以腈为底物的过渡金属催化氮杂环化合物新合成方法研究

N-Heterocyclic compounds are widely used as the biologically and pharmaceutically active molecules, so it is of importance to develop efficient methods to synthesize these N-Heterocyclic compounds. Currently，there are less high-tolerant and simple methods to prepare 2,4,5-trisubstituted imidazoles, 3,4,5-trisubstituted isoxazoles, 1,3,4,5-tetrasubstituted pyrazoles, 1,2,4-triazoles and 1,3,5-triazines from some simple and readily available substrates. In the present project, we will use simple and readily available nitriles as the starting material. Firstly the nitrile will be converted into amidoxime or imidate intermediate with higher reaction activity through the interaction with hydroxylamine or sodium ethoxide, then the intermediate will react with other simple and readily available substrates to form these five types of N-Heterocyclic compounds in an “one-pot” process via transition-metal-catalyzed methods by using iron, copper or zinc salts as the catalysts. In the present project, the designed synthetic methods efficiently overcome these disadvantages of synthetic methods, which are used to synthesize the five types of N-Heterocyclic compounds from simple and readily available substrates. And the disadvantages of these above-mentioned synthetic methods inculde the lack of efficient methods to synthesize the 2,4,5-trisubstituted imidazoles with aliphatic substituent, trisubstituted 1,2,4-triazoles and asymmetrically substituted 1,3,5-triazines with different substituents; the poor regioselectivity for the synthesis of 3,4,5-trisubstituted isoxazoles; the frequent use of carcinogenic hydrazine reagent for the synthesis of polysubstituted pyrazoles. In addition, each of designed reaction above is an “one-pot” process, so the steps are very simple in the whole reaction process.

氮杂环化合物广泛用作生物和药物活性分子，开展有效的氮杂环化合物新合成方法研究具有重要意义。目前，对于从简单、易得的底物出发，2,4,5-三取代咪唑，3,4,5-三取代异噁唑，多取代吡唑，三取代1,2,4-三唑，1,3,5-三嗪的催化合成还缺乏一些普适性更高且简单的方法。本项目将从简单、易得的腈出发，首先通过腈与亲核试剂羟胺或醇钠的相互作用，形成活性更高的脒肟或亚胺酯中间体，再在低毒、廉价的铁、铜或锌过渡金属催化剂的催化作用下，结合一些其他简单、易得的底物，一锅合成这五类氮杂环化合物。该项目所设计的合成方法，有效地克服了从简单底物出发，直接催化合成这五类氮杂环在合成方法上的缺点，包括：含有脂肪族取代基的2,4,5-三取代咪唑、三取代的1,2,4-三唑和取代基不同非对称的1,3,5-三嗪缺乏有效的合成方法；3,4,5-三取代异噁唑合成方法区域选择性差；多取代吡唑合成常需使用致癌的肼试剂。

氮杂环化合物广泛用作生物和药物活性分子，开展有效的氮杂环化合物新合成方法研究具有重要意义。腈作为一类廉价、易得的试剂，结构较稳定且化学反应相对较差；因此如能从腈出发，温和条件下高效合成目标氮杂环衍生物，将具有广阔的应用前景。在此基础上，我们开展了一系列基于腈的氮杂环合成工作，包括：（1）非对称1,3,5-三嗪胺衍生物的制备；（2）5-氨基-1,2,4-噻二唑衍生物的制备；（3）3,5-二取代1,2,4-噻二唑衍生物的制备（4）3,5-二取代1,2,4-噁二唑的制备。此外，我们还建立了（1）从简单、易得的炔烃出发，异噁唑合成的新方法；（2）在铁催化条件下，从腈和咪唑并吡啶出发，氰甲基取代的咪唑并吡啶衍生物的新方法等。在研究过程中，我们发现在清洁的光能或电能促进作用下，结构相对稳定的腈能够得到较好的活化；与其他的一些自由基中间体能够很好的结合，高效合成我们所需的目标氮杂环衍生物，该研究工作仍在进行之中。