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 br omine in acetic acid to give 3,7-dibromophenothiazin-5-ium bromide (8) , according to a reaction sequence that involves two electrophilic aro matic substitutions and one oxidation. Subsequently, 8 reacting with d iallylamine or allylmethylamine via two nucleophilic aromatic substitu tion steps gave 3,7-bis[di(2-propenyl)amino] phenothiazin-5-ium bromid e (3) or ,7-bis[methyl,(2-propenyl)amino]phenothiazin-5-ium bromide (4 ), compounds analogous to methylene blue. The choice of solvent for th e second step is critically important as 3,7-dibromophenothiazin-5-ium bromide is very reactive and prone to irreversible oxidation, reducti on, and ipso attack at the 3- and 7- positions. The best yields (simil ar to 63%) for the methylene blue analogues 3 and 4 were obtained when CHCl3 or CH2Cl2 were employed as solvents for the nucleophilic aromat ic substitution step. These solvents dissolve the methylene blue analo gue products, but not 3,7-dibromophenothiazin-5-ium bromide. (C) 1997 Elsevier Science Ltd.