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.

The Ugi reaction has been utilized as a new click reaction to synthesize middle-functional copolymers.

The synthesis of well-defined protein/peptide–polymer conjugates with interesting self-assembly behavior via single electron transfer living radical polymerization in water is described. A range of protein/peptides with different physical and chemical properties have been modified to macroinitiators and optimized polymerization conditions ensure successful polymerization from soluble, insoluble, and dispersed protein/peptide molecules or protein aggregates. This powerful strategy tolerates a range of functional monomers and mediates efficient homo or block copolymerization to generate hydrophilic polymers with controlled molecular weight (MW) and narrow MW distribution. The polymerizations from bovine insulin macroinitiators follow surface-initiated “grafting from” polymerization mechanism and may involve a series of self-assembly and disassembly processes. Synthesized insulin-polymer conjugates form spheres in water, and the self-assembly behavior could be controlled via thermal control, carbohydrate–protein interaction, and protein denaturation.

A multicomponent reaction (MCR) has been carried out on the platform of controlled radical polymerization (CRP) to construct a ‘one pot’ MCR-CRP system for the facile preparation of well-defined functional polymers. In the current work, a novel ‘one pot’ system has been built through a combination of the Kabachnik–Fields (KF) reaction and reversible addition fragmentation chain transfer (RAFT) polymerization. Compared to a traditional stepwise method and polymer post-polymerization modification, this novel ‘one pot’ system exhibited distinct advantages to much more facilely and efficiently prepared well-defined poly(aminophosphonate)s (polyAPPs). A series of unique polyAPPs have also been successfully prepared through this KF–RAFT system, suggesting this novel method is a general and versatile approach to prepare well-defined organophosphorous polymers.