Decarbonylative Fluoroalkylation at Palladium(II): From Fundamental Organometallic Studies to Catalysis

This Article describes the development of a decarbonylative Pd-catalyzed aryl–fluoroalkyl bond-forming reaction that couples fluoroalkylcarboxylic acid-derived electrophiles [R F C(O)X] with aryl organometallics (Ar–M′). This reaction was optimized by interrogating the individual steps of the catalytic cycle (oxidative addition, carbonyl de-insertion, transmetalation, and reductive elimination) to identify a compatible pair of coupling partners and an appropriate Pd catalyst. These stoichiometric organometallic studies revealed several critical elements for reaction design. First, uncatalyzed background reactions between R F C(O)X and Ar–M′ can be avoided by using M′ = boronate ester. Second, carbonyl de-insertion and Ar–R F reductive elimination are the two slowest steps of the catalytic cycle when R F = CF 3 . Both steps are dramatically accelerated upon changing to R F = CHF 2 . Computational studies reveal that a favorable F 2 C–H---X interaction contributes to accelerating carbonyl de-insertion in this system. Finally, transmetalation is slow with X = difluoroacetate but fast with X = F. Ultimately, these studies enabled the development of an (SPhos)Pd-catalyzed decarbonylative difluoromethylation of aryl neopentylglycol boronate esters with difluoroacetyl fluoride.