Edited byShu-Li You

Asymmetric DearomatizationReactions

Edited by Shu-Li You

Asymmetric Dearomatization Reactions

Editor

Prof. Shu-Li YouShanghai Institute of OrganicChemistryChinese Academy of SciencesState Key Laboratory ofOrganometallic Chemistry345 Lingling LuShanghai 200032China

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V

Contents

List of Contributors XIIIPreface XVII

1 Introduction 1Wei Zhang and Shu-Li You

1.1 Why Asymmetric Dearomatization Reactions? 11.2 Discovery of Aromatic Compounds and Dearomatization

Reactions 11.3 Development of Dearomatization Reactions 31.4 Asymmetric Dearomatization Reactions 7

References 8

2 Asymmetric Dearomatization with Chiral Auxiliaries andReagents 9E. Peter Kündig

2.1 Introduction 92.2 Chiral σ-Bound Auxiliaries 92.2.1 Oxazolines 92.2.2 Imines, Oxazolidines, and Hydrazones 152.2.3 Chiral Ethers and Amines 162.3 Diastereospecific Anionic Cyclizations 202.4 Use of Chiral Reagents 212.4.1 Chiral Bases in Dearomatizing Cyclizations 212.4.2 Chiral Nucleophiles 232.4.3 Chiral Ligands in Enantioselective Nucleophilic

Additions 232.5 Chiral π-Complexes 262.5.1 Planar Chiral η6-Arene Complexes 262.5.2 η6-Arene Complexes with a Chiral Ligand 282.5.3 Complexes with Stereogenic Metal Centers 292.6 Conclusion 30

References 30

VI Contents

3 Organocatalytic Asymmetric Transfer Hydrogenation of(Hetero)Arenes 33Gaëlle Mingat and Magnus Rueping

3.1 Introduction 333.2 Organocatalytic Asymmetric Transfer Hydrogenation of

Heteroaromatics 343.2.1 Quinolines 343.2.1.1 Proof-of-Concept 343.2.1.2 2-Substituted Quinolines 353.2.1.3 4-Substituted Quinolines 403.2.1.4 3-Substituted Quinolines 413.2.1.5 2,3-Disubstituted Quinolines 423.2.1.6 Spiro-Tetrahydroquinolines 453.2.2 Benzoxazines, Benzothiazines, and Benzoxazinones 473.2.3 Benzodiazepines and Benzodiazepinones 493.2.4 Pyridines 513.2.5 3H-Indoles 513.2.6 Quinoxalines and Quinoxalinones 523.3 Organocatalytic Asymmetric Transfer Hydrogenation in Aqueous

Solution 533.4 Cascade Reactions 543.4.1 Introduction 543.4.2 In situ Generation of the Heteroarene 543.4.3 Dearomatization of Pyridine/Asymmetric aza-Friedel–Crafts

Alkylation Cascade 563.4.4 Combining Photochemistry and Brønsted Acid Catalysis 573.4.4.1 Quinolines 573.4.4.2 Pyrylium ions 583.5 Cooperative and Relay Catalysis: Combining Brønsted Acid- and

Metal-Catalysis 593.5.1 Introduction 593.5.2 Improvements in Transfer Hydrogenation 603.5.2.1 Regenerable Hydrogen Sources 603.5.2.2 Asymmetric Relay Catalysis (ARC) 623.5.3 Cooperative Metal–Brønsted Acid Catalysis 633.6 Summary and Conclusion 65

References 66

4 Transition-Metal-Catalyzed Asymmetric Hydrogenation ofAromatics 69Ryoichi Kuwano

4.1 Introduction 694.2 Catalytic Asymmetric Hydrogenation of Five-Membered

Heteroarenes 714.2.1 Catalytic Asymmetric Hydrogenation of Azoles and Indoles 71

Contents VII

4.2.1.1 Rhodium-Catalyzed Asymmetric Hydrogenation of Indoles 714.2.1.2 Ruthenium-Catalyzed Asymmetric Hydrogenation of Azoles 734.2.1.3 Palladium-Catalyzed Asymmetric Hydrogenation of Azoles 754.2.1.4 Iridium-Catalyzed Asymmetric Hydrogenation of Indoles 774.2.2 Catalytic Asymmetric Hydrogenation of Oxygen-Containing

Heteroarenes 774.2.3 Catalytic Asymmetric Hydrogenation of Sulfur-Containing

Heteroarenes 794.3 Catalytic Asymmetric Hydrogenation of Six-Membered

Heteroarenes 794.3.1 Catalytic Asymmetric Hydrogenation of Azines 804.3.1.1 Iridium-Catalyzed Asymmetric Hydrogenation of Pyridines 804.3.1.2 Iridium-Catalyzed Asymmetric Hydrogenation of Pyrimidines 814.3.2 Catalytic Asymmetric Hydrogenation of Benzo-Fused Azines 824.3.2.1 Iridium-Catalyzed Asymmetric Hydrogenation of Quinolines 824.3.2.2 Ruthenium-Catalyzed Asymmetric Hydrogenation of

