Development of an Efficient Palladium-Catalyzed Intramolecular Carbometalation Reaction for the Synthesis of a Dibenzoxapine Containing Tetra-substituted Exocyclic Alkene†

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• 作者：Rachel N. Richey ; Hannah Yu*
• 刊名：Organic Process Research & Development
• 出版年：2009
• 出版时间：March 20, 2009
• 年：2009
• 卷：13
• 期：2
• 页码：315-320
• 全文大小：145K
• 年卷期：v.13,no.2(March 20, 2009)
• ISSN：1520-586X

文摘

A practical and scaleable synthesis of (Z)-3-(1-(8-bromodibenzo[b,e]oxepin-11(6H)-ylidene)ethyl)aniline hydrochloride (1·HCl), a key intermediate in the synthesis of a selective nuclear hormone receptor modulator, is described. The target compound is prepared in five steps from commercially available (5-bromo-2-iodophenyl)methanol (5) with a 47% overall yield. The key step involves a palladium-catalyzed intramolecular carbometalation of an alkyne, which affords the dibenzoxapine containing tetrasubstituted exocyclic alkene framework stereoselectively in a single step from readily available building blocks 4-bromo-2-(2-iodo-phenoxymethyl)-1-prop-1-ynyl-benzene (3) and 3-nitrophenylboronic acid (4). The development of each step is described. The main focus of the paper is the description and optimization of the intramolecular carbometalation of an alkyne. Eventually, the target compound 1·HCl was prepared in multikilogram quantities with >97% purity.