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Arynes hold immense potential as reactive intermediates in organic synthesis as they engage in a diverse range of mechanistically distinct chemical reactions. However, the poor functional group compatibility of generating arynes or their precursors has stymied their widespread use. Here, we show that generating arynes by deprotonation of an arene and elimination of an “onium” leaving group is mild, efficient and broad in scope. This is achieved by using aryl(TMP)iodonium salts (TMP = 2,4,6-trimethoxyphenyl) as the aryne precursor and potassium phosphate as the base, and a range of arynophiles are compatible. Additionally, we have performed the first quantitative analysis of functional group compatibility for several methods to generate arynes, including the method developed here and the current state of the art. Finally, we show that a range of “sensitive” functional groups such as Lewis and Brønsted acids and electrophiles are compatible under our conditions. 

Abstract Herein, the synthesis of 1,2,3,4‐tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described.^[1]In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4‐tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post‐synthetic elaboration via palladium‐catalyzed coupling. This concise strategy is predicated on two regioselective events: 1) ortho‐ deprotonation of aryl(Mes)iodonium salts to generate a substituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reported reaction conditions to generate arynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.