Quinolines 854.3.2.3 Iridium-Catalyzed Asymmetric Hydrogenation of Isoquinolines 874.3.2.4 Iridium-Catalyzed Asymmetric Hydrogenation of Quinoxalines 894.3.2.5 Ruthenium-Catalyzed Asymmetric Hydrogenation of

Quinoxalines 904.3.2.6 Iron-Catalyzed Asymmetric Hydrogenation of Quinoxalines 924.3.2.7 Catalytic Asymmetric Hydrogenation of Miscellaneous

Six-Membered Heteroarenes 924.3.3 Catalytic Asymmetric Reduction of Quinolines with Reducing

Agents Other Than H2 944.4 Catalytic Asymmetric Hydrogenation of Carbocyclic Arenes 954.4.1 Ruthenium-Catalyzed Asymmetric Hydrogenation of Carbocycles in

Benzo-Fused Heteroarenes 964.4.2 Ruthenium-Catalyzed Asymmetric Hydrogenation of

Naphthalenes 974.5 Summary and Conclusion 97

References 98

5 Stepwise Asymmetric Dearomatization of Phenols 103Qing Gu

5.1 Introduction 1035.2 Stepwise Asymmetric Dearomatization of Phenols 1035.2.1 Asymmetric [4+2] Reaction 1035.2.2 Asymmetric Heck Reaction 1065.2.3 Asymmetric (Hetero) Michael Reaction 1085.2.4 Asymmetric Stetter Reaction 1195.2.5 Asymmetric Rauhut–Currier Reaction 1205.2.6 Asymmetric 1,6-Dienyne Cyclized Reaction 122

VIII Contents

5.3 Conclusion and Perspective 126References 127

6 Asymmetric Oxidative Dearomatization Reaction 129Muhammet Uyanik and Kazuaki Ishihara

6.1 Introduction 1296.2 Diastereoselective Oxidative Dearomatization using Chiral

Auxiliaries 1296.3 Enantioselective Oxidative Dearomatization using Chiral Reagents

or Catalysts 1326.3.1 Chiral Transition Metal Complexes 1326.3.2 Chiral Hypervalent Iodines(III, V) and Hypoiodites(I) 1396.4 Conclusions and Perspectives 148

References 149

7 Asymmetric Dearomatization via Cycloaddition Reaction 153Sarah E. Reisman, Madeleine E. Kieffer, and Haoxuan Wang

7.1 Introduction 1537.2 [2+ 1] Cycloaddition 1537.2.1 Asymmetric Büchner Reaction 1537.2.2 Cyclopropanation of Heterocyclic Compounds 1557.3 [3+ 2] Cycloaddition 1567.4 [3+ 3] Cycloaddition 1617.5 [4+ 2] Cycloaddition 1637.6 [4+ 3] Cycloaddition 1707.7 Conclusion 173

References 173

8 Organocatalytic Asymmetric Dearomatization Reactions 175Susana S. Lopez, Sri K. Nimmagadda, and Jon C. Antilla

8.1 Introduction 1758.2 Diels–Alder 1758.3 Oxidative Dearomatization 1798.4 Cascade Reactions 1868.5 Stepwise 1938.6 Nucleophilic Dearomatization 2008.7 Summary and Conclusion 204

References 205

9 Dearomatization via Transition-Metal-Catalyzed Allylic SubstitutionReactions 207Tetsuhiro Nemoto and Yasumasa Hamada

9.1 Introduction 2079.2 Dearomatization of Indoles and Pyrroles via Transition-Metal-

Catalyzed Allylic Substitution Reactions 208

Contents IX

9.3 Dearomatization of Phenols via Transition-Metal-Catalyzed AllylicSubstitution Reactions 216

9.4 Dearomatization of Phenols and Indoles via Activation of PropargylCarbonates with Pd Catalyst 221

9.5 Conclusion 226References 226

10 Dearomatization via Transition-Metal-Catalyzed Cross-CouplingReactions 229Robin B. Bedford

10.1 Introduction: From Cross-Coupling to CatalyticDearomatization 229

10.2 Dearomatization of Phenolic Substrates 23110.3 Dearomatization of Nitrogen-Containing Substrates 24010.4 Conclusion and Outlook 244

