Benzo[b]thiophenes and benzo[b]furans: reactions and synthesis

The electrophilic substitution of the oxygen systems is much less regioselective than that of indole, even to the extent that the hetero-ring positions are only a little more reactive than some of the benzene ring positions. Halogen at a benzothiophene 2-position is subject to displacement with amine nucleophiles,25 and, surprisingly, rather more easily than halogen at the 3-position, even though an intermediate for 3-attack carries negative charge at C-2, adjacent to the hetero atom. In some of the earliest uses of n-butyllithium, 2-lithiobenzofuran was obtained by metal–halogen exchange between a 2-bromo-heterocycle and n-butyllithium,28 or by deprotonation of benzofuran. Reduction of the hetero-rings of both benzofuran and benzothiophene, in the latter case with retention of the sulfur, can be achieved using triethylsilane in acidic solution giving 2,3-dihydro-derivatives. Cyclisation of 2-arylthio- or 2-aryloxyaldehydes, -ketones or -acids via intramolecular electrophilic attack on the aromatic ring, with loss of water, creates the heterocyclic ring; this route is the commonest method for benzothiophenes.