Multicomponent Reactions in Organic Synthesis

Edited by Jieping Zhu, Qian Wang, and Mei-Xiang Wang Multicomponent Reactions in Organic Synthesis

Edited by Jieping Zhu Qian Wang Mei-Xiang Wang

Multicomponent Reactions in Organic Synthesis Related Titles

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Contents

List of Contributors XIII Preface XVII

1 General Introduction to MCRs: Past, Present, and Future 1 Alexander Dömling and AlAnod D. AlQahtani 1.1 Introduction 1 1.2 Advances in Chemistry 2 1.3 Total Syntheses 4 1.4 Applications in Pharmaceutical and Agrochemical Industry 4 1.5 Materials 10 1.6 Outlook 10 References 11

2 Discovery of MCRs 13 Eelco Ruijter and Romano V.A. Orru 2.1 General Introduction 13 2.2 The Concept 14 2.3 The Reaction Design Concept 15 2.3.1 Single Reactant Replacement 17 2.3.2 Modular Reaction Sequences 19 2.3.3 Condition-Based Divergence 21 2.3.4 Union of MCRs 23 2.4 Multicomponent Reactions and Biocatalysis 23 2.4.1 Multicomponent Reactions and (Dynamic) Enzymatic Kinetic Resolution 26 2.4.2 Multicomponent Reactions and Enzymatic Desymmetrization 29 2.5 Multicomponent Reactions in Green Pharmaceutical Production 31 2.6 Conclusions 36 Acknowledgments 36 References 36 VI Contents

3 Aryne-Based Multicomponent Reactions 39 Hiroto Yoshida 3.1 Introduction 39 3.2 Multicomponent Reactions of Arynes via Electrophilic Coupling 41 3.2.1 Multicomponent Reactions under Neutral Conditions 42 3.2.1.1 Isocyanide-Based Multicomponent Reactions 42 3.2.1.2 Imine-Based Multicomponent Reactions 46 3.2.1.3 Amine-Based Multicomponent Reactions 47 3.2.1.4 Carbonyl Compound-Based Multicomponent Reactions 49 3.2.1.5 Ether-Based Multicomponent Reactions 50 3.2.1.6 Miscellaneous 53 3.2.2 Multicomponent Reactions under Basic Conditions 53 3.3 Transition Metal-Catalyzed Multicomponent Reactions of Arynes 60 3.3.1 Annulations 60 3.3.2 Cross-Coupling-Type Reactions 65 3.3.3 Mizoroki–Heck-Type Reactions 65 3.3.4 Insertion into σ-Bond 65 3.4 Concluding Remarks 69 References 69

4 Ugi–Smiles and Passerini–Smiles Couplings 73 Laurent El Kaïm and Laurence Grimaud 4.1 Introduction 73 4.1.1 Carboxylic Acid Surrogates in Ugi Reactions 75 4.1.2 Smiles Rearrangements 76 4.2 Scope and Limitations 77 4.2.1 Phenols and Thiophenols 77 4.2.2 Six-Membered Ring Hydroxy Heteroaromatics and Related Mercaptans 84 4.2.3 Five-Membered Ring Hydroxy Heteroaromatic and Related Mercaptans 88 4.2.4 Related Couplings with Enol Derivatives 90 4.2.5 The Joullié–Smiles Coupling 90 4.2.6 The Passerini–Smiles Reaction 91 4.3 Ugi–Smiles Postcondensations 94 4.3.1 Postcondensations Involving Reduction of the Nitro Group 94 4.3.2 Transformations of Ugi–Smiles Thioamides 96 4.3.3 Postcondensations Involving Transition Metal-Catalyzed Processes 97 4.3.4 Reactivity of the Peptidyl Unit 101 4.3.5 Radical Reactions 103 4.3.6 Cycloaddition 103 4.4 Conclusions 105 References 105 Contents VII

5 1,3-Dicarbonyls in Multicomponent Reactions 109 Xavier Bugaut, Thierry Constantieux, Yoann Coquerel, and Jean Rodriguez 5.1 Introduction 109 5.2 Achiral and Racemic MCRs 111 5.2.1 Involving One Pronucleophilic Reactive Site 111 5.2.2 Involving Two Reactive Sites 115 5.2.2.1 Two Nucleophilic Sites 115 5.2.2.2 One Pronucleophilic Site and One Electrophilic Site 120 5.2.3 Involving Three Reactive Sites 134 5.2.4 Involving Four Reactive Sites 139 5.3 Enantioselective MCRs 142 5.3.1 Involving One Reactive Site 143 5.3.2 Involving Two Reactive Sites 146 5.3.3 Involving Three Reactive Sites 149 5.4 Conclusions and Outlook 150 References 151

6 Functionalization of Heterocycles by MCRs 159 Esther Vicente-García, Nicola Kielland, and Rodolfo Lavilla 6.1 Introduction 159 6.2 Mannich-Type Reactions and Related Processes 160 6.3 β-Dicarbonyl Chemistry 164 6.4 Hetero-Diels–Alder Cycloadditions and Related Processes 166 6.5 Metal-Mediated Processes 168 6.6 Isocyanide-Based Reactions 171 6.7 Dipole-Mediated Processes 175 6.8 Conclusions 176 Acknowledgments 178 References 178

7 Diazoacetate and Related Metal-Stabilized Carbene Species in MCRs 183 Dong Xing and Wenhao Hu 7.1 Introduction 183 7.2 MCRs via Carbonyl or Azomethine Ylide-Involved 1,3-Dipolar Cycloadditions 184 7.2.1 Azomethine Ylide 184 7.2.2 Carbonyl Ylide 185 7.3 MCRs via Electrophilic Trapping of Protic Onium Ylides 187 7.3.1 Initial Development 187 7.3.2 Asymmetric Examples 190 7.3.2.1 Chiral Reagent Induction 190 7.3.2.2 Chiral Dirhodium(II) Catalysis 190 7.3.2.3 Enantioselective Synergistic Catalysis 190 7.3.3 MCRs Followed by Tandem Cyclizations 196 VIII Contents

7.4 MCRs via Electrophilic Trapping of Zwitterionic Intermediates 198 7.5 MCRs via Metal Carbene Migratory Insertion 199 7.6 Summary and Outlook 203 References 204

