Multicomponent Reactions in the Synthesis of Biologically Active Heterocycles: A Comprehensive Review

Abstract

Multicomponent reactions (MCRs) have become an indispensable instrument in modern synthetic chemistry, mainly because they allow several covalent bonds, and a non-trivial amount of molecular complexity, to be assembled within a single operation. Heterocyclic compounds, which underpin the structural skeleton of roughly two thirds of the small-molecule drugs in clinical use, are particularly well served by such transformations. The aim of this review is to gather, from a wide pool of literature, the most important MCR-based approaches that lead to biologically active nitrogen-, oxygen- and sulfur-containing heterocycles. We start with a short historical and mechanistic background of the classical “named” multicomponent reactions – Strecker, Hantzsch, Biginelli, Passerini and Ugi – and then move to the rapidly expanding catalytic and green variants developed during the last two decades. The discussion is organised around the heterocyclic core that is produced (dihydropyrimidinones, 1,4-dihydropyridines, imidazoles, pyrroles, quinolines, pyrazoles, indoles, thiazolidinones and 4Hchromenes), and, in each case, we connect the synthetic route to its principal pharmacological context: anticancer, antimicrobial, antimalarial, anti-inflammatory and cardiovascular activity. Particular attention is given to recent strategies that employ water, deep eutectic solvents, magnetic nanocatalysts, microwave irradiation and ultrasonic activation. Five figures and one summary table illustrate the discussion. The review closes with a critical comment on current challenges, including the still-modest diastereoselectivity of many three-component routes, scope limitations of certain reagent combinations, and the unavoidable trade-off between sustainability and process robustness.