Cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides

Chao Li, Yi-Xuan Cao, Rui Wang, Yi-Ning Wang, Quan Lan and Xi-Sheng Wang ()
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Chao Li: University of Science and Technology of China
Yi-Xuan Cao: University of Science and Technology of China
Rui Wang: University of Science and Technology of China
Yi-Ning Wang: University of Science and Technology of China
Quan Lan: University of Science and Technology of China
Xi-Sheng Wang: University of Science and Technology of China

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: Abstract The selective incorporation of gem-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.

Date: 2018
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DOI: 10.1038/s41467-018-07525-y

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