Edited byJieping Zhu, Qian Wang, and Mei-Xiang Wang

Multicomponent Reactions in Organic Synthesis

Edited byJieping ZhuQian WangMei-Xiang Wang

MulticomponentReactions in OrganicSynthesis

Related Titles

Tietze, L.F. (ed.)

Domino ReactionsConcepts for Efficient OrganicSynthesis

2014

Print ISBN: 978-3-527-33432-2

Zhang, W., Cue, B.W. (eds.)

Green Techniques forOrganic Synthesis andMedicinal Chemistry

2012

Print ISBN: 978-0-470-71151-4

Anastas, P.T., Boethling, R., Li, C.,Voutchkova, A., Perosa, A., Selva, M.(eds.)

Handbook of GreenChemistry - Green Processes

2012

Print ISBN: 978-3-527-31576-5

Behr, A., Neubert, P.

Applied HomogeneousCatalysis

2012

Print ISBN: 978-3-527-32641-9

Nenajdenko, V. (ed.)

Isocyanide ChemistryApplications in Synthesis and MaterialScience

2012

Print ISBN: 978-3-527-33043-0

Hoz, A.d., Loupy, A. (eds.)

Microwaves in OrganicSynthesis3 Edition

2012

Print ISBN: 978-3-527-33116-1

Kappe, C.O., Stadler, A., Dallinger, D.

Microwaves in Organic andMedicinal Chemistry2 Edition

2012

Print ISBN: 978-3-527-33185-7

Ding, K., Dai, L. (eds.)

Organic Chemistry -Breakthroughs andPerspectives

2012

Print ISBN: 978-3-527-33377-6

ISBN: 978-3-527-66480-1

Ma, S. (ed.)

Handbook of CyclizationReactions

2010

Print ISBN: 978-3-527-32088-2

Edited by Jieping Zhu, Qian Wang, and Mei-Xiang Wang

Multicomponent Reactions inOrganic Synthesis

Editors

Prof. Jieping ZhuLaboratory of Synthesis and NaturalProductsInstitute of Chemical Sciences andEngineeringÉcole Polytechnique Fédérale de LausanneEPFL-SB-ISIC-LSPNBCH5304 (Bat BCH)1015 LausanneSwitzerland

Dr. Qian WangLaboratory of Synthesis and NaturalProductsInstitute of Chemical Sciences andEngineeringÉcole Polytechnique Fédérale de LausanneEPFL-SB-ISIC-LSPN1015 LausanneSwitzerland

Prof. Mei-Xiang WangMOE Key Laboratory of BioorganicPhosphorus Chemistry & Chemical BiologyDepartment of ChemistryTsinghua UniversityBeijing 100084China

All books published by Wiley-VCH are carefullyproduced. Nevertheless, authors, editors, andpublisher do not warrant the informationcontained in these books, including this book, tobe free of errors. Readers are advised to keep inmind that statements, data, illustrations,procedural details or other items mayinadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the

British Library.

Bibliographic information published by theDeutsche NationalbibliothekThe Deutsche Nationalbibliothek lists thispublication in the Deutsche Nationalbibliografie;detailed bibliographic data are available on theInternet at http://dnb.d-nb.de.

2015 Wiley-VCH Verlag GmbH & Co. KGaA,Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translationinto other languages). No part of this book maybe reproduced in any form – by photoprinting,microfilm, or any other means – nor transmittedor translated into a machine language withoutwritten permission from the publishers. Registerednames, trademarks, etc. used in this book, evenwhen not specifically marked as such, are not tobe considered unprotected by law.

Print ISBN: 978-3-527-33237-3

ePDF ISBN: 978-3-527-67819-8

ePub ISBN: 978-3-527-67820-4

Mobi ISBN: 978-3-527-67818-1

oBook ISBN: 978-3-527-67817-4

Cover Design Adam-Design, Weinheim, Germany

Typesetting Thomson Digital, Noida, India

Printing and Binding Markono PrintMedia Pte Ltd.,

Singapore

Printed on acid-free paper

Contents

List of Contributors XIIIPreface XVII

1 General Introduction to MCRs: Past, Present, and Future 1Alexander Dömling and AlAnod D. AlQahtani

1.1 Introduction 11.2 Advances in Chemistry 21.3 Total Syntheses 41.4 Applications in Pharmaceutical and Agrochemical

Industry 41.5 Materials 101.6 Outlook 10

References 11

2 Discovery of MCRs 13Eelco Ruijter and Romano V.A. Orru

2.1 General Introduction 132.2 The Concept 142.3 The Reaction Design Concept 152.3.1 Single Reactant Replacement 172.3.2 Modular Reaction Sequences 192.3.3 Condition-Based Divergence 212.3.4 Union of MCRs 232.4 Multicomponent Reactions and Biocatalysis 232.4.1 Multicomponent Reactions and (Dynamic) Enzymatic

Kinetic Resolution 262.4.2 Multicomponent Reactions and Enzymatic Desymmetrization 292.5 Multicomponent Reactions in Green Pharmaceutical

