Iridium-catalyzed C−H methylation and d3-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

Erik Weis, Martin A Hayes + Show 2 more

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https://doi.org/10.1016/j.isci.2021.102467

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Journal: iScience	Publication Date: Apr 24, 2021
Citations: 31	License type: cc-by

Affiliation: Stockholm University, AstraZeneca (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.

Highlights

CÀH bonds are ubiquitous in the vast majority of pharmaceuticals; in 2018, of the top small molecule pharmaceuticals by retail sales contained CÀH bonds (Njardarson 2018)
The potential impact of the CÀH methylation has been highlighted by Cernak (Schonherr and Cernak 2013), and the effect of methylation in medicinal chemistry has been extensively reviewed by Barreiro et al (2011)
With this work we aim to develop a methodology for ortho-CÀH methylation of benzoic acids, which fulfills the aforementioned criteria, tolerates a broad array of functional groups, and allows for functionalization of building blocks, advanced intermediates, as well as marketed drugs with high regioselectivity in a single step

Summary

Introduction

CÀH bonds are ubiquitous in the vast majority of pharmaceuticals; in 2018, of the top small molecule pharmaceuticals by retail sales contained CÀH bonds (Njardarson 2018). In the late-stage functionalization (LSF) context, this would allow to surpass the need of de novo synthesis of new analogues (Blakemore et al, 2018; Cernak et al, 2016; Borgel and Ritter 2020) This is beneficial with respect to time, overall step count, and atom economy and highly advantageous for the drug discovery process. The field of directed CÀH activation has been reviewed (Sambiagio et al, 2018; Rej et al, 2020), presenting an attractive strategy to functionalize otherwise unreactive CÀH bonds with high regioselectivity This approach has been applied to LSF in the context of medicinal chemistry (Moir et al, 2019), and the field is still developing. The substitutions of single CÀH for CÀMe functionality resulting in more than a 100-fold increase in potency have been reported (Angell et al, 2008; Coleman et al, 2012)

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