Mariateresa Giustiniano is an associate professor at the University of Naples Federico II in Italy. She has co-authored over 60 peer-reviewed publications and four book chapters, with research interests spanning multicomponent reactions, visible-light photocatalysis, and their application in medicinal chemistry for discovering new anticancer agents.

• Contents Volume 1Preface xi1 Multicomponent Reactions for a Sustainable Organic Synthesis 1Elena Cassera, Davide Ravelli, Mariateresa Giustiniano, and Maurizio Fagnoni1.1 Introduction 11.2 Passerini Reaction 41.3 Ugi Reaction 91.4 Ugi–Joullié Reaction 151.5 Greenness of MCRs in Drug Preparation 211.6 Conclusion and Outlook 242 Light-triggered Multicomponent Reactions 33Lorenzo Di Terlizzi and Stefano Protti2.1 Introduction 332.2 Photoredox Catalyzed MCRs 342.3 MCRs via Direct (d-HAT) or Indirect (i-HAT) Hydrogen Atom Transfer 402.4 MCRs via Halogen Atom Transfer 422.5 MCRs via Energy Transfer 452.6 Photochemical MCRs 462.7 Conclusions 503 Multicomponent Electrochemical Strategies for Modern Organic Synthesis 55Rajesh Kumar, Vinay Thatikonda, and Upendra K. Sharma3.1 Introduction 553.2 Electrochemical Alkene Dicarbofunctionalization 563.3 Multicomponent Electrochemical Alkene Hetero-Difunctionalization 583.4 Four-component Electrochemical Alkene Difunctionalization 633.5 Multicomponent Electrochemical Synthesis of Five-membered N-Heterocycles 653.6 Gases as Renewable Feedstocks in Electrocatalysis 693.7 Conclusion 754 Mechanochemical Multicomponent Reactions 79Francesco Basoccu, Dipak J. Fartade, and Andrea Porcheddu4.1 Introduction 794.2 Classical Mechanochemical MCRs 804.3 Pseudo-MCRs 954.4 Miscellaneous 1034.5 Limitations and Challenges 1104.6 Future Perspective 1104.7 Conclusion 1115 The Use of Microwave-assisted Multicomponent Reactions for the Synthesis of Heterocycles Containing Isatin or Organophosphorus Moiety 119Dániel Steinsits and Erika Bálint5.1 Introduction 1195.2 Microwave-assisted Multicomponent Reactions of Isatins 1215.3 Synthesis of Heterocycles Containing Organophosphorus Moiety 1305.4 Summary and Conclusions 1356 Biocatalytic Multicomponent Reactions 141Camilla Russo, Flora Antoniou, and Daniele Castagnolo6.1 Introduction 1416.2 "True" Biocatalytic Multicomponent Reactions 1436.3 Combined Biocatalytic Multicomponent Approaches 1616.4 Summary and Conclusions 1727 Isocyanide-based Multicomponent Reactions in Aqueous Media 185]Mohammad Taghi Nazeri, Tahereh Nasiriani, Nuhaa Shaheed, and Ahmad Shaabani7.1 Introduction 1857.2 Synthesizing Cyclic Compounds 1877.3 Synthesizing Acyclic Compounds 2167.4 Challenges and Future Perspective in Water-based Media 2307.5 Conclusion 2318 Non-Isocyanide-based Multicomponent Reactions in Aqueous Media 243Mohammad Taghi Nazeri, Tahereh Nasiriani, Nuhaa Shaheed, and Ahmad Shaabani8.1 Introduction 2438.2 Synthesizing Cyclic Compounds 2458.3 Synthesizing Acyclic Compounds 2678.4 Future Directions: Integrating Emerging Technologies 2858.5 Conclusion 2879 The Use of Nonconventional Solvents in Multicomponent Reactions 301Yavar Ahmadi and Ali Ramazani9.1 Introduction 3019.2 Properties and Structure of Deep Eutectic Solvents 3059.3 Multicomponent Reactions 3079.4 DES in Multicomponent Reactions 3089.5 Perspectives and Conclusions 31710 Nanoreactors Technology in Multicomponent Reactions 325Seyedmohammad Hosseininezhad, Melika Seydi, and Ali Ramazani10.1 Introduction 32510.2 Overview of MCRs 32610.3 Overview of Nanoreactors 33310.4 Applications of Nanoreactors in Key MCRs 33610.5 Conclusion 36410.6 Future Perspectives and Emerging Trends 36511 Multicomponent Reactions in Automated Synthetic Chemistry 375Imma Capriello and Alexander Dömling11.1 Why Automation? 