Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts*

Aleksandra Nilova; Paul A Sibbald; Edward J Valente; Gisela A González-Montiel; H Camille Richardson; Kevin S Brown; Paul Ha-Yeon Cheong; David R Stuart

doi:10.1002/chem.202100201

Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts*

Chemistry. 2021 Apr 26;27(24):7168-7175. doi: 10.1002/chem.202100201. Epub 2021 Mar 16.

Authors

Aleksandra Nilova¹, Paul A Sibbald², Edward J Valente³, Gisela A González-Montiel⁴, H Camille Richardson⁴, Kevin S Brown⁵, Paul Ha-Yeon Cheong⁴, David R Stuart¹

Affiliations

¹ Department of Chemistry, Portland State University, Portland, Oregon, 97201, USA.
² Department of Chemistry, Stetson University, DeLand, Florida, 32723, USA.
³ Department of Chemistry, University of Portland, Portland, Oregon, 97203, USA.
⁴ Department of Chemistry, Oregon State University, Corvallis, Oregon, 97331, USA.
⁵ Department of Pharmaceutical Sciences and Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, Oregon, 97331, USA.

PMID: 33501687
DOI: 10.1002/chem.202100201

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.

Keywords: arylation; aryne; deprotonation; diaryliodonium salt; hypervalent iodine.

Abstract

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