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的方法的发展对于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。我们研究了酰基氯活化的β取代缺电子烯丙基锡试剂与氮杂环的反应，并开发了一种高选择性地将这些迈克尔受体引入杂环的方法。研究发现，缺电子的烯丙基锡试剂与4-酰基吡啶的反应以区域选择性的1,4加成方式进行，得到多功能化的4,4-二取代1,4-二氢吡啶，而正常的烯丙基锡试剂则是1,2加成。另一方面，在缺电子的烯丙基锡试剂与4-氰吡啶、3-取代吡啶或3,5-二甲氧基羰基吡啶的反应中，未观察到主要的1,4加成反应。用半经验分子轨道法计算了各种烯丙基锡试剂和4-酰基吡啶离子的电子密度和前沿分子轨道，阐明了在缺电子的烯丙基锡试剂与4-酰基吡啶反应中特别观察到的区域选择性1,4加成的原因。计算结果表明，实际的HSAB原理不能解释上述1,4-区域选择性，而中间体中缺电子碳正离子与4-酰基之间的稳定相互作用将起重要作用。此外，可以用相同的方法将Michael受体引入异喹啉和-羰基羰基体系中，从而合成了一种新的多环α -亚甲基- γ -内酰胺。

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.