Production 312.6 Conclusions 36

Acknowledgments 36References 36

V

3 Aryne-Based Multicomponent Reactions 39Hiroto Yoshida

3.1 Introduction 393.2 Multicomponent Reactions of Arynes via Electrophilic

Coupling 413.2.1 Multicomponent Reactions under Neutral Conditions 423.2.1.1 Isocyanide-Based Multicomponent Reactions 423.2.1.2 Imine-Based Multicomponent Reactions 463.2.1.3 Amine-Based Multicomponent Reactions 473.2.1.4 Carbonyl Compound-Based Multicomponent Reactions 493.2.1.5 Ether-Based Multicomponent Reactions 503.2.1.6 Miscellaneous 533.2.2 Multicomponent Reactions under Basic Conditions 533.3 Transition Metal-Catalyzed Multicomponent Reactions of Arynes 603.3.1 Annulations 603.3.2 Cross-Coupling-Type Reactions 653.3.3 Mizoroki–Heck-Type Reactions 653.3.4 Insertion into σ-Bond 653.4 Concluding Remarks 69

References 69

4 Ugi–Smiles and Passerini–Smiles Couplings 73Laurent El Kaïm and Laurence Grimaud

4.1 Introduction 734.1.1 Carboxylic Acid Surrogates in Ugi Reactions 754.1.2 Smiles Rearrangements 764.2 Scope and Limitations 774.2.1 Phenols and Thiophenols 774.2.2 Six-Membered Ring Hydroxy Heteroaromatics and Related

Mercaptans 844.2.3 Five-Membered Ring Hydroxy Heteroaromatic and Related

Mercaptans 884.2.4 Related Couplings with Enol Derivatives 904.2.5 The Joullié–Smiles Coupling 904.2.6 The Passerini–Smiles Reaction 914.3 Ugi–Smiles Postcondensations 944.3.1 Postcondensations Involving Reduction of the Nitro Group 944.3.2 Transformations of Ugi–Smiles Thioamides 964.3.3 Postcondensations Involving Transition Metal-Catalyzed

Processes 974.3.4 Reactivity of the Peptidyl Unit 1014.3.5 Radical Reactions 1034.3.6 Cycloaddition 1034.4 Conclusions 105

References 105

VI Contents

5 1,3-Dicarbonyls in Multicomponent Reactions 109Xavier Bugaut, Thierry Constantieux, Yoann Coquerel, and Jean Rodriguez

5.1 Introduction 1095.2 Achiral and Racemic MCRs 1115.2.1 Involving One Pronucleophilic Reactive Site 1115.2.2 Involving Two Reactive Sites 1155.2.2.1 Two Nucleophilic Sites 1155.2.2.2 One Pronucleophilic Site and One Electrophilic Site 1205.2.3 Involving Three Reactive Sites 1345.2.4 Involving Four Reactive Sites 1395.3 Enantioselective MCRs 1425.3.1 Involving One Reactive Site 1435.3.2 Involving Two Reactive Sites 1465.3.3 Involving Three Reactive Sites 1495.4 Conclusions and Outlook 150

References 151

6 Functionalization of Heterocycles by MCRs 159Esther Vicente-García, Nicola Kielland, and Rodolfo Lavilla

6.1 Introduction 1596.2 Mannich-Type Reactions and Related Processes 1606.3 β-Dicarbonyl Chemistry 1646.4 Hetero-Diels–Alder Cycloadditions and Related Processes 1666.5 Metal-Mediated Processes 1686.6 Isocyanide-Based Reactions 1716.7 Dipole-Mediated Processes 1756.8 Conclusions 176

Acknowledgments 178References 178

7 Diazoacetate and Related Metal-Stabilized CarbeneSpecies in MCRs 183Dong Xing and Wenhao Hu

7.1 Introduction 1837.2 MCRs via Carbonyl or Azomethine Ylide-Involved

1,3-Dipolar Cycloadditions 1847.2.1 Azomethine Ylide 1847.2.2 Carbonyl Ylide 1857.3 MCRs via Electrophilic Trapping of Protic Onium Ylides 1877.3.1 Initial Development 1877.3.2 Asymmetric Examples 1907.3.2.1 Chiral Reagent Induction 1907.3.2.2 Chiral Dirhodium(II) Catalysis 1907.3.2.3 Enantioselective Synergistic Catalysis 1907.3.3 MCRs Followed by Tandem Cyclizations 196

Contents VII

7.4 MCRs via Electrophilic Trapping of Zwitterionic Intermediates 1987.5 MCRs via Metal Carbene Migratory Insertion 1997.6 Summary and Outlook 203

References 204

8 Metal-Catalyzed Multicomponent Synthesis of Heterocycles 207Fabio Lorenzini, Jevgenijs Tjutrins, Jeffrey S. Quesnel, and Bruce A. Arndtsen

8.1 Introduction 2078.2 Multicomponent Cross-Coupling and Carbonylation Reactions 2088.2.1 Cyclization with Alkyne- or Alkene-Containing Nucleophiles 2088.2.2 Cyclization via Palladium–Allyl Complexes 2108.2.3 Fused-Ring Heterocycles for ortho-Substituted Arene Building

