Development of methodology for introduction of useful functional carbon substituents into nitrogen heterocycles is of great importance for synthesis of various physiologically and pharmacologically active nitrogen heterocyclic compounds. We have studied reactions of beta-substituted electron deficient allylic tin reagents with nitrogen heterocycles activated by acyl chlorides and developed a highly selective method for introduction of those Michael acceptors to heterocycles.
It has benn found that reactions of electron deficient allylic tin reagents with 4-acylpyridines proceed in a regioselective 1,4-addition manner to give multi functionalized 4,4-disubstitued 1,4-dihydropyridines in contrast with the 1,2-addition observed in the reactions of normal allylic tin reagents. On the other hand, the predominant 1,4-addition has not been observed in the reactions of electron deficient allylic tin reagents with 4-cyanopyridine, 3-substituted pyridines, or 3,5-dimethoxycarbonylpyridine.
Electron densities and frontier molecular orbitals of various allylic tin reagents and 4-substituted pyridinium ions have been calculated by a semi-empirical molecular orbital method to clarify the reasons for the regioselective 1,4-addition observed specifically in the reactions of electron deficient allylic tin reagents with 4-acylpyridines. The calculations suggest that practical HSAB principle can not account for the above 1,4-regioselectivity and that some stabilizing interaction between the electron deficient carbocation and the 4-acyl group in the intermediate would make an important role.
In addition, the Michael acceptors can be introduced into isoquinoline and beta-carboline systems by the same method as above and a new synthesis of polycyclic alpha-methlene-gamma-lactams has been achieved.