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

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.