Synthesis of substituted phenothiazines analogous to methylene blue by electrophilic and nucleophilic aromatic substitutions in tandem. A mechanistic perspective.

3,7-Disubstituted phenothiazines analogous to methylene blue (1) were synthesized from phenothiazine (6) reacting first with an excess of bromine in acetic acid to give 3,7-dibromophenothiazin-5-ium bromide (8), according to a reaction sequence that involves two electrophilic aromatic substitutions and one oxidation. Subsequently, 8 reacting with diallylamine or allylmethylamine via two nucleophilic aromatic substitution steps gave 3,7-bis[di(2-propenyl)amino] phenothiazin-5-ium bromide (3) or 3,7-bis[methyl,(2-propenyl)amino]phenothiazin-5-ium bromide (4), compounds analogous to methylene blue. The choice of solvent for the second step is critically important as 3,7-dibromophenothiazin-5-ium bromide is very reactive and prone to irreversible oxidation, reduction, and ipso attack at the 3- and 7- positions. The best yields (similar to 63%) for the methylene blue analogues 3 and 4 were obtained when CHCl3 or CH2Cl2 were employed as solvents for the nucleophilic aromatic substitution step. These solvents dissolve the methylene blue analogue products, but not 3,7-dibromophenothiazin-5-ium bromide. (C) 1997 Elsevier Science Ltd.