Remote C–H Functionalizations by Ruthenium Catalysis

Abstract

Synthetic transformations of otherwise inert C–H bonds have emerged as a powerful tool for molecular modifications during the last decades, with broad applications towards pharmaceuticals, material sciences and crop protection. Consistently, a key challenge in C–H activation chemistry is the full control of site-selectivity. In addition to substrate control through steric hindrance or kinetic acidity of C–H bonds, one important approach for the site-selective C–H transformation of arenes is the use of chelation-assistance through directing groups, therefore leading to proximity-induced ortho-C–H metalation. In contrast, more challenging remote C–H activations at the meta- or para-positions continue to be scarce. Within this review, we demonstrate the distinct character of ruthenium catalysis for remote C–H activations until March 2021, highlighting among others late-stage modifications of bio-relevant molecules. Moreover, we highlight important mechanistic insights by experiments and computation, highlighting the key importance of carboxylate-assisted C–H activation with ruthenium(II) complexes.

Visible-Light-Mediated Ruthenium-Catalyzed para-Selective Alkylation of Unprotected Anilines

“…Meanwhile, styrene also afforded three component adduct 7 with 1a and 2a (see Section 6.2 in the Supporting Information). As ruthenation of arenes with the C–Ru bond is normally the key factor that controls the regioselectivity of para -C–H alkylation in σ -activation, , we used the deuterated substrate [D 5 ]-1a to probe the presence of a C–Ru bond. The product [D 4 ]-3a was observed by NMR analysis without any D/H exchange, which implied that no C–Ru bond formed with [RuCl 2 ( p -cymene)] 2 (Scheme B).…”

“…Nakao, Ong, Itami, and others achieved para -selectivity through the regulation of steric control using sterically hindered reagents and substrates via coordination with metal catalyst-bearing bulky ligands [Scheme A­(d)] . After the pioneering work on σ -activation-guided meta -selective C–H activation by Frost and Ackermann, Frost, Zhao, and Liang disclosed ruthenium­(II)-catalyzed para -selective difluoromethylation of ketoximes, indolines, and tetrahydroquinoline derivatives via σ -activation through ortho -cycloruthenated complexes [Scheme A­(e)] . Similar to σ -activation, coordination between Lewis acids and oxygen or nitrogen atoms of substrates was found to enhance electron density on arenes for para -functionalization of aromatic ketones, aldehydes, and benzoic acid derivatives through Lewis acid activation [Scheme A­(f)] .…”

“…However, the additional steps reduce the step-economy, and the harsh conditions limit both the functional group tolerance and the possibility for late-stage functionalization. Given the existing σ -activation strategies , and recent emergence of photoredox chemistry, we questioned whether a suitable photocatalyst could coordinate with anilines to both activate the para site and block the nitrogen atom against nucleophilic substitution, which enables a mild and straightforward para -alkylation of unprotected anilines. Based on the results of our investigation along these lines, we report herein the visible-light-mediated Ru­(II)-catalyzed para -alkylation of anilines (Scheme D).…”

Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules

“…Frost reported the first example of such remote functionalization in 2011, describing the ruthenium-catalyzed sulfonation of arenes at the position meta to the directing group, overriding the traditional ortho- selectivity seen with other transition metals . Since then, the installation of alkyl, halide, nitro, acyl, and even aryl groups have been reported, and these have been covered in recent reviews. , The majority of the reports on this topic are methods for meta -alkylation, and this section will focus on methods for remote C–H alkylation that contain examples of late-stage functionalization.…”

Experimental and theoretical studies of the rhodium(i)-catalysed C–H oxidative alkenylation/cyclization ofN-(2-(methylthio)phenyl)benzamides with maleimides

“…Over the past several decades, the transition-metal-catalysed functionalization of C–H bonds has become one of the most straightforward and ideal strategies for preparing complex molecules from structurally simple compounds. 1 Because of this, the direct functionalization of C–H bonds has now become a reliable tool for the synthesis of a wide variety of natural products, pharmaceuticals, and functional organic materials. 2 Our group previously reported a series of Rh( i )-catalysed C–H alkylation reactions of aromatic amides with various alkenes with the aid of an 8-aminoquinoline directing group.…”