References 245

11 Dearomatization Reactions of Electron-Deficient AromaticRings 247Chihiro Tsukano and Yoshiji Takemoto

11.1 Introduction 24711.2 Dearomatization of Activated Pyridines and Other

Electron-Deficient Heterocycles 24811.2.1 Dearomatization via Alkyl Pyridinium Salts 24811.2.1.1 Reduction with Borohydrides 24811.2.1.2 Reduction with Na2S2O4 24911.2.1.3 Reduction with Other Reducing Agents 25011.2.1.4 Nucleophilic Addition of Grignard Reagents 25111.2.1.5 Nucleophilic Addition of Cyanide 25211.2.1.6 Addition of Other Carbon Nucleophiles 25211.2.2 Dearomatization via Alkoxycarbonylpyridinium

Salts 25311.2.2.1 Reduction with Hydride Nucleophiles 25411.2.2.2 Addition of Metal Nucleophiles, Including Grignard

Reagents 25511.2.2.3 Addition of Enolates and Related Carbon Nucleophiles 26111.2.2.4 Nucleophilic Addition of Cyanide 26411.2.2.5 Addition of Other Nucleophiles 26511.2.3 Dearomatization via Acyl Pyridinium Salts 26611.2.3.1 Reduction with Hydride Reducing Agents 26611.2.3.2 Addition of Metal Nucleophiles Including Grignard Reagents 26911.2.3.3 Addition of Enolates and Related Carbon Nucleophiles 27011.2.4 Dearomatization through Other Pyridinium Cations 27011.3 Summary and Conclusion 274

References 274

X Contents

12 Asymmetric Dearomatization Under Enzymatic Conditions 279Simon E. Lewis

12.1 Introduction 27912.2 Dearomatizing Arene cis-Dihydroxylation 28012.2.1 Early Development 28012.2.2 Types of Arene Dioxygenase 28112.2.3 Substrate Scope and Regioselectivity 28312.2.3.1 Monocyclic Substituted Benzene Substrates (Excluding Biaryls) 29912.2.3.2 Biaryl Substrates 29912.2.3.3 Naphthalene Substrates 29912.2.3.4 Benzoic Acid Substrates 29912.2.3.5 Heterocyclic Substrates (Mono- and Bicyclic) 30012.2.3.6 Bicyclic Carbocyclic Substrates (Other than Naphthalenes) 30012.2.3.7 Tricyclic Substrates (Carbo- and Heterocyclic) 30012.2.4 Availability of Arene cis-Diols 30012.2.5 Uses in Synthesis 30212.2.5.1 Total Synthesis 30212.2.5.2 Pharmaceuticals and Agrochemicals 31512.2.5.3 Polymers 31712.2.5.4 Flavors and Fragrances 32012.2.5.5 Dyes 32112.2.5.6 Ligands and MOFs 32112.2.6 Increasing the Substrate Scope 32412.2.7 Accessing Both Enantiomeric Series 32612.2.8 Improvements to the Production Process 32812.3 Dearomatizing Arene Epoxidation 32812.4 Dearomatizing Arene Reduction 33012.5 Summary and Conclusion 330

List of Abbreviations 331References 332

13 Total Synthesis of Complex Natural Products viaDearomatization 347Weiqing Xie and Dawei Ma

13.1 Introduction 34713.2 Natural Products Synthesis via Oxidative Dearomatization 34813.2.1 Enzymatic Dihydroxylative Dearomatization of Arene 34813.2.2 Oxidative Dearomatization of Phenol 34913.2.3 Oxidative Cycloisomerization Reaction of Phenol 35513.2.4 Oxidative Dearomatization of Indole in Synthesis of Natural

Products 35713.3 Dearomatization via Cycloaddition in Synthesis of Natural

Products 36013.4 Dearomatization via Nucleophilic Addition in Synthesis of Natural

Products 367

Contents XI

13.5 Reductive Dearomatization in Synthesis of Natural Products 36713.6 Dearomatization via Electrophilic Addition in Synthesis of Natural

Products 36913.7 Dearomatization via Intramolecular Arylation in Natural Products

Synthesis 37113.8 Summary and Perspective 373

References 374

14 Miscellaneous Asymmetric Dearomatization Reactions 379Wei Zhang and Shu-Li You

14.1 Introduction 37914.2 Miscellaneous Asymmetric Dearomatization Reactions 37914.3 Conclusions and Perspectives 388

References 388

Index 391

XIII

List of Contributors

Jon C. AntillaUniversity of South FloridaDepartment of Chemistry4202 East Fowler AvenueTampa, FL 33620USA

Robin B. BedfordUniversity of BristolSchool of ChemistryCantock’s CloseBristol BS8 1TSUK

