A new insight into the Biginelli reaction: the dawn of multicomponent click chemistry?

Looking at 'old' reactions from new perspectives sometimes brings new breakthroughs in current hot research areas. We therefore reinvestigated the successful multicomponent reactions (MCRs) in organic chemistry, and are pleased to find the Biginelli reaction, one of the most famous MCRs, has almost all the 'clickable' features reported in 'click chemistry'. The modules of the Biginelli reaction are easily obtained with even more functionalities and diversity, and the reaction can be carried out under mild conditions quickly, compatibly and nearly quantitatively with only water as the byproduct. In current research, the Biginelli reaction has been demonstrated as a new 'click' reaction via application in polymer chemistry and chemical biology. Through the modification of polymer chains (side or chain end groups), and the combination with living radical polymerization in a one pot strategy, functional homopolymer and copolymer have been quantitatively prepared, demonstrating the high efficiency and compatibility of the Biginelli reaction in polymer chemistry. Furthermore, we are surprised and excited to find Biginelli reaction can be used as a 'catalyst free' bioorthogonal-click reaction to anchor dyes on cell membrane, indicating its possible application in chemical biology. Thus, we address here the 'clickable' aspects of the Biginelli reaction, a MCR that is more than 120 years 'old'. We hope the new insight into the MCRs might bring some new members to the click family as a new type of click reaction: multicomponent click reaction (MCR-Click) which might have potential applications in other areas, such as materials science, polymer chemistry and chemical biology in place of traditional organic chemistry.