37511.2 Why Miniaturization? 37911.3 Integrating Platforms 38511.4 The Future of Automated and Miniaturized Organic Synthesis 398Contents Volume 2Preface xi12 Scale-up and Automation of Multicomponent Reactions via Continuous Flow 405Johannes Bingold, Andreas Brunschweiger, and Norbert Kockmann12.1 Introduction, Motivation, and Overview 40512.2 Flow Reactions and Reactor Systems 40612.3 Exemplary Multicomponent Reactions Performed in Flow 41312.4 Scale-up Conditions for MCR Flow Chemistry 42112.5 Scale-up Examples in API Synthesis 42512.6 Summary and Conclusions 42613 Investigating Multicomponent Reactions Mechanisms 435Brenno A. D. Neto, Giovanni W. Amarante, and Alexandre A. M. Lapis13.1 Introduction 43513.2 Terminology Definitions 43713.3 The Reaction Pathway Control 43813.4 Mass Spectrometry—The Key Analysis to Understand MCRs 43913.5 Examples of Pioneering Works 44013.6 Examples of Mechanistic Studies of Well-established MCRs 44413.7 Selected Examples 44813.8 Outlook 45014 Reactive Intermediates in Isocyanide-based Multicomponent Reactions 457Ana G. Neo and Carlos F. Marcos14.1 Introduction 45714.2 Primary Adducts 45814.3 Other Intermediates 47314.4 Summary and Conclusions 48015 Heterocycle-based Multicomponent Reactions 489Pau Nadal-Rodríguez, Ouldouz Ghashghaei, and Rodolfo Lavilla15.1 Introduction and Scope 48915.2 Conceptual Approaches 49015.3 Polar MCRs 49215.4 Radical MCRs 49415.5 Metal-catalyzed MCRs 49715.6 Concerted MCRs 50015.7 Applications 50115.8 Summary and Outlook 50316 Multicomponent Synthesis of Functional Chromophores 513Larissa Brandner and Thomas J. J. Müller16.1 Functional Chromophores 51316.2 Scaffold and Chromophore Approach 51416.3 MCR to Functional Chromophores Based on Carbonyl Compounds 51516.4 MCR to Functional Chromophores Based on Isonitriles 52416.5 MCR to Functional Chromophores Based on Cycloadditions 52916.6 MCR to Functional Chromophores Based on Radical Reactions 53116.7 MCR to Functional Chromophores Based on Metal-mediated and Metal-catalyzed Reactions 53216.8 Conclusion and Outlook 53617 Atropisomers and Molecular Balances via Multicomponent Reactions 543Michael Fragkiadakis, Michael Kapsalis, and Constantinos Neochoritis17.1 Introduction 54317.2 Atropisomerism via Axis Generation 54617.3 Atropisomerism via Rigid Molecular Frameworks 55417.4 Atropisomerism via Specific Non-covalent Interactions 556viii Contents Volume 217.5 Summary and Conclusions 56118 Multicomponent Synthesis of Organoselenium Compounds 565Paola S. Hellwig, Thiago A. Ribeiro, Mateus W. Rambo, Kethelyn M. Rosa, Nicole M. N. Washio, Ricardo F. Schumacher, Eder J. Lenardão, and Filipe Penteado18.1 Introduction 56518.2 Use of Diorganyl Diselenides as a Selenium Source 56618.3 Use of Elemental Selenium as a Selenium Source 58418.4 Reactions Using Other Selenium Sources 60018.5 Conclusion 60419 Multicomponent Reactions in Isotope Labeling 613Kevin Schofield, Aidan McMahon, Vishal Kaleeswaran, Sean Ginn, and Christopher Hulme19.1 An Introduction to Radiotracers 61319.2 Radiotracers and MCRs 61519.3 Deuterium in Drug Discovery 62220 Harnessing Multicomponent Reactions for the Functionalization of Drugs and Bioactive Natural Products via Innate Reactivity 637Hélène Beucher and Tatiana Besset20.1 Introduction 63720.2 Multicomponent Reactions Involving Small Drugs and Bioactive Natural Compounds 63820.3 Application to the Functionalization of Peptides, Proteins, and DNA 64220.4 Conclusion 65221 Multicomponent Reactions for the Synthesis