Qing GuState Key Laboratory ofOrganometallic ChemistryShanghai Institute of OrganicChemistryChinese Academy of Sciences345 Lingling LuShanghai 200032China

Yasumasa HamadaChiba UniversityGraduate School ofPharmaceutical Sciences1-8-1 InohanaChuo-kuChiba 260-8675Japan

Kazuaki IshiharaNagoya UniversityGraduate School of EngineeringFuro-choChikusaNagoya 464-8603Japan

Madeleine E. KiefferCalifornia Institute ofTechnologyDivision of Chemistry andChemical Engineering1200 E. California Blvd.MC 101-20Pasadena, CA 91125USA

E. Peter KündigUniversity of GenevaDepartment of OrganicChemistry30 Quai Ernest Ansermet1211 Geneva 4Switzerland

XIV List of Contributors

Ryoichi KuwanoKyushu UniversityFaculty of ScienceDepartment of Chemistry744 MotookaNishi-kuFukuoka 819-0395Japan

Simon E. LewisUniversity of BathDepartment of ChemistryBath BA2 7AYUK

Susana S. LopezUniversity of South FloridaDepartment of Chemistry4202 East Fowler AvenueTampa, FL 33620USA

Dawei MaShanghai Institute of OrganicChemistryChinese Academy of SciencesState KeyLaboratory of Bioorganic &Natural Products Chemistry345 Lingling LuShanghai 200032China

Gaëlle MingatRWTH Aachen UniversityDepartment of ChemistryInstitute of Organic ChemistryLandoltweg 152074 AachenGermany

Tetsuhiro NemotoChiba UniversityGraduate School ofPharmaceutical Sciences1-8-1 InohanaChuo-kuChiba 260-8675Japan

Sri K. NimmagaddaUniversity of South FloridaDepartment of Chemistry4202 East Fowler AvenueTampa, FL 33620USA

Sarah E. ReismanCalifornia Institute ofTechnologyDivision of Chemistry andChemical Engineering1200 E. California Blvd.MC 101-20Pasadena, CA 91125USA

Magnus RuepingKing Abdullah University ofScience and Technology(KAUST)KAUST Catalysis Center (KCC)Thuwal 23955-6900Saudi Arabia

Yoshiji TakemotoKyoto UniversityGraduate School ofPharmaceutical SciencesDepartment of OrganicChemistryYoshidaSakyo-kuKyoto 606-8501Japan

List of Contributors XV

Chihiro TsukanoKyoto UniversityGraduate School ofPharmaceutical SciencesDepartment of OrganicChemistryYoshidaSakyo-kuKyoto 606-8501Japan

Muhammet UyanikNagoya UniversityGraduate School of EngineeringFuro-choChikusaNagoya 464-8603Japan

Haoxuan WangCalifornia Institute ofTechnologyDivision of Chemistry andChemical Engineering1200 E. California Blvd.MC 101-20Pasadena, CA 91125USA

Weiqing XieNorthwest A&F UniversityShaanxi Key Laboratory ofNatural Products & ChemicalBiologyCollege of ScienceDepartment of Chemistry22 Xinong RoadYangling 712100ShaanxiChina

Shu-Li YouShanghai Institute of OrganicChemistryChinese Academy of SciencesState Key Laboratory ofOrganometallic Chemistry345 Lingling LuShanghai 200032China

Wei ZhangShanghai Institute of OrganicChemistryChinese Academy of SciencesState Key Laboratory ofOrganometallic Chemistry345 Lingling LuShanghai 200032China

XVII

Preface

Aromatic compounds are widely distributed in nature. They serve as extremelyimportant synthetic materials in both academia and industry. Significant effortshave been devoted to the transformations of aromatic compounds, whichnow mainly focus on the introduction of substituents onto aromatic rings vianucleophilic, electrophilic, radical, and metal-mediated substitution reactions. Inaddition, dearomatization reactions, another important type of transformationsof aromatic compounds, have recently witnessed significant development dueto their unique potentials to convert relatively simple molecules into muchmore complicated structures. The existed rings of aromatic compounds providecarbocyclic or heterocyclic frameworks in a very straightforward manner duringthe dearomatization reaction. Moreover, the advantage of building quaternarycarbon centers makes the dearomatization reactions straightforward protocolsto construct spiro or bridged compounds via intramolecular dearomatizationreactions. As attractive strategies, dearomatization reactions have a long historyin the synthesis of natural products, pharmaceuticals, and other functionalmolecules. The earliest dearomatization reaction could be dated back to 1885when the Buchner ring expansion reaction was discovered. Although manydearomatization protocols have been either explored as new methodologies orapplied as the key steps during the synthesis of functional molecules, they havebeen rather limited within racemic studies for a long time. Asymmetric dearom-atization reactions, especially catalytic asymmetric dearomatization (CADA)reactions, are relatively rare. The vast majority of dearomatization reactionsconstructing chiral molecules rely on the chiral substrate-controlled strategy andthe utilization of chiral auxiliaries or reagents. The high energy barrier encoun-tered during the process of dearomatization generally requires harsh reactionconditions, which undoubtedly pose challenges for the control of regioselectivityand stereoselectivity. As powerful tools in synthetic chemistry, dearomatizationreactions have recently received their renaissance with the emerging of newlydesigned dearomative protocols and efficient stereoselective control of theseprocesses. Delightfully, asymmetric dearomatization reactions, especially thoseby catalytic methods, have gained rapid progress in the past few years.