8 Metal-Catalyzed Multicomponent Synthesis of Heterocycles 207 Fabio Lorenzini, Jevgenijs Tjutrins, Jeffrey S. Quesnel, and Bruce A. Arndtsen 8.1 Introduction 207 8.2 Multicomponent Cross-Coupling and Carbonylation Reactions 208 8.2.1 Cyclization with Alkyne- or Alkene-Containing Nucleophiles 208 8.2.2 Cyclization via Palladium–Allyl Complexes 210 8.2.3 Fused-Ring Heterocycles for ortho-Substituted Arene Building Blocks 211 8.2.4 Multicomponent Cyclocarbonylations 214 8.2.5 Cyclization of Cross-Coupling Reaction Products 216 8.2.6 C-H Functionalization in Multicomponent Reactions 218 8.3 Metallacycles in Multicomponent Reactions 221 8.4 Multicomponent Reactions via 1,3-Dipolar Cycloaddition 223 8.5 Concluding Remarks 227 References 227

9 Macrocycles from Multicomponent Reactions 231 Ludger A. Wessjohann, Ricardo A.W. Neves Filho, Alfredo R. Puentes, and Micjel C. Morejon 9.1 Introduction 231 9.2 IMCR-Based Macrocyclizations of Single Bifunctional Building Blocks 237 9.3 Multiple MCR-Based Macrocyclizations of Bifunctional Building Blocks 245 9.4 IMCR-Based Macrocyclizations of Trifunctionalized Building Blocks (MiB-3D) 256 9.5 Sequential IMCR-Based Macrocyclizations of Multiple Bifunctional Building Blocks 259 9.6 Final Remarks and Future Perspectives 261 References 261

10 Multicomponent Reactions under Oxidative Conditions 265 Andrea Basso, Lisa Moni, and Renata Riva 10.1 Introduction 265 10.2 Multicomponent Reactions Involving In Situ Oxidation of One Substrate 266 10.2.1 Isocyanide-Based Multicomponent Reactions 266 10.2.1.1 Passerini Reactions 266 10.2.1.2 Ugi Reactions with In Situ Oxidation of Alcohols 271 10.2.1.3 Ugi Reaction with In Situ Oxidation of Secondary Amines 273 Contents IX

10.2.1.4 Ugi–Smiles Reaction with In Situ Oxidation of Secondary Amines 275 10.2.1.5 Ugi-Type Reactions by In Situ Oxidation of Tertiary Amines 277 10.2.1.6 Synthesis of Other Derivatives 279 10.2.2 Other Multicomponent Reactions 280 10.3 Multicomponent Reactions Involving Oxidation of a Reaction Intermediate 284 10.3.1 Reactions without Transition Metal-Mediated Oxidation 285 10.3.2 Reactions Mediated by Transition Metal Catalysis 292 10.4 Multicomponent Reactions Involving Oxidants as Lewis Acids 295 10.5 Conclusions 297 References 297

11 Allenes in Multicomponent Synthesis of Heterocycles 301 Hans-Ulrich Reissig and Reinhold Zimmer 11.1 Introduction 301 11.2 Reactions with 1,2-Propadiene and Unactivated Allenes 302 11.2.1 Palladium-Catalyzed Multicomponent Reactions 302 11.2.2 Copper-, Nickel-, and Rhodium-Promoted Multicomponent Reactions 310 11.2.3 Multicomponent Reactions without Transition Metals 314 11.3 Reactions with Acceptor-Substituted Allenes 316 11.3.1 Catalyzed Multicomponent Reactions 316 11.3.2 Uncatalyzed Multicomponent Reactions 318 11.4 Reactions with Donor-Substituted Allenes 323 11.5 Conclusions 329 List of Abbreviations 329 References 329

12 Alkynes in Multicomponent Synthesis of Heterocycles 333 Thomas J.J. Müller and Konstantin Deilhof 12.1 Introduction 333 12.2 σ-Nucleophilic Reactivity of Alkynes 335 12.2.1 Acetylide Additions to Electrophiles 335 12.2.1.1 Alkyne–Aldehyde–Amine Condensation – A3-Coupling 335 12.2.1.2 Alkyne–(Hetero)Aryl Halide (Sonogashira) Coupling as Key Reaction 337 12.2.2 Conversion of Terminal Alkynes into Electrophiles as Key Reactions 341 12.3 π-Nucleophilic Reactivity of Alkynes 345 12.4 Alkynes as Electrophilic Partners 351 12.5 Alkynes in Cycloadditions 356 12.5.1 Alkynes as Dipolarophiles 356 12.5.2 Alkynes in Cu(I)-Catalyzed 1,3-Dipolar Azide–Alkyne Cycloaddition 358 X Contents

12.5.3 Alkynes as Dienophiles in MCRs 366 12.6 Alkynes as Reaction Partners in Organometallic MCRs 370 12.7 Conclusions 374 List of Abbreviations 374 Acknowledgment 375 References 375

13 Anhydride-Based Multicomponent Reactions 379 Kevin S. Martin, Jared T. Shaw, and Ashkaan Younai 13.1 Introduction 379 13.2 Quinolones and Related Heterocycles from Homophthalic and Isatoic Anhydrides 380 13.2.1 Introduction: Reactivity of Homophthalic and Isatoic Anhydrides 380 13.2.2 Imine–Anhydride Reactions of Homophthalic Anhydride 380 13.2.3 MCRs Employing Homophthalic Anhydride 382 13.2.4 Imine–Anhydride Reactions of Isatoic Anhydride 383 13.3 α,β-Unsaturated Cyclic Anhydrides: MCRs Involving Conjugate Addition and Cycloaddition Reactions 385 13.3.1 Maleic Anhydride MCRs 385 13.3.2 MCRs of Itaconic Anhydrides 388 13.3.3 Diels–Alder Reactions 390 13.4 MCRs of Cyclic Anhydrides in Annulation Reactions and Related Processes 392 13.4.1 MCR-Based Annulations: Succinic and Phthalic Anhydrides 393 13.5 MCRs of Acyclic Anhydrides 395 13.6 Conclusions 398 References 399