of Protein Degraders 659Laura Gioiello, Tracey Pirali, and Rita Maria Concetta Di Martino21.1 Introduction on Induced Protein Degradation 65921.2 MCRs in the Synthesis of Degraders 67121.3 Summary and Conclusions 68322 Synthesis of Natural Compounds via Multicomponent Reactions 689Ana Barbero-Moreno, Miriam Ruiz, and J. Carlos Menéndez22.1 Introduction 68922.2 Imine-initiated MCRs 68922.3 Isonitrile-based MCRs 69622.4 Cycloaddition-based Multicomponent Reactions 70222.5 Combination of Multicomponent Reactions 70422.6 Conclusions 70623 Multicomponent Reactions in the Total Synthesis of Biologically Active Natural Products – Part I: Reactions Based on the Use of Isocyanides, Transition Metal Catalysis, and Tandem Conjugate Addition/Electrophilic Enolate Trapping on α,β-Unsaturated Carbonyls 711Enrique L. Larghi, Andrea B. J. Bracca, Sebastián O. Simonetti, and Teodoro S. Kaufman23.1 Introduction 71123.2 MCRs Based on the Use of Isocyanides 71123.3 Tandem Conjugate Addition/Electrophilic Enolate Trapping on α,β-Unsaturated Carbonyl Compounds 72023.4 MCRs Centered on Transition Metal Catalysis 72523.5 Conclusions and Perspective 73024 Multicomponent Reactions in the Total Synthesis of Biologically Active Natural Products – Part II: MCRs Initiated by Nucleophilic Addition to Carbonyl Compounds, Mannich and Related Reactions, Anion Relay Chemistry, [4+2]-Cycloadditions and Other Transformations 741Enrique L. Larghi, Andrea B. J. Bracca, Sebastián O. Simonetti, and Teodoro S. Kaufman24.1 Introduction 74124.2 MCRs Initiated by a Nucleophilic Addition to Carbonyl Compounds 74224.3 Three-component Mannich and Related Reactions 74624.4 MCRs Initiated by a Nucleophilic Addition to Epoxides 75324.5 MCRs Involving [4+2]-Cycloadditions 75624.6 Miscellaneous MCRs 75824.7 Conclusions and Perspective 76025 Multicomponent Reactions in Polymer Chemistry 767Siamak Javanbakht, Reza Mohammadi, and Ahmad Shaabani25.1 Introduction 76725.2 MCRs in Polymer Synthesis 76825.3 Innovations and Applications of MCRs in Polymer Chemistry 77125.4 Functionalization of Natural and Renewable Polymers 77425.5 Sustainability and Green Chemistry in Multicomponent Polymer Synthesis 77525.6 Summary and Future Outlook 77826 Multicomponent Derivatization for Advanced Gas and Liquid Chromatographic Methods 785Serban C. Moldoveanu and Victor David26.1 Role of Derivatization in Chromatographic Analysis 78526.2 Molecularity, Number of Components, and Reaction Rate Order in a Derivatization Reaction 78826.3 Alkylation and Arylation Reactions Used for Derivatization 79326.4 Silylation Reactions Used for Derivatization 79526.5 Acylation and Other Similar Reactions Used for Derivatization 79626.6 Derivatizations by Addition to Carbon-Heteroatom Multiple Bonds 80026.7 Derivatizations with Formation of Cyclic Compounds 80226.8 Other Derivatization Types Used in Chemical Analysis 80426.9 Conclusions and Future Perspectives 80527 Multicomponent Reactions in Chemical Education 809Cristina Martini and Andrea Basso27.1 Introduction 80927.2 MCRs for the Synthesis of Biologically Relevant Compounds 81027.3 Catalyzed MCRs 81227.4 MCRs for the Generation of Molecular Complexity 81727.5 Miscellaneous 81927.6 Summary and Conclusions 826References 827Index 831

Mariateresa Giustiniano is an associate professor at the University of Naples Federico II in Italy. She has co-authored over 60 peer-reviewed publications and four book chapters, with research interests spanning multicomponent reactions, visible-light photocatalysis, and their application in medicinal chemistry for discovering new anticancer agents.

