Zinc-Catalyzed Hydroamination Route to Di- and Trisubstituted Imidazoles

Significance

Reported is the synthesis of di- and trisubstituted imidazoles 3 via the zinc-catalyzed hydroamination of propargyl amides 2 with amines 1. Both aliphatic and aromatic amines perform equally well in the reaction, providing good to excellent yields of observed products in most cases. Several functional groups, such as halogens, olefins and a free hydroxyl, are all well tolerated. The use of gaseous ammonia in an autoclave leads to an N-unsubstituted imidazole in 91% yield. Various propargyl amides (prepared by the reaction of propargyl amine with acid chlorides) were shown to participate efficiently in this process. Based on a previous related report on the synthesis of indoles by the same group (Angew. Chem. Int. Ed. 2008, 47, 2304), this reaction is proposed to ­proceed via zinc-catalyzed hydroamination-isomerization to give imine 4, which undergoes ­intramolecular cyclization and dehydration to give the desired imidazoles.