Recent advances of the site-specific direct methylation on aromatic rings

Abstract

Five- and six-membered aromatic rings bearing a methyl group are important molecular fragments in drug discovery. From the medicinal chemistry standpoint, the methyl group might play a pivotal role in improving the biological activities and druggability due to its capability in modulating the molecular conformation as well as the physical and chemical properties (such as lipophilicity and metabolism, etc.). How to effectively install a methyl group in a designated position of an aromatic ring is a long-stand quest and a research hot spot for both medicinal chemists and synthetic organic chemists. In the past few years, significant progresses have been achieved in this field wherein the C–H bond activation and direct methylation become achievable in one step under catalytic conditions. A variety of metal catalysts reported by several research groups are capable of such transformation. The relatively mild reaction conditions and high functional group compatibility make such transformation very attractive for final step synthesis. This paper summarizes such transformation based on their reaction mechanisms, and systematically discusses the reaction conditions and their application of a variety of substrates. It provides both medicinal and synthetic organic chemists the convenience for accessing the most up-to-date methodology, and would foster the potential applications in drug discovery and organic synthesis projects.

Introduction

In view of atom economic and eco-friendly process, the selective functionalization of carbon-hydrogen bonds (C–H) via directing group (DG) mediated approach or radical approach is an extremely important topic in today's organic synthesis [1,2]. Among the direct functionalization of a C–H bond, direct alkylation represents an important subclass organic transformation, which can introduce a preferred alkyl group into aryl or heteroaryl ring systems. A review article published recently by Punji et al. summarized the progresses of the direct alkylation of unactivated hydrocarbons and heteroaromatics with limited efforts devoted to direct methylation examples [3]. It has been well documented that aromatic rings bearing a methyl group are common fragments in drugs and bioactive molecules [4,5]. The methyl group is capable of changing the molecular conformation, lipophilicity, and metabolism of the drug candidates, hence affecting biological activities, pharmacokinetic parameters, and pharmacodynamic effects [[6], [7], [8], [9], [10], [11]]. Analyses of the literature reveal that in about 8 % of the cases a methyl group show more than 10 times improvement in biological activities. Furthermore, in about 0.5 % of the cases, a “magic” methyl group could improve the biological activities greater or equal to 100-fold [12].

Fig. 1 listed three examples where the “magic” methyl group enhances the biological activities. The introduction of dimethyl at the ortho-position of the left side aniline of ACK1 inhibitor 1 improves the activity more than 1000 fold (2 vs 1) due to the more lipophilic 2,6-dimethyl aniline better fitting into the hydrophobic region arranged by the side chains of Ile190, Leu259, and Phe271. The second example is about phenylthiophene inhibitors of PTP1B. The methyl group at C4 of the thiophene ring positions into a well-formed hydrophobic pocket lined by the side chain of Ile219 and C_β and C_γ of Gln262, contributing to the significant activity improvement (4 vs 3). In the last example, the introduction of a methyl group to thrombin inhibitor 5 enhances hydrophobic contacts and conformational bindings of the inhibitor to the protein, resulting in greater than 180 fold increase of the K_i value (6 vs 5).

Additionally, the methyl group on aromatic rings can also serve as an important surrogate for generating various functional groups such as aldehyde, carboxylic acid, alcohol, halogenated methyl, or directly be used in C–N coupling reactions [13]. Those functional groups are either important fragments or useful building blocks in organic synthesis. Therefore, the facile installation of a methyl group is very important for medicinal chemists in drug discovery programs, especially when such transformation is demanded as the last step process. Several previously reviewed methylation reactions for transforming a C-X bond (wherein X is a leaving group such as halogen [14], OTf, OTs, OMs, Bpin [15], etc.) to a C–Me bond have been well documented in the literature, for example, Stille coupling reaction, the organocuprate approach, and the halogen-metal exchange protocol etc. However, the X surrogates demanded by in convention methods might not be compatible in one of the reaction steps during the synthetic sequence. In addition, these X surrogates need to be pre-installed using extra synthetic steps, making those methods less attractive due to the relative low atom economy and atom efficiency (Fig. 2). In the past few years, the catalytic C–H bond activation and simultaneous methylation on a site-specific aromatic ring have attracted great attention from the organic chemistry community. Schnürch et al. gave a comprehensive overview of the advances of C–H bond functionalization from 2015 to 2017 [16]. However, the review only focused on the metal-mediated directing group approaches, and did not cover the radical approaches. Early this year, Dixon et al. gave a high level review on the advances of the direct methylation on sp² and sp³ carbons [17]. However their review did not list comprehensive up-to-date examples of the direct methylation of aromatic rings. Due to the rapid advancement in this field, it's necessary to summarize the most recent developments. This article aims to summarize the recent advances of the direct methylation on aromatic rings using both the DG mediated method and the radical approach. It will cover these examples did not appear in previous review articles.