14 Free-Radical Multicomponent Processes 401 Virginie Liautard and Yannick Landais 14.1 Introduction 401 14.2 MCRs Involving Addition Across OlefinCC Bonds 402 14.2.1 Addition of Aryl Radicals to Olefins 402 14.2.2 MCRs Using Sulfonyl Derivatives as Terminal Trap 404 14.2.3 Carboallylation of Electron-Poor Olefins 406 14.2.4 Carbohydroxylation, Sulfenylation, and Phosphorylation of Olefins 407 14.2.5 Radical Addition to Olefins Using Photoredox Catalysis 410 14.2.6 MCRs Based on Radical–Polar Crossover Processes 414 14.3 Free-Radical Carbonylation 419 14.3.1 Alkyl Halide Carbonylation 419 14.3.2 Metal-Mediated Atom-Transfer Radical Carbonylation 420 14.3.3 Alkane Carbonylation 421 14.3.4 Miscellaneous Carbonylation Reactions 423 Contents XI

14.4 Free-Radical Oxygenation 424 14.5 MCRs Involving Addition Across π-CN Bonds 427 14.5.1 Free-Radical Strecker Process 427 14.5.2 Free-Radical Mannich-Type Processes 429 14.6 Miscellaneous Free-Radical Multicomponent Reactions 432 14.7 Conclusions 434 References 435

15 Chiral Phosphoric Acid-Catalyzed Asymmetric Multicomponent Reactions 439 Xiang Wu and Liu-Zhu Gong 15.1 Introduction 439 15.2 Mannich Reaction 439 15.3 Ugi-Type Reaction 442 15.4 Biginelli Reaction 444 15.5 Aza-Diels–Alder Reaction 446 15.6 1,3-Dipolar Cycloaddition 454 15.7 Hantzsch Dihydropyridine Synthesis 458 15.8 The Combination of Metal and Chiral Phosphoric Acid for Multicomponent Reaction 459 15.9 Other Phosphoric Acid-Catalyzed Multicomponent Reactions 465 15.10 Summary 467 References 467

Index 471

XIII

List of Contributors

AlAnod D. AlQahtani Xavier Bugaut Anti-Doping Lab Qatar Aix Marseille University Doha CNRS Qatar Centrale Marseille iSm2 UMR 7313 Service 531 Centre de St Jérôme and 13397 Marseille cedex 20 France University of Groningen Department of Pharmacy Thierry Constantieux Antonius Deusinglaan 1 Aix Marseille University 9700 AD Groningen CNRS The Netherlands Centrale Marseille iSm2 UMR 7313 Service 531 Centre de St Jérôme Bruce A. Arndtsen 13397 Marseille cedex 20 McGill University France Department of Chemistry 801 Sherbrooke Street West Yoann Coquerel Montreal, QC H3A 0B8 Aix Marseille University Canada CNRS Centrale Marseille iSm2 UMR 7313 Andrea Basso Service 531 Centre de St Jérôme Università degli Studi di Genova 13397 Marseille cedex 20 Dipartimento di Chimica e Chimica France Industriale Via Dodecaneso 31 Konstantin Deilhof 16146 Genoa Heinrich-Heine-Universität Italy Düsseldorf Institut für Organische Chemie und Makromolekulare Chemie Universitätsstrasse 1 40225 Düsseldorf Germany XIV List of Contributors

Alexander Dömling Nicola Kielland University of Groningen University of Barcelona Department of Pharmacy Barcelona Science Park Antonius Deusinglaan 1 Baldiri Reixac 10–12 9700 AD Groningen 08028 Barcelona The Netherlands Spain

Laurent El Kaïm Yannick Landais ENSTA Paris Tech University of Bordeaux UMR 7652 Institut des Sciences Moléculaires 828 boulevard des Maréchaux UMR-CNRS 5255 91 762 Palaiseau Cedex 351, cours de la libération France 33405 Talence Cedex France Liu-Zhu Gong University of Science and Rodolfo Lavilla Technology of China Laboratory of Organic Chemistry Hefei National Laboratory for Faculty of Pharmacy Physical Sciences at the Microscale University of Barcelona and Department of Chemistry Barcelona Science Park No. 96 Jinzhai Road Baldiri Reixac 10–12 Hefei, Anhui 230026 08028 Barcelona China Spain

Laurence Grimaud Virginie Liautard Laboratoire d’électrochimie University of Bordeaux UPMC-ENS-CNRS-UMR 8640 Institut des Sciences Moléculaires Ecole Normale UMR-CNRS 5255 Supérieure-Département de chimie 351, cours de la libération 24 rue Lhomond 33405 Talence Cedex 75231 Paris cedex 05 France France Fabio Lorenzini Wenhao Hu McGill University East China Normal University Department of Chemistry Department of Chemistry 801 Sherbrooke Street West Shanghai Engineering Research Montreal, QC H3A 0B8 Center of Molecular Therapeutics Canada and New Drug Development 3663 Zhongshan Bei Road Shanghai 200062 China List of Contributors XV

Kevin S. Martin Romano V.A. Orru University of California VU University Amsterdam Department of Chemistry Faculty of Sciences One Shields Avenue Amsterdam Institute for Molecules, Davis, CA 95616 Medicines & Systems USA Department of Chemistry & Pharmaceutical Sciences Lisa Moni De Boelelaan 1083 Università degli Studi di Genova 1081 HV Amsterdam Dipartimento di Chimica e Chimica The Netherlands Industriale Via Dodecaneso 31 Alfredo R. Puentes 16146 Genoa Department of Bioorganic Italy Chemistry Weinberg 3 Micjel C. Morejon 06120 Halle (Saale) Department of Bioorganic Germany Chemistry Jeffrey S. Quesnel Weinberg 3 McGill University 06120 Halle (Saale) Department of Chemistry Germany 801 Sherbrooke Street West Montreal, QC H3A 0B8 Thomas J.J. Müller Canada Heinrich-Heine-Universität Düsseldorf Hans-Ulrich Reissig Institut für Organische Chemie und Freie Universität Berlin Makromolekulare Chemie Institut für Chemie und Biochemie Universitätsstrasse 1 Takustrasse 3 40225 Düsseldorf 14195 Berlin Germany Germany

Ricardo A.W. Neves Filho Renata Riva Department of Bioorganic Università degli Studi di Genova Chemistry Dipartimento di Chimica e Chimica Weinberg 3 Industriale 06120 Halle (Saale) Via Dodecaneso 31 Germany 16146 Genoa Italy

Jean Rodriguez Aix Marseille University CNRS Centrale Marseille iSm2 UMR 7313 Service 531 Campus Scientiﬁque de St Jérôme 13397 Marseille cedex 20 France XVI List of Contributors

