SYNTHESIS OF 5,6-DISUBSTITUTED THIENO[2,3-d]PYRIMIDINES FROM 4-CHLOROPYRIMIDINES

• Published in: Heterocycles Vol. 85; no. 6; pp. 1405 - 1416
• Main Authors: Kobayashi, Kazuhiro, Suzuki, Teruhiko, Kozuki, Taketoshi, Matsumoto, Naoki, Hiyoshi, Hidetaka, Umezu, Kazuto
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 2012
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; 4-Chloro-5-lithiopyrimidine; ONE-POT SYNTHESIS; THIENOPYRIMIDINES; KINASE INHIBITORS; Thiophene Ring Formation; IDENTIFICATION; ANTITUMOR; DISCOVERY; 4-Chloropyrimidine; Sodium Sulfide; RING; FUSED THIOPHENE; ANTAGONISTS; Thieno[2,3-d]pyrimidine; DERIVATIVES
• ISSN: 0385-5414; 1881-0942
• DOI: 10.3987/COM-12-12463

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-N-methylbenzamides 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-5-carboxaldehydes, 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.