Recyclable Aliphatic Nitrile-Template Enabled Remote meta-C–H Functionalization at Room Temperature

Abstract

This article describes the development of a new aliphatic nitrile-template-directed remote meta-selective C−H olefin functionalization reaction of arenes. Remarkably, unlike the previous reports, this process is feasible at room temperature and enabled the formation of products with excellent regioselectivity. The present protocol encompasses a broad spectrum of substituted dihydrocinnamic acids and olefins, producing meta-C−H olefinated products (up to 96% yield). In addition, the efficacy of the present method has been showcased by the synthesis of various drug analogues (e.g., cholesterol, estrone, ibuprofen, and naproxen). Significantly, the robustness of meta-olefination was also demonstrated by gram-scale synthesis. The new nitrile-based meta-directing template, in particular, could be easily synthesized in two steps and recycled under mild conditions.

Functionalization of arylacetic acids via directing-group-assisted remote meta-C–H activation

“…Notably, a breakthrough study by Yu et al for selective meta-C-H bond activation achieved using a macrocyclic U-shaped template, 6 and a few more studies by the same research group, [7][8][9][10][11][12] Maiti, [13][14][15][16][17][18][19][20][21][22][23] and others [24][25][26][27][28][29][30][31] have been reported. Quite recently, our group [32][33][34] has also ventured into the toolbox of distal C-H functionalizations. Note, however, that only one report has been published to date for the meta-selective arylation of phenylacetic acid; this report was from Yu et al and the arylation involved the use of ArBF 3 K as the aryl source (Scheme 1a).…”

“…As part of our continuous investigation of meta-C-H activation methodologies, 32,34 and inspired by our previous results on olefination 33 using 2-cyanobenzyl as the directing group, we set out here to establish a strategy involving remote meta-functionalization through C-H bond activation aided by a distal nitrile template. Thus, initially, the reaction was carried out between substrate 1a (1 equiv.)…”

Access to distal meta-C–H functionalization of arylmethanesulfonic acid derivatives

“…[32][33][34] Recently, our group also invented versatile nitrile directing groups (aliphatic and aromatic), which are reversible/reusable upon C-H activation, followed by subsequent functionalization. [35][36][37][38] On the other hand, sulfonic acids are privileged precursors in chemical biology and molecular pharmacology for synthesizing biological probes and protein inhibitors. 39,40 In addition, being a strong acid, sulfonic acid is widely used as a catalyst in many transformations.…”

“…[41][42][43][44][45] Recently, we have disclosed a simple, practical, cost-effective, and versatile nitrile template-assisted meta-selective C-H functionalization of aromatic scaffolds. [35][36][37] Encouraged by these interesting results, it was envisioned that the meta-C-H bond of arylmethanesulfonate bearing an aliphatic nitrile template would assist the remote meta-C-H bond functionalization. Herein, we present the meta-C-H olefination of aliphatic nitrile flanked arylmethanesulfonate esters (Scheme 1b).…”

Palladium(II)-Catalyzed Remote meta-C–H Functionalization of Arenes Enabled by Multitasking Oxyamides as the Linker

“…Interestingly, it enabled positioning of the transition metal catalyst in the proximity of the remote meta -C–H bond. Subsequently, various nitrile-, N -heteroaryl-, and carboxy-based templates were then reported to furnish the meta -C–H functionalization of arenes by Maiti, Li, Jin, and Lu et al The aforementioned C–H bond substrates were linked to the directing templates by different linkage groups, such as esters, amides, and ethers, and were transformed into a singular category of meta -C–H functionalized products, including but not limited to carboxylic acids, amines, alcohols, and other analogous compounds . However, multifunctional linking groups have rarely been reported to activate meta -C–H bonds.…”