Highly regioselective synthesis of 3,4-disubstituted 1H-pyrrole

A highly regioselective method for the synthesis of 3,4-disubstituted 1H-pyrroles has been developed employing the ipso-directing property of a trimethylsilyl group. As a key starting material in this study, the known 3,4-bis(trimethylsilyl)-1H-pyrrole (3), was protected with carefully chosen groups, namely tert-butoxycarbonyl, N,N-dimethylaminosulfonyl, p-toluenesulfonyl, and triisopropylsilyl. A highly regioselective monoiodination of these 1-protected pyrroles was achieved by reaction with iodine-silver trifluoroacetate at low temperatures. Subsequent palladium-catalyzed cross-coupling reactions afforded 1-protected-4-substituted 3-trimethylsilyl-1H-pyrroles, which again underwent further room-temperature ipso-iodination and palladium-catalyzed cross-coupling reactions to provide symmetrical and unsymmetrical 1-protected-3,4-disubstituted 1H-pyrroles. Deprotection of 1-(tert-butoxycarbonyl) and 1-(N,N'-dimethylaminosulfonyl) groups was found to be nontrivial. The 1-(p-toluenesulfonyl) protecting group was eventually proved to be superior to other protection groups, because it was readily removed after stepwise ipso monoiodinations and palladium-catalyzed cross-coupling reactions.