过渡金属催化官能团化腈与有机硼试剂的串联反应研究-氮杂环构建新策略

Transition metal-catalyzed reaction of nitriles with organoboron reagents is usually used to synthesize ketone compounds. However, the nitrogen atoms of nitriles have not been used and therefore low utilization of reactant atoms. This project will develop a new strategy for the synthesis of N-heterocycles involving transition metal-catalyzed tandem reaction of functionalized nitriles with organoboron reagents, leading to incorporate the nitrogen atoms of nitriles into the organic framework of target products with high atomic economy by one-pot formation of C-C and C-N bonds. This strategy will not only provides effective and convenient routes for the synthesis of a series of important N-heterocycles through the skillful design of substrate structure, but also solve the problem of the preparation of some unavailable N-heterocycles from the existing traditional methods. Transition metal-catalyzed addition/cyclization tandem reaction of functionalized nitriles (or quinazolinone-fused nitriles) with organoboron reagents, and addition/C-H amination tandem reaction of nitriles with organoboron reagents will be investigated. On the basis of the abovementioned progress, the project will further apply these new protocols for the pharmaceutical synthesis of benzodiazepines. The implementation of the project would be an important development and compliment for the reported examples on transition metal-catalyzed reaction of nitriles with organoboron reagents, afford a new strategy for the synthesis/design of N-heterocycles and pharmaceutical compounds, and broaden the application scope of nitriles. Therefore, this project is of significance both in academic and practical areas.

过渡金属催化腈与有机硼试剂的反应通常被用于合成酮类化合物，但腈底物中的N原子未被利用，存在原子利用率低的缺点。本项目拟发展过渡金属催化官能团化腈与有机硼试剂的串联反应策略，一锅法高效构建C-C和C-N多重键，将腈底物的N原子直接转入产物中，具有较高的原子经济性。该方法不仅为系列重要氮杂环化合物提供了巧妙而简便可行的合成路线，同时也解决一些传统方法难以制备的氮杂环化合物的合成问题。研究过渡金属催化官能化腈与有机硼试剂的加成/环化串联反应；含喹唑啉酮骨架腈与有机硼试剂的加成/环化串联反应；腈与有机硼试剂的加成/C-H键活化氨化串联反应。进一步将上述方法应用于相关药物的合成，为苯二氮卓类氮杂环药物分子的合成提供可借鉴的新思路。该项目的顺利实施，将是对过渡金属催化腈与有机硼试剂反应研究的重要发展和补充，为氮杂环化合物及药物分子设计与合成提供新策略，拓展了腈的应用范围，具有重要的理论价值和应用价值。

过渡金属催化腈与芳基硼酸的加成反应通常被用于合成芳基酮类化合物，但腈底物中的氮原子未完全被利用，存在原子利用率低的缺点。本项目发展了钯催化或镍催化官能团化腈与芳基硼酸的串联反应策略，一锅法高效构建碳碳键和碳氮键，将腈类底物中的氮原子转入目标含氮杂环产物中，具有较高的原子经济性。本项目主要研究了：（1）钯催化官能化腈与芳基硼酸的加成/环化串联反应，合成了异喹啉、异喹啉酮、喹唑啉、喹啉、吡啶、吡咯、吲哚、苯并呋喃并[2,3-c]吡啶和二芳基并[c,e]吖庚因等系列含氮杂环化合物；（2）钯催化含喹唑啉酮骨架腈与芳基硼酸的加成/环化串联反应，高效地合成含游离氨基的2，4-二取代喹唑啉衍生物；（3）镍催化官能化腈与芳基硼酸的加成/环化串联反应，合成了氨基异喹啉、异喹啉酮、吡啶、吡咯等含氮杂环化合物；（4）基于钯催化腈与芳香杂环化合物（如噻吩、呋喃、吡咯和吲哚）的C-H键活化/加成/环化串联反应，合成了噻吩取代苯并呋喃并[2,3-c]吡啶、呋喃取代苯并呋喃并[2,3-c]吡啶、吡咯取代苯并呋喃并[2,3-c]吡啶和吲哚取代苯并呋喃并[2,3-c]吡啶衍生物。该方法不仅为系列重要氮杂环化合物提供了巧妙而简便可行的合成路线，同时也解决一些传统方法难以制备的氮杂环化合物的合成问题。进一步将上述方法应用于相关药物中间体拓扑异构酶I抑制活性如CWJ-a-5的合成，为异喹啉类含氮杂环药物分子的合成提供可借鉴的新思路。该项目的顺利实施，将是对过渡金属催化腈与有机硼试剂反应研究的重要发展和补充，为氮杂环化合物及药物分子设计与合成提供新策略，拓展了腈的应用范围，具有重要的理论价值和应用价值。