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.
Highlights
Quinoline, known as benzo[b]pyridine, is a remarkable heteroaromatic scaffold that belongs to the category of the privileged structures [1,2,3]
While the C2-arylation has been reported with different metals, introduction of heteroaromatics in position 2 was exclusively described with Pd-based catalytic systems
Metal-catalyzed remote C-H functionalization in position 5 of quinolines has been widely explored in the last years [99], especially with 8-aminoquinolines as substrate, but only three examples are relying on a true C-H activation mechanism
Summary
Known as benzo[b]pyridine, is a remarkable heteroaromatic scaffold that belongs to the category of the privileged structures [1,2,3]. The model arylation of pyridine N-oxide (4 equiv) with 3,5-dimethylphenyl tosylate (1 equiv) catalyzed by Pd(OAc) (5 mol%) was optimized through the screening of various ligands, organic and inorganic bases, solvent systems and additives, which highlighted that superior results are obtained with X-Phos (10 mol%) and CsF (2 equiv) in a t-BuOH/toluene 2:1 solvent mixture In these conditions, the selective C2-arylation of quinoline N-oxide with two differently substituted aryl tosylates was achieved in good yields (Scheme 7). Concentration and temperature were once again studied as influential parameters for the [RhCl(CO)2]2-catalyzed arylation of quinoline (6 equiv) with benzoyl chloride (1 equiv) and it was found that switching the solvent from dioxane to toluene had a positive impact whereas the addition of a base or the variation of concentration proved to be deleterious for the reaction In these optimized conditions, six different aroyl chlorides were used as coupling partners and led to the synthesis of the corresponding C2-arylated QNs in modest to good yields (Scheme 10). The mechanism proposed by the authors does not correspond to any of the pathways described above in the Scheme 3 and the reader is invited to consult the original article for a detailed description if desired
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