Tandem Michael Addition/Amino-Nitrile Cyclization from 2-Formyl-1,4-DHP in the Synthesis of Novel Dihydroindolizine-Based Compounds

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• 作者：//pubs.acs.org/images/entities/Scaron.gif" border="0">tefan Marchalí ; n ; Barbora Baumlov&aacute ; Peter Baran ; Hassan Oulyadi ; Adam Daï ; ch
• 刊名：Journal of Organic Chemistry
• 出版年：2006
• 出版时间：November 24, 2006
• 年：2006
• 卷：71
• 期：24
• 页码：9114 - 9127
• 全文大小：400K
• 年卷期：v.71,no.24(November 24, 2006)
• ISSN：1520-6904

文摘

A simple and efficient methodology for the synthesis of a small library of substituted indolizines withdifferent degrees of saturation starting from the racemic 2-formyl-1,4-DHP reagent 5 was described. Thelarge synthetic possibilities of this reagent as well as of its Knoevenagel corresponding 2-dicyanovinyl-1,4-DHP reagent 14 were investigated using four kinds of activated methylenes as nucleophiles. The keystep of the sequential reaction was based on the highly diastereoselective tandem Michael addition/intramolecular amino-nitrile cyclization catalyzed by an organic base, which resulted in the formation of1,7-dihydroindolizines in a diastereoselective manner. The process seems to be a straightforward oneand can be extended to numerous active methylenes such as malononitrile, 1,3-diketones, and alkylacetoacetates. The 1,3-hydrogen shift of partially hydrogenated indolizines was accomplished easily witha base at room temperature, giving rise to the corresponding 7,8-dihydroindolizines in very good yields.Interestingly, when the active methylene bears a leaving group, the latter process could not be accomplishedbecause a rare cis-elimination of phenylsulfinic acid and nitrous acid preceded the hydrogen shift. Theresulting 1,7-dihydroindolizines bearing an exo-methylene group at C₁ were not isolated in all cases, asthey turned rapidly to indolizines as the thermodynamically more stable products. During theseinvestigations, oxidization of 1,7-dihydroindolizines with CuCl₂ resulted in the formation of polysubstitutedpyridines. Also, the epimerization of certain 1,7-dihydroindolizines was evidenced in the solution studiedby NMR spectroscopy, whereas in the solid state, they existed only in a unique form as shown by X-raydiffraction analysis of a representative structure. Finally, all products reported herein bear a primaryamine and a nitrile function crucial for further transformations. These include the introduction of variouspharmacophore groups at either NH₂ or CN groups as well as at both groups at the same time to accessthe more elaborated indolizines fused to N- or N,N-heterocycles.