2,3-Dihydrospiro[1H-4- and 5-azabenzimidazole-2,1'-cyclohexane] (= spiro[cyclohexane-1,2'(3'H)-1'H-imidazo[4,5-b]pyridine] and spiro[cyclohexane-1,2'(3'H)-1'H-imidazo[4,5-c]pyridine]): Reactions with nucleophiles

Article abstract of DOI:10.1002/hlca.19940770811

The readily available title compounds 4a and 24 react with N-, O-, S-, and C-nucleophiles in presence of MnO₂ to give the corresponding mono- or disubstituted 2H-azabenzimidazoles (= azaisobenzimidazoles), e.g., 11-18 and 26a-h, respectively, or 2,3-dihydro-1H-azabenzimidazoles (= dihydro-azabenzimidazoles) such as 9 and 10 and 27 and 28, respectively, by a 1,4- or 1,6-Michael addition (Schemes 2 and 4). The bromo-dihydro-1H-azabenzimidazole 4b lost the Br-atom when treated with piperidine or morpholine yielding the corresponding disubstituted 2H-azabenzimidazole 21 (Scheme 3). Reductive ring opening of the substituted spiro compounds leads to mono- and disubstituted diaminopyridines which are intermediates for fused pyridine ring systems with substituents often not available by conventional routes and of potential pharmaceutical interest (see 32-37). E.g., starting from 4a, a three-step synthesis of the analgesic flupirtine maleate (= ethyl {2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl}carbamate maleate = Katadolon; 39) and of its non-fluorinated derivative D-7195 is described. Its analogue 40 was similarly made from the spiro compound 24.