Science of Synthesis

Science of Synthesis is the authoritative and comprehensive reference work for the entire field of organic and organometallic synthesis.

Science of Synthesis presents the important synthetic methods for all classes of compounds and includes:

Methods critically evaluated by leading scientists

Background information and detailed experimental procedures

Schemes and tables which illustrate the reaction scope

Preface

As the pace and breadth of research intensifies, organic synthesis is playing an increasingly central role in the discovery process within all imaginable areas of science: from pharmaceuticals, agrochemicals, and materials science to areas of biology and physics, the most impactful investigations are becoming more and more molecular. As an enabling science, synthetic organic chemistry is uniquely poised to provide access to compounds with exciting and valuable new properties. Organic molecules of extreme complexity can, given expert knowledge, be prepared with exquisite efficiency and selectivity, allowing virtually any phenomenon to be probed at levels never before imagined. With ready access to materials of remarkable structural diversity, critical studies can be conducted that reveal the intimate workings of chemical, biological, or physical processes with stunning detail.

The sheer variety of chemical structural space required for these investigations and the design elements necessary to assemble molecular targets of increasing intricacy place extraordinary demands on the individual synthetic methods used. They must be robust and provide reliably high yields on both small and large scales, have broad applicability, and exhibit high selectivity. Increasingly, synthetic approaches to organic molecules must take into account environmental sustainability. Thus, atom economy and the overall environmental impact of the transformations are taking on increased importance.

The need to provide a dependable source of information on evaluated synthetic methods in organic chemistry embracing these characteristics was first acknowledged over 100 years ago, when the highly regarded reference source Houben–Weyl Methoden der Organischen Chemie was first introduced. Recognizing the necessity to provide a modernized, comprehensive, and critical assessment of synthetic organic chemistry, in 2000 Thieme launched Science of Synthesis, Houben–Weyl Methods of Molecular Transformations. This effort, assembled by almost 1000 leading experts from both industry and academia, provides a balanced and critical analysis of the entire literature from the early 1800s until the year of publication. The accompanying online version of Science of Synthesis provides text, structure, substructure, and reaction searching capabilities by a powerful, yet easy-to-use, intuitive interface.

From 2010 onward, Science of Synthesis is being updated quarterly with high-quality content via Science of Synthesis Knowledge Updates. The goal of the Science of Synthesis Knowledge Updates is to provide a continuous review of the field of synthetic organic chemistry, with an eye toward evaluating and analyzing significant new developments in synthetic methods. A list of stringent criteria for inclusion of each synthetic transformation ensures that only the best and most reliable synthetic methods are incorporated. These efforts guarantee that Science of Synthesis will continue to be the most up-to-date electronic database available for the documentation of validated synthetic methods.

Also from 2010, Science of Synthesis includes the Science of Synthesis Reference Library, comprising volumes covering special topics of organic chemistry in a modular fashion, with six main classifications: (1) Classical, (2) Advances, (3) Transformations, (4) Applications, (5) Structures, and (6) Techniques. Titles will include Stereoselective Synthesis, Water in Organic Synthesis, and Asymmetric Organocatalysis, among others. With expertevaluated content focusing on subjects of particular current interest, the Science of Synthesis Reference Library complements the Science of Synthesis Knowledge Updates, to make Science of Synthesis the complete information source for the modern synthetic chemist.

The overarching goal of the Science of Synthesis Editorial Board is to make the suite of Science of Synthesis resources the first and foremost focal point for critically evaluated information on chemical transformations for those individuals involved in the design and construction of organic molecules.

Throughout the years, the chemical community has benefited tremendously from the outstanding contribution of hundreds of highly dedicated expert authors who have devoted their energies and intellectual capital to these projects. We thank all of these individuals for the heroic efforts they have made throughout the entire publication process to make Science of Synthesis a reference work of the highest integrity and quality.

July 2010

The Editorial Board

E. M. Carreira (Zurich, Switzerland)

C. P. Decicco (Princeton, USA)

A. Fuerstner (Muelheim, Germany)

G. A. Molander (Philadelphia, USA)

P. J. Reider (Princeton, USA)

E. Schaumann (Clausthal-Zellerfeld, Germany)

M. Shibasaki (Tokyo, Japan)

E. J. Thomas (Manchester, UK)

B. M. Trost (Stanford, USA)

Science of Synthesis Reference Library

Applications of Domino Transformations in Organic Synthesis (2 Vols.)

Catalytic Transformations via C—H Activation (2 Vols.)

Biocatalysis in Organic Synthesis (3 Vols.)

C-1 Building Blocks in Organic Synthesis (2 Vols.)

Multicomponent Reactions (2 Vols.)

Cross Coupling and Heck-Type Reactions (3 Vols.)

