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. 2019 Aug 20;10(40):9285-9291.
doi: 10.1039/c9sc02806d. eCollection 2019 Oct 28.

Highly stereoselective nickel-catalyzed difluoroalkylation of aryl ketones to tetrasubstituted monofluoroalkenes and quaternary alkyl difluorides

Chao Li  1 , Yi-Xuan Cao  1 , Ruo-Xing Jin  1 , Kang-Jie Bian  1 , Zi-Yang Qin  1 , Quan Lan  1 , Xi-Sheng Wang  1
Affiliations

Highly stereoselective nickel-catalyzed difluoroalkylation of aryl ketones to tetrasubstituted monofluoroalkenes and quaternary alkyl difluorides

Chao Li et al. Chem Sci. .

Abstract

A nickel-catalyzed difluoroalkylation of α-C-H bonds of aryl ketones to furnish highly stereo-defined tetrasubstituted monofluoroalkenes or quaternary alkyl difluorides from secondary or tertiary ketones, respectively, has been established. Mechanistic investigations indicated that these C-H fluoroalkylations proceed via a Ni(i)/Ni(iii) catalytic cycle. An obvious fluorine effect was observed in the reaction, and this reaction has demonstrated high stereoselectivity, mild conditions, and broad substrate scopes, thus enabling the late-stage fluoroalkylation of bioactive molecules. This method offers a solution for expedient construction of monofluoroalkenes from readily available materials, and provides an efficient approach for the synthesis of bioactive fluorinated compounds for the discovery of lead compounds in medicinal chemistry.

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Figures

Scheme 1
Scheme 1. Biologically active molecules containing stereodefined monofluoroalkenes.
Scheme 2
Scheme 2. Nickel-catalyzed difluoroalkylation of alkyl reagents.
Scheme 3
Scheme 3. The synthetic application of monofluoroalkenes.
Scheme 4
Scheme 4. Late-stage modification of biologically active complex molecules.
Scheme 5
Scheme 5. Fluorine effect.
Scheme 6
Scheme 6. Mechanistic studies.
Scheme 7
Scheme 7. The possible reaction mechanism.
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