Blocks 2118.2.4 Multicomponent Cyclocarbonylations 2148.2.5 Cyclization of Cross-Coupling Reaction Products 2168.2.6 C-H Functionalization in Multicomponent Reactions 2188.3 Metallacycles in Multicomponent Reactions 2218.4 Multicomponent Reactions via 1,3-Dipolar Cycloaddition 2238.5 Concluding Remarks 227

References 227

9 Macrocycles from Multicomponent Reactions 231Ludger A. Wessjohann, Ricardo A.W. Neves Filho, Alfredo R. Puentes, andMicjel C. Morejon

9.1 Introduction 2319.2 IMCR-Based Macrocyclizations of Single Bifunctional Building

Blocks 2379.3 Multiple MCR-Based Macrocyclizations of Bifunctional Building

Blocks 2459.4 IMCR-Based Macrocyclizations of Trifunctionalized Building

Blocks (MiB-3D) 2569.5 Sequential IMCR-Based Macrocyclizations of Multiple Bifunctional

Building Blocks 2599.6 Final Remarks and Future Perspectives 261

References 261

10 Multicomponent Reactions under Oxidative Conditions 265Andrea Basso, Lisa Moni, and Renata Riva

10.1 Introduction 26510.2 Multicomponent Reactions Involving In Situ Oxidation of One

Substrate 26610.2.1 Isocyanide-Based Multicomponent Reactions 26610.2.1.1 Passerini Reactions 26610.2.1.2 Ugi Reactions with In Situ Oxidation of Alcohols 27110.2.1.3 Ugi Reaction with In Situ Oxidation of Secondary Amines 273

VIII Contents

10.2.1.4 Ugi–Smiles Reaction with In Situ Oxidation of SecondaryAmines 275

10.2.1.5 Ugi-Type Reactions by In Situ Oxidation of Tertiary Amines 27710.2.1.6 Synthesis of Other Derivatives 27910.2.2 Other Multicomponent Reactions 28010.3 Multicomponent Reactions Involving Oxidation of a Reaction

Intermediate 28410.3.1 Reactions without Transition Metal-Mediated Oxidation 28510.3.2 Reactions Mediated by Transition Metal Catalysis 29210.4 Multicomponent Reactions Involving Oxidants as Lewis Acids 29510.5 Conclusions 297

References 297

11 Allenes in Multicomponent Synthesis of Heterocycles 301Hans-Ulrich Reissig and Reinhold Zimmer

11.1 Introduction 30111.2 Reactions with 1,2-Propadiene and Unactivated Allenes 30211.2.1 Palladium-Catalyzed Multicomponent Reactions 30211.2.2 Copper-, Nickel-, and Rhodium-Promoted Multicomponent

Reactions 31011.2.3 Multicomponent Reactions without Transition Metals 31411.3 Reactions with Acceptor-Substituted Allenes 31611.3.1 Catalyzed Multicomponent Reactions 31611.3.2 Uncatalyzed Multicomponent Reactions 31811.4 Reactions with Donor-Substituted Allenes 32311.5 Conclusions 329

List of Abbreviations 329References 329

12 Alkynes in Multicomponent Synthesis of Heterocycles 333Thomas J.J. Müller and Konstantin Deilhof

12.1 Introduction 33312.2 σ-Nucleophilic Reactivity of Alkynes 33512.2.1 Acetylide Additions to Electrophiles 33512.2.1.1 Alkyne–Aldehyde–Amine Condensation – A3-Coupling 33512.2.1.2 Alkyne–(Hetero)Aryl Halide (Sonogashira) Coupling as Key

Reaction 33712.2.2 Conversion of Terminal Alkynes into Electrophiles as

Key Reactions 34112.3 π-Nucleophilic Reactivity of Alkynes 34512.4 Alkynes as Electrophilic Partners 35112.5 Alkynes in Cycloadditions 35612.5.1 Alkynes as Dipolarophiles 35612.5.2 Alkynes in Cu(I)-Catalyzed 1,3-Dipolar Azide–Alkyne

Cycloaddition 358

Contents IX

12.5.3 Alkynes as Dienophiles in MCRs 36612.6 Alkynes as Reaction Partners in Organometallic MCRs 37012.7 Conclusions 374

List of Abbreviations 374Acknowledgment 375References 375

13 Anhydride-Based Multicomponent Reactions 379Kevin S. Martin, Jared T. Shaw, and Ashkaan Younai

13.1 Introduction 37913.2 Quinolones and Related Heterocycles from Homophthalic

and Isatoic Anhydrides 38013.2.1 Introduction: Reactivity of Homophthalic and Isatoic

Anhydrides 38013.2.2 Imine–Anhydride Reactions of Homophthalic Anhydride 38013.2.3 MCRs Employing Homophthalic Anhydride 38213.2.4 Imine–Anhydride Reactions of Isatoic Anhydride 38313.3 α,β-Unsaturated Cyclic Anhydrides: MCRs Involving Conjugate

Addition and Cycloaddition Reactions 38513.3.1 Maleic Anhydride MCRs 38513.3.2 MCRs of Itaconic Anhydrides 38813.3.3 Diels–Alder Reactions 39013.4 MCRs of Cyclic Anhydrides in Annulation Reactions and

Related Processes 39213.4.1 MCR-Based Annulations: Succinic and Phthalic Anhydrides 39313.5 MCRs of Acyclic Anhydrides 39513.6 Conclusions 398

