Radical Cyclization onto Polar Unsaturated Bonds. A New Method for the Synthesis of Nitrogen-Heterocycles

本工作的目的是发展一类新的自由基环化反应，用于合成氮杂环化合物。我们研究了自由基环化反应，它采用了一个系统，攻击自由基和接受不饱和度都有极性，在假设极性匹配将提高所需的环化模式。酰基自由基通常表现为亲核自由基，然而羰基碳应该具有亲电性质。因此，我们详细研究了ω-亚氨基烷基自由基与CO的反应，并观察到完全的外模环化导致内酰胺环。从头算和DFT分子轨道计算表明，环化反应的过渡态类似于亚胺氮对醛的亲核进攻，支持进攻自由基和接受N-C双键之间的极性相互作用是关键.在计算的有力支持下，我们开始寻找极性匹配促进的强有力的自由基环化反应体系，并发现氮杂烯炔的甲锡烷基羰基化反应在4-exo，5-exo，6-exo，7-exo，甚至8-exo的环化模式中是特别有用的反应。利用这种新的环化方法，可以方便地制备具有α-甲锡烷基亚甲基的四至八元环内酰胺。通过随后的质子化、碘化和Stille偶联反应，将所得的Sn-C键成功地转化为相应的H-C、I-C和C-C键。烯炔的羰基环化反应进一步扩展到以（TMS）_3SiH和烷硫醇为自由基介体的烯炔。因此，我们建立了极性控制自由基环化反应的新概念，并在α-亚甲基内酰胺的合成中得到了令人信服的结果，其基本原理在自由基反应中具有普遍的应用。

The aim of this work is to develop a new class of radical cyclization reactions available for the synthesis of nitrogen-heterocycles. We investigated radical cyclization which employs a system that both attacking radical and accepting unsaturation have a polarity, under the hypothesis that the polarity-matching would boost the desired cyclization mode. Acyl radicals generally behave as nucleophilic radical, however the carbonyl carbon should have an electrophilic nature. Thus, we examined the reaction of ω-imino alkyl radicals with CO in detail and observed that the complete exo-mode cyclization leading to lactam rings. Ab initio and DFT MO calculations revealed the transition state of the cyclization is akin to that of nucleophilic attack of imine-nitrogen to aldehyde, supporting that polar interaction between attacking radical site and accepting N-C double bond is crucial. Having a strong support from the calculation, we then embarked on the work to find powerful radical cyclization systems boosted by polarity-matching, and found that stannylcarbonylation reaction of azaenynes is particularly useful reaction in its unusual breath in the cyclization modes covering 4-exo, 5-exo, 6-exo, 7-exo, and even 8-exo. With this novel cyclization method in hand, four to eight membered ring lactarns having an α-stannylmethylene group can be prepared conveniently. The resulting Sn-C bond was successfully converted to the corresponding H-C, I-C, and C-C bonds by the subsequent protonation, iodination, and Stille coupling reaction. The carbonylative cyclization of enynes was further extended to include those with (TMS)_3SiH and alkane thiols as radical mediators. Thus, we have established a new concept of polarity-governed radical cyclization with convincing results available for α-methylene lactam synthesis, whose basic principle would have a general applications in radical reactions.