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 beta,beta -difluoro-alpha -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 alpha,alpha -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 S(RN)1 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. (C) 2001 Elsevier Science B.V. All rights reserved.