Eelco Ruijter Xiang Wu VU University Amsterdam University of Science and Faculty of Sciences Technology of China Amsterdam Institute for Molecules, Hefei National Laboratory for Medicines & Systems Physical Sciences at the Microscale Department of Chemistry & and Department of Chemistry Pharmaceutical Sciences No. 96 Jinzhai Road De Boelelaan 1083 Hefei, Anhui 230026 1081 HV Amsterdam China The Netherlands Dong Xing Jared T. Shaw East China Normal University University of California Department of Chemistry Department of Chemistry Shanghai Engineering Research One Shields Avenue Center of Molecular Therapeutics Davis, CA 95616 and New Drug Development USA 3663 Zhongshan Bei Road Shanghai 200062 Jevgenijs Tjutrins China McGill University Department of Chemistry Hiroto Yoshida 801 Sherbrooke Street West Hiroshima University Montreal, QC H3A 0B8 Department of Applied Chemistry Canada 1-4-1 Kagamiyama Higashi-Hiroshima 739-8527 Esther Vicente-García Japan University of Barcelona Barcelona Science Park Ashkaan Younai Baldiri Reixac 10–12 University of California 08028 Barcelona Department of Chemistry Spain One Shields Avenue Davis, CA 95616 Ludger A. Wessjohann USA Department of Bioorganic Chemistry Reinhold Zimmer Weinberg 3 Freie Universität Berlin 06120 Halle (Saale) Institut für Chemie und Biochemie Germany Takustrasse 3 14195 Berlin Germany XVII

Preface

The quote by Aristotle “the whole is greater than the sum of its parts” nicely reflects the power of multicomponent reactions (MCRs) in which three or more reactants are combined in a single operation to produce adducts that incorpo- rate substantial portions of all the components. Indeed, the ability of MCRs to create value-added molecules from simple building blocks is now well appreciated. The Wiley-VCH book entitled “Multicomponent Reactions” published in 2005 was warmly received by research communities in academia and industry alike. As predicted in the preface of the very first monograph on the subject, extensive research on the development of new MCRs and their applications in the synthesis 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 the broad area of organic chemistry that does not contain papers related to multicomponent reactions. In light of the recent tremendous advances in the field, it became clear to us that a follow-up of this book is needed. While planning the contents of this book, we tried to focus on the synthesis aspects and to make the book complementary rather than an update to the first edition. The book starts with a general introduction to MCRs (Chapter 1) followed by a 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 one substrate with multireactive centers. We therefore classified the MCRs according to 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 a more broad sense, metal-catalyzed (Chapter 8), radical-based (Chapter 14), oxidative (Chapter 10), and enantioselective (Chapter 15) MCRs and synthesis of macrocyclesbyMCRs(Chapter9)aresubjectsofotherfive chapters. The authors of 15 chapters who outline the essence of the each subject and provide valuable perspectives of the field are all world leaders. It is interesting to point out that some of these subjects were virtually unexplored before 2005, the year the 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 XVIII Preface

important topics of the field and to provide an efficient entry point to the key literature and background knowledge for those who plan to be involved in MCRs. We hope that the book will be of value to chemists at all levels in both academic and industrial laboratories. Finally, we hope that this monograph will stimulate the further development and application of this exciting research field. We would like to express our profound gratitude to the chapter authors for their professionalism, their adherence to schedules, their enthusiasm, their patience, 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 Wang Beijing, China Mei-Xiang Wang August 2014 1

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

1.1 Introduction

Multicomponent reactions (MCRs) are generally deﬁned as reactions in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product [1]. Their usefulness can be rationalized by multiple advantages of MCRs over traditional multistep sequential assembly of target compounds. In MCRs, a molecule is assembled in one convergent chemical step in one pot by simply mixing the corresponding starting materials as opposed to traditional ways of synthesizing a target molecule over multiple sequential steps. At the same time, considerably complex molecules can be assembled by MCRs. This has considerable advantages as it saves precious time and drastically reduces effort. MCRs are mostly experimentally simple to perform, often without the need of dry conditions and inert atmosphere. Molecules are assembled in a convergent way and not in a linear approach using MCRs. Therefore, structure–activity relationships (SARs) can be rapidly generated using MCRs, since all property- determining moieties are introduced in one step instead of sequentially [2]. Last but not least, MCRs provide a huge chemical diversity and currently more than 300 different scaffolds have been described in the chemical literature. For example, more than 40 different ways to access differentially substituted piperazine scaffolds using MCRs have been recently reviewed [3]. Although MCR chemistry is almost as old as organic chemistry and was ﬁrst described as early as 1851, it should be noted that early chemists did not recognize the enormous engineering potential of MCRs. However, it took another >100 years until Ivar Ugi in a strike of a genius discovered his four- component condensation and also recognized the enormous potential of MCRs in applied chemistry (Figure 1.1) [4].

Multicomponent Reactions in Organic Synthesis, First Edition. Edited by Jieping Zhu, Qian Wang, and Mei-Xiang Wang.  2015 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2015 by Wiley-VCH Verlag GmbH & Co. KGaA. 2 1 General Introduction to MCRs: Past, Present, and Future

H NC N N + CH2O + N H O Xylocaine

H H H N N N N CO2H N N O O O CO2H

H H H N N N N N N H H O O O

CO Me Cl 2 H H H N N N N N N H O O O

CO2Me H H H N N N N N NH2 S O O O CO2Me

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

1.2 Advances in Chemistry

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

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

(a)

O H2N N S + OHC O 1. Asinger-4CR 1. Ugi-4CR Br CHO O N O N COOtBu O + S 2. Deprotection COOH 2. H COOH + NH + NaSH 6-APA 3 N

(b)

OMe O O OH

OH O N H N N MeO OH N H H H Ac H N N H OH O O OMe H MeOOC N O OH 11-Methoxy mitragynine H N OMe O MeO Psymberin (–)-5- -Acetylardeemin pseudoindoxyl

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

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

1.3 Total Syntheses

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

1.4 Applications in Pharmaceutical and Agrochemical Industry

Two decades ago, MCR chemistry was almost generally neglected in pharmaceutical and agro industry. The knowledge of these reactions was often low and it 1.4 Applications in Pharmaceutical and Agrochemical Industry 5

O OEt HN F NN O HN Cl N N F HN CO2H H2N N N F F Brequinar S N COOH

HN NH2 HO O OH H N N O O O O N N O NH O N N O H H O C HN O N N H2N N Omuralide Vildagliptin H Retosiban O O N

