铜催化羰基化／三氟甲基化合成三氟甲基酮及其衍生物的研究

Copper salts or complexes now serve as outstanding catalysts for trifluoromethylation to introduce CF3 group into organic compounds. However, its utility in carbonylation is much less explored, even rarer in carbonylative coupling reactions. The development of novel and improved copper-catalyzed carbonylation reactions is of particular interest. To further explore the role of copper catalyst in trifluoromethylation and carbonylation, copper mediated or catalyzed trifluoromethylative/carbonylative reactions with aryl halides would be developed, which could provide an efficient approach to the trifluoromethyl ketones that are critical intermediates in constructing trifluoromethylated heterocycles, medicinal compounds, and fluorinated analogues of natural products. The project would focus on the followings: (1) copper-mediated trifluoromethylative/carbonylative reactions starting from copper(I)- trifluoromethyl complexes or copper(I)-carbon monoxide complexes; (2) copper-catalyzed trifluoromethylative/carbonylative reactions using simple copper(I) salt as catalyst, which is challenged by the side route to direct trifluoromethylation of aryl halides; (3) mechanism studies through capture of intermediates and the data collected by IR, NMR.

本项目拟发展铜催化的羰基化/三氟甲基化反应，高效原子经济性地合成具有潜在药用价值的三氟甲基酮类化合物。金属铜作为三氟甲基化反应中最普遍有效的催化剂，其在羰基化反应中的研究却还处于起始阶段，运用较少。在铜催化三氟甲基化反应基础上，进行羰基化串联反应，不仅可以加深对铜催化羰基化反应的认识，填补铜催化羰基化偶联领域的空缺; 还可拓展三氟甲基化反应运用范围，发展新型多官能团化反应。本项目拟完成：(1) 从三氟甲基铜或羰基铜络合物出发，发展不同路径条件下铜参与促进的芳基碘化物的羰基化/三氟甲基化反应；(2)从简单铜盐出发，一锅法进行铜催化的芳基碘化物的羰基化/三氟甲基化反应，解决催化循环中竞争反应芳基卤化物直接三氟甲基化等问题；(3) 通过关键中间体的捕捉、合成与表征，运用核磁、红外等手段对反应进行跟踪，了解反应历程中相关物种的转化，结合计算手段，阐明合理的反应机理与历程。

金属铜作为三氟甲基化反应中最普遍有效的催化剂，其在羰基化反应中的研究却还处于起始阶段，运用较少。本项目拟发展铜催化的羰基化/三氟甲基化反应，高效原子经济性地合成具有潜在药用价值的三氟甲基酮类化合物。我们开展了相关研究：（1）以铜为催化剂，从芳基卤化合物出发，筛选了不同的配体、溶剂、添加剂等条件，没有达到预期目标；（2）当使用全氟碘代烷烃作为底物时，在钯的催化下可以分别与端炔和苯乙烯发生偶联反应，得到相应的全氟烷基烯炔及全氟烷基烯烃类化合物；此外，全氟碘代烷烃还可以在非金属催化下与叔丁基异氰酸酯和胺类化合物反应生成全氟烷基脒类化合物；（3）针对CO毒性高，难以操控的缺点，发展了以甲酸、Mo(CO)6为羰源的羰基化反应，合成了一系列含羰基化合物。在本项目支持下，相关研究在Org. Lett., J. Catal., Adv. Synth. Catal.等国际著名学术期刊上发表10篇研究论文。