Wiley & Sons, Inc.

1

2 ORGANIC REACTIONS

Applications to Synthesis . . . . . . . . . . . . . . 104Comparison With Other Methods . . . . . . . . . . . . 116Experimental Conditions . . . . . . . . . . . . . . 120Experimental Procedures . . . . . . . . . . . . . . 121

(3S*,4S*,5R*)-3,4-Epoxy-4-methyl-l,6-dioxaspiro[4,5]dec-7-ene [ZnCl2-CatalyzedHetero-Diels–Alder Reaction of an Unactivated α, β-UnsaturatedAldehyde] . . . . . . . . . . . . . . . . 121

7-Methyl-2-phenyl-1,4-dioxaspiro[4,5]dec-7-ene [Hetero-Diels–Alder Reaction of anUnactivated α, β-Unsaturated α′-Alkyl Ketone Under MicrowaveIrradiation] . . . . . . . . . . . . . . . . 121

(2S*,3R*,4R*)-2-Ethoxy-4-methyl-3-phenyl-6-((phenylsulfonyl)methyl)-3,4-dihydro-2H-pyran [TiCl2(Oi-Pr)2-Catalyzed Hetero-Diels–Alder Reaction of an Unactivatedα, β-Unsaturated α′-Alkyl Ketone] . . . . . . . . . . 122

(2S*,4R*)-8-Benzylidene-2-ethoxy-4-phenyl-3,4,5,6,7,8-hexahydro-2H-benzopyran[Yb(fod)3-Catalyzed Hetero-Diels–Alder Reaction of an Unactivated α, β-Unsaturatedα′-Alkyl Ketone] . . . . . . . . . . . . . . 123

(2S)-Ethoxy-(4S)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyran[Chromium(III)-Catalyzed, Asymmetric Hetero-Diels–Alder Reaction of an OxadieneMonofunctionalized at C4] . . . . . . . . . . . . 123

(2S,SS)-2-(4-Methoxyphenyl)-2,6-dimethyl-5-(4-tolylsulfinyl)-3,4-dihydro-2H-pyran[Thermal Hetero-Diels–Alder Reaction of an Oxadiene Heterosubstitutedat C3] . . . . . . . . . . . . . . . . . 124

(4R*,4aR*,8aR*)-2-Methoxy-4-phenyl-4a,5,6,7,8,8a-hexahydro-4H-chromene-3-carbonitrile [Hyperbaric Hetero-Diels–Alder Reaction of an Oxadiene Activated atC3] . . . . . . . . . . . . . . . . . 125

(4S*,5R*,6R*)-Ethyl 5,6-Dihydro-5-isopropyl-2-methyl-4-phenyl-6-(piperidin-1-yl)-4H-pyran-3-carboxylate [Thermal Hetero-Diels–Alder Reaction of an Oxadiene Activatedat C3 with an Enamine] . . . . . . . . . . . . . 125

Dimethyl ((2R,4R)-2-Ethoxy-4-methyl-3,4-dihydro-2H-pyran-6-yl)phosphonate[Copper(II)-Catalyzed Enantioselective Hetero-Diels–Alder Reaction of an OxadieneHeterosubstituted at C2] . . . . . . . . . . . . 126

(2R,3S,4S,4′S)-3-Acetoxy-2,4-diethoxy-6-(carbonyl-4′-tert-butyloxazolidin-2′-one)-3,4-dihydro-2H-pyran [Me2AlCl-Catalyzed Hetero-Diels–Alder Reaction of an OxadieneActivated at C2] . . . . . . . . . . . . . . 127

Methyl (4S,4aS,8aS)-8a-tert-Butyldimethylsiloxy-4-phenyl-4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate [Scandium(III)-Catalyzed, Enantioselective Hetero-Diels–Alder Reaction of an Oxadiene Heterosubstituted at C2] . . . 128

(2R,3R,4S)-Methyl 2-((R)-4-Ethyl-2-oxooxazolidin-3-yl)-3-tetracosyl-4-tridecyl-3,4-dihydro-2H-pyran-6-carboxylate [Eu(fod)3-Catalyzed Hetero-Diels–Alder Reaction ofan Oxadiene Activated at C2] . . . . . . . . . . . 129

(4R,5S,6S)-Methyl 6-((R)-4-Ethyl-2-oxo-oxazolidin-3-yl)-5,6-dihydro-5-methyl-4-phenyl-4H-pyran-2-carboxylate (Endo β) [SnCl4-Catalyzed Hetero-Diels–AlderReaction of an Oxadiene Activated at C2] . . . . . . . . 130

