Syntheses of aza and fluorine-substituted 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-ones

A practical and expedient synthesis of the title compounds is described. They were prepared by Stille reaction of nitro halopyridines 4 or nitro fluro-halobenzenes 10, followed by Michael addition of tert-butyl 4-aminopiperidine-1-carboxylate to the resulting activated vinyl compounds 5 and 11, hydrogenation (–NO2→–NH2), cyclic urea formation, Boc removal, and HCl salt formation. However, N3 and F1 analogs could not be made by this general strategy. Activated vinyl compounds 5a and 5d when reacted with tert-butyl 4-aminopiperidine-1-carboxylate did not stop at the desired Michael addition stage; but proceeded to produce azaindolines 8 and 9. Michael addition did not occur to compound 11d; instead, the fluorine atom was displaced.