Efficient Synthesis of a Trisubstituted 1,6-Naphthyridone from Acetonedicarboxylate and Regioselective Suzuki Arylation

• Published in: Journal of organic chemistry Vol. 70; no. 25; pp. 10342 - 10347
• Main Authors: Chung, John Y. L, Cai, Chaoxian, McWilliams, J. Christopher, Reamer, Robert A, Dormer, Peter G, Cvetovich, Raymond J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.12.2005; Amer Chemical Soc
• Subjects: Acetone - chemistry; Chemistry; Chemistry, Organic; Dicarboxylic Acids - chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Ketones - chemical synthesis; Naphthyridines - chemical synthesis; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; CROSS-COUPLING REACTIONS; ACID; DIETHYL ACETONEDICARBOXYLATE; ISOQUINOLINES; LIGANDS; MAGNESIUM COMPLEX; CONDENSATION; MEDORINONE; Suzuki coupling; Arylation; Regioselectivity; Nitrogen heterocycle; Diester; Naphtyridine derivatives; Chemical synthesis
• DOI: 10.1021/jo0514927
• ISSN: 0022-3263

An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9. A novel concomitant enamine formation and an imide cyclization afforded the nitrogen differentially protected enamide imide 12. Treatment of 12 with KO t Bu and 3-ethoxyacrylate produced lactam 15 quantitatively, which was converted to tetrachloronaphthyridone 19 via a one-pot p-methoxybenzyl (PMB) deprotection and bischlorination. A highly regioselective Pd(OAc)2/IMes-catalyzed Suzuki coupling completed the synthesis.