An Unique Reaction Selctivity of Electron Deficient Allylic Tin Reagonts and Synthesis of Multi Functionalized 1,4-Dihydropyridines

在氮杂环中引入有用的功能碳取代基对合成各种具有生理和药理活性的氮杂环化合物具有重要意义。我们研究了β-取代缺电子烯丙基锡试剂与被酰氯活化的氮杂环的反应，并发展了一种将这些Michael受体引入杂环的高选择性方法。我们发现，与正常的烯丙基锡试剂反应中观察到的1，2-加成反应不同，缺电子的烯丙基锡试剂与4-酰基吡啶以区域选择性的1，4-加成反应得到多官能团的4，4-二取代1，4-二氢吡啶。另一方面，在缺电子的烯丙基锡试剂与4-氰基吡啶、3-取代吡啶或3，5-二甲氧基酮基吡啶的反应中没有观察到主要的1，4-加成反应。用半经验分子轨道方法计算了不同的烯丙基锡试剂与4-取代吡啶离子的电子密度和前线分子轨道，以阐明在缺电子的烯丙基锡试剂与4-酰基吡啶的反应中出现区域选择性加成反应的原因。计算表明，实际的HSAB原理不能解释上述1，4-区域选择性，而中间体中的缺电子碳正离子与4-酰基之间的某种稳定作用将起到重要作用。此外，可以通过与上述相同的方法将Michael受体引入到异喹啉和β-咔啉体系中，实现了多环α-亚甲基-伽马-内酰胺类化合物的新合成。

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.