Decarbonylative Fluoroalkylation at Palladium(II): From Fundamental Organometallic Studies to Catalysis Article Swipe
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· 2021
· Open Access
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· DOI: https://doi.org/10.1021/jacs.1c08551
· OA: W3208641576
This Article describes the development of a decarbonylative Pd-catalyzed aryl-fluoroalkyl bond-forming reaction that couples fluoroalkylcarboxylic acid-derived electrophiles [R<sub>F</sub>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<sub>F</sub>C(O)X and Ar-M' can be avoided by using M' = boronate ester. Second, carbonyl de-insertion and Ar-R<sub>F</sub> reductive elimination are the two slowest steps of the catalytic cycle when R<sub>F</sub> = CF<sub>3</sub>. Both steps are dramatically accelerated upon changing to R<sub>F</sub> = CHF<sub>2</sub>. Computational studies reveal that a favorable F<sub>2</sub>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.