References 399

14 Free-Radical Multicomponent Processes 401Virginie Liautard and Yannick Landais

14.1 Introduction 40114.2 MCRs Involving Addition Across Olefin C�C Bonds 40214.2.1 Addition of Aryl Radicals to Olefins 40214.2.2 MCRs Using Sulfonyl Derivatives as Terminal Trap 40414.2.3 Carboallylation of Electron-Poor Olefins 40614.2.4 Carbohydroxylation, Sulfenylation, and Phosphorylation

of Olefins 40714.2.5 Radical Addition to Olefins Using Photoredox Catalysis 41014.2.6 MCRs Based on Radical–Polar Crossover Processes 41414.3 Free-Radical Carbonylation 41914.3.1 Alkyl Halide Carbonylation 41914.3.2 Metal-Mediated Atom-Transfer Radical Carbonylation 42014.3.3 Alkane Carbonylation 42114.3.4 Miscellaneous Carbonylation Reactions 423

X Contents

14.4 Free-Radical Oxygenation 42414.5 MCRs Involving Addition Across π-C�N Bonds 42714.5.1 Free-Radical Strecker Process 42714.5.2 Free-Radical Mannich-Type Processes 42914.6 Miscellaneous Free-Radical Multicomponent Reactions 43214.7 Conclusions 434

References 435

15 Chiral Phosphoric Acid-Catalyzed Asymmetric MulticomponentReactions 439Xiang Wu and Liu-Zhu Gong

15.1 Introduction 43915.2 Mannich Reaction 43915.3 Ugi-Type Reaction 44215.4 Biginelli Reaction 44415.5 Aza-Diels–Alder Reaction 44615.6 1,3-Dipolar Cycloaddition 45415.7 Hantzsch Dihydropyridine Synthesis 45815.8 The Combination of Metal and Chiral Phosphoric Acid

for Multicomponent Reaction 45915.9 Other Phosphoric Acid-Catalyzed Multicomponent Reactions 46515.10 Summary 467

References 467

Index 471

Contents XI

List of Contributors

AlAnod D. AlQahtaniAnti-Doping Lab QatarDohaQatar

and

University of GroningenDepartment of PharmacyAntonius Deusinglaan 19700 AD GroningenThe Netherlands

Bruce A. ArndtsenMcGill UniversityDepartment of Chemistry801 Sherbrooke Street WestMontreal, QC H3A 0B8Canada

Andrea BassoUniversità degli Studi di GenovaDipartimento di Chimica e ChimicaIndustrialeVia Dodecaneso 3116146 GenoaItaly

Xavier BugautAix Marseille UniversityCNRSCentrale Marseille iSm2 UMR 7313Service 531 Centre de St Jérôme13397 Marseille cedex 20France

Thierry ConstantieuxAix Marseille UniversityCNRSCentrale Marseille iSm2 UMR 7313Service 531 Centre de St Jérôme13397 Marseille cedex 20France

Yoann CoquerelAix Marseille UniversityCNRSCentrale Marseille iSm2 UMR 7313Service 531 Centre de St Jérôme13397 Marseille cedex 20France

Konstantin DeilhofHeinrich-Heine-UniversitätDüsseldorfInstitut für Organische Chemie undMakromolekulare ChemieUniversitätsstrasse 140225 DüsseldorfGermany

XIII

Alexander DömlingUniversity of GroningenDepartment of PharmacyAntonius Deusinglaan 19700 AD GroningenThe Netherlands

Laurent El KaïmENSTA Paris TechUMR 7652828 boulevard des Maréchaux91 762 Palaiseau CedexFrance

Liu-Zhu GongUniversity of Science andTechnology of ChinaHefei National Laboratory forPhysical Sciences at the Microscaleand Department of ChemistryNo. 96 Jinzhai RoadHefei, Anhui 230026China

Laurence GrimaudLaboratoire d’électrochimieUPMC-ENS-CNRS-UMR 8640Ecole NormaleSupérieure-Département de chimie24 rue Lhomond75231 Paris cedex 05France

Wenhao HuEast China Normal UniversityDepartment of ChemistryShanghai Engineering ResearchCenter of Molecular Therapeuticsand New Drug Development3663 Zhongshan Bei RoadShanghai 200062China

Nicola KiellandUniversity of BarcelonaBarcelona Science ParkBaldiri Reixac 10–1208028 BarcelonaSpain

Yannick LandaisUniversity of BordeauxInstitut des Sciences MoléculairesUMR-CNRS 5255351, cours de la libération33405 Talence CedexFrance

Rodolfo LavillaLaboratory of Organic ChemistryFaculty of PharmacyUniversity of BarcelonaBarcelona Science ParkBaldiri Reixac 10–1208028 BarcelonaSpain

Virginie LiautardUniversity of BordeauxInstitut des Sciences MoléculairesUMR-CNRS 5255351, cours de la libération33405 Talence CedexFrance

Fabio LorenziniMcGill UniversityDepartment of Chemistry801 Sherbrooke Street WestMontreal, QC H3A 0B8Canada

