Energy-Activated and Diversifiable Aryne Precursors from Carboxylic Acids

Densely substituted arene rings are ubiquitous in pharmaceuticals and agrochemicals which support human health and wellbeing. Arynes–a triple bond in a benzene ring–are an intriguing solution to the problem of generating decorated arenes. State-of-the-art aryne precursors are plagued by two issues: 1) the additives required for activation are incompatible with many desirable functional groups intrinsic to the aryne itself as well as the coupling partners which limits the scope, and 2) derivatization of the precursors requires lengthy linear sequences often using harsh conditions rendering them impractical for discovery chemists. Here, we show the design of an aryne precursor made in a single step from a commercially available carboxylic acid and then derivatized in a single SNAr step. Unprecedented aryne activation proceeds using blue light or mild heat, avoiding the use of additives. The model system for this precursor incorporates an ortho-amino group in the final stage because anilines are found in 40% of medicinal chemistry patents and are highly underrepresented in aryne methodology. These precursors have the potential to supersede existing precursors and enable broad access to this desirable synthon.