Numerous elegant books have been contributed to the topics on aromaticcompounds. However, few of them describe dearomatization reactions, and none

XVIII Preface

of them introduces the achievement in the area of asymmetric dearomatizationreactions. In contrast, several comprehensive reviews have introduced either theapplication of dearomatization strategies in the total synthesis of natural productsor the development of various CADA methodologies for the construction ofcomplex chiral molecules. Given the dramatic progress and increasing interestin the area of asymmetric dearomatization reactions, a comprehensive bookdetailing the state-of-the-art in this area should be timely and necessary. Thisbook is aiming to provide readers the historical respect, recent development, andfuture perspectives in the field of asymmetric dearomatization reactions.

There are 14 chapters in this book. In Chapter 1, an introduction on asym-metric dearomatization reactions has been provided, with an emphasis on thehistorical retrospect of the reaction development of aromatic compounds andearly contributions toward the dearomatization reactions. The following chapteris focused on the asymmetric dearomatization reactions of substituted benzenesand naphthalenes with chiral auxiliaries and chiral reagents by Peter Kündig, oneof the pioneering contributors in the area of diastereoselective dearomatizationreactions. Chapter 3 by Gaëlle Mingat and Magnus Rueping covers the develop-ment of asymmetric transfer hydrogenation reactions of aromatic compoundsusing organocatalysts as well as the relay catalysis combining metal and chiralorganocatalysts. This chapter is followed by transition-metal-catalyzed asym-metric hydrogenation of aromatic compounds in Chapter 4 by Ryoichi Kuwano.In Chapter 5, by summarizing the asymmetric reactions of dearomatized inter-mediates, Qing Gu introduces a stepwise strategy combining dearomatizationreaction (achiral in general) and asymmetric catalysis with the dearomatizedintermediates. In Chapter 6, the asymmetric oxidative dearomatization reactionsof electron-rich arenes are introduced by Muhammet Uyanik and KazuakiIshihara, major contributors in this area. The following chapter by Sarah E. Reis-man thoroughly summarizes the asymmetric dearomatization via cycloadditionreactions including the Diels–Alder reaction, [4+ 3] or [3+ 2] cycloadditionreaction, cyclopropanation reaction, and rearrangement reaction. In Chapter8, Susana S. Lopez, Sri Krishna Nimmagadda, and Jon C. Antilla discuss theorganocatalytic asymmetric dearomatization reactions enabled by iminiumcatalysis, iminium–enamine catalysis cascade, hydrogen-bonding catalysis, andso on. In Chapter 9, dearomatization reactions of various arenes via transition-metal-catalyzed allylic substitutions have been introduced by Tetsuhiro Nemotoand Yasumasa Hamada, who have contributed significantly in this area. Thedearomatization via transition-metal-catalyzed cross-coupling reactions isintroduced by Robin B. Bedford. Although the existed examples are limited atthis stage, this is a promising area as the fast pace of the development of cross-coupling reactions together with the availability of vast potentially suitable chiralligands. Next, Chihiro Tsukano and Yoshiji Takemoto provide a summary on thedearomatization reactions of electron-deficient aromatic rings such as pyridines,quinolines, and isoquinolines. These reactions generally proceed by N-acylationor alkylation and then a subsequent nucleophilic attack to break the aromaticityof rings. As an important branch of dearomatization reactions, the asymmetric

Preface XIX

dearomatization reactions under enzymatic conditions are introduced by SimonE. Lewis in Chapter 12. Chapter 13 is devoted to the dearomatization strategiesin the synthesis of complex natural products by Weiqing Xie and Dawei Ma,who have made significant contributions in this area. Finally, miscellaneousasymmetric dearomatization reactions, which cannot be covered in the previouschapters, are introduced in Chapter 14.