Water in Organic Synthesis

Asymmetric Organocatalysis (2 Vols.)

Stereoselective Synthesis (3 Vols.)

Volume Editor's Preface

Domino reactions have been a mainstay of synthetic chemistry for much of its history. Domino chemistry's roots trace to achievements such as the one-pot synthesis of tropinone in 1917 by Robinson and the generation of steroidal frameworks through polyene cyclizations, as originally predicted by the Stork–Eschenmoser hypothesis. In the ensuing decades, chemists have used these, and other inspiring precedents, to develop even more complicated domino sequences that rapidly and efficiently build molecular complexity, whether in the form of natural products, novel pharmaceuticals, or materials such as buckminsterfullerene.

Despite this body of achievements, however, the development of such processes remains a deeply challenging endeavor. Indeed, effective domino chemistry at the highest levels requires not only creativity and mechanistic acumen, but also careful planning at all stages of a typical experiment, from substrate design, to reagent and solvent choice, to timing of additions, and even the quench. Thus, if the frontiers are to be pushed even further, there is certainly much to master.

It was with these parameters in mind that the Editorial Board of Science of Synthesis decided to focus one of its Reference Library works on domino chemistry, covering the myriad ways that these sequences can be achieved with the full array of reactivity available, whether in the form of pericyclic reactions, radical transformations, anionic and cationic chemistry, metal-based cross couplings, and combinations thereof. In an effort to provide a unique approach in organizing and presenting such transformations relative to other texts and reviews on the subject, the sections within this book have been organized principally by the type of reaction that initiates the sequence. Importantly, only key and representative examples have been provided to highlight the best practices and procedures that have broad applicability. The hope is that this structure will afford a clear sense of current capabilities as well as highlight areas for future development and research.

A work on such a vibrant area of science would not have been possible, first and foremost, without a talented and distinguished author team. Each is mentioned in the introductory chapter, and I wish to thank all of them for their professionalism, dedication, and expertise. I am also grateful to all of the coaching, advice, and assistance provided by Ernst Schaumann, member of the Editorial Board of Science of Synthesis. Deep thanks also go, of course, to the entire editorial team at Thieme, particularly to Robin Padilla and Karen Muirhead-Hofmann who served as the scientific editors in charge of coordinating this reference work; Robin started the project, and Karen saw it through to the end. Their attention to detail and passion to produce an excellent final product made this project a true pleasure. Last, but not least, I also wish to thank my wife Cathy and my son Sebastian for their support of this project over the past two years.

Finally, I wish to dedicate this work, on behalf of the chapter authors and myself, to our scientific mentors. It was through their training that we learned how to better understand reactivity, propose novel chemistry, and identify the means to actually bring those ideas to fruition. Hopefully this text will serve the same role to those who study its contents, with even greater wisdom achieved as a result.

Scott A. Snyder

Chicago, October 2015

Abstracts

2.1.1 The Diels–Alder Cycloaddition Reaction in the Context of Domino Processes

J. G. West and E. J. Sorensen

The Diels–Alder cycloaddition has been a key component in innumerable, creative domino transformations in organic synthesis. This chapter provides examples of how this [4 + 2] cycloaddition has been incorporated into the said cascades, with particular attention to its interplay with the other reactions in the sequence. We hope that this review will assist the interested reader to approach the design of novel cascades involving the Diels–Alder reaction.

Keywords: Diels–Alder • cascade • domino reactions • pericyclic • [4 + 2] cycloaddition

2.1.2 Domino Reactions Including [2 + 2], [3 + 2], or [5 + 2] Cycloadditions

I. Coldham and N. S. Sheikh

This chapter covers examples of domino reactions that include a [2 + 2]-, [3 + 2]-, or [5 + 2]-cycloaddition reaction. The focus is on concerted reactions that occur in a tandem sequence in one pot, rather than overall “formal cycloadditions” or multicomponent couplings. The cycloaddition step typically involves an alkene or alkyne as one of the components in the ring-forming reaction. In addition to the key cycloaddition step, another bond-forming reaction will be involved that can precede or follow the cycloaddition. This other reaction is often an alkylation that generates the substrate for the cycloaddition, or is a ring-opening or rearrangement reaction that occurs after the cycloaddition. As the chemistry involves sequential reactions including at least one ring-forming reaction, unusual molecular structures or compounds that can be difficult to prepare by other means can be obtained. As a result, this strategy has been used for the regio- and stereoselective preparation of a vast array of polycyclic, complex compounds of interest to diverse scientific communities.

