Regioselective Synthesis of 2,8-Disubstituted 4-Aminopyrido[3,2-d]pyrimidine-6-carboxylic Acid Methyl Ester Compounds

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• 作者：Gwenaelle Bouscary-Desforges ; Agnes Bombrun ; John Kallikat Augustine ; G茅rald Bernardinelli ; Anna Quattropani
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：January 6, 2012
• 年：2012
• 卷：77
• 期：1
• 页码：243-252
• 全文大小：346K
• 年卷期：v.77,no.1(January 6, 2012)
• ISSN：1520-6904

文摘

We report herein the synthesis of 4-amino-2,8-dichloropyrido[3,2-d]pyrimidine derivatives 2 and their regioselective diversification through S_NAr and metal-catalyzed cross-coupling reactions. While amination of 2 took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with H眉nig鈥檚 base and C-2 addition in ⁱPrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki鈥揗iyaura reaction and the sulfanyl group by Liebeskind鈥揝rogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido[3,2-d]pyrimidine derivatives, with various substituents.