Copper-Catalyzed Selective 1,2-Difunctionalization of N-Heteroaromatics through Cascade C–N/C═C/C═O Bond Formation

Abstract

This study presents an efficient strategy for constructing 1,2-difunctionalized quinoline derivatives via the multicomponent cascade coupling of N-heteroaromatics with alkyl halides and different terminal alkynes. This reaction was achieved through sequential functionalization at the one- and two-positions of quinolines, which displayed a broad substrate scope, environmental friendliness, excellent functional group tolerance, high atom efficiency, and chemoselectivity. The multicomponent coupling involved the abnormal construction of new C–N, CC, and CO bonds in one pot. The applicability of this method was further demonstrated by the late-stage functionalization of complex drug molecules under the established conditions.

Site‐Selective 1,4‐Difunctionalization of Nitrogen Heteroaromatics for Constructing Vinylidene Heterocycles

“…As part of our ongoing research on the construction of functional N‐heterocycles via dearomatization strategies, [13] we recently reported a copper‐catalyzed selective 1,2‐difunctionalization of N‐heteroaromatics via cascade C−N/C=C/C=O bond formation [14] . These previous studies prompted us to investigate the use of an in situ activation strategy for the direct C4 functionalization of azaarenes.…”

“…As part of our ongoing research on the construction of functional N-heterocycles via dearomatization strategies, [13] we recently reported a copper-catalyzed selective 1,2-difunctionalization of N-heteroaromatics via cascade CÀ N/C=C/C=O bond formation. [14] These previous studies prompted us to investigate the use of an in situ activation strategy for the direct C4 functionalization of azaarenes. In this protocol, N-alkylazaarene zwitterionic species were formed in situ, which activated the azaarene by improving the electrophilicity to couple with different nucleophiles.…”

Recent Strategies in the Nucleophilic Dearomatization of Pyridines, Quinolines, and Isoquinolines

“…An efficient strategy for constructing 1,2-difunctionalized quinoline derivatives entailed the copper-catalyzed three-component cascade coupling of quinolines, benzyl bromides 323 and terminal alkynes 260 ( Scheme 154 ). 222 The combination of these type of compounds with CuI as the catalyst and NaOAc as a base under air atmosphere, provided 1,2-dihydroquinoline derivatives 327 bearing a conjugated ketone moiety. Alkyl, aryl, and heteroaryl alkynes and propiolates were tolerated in the process.…”

Copper‐Catalyzed C(sp2)−C(sp2) Bond Formation via Single C(sp2)−H Activation

“…In another work, Chen and his research team [46] carried out the synthesis of 1,2‐difunctionalized derivatives of quinoline using a complex cascade coupling reaction involving alkyl halides and various terminal alkynes. The reaction conditions exhibited a broad range of applicability, demonstrating favorable tolerance towards different functional groups and achieving efficient atom conversion.…”