• Contents Volume 1Preface xi1 Multicomponent Reactions for a Sustainable Organic Synthesis 1Elena Cassera, Davide Ravelli, Mariateresa Giustiniano, and Maurizio Fagnoni1.1 Introduction 11.2 Passerini Reaction 41.3 Ugi Reaction 91.4 Ugi–Joullié Reaction 151.5 Greenness of MCRs in Drug Preparation 211.6 Conclusion and Outlook 242 Light-triggered Multicomponent Reactions 33Lorenzo Di Terlizzi and Stefano Protti2.1 Introduction 332.2 Photoredox Catalyzed MCRs 342.3 MCRs via Direct (d-HAT) or Indirect (i-HAT) Hydrogen Atom Transfer 402.4 MCRs via Halogen Atom Transfer 422.5 MCRs via Energy Transfer 452.6 Photochemical MCRs 462.7 Conclusions 503 Multicomponent Electrochemical Strategies for Modern Organic Synthesis 55Rajesh Kumar, Vinay Thatikonda, and Upendra K. Sharma3.1 Introduction 553.2 Electrochemical Alkene Dicarbofunctionalization 563.3 Multicomponent Electrochemical Alkene Hetero-Difunctionalization 583.4 Four-component Electrochemical Alkene Difunctionalization 633.5 Multicomponent Electrochemical Synthesis of Five-membered N-Heterocycles 653.6 Gases as Renewable Feedstocks in Electrocatalysis 693.7 Conclusion 754 Mechanochemical Multicomponent Reactions 79Francesco Basoccu, Dipak J. Fartade, and Andrea Porcheddu4.1 Introduction 794.2 Classical Mechanochemical MCRs 804.3 Pseudo-MCRs 954.4 Miscellaneous 1034.5 Limitations and Challenges 1104.6 Future Perspective 1104.7 Conclusion 1115 The Use of Microwave-assisted Multicomponent Reactions for the Synthesis of Heterocycles Containing Isatin or Organophosphorus Moiety 119Dániel Steinsits and Erika Bálint5.1 Introduction 1195.2 Microwave-assisted Multicomponent Reactions of Isatins 1215.3 Synthesis of Heterocycles Containing Organophosphorus Moiety 1305.4 Summary and Conclusions 1356 Biocatalytic Multicomponent Reactions 141Camilla Russo, Flora Antoniou, and Daniele Castagnolo6.1 Introduction 1416.2 "True" Biocatalytic Multicomponent Reactions 1436.3 Combined Biocatalytic Multicomponent Approaches 1616.4 Summary and Conclusions 1727 Isocyanide-based Multicomponent Reactions in Aqueous Media 185]Mohammad Taghi Nazeri, Tahereh Nasiriani, Nuhaa Shaheed, and Ahmad Shaabani7.1 Introduction 1857.2 Synthesizing Cyclic Compounds 1877.3 Synthesizing Acyclic Compounds 2167.4 Challenges and Future Perspective in Water-based Media 2307.5 Conclusion 2318 Non-Isocyanide-based Multicomponent Reactions in Aqueous Media 243Mohammad Taghi Nazeri, Tahereh Nasiriani, Nuhaa Shaheed, and Ahmad Shaabani8.1 Introduction 2438.2 Synthesizing Cyclic Compounds 2458.3 Synthesizing Acyclic Compounds 2678.4 Future Directions: Integrating Emerging Technologies 2858.5 Conclusion 2879 The Use of Nonconventional Solvents in Multicomponent Reactions 301Yavar Ahmadi and Ali Ramazani9.1 Introduction 3019.2 Properties and Structure of Deep Eutectic Solvents 3059.3 Multicomponent Reactions 3079.4 DES in Multicomponent Reactions 3089.5 Perspectives and Conclusions 31710 Nanoreactors Technology in Multicomponent Reactions 325Seyedmohammad Hosseininezhad, Melika Seydi, and Ali Ramazani10.1 Introduction 32510.2 Overview of MCRs 32610.3 Overview of Nanoreactors 33310.4 Applications of Nanoreactors in Key MCRs 33610.5 Conclusion 36410.6 Future Perspectives and Emerging Trends 36511 Multicomponent Reactions in Automated Synthetic Chemistry 375Imma Capriello and Alexander Dömling11.1 Why Automation? 