基于廉价硝酸铜的可控化学转化与含氮杂环构建

Recent years have witnessed the renaissance and improvement of copper-catalyzed and copper-mediated organic reactions. In addition to the notable advantages such as the natural abundance, cost effectiveness, and eco-friendliness of copper in comparison to precious metals (palladium, rhodium, iridium and gold, etc.), copper salts have also been disclosed to exhibit unexpected versatility in effecting diverse carbon−carbon and carbon−heteroatom bond forming reactions. There was no doubt that copper has been explored as an ideal candidate to replace noble metals in organic synthesis, especially for practical large scale preparation. ..Copper nitrate is one of the most common cupric salts and presents as a blue crystalline solid, which features low-toxicity, inexpensiveness, commercial availability and operational easiness. Owing to the unique physical property and variable reactivity, along with its environmentally benign nature, copper nitrate has attracted evergrowing attention of organic chemists and emerged as a versatile reagent for organic synthesis. However, despite many synthetic efforts and the impressive achievements, in a stark contrast to other frequently used copper salts, copper nitrate is still employed at a limited level in organic synthesis at this stage, and was only regarded as a nitration reagent, a Lewis acid, an oxidant and a catalyst or promoter. Thus, finding new approachs of copper nitrate to promote the chemical transformation in a selective manner and construct drug-like nitrogen-containing heterocycles in a prompt and efficient way, still remains both challenging and of great value, and more efforts should be taken to desire great progress. In this proposal, copper nitrate participated controllable chemical transformation and construction of nitrogen-containing heterocycles will be developed from easily available starting materials. More attentions will be paid to solve some key scientific problems related to copper nitrate, for example, 1) the utilization of the nitrate anion of copper nitrate; 2) the high degrees of chem-, regio- and enantioselective reactions with copper nitrate, regarding cyclization, inert bond activation, nitration, difunctionalization processes as well as the asymmetric synthesis; and 3) new types of reactions by ligand-assisted copper nitrate. The mechanistic studies for these reactions will be speculated accordingly by using quantum computational method, operando infrared spectroscopy, ESI-MS/MS technology together with experimental technics. By the given approaches, some important synthetic building blocks and versatile and highly functionalized nitrogen-containing heterocycles will be developed which will be used for specific biological targets. Furthermore, this strategy will be applied for the efficient total synthesis of some commercial drugs and bioactive natural products.

随着金属有机化学的发展，廉价易得的铜盐被认为是理想的贵金属催化剂的替代品。作为常见的廉价、稳定、低毒的铜试剂，硝酸铜参与的化学反应虽已得到一些发展，但仍局限于利用其氧化性和路易斯酸性质或作为富电子底物的硝基化试剂开展研究，如何进一步挖掘硝酸铜的特殊性质，发展一些新颖、高效的有机合成反应亟待突破。本项目将在前期工作基础上，利用硝酸铜作为一类新颖的“氮源”试剂，发展有机合成新策略、新方法，高效、高选择性地构建重要的有机合成中间体及含氮杂环骨架。我们将着力研究目前硝酸铜研究中涉及的几个关键科学问题：1）挖掘和发现基于硝酸铜中硝酸根的可控化学转化；2）探讨解决硝酸铜作为催化剂或反应试剂参与的环化反应、硝基化反应、惰性键活化、双官能团化以及不对称合成等研究；3）开展硝酸铜与一些含氮或含膦配体络合后的反应、机理及应用研究。通过对反应过程、机理和应用的研究，为深入发展硝酸铜参与的反应提供新的内容和思路。

含氮分子在合成化学、生物医药以及材料科学中具有较高的学术和应用价值，但传统的合成方法一般效率较低，因此寻找新颖广谱、廉价易得的氮源试剂，发展高效、高选择性的化学反应亟待突破。本项目在实施过程中，基于对简单高效氮源试剂的系统研究，发展了一些新颖的有机合成新方法，构建了多个含氮分子库，并研究了其在生物活性方面的应用。项目从以下几个方面开展了研究工作: (1)基于硝酸铜的可控化学转化及合成应用。首次利用硝酸铜促进的高选择性烯烃断裂反应，合成了具有潜在生物活性的二氢异噁唑类化合物；利用新颖的碳-碳双键断裂反应，发展了基于烯吖内酯和简单烯烃的新型[2+2+1]环加成反应；通过新颖的-酮酸中碳-碳单键的断裂方式，实现了氧化腈中间体与亲双烯体的[3+2]环加成反应；利用铜催化下亚磺酰交叉偶联反应，实现了新颖的硫-氮键裂解和硫-碳键生成；实现了钯催化下硫醇/硫酚与对称二硫醚的非对称二硫醚合成；利用亚胺为“四碳合成子”，实现了与酮的[4+2]环加成反应，高效构建了多取代吡啶；首次利用硝酸铜作为新颖的硝酸酯源，实现了β-溴代硝酸酯和二苯磺酰胺基取代硝酸酯类化合物的高效合成；发现了部分化合物具有抗结直肠癌、抑制心血管疾病和抗肌肉萎缩等生物活性。(2)基于异腈的可控化学转化。基于异腈对硝酸铜中硝酸根阴离子转化的促进和调控作用，发展了一些异腈参与的多组分反应。实现了银催化下异腈对杂原子邻位C(sp3)-H键的连续插入反应，构建了氰基亚胺骨架；利用协同级联反应，实现了异腈对开链醚C(sp3)-H键的连续插入反应；通过异腈对酰基C-H键的三次连续插入反应，合成了4-氰基噁唑类化合物；通过简单炔烃的C(sp)-H键官能团化反应，首次发展了钯催化下异腈与炔烃和羧酸的多组分串联反应；实现了银催化下联苯异腈与羧酸的串联成环氧化脱羧C-H键烷基化反应；发展了异腈、二碲化物和羧酸锰的多组分反应，合成了N-酰基碲氨基甲酸酯类化合物。