Cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Li, Chao; Cao, Yi-Xuan; Wang, Rui; Wang, Yi-Ning; Lan, Quan; Wang, Xi-Sheng
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 7
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07525-y
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract The selective incorporation ofgem -difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery. However, the catalytic C(sp3 )-CF2 bond-forming cross-coupling reaction for selective incorporation of difluoromethylene group into diverse alkyl chains, especially more sterically demanding secondary and tertiary functionalized alkanes, still remains as a major challenge. Herein, we describe a cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides, which exhibited high efficiency, broad scope and mild conditions. The synthetic utility of this method is demonstrated by late-stage difluoroalkylation of donepezil, a well-known acetylcholinesterase inhibitor used to treat the Alzheimer's disease. Preliminary mechanistic investigations indicate that a difluoroalkyl radical is involved in a Co(I)/Co(III) catalytic cycle. This cobalt-catalyzed fluoroalkylation thus offers insights into an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery. The catalytic C(sp3 )-CF2 bond formation is of high interest in drug design and discovery. Here, the authors report a cobalt-catalyzed difluoroalkylation of tertiary α-C-H bonds of aryl ketones for facile synthesis of quaternary alkyl difluorides and show the late-stage functionalization of marketed drugs.