XIV List of Contributors

Kevin S. MartinUniversity of CaliforniaDepartment of ChemistryOne Shields AvenueDavis, CA 95616USA

Lisa MoniUniversità degli Studi di GenovaDipartimento di Chimica e ChimicaIndustrialeVia Dodecaneso 3116146 GenoaItaly

Micjel C. MorejonDepartment of BioorganicChemistryWeinberg 306120 Halle (Saale)Germany

Thomas J.J. MüllerHeinrich-Heine-UniversitätDüsseldorfInstitut für Organische Chemie undMakromolekulare ChemieUniversitätsstrasse 140225 DüsseldorfGermany

Ricardo A.W. Neves FilhoDepartment of BioorganicChemistryWeinberg 306120 Halle (Saale)Germany

Romano V.A. OrruVU University AmsterdamFaculty of SciencesAmsterdam Institute for Molecules,Medicines & SystemsDepartment of Chemistry &Pharmaceutical SciencesDe Boelelaan 10831081 HV AmsterdamThe Netherlands

Alfredo R. PuentesDepartment of BioorganicChemistryWeinberg 306120 Halle (Saale)Germany

Jeffrey S. QuesnelMcGill UniversityDepartment of Chemistry801 Sherbrooke Street WestMontreal, QC H3A 0B8Canada

Hans-Ulrich ReissigFreie Universität BerlinInstitut für Chemie und BiochemieTakustrasse 314195 BerlinGermany

Renata RivaUniversità degli Studi di GenovaDipartimento di Chimica e ChimicaIndustrialeVia Dodecaneso 3116146 GenoaItaly

Jean RodriguezAix Marseille University CNRSCentrale Marseille iSm2 UMR 7313Service 531 Campus Scientifiquede St Jérôme13397 Marseille cedex 20France

List of Contributors XV

Eelco RuijterVU University AmsterdamFaculty of SciencesAmsterdam Institute for Molecules,Medicines & SystemsDepartment of Chemistry &Pharmaceutical SciencesDe Boelelaan 10831081 HV AmsterdamThe Netherlands

Jared T. ShawUniversity of CaliforniaDepartment of ChemistryOne Shields AvenueDavis, CA 95616USA

Jevgenijs TjutrinsMcGill UniversityDepartment of Chemistry801 Sherbrooke Street WestMontreal, QC H3A 0B8Canada

Esther Vicente-GarcíaUniversity of BarcelonaBarcelona Science ParkBaldiri Reixac 10–1208028 BarcelonaSpain

Ludger A. WessjohannDepartment of BioorganicChemistryWeinberg 306120 Halle (Saale)Germany

Xiang WuUniversity of Science andTechnology of ChinaHefei National Laboratory forPhysical Sciences at the Microscaleand Department of ChemistryNo. 96 Jinzhai RoadHefei, Anhui 230026China

Dong XingEast China Normal UniversityDepartment of ChemistryShanghai Engineering ResearchCenter of Molecular Therapeuticsand New Drug Development3663 Zhongshan Bei RoadShanghai 200062China

Hiroto YoshidaHiroshima UniversityDepartment of Applied Chemistry1-4-1 KagamiyamaHigashi-Hiroshima 739-8527Japan

Ashkaan YounaiUniversity of CaliforniaDepartment of ChemistryOne Shields AvenueDavis, CA 95616USA

Reinhold ZimmerFreie Universität BerlinInstitut für Chemie und BiochemieTakustrasse 314195 BerlinGermany

XVI List of Contributors

Preface

The quote by Aristotle “the whole is greater than the sum of its parts” nicelyreflects the power of multicomponent reactions (MCRs) in which three or morereactants are combined in a single operation to produce adducts that incorpo-rate substantial portions of all the components. Indeed, the ability of MCRs tocreate value-added molecules from simple building blocks is now wellappreciated.

The Wiley-VCH book entitled “Multicomponent Reactions” published in 2005was warmly received by research communities in academia and industry alike.As predicted in the preface of the very first monograph on the subject, extensiveresearch on the development of new MCRs and their applications in the synthe-sis of natural products as well as designed bioactive molecules have been con-tinuing at an explosive pace. Nowadays, there is hardly a chemical journal in thebroad area of organic chemistry that does not contain papers related to multi-component reactions. In light of the recent tremendous advances in the field, itbecame clear to us that a follow-up of this book is needed. While planning thecontents of this book, we tried to focus on the synthesis aspects and to make thebook complementary rather than an update to the first edition.

The book starts with a general introduction to MCRs (Chapter 1) followed bya detailed discussion on the many facets of discovering novel MCRs (Chapter 2).Inherent to the nature of the reaction, the MCR employs generally at least onesubstrate with multireactive centers. We therefore classified the MCRs accordingto the key substrate used, including arynes (Chapter 3), isonitriles (Chapter 4),1,3-dicarbonyls (Chapter 5), heterocycles (Chapter 6), diazoacetate (Chapter 7),allenes (Chapter 11), alkynes (Chapter 12), and anhydrides (Chapter 13). In amore broad sense, metal-catalyzed (Chapter 8), radical-based (Chapter 14), oxi-dative (Chapter 10), and enantioselective (Chapter 15) MCRs and synthesis ofmacrocycles by MCRs (Chapter 9) are subjects of other five chapters. Theauthors of 15 chapters who outline the essence of the each subject and providevaluable perspectives of the field are all world leaders. It is interesting to pointout that some of these subjects were virtually unexplored before 2005, the yearthe first book was published.

