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 C
1 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 CuCl
2 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 NH
2 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.