The thallation-halogenation method shown in the equations, (1) and (2), was successfully applied for a regioselective and common synthetic method for indoles carrying two different kinds of halogens and consequently 4,5-, 4,6- and 4,7-dihalogenoindole-3-carboxaldehydes (13, 16 and 18) were prepared from 5-, 6- and 7-halogenoindole-3-carboxaldehydes (11, 15 and 17), respectively. Indoles having 5,7- and 6,7-dihalogens (21 and 22) were also prepared from N-acetyl-5- and 6-halogenoindolines (12 and 14), respectively. Thus, regioselective and reliable synthetic method for every dihalogenated type indoles is established. Direct bromination of methyl 4- and 7-halogenoindole-3-carboxylates (24 and 27) was found to afford regioselectively 4,5-, 4,7- and 6,7-dihalogenated type indoles (25, 26 and 28). Their structures were unequivocally proved by the direct comparisons with the authentic samples prepared from the compounds (13, 18b and 22) by means of the thallation-halogenation method. Marine indolealkaloids, 4,6-dibromo- and 3,4,6-tribromoindoles (1a and 1c) were synthesized from 4,6-dibromoindole-3-carboxaldehyde (16) prepared by the thallation-halogenation method. The first total synthesis of 4,6-dibromo-2-methylindole (1b) is achieved as shown in the Scheme 3. A synthetic approch to 4,5,6-tribromoindole (33) from N-acetyl-5-aminoindoline (34) is also reported.
