Efficient and regioselective synthesis of pyrimido[5,4-d]pyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones with diversified substitutions

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• 作者：Xianhai Huang ; ^{xianhai.huang@merck.com} ; Nicolas Zorn ; Anandan Palani ; Robert Aslanian
• 关键词：Pyrimidopyrimidinetetraone ; Cyclization ; Heterocycles ; Regioselectivity ; Palladium catalyst ; Pyrimidinedione
• 刊名：Tetrahedron Letters
• 出版年：2012
• 出版时间：26 December, 2012
• 年：2012
• 卷：53
• 期：52
• 页码：7154-7158
• 全文大小：697 K

文摘

A highly regioselective synthesis of N3-, N5-, and N7-substituted pyrimidopyrimidinetetraones is reported. The synthesis of N5-monosubstituted and N5-, N7-disubstituted compounds was achieved through selective alkylation and urea mediated pyrimidinedione formation reactions. For the more synthetically challenging N3-, N5-, and N7-trisubstituted structures, in combination with computational studies, a palladium catalyzed cascade reaction was successfully employed for the simultaneous formation of the pyrimidinedione ring and functionalization of the N3 position, which provided the trisubstituted products in high yields with full control of regioselectivity. By applying this methodology, key intermediate 26 was prepared in a few synthetic steps in good overall yield for further functionalization and quick SAR development.