Milder Benzyne Click Chemistry

With a safer, easier way of obtaining a reactive intermediate from an aromatic system, Richard C. Larock and colleagues at Iowa State University have improved the versatility of click chemistry, a ring-forming reaction that is already used in diverse areas from materials science to chemical biology (Org. Lett., DOI: 10.1021/ol800675u). The term "click chemistry" usually refers to the copper-catalyzed ring-forming reaction between azides and alkynes. This reaction efficiently snaps these groups together into five-membered rings called triazoles. Despite its appeal as an alkynelike building block, the reactive intermediate benzyne has not previously been useful in this reaction. Although benzyne readily reacts with azides, the potentially explosive conditions once required to generate the molecule had made it difficult to use in click reactions. Larock's team, however, employed fluoride ions, now commonly used to make benzynes, under mild conditions previously established in their group. This method of benzyne generation and subsequent click-based cyclization worked with a variety of functional groups (one example shown). The overall process yields benzotriazoles, aromatic motifs which can be found in antimicrobial agents.