Study on The Generation of Reactive Intermediates through Thermal Hydrogen Shift and Their Application to Selective Heterocycle Synthesis

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In order to apply the 1,3-dipolar intermediates generated by thermal hydrogen shift of oximes and hydrazones to heterocycles synthesis, investigations on the hydrogen shift process were done. The resultant N-unsubstituted 1,3-dipoles were stabilizing by forming an hydrogen bond between the NH of the dipoles and the carbonyl oxygen located in the same molecule. Consequently, an increase of the concentration of the dipoles should be allowed to apply the dipoles to intermolecular cycloaddition reactions with dipolarophiles, which were found in few literatures. Although the reaction of the heterocyclic aldehyde oximes provided the second example for the intermolecular cycloaddition of NH-nitrone, maleimides were limited as a dipolarophile.The facile hydrazone-azomethine imine isomerization in the system was accomplished and the intermolecular cycloaddtion of the resultant dipole with olefinic dipolarophiles to afford cycloadducts efficiently and stereoselectively. The acid treatment of the … More cycloadducts caused the fission of the heterocyclic moiety to afford 2-pyrroline derivatives, which were also considered as cycloadducts of a C-unsubstituted nitrile imine and the olefinic dipolarophiles. Since only few papers on C-unsubstituted nitrile imines were found, it is very interesting from a synthetic point of view to consider these results as an equivalent reaction to C-unsubstituted nitrile imines' one.The thermal reaction of N-phenyl imines of the heterocyclic aldehyde bearing amino acid ester moieties at the adjacent position gave 2-pyrroline derivatives fused by the heterocyclic system, in which the 1,5-electrocyclic ring-closure of the α,β-unsaturated azomethine ylides generated by thermal 1,6-hydrogen shift of the imines. The relative configuration between the anilino group and the ester moiety depended on the structure of the amino acid esters; a cis configuration for acyclic amino acid esters and a trans one for cyclic amino acid esters. The discrepancy of the configuration is explained by the steric interaction in the transition state geometries of the cyclization process.As mentioned above, these synthetic reactions were performed by a simple procedure, only "heating", and afforded many heterocycles efficientiy and stereoselectively. I think that I have proposed a novel synthetic methodology matching to ecological and environmental points. Less