Trifluoroethylation and Pentafluoropropylation of C(sp³)−H Bonds

Abstract

Polyfluorinated substituents often enhance effectiveness, improve the stability within metabolic processes, and boost the lipophilicity of biologically active compounds. However, methods for their introduction into aliphatic carbon chains remain very limited. A potentially general route to integrate the fluorinated scaffolds into organic molecules involves insertion of fluorine‐containing carbenes into C(sp3)–H bonds. The electron‐withdrawing characteristics of perfluoroalkyl groups enhances the reactivity of these carbenes which should enable the functionalization of unactivated C(sp3)–H bonds. Curiously, it appears that use of perfluoroalkyl‐containing carbenes in alkane C–H functionalization is exceedingly rare. This concept describes photolysis, enzymatic catalysis, and transition metal catalysis as three primary approaches to C(sp3)–H functionalization by trifluoromethylcarbene and its homologues.

Coinage metal-ethylene complexes of sterically demanding 1,10-phenanthroline ligands

“…The functionalization of C(sp 3 )–H bonds to obtain fluorinated molecules via the insertion of fluorinated carbene moieties is quite attractive, yet rare and of significant current interest. 54 We set out to probe this chemistry utilizing 2,2,2-trifluorodiazoethane as the carbene source and the copper( i ) catalysts 1 and 4 , following the recent important contributions of Daugulis involving “sandwich” diimine copper adducts in related chemistry. 55 The adamantane was chosen as the hydrocarbon substrate.…”

“…However, it essentially gave the same carbene insertion product yields as observed with 1 . This suggests that the high electrophilicity at the copper center, as in [ L2 Cu][BArF] is important to drive the reaction between the likely copper-carbene intermediate {[ L2 Cu]CHCF 3 } + and adamantane effectively affording the desired carbene insertion products before it reacts competitively with another molecule of 2,2,2-trifluorodiazoethane 54 producing undesired bis(trifluoromethyl)ethylene byproducts. Interestingly, silver( i ) and gold( i ) complexes 2 and 3 did not produce carbene insertion products to adamantane under these conditions.…”