CF3 MeO H O N Me N N N F N H Cl N N N N N N N H O NC H N MeO N H N N N O MeO Ac N Almorexant H Cl OH OH NO2 H EtO C CO Et N 2 2 Cl O N N F HN O N N ZetiaTM N H H O Xylocaine Nifedipine

Figure 1.4 Examples of marketed drugs or drugs under (pre)clinical development and incor- porating MCR chemistry. was generally believed that MCR scaffolds are associated with useless drug-like properties (absorption, distribution, metabolism, excretion, and toxicity (ADMET)). Now MCR technology is widely recognized for its impact on drug discovery projects and is strongly endorsed by industry as well as academia [18]. An increasing number of clinical and marketed drugs were discovered and assembled by MCR since then (Figure 1.4). Examples include nifedipine (Hantzsch-3CR), praziquantel, or ZetiaTM. Two oxytocin receptor antagonists for the treatment of preterm birth and premature ejaculation, epelsiban and ato- siban, are currently undergoing human clinical trials. They are both assembled by the classical Ugi MCR [19–21]. Interestingly, they show superior activity for the oxytocin receptor and selectivity toward the related vasopressin receptors 6 1 General Introduction to MCRs: Past, Present, and Future

Figure 1.5 MCR-based computational meth- 3D structure, screening of the pharmacophore ods can help to effectively query the very model against a very large MCR 3D compound large chemical MCR space. Clockwise: genera- database (AnchorQuery), synthesis, and reﬁne- tion of a pharmacophore model based on a ment of hits.

than the peptide-based compounds currently used clinically. Perhaps against the intuition of many medicinal chemists, the Ugi diketopiperazines are orally bioavailable, while the currently used peptide derivatives are i.v. only and must be stabilized by the introduction of terminal protecting groups and unnatural amino acids. An example of a MCR-based plant protecting antifungal includes mandipropamide [22]. These examples show that pharmaceutical and agrochemical compounds with preferred ADMET properties and superior activities can be engineered based on MCR chemistry. The very high compound numbers per scaffold based on MCR may be regarded as friend or foe. On the one hand, it can be fortunate to have a MCR product as a medicinal chemistry starting point, since a fast and efficient SAR elaboration can be accomplished; on the other hand, the known chemical space based on MCRs is incredibly large and can neither be screened nor exhaustively synthesized with reasonable efforts. The currently preferred path 1.4 Applications in Pharmaceutical and Agrochemical Industry 7 to medicinal chemistry starting points in industry, the high-throughput screening (HTS), however, is an expensive process with rather low efficiency yielding hits often only in low double-digit or single-digit percentage. Modern postgenomic targets often yield zero hits. The initial hits are often ineffective to elaborate due to their complex multistep synthesis. Thus, neither the screening even of a very small fraction of the chemical space accessible by the classical Ugi-4CR and other scaffolds, nor the synthesis is possible. Recent advances in computational chemical space enumeration and screening, however, allow for an alternative process to efficiently foster a very large chemical space. The free web-, anchor-, and pharmacophore-based server AnchorQueryTM (anchorquery.ccbb.pitt.edu/), for example, allows for the screening of a very large 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 anchors play in protein–protein interactions. Proposed virtual screening hits can be instantaneously synthesized and tested using convergent MCR chemistry. The software was instrumental to the discovery of multiple potent and selective MCR-based antagonists of the protein–protein interaction between p53 and MDM2 [24–26]. Thus, computational approaches to screen MCR libraries will likely play a more and more important role in the early drug discovery process in the future. More and more high-resolution structural information on MCR molecules bound to biological receptors is available (Figure 1.6) [18]. With the advent of

Figure 1.6 Examples of cocrystal structures FVIIa (PDB ID 2BZ6) [28], Ugi-4CR molecule of MCR molecules bound to biological bound to MDM2 (PDB ID 4MDN) [26], and receptors. Clockwise left: Povarov-3CR Gewald-3CR molecule targeting motor molecule bound to kinesin-5 (PDB ID protein KSP (PDB ID 2UYM) [29]. 3L9H) [27], Ugi-3CR molecule bound to 8 1 General Introduction to MCRs: Past, Present, and Future

structure-based design and fragment-based approaches in drug discovery, access to binding information of MCR molecules to their receptors is becoming crucial. OncethebindingmodeofaMCRmoleculeisdeﬁned, hit-to-lead transitions become more facile and time to market can be shortened and attrition rate in later clinical trials can be potentially reduced. Other worthwhile applications of MCRs in medicinal chemistry are in route scouting for shorter, convergent, and cheaper syntheses. An excellent showcase is the synthesis of the recently approved HCV protease inhibitor telaprevir [30]. The complex compound is industrially produced using a lengthy, highly linear strategy relying on standard peptide chemistry exceeding 20 synthetic steps. Orru and coworkers were able to reduce the complexity of the synthesis of telap- revirbyalmosthalfusingabiotransformation and two multicomponent reactions as the key steps. Another example is the convergent synthesis of the schistosomiasis drug praziquantel using key Ugi and Pictet–Spengler reactions (Figure 1.7) [31]. Clearly, more synthetic targets are out there, which can be

(a)

O H N N COOH O N H H H N N O O N N H N N O O N O H O N Telaprevir N N H O H NC CN N

AcOH O

OHCHN OHCHN CHO OH

(b)

CH2O OMe H2N O N O NC N O NH2 OMe NH OMe N COOH OMe O

Praziquantel

Figure 1.7 Use of MCR chemistry for the easy and cheap synthesis and process improvement of marketed drugs. (a) Telaprevir structure and MCR retrosynthesis. (b) Three-step praziquantel synthesis involving Ugi and Pictet–Spengler reactions. 1.4 Applications in Pharmaceutical and Agrochemical Industry 9

Figure 1.8 Examples of the use of MCRs in Ugi products for the affinity purification of material chemistry. (a) Sequence-specific poly- therapeutic Fab fragments. Docking of the mer synthesis as exemplified for Passerini best Ugi ligand (blue sticks) into human Fab reaction-derived acrylic acid monomers. fragment. (d) GBB-3CR-derived fluorescent (b) PNA synthesis using the sequential Ugi pharmacophores. reaction. (c) Sepharose solid support-bound 10 1 General Introduction to MCRs: Past, Present, and Future

