Matthew J. Gaunt

A meta-selective copper-catalyzed C-H bond arylation.

For over a century, chemical transformations of benzene derivatives have been guided by the high selectivity for electrophilic attack at the ortho/para positions in electron-rich substrates and at the meta position in electron-deficient molecules. We have developed a copper-catalyzed arylation reaction that, in contrast, selectively substitutes phenyl electrophiles at the aromatic carbon–hydrogen sites meta to an amido substituent. This previously elusive class of transformation is applicable to a broad range of aromatic compounds.

Cu(II)-Catalyzed Direct and Site-Selective Arylation of Indoles Under Mild Conditions

We have developed a new site-selective Cu(II)-catalyzed C-H bond functionalization process that can selectively arylate indoles at either the C3 or C2 position under mild conditions. The scope of the arylation process is broad and tolerates broad functionality on both the indole and aryl unit, which makes it amenable to further elaboration. The mechanism of the arylation reaction is proposed to proceed via a Cu(III)-aryl species that undergoes initial electrophilic addition at the C3 position of the indole motif. We speculate that site of indole arylation arises through a migration of the Cu(III)-aryl group from C3 to C2, and this can be controlled by the nature of the group on the nitrogen atom; free (NH)- and N-alkylindoles deliver the C3-arylated product, whereas N-acetylindoles afford the C2 isomer, both with excellent yield and selectivity.

Oxidative Pd(II)-Catalyzed C−H Bond Amination to Carbazole at Ambient Temperature

We report a new Pd(II)-catalyzed C-H bond amination reaction to form carbazoles, an important motif that is prevalent in a range of systems. The catalytic amination process operates under extremely mild conditions and produces carbazole products in good to excellent yields. Carbazoles possessing complex molecular architecture can also be formed using this reaction, highlighting its potential in natural product synthesis applications. Preliminary mechanistic investigations reveal the reaction proceeds through a Pd(II)/Pd(IV) manifold and that reductive elimination from a high oxidation state Pd(IV) complex facilitates the mild conditions of this transformation.

Palladium-catalysed C–H activation of aliphatic amines to give strained nitrogen heterocycles

The development of new chemical transformations based on catalytic functionalization of unactivated C−H bonds has the potential to simplify the synthesis of complex molecules dramatically. Transition metal catalysis has emerged as a powerful tool with which to convert these unreactive bonds into carbon−carbon and carbon−heteroatom bonds, but the selective transformation of aliphatic C−H bonds is still a challenge. The most successful approaches involve a ‘directing group’, which positions the metal catalyst near a particular C−H bond, so that the C−H functionalization step occurs via cyclometallation. Most directed aliphatic C−H activation processes proceed through a five-membered-ring cyclometallated intermediate. Considering the number of new reactions that have arisen from such intermediates, it seems likely that identification of distinct cyclometallation pathways would lead to the development of other useful chemical transformations. Here we report a palladium-catalysed C−H bond activation mode that proceeds through a four-membered-ring cyclopalladation pathway. The chemistry described here leads to the selective transformation of a methyl group that is adjacent to an unprotected secondary amine into a synthetically versatile nitrogen heterocycle. The scope of this previously unknown bond disconnection is highlighted through the development of C−H amination and carbonylation processes, leading to the synthesis of aziridines and β-lactams (respectively), and is suggestive of a generic C−H functionalization platform that could simplify the synthesis of aliphatic secondary amines, a class of small molecules that are particularly important features of many pharmaceutical agents.

A Highly Para‐Selective Copper(II)‐Catalyzed Direct Arylation of Aniline and Phenol Derivatives

The ubiquity of the biaryl motif in natural products, medicines, and novel materials ensures a constant demand for their efficient and selective synthesis. The most widespread biaryl-forming processes are cross-coupling reactions in which two prefunctionalized arene partners are connected by a transition-metal catalyst. Although selectivity in these cross-coupling reactions is not an issue, a compromise is made on efficiency; prior chemical transformations are required to obtain the coupling partners as the prefunctionalization events must be carried out regioselectively, and in some cases this can prove a significant challenge. Much recent attention has been devoted to the development of new concepts to utilize a C H bond in place of one or both of the cross-coupling partners. The benefits of this strategy are considerable, but the crucial issue of selectivity is now relocated to the biaryl bond-forming step. Cyclometalation-based approaches constitute the most common strategy towards the arylation of C H bonds, which results in functionalization ortho to a directing group. Considering the wealth of electrophilic aromatic substitution reactions employed in synthesis, it is surprising that few para-selective direct arylation reactions are known. Several research groups have reported methods to achieve direct metal-catalyzed arylation of electron-rich benzenes, but only moderate selectivity has been observed; in most cases, all three possible isomers were obtained. Higher selectivity was reported by Buchwald and co-workers in a specific case during an oxidative coupling of anisole with anilides, wherein 1:2:12 o/m/p selectivity was achieved. Kita et al. have reported a metal-free thiophenylation of some electron-rich arenes and heteroarenes with high selectivity. Recently, we reported a C3-selective copper-catalyzed direct arylation of indoles with diaryliodonium salts; this selectivity would be expected from an electrophilic substitution-type (SEAr) mechanism (Figure 1). [7a] Intriguingly, we

Amine directed Pd(II)-catalyzed C–H bond functionalization under ambient conditions

Pd(II)-catalyzed C–H bond functionalizations that proceed under ambient conditions are a pivotal part of the future of chemical synthesis. Herein, an amine directed Pd(II)-catalyzed C–H bond functionalization strategy is described that generates a diversity of molecular frameworks via C–H carbonylation, C–H arylation and C–H amination. The new reactions work for a variety of substrates and are tolerant of delicate stereogenic centres and functionality. Furthermore, the new reactions can be sequenced to generate complex architectures from simple building blocks via iterative Pd(II)-catalyzed C–H bond functionalization.

Pd-Catalyzed C–H Bond Functionalization on the Indole and Pyrrole Nucleus

This review details recent developments in the Pd-catalyzed C-H bond arylation and alkenylation of indoles and pyrroles, aromatic heterocycles that are frequently displayed in natural products and medicinal agents.

Enantioselective α-Arylation of N-Acyloxazolidinones with Copper(II)-bisoxazoline Catalysts and Diaryliodonium Salts

A new strategy for the catalytic enantioselective α-arylation of N-acyloxazolidinones with chiral copper(II)-bisoxazoline complexes and diaryliodonium salts is described. The mild catalytic conditions are operationally simple, produce valuable synthetic building blocks in excellent yields and enantioselectivities, and can be applied to the synthesis of important nonsteroidal anti-inflammatory agents and their analogues.

Copper-catalyzed alkene arylation with diaryliodonium salts.

Alkenes and arenes represent two classes of feedstock compounds whose union has fundamental importance to synthetic organic chemistry. We report a new approach to alkene arylation using diaryliodonium salts and Cu catalysis. Using a range of simple alkenes, we have shown that the product outcomes differ significantly from those commonly obtained by the Heck reaction. We have used these insights to develop a number of new tandem and cascade reactions that transform readily available alkenes into complex arylated products that may have broad applications in chemical synthesis.

Copper-Catalyzed Electrophilic Carbofunctionalization of Alkynes to Highly Functionalized Tetrasubstituted Alkenes

Copper catalysts enable the electrophilic carbofunctionalization of alkynes with vinyl- and diaryliodonium triflates. The new process forms highly substituted alkenyl triflates from a range of alkynes via a pathway that is opposite to classical carbometalation. The alkenyl triflate products can be elaborated through cross-coupling reactions to generate synthetically useful tetrasubstituted alkenes.