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Review
. 2022 Dec 2;27(23):8461.
doi: 10.3390/molecules27238461.

Copper-Catalyzed Difluoroalkylation Reaction

Dao-Qing Dong  1 , Shao-Hui Yang  1 , Pei Wu  2 , Jin-Zhi Wang  3 , Ling-Hao Min  4 , Hao Yang  1 , Meng-Yu Zhou  1 , Ze-Hui Wei  1 , Cai-Zhen Ding  1 , Yan-Li Wang  1 , Jia-Hui Gao  1 , Shu-Jie Wang  1 , Zu-Li Wang  1   5
Affiliations
Review

Copper-Catalyzed Difluoroalkylation Reaction

Dao-Qing Dong et al. Molecules. .

Abstract

This review describes recent advances in copper-catalyzed difluoroalkylation reactions. The RCF2 radical is generally proposed in the mechanism of these reactions. At present, various types of copper-catalyzed difluoroalkylation reactions have been realized. According to their characteristics, we classify these difluoroalkylation reactions into three types.

Keywords: copper; coupling reaction; cyclization; difluoroalkylation; multicomponent; radical.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Difluoroalkylated drugs or candidates.
Figure 2
Figure 2
Copper-catalyzed difluoroalkylation reactions.
Scheme 1
Scheme 1
The copper-catalyzed difluoromethylenation of N-arylacrylamides.
Scheme 2
Scheme 2
Difluorinated quinoline-2,4-diones catalyzed by copper.
Scheme 3
Scheme 3
The copper/B2pin2-catalyzed difluoroalkylation of methylenecyclopropanes.
Scheme 4
Scheme 4
The copper-mediated radical cyclization of naphthalenyl iododifluoromethyl ketones.
Scheme 5
Scheme 5
The difunctionalization of unactivated alkenes through desulfonylation.
Scheme 6
Scheme 6
The copper/B2pin2-catalyzed C–H difluoroacetylation–cycloamidation of anilines.
Scheme 7
Scheme 7
The copper-catalyzed annulation of N-substituted anilines.
Scheme 8
Scheme 8
The difluoroalkylation of an olefin/nitrile insertion/cyclization catalyzed by copper.
Scheme 9
Scheme 9
The cyclization between alkenyl carboxylic acids and difluoroalkyl reagents.
Scheme 10
Scheme 10
The copper-catalyzed cyclization of unsaturated carboxylic acids.
Scheme 11
Scheme 11
The intramolecular oxydifluoroalkylation of hydroxyl-containing alkenes catalyzed by copper.
Scheme 12
Scheme 12
The copper-catalyzed reaction for synthesis of difluorinated polycycles.
Scheme 13
Scheme 13
The copper-catalyzed redox cycloisomerization.
Scheme 14
Scheme 14
The Cu/B2pin2-promoted cascade cyclization of vinyl isocyanides.
Scheme 15
Scheme 15
The reaction of BrCF2COOEt with primary amines.
Scheme 16
Scheme 16
The oxydifluoroalkylation of unsaturated oximes.
Scheme 17
Scheme 17
The copper-catalyzed bromodifluoroacetylation cyclization reaction.
Scheme 18
Scheme 18
The copper-catalyzed spirocyclization of biaryl ynones.
Scheme 19
Scheme 19
The synthesis of difluoroalkyl 2-azaspiro [4.5] decane.
Scheme 20
Scheme 20
The synthesis of γ-arylation of carbonyl compounds.
Scheme 21
Scheme 21
The Truce–Smiles rearrangement.
Scheme 22
Scheme 22
(a)The three-component difluoroalkylation of alkenes with BrCF2CO2Et and alcohol. (b) The three-component 1,4-difluoroalkylesterification of 1-aryl-1,3-dienes with BrCF2CO2Et and acids.
Scheme 23
Scheme 23
Photooxidation and copper-catalyzed fluoroalkyl thionation reaction.
Scheme 24
Scheme 24
Synthesis of difluoroacyl-substituted nitriles catalyzed by copper.
Scheme 25
Scheme 25
The difluoroalkylation of olefins catalyzed by Cu/Na2S2O5 system.
Scheme 26
Scheme 26
The copper-mediated difluoroalkylation reaction of alkynes with ethyl iododifluoroacetate.
Scheme 27
Scheme 27
The Cu-catalyzed oxidation of alcohols with BrCF2CO2Et.
Scheme 28
Scheme 28
The Cu2O-catalyzed difluoromethylation of allylic alcohols.
Scheme 29
Scheme 29
The copper-mediated difluoroacetylation of alkenes.
Scheme 30
Scheme 30
The copper-catalyzed hydrodifluoroalkylation of alkynes.
Scheme 31
Scheme 31
(a) Copper-catalyzed difluoroalkylation of indoles. (b) Ru-catalyzed difluoroalkylation of indoles. (c) Copper-catalyzed difluoroalkylation of indoles directed by pyrimidyl group.
Scheme 32
Scheme 32
(a) Copper-catalyzed difluoroalkylation of imidazopyridines. (b) Ir-catalyzed difluoroalkylation of imidazopyridines. (c) Organophotoredox-catalyzed difluoromethylenephosphonation of imidazoheterocycles.
Scheme 33
Scheme 33
(a)The Cu-catalyzed difluoroalkylation of 8-aminoquinoline. (b) The Ni-catalyzed difluoroalkylation of 8-aminoquinoline. (c) The Ru-catalyzed difluoroalkylation of 8-aminoquinoline.
Scheme 34
Scheme 34
The copper-catalyzed direct C-3 difluoroacetylation of quinoxalinones.
Scheme 35
Scheme 35
Visible-light-induced difluoroalkylation of arenes.
Scheme 36
Scheme 36
(a) Copper-catalyzed difluoroalkylation of hydrazones. (b) Pd-catalyzed difluoroalkylation of hydrazones. (c) Ir-catalyzed difluoroalkylation of hydrazones. (d) Au-catalyzed difluoroalkylation of hydrazones.
Scheme 37
Scheme 37
The Cu/B2pin2-catalyzed difluoroalkylation of hydrazones.
Scheme 38
Scheme 38
The Cu/B2pin2-catalyzed difluoroalkylation of hydrazones.
Scheme 39
Scheme 39
The Cu/B2pin2-catalyzed difluoroalkylation of hydrazones.
Scheme 40
Scheme 40
The selective C-H difluoroalkylation of coumarins catalyzed by copper.
Scheme 41
Scheme 41
The microwave-assisted copper catalysis of α-difluorinated gem-diol.
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