It is a great fortune for me to work with the above-mentioned fantastic groupsof prominent scientists who have made this book project very successful one. Allthe invited authors are the leading experts in the field and have made significantcontributions in the area covered in their chapters. I would also like to expressmy great gratitude to Professor Wei Zhang (SIOC) who has assisted me greatly inthe preparation of the whole book. Drs Anne Brennführer and Stefanie Volk fromWiley-VCH are highly appreciated for their kind assistance and great patience.I hope all the 14 chapters from these leading experts will promote the develop-ment of this fast growing field and benefit the professional synthetic and medicinalchemists who are interested in dearomatization reactions.

Our works appeared in this book are supported by the National Basic ResearchProgram of China (973 Program 2015CB856600) and the National Natural ScienceFoundation of China (21332009).

Shanghai, October 2015 Shu-Li You

1

1IntroductionWei Zhang and Shu-Li You

1.1Why Asymmetric Dearomatization Reactions?

Arenes and heteroarenes are widely distributed in nature, and some simplearenes are produced multimillion metric tons annually. They are recognized asfundamental synthetic materials in both academia and industry. The chemistryinvolving aromatic compounds is thus rich and of prime importance. Tremen-dous efforts have been devoted to various substitution reactions of aromaticcompounds, and many name reactions such as Friedel–Crafts reaction andSandmeyer reaction have become elementary contents of organic chemistrytextbooks. These fully developed processes are undoubtedly essential tools forthe total synthesis of natural products. Moreover, they provide chemists with theaccess to a huge library of aromatic compounds, which are extremely importantin the discovery of pharmaceuticals, materials, and other functional molecules.In contrast, dearomatization reactions, another important branch of transfor-mations of aromatic compounds, have been undervalued for a long time despitetheir potentials to convert simple molecules into complex structures. The specificfeature of building quaternary carbon centers and interesting structures makesthem straightforward protocols to construct spiro or bridged compounds. In spiteof a long history of application in the total synthesis of natural products, onlyrecently the systematic methodology exploration of dearomatization reactionshas received huge interest. In this area, asymmetric dearomatization reactionsare of particular importance due to the great demand of highly efficient strategiestoward the construction of complex chiral molecules.

1.2Discovery of Aromatic Compounds and Dearomatization Reactions

Although aromatic compounds exist widely in nature, it was only in 1825that benzene was first isolated by Michael Faraday. Several years later, EilhardMitscherlich also obtained this substance and identified its molecular formula

Asymmetric Dearomatization Reactions, First Edition. Edited by Shu-Li You.© 2016 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2016 by Wiley-VCH Verlag GmbH & Co. KGaA.

2 1 Introduction

as C6H6. He gave it the name “benzin.” The highly unsaturated structure ofbenzene remained controversial for a long time, and various proposed structureswere full of imagination. In 1865, Friedrich A. Kekulé postulated that benzenecontains a six-membered ring of carbon atoms with alternating single anddouble bonds. Today, the famous Kekulé formula is still widely used. In 1931, byquantum mechanical calculations, Erich Hückel explained the unique stabilityof benzene different from other unsaturated hydrocarbons, namely, aromaticity.He differentiated the bonding electrons as π electrons and σ electrons, and theHückel “4n+ 2” rule becomes a basis for estimation of aromatic compounds.Around the same time with or after the discovery of benzene, several otheraromatic compounds have been discovered, and today, most of them havebecome extremely important industrial chemical starting materials (Figure 1.1).

Great demand on diverse arenes and heteroarenes has stimulated the relatedsynthetic chemistry. Besides some very simple ones coming from petrochemicals(e.g., benzene, toluene, xylene, phenol), the vast majority of aromatic com-pounds need to be synthesized. Fundamental electrophilic aromatic substitutionreactions including nitration, sulfonation, halogenation, Friedel–Crafts alkyla-tion, and Friedel–Crafts acylation are frequently used synthetic tools, and thenucleophilic aromatic substitution reactions via diazonium ions also providereliable routes to complicated aryl compounds. Moreover, recent developmentof transition-metal-catalyzed cross-coupling reactions between aryl halides (orequivalent) and organometallic compounds has enriched the transformationsof aromatic compounds, and the direct use of aryl compounds through C–Hfunctionalization is an alternative straightforward method. Meanwhile, thechemistry of heteroarene synthesis has also gained significant progress.

Compared with the chemistry to synthesize aromatic compounds, dearoma-tization reactions also have a long history. In 1885, the Buchner ring expansionof benzene with ethyl diazoacetate was reported to provide cycloheptatrieneunder thermal or photochemical conditions, and this methodology was furtherimproved by the introduction of transition metal catalysts (Scheme 1.1) [1, 2]. TheBirch reduction was first reported in 1944 to partially hydrogenate benzene to 1,4-cyclohexadiene (Scheme 1.2) [3]. The Reimer–Tiemann reaction discovered in1876 was originally used for the ortho-formylation of phenols, and an interestingphenomenon was observed later that a dearomative by-product was generatedwhen para-methyl phenol reacted with dichlorocarbene (Scheme 1.3) [4].

