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

Chao Li,Rui Wang,Quan Lan,Xi-Sheng Wang,Yi-Xuan Cao,Yi-Ning Wang

doi:10.1038/s41467-018-07525-y

Chao Li, Rui Wang + Show 4 more

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https://doi.org/10.1038/s41467-018-07525-y

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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.

Highlights

The selective incorporation of gem-difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery
The selective incorporation of gem-difluoroalkyl groups into drug-like molecules has long been known as a powerful strategy for drug design and discovery, as their structural diversity and the ability to modulate the electronic properties of parent molecules[51,52,53,54]
A number of difluoroalkylation reactions have been well-developed into the construction of C(sp[2] or sp)-CF2R bonds, in which fluorine atoms were normally oriented at relatively unique benzyl, allyl, and propargyl positions[12,13,14,15,16,17,18,19,20,23,24,25,26,27,28,46,47,48,55,56,57]

Summary

Introduction

The selective incorporation of gem-difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery. 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. Preliminary mechanistic investigations indicate that a difluoroalkyl radical is involved in a Co(I)/Co(III) catalytic cycle This cobalt-catalyzed fluoroalkylation offers insights into an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery. We report a cobalt-catalyzed difluoroalkylation of tertiary aryl ketones with fluoroalkyl bromides (Fig. 1b) This approach has demonstrated high-catalytic reactivity and broad substrate scope, enabling the late-stage fluoroalkylation of biologically active molecules. This strategy offers a solution for facile synthesis of quaternary alkyl difluorides, and provides an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery

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