(2-Ethoxy-3,4-dihydro-4-phenyl-2H-pyran-6-yl)methanol [Eu(fod)3-CatalyzedHetero-Diels–Alder Reaction of an Oxadiene on Solid Support] . . . 131

2,5-Diethyl-3,4-dihydro-2H-pyran-2-carbaldehyde [Thermal Dimerization of anOxadiene] . . . . . . . . . . . . . . . . 132

(4aS,8aS,SS)-(–)-4a,5,6,7,8,8a-Hexahydro-1,1,3,6,6-pentamethyl-4-(4-toluenesulfinyl)-1H-2-benzopyran [Et2AlCl-Catalyzed, Intramolecular Hetero-Diels–Alder Reaction ofan Oxadiene] . . . . . . . . . . . . . . . 132

Tabular Survey . . . . . . . . . . . . . . . . 134Chart 1. Asymmetric Catalysts and Ligands Used in Tables . . . . . 137Table 1. Cycloaddition of Unactivated α, β-Unsaturated Aldehydes . . . . 144

DIHYDROPYRANS BY CYCLOADDITIONS OF OXADIENES 3

Table 2. Cycloaddition of Unactivated α, β-Unsaturated α′-AlkylKetones . . . . . . . . . . . . . . . . 199

Table 3. Cycloaddition of Unactivated α, β-Unsaturated α′-ArylKetones . . . . . . . . . . . . . . . . 240

Table 4. Cycloaddition of Unactivated α, β-Unsaturated α′-HeteroarylKetones . . . . . . . . . . . . . . . . 251

Table 5. Cycloaddition of Oxadienes Monofunctionalized at C4 . . . . 267Table 6. Cycloaddition of Oxadienes Heterosubstituted at C3 . . . . . 278Table 7. Cycloaddition of Oxadienes Activated at C3 . . . . . . . 319Table 8. Cycloaddition of Oxadienes Heterosubstituted at C2 . . . . . 407Table 9. Cycloaddition of Oxadienes Activated at C2 . . . . . . . 479Table 10. Cycloaddition of Oxadienes on Solid Support . . . . . . 670Table 11. Dimerization of Oxadienes . . . . . . . . . . . 681Table 12. Intramolecular Cycloaddition of Oxadienes . . . . . . . 698Table 13. Domino Reactions Involving Intermolecular IODA of

Oxadienes . . . . . . . . . . . . . . . . 734Table 14. Domino Reactions Involving Intramolecular IODA of

Oxadienes . . . . . . . . . . . . . . . . 826References . . . . . . . . . . . . . . . . . 916

ACKNOWLEDGMENTS

We are grateful to the National Center of Scientific Research (CNRS) and theFrench Ministry of Research for financial support of the research on heterocycload-ditions performed at the Le Mans Université.

INTRODUCTION

Among the most common types of hetero-Diels–Alder reaction is the formationof dihydropyrans by a [4 + 2] process involving a carbonyl group acting either as adienophile or as part of a heterodienic framework. These two complementary versionsof the oxa-Diels–Alder reaction (ODA) have created opportunities for the regio-,diastereo-, and enantiocontrolled access to natural products and bioactive molecules,including important carbohydrate derivatives, given the presence of tetrahydropyranframeworks in such compounds.

Inverse-electron-demand oxa-Diels–Alder reactions (IODA) of α,β-unsaturatedcarbonyl compounds with electron-rich dienophiles lead to 3,4-dihydro-2H-pyrans(Scheme 1). These site-selective reactions have been known for a long time andwere first observed with the dimerization reactions of acrolein1 and methyl vinylketone.2 Initially restricted to highly electron-rich dienophiles such as enamines andenol ethers under thermal conditions, intermolecular IODA reactions have since beenextended to a variety of alkenes using a range of activated oxadienes bearing an arylor electron-withdrawing group at the C3 or C2 position. These developments havealso taken advantage of Lewis acids as promoters or catalysts, and have sometimesused high pressure, which has resulted in improvements in diastereocontrol. Enantio-enriched IODA adducts bearing up to three stereogenic centers can be prepared byusing chiral auxiliaries or, more recently, by employing chiral Lewis acid catalysts ororganocatalysts.