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

1.5 Materials

Another application of MCR chemistry far from being leveraged to its full extent is in materials science (Figure 1.8). Precise engineering of macro- molecular architectures is of utmost importance for designing future materials. Like no other technology, MCRs can help to meet this goal. Recently, the synthesis of sequence-defined macromolecules without the utilization of any protecting group using a Passerini-3CR has been described [32]. Another sequence-specific polymer synthesis with biological applications comprises the peptide nucleic acid (PNA), which is metabolically stable and can recognize 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 stationary phases have been recently introduced to efficiently separate immunoglobulins (Igs) [34]. Currently, more than 300 monoclonal antibodies (mAbs) are moving toward the market. However, the efficient and high-yielding cleaning of the raw fermentation brew is still a holy grail in technical antibody processing. Thus, it is estimated that approximately half of the fermentation yield of mAbs is lost during purification. Ugi-modified stationary phases 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 werediscoveredbytheGroebke–Blackburn– Bienaymè MCR (GBB-3CR) with potential applications as specificimaging probes using a droplet array technique on glass slides [35]. Another group described the discovery of BODIPY dyes for the in vivo imaging of phagocytotic macrophages and assembled by MCRs [36].

1.6 Outlook

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 in property-driven chemistry has just been scratched at the surface. In which areas will be the next applications of MCR chemistry? Will it be in functional materials, 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)will determine future directions or as in the saying “Only the sky is the limit.” References 11

References

1 Ugi, I., Domling, A., and Horl, W. (1994) bicyclomycin: synthesis of the bicyclic Multicomponent reaction in organic system of bicyclomycin. Tetrahedron Lett., chemistry. Endeavor, 18 (3), 115. 22 (42), 4155. 2 Hulme, C. and Gore, V. (2003) “Multi- 14 Semple, J.E., Wang, P.C., Lysenko, Z., and component reactions: emerging chemistry Joullié, M.M. (1980) Total synthesis of in drug discovery”‘from xylocain to (+)-furanomycin and stereoisomers. J. Am. crixivan’. Curr. Med. Chem., 1 (10), 51. Chem. Soc., 102 (25), 7505. 3 Domling, A. and Huang, Y. (2010) 15 Takiguchi, S. et al. (2010) Total synthesis Piperazine scaffolds via isocyanide based of ()-fructigenine A and ()-5-N- multicomponent reaction. Synthesis, (17), acetylardeemin. J. Org. Chem., 75 (4), 2859. 1126. 4 Ugi, I. and Steinbruckner, C. (1960) 16 Wan, S. et al. (2011) Total syntheses of Concerning a new condensation principle. ()-fructigenine A and ()-5-N- Angew. Chem., 72, 267. acetylardeemin: total synthesis and 5 Bienayme, H. and Bouzid, K. (1998) A new biological evaluation of pederin, heterocyclic multicomponent reaction for psymberin, and highly potent analogs. the combinatorial synthesis of fused 3- J. Am. Chem. Soc., 133 (41), 16668. aminoimidazoles. Angew. Chem., Int. Ed., 17 Toure, B. and Hall, D. (2009) Natural 37 (16), 2234. product synthesis using multicomponent 6 Groebcke, K., Weber, L., and Mehlin, F. reaction strategies. Chem. Rev., 109 (9), (1998) Synthesis of imidazo[1,2-a] 4439. annulated pyridines, pyrazines and 18 Dömling, A., Wang, W., and Wang, K. pyrimidines by a novel three-component (2012) Chemistry and biology of condensation. Synlett, (6), 661. multicomponent reactions. Chem. Rev., 7 Kaïm, L.E., Grimaud, L., and Oble, J. 112 (6), 3083. (2005) Phenol Ugi–Smiles systems: 19 Wyatt, P. et al. (2005) 2,5- strategies for the multicomponent Diketopiperazines as potent and selective N-arylation of primary amines with oxytocin antagonists. 1. Identiﬁcation, isocyanides, aldehydes, and phenols. stereochemistry and initial SAR. Bioorg. Angew. Chem., Int. Ed., 44 (48), 7961. Med. Chem. Lett., 10 (15), 2579. 8 Sinha, M. et al. (2013) Tricycles by a new 20 Borthwick, A., Davies, D., and Exall, A. Ugi variation and Pictet–Spengler reaction (2005) 2,5-Diketopiperazines as potent, in one pot. Chem. Eur. J., 19 (25), 8048. selective, and orally bioavailable oxytocin 9 Sinha, M. et al. (2013) Various cyclization antagonists. 2. Synthesis, chirality, and scaffolds by a truly Ugi 4-CR. Org. Biomol. pharmacokinetics. J. Med. Chem., Chem., 11 (29), 4792. 48 (22), 6956. 10 Khoury, K. et al. (2012) Efﬁcient assembly 21 Borthwick, A. et al. (2006) 2,5- of iminodicarboxamides by a “truly” four- Diketopiperazines as potent, selective, and component reaction. Angew. Chem., Int. orally bioavailable oxytocin antagonists. 3. Ed., 51 (41), 10280. Synthesis, pharmacokinetics, and in vivo 11 Ugi, I. (1982) From isocyanides via four- potency. J. Med. Chem., 49 (14), 4159. component condensations to antibiotic 22 Lamberth, C. (2008) Multicomponent syntheses. Angew. Chem., Int. Ed. Engl., reaction in fungicide research: the 21 (11), 810. discovery of mandipropamid. Bioorg. Med. 12 Beck, B., Hessa, S., and Doemling, A. Chem., 16, 1531. (2000) One-pot synthesis and biological 23 Koes, D. et al. (2012) Enabling large-scale evaluation of aspergillamides and design, synthesis and validation of small analogues. Bioorg. Med. Chem. Lett., 10, molecule protein–protein antagonists. 1701–1705. PLoS One, 7 (3), e32839. 13 Fukuyama, T., Robins, B., and Sachleben, 24 Czarna, A. et al. (2010) Robust generation R. (1981) Synthetic approach to of lead compounds for protein–protein 12 1 General Introduction to MCRs: Past, Present, and Future

