Six-Component Reactions and Beyond: The Nuts and Bolts

The deployment of multicomponent reactions (MCRs), defined as containing three or more reactants, not only enjoys pot, atom, and step-economy in the synthesis of novel complex molecules but also aligns with sustainable chemistry principles as a green symphony. Generally, more components lead to more complexity, and are taken to an extreme ‘‘higher-order’’ MCRs, where six or even more components react in a one-pot, have been developed, although they remain scarce compared to their 3, 4 and 5-component relatives. On this topic, the rich footprint of isocyanides in MCRs has been fruitful in delivering higher order six to eight-component reactions through mechanistically similar pathways. The present review encompasses a brief history of MCRs and their product utility, followed by a thorough discussion of the principles of reaction design that enabled the discovery of higher-order MCRs, spanning 6 to 8-components. Future challenges and opportunities will also be elaborated.