Cobalt-catalyzed conformationally restricted alkylarylation enables divergent access to Csp3-rich N-heterocycles
Kaixin Chen1, Jie Lin1, Jing Jing1, Junda Wang1, Jiayu Hu2, Hong Yi2, Aiwen Lei2（雷爱文）*, Jie Li1（李杰）*
1Key Laboratory of Organic Synthesis of Jiangsu Province, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China.
2College of Chemistry and Molecular Sciences, The Institute for Advanced Studies (IAS), Wuhan University, Wuhan, 430072, China.
Chem. Sci. 2024,15, 16250-16258
Abstract: Due to the intrinsic spatial orientation and structural novelty, Csp3-rich N-heterocycles have been recognized as increasingly sought-after scaffolds as compared to the aromatic ring-based moieties, which have generated considerable recent attention in drug discovery. Hence, we disclose a modular cobalt-catalyzed conformationally restricted alkylarylation strategy for the divergent access to Csp3-rich N-hetero(spiro)cycles. Herein, multiple effects, including radical rebound and conformational restriction, play critical roles in the stabilization of the stereospecific alkyl-cobalt-aryl intermediate. Under simple and mild reaction conditions, cobalt catalyst combines a range of polyfunctionalized cyclenyl bromides and organozinc pivalates to rapidly and reliably forge the architecturally complex Csp3-rich N-hetero(spiro)cycles (>70 examples, >20 : 1 dr), including but not limited to the [5,5]-, [5,6]-, [5,7]-, [5,12]-bicycles, tri- and tetracyclic N-heterocycles, as well as various novel N-heterospirocyclic scaffolds in one synthetic operation. Preliminary kinetic investigations suggested that the final reductive elimination might be the rate-determining step. Moreover, ample substrate scope, good functional group compatibility and facile derivatizations to the pharmaceutically active molecules show the potential applications of this technology to organic syntheses and drug discoveries in medicinal chemistry.
链接：//pubs.rsc.org/en/content/articlelanding/2024/sc/d4sc04056b
