Mechanistic aspects of the bromination of 10-substituted phenothiazines

The addition of 1 and 2 molar equivalents of bromine to a series of 10-alkylphenothiazines, 1a-d (methyl, ethyl, n-propyl, and isopropyl, respectively), yields the corresponding 3-bromo- and 3,7-dibromo-10-alkylphenothiazines (11a-d and 12a-d, respectively). Evidence which supports the typical clectrophilic aromatic substitution mechanism is presented. Radical cations (12a-d.+) arc produced when 12a-d are treated with 1 or 2 molar equivalents of bromine. Upon boiling in acetic acid these radical cations are converted predominantly to 1,3,7,9-lelrabromophenothiazine (5) and the parent 3,7-dibromo-10-alkylphenothiazine (12a-d) with the evolution of hydrogen bromide. The 10-methyl radical (12a) gives, in addition, 1,3,7-tribromo-10-methylphenothiazine (15). A mechanism if proposed for these reactions in which initial dealkylution of 12b-d.+ to 3.7-dibromophenothiazine radical cation (13) occurs followed by reduction of 13.+ by bromide ion to parent 3,7-dibromophenothiazine (13). Subsequent bromination of 13 by molecular bromine produced in the previous redox reaction yields 1,3,7-tribromo-(14) and 1,3,7,9-tetra-bromo-(5) phenothiazines. The small size of the methyl group allows 12a to be brominated at the 1-position prior to dealkylation. In addition to undergoing bromination at the 3- and 7-position, 10-isopropylphenothiazine (1d) is oxidized to the radical cation 12e.+ when treated with bromine. 10-Benzylphenothiazine (1e), however, undergoes oxidation to radical cation 1e.+ exclusively. This radical cation debenzylates readily at room temperature and is converted finally into phenothiazine.