Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(mes)iodonium Salts.
National Science Foundation. Grant Numbers: 1828573, 0604188 Division of Chemistry. Grant Number: 1352663
Herein, we describe the synthesis of 1,2,3,4-tetra-substituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products. In the past, the regioselective syntheses of such compounds have been a significant challenge. We now report 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, we show 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. We have improved upon our previous 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 functional groups on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryne precursors.
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Nilova, A., Sibbald, P. A., Valente, E. J., González‐Montiel, G. A., Richardson, H. C., Brown, K. S., Cheong, P. H. Y., & Stuart, D. R. (2021). Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**. Chemistry – A European Journal, chem.202100201. https://doi.org/10.1002/chem.202100201