Small Heterocycles in Multicomponent Reactions Benjamin H. Rotstein, †,‡ Serge Zaretsky, † Vishal Rai, †,§ and Andrei K. Yudin* ,† † Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario Canada, M5S 3H6 ‡ Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States § Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, Indore By-pass Road, Bhauri, Bhopal 462 066, MP India CONTENTS 1. Introduction 8323 2. Multicomponent Reactions with Heterocyclic Substrates 8324 2.1. Passerini Reactions 8324 2.2. Ugi Reactions 8325 2.3. Intercepted Ugi Reactions 8326 2.4. Epoxide Ring Openings 8328 2.5. Oxetane Openings 8331 2.6. Anion-Relay Chemistry 8333 2.7. Metal-Catalyzed Carbonylations 8334 2.8. Reactions Involving Benzyne Intermediates 8337 2.9. Azide-Alkyne Cycloadditions 8339 2.10. Other Cycloadditions 8340 2.11. Condensations 8341 2.12. Stereoinduction by Small Rings 8341 3. Multicomponent Reactions Producing Hetero- cycles 8343 3.1. Reactions of Isocyanides with Oxo Com- pounds 8343 3.2. Ugi Reactions 8345 3.3. Condensations 8348 3.4. Addition-Elimination Reactions 8348 3.5. Reactions of Diazo Compounds 8349 3.6. Reactions Involving Benzyne Intermediates 8351 3.7. Azide-Alkyne Couplings 8353 3.8. Other Cycloadditions 8354 4. Conclusions 8355 Author Information 8355 Corresponding Author 8355 Notes 8355 Biographies 8355 Acknowledgments 8356 Abbreviations Used 8356 References 8356 1. INTRODUCTION Small-ring heterocycles have found many applications both as useful starting materials in the synthesis of more elaborate structures and as valuable targets of synthesis. Our review summarizes progress made in multicomponent reactions (MCRs) that either produce small heterocycles or employ them as starting materials. For the purposes of this paper, we have considered heterocycles consisting of three and four atoms as “small”. By definition, MCRs simultaneously engage three or more components, resulting in products that incorporate the elements of all starting materials in their frameworks. This integrative nature of MCRs is attractive when a rapid increase in molecular diversity is desired. Using a combinatorial approach, sets of components (such as amines, carboxylic acids, alcohols, etc.) can be systematically distributed in arrays of reactions to generate iterations on a common MCR-product scaffold. Given the central role of strained rings in synthesis, we felt compelled to evaluate their involvement in MCRs. The most well recognized function of small heterocycles is their propensity to undergo ring-opening reactions by cleavage of a carbon-heteroatom bond and formation of a new bond with an incoming nucleophile. This process can lead to subsequent bond formation, whereby a small heterocycle effectively links two other reactants that may not otherwise react with one another. The analogous process leading to small-ring formation operating on the same principles is also true in MCRs. By building up an electrophilic center at a selected atom, an appropriately placed heteroatom may be compelled into ring formation by carbon-heteroatom bond formation. In the section titled “Multicomponent Reactions with Heterocyclic Substrates”, the reader will find a discussion of examples of MCRs in which a reactant features a small heterocycle. In most of these cases, a heterocycle is engaged as an electrophile and undergoes ring opening or ring expansion. In other cases, the heterocycle survives the transformation and acts as nucleophile or a directing group for nearby stereo- selective MCRs. The many ways in which small rings are deployed in synthesis and MCRs is illustrative of their versatility. On one hand, small ring heterocycles can provide new ways of designing the thermodynamic driving forces of Special Issue: 2014 Small Heterocycles in Synthesis Received: October 29, 2013 Published: July 17, 2014 Review pubs.acs.org/CR © 2014 American Chemical Society 8323 dx.doi.org/10.1021/cr400615v | Chem. Rev. 2014, 114, 8323-8359