Regioselective Functionalization of Quinolines through C-H Activation: A Comprehensive Review

Abstract

Quinoline is a versatile heterocycle that is part of numerous natural products and countless drugs. During the last decades, this scaffold also became widely used as ligand in organometallic catalysis. Therefore, access to functionalized quinolines is of great importance and continuous efforts have been made to develop efficient and regioselective synthetic methods. In this regard, C-H functionalization through transition metal catalysis, which is nowadays the Graal of organic green chemistry, represents the most attractive strategy. We aim herein at providing a comprehensive review of methods that allow site-selective metal-catalyzed C-H functionalization of quinolines, or their quinoline N-oxides counterparts, with a specific focus on their scope and limitations, as well as mechanistic aspects if that accounts for the selectivity.

Chemo- and regioselective synthesis of C3-sulfonate esters and C4-chlorides of quinolines under metal-free conditions

“…For instance, Yu recently reported the C3–C7 selective functionalization of bicyclic aza-arenes via directing templates or ligands with distinctive designs. 6 This report in combination with those of others on complementary methods 5 now fully establishes a unified late-stage ‘molecular editing’ strategy to directly modify the quinoline ring at any given site in various orders. Despite the remarkable achievements made so far, this field is still in its infancy.…”

“…4 Accordingly, the development of short routes for accessing substituted quinolines has attracted extensive attention. 5 Among those efforts, the transition-metal-catalyzed selective functionalization of C–H bonds on the quinoline ring has become an elegant strategy for the expeditious generation of structural diversity. For instance, Yu recently reported the C3–C7 selective functionalization of bicyclic aza-arenes via directing templates or ligands with distinctive designs.…”

Rhodium-Promoted C–H Bond Activation of Quinoline, Methylquinolines, and Related Mono-Substituted Quinolines

“…A quinoline core is present in many natural products and as a unit is a remarkable scaffold for the assembly of new pharmacological and agrochemical entities, given the diverse biological activity of this heterocycle and its derivatives . Transition-metal-catalyzed C–H functionalization of quinolines is currently receiving great attention as an environmentally sustainable alternative to the classical functionalization procedures, which generate more wastes . Functionalization of the C2 position is well established with a variety of transition-metal catalysts .…”

Thioether-Assisted Cu-Catalyzed C5–H Arylation of Imidazo[1,5-a]pyridines

“…In recent years, there has been considerable interest in the use of various directing groups to assist the transition-metal-catalyzed C–H functionalization at the less-active sites of fused bi­(hetero)­cyclic frameworks . For example, phosphine, phosphinoyl, pivaloyl, N -oxide, amide, and thioether groups have been installed at the N1 and C3 positions of indole, the N1 position of quinoline, and the C1 position of naphthalene to accomplish C–H arylation, alkenylation, alkynylation, amidation, acylation, etc., at the C7 and C4 positions of indole and the C8 positions of quinoline , and naphthalene under the catalysis of Pd, Rh, Ir, and Ru. We therefore envisaged that the judicious installation of a directing group at the C3 position of the Im5Py core would not only block arylation at this most-active site but also direct C–H arylation at the less-active C5 position.…”