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 stereoselective 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