4 ORGANIC REACTIONS

OO

R4

R1

R2R3 R3 R4

R5

R6

R7

R8R1

R2

+R5 R6

R7 R8

[4 + 2]* **

Scheme 1

This chapter reviews the construction of 3,4-dihydro-2H-pyrans by both inter- andintramolecular cycloadditions of oxadienes, including dimerizations of these species,by methods published through the end of 2017. Several updated reviews on this topichave appeared3–11 since the first was published in 1975.3 The syntheses of dihy-dropyrans by cycloadditions of oxadienes described herein involve a wide range ofconditions (acid-catalyzed/promoted or not) and media (solution versus solid phase).The mechanisms (i.e., concerted or stepwise) of these reactions are discussed in rela-tion to the stereochemical outcomes, especially in those cases that employ Lewis acidcatalysis. Cis/trans diastereoselectivity, in addition to facial diastereo- or enantio-control, are addressed for each type of oxadiene. In many cases, IODA reactionsinvolve oxadienes with an activating substituent at the C3 or C2 position that iscritical for both reactivity and stereocontrol. The presence of such functionalities inthe dihydropyran framework has significantly increased the potential of IODA reac-tions for synthetic applications. The scope of coverage is limited to dihydropyransynthesis using uncharged heterodienes. Cycloadditions of quinone methides, hetero-1-oxabutadienes (e.g., nitrosoalkenes, acylimines, etc.), and cationic oxabutadienes([4+ + 2] reactions) are not discussed herein.

MECHANISM AND STEREOCHEMISTRY

The mechanism and stereochemistry of cycloadditions involving oxadienes arehighly dependent on the substituents on the oxadiene and on the dienophile, as wellas on the reaction conditions (temperature, catalyst, etc.). This section is dividedinto three parts: (1) thermal cycloadditions, (2) Lewis acid catalyzed cycloadditions,and (3) an overview of facially controlled cycloadditions.

Thermal Cycloadditions

1-Oxabutadienes generally react by one of two mechanisms, which is determinedby the substituents on the heterodiene and the dienophile, in addition to the reac-tion conditions. The cycloaddition can proceed either by a concerted mechanismleading to the simultaneous (asynchronous) formation of the carbon–carbon andcarbon–oxygen bonds or by a stepwise process involving an initial Michael-typeaddition of the α,β-unsaturated ketone or aldehyde, followed by a cyclization step(Scheme 2).12

Both the solvent13 and substituents on the dienophile (R5 group) impact the mech-anism of the reaction. Most polar solvents favor stepwise processes, as do R5 groupsthat increase the polarity of the double bond of the dienophile. For example, the


O

[4 + 2] cycloaddition

O–

zwitterionicintermediate

R3

R3

R2

R1

R1

R2

R4

R5

R4

R5

+R4

R5OR1

R2R3

R4

R5

* **

concerted pathway

stepwise pathway

5

6

+

R3

O1

34

2R1

R2

‡

16

53

2

4

Scheme 2

cycloaddition of an enamine14 is proposed to proceed through the formation of animinium ion intermediate that cyclizes to afford a dihydropyran (Scheme 3).15

NMe2O NMe2O– O NMe2+

+

2.2 equiv

rt, neat, 20 min

Scheme 3

In contrast, less-polarized dienophiles, such as unactivated alkenes or electron-deficient dienophiles, usually react in a concerted manner. The synthetic utility of enolethers as dienophiles has also been studied in these cycloaddition reactions. Theseprocesses can proceed by either a concerted or a stepwise mechanism depending onthe reaction conditions.16

Frontier molecular orbital energy levels and coefficients are frequently usedto rationalize the reactivity of the diene/dienophile pair and the regioselectivityof cycloaddition reactions. The HOMO–LUMO energy levels of various het-erodienes/dienophiles have been calculated by different semi-empirical methods(PM3/RHF,17 AM1/PM3,18 CNDO/2,13,19), ab initio,9,20 and DFT methods.21–23

Hetero-Diels–Alder reactions of 1-oxabutadienes are mainly controlled by a domi-nant interaction between the LUMO of the diene and the HOMO of the dienophileand are thus termed inverse electron demand Diels–Alder (DA) reactions (Figure 1).3

Because energy levels of the LUMOs of simple 1-oxabutadienes are low, thesecycloadditions have been mainly performed with electron-rich dienophiles thatpossess a high HOMO, such as enamines, enol ethers, ketene acetals, and enamides.Various electron-withdrawing groups such as esters, ketones, aldehydes, nitriles,sulfoxides, sulfones, phosphonates, and phosphine oxides, located at the C3 or C2position on the heterodiene, lower the energy level of the LUMO, thus increasing thereactivity of the diene component. The presence of an aromatic or heteroaromatic