37511.2 Why Miniaturization? 37911.3 Integrating Platforms 38511.4 The Future of Automated and Miniaturized Organic Synthesis 398Contents Volume 2Preface xi12 Scale-up and Automation of Multicomponent Reactions via Continuous Flow 405Johannes Bingold, Andreas Brunschweiger, and Norbert Kockmann12.1 Introduction, Motivation, and Overview 40512.2 Flow Reactions and Reactor Systems 40612.3 Exemplary Multicomponent Reactions Performed in Flow 41312.4 Scale-up Conditions for MCR Flow Chemistry 42112.5 Scale-up Examples in API Synthesis 42512.6 Summary and Conclusions 42613 Investigating Multicomponent Reactions Mechanisms 435Brenno A. D. Neto, Giovanni W. Amarante, and Alexandre A. M. Lapis13.1 Introduction 43513.2 Terminology Definitions 43713.3 The Reaction Pathway Control 43813.4 Mass Spectrometry—The Key Analysis to Understand MCRs 43913.5 Examples of Pioneering Works 44013.6 Examples of Mechanistic Studies of Well-established MCRs 44413.7 Selected Examples 44813.8 Outlook 45014 Reactive Intermediates in Isocyanide-based Multicomponent Reactions 457Ana G. Neo and Carlos F. Marcos14.1 Introduction 45714.2 Primary Adducts 45814.3 Other Intermediates 47314.4 Summary and Conclusions 48015 Heterocycle-based Multicomponent Reactions 489Pau Nadal-Rodríguez, Ouldouz Ghashghaei, and Rodolfo Lavilla15.1 Introduction and Scope 48915.2 Conceptual Approaches 49015.3 Polar MCRs 49215.4 Radical MCRs 49415.5 Metal-catalyzed MCRs 49715.6 Concerted MCRs 50015.7 Applications 50115.8 Summary and Outlook 50316 Multicomponent Synthesis of Functional Chromophores 513Larissa Brandner and Thomas J. J. Müller16.1 Functional Chromophores 51316.2 Scaffold and Chromophore Approach 51416.3 MCR to Functional Chromophores Based on Carbonyl Compounds 51516.4 MCR to Functional Chromophores Based on Isonitriles 52416.5 MCR to Functional Chromophores Based on Cycloadditions 52916.6 MCR to Functional Chromophores Based on Radical Reactions 53116.7 MCR to Functional Chromophores Based on Metal-mediated and Metal-catalyzed Reactions 53216.8 Conclusion and Outlook 53617 Atropisomers and Molecular Balances via Multicomponent Reactions 543Michael Fragkiadakis, Michael Kapsalis, and Constantinos Neochoritis17.1 Introduction 54317.2 Atropisomerism via Axis Generation 54617.3 Atropisomerism via Rigid Molecular Frameworks 55417.4 Atropisomerism via Specific Non-covalent Interactions 556viii Contents Volume 217.5 Summary and Conclusions 56118 Multicomponent Synthesis of Organoselenium Compounds 565Paola S. Hellwig, Thiago A. Ribeiro, Mateus W. Rambo, Kethelyn M. Rosa, Nicole M. N. Washio, Ricardo F. Schumacher, Eder J. Lenardão, and Filipe Penteado18.1 Introduction 56518.2 Use of Diorganyl Diselenides as a Selenium Source 56618.3 Use of Elemental Selenium as a Selenium Source 58418.4 Reactions Using Other Selenium Sources 60018.5 Conclusion 60419 Multicomponent Reactions in Isotope Labeling 613Kevin Schofield, Aidan McMahon, Vishal Kaleeswaran, Sean Ginn, and Christopher Hulme19.1 An Introduction to Radiotracers 61319.2 Radiotracers and MCRs 61519.3 Deuterium in Drug Discovery 62220 Harnessing Multicomponent Reactions for the Functionalization of Drugs and Bioactive Natural Products via Innate Reactivity 637Hélène Beucher and Tatiana Besset20.1 Introduction 63720.2 Multicomponent Reactions Involving Small Drugs and Bioactive Natural Compounds 63820.3 Application to