Keywords: alkylation • [2 + 2] cycloaddition • [3 + 2] cycloaddition • [5 + 2] cycloaddition • dipolar cycloaddition • domino reactions • Nazarov cyclization • ring formation • [3,3]-sigmatropic rearrangement • tandem reactions

2.1.3 Domino Transformations Involving an Electrocyclization Reaction

J. Suffert, M. Gulea, G. Blond, and M. Donnard

Electrocyclization processes represent a powerful and efficient way to produce carbo- or heterocycles stereoselectively. Moreover, when electrocyclizations are involved in domino processes, the overall transformation becomes highly atom and step economic, enabling access to structurally complex molecules. This chapter is devoted to significant contributions published in the last 15 years, focusing on synthetic methodologies using electrocyclization as a key step in a domino process.

Keywords: electrocyclization • hetero-electrocyclization • domino reactions • cascade reactions

2.1.4 Sigmatropic Shifts and Ene Reactions (Excluding [3,3])

A. V. Novikov and A. Zakarian

This chapter features a review and discussion of the domino transformations initiated by ene reactions and sigmatropic rearrangements, particularly focusing on [2,3]-sigmatropic shifts, such as Mislow–Evans and Wittig rearrangements, and [1,n] hydrogen shifts. A variety of examples of these domino processes are reviewed, featuring such follow-up processes to the initial reaction as additional ene reactions or sigmatropic shifts, Diels–Alder cycloaddition, [3 + 2] cycloaddition, electrocyclization, condensation, and radical cyclization. General practical considerations and specific features in the examples of the reported cascade transformation are highlighted. To complete the discussion, uses of these cascade processes in the synthesis of natural products are discussed, demonstrating the rapid assembly of structural complexity that is characteristic of domino processes. Overall, the domino transformations initiated by ene reactions and sigmatropic shifts represent an important subset of domino processes, the study of which is highly valuable for understanding key aspects of chemical reactivity and development of efficient synthetic methods.

Keywords: ene reaction • sigmatropic shift • domino reactions • cascade reactions • hydrogen shift • [1,3]-shift • [1,5]-shift • [1,7]-shift • [2,3]-shift • [3,3]-shift • Mislow–Evans rearrangement • Wittig rearrangement • Diels–Alder cycloaddition • Claisen rearrangement • oxy-Cope rearrangement • electrocyclization • chloropupukeanolide D • isocedrene • steroids • mesembrine • joubertinamine • pinnatoxins • sterpurene • arteannuin M • pseudomonic acid A

2.1.5 Domino Transformations Initiated by or Proceeding Through [3,3]-Sigmatropic Rearrangements

C. A. Guerrero

This chapter concerns itself with domino transformations (i.e., cascade sequences and/or tandem reactions) that are either initiated by or proceed through at least one [3,3]-sigmatropic rearrangement. Excluded from this discussion are domino transformations that end with sigmatropy. The reactions included contain diverse forms of [3,3]-sigmatropic rearrangements and are followed by both polar chemistry or further concerted rearrangement.

Keywords: rearrangement • sigmatropic • Bellus–Claisen • Cope • Overman • concerted • stereoselective • stereospecific • ene • trichloroacetimidate • Diels–Alder

2.2 Intermolecular Alkylative Dearomatizations of Phenolic Derivatives in Organic Synthesis

J. A. Porco, Jr., and J. Boyce

Intermolecular alkylative dearomatization products have shown promise as synthetic intermediates with diverse capabilities. This chapter describes the available methods for constructing these dearomatized molecules and demonstrates their value as synthetic intermediates for efficient total syntheses.

Keywords: alkylative dearomatization • dearomative alkylation • dearomative substitution • domino transformations • domino sequences • dearomative domino transformations • cationic cyclization • radical cyclization • alkylative dearomatization/annulation

2.3.1 Additions to Nonactivated C=C Bonds

Z. W. Yu and Y.-Y. Yeung

Electrophilic additions to nonactivated C=C bonds are one of the well-known classical reactions utilized by synthetic chemists as a starting point to construct useful complex organic molecules. This chapter covers a collection of electrophile-initiated domino transformations involving alkenes as the first reaction, followed by reaction with suitable nucleophiles in the succession and termination reactions under identical conditions. The discussion focuses on recent advances in catalysis, strategically designed alkenes, and new electrophilic reagents employed to improve reactivity and control of stereochemistry in the sequence of bond-forming steps.

Keywords: nonactivated alkenes • addition • domino reactions • amination • etherification • carbonylation • polyenes • protons • halogens • transition metals • chalcogens

2.3.2 Organocatalyzed Addition to Activated C=C Bonds

P. Renzi, M. Moliterno, R. Salvio, and M. Bella

In this chapter, several examples of organocatalyzed additions to C=C bonds carried out through a domino approach are reviewed, from the early examples to recent applications of these strategies in industry.