6 ORGANIC REACTIONS

ring on either the heterodiene or dienophile activates both reactants. In these cases,an aromatic ring causes a decrease in the HOMO–LUMO energy gap, therebyincreasing the reactivity of both IODA partners. Furthermore, when a stepwisemechanism is involved, the presence of an aromatic ring as R5 (Scheme 2) stabilizesthe intermediate carbocation, thus increasing the reactivity, and assists in controllingthe regioselectivity.24 The reaction rate is not only dependent on the energy gapsbetween the dominant orbitals but also the size of the coefficients of the overlappingorbitals (Figure 1). This fact has been illustrated by the frontier molecular orbitaldata with several 1-oxabutadienes and enol ethers.9,22

O HH

H

H

LUMO HOMO

1

2

34

6

5

E (au)

0

–0.386

HOMO

+0.086

LUMO

acrolein

–0.370

HOMO

+0.179LUMO

ethylene

0

E (kcal/mol)

TS24.0

–23.4

2.04 Å 2.19 ÅO

Figure 1. Orbital interactions for acrolein and ethylene as a model representation of the energyprofile for cycloadditions.

The regioselective outcome in IODA reactions is generally controlled by the inter-actions between the largest lobe at C4 (Figure 1) in the LUMO of the heterodiene andthe largest lobe of the HOMO of the dienophile at C6. These interactions also have astrong influence on the mechanism of the cycloaddition (i.e., concerted versus step-wise) and on the degree of asynchronicity in the formation of the carbon–carbon andcarbon–oxygen bonds, as confirmed by DFT studies.22,25,26 The calculated transitionstates illustrate this asynchronicity; namely, the carbon–carbon and carbon–oxygenbond lengths are calculated to be 1.96–2.04 Å and 2.19–2.41 Å, respectively. Fordienophiles with a strongly polarized double bond, the asynchronicity in the forma-tion of the two bonds is further increased,27 and the components are more inclined toreact in a stepwise manner. Dissymmetry in the orbital coefficients of the HOMO of


the dienophile favors the reaction by decreasing the effects of destructive secondaryorbital overlap, thus leading to a mechanism similar to that of a Michael addition.28

The stereochemistry of the cycloadduct is governed by the double bond geometryand the approach of both partners. Using a β-unsubstituted dienophile, up to fourstereoisomers can result from the endo/exo and facial approaches of the dienophilein the transition state (Scheme 4). The cycloadducts will hereafter be termed “endo”or “exo” even when the reaction proceeds through a non-concerted mechanism.

R2

R3

OR1

R5

OR1

R2

R5

R5

R5

R5

OR1

R2

R3

R5

OR1

R2R3

R5

OR1

R2

R3

R5

α-side approach

β-side approach

endo approach of the dienophile exo approach of the dienophile

R2

R3

OR1

R5

OR1

R2

R3

R5

R5

R5

R5

OR1

R2R3

R5

OR1

R2

R3

R5

OR1

R2R3

R5

α-side approach

β-side approach

"anti" oxadiene 21

3 4

4

2

3

1

"syn" oxadiene

R3

Scheme 4

Oxadienes monosubstituted at C4 lead to dihydropyran adducts 1 or 3 in a4,6-cis relationship following either an endo approach of “anti” oxadienes or anexo approach of “syn” oxadienes. Accordingly, a 4,6-trans relationship (adducts2 and 4) will result from either an exo approach of “anti” oxadienes or an endoapproach of “syn” oxadienes. Similarly, a specific enantiomer such as cycloadduct 1(Scheme 4) can result from both facial approaches: cycloadduct 1 can either resultfrom an endo approach on the α side with the “anti” oxadiene or an exo approachon the β side of a “syn” oxadiene. In the case of 1,2-disubstituted dienophiles, thealkene geometry of the dienophile will control the 5,6-relationship in the adduct,with (E) and (Z) alkenes leading to 5,6-trans and 5,6-cis relationships, respectively,unless a stepwise mechanism is involved.

8 ORGANIC REACTIONS

IODA Reactions Promoted by Hyperbaric Conditions

Similar to other Diels–Alder cycloadditions, IODA reactions can be promotedby hyperbaric conditions, which is ascribed to the negative activation volume of thereaction (Eq. 1).

