Picking One out of Three: Selective Single C−F Activation in Trifluoromethyl Groups

Abstract

The introduction of a trifluoromethyl (CF ) group into an organic molecule can modify its chemical behavior and lead to changes in its physicochemical and pharmacological properties. The CF group is often chosen for its chemical inertness and stability, which are related to the strong C-F bonds. In recent years, the potential of gaining straightforward access to difluorinated compounds through selective single C-F activation in CF groups has been unveiled. This review describes the latest methodologies for the synthesis of difluoromethylated arenes, difluoroalkenes and difluorinated aldol products of potential synthetic and/or biological interest, employing low-valent metals, transition metal catalysis, FLP and Lewis acid mediated transformations as well as photoredox catalysis.

Transition‐Metal‐Mediated and ‐Catalyzed C−F Bond Activation by Fluorine Elimination

“…Tr ansformations of carbon-fluorine (C À F) bonds have been considered to be much more difficult than those of other carbon-halogen (CÀI, CÀBr, and CÀCl) bonds because of their high bond dissociation energies. [1] Fluoroalkenes exhibit unique reactivities in their CÀFb ond activation, which involves cleavage of the C À Fb onds and the formation of new bonds such as C À C, C À O, and C À Nbonds,because of the chemical properties of the fluorine substituents.F or example, a) 1,1-difluoro-1-alkenes [2] and b) 2-trifluoromethyl-1-alkenes [3] undergo nucleophilic substitution of fluorine by an addition-elimination process using 1) the electron-withdrawing inductive effect of fluorine (a,b), 2) the repulsive interaction between the fluorine lone pairs of electrons and pelectrons (a), and 3) the substantial leaving group ability of fluorine (a,b). [4] Electron-deficient 1,1-difluoro-1-alkenes and 2-trifluoromethyl-1-alkenes undergo nucleophilic attack at the carbon atoms a and g to the fluorine substituents, respectively.Intermediary b-carbanions are generated, which are stabilized by electron-withdrawing fluorine substituents and negative hyperconjugation (Scheme 1).…”

“…[4] Electron-deficient 1,1-difluoro-1-alkenes and 2-trifluoromethyl-1-alkenes undergo nucleophilic attack at the carbon atoms a and g to the fluorine substituents, respectively.Intermediary b-carbanions are generated, which are stabilized by electron-withdrawing fluorine substituents and negative hyperconjugation (Scheme 1). [4] Subsequent bfluorine elimination readily proceeds in the two cases to afford substituted 1-fluoro-and 1,1-difluoroalkenes,r espectively.W eh ave used these procedures in an intramolecular manner to construct aw ide variety of fluorine-containing hetero-and carbocycles,w ith the nucleophiles used in these addition-elimination reactions of fluoroalkenes [2,3] being limited mostly to ionic species with alkali metal and alkaline earth metal cations.…”

2,2-difluorovinyl benzoates for diverse synthesis of gem-difluoroenol ethers by Ni-catalyzed cross-coupling reactions

“…Transition metal-catalyzed defluorinative cross-coupling reactions are attracting considerable attention for the synthesis of structurally diverse gem -difluoroalkenes (Fig. 1b ) 23 – 26 . For instance, Hu 27 pioneered the Cu-catalyzed defluorinative coupling of trifluoromethylsilane and diazoalkanes.…”

Synthesis of Polycyclic Furan and Chromene Derivatives via Cascade Reactions Enabled by Cleavage of Multiple C(sp3)−F Bonds

“…Compared with more activated aromatic [21][22][23][24][25] or vinylic analogues, [26][27][28][29][30][31][32][33] selective aliphatic C(sp 3 )À F functionalization of unreactive perfluoroalkyl substance with multiple CÀ F bonds attached remote to π-system is relatively uncommon. [34][35][36][37][38][39][40][41][42][43][44][45][46][47] The successful realization of this challenging issue is complicated by several apparent factors (Scheme 1A). First, the high strength and activation barrier of CÀ F bond (BDE CÀ F = 500 � 50 kJ/ mol) result in chemical robustness of fluorocarbon in terms of thermodynamic stability and kinetic inertness.…”