interactions by computational and MCR 31 Cao, H., Liu, H., and Dömling, A. (2010) chemistry: p53/Hdm2 antagonists. Angew. Efficient multicomponent reaction Chem., Int. Ed., 49 (31), 5342. synthesis of the schistosomiasis drug 25 Huang, Y. et al. (2012) Exhaustive fluorine praziquantel. Chem. Eur. J., 16 (41), scanning towards potent p53–Mdm2 12296–12298. antagonists. Chem. Med. Chem., 7 (1), 49. 32 Solleder, S. and Meier, M. (2014) 26 Bista, M. et al. (2013) Transient protein Sequence control in polymer chemistry states in designing inhibitors of the through the Passerini three-component MDM2–p53 interaction. Structure, reaction. Angew. Chem., Int. Ed., 21 (12), 2143. 53 (3), 711. 27 Yan, Y. et al. (2004) Inhibition of a mitotic 33 Chi, K.-Z., Dömling, A., and Barrère, M. motor protein: where, how, and (1999) A novel method to highly versatile conformational consequences. J. Mol. monomeric PNA building blocks by Biol., 335 (2), 547. multicomponent reactions. Bioorg. Med. 28 Groebke Zbinden, K. et al. (2006) Dose- Chem. Lett., 9 (19), 2871. dependent antithrombotic activity of an 34 Haigh, J.M. et al. (2009) Affinity ligands orally active tissue factor/factor VIIa for immunoglobulins based on the inhibitor without concomitant multicomponent Ugi reaction. J. enhancement of bleeding propensity. Chromatogr. A, 877, 1440. Bioorg. Med. Chem. Lett., 14 (15), 5357. 35 Burchak, O. et al. (2011) Combinatorial 29 Pinkerton, A.B. et al. (2007) Synthesis discovery of fluorescent pharmacophores and SAR of thiophene containing kinesin by multicomponent reactions in droplet spindle protein (KSP) inhibitors. Bioorg. arrays. J. Am. Chem. Soc., 133 (26), 10058. Med. Chem. Lett., 17 (13), 3562. 36 Vázquez-Romero, A. et al. (2013) 30 Znabet, A. et al. (2010) A highly efficient Multicomponent reactions for de novo synthesis of telaprevir by strategic use of synthesis of BODIPY probes: in vivo biocatalysis and multicomponent reactions. imaging of phagocytic macrophages. Chem. Commun., 46 (42), 7918–7920. J. Am. Chem. Soc., 135 (46), 16018. 13

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

2.1 General Introduction

Synthetic organic chemistry has arrived at a point where it is possible to design a multistep synthesis for almost any conceivable chemical structure by a rational ret- rosynthetic approach based on the large toolbox of synthetic methods available. To be useful for larger scale production, methods must be reliable and proceed with good yields and with ease of handling for a broad range of substrates. This might sound trivial, yet we are far from realizing this today. Especially for the “total” multistep synthesis of complex organic molecules, the routes are often lengthy with many reaction steps employing a multitude of different, sometimes highly creative, reagents, catalysts, and protective group strategies. Truly sustainable production of complex, highly functionalized molecules for advanced application as (fine) chemicals and pharmaceuticals or in food, materials, and catalysis is still beyond any state of maturity. Moreover, the challenges in chemical biology and medicinal research to use the wealth of information hidden in over 25 000 genes in the human genome that encode for hundreds of thousands of proteins are enormous. Small molecules are crucial as they enable us to study perturbation of biological ground states at the molecular level. Easy access to collections of small molecules with adequate levels of molecular diversity and complexity is key to fuel such stud- ies. However, efficient synthetic strategies to actually make the desired diverse sets of complex structures have proven hard to develop. Thus, there is a clear need for the discovery and development of clean, atom- and step-efficient one-pot syntheses for sustainable production of molecularly diverse and structurally complex organic molecules with high added values. In fact, synthetic strategies are required that can enable the “ideal synthesis” (Fig- ure 2.1) leading to the desired product from readily available starting materials in a limited number of reaction steps and in good overall yield [1]. For the production of fine chemicals, the waste/product ratio ranges between 5 and 50; for pharmaceuticals, this ratio may even be as high as 100. To ensure the high standards set by the high-tech twenty-first century society and deliver, for example, food, medicines, or materials wherever and whenever they are

readily available starting materials safe simple

resource Ideal 100% effective Synthesis yield

total one pot conversion environmentally friendly

Figure 2.1 The ideal synthesis as described by Wender and Miller [1b].

needed, we need ways to effectively design and make molecules and produce the materials made from them. Multicomponent reactions (MCRs) are increasingly appreciated as efficient synthesis tools to rapidly access complex products [2]. With MCRs, molecules can be assembled from three or more starting materials in a one-pot process. MCRs involve the inherent formation of several bonds in a single operation, without isolating the intermediates, changing the reaction conditions, and often without adding further reagents. Therefore, MCRs address sustainability by atom, step, and thus eco-efficiency, reducing the number of intermediate steps and functional group manipulations and avoiding protective group strategies. Syntheses involving MCRs save time and energy (step efficiency) and proceed with high convergence (process efficiency). In addition, MCRs are ideally suited for combinatorial chemistry and library design, and are of great utility in medicinal chemistry, materials science, recognition (host–guest) chemistry, and catalyst design. Especially, MCRs are believed to be crucial in exploiting the full potential of “diversity-oriented synthesis” (DOS) and “biology-oriented synthesis” (BIOS) design strategies for effective and functional library synthesis uncovering virgin areas of biologically relevant chemical space [3].

2.2 The Concept

The general concept of MCRs is depicted in Scheme 2.1. Many new MCRs have been discovered in the past decade, ranging from rather straightforward novel 3CRs to a highly complex 8CR in which as much as nine covalent bonds are 2.3 The Reaction Design Concept 15

FG1

+ FG2 FG3

Scheme 2.1 The general concept of MCRs. formed (with 11 potential diversity points) in a highly effective single-pot process [4]. The most obvious application of MCRs in the pharmaceutical industry is the lead discovery and optimization stage [5]. However, MCRs also show great potential for the realization of green production processes of active pharmaceutical ingredients [6], for the production of materials, for catalyst development, and so on. In this chapter, we will describe ways to discover new MCRs. First, a couple of design strategies are discussed, after that we will touch on some recent develop- ments including application of biocatalysis and green chemistry principles. In the remainder of this book, many examples of exciting new MCR chemistry will be presented; therefore, in this chapter the concepts are not covered comprehen- sively but rather by illustrative examples.

