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

Abstract

A simple and efficient methodology for the synthesis of a small library of substituted indolizines with different degrees of saturation starting from the racemic 2-formyl-1,4-DHP reagent 5 was described. The large 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 key step 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 of 1,7-dihydroindolizines in a diastereoselective manner. The process seems to be a straightforward one and can be extended to numerous active methylenes such as malononitrile, 1,3-diketones, and alkyl acetoacetates. The 1,3-hydrogen shift of partially hydrogenated indolizines was accomplished easily with a 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 accomplished because a rare cis-elimination of phenylsulfinic acid and nitrous acid preceded the hydrogen shift. The resulting 1,7-dihydroindolizines bearing an exo-methylene group at C₁ were not isolated in all cases, as they turned rapidly to indolizines as the thermodynamically more stable products. During these investigations, oxidization of 1,7-dihydroindolizines with CuCl₂ resulted in the formation of polysubstituted pyridines. Also, the epimerization of certain 1,7-dihydroindolizines was evidenced in the solution studied by NMR spectroscopy, whereas in the solid state, they existed only in a unique form as shown by X-ray diffraction analysis of a representative structure. Finally, all products reported herein bear a primary amine and a nitrile function crucial for further transformations. These include the introduction of various pharmacophore groups at either NH₂ or CN groups as well as at both groups at the same time to access the more elaborated indolizines fused to N- or N,N-heterocycles.