OH NH2

NH

NH O S

1834 1826 1820 1866 1849 1870 1883

Figure 1.1 The representative arenes and heteroarenes and their discovery years.

1.3 Development of Dearomatization Reactions 3

O

OEtN2

H

+

H CO2EtH CO2Ethv or heat

Cycloheptatriene

O

OEtN2

H

+

H CO2Et

100% yield

Rh2(CF3COO)4 (0.4 mol%)

20 equiv.

Scheme 1.1 Buchner ring expansion reaction (first reported in 1885).

Na, NH3

HH

HHEtOH Scheme 1.2 Birch reaction (first reported in

1944).

Reimer–Tiemann reaction (first reported in 1876)

Dearomative by-product of Reimer–Tiemann reaction (reported in 1884)

OH OH OCHCl3

10% NaOH (aq.); 60 °C; 3 h

OH OH O

CHCl3

10% NaOH (aq.); 60 °C

O

H3C CHCl2

+

35%

51% yield; 1 : 1

Scheme 1.3 Reimer–Tiemann reaction.

1.3Development of Dearomatization Reactions

The history of dearomatization reactions can be dated back to the nineteenthcentury. Early studies on dearomatization reactions include photochemical pro-cesses, transition-metal-mediated processes, hydrogenation processes, enzyme-catalyzed processes, and so on.

In 1957, Blair and Bryce-Smith discovered that fulvene was generated bysubjecting pure benzene under the irradiation conditions (Scheme 1.4, eq 1) [5].

4 1 Introduction

hv

50 ° C, N2

hveq 1

hveq 2

tBu

tBu tBu

Yellow low convesion

eq 3

tBu

tButButBu

tBu

tBu

+ +

tBu

tButBu

+

tButBu

tBu

N2

R3

R2

R4

R1

R3 R4

R1

R2

Scheme 1.4 Dearomatization reactions via photochemical process.

Although the conversion of this dearomatization reaction was low, it wasbelieved to be the “first example of the direct isomerization of an aromatic to anonaromatic hydrocarbon” [5]. Soon after, many related studies emerged, suchas the irradiation of substituted benzenes (Scheme 1.4, eq 2) [6]. Meanwhile,the photochemical reaction between benzene and alkene was also investigated(Scheme 1.4, eq 3) [7]. However, this type of dearomatization reaction was notdeveloped into an applicable level due to the multiple reaction pathways to delivercomplicated mixtures of dearomatized products.

Early studies of transition metal–arene complexes in the 1950s wereemphasized on their preparation, as exemplified by the synthesis of C6H5Cr(CO)3by Fischer in 1957 [8]. Activation of the aromatic ligands by transition metalcenters toward nucleophiles was then discovered and explored [9]. Among the ver-satile transformations of the nucleophilic addition intermediates (Scheme 1.5, A),protonation and other electrophilic trapping generally deliver dearomatizedproducts [10]. However, this type of dearomatization reaction is mediated bystoichiometric amount of transition metal complexes, and recent rapid growthis focused on transition-metal-catalyzed dearomatization processes. Chapters 4,6, 7, and 9–11 elucidate the detailed development of transition-metal-catalyzedasymmetric dearomatization reactions.

Dearomatization reactions of aromatic compounds by hydrogenation process(Scheme 1.2) and enzymatic process also have a long history. Chapters 3 and 4introduce organocatalytic and transition-metal-catalyzed asymmetric dearoma-tization reactions by hydrogenation process, respectively. Chapter 12 is devoted

1.3 Development of Dearomatization Reactions 5

R

MLn

M = Cr, Mn, Os...

Nu–

R

MLn

Nu E+ Nu

E

RNu

R

and the isomers

E+ = H+

A

Cr(CO)3Cr(CO)3

LiC(CH3)2CNNC

CH3H3C

CF3COOH

–70 °CNC

CH3H3C

+ Isomers

Scheme 1.5 Dearomatization through arene metal complexes.

to the development of enzymatic dearomatization reactions including the detailson both history of discovery and current status.

Meanwhile, some interesting approaches taking advantage of the steric effectprovide alternative strategies for dearomatization. For instance, Yamamoto andcoworkers designed the bulky Lewis acid ATPH that enabled the addition oftBuLi to phenyl methyl ketone occurring at the para position of the phenyl ring,delivering dearomatized product in excellent yield (Scheme 1.6) [11].