Keywords: organocatalysis • domino reactions • iminium ions • enamines • Michael/aldol reactions • nucleophilic/electrophilic addition • α,β-unsaturated carbonyl compounds • spirocyclic oxindoles • cinchona alkaloid derivatives • chiral secondary amines • Knoevenagel condensation • methyleneindolinones

2.3.3 Addition to Monofunctional C=O Bonds

A. Song and W. Wang

Catalytic asymmetric domino addition to monofunctional C=O bonds is a powerful group of methods for the rapid construction of valuable chiral building blocks from readily available substances. Impressive progress has been made on transition-metal-catalyzed and organocatalytic systems that promote such addition processes through reductive aldol, Michael/aldol, or Michael/Henry sequences. In addition, Lewis acid catalysis has also been developed in this area for the synthesis of optically active chiral molecules. This chapter covers the most impressive examples of these recent developments in domino chemistry.

Keywords: aldol reactions • carbonyl ylides • chiral amine catalysis • domino reactions • epoxy alcohols • Lewis acid catalysis • Michael addition • organocatalysis • phosphoric acid catalysis • thiourea catalysis

2.3.4 Additions to C=N Bonds and Nitriles

E. Kroon, T. Zarganes Tzitzikas, C. G. Neochoritis, and A. Dçmling

This chapter describes additions to imines and nitriles and their post-modifications within the context of domino reactions and multicomponent reaction chemistry.

Keywords: multicomponent reactions • domino reactions • isocyanides • Ugi reaction • Pictet–Spengler reaction • Gewald reaction • isoindoles • benzodiazepines • cyanoacetamides • thiophenes

