Synthesis of Difluoroethanols by the Unexpected Nucleophilic Addition of Lactones to Difluoromethyl Ketones and Dimerization of Difluoromethyl Ketones.

Difluoroethanols have increasing relevance in medicinal chemistry as fluorinated building blocks but are underexplored in synthetic chemistry. During our studies of the generation of difluoroenolates in the presence of lactones, we observed unexpected (or umpolung) reactivity in which the difluoroenolates are protonated in situ to form difluoromethyl ketones that subsequently act as electrophiles. In addition, using related conditions, the difluoromethyl ketones undergo dimerization to assemble another class of difluoroethanols, which further expands the scope of this process.