Aromatic compounds containing a fluorine atom or a trifluoromethyl group on an aromatic ring are now widespread in medicinal chemistry. However, compounds containing more complex alkyl groups with fluorine atoms at the benzylic position are less studied because they are challenging to prepare. This limitation on the synthesis of a,a-difluoroalkyl arenes by cross-coupling chemistry arises from several properties of fluoroalkyl groups. First, a majority of coupling reactions mediated by transition metal complexes form the aryl-alkyl bond by reductive elimination from an arylmetal alkyl intermediate, and this reductive elimination is slow when the alkyl group contains fluorine on the a carbon. Second, there are few methods to prepare a,a-difluoroalkylmetal reagents.The carbonyl functionality is one of the cornerstones of organic chemistry because it can be transformed into a wide range of functional groups, including alcohols, amines, alkyl groups, and esters. Considering the versatile chemistry of the carbonyl functionality, we envisioned that an approach to prepare a variety of alkylarenes containing fluorine on the benzylic carbon atom would result from the coupling of aryl reagents with fluorinated enolates. Herein, we will present Pd- and Ni-catalyzed arylation reactions of a,a-difluoroenolates and subsequent derivatization of the resulting a-aryl-a,a-difluoro carbonyl compounds.

Pd- and Ni-catalyzed synthesis of a,a-difluorobenzylic compounds

248th National Meeting (2014)

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