Synthesis and reactivity of halogeno-difluoromethyl aromatics and heterocycles: Application to the synthesis of gem-difluorinated bioactive compounds

In an effort to prepare new fluorine-containing compounds which are active against HIV, and based on the electrochemical reduction of a series of bromodifluoromethyl compounds, the tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant of the 2-(bromodifluoromethyl)benzoxazole 1 and of the 5-(bromodifluoromethyl)-3-phenyl-1,2,4-oxadiazole 3. A stepwise electron transfer with a difluoromethyl radical as intermediate is assumed to take place in this reaction. Under mild conditions, the generated difluoromethyl heterocyclic anion was efficiently trapped with aromatic and heterocyclic aldehydes 7–14 and ketones 15–16. In this way the corresponding β,β-difluoro-α-heteroarylated alcohols 17–32 were obtained in moderate to good yields. The same methodology was successfully applied to the reduction of chlorodifluoromethylated ketones 4–6 and the generated α,α-difluoroacetyl anion was trapped with several aldehydes 7, 8, 10, 11, under mild conditions, to give the corresponding 2,2-difluoro-3-hydroxy ketone derivatives 33–38, in moderate yields. The SRN1 reactions of 2-(bromodifluoromethyl)benzoxazole (1) with the anions of heterocyclic thiols and phenolic compounds were also carried out. The products 39–54, which all have a CF2 group, were tested for activity against HIV, and several were found to be active, including 44 which was very active.