The present monograph, in combination with “Multicomponent Reactions(2005),” is intended to provide an essential reference source for most of the

XVII

important topics of the field and to provide an efficient entry point to the keyliterature and background knowledge for those who plan to be involved inMCRs. We hope that the book will be of value to chemists at all levels in bothacademic and industrial laboratories. Finally, we hope that this monograph willstimulate the further development and application of this exciting research field.

We would like to express our profound gratitude to the chapter authors fortheir professionalism, their adherence to schedules, their enthusiasm, theirpatience, and, most of all, their high-quality contributions. We thank our collab-orators at Wiley-VCH, especially Dr. Anne Brennführer and Dr. Stefanie Volk,for their invaluable help from the conception to the realization of this project,and our project manager, Mamta Pujari, for unifying text and style.

Lausanne, Switzerland Jieping Zhu, Qian WangBeijing, China Mei-Xiang WangAugust 2014

XVIII Preface

1General Introduction to MCRs: Past, Present, and FutureAlexander Dömling and AlAnod D. AlQahtani

1.1Introduction

Multicomponent reactions (MCRs) are generally defined as reactions in whichthree or more starting materials react to form a product, where basically all ormost of the atoms contribute to the newly formed product [1]. Their usefulnesscan be rationalized by multiple advantages of MCRs over traditional multistepsequential assembly of target compounds. In MCRs, a molecule is assembled inone convergent chemical step in one pot by simply mixing the correspondingstarting materials as opposed to traditional ways of synthesizing a target mole-cule over multiple sequential steps. At the same time, considerably complexmolecules can be assembled by MCRs. This has considerable advantages as itsaves precious time and drastically reduces effort.

MCRs are mostly experimentally simple to perform, often without the need ofdry conditions and inert atmosphere. Molecules are assembled in a convergentway and not in a linear approach using MCRs. Therefore, structure–activityrelationships (SARs) can be rapidly generated using MCRs, since all property-determining moieties are introduced in one step instead of sequentially [2]. Lastbut not least, MCRs provide a huge chemical diversity and currently more than300 different scaffolds have been described in the chemical literature. For exam-ple, more than 40 different ways to access differentially substituted piperazinescaffolds using MCRs have been recently reviewed [3].

Although MCR chemistry is almost as old as organic chemistry and wasfirst described as early as 1851, it should be noted that early chemists didnot recognize the enormous engineering potential of MCRs. However, it tookanother >100 years until Ivar Ugi in a strike of a genius discovered his four-component condensation and also recognized the enormous potential ofMCRs in applied chemistry (Figure 1.1) [4].

1

Multicomponent Reactions in Organic Synthesis, First Edition. Edited by Jieping Zhu, Qian Wang, andMei-Xiang Wang. 2015 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2015 by Wiley-VCH Verlag GmbH & Co. KGaA.

1.2Advances in Chemistry

Many MCRs have been described in the past one and a half century andrecently not many fundamental advances in finding new MCRs have beenmade [5–7]. A strategy to enhance the size and diversity of current MCRchemical space is the concept of combining a MCR and a subsequent second-ary reaction, also known as postcondensation or Ugi–deprotection–cyclization(UDC) [2]. Herein, bifunctional orthogonally protected starting materials areused and ring cyclizations can take place in a secondary step upon deprotec-tion of the secondary functional groups. Many different scaffolds have beenrecently described using this strategy. One example is shown in Figure 1.2.

NC

+ CH2O + NH

HN

O

Xylocaine

N

HN

O

N CO2H

CO2H

HN

O

N

HN

O

N

HN

O

NH

HN

O

N

HN

O

NH

ClHN

O

NH

CO2Me

CO2Me

CO2Me

HN

O

N

HN

O

N

HN

O

N

HN

O

N

HN

O

NH2

S

Figure 1.1 A three-component reaction toward the local anesthetic xylocaine and the firstcombinatorial library of small molecules proposed by Ivar Ugi in the 1960.

2 1 General Introduction to MCRs: Past, Present, and Future

It is based on a recently discovered variation of the Ugi reaction of α-aminoacids, oxo components, and isocyanides, now including primary and secondaryamines [8–10].

1.3Total Syntheses

While the Bucherer–Bergs and the related Strecker synthesis are well-established methods for the one-pot synthesis of natural and unnatural aminoacids, the complex antibiotic penicillin was synthesized 50 years ago in a highlyconvergent approach by Ivar Ugi by using two MCRs, the Asinger reaction andhis own reaction (Figure 1.3) [11]. Other recent natural product targets usingMCR as a key step in their synthesis are also shown in Figure 1.3. Although earlyexample of the advantageous use of MCR in the conscious total synthesis ofcomplex natural products leads the way, its use has been neglected for decadesand only recently realized by a few organic chemists [12–17].

