Click Chemistry beyond Metal‐Catalyzed Cycloaddition

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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. 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.