Ball-milling multicomponent reactions for diverse organic transformations

Over the past two decades, the search for environmentally friendly, novel, and cleaner synthetic methods has been extended. Owing to their unique reactivity, practicality, and efficiency, the ball-milling processing of solids has developed into a powerful tool for transforming, screening, and synthesizing various classes of molecules and materials within the strongly invoked green and sustainable chemistry paradigm. This green and sustainable technique has significant advantages encompassing improved yields, safety and selectivity, use of insoluble starting materials, moisture- and air-sensitivity precaution-free setup, telescoping of reactions, reduced operational reaction times, new types of reactivity, and reduced use of organic solvents. On the other hand, multicomponent reactions (MCRs) lead to the expeditious preparation of novel complex molecules, active pharmaceutical ingredients (APIs), and biologically active molecules with a low E-factor and atom economy, as well as high efficiency. They can be carried out in one-pot operations using three or more reactants. This review intends to focus on MCRs under ball-milling processing. It covers the most recent developments in the newly established area of ball-milling synthesis of MCRs. Future opportunities and challenges will also be elaborated.