Iridium-catalyzed C-H methylation and d 3-methylation of benzoic acids with application to late-stage functionalizations

Erik Weis; Martin A Hayes; Magnus J Johansson; Belén Martín-Matute

doi:10.1016/j.isci.2021.102467

Iridium-catalyzed C-H methylation and d ₃-methylation of benzoic acids with application to late-stage functionalizations

iScience. 2021 Apr 24;24(5):102467. doi: 10.1016/j.isci.2021.102467. eCollection 2021 May 21.

Authors

Erik Weis^{1

2}, Martin A Hayes³, Magnus J Johansson², Belén Martín-Matute¹

Affiliations

¹ Department of Organic Chemistry, Stockholm University, Stockholm 106 91, Sweden.
² Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
³ Hit Discovery, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Abstract

Late-stage functionalization (LSF) has over the past years emerged as a powerful approach in the drug discovery process. At its best, it allows for rapid access to new analogues from a single drug-like molecule, bypassing the need for de novo synthesis. To be successful, methods able to tolerate the diverse functional groups present in drug-like molecules that perform under mild conditions are required. C-H methylation is of particular interest due to the magic methyl effect in medicinal chemistry. Herein we report an iridium-catalyzed carboxylate-directed ortho C-H methylation and d ₃-methylation of benzoic acids. The method uses commercially available reagents and precatalyst and requires no inert atmosphere or exclusion of moisture. Substrates bearing electron-rich and electron-poor groups were successfully methylated, including compounds with competing directing/coordinating groups. The method was also applied to the LSF of several marketed drugs, forming analogues with increased metabolic stability compared with the parent drug.

Keywords: Applied chemistry; Chemistry; Green chemistry; Organic chemistry.