Synthesis of 5,6-Disubstituted Thieno[2,3-d]pyrimidines from 4-Chloropyrimidines

Abstract

Facile reaction sequences for the preparation of 5,6-disubstituted thieno[2,3-d]pyrimidines starting with 4-chloropyrimidines have been developed.4-Chloro-6-methoxypyrimidines were aroylated at the 5-positions via lithiation with LDA and subsequent treatment with benzaldehyde or N-methoxy-Nmethylbenzamides to give aryl(4-chloro-6-methoxypyrimidin-5-yl)methanones.These pyrimidinyl ketones were transformed in one-pot into 5,6-disubstituted 4-methoxythieno[2,3-d]pyrimidines by a successive treatment with sodium sulfide, BrCH 2 EWGs, and sodium hydride.Lithiation of 4,6-dichloro-2-(methylsulfanyl)pyrimidine at the 5-position was followed by treatment with tertiary formamides to give 4-chloro-6-(dialkylamino)pyrimidine-5carboxaldehydes, which could be transformed into 5,6-disubstituted 4-(dialkylamino)thieno[2,3-d]pyrimidines via aryl[4-chloro-6-(dialkylamino)pyrimidin-5-yl]methanones using the same one-pot thiophene ring forming sequence.