Applications of Domino Transformations in Organic Synthesis 2

Preface

Volume Editor's Preface

Abstracts

Table of Contents

2.1 Pericyclic Reactions

2.1.1 The Diels–Alder Cycloaddition Reaction in the Context of Domino Processes

J. G. West and E. J. Sorensen

2.1.2 Domino Reactions Including [2 + 2], [3 + 2], or [5 + 2] Cycloadditions

I. Coldham and N. S. Sheikh

2.1.3 Domino Transformations Involving an Electrocyclization Reaction

J. Suffert, M. Gulea, G. Blond, and M. Donnard

2.1.4 Sigmatropic Shifts and Ene Reactions (Excluding [3,3])

A. V. Novikov and A. Zakarian

2.1.5 Domino Transformations Initiated by or Proceeding Through [3,3]-Sigmatropic Rearrangements

C. A. Guerrero

2.2 Intermolecular Alkylative Dearomatizations of Phenolic Derivatives in Organic Synthesis

J. A. Porco, Jr., and J. Boyce

2.3 Additions to Alkenes and C=O and C=N Bonds

2.3.1 Additions to Nonactivated C=C Bonds

Z. W. Yu and Y.-Y. Yeung

2.3.2 Organocatalyzed Addition to Activated C=C Bonds

P. Renzi, M. Moliterno, R. Salvio, and M. Bella

2.3.3 Addition to Monofunctional C=O Bonds

A. Song and W. Wang

2.3.4 Additions to C=N Bonds and Nitriles

E. Kroon, T. Zarganes Tzitzikas, C. G. Neochoritis, and A. Dömling

Keyword Index

Author Index

Abbreviations

Table of Contents

2.1 Pericyclic Reactions

2.1.1 The Diels–Alder Cycloaddition Reaction in the Context of Domino Processes

J. G. West and E. J. Sorensen

2.1.1 The Diels–Alder Cycloaddition Reaction in the Context of Domino Processes

2.1.1.1 Cascades Not Initiated by Diels–Alder Reaction

2.1.1.1.1 Cascades Generating a Diene

2.1.1.1.1.1 Ionic Generation of a Diene

2.1.1.1.1.1.1 Through Wessely Oxidation of Phenols

2.1.1.1.1.1.2 Through Ionic Cyclization

2.1.1.1.1.1.3 Through Deprotonation of an Alkene

2.1.1.1.1.1.4 Through Elimination Reactions

2.1.1.1.1.1.5 Through Allylation

2.1.1.1.1.2 Pericyclic Generation of a Diene

2.1.1.1.1.2.1 Through Electrocyclization

2.1.1.1.1.2.1.1 Through Benzocyclobutene Ring Opening

2.1.1.1.1.2.1.2 Through Electrocyclic Ring Closure

2.1.1.1.1.2.2 Through Cycloaddition or Retrocycloaddition

2.1.1.1.1.2.3 Through Sigmatropic Reactions

2.1.1.1.1.3 Photochemical Generation of a Diene

2.1.1.1.1.4 Metal-Mediated Generation of a Diene

2.1.1.1.2 Cascades Generating a Dienophile

2.1.1.1.2.1 Ionic Generation of a Dienophile

2.1.1.1.2.1.1 Through Himbert Cycloadditions

2.1.1.1.2.1.2 Through Benzyne Formation

2.1.1.1.2.1.3 Through Wessely Oxidation

2.1.1.1.2.2 Pericyclic Generation of a Dienophile

2.1.1.1.2.2.1 Through Cycloaddition/Retrocycloaddition

2.1.1.1.2.2.2 Through Sigmatropic Rearrangement

2.1.1.1.2.2.3 Through Electrocyclization

2.1.1.1.3 Proximity-Induced Diels–Alder Reactions

2.1.1.2 Diels–Alder as the Initiator of a Cascade

2.1.1.2.1 Pericyclic Reactions Occurring in the Wake of a Diels–Alder Reaction

2.1.1.2.1.1 Cascades Featuring Diels–Alder/Diels–Alder Processes

2.1.1.2.1.2 Cascades Featuring Diels–Alder/Retro-Diels–Alder Processes

2.1.1.2.1.3 [4 + 2] Cycloaddition with Subsequent Desaturation

2.1.1.2.2 Diels–Alder Reactions with Concomitant Ionic Structural Rearrangements

2.1.1.2.2.1 Pairings of Diels–Alder Reactions with Structural Fragmentations

2.1.1.2.2.2 Combining a Diels–Alder Reaction with Ionic Cyclization

2.1.1.3 Conclusions

2.1.2 Domino Reactions Including [2 + 2], [3 + 2], or [5 + 2] Cycloadditions

I. Coldham and N. S. Sheikh

2.1.2 Domino Reactions Including [2 + 2], [3 + 2], or [5 + 2] Cycloadditions

2.1.2.1 Domino [2 + 2] Cycloadditions

2.1.2.1.1 Cycloaddition of an Enaminone and β-Diketone with Fragmentation

2.1.2.1.2 Cycloaddition of Ynolate Anions Followed by Dieckmann Condensation/Michael Reaction

2.1.2.1.3 Cycloaddition Cascade Involving Benzyne–Enamide Cycloaddition or a Fischer Carbene Complex

2.1.2.1.4 Cycloadditions with Rearrangement

2.1.2.1.4.1 Cycloaddition of an Azatriene Followed by Cope Rearrangement

2.1.2.1.4.2 Cycloaddition of a Propargylic Ether and Propargylic Thioether Followed by [3,3]-Sigmatropic Rearrangement

2.1.2.1.4.3 [3,3]-Sigmatropic Rearrangement of Propargylic Ester and Propargylic Acetate Followed by Cycloaddition