the Functionalization of Peptides, Proteins, and DNA 64220.4 Conclusion 65221 Multicomponent Reactions for the Synthesis of Protein Degraders 659Laura Gioiello, Tracey Pirali, and Rita Maria Concetta Di Martino21.1 Introduction on Induced Protein Degradation 65921.2 MCRs in the Synthesis of Degraders 67121.3 Summary and Conclusions 68322 Synthesis of Natural Compounds via Multicomponent Reactions 689Ana Barbero-Moreno, Miriam Ruiz, and J. Carlos Menéndez22.1 Introduction 68922.2 Imine-initiated MCRs 68922.3 Isonitrile-based MCRs 69622.4 Cycloaddition-based Multicomponent Reactions 70222.5 Combination of Multicomponent Reactions 70422.6 Conclusions 70623 Multicomponent Reactions in the Total Synthesis of Biologically Active Natural Products – Part I: Reactions Based on the Use of Isocyanides, Transition Metal Catalysis, and Tandem Conjugate Addition/Electrophilic Enolate Trapping on α,β-Unsaturated Carbonyls 711Enrique L. Larghi, Andrea B. J. Bracca, Sebastián O. Simonetti, and Teodoro S. Kaufman23.1 Introduction 71123.2 MCRs Based on the Use of Isocyanides 71123.3 Tandem Conjugate Addition/Electrophilic Enolate Trapping on α,β-Unsaturated Carbonyl Compounds 72023.4 MCRs Centered on Transition Metal Catalysis 72523.5 Conclusions and Perspective 73024 Multicomponent Reactions in the Total Synthesis of Biologically Active Natural Products – Part II: MCRs Initiated by Nucleophilic Addition to Carbonyl Compounds, Mannich and Related Reactions, Anion Relay Chemistry, [4+2]-Cycloadditions and Other Transformations 741Enrique L. Larghi, Andrea B. J. Bracca, Sebastián O. Simonetti, and Teodoro S. Kaufman24.1 Introduction 74124.2 MCRs Initiated by a Nucleophilic Addition to Carbonyl Compounds 74224.3 Three-component Mannich and Related Reactions 74624.4 MCRs Initiated by a Nucleophilic Addition to Epoxides 75324.5 MCRs Involving [4+2]-Cycloadditions 75624.6 Miscellaneous MCRs 75824.7 Conclusions and Perspective 76025 Multicomponent Reactions in Polymer Chemistry 767Siamak Javanbakht, Reza Mohammadi, and Ahmad Shaabani25.1 Introduction 76725.2 MCRs in Polymer Synthesis 76825.3 Innovations and Applications of MCRs in Polymer Chemistry 77125.4 Functionalization of Natural and Renewable Polymers 77425.5 Sustainability and Green Chemistry in Multicomponent Polymer Synthesis 77525.6 Summary and Future Outlook 77826 Multicomponent Derivatization for Advanced Gas and Liquid Chromatographic Methods 785Serban C. Moldoveanu and Victor David26.1 Role of Derivatization in Chromatographic Analysis 78526.2 Molecularity, Number of Components, and Reaction Rate Order in a Derivatization Reaction 78826.3 Alkylation and Arylation Reactions Used for Derivatization 79326.4 Silylation Reactions Used for Derivatization 79526.5 Acylation and Other Similar Reactions Used for Derivatization 79626.6 Derivatizations by Addition to Carbon-Heteroatom Multiple Bonds 80026.7 Derivatizations with Formation of Cyclic Compounds 80226.8 Other Derivatization Types Used in Chemical Analysis 80426.9 Conclusions and Future Perspectives 80527 Multicomponent Reactions in Chemical Education 809Cristina Martini and Andrea Basso27.1 Introduction 80927.2 MCRs for the Synthesis of Biologically Relevant Compounds 81027.3 Catalyzed MCRs 81227.4 MCRs for the Generation of Molecular Complexity 81727.5 Miscellaneous 81927.6 Summary and Conclusions 826References 827Index 831