ΔV‡ = −RT(∂ ln k

∂P

)T

(Eq. 1)

This negative activation volume is a consequence of the transition state (which ismore compact than the ground state) that is involved in a Diels–Alder reaction andthe overlapping volumes, particularly for the endo approach. The entropic term isunfavorable in Diels–Alder reactions, allowing the retro-Diels–Alder reaction to bepossible at high temperature. By hyperbaric activation, the cycloaddition can be per-formed with relatively unreactive partners at ambient temperature, thereby enablingthe formation of cycloadducts that could not be produced by simple thermal acti-vation. This situation is particularly relevant for reactions with sterically hinderedsubstituents in either the oxadiene or the dienophile; in such cases, the use of hyper-baric conditions is most suitable. In addition, when differences exist between theactivation volumes of the endo and the exo approaches, a significant improvement inthe diastereoselectivity of the reaction is observed.29–31

Lewis Acid Catalyzed/Promoted Cycloadditions

Among the most commonly used Lewis acids in IODA reactions, some arespecifically involved as monocoordinating catalysts or promoters (TMSOTf,32–37

BF3•Et2O,35,38,39 and chromium(III) salen complexes40), whereas others (suchas SnCl4,16,24,35,36,41–44 TiCl4,39,45–47 Me2AlCl,32,33,36,37,48 Et2AlCl,39,45,47

Eu(fod)3,16,25,35,49–63 and copper(II) salts64–66) are thought to take advantageof the activating group at the C2 position of the 1-oxabutadiene for chelation(Figure 2). Lewis acids such as ZnCl2

35,38,39,41,45,47,67–71 or Yb(fod)3 (fod =6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate)60,64,71–91 can be mono-or biscoordinating depending on the oxadiene. When a mild Lewis acid, such asEu(fod)3, is employed in a non-polar solvent, the starting materials react by anasynchronous but concerted pathway and favor an endo adduct. Transition metals andlanthanide triflates generally do not catalyze IODA reactions alone, but rather, theyrequire the presence of a ligand, often chiral, to attenuate their intrinsic strong Lewisacidity. Strong Lewis acids, such as tin(IV) chloride or titanium(IV) chloride, favora stepwise mechanism.16 The mechanism of tin(IV) chloride catalyzed cycload-ditions of deuterated or cyclic dienophiles with arylidene- or alkylidenepyruvicacid derivatives as heterodienes is reported to occur by bidentate chelation of themetal to the 1,2-dicarbonyl groups.16,24,92 Such strong Lewis acids are generallyused in cycloadditions at low temperature to avoid degradation of the dienophile.Furthermore, product epimerization at the C6 position in the cycloadduct occurs inthe presence of a strong Lewis acid, such as tin(IV) chloride, via an open zwitterionicintermediate similar to that involved in the cycloaddition (Scheme 2). The formationof the zwitterionic intermediate, common to both the cyclization and epimerization,is proposed to be responsible for the mixture of C6 diastereomers, which are formedunder thermodynamic control.16


OR2

R1

OY

R1

OO

R1

SOnR3M M M

Y = P(OR4)2, COR4

Lewis acidL = ligand

TMSOTf, BF3•Et2O,ZnCl2, Yb(fod)3, Cr(III)L*

TiX2OR*2, ZnI2 SnCl4, Me2AlCl, Et2AlCl, Ln(fod)3, ZnCl2, Cu(II)L*, Ln(OTf)3L*

R2 = H, alkyl, aryl n = 1, 2

Figure 2. Representation of the mode of oxadiene interaction of some of the most commonlyused Lewis acid catalysts.

Cases of diastereo- and enantioselective cycloadditions involving a Lewis acid asthe catalyst or promoter will be discussed below.

Facially Controlled Cycloadditions

Two strategies have been developed to control the absolute configuration of thecycloadducts formed: the introduction of a chiral auxiliary into the heterodiene,the dienophile, or both and, more recently, the use of a chiral catalyst. Undernon-catalyzed conditions, facial control of the cycloaddition may result fromsteric interactions as described for C2-symmetric ketene acetals bearing bulkyaromatic rings.93,94 The selectivity of the cycloaddition, in this case, arises from theunfavorable steric interactions between the aromatic ring and the heterodiene whenthe dienophile approaches from the Re face of the oxabutadiene (Scheme 5).