2.1.2.1.4.4 Cycloaddition of a Ketene Followed by Allylic Rearrangement

2.1.2.1.4.5 Allyl Migration in Ynamides Followed by Cycloaddition

2.1.2.1.4.6 1,3-Migration in Propargyl Benzoates Followed by Cycloaddition

2.1.2.2 Domino [3 + 2] Cycloadditions

2.1.2.2.1 Cycloadditions with Nitrones, Nitronates, and Nitrile Oxides

2.1.2.2.1.1 Reaction To Give a Nitrone Followed by Cycloaddition

2.1.2.2.1.2 Cycloaddition with a Nitrone and Subsequent Reaction

2.1.2.2.1.3 Reaction To Give a Nitronate Followed by Cycloaddition

2.1.2.2.1.4 Reaction To Give a Nitrile Oxide Followed by Cycloaddition

2.1.2.2.1.5 Cycloaddition with a Nitrile Oxide and Subsequent Reaction

2.1.2.2.2 Cycloadditions with Carbonyl Ylides

2.1.2.2.2.1 Reaction of an α-Diazo Compound To Give a Carbonyl Ylide Followed by Cycloaddition

2.1.2.2.2.2 Reaction of an Alkyne To Give a Carbonyl Ylide Followed by Cycloaddition

2.1.2.2.3 Cycloadditions with Azomethine Ylides

2.1.2.2.4 Cycloadditions with Azomethine Imines

2.1.2.2.5 Cycloadditions with Azides

2.1.2.2.5.1 Reaction To Give an Azido-Substituted Alkyne Followed by Cycloaddition

2.1.2.2.5.2 Cycloaddition of an Azide and Subsequent Reaction

2.1.2.3 Domino [5 + 2] Cycloadditions

2.1.2.3.1 Cycloaddition of a Vinylic Oxirane Followed by Claisen Rearrangement

2.1.2.3.2 Cycloaddition of an Ynone Followed by Nazarov Cyclization

2.1.2.3.3 Cycloaddition of an Acetoxypyranone Followed by Conjugate Addition

2.1.2.3.4 Cycloaddition Cascade Involving γ-Pyranone and Quinone Systems

2.1.3 Domino Transformations Involving an Electrocyclization Reaction

J. Suffert, M. Gulea, G. Blond, and M. Donnard

2.1.3 Domino Transformations Involving an Electrocyclization Reaction

2.1.3.1 Metal-Mediated Cross Coupling Followed by Electrocyclization

2.1.3.1.1 Palladium-Mediated Cross Coupling/Electrocyclization Reactions

2.1.3.1.1.1 Cross Coupling/6π-Electrocyclization

2.1.3.1.1.2 Cross Coupling/8π-Electrocyclization

2.1.3.1.1.3 Cross Coupling/8π-Electrocyclization/6π-Electrocyclization

2.1.3.1.2 Copper-Catalyzed Tandem Reactions

2.1.3.1.3 Zinc-Catalyzed Tandem Reactions

2.1.3.1.4 Ruthenium-Catalyzed Formal [2 + 2 + 2] Cycloaddition Reactions

2.1.3.2 Alkyne Transformation Followed by Electrocyclization

2.1.3.3 Isomerization Followed by Electrocyclization

2.1.3.3.1 1,3-Hydrogen Shift/Electrocyclization

2.1.3.3.2 1,5-Hydrogen Shift/Electrocyclization

2.1.3.3.3 1,7-Hydrogen Shift/Electrocyclization

2.1.3.4 Consecutive Electrocyclization Reaction Cascades

2.1.3.5 Alkenation Followed by Electrocyclization

2.1.3.6 Electrocyclization Followed by Cycloaddition

2.1.3.7 Miscellaneous Reactions

2.1.3.7.1 Electrocyclization/Oxidation

2.1.3.7.2 Photochemical Elimination/Electrocyclization

2.1.3.7.3 Domino Retro-electrocyclization Reactions

2.1.3.8 Hetero-electrocyclization

2.1.3.8.1 Aza-electrocyclization

2.1.3.8.1.1 Metal-Mediated Reaction/Hetero-electrocyclization

2.1.3.8.1.2 Imine or Iminium Formation/Hetero-electrocyclization

2.1.3.8.1.3 Isomerization or Rearrangement/Hetero-electrocyclization

2.1.3.8.2 Oxa-electrocyclization

2.1.3.8.3 Thia-electrocyclization

2.1.4 Sigmatropic Shifts and Ene Reactions (Excluding [3,3])

A. V. Novikov and A. Zakarian

2.1.4 Sigmatropic Shifts and Ene Reactions (Excluding [3,3])

2.1.4.1 Practical Considerations

2.1.4.2 Domino Processes Initiated by Ene Reactions

2.1.4.3 Domino Processes Initiated by [2,3]-Sigmatropic Rearrangements

2.1.4.4 Domino Processes Initiated by Other Sigmatropic Rearrangements

2.1.4.5 Domino Processes in the Synthesis of Natural Products

2.1.4.6 Conclusions

2.1.5 Domino Transformations Initiated by or Proceeding Through [3,3]-Sigmatropic Rearrangements

C. A. Guerrero

2.1.5 Domino Transformations Initiated by or Proceeding Through [3,3]-Sigmatropic Rearrangements

2.1.5.1 Cope Rearrangement Followed by Enolate Functionalization

2.1.5.1.1 Anionic Oxy-Cope Rearrangement Followed by Intermolecular Enolate Alkylation with Alkyl Halides

2.1.5.1.2 Anionic Oxy-Cope Rearrangement Followed by Enolate Alkylation by Pendant Allylic Ethers

2.1.5.1.3 Anionic Oxy-Cope Rearrangement Followed by Enolate Acylation

2.1.5.2 Aza- and Oxonia-Cope-Containing Domino Sequences

2.1.5.2.1 Ionization-Triggered Oxonia-Cope Rearrangement Followed by Intramolecular Nucleophilic Trapping by an Enol Silyl Ether

2.1.5.2.2 Intermolecular 1,4-Addition-Triggered Oxonia-Cope Rearrangement Followed by Intramolecular Nucleophilic Trapping by a Nascent Enolate

2.1.5.2.3 Iminium-Ion-Formation-Triggered Azonia-Cope Rearrangement Followed by Intramolecular Nucleophilic Trapping by a Nascent Enamine

2.1.5.3 Double, Tandem Hetero-Cope Rearrangement Processes

2.1.5.3.1 Double, Tandem [3,3]-Sigmatropic Rearrangement of Allylic, Homoallylic Bis (trichloroacetimidates)

2.1.5.4 Neutral Claisen Rearrangement Followed by Further (Non-Claisen) Processes

2.1.5.4.1 Oxy-Cope Rearrangement/Ene Reaction Domino Sequences

2.1.5.4.2 Oxy-Cope Rearrangement/Ene Reaction/Claisen Rearrangement and Oxy-Cope Rearrangement/Claisen Rearrangement/Ene Reaction Domino Sequences

