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. 2021 Nov;53(21):3935-3950.
doi: 10.1055/a-1547-9270.

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

Jacob P Sorrentino  1 , Ryan A Altman  2
Affiliations

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

Jacob P Sorrentino et al. Synthesis (Stuttg). 2021 Nov.

Abstract

gem-Difluoroalkenes are readily available fluorinated building blocks, and the fluorine-induced electronic perturbations of the alkenes enables a wide array of selective functionalization reactions. However, many reactions of gem-difluoroalkenes result in a net C─F functionalization to generate monofluorovinyl products or addition of F to generate trifluoromethyl-containing products. In contrast, fluorine-retentive strategies for the functionalization of gem-difluoroalkenes remain less generally developed, and is now becoming a rapidly developing area. This review will present the development of fluorine-retentive strategies including electrophilic, nucleophilic, radical, and transition metal catalytic strategies with an emphasis on key physical organic and mechanistic aspects that enable reactivities.

Keywords: Fluorination; Organofluorine; Synthetic Methodology; gem-Difluoroalkene.

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Figures

Scheme 1
Scheme 1
Overview of gem-Difluoroalkene Reactivity
Scheme 2
Scheme 2
Fluorinative Difunctionalization of gem-Difluoroalkenes
Scheme 3
Scheme 3
SN2’ Strategy for Functionalization of gem-Difluoroalkenes
Scheme 4
Scheme 4
Reactivity of gem-Difluoroalkenes Bearing γ-Epoxides
Scheme 5
Scheme 5
Reactions of gem-Difluoroalkenes Bearing γ-Epoxides
Scheme 6
Scheme 6
Reactions of gem-Difluoroalkenes Bearing an Allylic Ammonium Group
Scheme 7
Scheme 7
Silver-Catalyzed Synthesis of α,α-Difluoro-β-ketosulfones
Scheme 8
Scheme 8
Doyle-Kirmse-Type Rearrangement with gem-Difluoroalkenes
Scheme 9
Scheme 9
Charge Density and Resonance Structures of gem-Difluoroalkenes
Scheme 10
Scheme 10
Haloacylation of gem-Difluoroalkenes
Scheme 11
Scheme 11
Aggarwal Carbonyl Allylation of gem-Difluoroalkenes
Scheme 12
Scheme 12
Mechanistic Overview of Reactions Involving Halonium and Thiiranium Intermediates
Scheme 13
Scheme 13
Halocyclization of gem-Difluoroalkenes Bearing Carboxylic Acids and Alcohols
Scheme 14
Scheme 14
Intramolecular Friedel-Crafts-type Halocyclization of gem-Difluoroalkenes
Scheme 15
Scheme 15
Regio- and Enantioselective Halocyclization of gem-Difluoroalkenes to Generate Oxazoline and Oxazine Products
Scheme 16
Scheme 16
Chalcogenide-Catalyzed Functionalization of gem-Difluoroalkenes
Scheme 17
Scheme 17
Base-Catalyzed Hydrofunctionalization of gem-Difluoroalkenes with Phenols
Scheme 18
Scheme 18
Addition of Thiophenols into Fluorinated Alkenes
Scheme 19
Scheme 19
[4 + 2] Annulation of gem-Difluoroalkenes
Scheme 20
Scheme 20
Base-Catalyzed Hydrofunctionalization of gem-Difluoroalkenes
Scheme 21
Scheme 21
Hydrofunctionalization of gem-Difluoroalkenes with Phenol Nucleophiles
Scheme 22
Scheme 22
Acid-Catalyzed Hydrofunctionalization of gem-Difluoroalkenes
Scheme 23
Scheme 23
Aerobic Quench of the Anionic Intermediate
Scheme 24
Scheme 24
Reaction with a 1,3-Dipole
Scheme 25
Scheme 25
Reactions of gem-Difluoroalkenes with Nitrones
Scheme 26
Scheme 26
Cycloaddition Reactions of gem-Difluoroenamides
Scheme 27
Scheme 27
Reactions of gem-Difluoroalkenes with Dichlorocarbene
Scheme 28
Scheme 28
Reactions of gem-Difluoroalkenes with Difluorocarbene
Scheme 29
Scheme 29
Cyclization Reactions Involving Formation of Diradicals from gem-Difluoroalkenes
Scheme 30
Scheme 30
Peroxide Initiated Reactions with gem-Dilfuoroalkenes
Scheme 31
Scheme 31
Hydroborylation of gem-Difluoroalkenes
Scheme 32
Scheme 32
Hydroborylation and Hydrosilylation of gem-Difluoroalkenes
Scheme 33
Scheme 33
Photoredox Hydrothiolation of gem-Difluoroalkenes
Scheme 34
Scheme 34
Light-Mediated Atom Transfer Radical Addition
Scheme 35
Scheme 35
Silver-Catalyzed Synthesis of 3,4-Dihydroquinolin-2-ones
Scheme 36
Scheme 36
Cobalt-Catalyzed Dioxygenation of gem-Difluoroalkenes
Scheme 37
Scheme 37
Reduction of gem-Difluoroalkenes
Scheme 38
Scheme 38
Mechanistic Overview of Reactions of Transition Metals with gem-Difluoroalkenes
Scheme 39
Scheme 39
Selective β-OAc Elimination to Avoid the Loss of Fluorine
Scheme 40
Scheme 40
Selective β-Hydride Elimination to Avoid the Loss of Fluorine
Scheme 41
Scheme 41
Carbonylation of gem-Difluoroalkenes
See this image and copyright information in PMC

References

    1. Zhang X; Cao S Recent Advances in the Synthesis and C-F Functionalization of Gem-Difluoroalkenes. Tetrahedron Lett. 2017, 58 (5), 375–392.
    1. Koley S; Altman RA Recent Advances in Transition Metal-Catalyzed Functionalization of Gem-Difluoroalkenes. Isr. J. Chem 2020, 60, 313–339. - PMC - PubMed
    1. Liu C; Zeng H; Zhu C; Jiang H Recent Advances in Three-Component Difunctionalization of Gem-Difluoroalkenes. Chem. Comm 2020, 56, 10442–10452. - PubMed
    1. Orsi DL; Altman RA Exploiting the Unusual Effects of Fluorine in Methodology. Chem. Comm 2017, 53, 7168–7181. - PubMed
    1. Hagan DO Understanding Organofluorine Chemistry. An Introduction to the C─F Bond. Chem. Soc. Rev 2008, 37, 308–319. - PubMed