Remote Formation of Arynes via Formal Dehydrogenation of Arenes

Arynes offer immense potential for diversification of benezenoid cores, which occur in pharmaceuticals, agrochemicals, and liquid crystals. However, accessing these high-energy intermediates requires either harsh conditions or multi-step syntheses of designer reagents, and alternative methods with simpler substrates and milder conditions remain under- developed. Here, we describe a two-step formal dehydrogenation of simple arenes to generate arynes at a remote position relative to traditionally reactive groups, i.e., halides. This approach is enabled by regioselective installation and ejection of an “onium” leaving group, and we demonstrate the compatibility of simple arenes (20 examples) and arynophiles (6 examples). The mildness of this strategy is highlighted by formal dehydrogenation of clofibrate, an active pharmaceutical ingredient, and demonstrates that arynes are viable intermediates for late-stage functionalization. Finally, we show that aryne intermediates offer opportunities for orthogonal C-H amination relative to other methods.