1.4Applications in Pharmaceutical and Agrochemical Industry

Two decades ago, MCR chemistry was almost generally neglected in pharmaceu-tical and agro industry. The knowledge of these reactions was often low and it

Br

(a)

(b)

CHO OHC

N

COOtBu

O

O

+ NH3 + NaSH

+

COOH

N

S

N

O O N

S

O

H2N

COOH

6-APA

1. Asinger-4CR

2. H+

1. Ugi-4CR

2. Deprotection

NN

N

N

O

O

Ac H

H

(–)-5-N-Acetylardeemin

NH

N

OMe

OOMe

MeOH

H

H

MeOOC

11-Methoxy mitragynine pseudoindoxyl

O MeO

HN

O

OH O

OMe

OH

HOH

OH

OH

O

Psymberin

Figure 1.3 (a) The union of the Asinger-4CR and the Ugi-4CR allows for the convergent andfast assembly of 6-aminopenicillanic acid natural product. (b) Recent synthetic targets of MCRnatural product chemistry.

4 1 General Introduction to MCRs: Past, Present, and Future

was generally believed that MCR scaffolds are associated with useless drug-likeproperties (absorption, distribution, metabolism, excretion, and toxicity(ADMET)). Now MCR technology is widely recognized for its impact on drugdiscovery projects and is strongly endorsed by industry as well as academia [18].An increasing number of clinical and marketed drugs were discovered andassembled by MCR since then (Figure 1.4). Examples include nifedipine(Hantzsch-3CR), praziquantel, or ZetiaTM. Two oxytocin receptor antagonistsfor the treatment of preterm birth and premature ejaculation, epelsiban and ato-siban, are currently undergoing human clinical trials. They are both assembledby the classical Ugi MCR [19–21]. Interestingly, they show superior activity forthe oxytocin receptor and selectivity toward the related vasopressin receptors

OEtO

CO2HHN

HN NH2

ONN

HN

F

N

N

H2N

N

COOH

FBrequinar

F

N

HN

O

OH

N

O

O

O

N

Retosiban

N

N

O NHO

HN

O

H2N

HN

O

O

OH

O

Omuralide

HO

NH

N

O CN

Vildagliptin

N

N

N

NH

O

F

NH

Ac

N

N

S

HN

F

Cl

MeO

N

HN Me

HN

O

N

NH

N

N

O

HNMeO

MeO

CF3

Almorexant

Cl

Cl

HN

O

NH

N

NH

EtO2C CO2Et

NO2

Nifedipine

O

N

HN

XylocaineN

O

OHOH

F

F

ZetiaTM

Cl

NC

NN

N

NN

Figure 1.4 Examples of marketed drugs or drugs under (pre)clinical development and incor-porating MCR chemistry.

1.4 Applications in Pharmaceutical and Agrochemical Industry 5

than the peptide-based compounds currently used clinically. Perhaps against theintuition of many medicinal chemists, the Ugi diketopiperazines are orally bio-available, while the currently used peptide derivatives are i.v. only and must bestabilized by the introduction of terminal protecting groups and unnaturalamino acids. An example of a MCR-based plant protecting antifungal includesmandipropamide [22]. These examples show that pharmaceutical and agro-chemical compounds with preferred ADMET properties and superior activitiescan be engineered based on MCR chemistry.

The very high compound numbers per scaffold based on MCR may beregarded as friend or foe. On the one hand, it can be fortunate to have a MCRproduct as a medicinal chemistry starting point, since a fast and efficient SARelaboration can be accomplished; on the other hand, the known chemicalspace based on MCRs is incredibly large and can neither be screened norexhaustively synthesized with reasonable efforts. The currently preferred path

Figure 1.5 MCR-based computational meth-ods can help to effectively query the verylarge chemical MCR space. Clockwise: genera-tion of a pharmacophore model based on a

3D structure, screening of the pharmacophoremodel against a very large MCR 3D compounddatabase (AnchorQuery), synthesis, and refine-ment of hits.

6 1 General Introduction to MCRs: Past, Present, and Future

to medicinal chemistry starting points in industry, the high-throughputscreening (HTS), however, is an expensive process with rather low efficiencyyielding hits often only in low double-digit or single-digit percentage. Modernpostgenomic targets often yield zero hits. The initial hits are often ineffectiveto elaborate due to their complex multistep synthesis. Thus, neither thescreening even of a very small fraction of the chemical space accessible by theclassical Ugi-4CR and other scaffolds, nor the synthesis is possible. Recentadvances in computational chemical space enumeration and screening, how-ever, allow for an alternative process to efficiently foster a very large chemicalspace. The free web-, anchor-, and pharmacophore-based server AnchorQueryTM

(anchorquery.ccbb.pitt.edu/), for example, allows for the screening of a verylarge virtual MCR library with over a billion members (Figure 1.5) [23]. Anchor-Query builds on the role deeply buried amino acid side chains or other anchorsplay in protein–protein interactions. Proposed virtual screening hits can beinstantaneously synthesized and tested using convergent MCR chemistry. Thesoftware was instrumental to the discovery of multiple potent and selectiveMCR-based antagonists of the protein–protein interaction between p53 andMDM2 [24–26]. Thus, computational approaches to screen MCR libraries willlikely play a more and more important role in the early drug discovery processin the future.

