发展以3-乙氧基环丁酮为原料合成多种氮杂芳环的新方法

Owing to the important applications of heterocycle compounds, such as pyridine, pyrimidne，naphthyridine，furo[2,3-b]pyridine，thieno[2,3-b]pyridine and pyrrolo[2,3-b]pyridine, their synthesis had been extensively studied. By far the most prevalent strategies for constructing those rings are the classic annulation reactions such as Friedl€ander, Combes, Doebner_Miller, and Skraup syntheses, etc. However, these methods usually suffer from one or more limitations which include poor regioselectivity, low yield, high temperature, long reaction time, harsh reaction conditions, and tedious reaction procedures. Therefore, the development of mild, simple, and complementary approaches to those heterocyle derivatives is still highly desired because of their extreme significance. A concise, one-pot method is proposed for the facile synthesis of functionalized N-heterocyclic compounds from easily accessible starting materials at ambient temperature. This method could be generally useful for the preparation of a variety of substituted N-heteroaromatic compound some of which are difficult tomake via conventional approaches. The reaction could demonstrate excellent reactivity, good functional group tolerance, complete regioselectivity, and high yields. By employing 3-ethoxycyclobutanones as synthons for a Lewis acid promoted union with aromatic amines, we could show that this masked 1,3-dicarbonyl synthon might efficiently act as a three-carbon synthon of 3-ethoxycyclobutanones in the preparation of multisubstituted pyridine, pyrimidne，naphthyridine，furo[2,3-b]pyridine，thieno[2,3-b]pyridine and pyrrolo[2,3-b]pyridine which could be useful intermediates for making biologically active molecules.

经典的合成含氮芳香杂环化合物吡啶，喹啉和嘧啶制备方法如缩合反应及偶极环加成反应，常存在着诸如；反应温度高，区域选择性差，反应时间较长，产率不高，制备操作较繁琐等缺点。本研究试图发展一种新型的'3+3'表环加成反应方法来制备多种重要的杂环化合物如：naphthyridine，furo[2,3-b]pyridine， thieno[2,3-b]pyridine，pyridne，pyrimidine等。相对于传统的方法，我们希望发展的新方法具备以下特点：反应无需加热，在室温即可进行；区域选择性高；反应操作简便，原料制备简单。具体计划为设计并合成一系列取代的3-乙氧基环丁酮， 并以其为原料和取代的芳香胺，烯胺,脒，脲及硫脲反应（先进行缩合生成亚胺和腙，然后开环，关环，消除并芳香化）来制备一系列吡啶,喹啉和嘧啶类杂环化合物。这些研究将为重要杂环化合物合成提供新的有效途径，可作为现有方法学的有效补充。

本课题利用3-乙氧基环丁酮和多种杂环胺为原料，通过路易斯酸催化，发展了[3+3]环化一步合成多种含吡啶杂环化合物的方法，且具有高度的区域选择性。此法可应用于制备多种含取代基的呋喃并吡啶、吡唑并吡啶、吡咯并吡啶、吡唑并喹啉、吡咯并喹啉和噻吩并吡啶等类化合物。传统合成含吡啶杂环化合物的方法，存在着以下缺点：通常需要多种合成路线来制备不同的含吡啶杂环；此外，传统的方法需要经受不利的条件，包括苛刻的条件、难以处理的步骤和复杂的操作；再者，通过目前的方法仍然很难制备诸如吡啶并[3,2-g]吲哚、噻吩并[3,2-b]吡啶、吡咯并[3,4-b]吡啶和2H-吡唑并[3,4-f]喹啉等类化合物。相较于经典的方法，我们发展的新方法具有以下优点：一步合成且在室温下进行，操作简便，区域选择性高，方法通用，可平滑地合成多种复杂的杂环化合物，利于构建多种杂环骨架组成了的小分子库。