Click Chemistry beyond Metal‐Catalyzed Cycloaddition

TLDR

Metal‑free click reactions such as thiol‑ene radical additions, Diels–Alder, and Michael additions have emerged as alternatives to the copper(I)-catalyzed azide‑alkyne cycloaddition, offering simple procedures and high yields and expanding the scope of click chemistry beyond the original copper‑mediated reaction. This minireview evaluates the advantages and limitations of metal‑free click reactions to determine whether they can surpass the success of copper(I)-catalyzed azide‑alkyne cycloaddition and discusses their applicability. Metal‑free click reactions are physiologically compatible, yield high efficiency, and enable synthesis of small molecules, macromolecules, and bioconjugates, thereby broadening the opportunities for chemical synthesis.

Abstract

Abstract No copper needed : In recent years, a large number of metal‐free click reactions have been reported based on thiol‐ene radical additions, Diels–Alder reactions, and Michael additions. In this Minireview, special attention is given to the advantages and limitations of the different methods to evaluate whether they have the potential to surpass the overwhelming success of the copper(I)‐catalyzed azide‐alkyne cycloaddition. magnified image The overwhelming success of click chemistry encouraged researchers to develop alternative “spring‐loaded” chemical reactions for use in different fields of chemistry. Initially, the copper(I)‐catalyzed azide‐alkyne cycloaddition was the only click reaction. In recent years, metal‐free [3+2] cycloaddition reactions, Diels–Alder reactions, and thiol‐alkene radical addition reactions have come to the fore as click reactions because of their simple synthetic procedures and high yields. Furthermore, these metal‐free reactions have wide applicability and are physiologically compatible. These and other alternative click reactions expand the opportunities for synthesizing small organic compounds as well as tailor‐made macromolecules and bioconjugates. This Minireview discusses the success and applicability of new, in particular metal‐free, click reactions.