SYNTHESIS OF 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE (3-AP)

Palladium-catalyzed cross-coupling of methylboronic acid with 2-chloro -3-nitropyridine produced 2-methyl-3-nitropyridine 4 in one step in hi gh yield. Oxidation of 4 with selenium dioxide gave aldehyde 5. Altern atively, condensation of 4 with DMFDMA followed by oxidation gave 5 in a two step higher yielding conversion. Subsequent direct coupling of 5 with thiosemicarbazide followed by reduction of the nitro group usin g stannous chloride or sodium sulfide provided 3-AP (3). Reduction wit h sodium hydrosulfite gave 3-HAP (8). Finally a route which avoids the reduction of a nitro function was devised. Thus direct coupling of st yrene with 2-chloro-3-aminopyridine 9 under Heck reaction conditions g ave 16 which was converted to 17, oxidized to the aldehyde 18 and conv erted to 3-AP (3) with in situ deblocking of the t-Boc functionality. (C) 1998 Elsevier Science Ltd. All rights reserved.