NO

HO

OAr

Ar

O

OR1O

Si additionfavored

NO

HO

OAr

Ar

O

OR1O

Re addition

R2

R2

AcHN

R1O2C

O

OO

versus

Scheme 5

10 ORGANIC REACTIONS

Chiral oxazolidinones as N-acyl C2-substituents on the heterodiene are usefulauxiliaries, albeit the stereocontrol in these cases is highly dependent on the Lewisacid catalyst employed. In one example, a monodentate (trimethylsilyl triflate) and abidentate Lewis acid (dimethylaluminum chloride) catalyst promote facial stereodi-vergence of the cycloaddition, which in both cases occurs via an “endo” approach(Scheme 6).32

OO

OEt

N

O O

t-Bu

OO

OEt

N

O

Ot-Bu

AlMe

Me

OO

OEt

N

O O

t-BuSiMe3

+

TfO–

Cl–

TMSOTf (1.5 equiv)

CH2Cl2, –78°, 48 h

AlMe2Cl (1.5 equiv)

CH2Cl2, –35°, 24 h

+

O

OEtOAc

OEtO

N

OO

t-Bu

(78%)endo/exo = 97:3

endo er 83:17

O

OEtOAc

OEtO

N

OO

t-Bu

(97%)endo/exo > 98:2

endo er 98:2

OAc

OEt

OAc

OEt

Scheme 6

Varying the Lewis acid to achieve facial stereodivergence has also been describedusing N-alkenyloxazolidinone derivatives as chiral dienophiles.35,49,51 As previouslymentioned, tin(IV) chloride is chelated by an α-keto ester moiety and presumablyalso complexes with the carbonyl group of the oxazolidinone moiety, thus induc-ing the specific orientation illustrated in Scheme 7.35,95 The use of Eu(fod)3 causesthe heterodiene to attack the opposite face of the dienophile. In this case, facial


stereodivergence is presumably the result of preferential coordination of the metalcatalyst to either one or both of the carbonyl groups within the oxadiene.

N

O O

Et

O

O

Ph

MeO

SnCl4

NO

O

OO

MeO

Ph

EuL3

Et

O

O

Ph

Ph

MeO

O

MeO

O

N O

O

N O

O

Et

Et

O

Ph

MeO

ON O

O

Et

+

SnCl4 (50 mol %)

CH2Cl2, –78°, 3 h

Eu(fod)3 (5 mol %)

cyclohexane, reflux

(62%)endo/exo > 98:2

endo er >98:2

(71%)endo/exo > 95:5

endo er >98:2

1 equiv

‡‡

Scheme 7

The development of chiral catalysts in IODA reactions has relied on ligand effectsto adjust the Lewis acidity (of titanium(IV), copper(II), or chromium(III)) to ensurecompatibility with the reactants. The first example of asymmetric catalysis in anintermolecular IODA reaction involves a TADDOL complex of titanium(IV) witha 2-sulfonylmethyl oxadiene.96,97 The sulfone group plays a key role as the chelationsite for titanium and enables high diastereo- and enantioselectivity in the reaction.

Chiral bis(oxazoline) (BOX) copper(II) complexes, such as [Cu((S,S)-t-Bu-BOX)](OTf)2, catalyze enantioselective cycloadditions of both α,β-unsaturatedacyl phosphonates and β,γ-unsaturated α-keto esters with vinyl ethers.64–66 Theketophosphonate and pyruvate groups are presumed to chelate the C2-symmetricbis(oxazoline)copper(II) complex in a distorted square-planar geometry in whichthe tert-butyl group blocks the upper side of the heterodiene, leading to an endoapproach of the dienophile on the lower face of the heterodiene (Scheme 8).64


OMeO

OOEt

OPMeOO

OEtMeO

N NO O

Cut-Bu

t-Bu

OP

O

OMeOMe

N NO

O

Cu t-Bu

t-Bu

O O

favored approachof the dienophile

favored approachof the dienophile

O Me

Scheme 8

When applied to silyl enol ethers, chiral Cu(BOX)-catalyzed cycloadditions pro-ceed by a stepwise mechanism that can result in the migration of the silyl groupto the enol oxygen atom during the cycloaddition, thereby preventing cyclization(Scheme 9).64

P O OSiR3

O

Ph+

[Cu((S,S)-t-Bu-BOX)](SbF6)2 (10 mol %)

CH2Cl2MeOMeO

1.2 equiv

O OSiR3PO

PhP OSiR3

O

Ph

O

MeOMeO

MeOMeO

R3SiMe2t-BuSiMe3Si

Cyclic Adduct

Cyclic/Linear100:062:38

Yield (%)99—

*dr92:892:8

er (major)99.5:0.599.5:0.5

er (minor)91:987:13

er (linear)—

85:15

*+

P OO

Cu

L

L

Ph

OSiR3

MeOMeO

+

–

Temp (°)–60–40

Time (h)25.516

Scheme 9


A chiral, tridentate Schiff base/chromium(III) complex has also been successfullyemployed for the cycloaddition of α,β-unsaturated aldehydes, based on its ability tocomplex and activate simple aldehydes. This complex is the first efficient monocoor-dinating chiral catalyst used for IODA reactions.40 This endo-controlled and enantio-selective process requires the presence of molecular sieves. The crucial role of thisdesiccant is presumably to dissociate the chromium–oxygen–chromium bonds of thedimeric complex that the catalyst forms with water, thereby creating a coordinationsite for complexation with the aldehyde.

