Synthesis and Selective N,O-Functionalization of Pyrazolone-Fused 3-Aminoazepinones

A new class of pyrazolone-fused 3-amino-1,3,4,7-tetrahydro-2H-azepin-2-ones was synthesized from azepane-based α,β-unsaturated esters. The latter compounds were obtained efficiently from 2-Cbz-amino-N-(2-bromoallyl)-4-pentenamide derivatives through initial Pd-catalyzed methoxycarbonylation followed by ring-closing metathesis. These new 3-aminotetrahydroazepinone esters were condensed with hydrazine and oxidized under mild conditions using CuCl2. The resulting bicyclic pyrazolones were transformed into valuable building blocks for medicinal chemistry through O-triflation and through selective N-1- and O-alkylation of the pyrazolone core using (bis)electrophiles.