More and more high-resolution structural information on MCR moleculesbound to biological receptors is available (Figure 1.6) [18]. With the advent of

Figure 1.6 Examples of cocrystal structuresof MCR molecules bound to biologicalreceptors. Clockwise left: Povarov-3CRmolecule bound to kinesin-5 (PDB ID3L9H) [27], Ugi-3CR molecule bound to

FVIIa (PDB ID 2BZ6) [28], Ugi-4CR moleculebound to MDM2 (PDB ID 4MDN) [26], andGewald-3CR molecule targeting motorprotein KSP (PDB ID 2UYM) [29].

1.4 Applications in Pharmaceutical and Agrochemical Industry 7

structure-based design and fragment-based approaches in drug discovery, accessto binding information of MCR molecules to their receptors is becoming crucial.Once the binding mode of a MCR molecule is defined, hit-to-lead transitionsbecome more facile and time to market can be shortened and attrition rate inlater clinical trials can be potentially reduced.

Other worthwhile applications of MCRs in medicinal chemistry are in routescouting for shorter, convergent, and cheaper syntheses. An excellent showcaseis the synthesis of the recently approved HCV protease inhibitor telaprevir [30].The complex compound is industrially produced using a lengthy, highly linearstrategy relying on standard peptide chemistry exceeding 20 synthetic steps.Orru and coworkers were able to reduce the complexity of the synthesis of telap-revir by almost half using a biotransformation and two multicomponentreactions as the key steps. Another example is the convergent synthesis of theschistosomiasis drug praziquantel using key Ugi and Pictet–Spengler reactions(Figure 1.7) [31]. Clearly, more synthetic targets are out there, which can be

N

NNH

OHN

O

O

N

HN

O

HN

O

O

N

NNH

OHN

O

COOH

N NH

CNHN

O

O

NC

AcOH

OHCHN CHOOHCHN

(a)

(b)

OH

Telaprevir

NH2NC

CH2O

H2NOMe

OMe

COOH

NH

ON O

OMe

OMe

N

N

O

O

Praziquantel

Figure 1.7 Use of MCR chemistry for the easy and cheap synthesis and process improvementof marketed drugs. (a) Telaprevir structure and MCR retrosynthesis. (b) Three-step praziquantelsynthesis involving Ugi and Pictet–Spengler reactions.

8 1 General Introduction to MCRs: Past, Present, and Future

Figure 1.8 Examples of the use of MCRs inmaterial chemistry. (a) Sequence-specific poly-mer synthesis as exemplified for Passerinireaction-derived acrylic acid monomers.(b) PNA synthesis using the sequential Ugireaction. (c) Sepharose solid support-bound

Ugi products for the affinity purification oftherapeutic Fab fragments. Docking of thebest Ugi ligand (blue sticks) into human Fabfragment. (d) GBB-3CR-derived fluorescentpharmacophores.

1.4 Applications in Pharmaceutical and Agrochemical Industry 9

potentially accessed in a more convergent and cheaper way using MCR chemis-try, thus potentially benefitting the patient.

1.5Materials

Another application of MCR chemistry far from being leveraged to its fullextent is in materials science (Figure 1.8). Precise engineering of macro-molecular architectures is of utmost importance for designing future materi-als. Like no other technology, MCRs can help to meet this goal. Recently, thesynthesis of sequence-defined macromolecules without the utilization of anyprotecting group using a Passerini-3CR has been described [32]. Anothersequence-specific polymer synthesis with biological applications comprisesthe peptide nucleic acid (PNA), which is metabolically stable and can recog-nize DNA and RNA polymers and which can be accomplished by the Ugi-4CR [33]. Yet another application of MCRs in materials science might under-score the potential opportunities to uncover. Ugi molecule-modified station-ary phases have been recently introduced to efficiently separateimmunoglobulins (Igs) [34]. Currently, more than 300 monoclonal antibodies(mAbs) are moving toward the market. However, the efficient and high-yield-ing cleaning of the raw fermentation brew is still a holy grail in technicalantibody processing. Thus, it is estimated that approximately half of the fer-mentation yield of mAbs is lost during purification. Ugi-modified stationaryphases have been found in this context to be far superior to purification pro-tocols based on natural Ig-binding proteins, which are expensive to produce,labile, unstable, and exhibit lot-to-lot variability.

Fluorescent pharmacophores were discovered by the Groebke–Blackburn–Bienaymè MCR (GBB-3CR) with potential applications as specific imagingprobes using a droplet array technique on glass slides [35]. Another groupdescribed the discovery of BODIPY dyes for the in vivo imaging of phagocytoticmacrophages and assembled by MCRs [36].

1.6Outlook

From the many applied chemistry examples published in the recent literature,it is obvious that MCR chemistry has a bright future. The use of MCRs inproperty-driven chemistry has just been scratched at the surface. In whichareas will be the next applications of MCR chemistry? Will it be in functionalmaterials, imaging, molecular computing, artificial life, “omics” (lipidomics),theragnostics, functional magnetic resonance imaging, or in different upcom-ing fields? Clearly, the imagination of molecular engineers (sic chemists) willdetermine future directions or as in the saying “Only the sky is the limit.”

10 1 General Introduction to MCRs: Past, Present, and Future