Most of the catalysts developed for enantioselective IODA reactions involveactivation of the heterodiene with a Lewis acid using a chiral ligand for the facialinduction, and for attenuating the strength of the Lewis acid. Nevertheless, a feworganocatalyzed domino reactions involving activation of the dienophile haveappeared. The first examples of enantioselective organocatalyzed IODA reactionsuse L-proline derivatives and proceed through a catalytic cycle involving theformation of an intermediate enamine from an alkanal that is sufficiently reactive toadd to the heterodiene (Scheme 10).98 Chiral amine 5 is regenerated in situ usingwet silica gel to furnish lactol 6, which is subsequently trapped by oxidation to thecorresponding lactone. The absolute configuration of the lactol is believed to becontrolled by the steric hindrance presented on one side of the enamine. Therefore,the heterodiene approaches from the least hindered face of the enamine to avoidsteric interactions induced by the diarylmethyl moiety in the catalyst.

NH

Ar

Ar

NAr

Ar

i-Pr

OMeO2C

Ph

N

i-Pr

Ar

Ar

MeO2C O

Ph

silica

OMeO2C

Ph

OH

i-Pr H2O

O

Hi-Pr

H2O

N

Ar

Ar

i-PrMeO2C O

PhAr = 3,5-Me2C6H3

6

5

via

‡

Scheme 10

Interestingly, the dienophile in an IODA reaction can be activated by generatinga zwitterionic species. Thus, allenic ester 7 reacts readily at room temperature toform zwitterionic intermediate 9, which undergoes the IODA cycloaddition by astepwise mechanism. Computational studies on the key transition state indicate that


the reaction likely proceeds by activation of the heterodiene to promote a stepwisesequence, which results in carbon–carbon bond formation followed by cyclizationto form adduct 10. The covalent bond formed via intermediate 9 permits highfacial control, which is governed by steric interactions with quinidine catalyst 8(Scheme 11).99

O(i-PrO)2OP

Ph

+

N

N

OMe

O

R1R2R3N

OEt

–O

•

CO2Et O(i-PrO)2OP

Ph8 (20 mol %)

MeCN, rt, 24 h CO2Et

+N

N

OMe

O

CO2Et

O–

PO(Oi-Pr)2Ph

2.31Å

9

10 (90%)er 97:3

71.2 equiv

R1R2R3N

OEt

O

+–

+

via

‡

Scheme 11

SCOPE AND LIMITATIONS

Synthesis of Oxadienes

A limited number of oxadienes are commercially available. For the others,including complex, highly functionalized oxadienes, the choice of synthetic methodis generally dependent on the structure of the specific oxadiene. The most commonsynthetic methods are outlined in Figure 3.


R1 O

R2

R4

R3

12

3

4

5

67

9

10

11

12

8

Wittig

1

2

3 4

OR1

R2

R3 R4

O+

Knoevenagel Aldolization–Crotonization

OR1

PPh3

+ R3CHOOR1

(RO)2PO

or

OR1

R2 O R4

Ph3P+

OR1

R2

+ HCY(OR)2

Y = RO, Me2N

OR1

Y

Y = RO, HO, ...

OTMS

+ R3CH(OMe)2

R1

OR

OR1

Cl+ or

OCF3

O

CF3

O

OCl

R3

OR1

+ RSOH or R2BH

OR1

R2SMe

OR

R2OMe

or

R2R3

M

+ R1COY

+ R1MR2

R3

O

OHR1

R2R3

R2R3

M

+R1CHO 13

M = MgBr, Li, etc.

14

Figure 3. Most common synthetic pathways to oxadienes.

