腈亚胺参与的多样性导向合成吡唑类杂环

1,3-Dipolar cycloaddition reactions play a pivotal role in the area of heterocycles synthesis. However, regioselective synthesis of the pyrazole ring via the 1,3-dipolar cycloaddition reaction of nitrile imine with multiple-bond remains a significant challenge for organic chemists. In this proposal, we will focus on diversity-oriented constructions of pyrazole scaffolds through the 1,3-dipolar cycloaddition between nitrile imine dipolars with dipolarophiles: (1) design and synthesize some strained cyclopropenes and cyclooctynes, then explore the cycloaddition reactions induced by the ring-strain; (2) examine the reactivity of a range of 1,3-dipolarophiles toward nitrile imine, such as arynes and ketenes; (3) evaluate the reactivity of alkynes or cyclopropane derivatives with nitrile imines promoted by modified substrates and metal. Ultimately, we hope to provide a facile and practical protocol for synthesis of diverse pyrazole, as well as drug intermediates.

1,3-偶极环加成反应已经在合成五元杂环中显示了极佳的应用前景，但是利用偶极子腈亚胺参与的1,3-偶极环加成反应来合成区域选择性的吡唑类衍生物仍极具挑战。在本课题中,我们将采取多样性导向的有机合成策略，通过原位生成的腈亚胺参与的环加成反应来构建吡唑类衍生物:(1)设计合成一些具有张力的环丙烯及环辛炔衍生物作为亲偶极体，通过环张力来促进普通烯烃及炔烃与腈亚胺的环加成反应；(2)发展其它一些高活性的亲偶极体，如芳炔、烯酮等与腈亚胺的新型1,3-偶极环加成反应；(3)采用底物结构修饰与金属催化策略，探索普通炔烃及环丙烷衍生物与腈亚胺的1,3-偶极环加成反应。项目预期将提供一条多样性导向合成吡唑类杂环的新路径，为含吡唑类药物中间体的合成提供具有实际应用价值的方案，丰富有机合成反应方法学。

1,3-偶极环加成反应已经在合成五元杂环中显示了极佳的应用前景，但是利用偶极子腈亚胺参与的1,3-偶极环加成反应来合成区域选择性的吡唑类衍生物仍极具挑战。我们通过努力，实现了张力促进的亲偶极体环丙烯衍生物（1,1-二酯基环丙烯，1,1-二氰基环丙烯）与腈亚胺的1,3-偶极环加成反应，区域选择性的得到多取代吡唑；发展了活泼亲偶极体（三氟甲基取代炔）与腈亚胺的1,3-偶极环加成反应，高区域选择性的得到4-三氟甲基-1,3-5-三芳基吡唑；实现了碘化亚铜促进下，α-氯代腙（腈亚胺前体）与末端炔的串联的加成-环化反应，区域选择性的得到1,3-5-三取代吡唑。项目的研究结果成功的提供一条多样性导向合成吡唑类杂环的新路径。