COMe

Ph

Ph

OAl 3

COMe

COR1

R2

R2

OR1

Al

R3Li

C

R2

R3R1

OH

ATPH

R3LiCOR1

R2R3

ATPH, tBuLi

toluene, THF–78 °C, 3 h

ATPH

tBu93%

Scheme 1.6 Alternative strategy for dearomatization processes.

As attractive strategies, dearomatization reactions are frequently applied to thetotal synthesis of natural products, providing more efficient synthetic routes, inmany cases biomimetic synthesis as a result of inspiration by nature. In 1954,

6 1 Introduction

Woodward and coworkers first reported an elegant total synthesis of strychnine,in which the Pictet–Spengler-type dearomatization of indole core was employedas one key step to construct the complex polycyclic framework (Scheme 1.7) [12].In 1960, Day and coworkers first completed the total synthesis of racemic griseo-fulvin, in which the dearomatization step was inspired by its biosynthetic pathway(Scheme 1.8) [13]. Numerous fabulous total syntheses were then reported with theapplication of dearomatization strategy, and Chapter 13 introduces this topic indetail.

1954 by Woodward et al.

N

O

N

O

H

H

NH

OMe

OMe

N CHCOOEtTsCl

PyridineN

OMe

OMe

NEtOOCTs

OMe

OMe

Me

O HN

NH2+ NH

OMe

OMe

Polyphosphoric acid

Strychnine

Dearomatization of indole

Scheme 1.7 Dearomatization step in the total synthesis of strychnine .

1960 by Day et al.

OMe

MeOCl

OH

OMe

Me O OMe

OHO

O

+

OMe

MeOCl

O OMe

OHOHMe

Na2CO3, K3Fe(CN)6

H2O

OMe

MeOCl

O

O OMe

OMe

rac. 60%

OMe

MeOCl

O

O OMe

OMe

5% Rh/C w/ 3% Se

H2, EtOH

( ) Griseofulvin8%

Dearomatization of phenol

Scheme 1.8 Dearomatization step in the total synthesis of griseofulvin.

1.4 Asymmetric Dearomatization Reactions 7

Despite the wide utilization of dearomatization reactions in total synthesis ofnatural products, the systematic studies to develop practical dearomatizationmethodologies are still rare. Many of the known dearomatization methodsare limited with scope and selectivity, and difficult to be practically used. Forinstance, the photochemical processes of arenes generally deliver a complicatedmixture of dearomative products due to the poor selectivity (Scheme 1.4).The transition-metal-mediated processes require stoichiometric metal sourcesand the subsequent removal of metal is also needed to make it less appealing(Scheme 1.5). Various hydrogenation processes could only generate simple skele-tons from the corresponding aromatic compounds, as the hydrogenation reactiongenerally forms C(X)–H bonds only (Scheme 1.2). For the enzyme-catalyzedprocesses, only specific substrates could be used. As said, the great potentialsof dearomatization reactions, especially in an enantioselective manner, havebeen much more underdeveloped. On the other hand, dearomatization reactionsare such powerful tools to provide various ring systems including heterocyclicskeletons directly from relatively simple planar aromatic rings. The advantage tobuild quaternary carbon centers makes them extremely straightforward routesto construct spiro or bridged compounds via intramolecular dearomatizationreactions. Due to these features and great demand on chiral molecules, dearom-atization reactions, particularly asymmetric ones, have received the renaissancerecently.

1.4Asymmetric Dearomatization Reactions

We have briefly introduced the history and early development of dearomatizationreactions, and have shown their application in the total synthesis of natural prod-ucts. Although quite a number of dearomatization protocols have been reportedeither in the methodology development or during the synthesis of functionalmolecules, the vast majority of them are limited within racemic studies. Theenantioselective versions of dearomatization reactions are rather rare, especiallythose employing catalytic methods. The known asymmetric dearomatizationreactions rely heavily on the chiral substrate–controlled strategy. The challengingof high energy barrier encountered during the process of dearomatizationgenerally requires harsh reaction conditions, which pose formidable challenges inthe control of regioselectivity and stereoselectivity. Delightfully, both asymmetricdearomatization reactions by chiral reagents and catalytic asymmetric dearom-atization (CADA) reactions have received great attention and gained fruitfulprogress in the past few years. With the worldwide increased efforts in thisfield, we believe that every single type of asymmetric reaction would eventuallybecome compatible with dearomatization process. In addition, more and moretypes of aromatic compounds can undergo the CADA reactions sooner or later.

There are many books focusing on the topic of aromatic compounds, but few ofthem describe dearomatization reactions. Given the dramatic progress in the field

8 1 Introduction

of asymmetric dearomatization reactions, this book is aiming to provide readersvery detailed information about recent developments of asymmetric dearomati-zation reactions, especially the CADA approaches.

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