基于1,3-共轭烯炔参与的串联环化及官能化反应构建含氟杂环

吡咯、吡唑、吡啶和呋喃等杂环被公认为优势骨架，广泛存在于具有生物活性的天然产物和药物分子中。有机分子中的氢原子被氟取代后通常会导致其溶解度、代谢稳定性和生物药效率等性质发生戏剧性变化。因此,含氟杂环在有机合成和药物化学中被广泛用作为多功能合成砌块, 发展高效合成含氟杂环的方法也就倍受青睐。另一方面，活化或官能化1,3-烯炔是合成众多杂环的重要前体。本项目拟利用串联反应策略基于该类前体发展若干多取代的含氟杂环(如：吡咯、吡唑、吡喃、呋喃、吡啶和噻吩等衍生物)。具体涉及：(1) 基于活化的1,3-共轭烯炔与亲核试剂(胺、肼、羟胺、醇和硫醇等)和含氟试剂的串联加成环化及官能化反应；(2) 基于官能化1,3-烯炔(1,3-烯炔基甲酸酯、醚、硫醚、胺和酮)与含氟试剂的串联分子内环化及官能化反应。预期将获得若干氟化、三氟甲基化和三氟甲硫基化的杂环，以满足新型医药、农药、材料、日用化学品等研发需求。

Heterocycles, such as pyrroles, pyrazoles, pyridines, and furans are well-recognized as privileged scaffolds， which are usually present in a broad range of biologically active natural products and drug molecules. It is well-known that the replacement of hydrogen by fluorine in organic molecules frequently leads to dramatic changes of their properties, such as solubility, metabolic stability, and bioavailability. Fluorine-containing heterocycles have been extensively used as versatile building blocks in synthetic organic and medicinal chemistry. Therefore, the development of efficient methods for the synthesis of these fluorine-containing heterocycles has attracted great attention. Activated or functionalized 1,3-enynes are important synthetic precursors for diverse heterocycles formation. This project will focus on the development of novel tandem reactions for the synthesis of some multi-substituted fluorine-containing heterocycles, such as pyrrole, pyrazole, pyran, furan, pyridine, and thiophene derivatives. Our study involves two parts: (1) Tandem cyclization/functionalization of activated 1,3-enynes with nucleophiles (such as: amines, hydrazines, hydroxylamines, alcohols, thiols, and etc) and fluorine-containing reagents; (2) Tandem intramolecular cyclization/functionalization of functionalizated 1,3-enynes (such as 1-en-3-yn-1-yl esters, 1-en-3-yn-1-yl ethers, 1-en-3-yn-1-yl thioethers, 1-en-3-yn-1-yl amines, and 1-en-3-yn-1-yl ketones). We will expect to obtain some fluorinated, trifluoromethylated, and trifluoromethylthiolated heterocycles, to promote the development of new pharmaceuticals, pesticides, materials, daily chemicals, and etc.