Palladium(II)-catalyzed oxidative a-fluorine and fluorine-containing functionalization of less acidic carbonyls

As fluorine-containing compounds display favorable physicochemical properties, metabolic stability, and bioavailability, they are widely being used in pharmaceuticals and agrochemicals, as well as material science. However, due to the weak nucleophilicity and strong basicity of fluoride, and the poor stabilities and steric hindrances of trifluoromethanide, trifluoromethoxide and trifluoromethylsulfide, the methodologies introducing fluorine and fluorine-containing substituents (CF3, OCF3, SCF3) still remain a challenge. a-Functionalization (with fluorine and fluorinated functional groups) of carbonyl compounds has so far been limited to acidic carbonyls, such as ß-ketoesters, aldehydes, and ketones. Functionalization of less acidic substrates, such as esters, nitriles, and amides remains an underdeveloped area.Palladium-allyl chemistry has mainly been used for electrophilic allylations since the 1970s. Utilizing this complex for dehydrogenations adjacent to less-acidic carbonyls was recently reported by the Newhouse group. After formation of zinc enolates from the carbonyls, transmetalation led to Pd(II) enolates and subsequent ß-hydride elimination afforded the a,ß-unsaturated products. Here, allyl esters acted as mild oxidants, which oxidize the Pd (0) back to Pd(II) species, while the allyl on the palladium acts as a ligand instead of an electrophile. Less acidic substrates, such as carboxylic acid, esters, nitriles, and amides, were successfully dehydrogenated by employing this methodology. From this view, if the Pd(II) enolates can be oxidized to high-valent palladium intermediates, a wider range of transformations could be developed.Herein, I propose a Pd(II)-catalyzed oxidative a-fluorine and fluorine-containing functionalization of less acidic carbonyls. The proposed catalytic cycle starts similarly to the one above, with transmetalation between a zinc enolate and a Pd(II) catalyst providing the palladium enolate. Oxidation of it with a strong oxidant would deliver a high-oxidation-state Pd(IV) intermediate or Pd(III) intermediate. Subsequently, either reductive elimination from the Pd(IV) species or radical transfer from the Pd(III) species would afford the functionalization product.