Palladium catalysed reactions of halogenated heterocycles

Abstract

1- The synthesis of unusually substituted halo-fluoroheterocycles has been achieved. 2,4,6-Tribromo-3,5-difluoropyridine and 4-bromo-2,3,5,6-tetrafluoropyridine were prepared from pentafluoropyridine, aluminium bromide and hydrogen bromide Reactions with lithium halides allowed the preparation of 4-iodo-2,3,5,6- tetrafluoropyridine, 4-iodo-2,6-dibromo-3,5-difluoropyridine, 4-iodo-2,3,5,6- tetrafluoropyridine and 4-chloro-2,6-dibromo-3,5-difluoropyridine.2- Reactions of 2,4,6-tribromo-3, 5-difluoropyridine with nucleophiles showed that selective substitution at the C-F centre can be achieved using hard (sodium ethoxide, phenoxide) nucleophiles.3- Lithium mediated reactions of 2,4,6-tribromo-3,5-difluoropyridine allowed selective functionalisation of the 4-position; lithium-halogen exchange occurred exclusively at this position giving a stable lithium derivative, which was successfully trapped with a range of electrophiles (trimethylsilyl chloride, acid chlorides).4- Palladium mediated couplings of 2,4,6-tribromo-3,5-difluoropyridine with a range of substituted phenylacetylenes was successful and the 2- and 6-positions were the most activated sites. Coupling with boronic acids gave the disubstituted or trisubstituted products; in the case of trisubstitution, all three positions (2-,4- and 6-) were activated towards coupling. 2,4,6-Tribromo-3,5-difluoropyridine formed a stable zinc derivative, which was coupled with iodoaromatics (iodobenzene, diiodobenzene).