Synthetic Studies on Quinazoline Derivatives. II. : The Reactions of 2-Trichloro-and 2-Trifluoroacetamidobenzophenones with Primary Amines

Abstract

The reaction of 5-chloro-2-trichloroacetamidobenzophenone (2a) with several primary alkylamines in DMSO gave high yields of 3-substituted 6-chloro-3, 4-dihydro-4-phenyl-4-trichloromethyl-2(1H)-quinazolinones 6, which were found to be formed by base-catalyzed and/or thermal cyclization and simultaneous rearrangement of the isomeric 5-chloro-2-trichloroacetamidobenzophenone alkylimines 5. Both compounds 5 and 6 were obtained when the reaction was effected in benzene. Treatment of the compound 2a with bulky amines such as isopropylamine and cyclohexylamine gave, under similar conditions, the corresponding benzophenone imines 5d and 5e exclusively, and these could be transformed into the quinazolinones 6d and 6e, respectively, on heating in pyridine or HMPT. The reaction of N-substituted trichloroacetamidobenzophenones 2m and 3n with N-(2-aminoethyl) morpholine as well as ammonia in DMSO yielded the 1-alkylaminobenzophenone imines 4m-o, which on treatment with trichloroacetyl chloride were readily cyclized to give the corresponding 1-substituted 4-trichloromethylquinazolinones 6m-o. The trichloromethyl group of the 1-unsubstituted quinazolinones 6 was easily displaced by a nucleophile such as hydride, alkoxide or hydroxide under base catalysis to give the 3, 4-dihydro-2 (1H)-quinazolinone derivative 9, 10 or 11 almost quantitatively, whereas the 1, 3-disubstituted quinazolinone 6o was not affected. The sodium borohydride reduction of the methylimine 5a at room temperature mainly afforded the trichloroacetamidobenzhydrylamine 8a, which underwent thermal cyclization to the quinazolinone 9a via split of chloroform. In contrast, the reaction of 5-chloro-2-trifluoroacetamidobenzophenone (2p) with some primary alkylamines in DMSO produced the trifluoroacetamidobenzophenone alkylimines 5p-r, which on treatment with sodium borohydride could be converted only to 3-substituted 6-chloro-3, 4-dihydro-4-phenyl-2-trifluoromethylquinazolines 15. These procedures were successfully utilized in syntheses of the imidazo [1, 2-c] quinazolinone 16, oxazolo [3, 2-c] quinazolinones 17t and 17v, and 1, 3-oxazino [3, 2-c] quinazolinone 17u.