2.3 The Reaction Design Concept

Most MCR-based methods developed during the past decade are targeted and tailored for combinatorial chemistry purposes, which indeed focus on a certain required substituent diversity in the frame of a fixed molecular scaffold. In addition to substituent diversity, scaffold diversity, structural complexity, and stereo- chemical diversity are important for the design and construction of compounds aiming to find new chemical entities with desirable biological, material, or catalyst properties (Figure 2.2). MCRs as complexity-generating one-pot reactions are ideal synthetic tools to generate multiple advanced molecular scaffolds in an atom- and step-efficient manner. Next to molecular complexity, MCRs can be applied to increase especially structural or skeletal diversity and have high relevance within the concept of DOS/BIOS as scaffold diversity is indeed one of the major hurdles to over- come. Some recent reviews discuss various strategies for finding new MCRs [7]. These ideas for the rational design of novel MCRs are conceptually summarized in Figure 2.3 and discussed below in more detail. The single reactant replacement strategy (SRR, Figure 2.3a) allows development of new MCRs by systematic assessment of the mechanistic or functional role of each component in a known MCR. In this method, one reactant (A) is

2.3 The Reaction Design Concept 17 replaced with a different reactant (D) that mimics the key chemical reactivity or property necessary for condensation to occur with B and C. By embedding additional reactivity or functionality into D, the resulting MCR might be directed to a different outcome, for example, either a new structural frame- work or ring system. The modular reaction sequences (MRS, Figure 2.3b) strategy is closely related to SRR, but involves a versatile reactive intermediate that is generated from A, B, and C by an initial MCR. This is then reacted in situ with a range of ﬁnal differentiating components (D, E, and F). Condition-based divergence (CBD) in MCRs (Figure 2.3c) generates multiple molecular scaffolds from the same starting materials by merely applying different conditions. For example, depending on the catalyst, solvent, or heating mode (microwave versus conventional) that is used, a set of inputs A, B, and C may react via different pathways to produce distinct scaffolds. The union of MCRs (Figure 2.3d) is a fourth strategy for the rational design of novel MCRs that combines two (or more) different types of MCRs in a one-pot process. The presence of orthogonal reactive groups in the product of the primary MCR, which is either formed during the primary MCR or present in one of the inputs, allows the union with the secondary MCR. These four rational design concepts are illustrated below with a couple of examples to give you a feel of how to approach discovery of new MCRs and higher order MCRs in order to address process efﬁciency and molecular diversity and complexity.

2.3.1 Single Reactant Replacement

The phrase single reactant replacement (Figure 2.3a) was ﬁrst coined by Ganem [6] and involves the development of new MCRs by systematic assessment of the mechanistic or functional role of each component in a known MCR. Probably, one of the ﬁrstexamplesofSRRwasreportedbyUgi,who replaced the carbonyl component used in the Passerini-3CR [8,9] by an imine, resulting in the well-known Ugi reaction [10–12].ThemechanismoftheUgi reaction is generally believed to involveprotonationoftheiminebyaweak acid (e.g., a carboxylic acid) followed by nucleophilic addition of the isocyanide to the iminium ion. The resulting nitrilium ion is subsequently attacked by the conjugate base of the weak acid (e.g., a carboxylate), which only needs to be weakly nucleophilic. Thus, the carboxylic acid in the classical Ugi reaction may be replaced by a host of weak inorganic acids. For example, HOCN and HSCN could be used to afford (thio)hydantoinimides, respectively. These are formed from the corresponding α-adducts by cyclization of the intermediate β-amino iso(thio)cyanates. The use of HN3 resulted in the formation of tetrazoles by spontaneous cyclization of the α-adduct. When water or hydrogen selenide is used, the corresponding α-adducts undergo tautomeriza- tion to afford amides and selenoamides, respectively.

2.3 The Reaction Design Concept 19

In a related approach, Xia and Ganem changed the carboxylic acid in the Pass- erini reaction to a Lewis acid (TMSOTf) to activate the carbonyl component [13]. Reaction of several aldehydes and ketones, morpholinoethyl isocyanide 1,and

Zn(OTf)2/TMSCl (forming TMSOTf in situ) resulted in the formation of α-hydroxyamides 2 (Scheme 2.2). A neighboring stabilizing group (such as the morpholine ring in this example) was shown to be required to stabilize the intermediate nitrilium ion 3, since the use of simple isocyanides did not afford products 2 [13]. The involvement of cyclic intermediate 4 suggested that cyclic products may be generated when a nucleophile (e.g., a carbonyl oxygen) is present in the isocyanide component. Indeed, the use of isocyano esters or amides (5) led to the formation of ethoxy- and morpholino-oxazoles 6 [13]. Further SRR could be achieved by replacing the aldehyde or ketone for an imine (cf. Passerini → Ugi reaction), which resulted in the formation of bis- amino oxazoles 7 (by Brønsted acid catalysis) [13,14]. Finally, our research group serendipitously discovered the formation of N-(cyanomethyl)amides 8 when primary α-isocyano amides 9 were used as inputs (Scheme 2.2, SRR4) [15].

2.3.2 Modular Reaction Sequences

A second strategy for the discovery of novel MCRs involves modular reaction sequences (Figure 2.3b). This approach is related to SRR, but involves a versatile reactive intermediate that is generated from substrates A, B, and C by an initial MCR. This reactive intermediate is then reacted in situ with a range of final differentiating components (D, E, and F) yielding a diverse set of scaffolds. An illustrative approach that uses modular reaction sequences was reported by Zhu and coworkers. They combined the 5-amino oxazole (10)MCRwithpri- mary amines with a subsequent N-acylation using α,β-unsaturated acid chlo- rides 11 (fourth component) to afford polysubstituted pyrrolopyridinones 13 (Scheme 2.3) [14,16]. After acylation and heating, the formation of 13 can be explained by an intramolecular Diels–Alder reaction affording the bridged tri- cyclic intermediate 12. Subsequent base-catalyzed retro-Michael cyclorever- sion, with loss of morpholine and aromatization, gives 13. A variation of this reaction involving the same intermediate oxazole MCR product 10 uses activated alkynoic acids 14 as the fourth component [17]. The resulting intermediate undergoes an intramolecular Diels–Alder reaction followed by a retro-Diels–Alder reaction with loss of a nitrile to furnish dihydrofur- opyrrolones 15. The furan moiety in this product is a diene that can react with a fifth component (a dienophile) in a second Diels–Alder reaction to give hexasub- stituted benzenes 16 after loss of water. Since all reactions occur in one pot, this MCR has evolved from a three- to a five-component reaction by applying a very elegant modular reaction sequence. This approach has resulted in three different highly functionalized scaffolds originating from a single 3CR. In summary, modular reaction sequences have proven to be extremely useful for the rapid generation of scaffold diversity. This strategy can be regarded as a