2.1.5.5 Claisen Rearrangement Followed by Another Pericyclic Process

2.1.5.5.1 Double, Tandem Bellus–Claisen Rearrangement Reactions

2.1.5.5.2 Claisen Rearrangement Followed by [2,3]-Sigmatropic Rearrangement

2.1.5.5.3 Claisen Rearrangement/Diels–Alder Cycloaddition Domino Sequences

2.1.5.5.4 Claisen Rearrangement/[1,5]-H-Shift/6π-Electrocyclization Domino Sequences

2.1.5.6 Claisen Rearrangement Followed by Multiple Processes

2.1.5.6.1 Propargyl Claisen Rearrangement Followed by Tautomerization, Acylketene Generation, 6π-Electrocyclization, and Aromatization

2.1.5.6.2 Propargyl Claisen Rearrangement Followed by Imine Formation, Tautomerization, and 6π-Electrocyclization

2.2 Intermolecular Alkylative Dearomatizations of Phenolic Derivatives in Organic Synthesis

J. A. Porco, Jr., and J. Boyce

2.2 Intermolecular Alkylative Dearomatizations of Phenolic Derivatives in Organic Synthesis

2.2.1 Metal-Mediated Intermolecular Alkylative Dearomatization

2.2.1.1 Osmium (II)-Mediated Intermolecular Alkylative Dearomatization

2.2.1.2 Palladium-Catalyzed Intermolecular Alkylative Dearomatization

2.2.1.3 Tandem Palladium-Catalyzed Intermolecular Alkylative Dearomatization/Annulation

2.2.2 Non-Metal-Mediated Intermolecular Alkylative Dearomatization

2.2.2.1 Alkylative Dearomatizations of Phenolic Derivatives with Activated Electrophiles

2.2.2.2 Alkylative Dearomatizations of Phenolic Derivatives with Unactivated Electrophiles

2.2.3 Tandem Intermolecular Alkylative Dearomatization/Annulation

2.2.3.1 Tandem Alkylative Dearomatization/[4 + 2] Cycloaddition

2.2.3.2 Tandem Alkylative Dearomatization/Hydrogenation Followed by Lewis Acid Catalyzed Cyclization

2.2.3.3 Tandem Alkylative Dearomatization/Annulation To Access Type A and B Polyprenylated Acylphloroglucinol Derivatives

2.2.3.4 Enantioselective, Tandem Alkylative Dearomatization/Annulation

2.2.3.5 Tandem Alkylative Dearomatization/Radical Cyclization

2.2.4 Recent Methods for Alkylative Dearomatization of Phenolic Derivatives

2.2.4.1 Recent Applications to Intermolecular Alkylative Dearomatization of Naphthols

2.2.4.2 Dearomatization Reactions as Domino Transformations To Access Type A and B Polyprenylated Acylphloroglucinol Analogues