Owing to the presence of the carbonyl group, most of the syntheses ofoxadienes involve the formation of the bond between C3 and C4, as in analdolization–crotonization sequence (pathway 1), leading to enones, α,β-unsaturatedaldehydes,75,76,100,101 or oxadienes activated at the C2 position.64,102–107 Cor-respondingly, C3-activated oxadienes are mainly prepared via a Knoevenagelcondensation (pathway 1, R2 = EWG) with an aldehyde or a ketone. Thus, a widerange of oxadienes activated at the C3 position by an ester,38,108 nitrile,18,109–112

ketone,113 amide,114 phosphonate,115 or sulfone116,117 functionality and possessingone or two aryl/alkyl substituent(s) at C4 are prepared. This strategy is particularlyuseful for domino oxadiene–cycloaddition sequences.

The Knoevenagel condensation also produces oxadienes in which the car-bonyl is incorporated into a heterocyclic moiety (i.e., pyrazolones,118–120

isoxazolones,121,122 Meldrum’s acid,123 barbiturates and thiobarbiturates,110,124–127

2- and 3-oxoindoles77,122,128) or even substituted at C3 by a phenylthio group.129


Alternatively, the Wittig reaction of a ketophosphorane with an aldehyde (path-way 2)130 is used for the preparation of enones and enals, as is the analogouscondensation of a phosphorane with a 1,2-diketone (pathway 3).131 A Wittig–Hornersequence is also used for the formation of the C3–C4 double bond of oxadienesfunctionalized by a carbonyl group at C2 (pathway 2).87

C3-Activated oxadienes bearing a heterosubstituent at the C4 position are gener-ally sensitive to hydrolysis, which can limit their synthetic accessibility and purifi-cation. One strategy for preparing such oxadienes involves condensation of a ketonewith an orthoester132–135 (Y = MeO) or with formamide dimethyl acetal (Y = Me2N)(pathway 4), followed by the exchange of the heterosubstituent at C4 by hydrolysisor aminolysis and subsequent protection as necessary (pathway 5). These transfor-mations at C4 are successfully applied to aldehydes,38,136–143 ketones,93,144–146 andoxadienes bearing a phenylthio group at C3.147–151

In the case of pyruvate derivatives, a sequence involving a Mukaiyama aldol reac-tion between silyl enol ethers of pyruvates and aldehyde dimethyl acetals is highlyefficient (pathway 6, R1 = RO2C).64,102,103

The most commonly employed method for the synthesis of C2-activated hetero-dienes involves forming the C2–C3 connection by an addition–elimination sequencebetween a vinyl ether and oxalyl chloride (pathway 7, R1 = ClOC),32,36,152 alkoxalylchloride (pathway 7, R1 = RO2C),21,64,153 or trifluoroacetic anhydride.154–157

A complementary approach for installing a specific activating group at C2,such as a nitrile or a phosphonate, relies on a cyanide condensation158,159 orthe Michaelis–Arbusov reaction64 of an unsaturated acyl chloride (pathway 8).Alternatively, ketophosphonates substituted with an aryl group at C4 can be obtainedby the addition of a phosphite to a cinnamaldehyde derivative, followed by oxidationof the resulting alcohol (pathway 14).64

Numerous strategies have been developed for the synthesis of oxadienes having anactivating group at C4. One elegant method developed for the synthesis of oxadienesborylated160,161 or sulfinylated162 at C4 consists of an anti-Markovnikov addition toan α,β-acetylenic compound (pathway 9).

Highly reactive 2-methylene-1,3-dicarbonyl compounds (R3 = R4 = H) are pre-pared by a two-step procedure, which involves the introduction of a thiomethyl at C4that undergoes a subsequent elimination (pathway 10).163 A similar strategy is usedto prepare phosphonoacrolein by alkylation of a β-ethoxy-α-phosphovinyl anionwith chloromethyl methyl ether (MOMCl) followed by elimination of methanol(pathway 10).164

Following a similar route, 2-formylcycloalkenes can be prepared by treatment ofthe corresponding alkenylmetal with DMF (pathway 11, R1 = H, Y = NMe2).165,166

The addition to aldehydes affords the secondary alcohol (pathway 13), which isthen oxidized (pathway 12) to furnish the desired oxadiene. Pathway 12 is alsoused for the synthesis of vinyl alkyl ketones by organometallic addition to acrolein(pathway 14).165,166

Some oxadienes activated at the C2 position by an ester or amide group can be pre-pared by the addition of the appropriate alkenyl Grignard reagent to the correspondingoxalate or oxamide. This method has the advantage of enabling the introduction ofan alkyl substituent at C3 (pathway 11).64,167,168

organicreactions€¦ · catalytic methods. notably, the chapter outlines the scope and...

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