2.3 Additions to Alkenes and C=O and C=N Bonds

2.3.1 Additions to Nonactivated C=C Bonds

Z. W. Yu and Y.-Y. Yeung

2.3.1 Additions to Nonactivated C=C Bonds

2.3.1.1 Domino Amination

2.3.1.1.1 Proton-Initiated Events

2.3.1.1.2 Transition-Metal-Initiated Events

2.3.1.1.3 Halogen-Initiated Events

2.3.1.2 Domino Etherification

2.3.1.2.1 Halogen-Initiated Events

2.3.1.3 Domino Carbonylation

2.3.1.3.1 Transition-Metal-Initiated Events

2.3.1.3.2 Halogen-Initiated Events

2.3.1.4 Domino Polyene Cyclization

2.3.1.4.1 Transition-Metal-Initiated Events

2.3.1.4.2 Halogen-Initiated Events

2.3.1.4.3 Chalcogen-Initiated Events

2.3.2 Organocatalyzed Addition to Activated C=C Bonds

P. Renzi, M. Moliterno, R. Salvio, and M. Bella

2.3.2 Organocatalyzed Addition to Activated C=C Bonds

2.3.2.1 Organocatalyzed Domino Reactions with Activated Alkenes: The First Examples

2.3.2.1.1 Prolinol Trimethylsilyl Ethers as Privileged Catalysts for Enamine and Iminium Ion Activation

2.3.2.1.2 Increasing Complexity in Organocatalyzed Domino Reactions

2.3.2.2 Domino Organocatalyzed Reactions of Oxindole Derivatives

2.3.2.2.1 From Enders, Domino Reactions to Melchiorre's Methylene Oxindole

2.3.2.2.2 Michael Addition to Oxindoles

2.3.2.3 Synthesis of Tamiflu: The Hayashi Approach

2.3.2.4 One-Pot Synthesis of ABT-341, a DPP4-Selective Inhibitor

2.3.2.5 Large-Scale Industrial Application of Organocatalytic Domino Reactions: A Case Study

2.3.2.5.1 Transferring Organocatalytic Reactions from Academia to Industry: Not Straightforward

2.3.2.5.2 The Reaction Developed in the Academic Environment

2.3.2.5.3 The Reaction Developed in the Industrial Environment

2.3.3 Addition to Monofunctional C=O Bonds

A. Song and W. Wang

2.3.3 Addition to Monofunctional C=O Bonds

2.3.3.1 Transition-Metal-Catalyzed Domino Addition to C=O Bonds

2.3.3.1.1 Domino Reactions Involving Carbonyl Ylides

2.3.3.1.2 Reductive Aldol Reactions

2.3.3.1.3 Michael/Aldol Reactions

2.3.3.1.4 Other Domino Addition Reactions

2.3.3.2 Organocatalytic Domino Addition to C=O Bonds

2.3.3.2.1 Amine-Catalyzed Domino Addition to C=O Bonds

2.3.3.2.1.1 Enamine-Catalyzed Aldol/Aldol Reactions

2.3.3.2.1.2 Enamine-Catalyzed Aldol/Michael Reactions

2.3.3.2.1.3 Enamine-Catalyzed Diels–Alder Reactions

2.3.3.2.1.4 Enamine-Catalyzed Michael/Henry Reactions

2.3.3.2.1.5 Enamine-Catalyzed Michael/Aldol Reactions

2.3.3.2.1.6 Enamine-Catalyzed Michael/Hemiacetalization Reactions

2.3.3.2.1.7 Iminium-Catalyzed Michael/Aldol Reactions

2.3.3.2.1.8 Iminium-Catalyzed Michael/Henry Reactions

2.3.3.2.1.9 Iminium-Catalyzed Michael/Morita–Baylis–Hillman Reactions

2.3.3.2.1.10 Iminium-Catalyzed Michael/Hemiacetalization Reactions

2.3.3.2.2 Thiourea-Catalyzed Domino Addition to C=O Bonds

2.3.3.2.2.1 Aldol/Cyclization Reactions

2.3.3.2.2.2 Michael/Aldol Reactions

2.3.3.2.2.3 Michael/Henry Reactions

2.3.3.2.2.4 Michael/Hemiacetalization Reactions

2.3.3.2.3 Phosphoric Acid Catalyzed Domino Addition to C=O Bonds

2.3.3.3 Lewis Acid Catalyzed Domino Addition to C=O Bonds

2.3.3.4 Conclusions

2.3.4 Additions to C=N Bonds and Nitriles

E. Kroon, T. Zarganes Tzitzikas, C. G. Neochoritis, and A. Dömling

2.3.4 Additions to C=N Bonds and Nitriles

2.3.4.1 Addition to C=N Bonds and the Pictet–Spengler Strategy

2.3.4.2 Ugi Five-Center Four-Component Reaction Followed by Postcondensations

2.3.4.3 Addition to Nitriles

Keyword Index

Author Index

Abbreviations

2.1 Pericyclic Reactions

2.1.1 The Diels–Alder Cycloaddition Reaction in the Context of Domino Processes

J. G. West and E. J. Sorensen

General Introduction

The title that Otto Diels and Kurt Alder chose for their 1928 publication, “Syntheses in the Hydroaromatic Series”, in Annalen[1] did not signal the revolution that their new insights would bring to the field of organic chemistry. Their pioneering paper described cycloadditions of 4π-electron systems (dienes) with 2π-electron systems (dienophiles), and captured the significance that [4 + 2] cycloadditions would hold for the field of organic chemical synthesis: “Thus, it appears to us that the possibility of synthesis of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps also alkaloids, has been moved to the near prospect.” The very next sentence, “We explicitly reserve for ourselves the application of the reaction discovered by us to the solution of such problems”, is even more colorful, but, in reality, nearly a quarter of a century would pass before the power of the “Diels–Alder” reaction was demonstrated in the context of natural product synthesis. In the year following the awarding of the 1950 Nobel Prize in Chemistry to Diels and Alder “for their discovery and development of the diene synthesis”, R. B. Woodward and co-workers described their non-obvious use of a Diels–Alder construction to contend with the trans-fused C–D ring junction in cortisone,[2] and Gilbert Stork and his co-workers reported their stereospecific synthesis of cantharidin featuring a creative twofold Diels–Alder strategy. Woodward's landmark 1956 synthesis of reserpine and Eschenmoser's synthesis of colchicine by way of pericyclic reactions provided further, powerful, demonstrations of the value of the Diels–Alder reaction as a structure-building process. On the foundation of these early achievements, the Diels–Alder reaction took its place beside the most reliable bond- and ring-forming methods in organic chemistry.

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