铜催化环丙醇开环氰基化反应研究
发布时间：2018-10-30 19:42
【摘要】：β位取代酮是有机化学领域一种重要的医药中间体,是合成烯酮、杂环衍生物、环化合物、二羰基化合物等的前体。近年来利用过渡金属催化环丙醇开环反应区域选择性合成β位取代酮已经被广泛报道。已经有前人工作证明铜作为催化剂催化环丙醇开环后β位C-C键构建的交叉偶联反应很有效。而氰基是一种重要的有机官能团,被广泛用于制备胺、酰胺、醛、酯和羧酸。在农药、染料、生物探针等方面均有重要的应用。因此本文致力于铜催化环丙醇开环氰基化反应的研究。以苯丁基环丙醇为模型底物,主要考察了氰基源的选择、铜催化剂的种类、溶剂的种类、反应温度、时间、各反应物的投料量等因素对反应的影响。最后确定了反应的最优条件为:环丙醇底物(0.2mmol),碘化亚铜(1Omol%),高碘氰基源(0.3mmol), 1,2-二氯乙烷(0.5ml),在氮气保护下室温反应12小时。在最优化反应条件基础上,研究反应适应性,结果显示对于芳香族和脂肪族环丙醇底物均有很高的收率(40%-79%)。对于含布洛芬、噻吩、石胆酸等药物分子结构的底物也取得了较好的反应效果,显示了在药物合成中的潜在价值。我们扩大反应规模到克级,仍然获得了 60%的收率,显示了巨大的工业化潜能。为了验证反应在药物合成领域的应用前景,我们对β位氰基代酮设计了羰基的还原以及羰基和氰基的合环反应,均取得了不错的结果。利用自由基捕捉剂TEMPO、BHT和N-叔丁基-α-苯基硝酮参与的控制反应,验证了反应可能是通过自由基机理进行的。铜催化环丙醇开环氰基化反应原料易得,条件温和,实验操作简便,官能团兼容性好。反应拓展了 C-C键断裂重排和C-C键偶联策略的概念,丰富了环丙醇开环官能团化反应的内容,为合成β位氰基酮提供了一种新的方法。
[Abstract]:尾-substituted ketones are important pharmaceutical intermediates in the field of organic chemistry. They are precursors for the synthesis of enones, heterocyclic derivatives, cyclic compounds, dicarbonyl compounds and so on. In recent years, the selective synthesis of 尾-substituted ketones by transition metal catalyzed ring opening reaction of cyclopropanol has been widely reported. It has been proved that the cross-coupling reaction of 尾 -C-C bond after ring opening of cyclopropanol catalyzed by copper as catalyst has been proved to be very effective. Cyanide is an important organic functional group, which is widely used in the preparation of amines, amides, aldehydes, esters and carboxylic acids. It has important applications in pesticide, dye, biological probe and so on. Therefore, copper-catalyzed cyclization of cyclopropanol was studied in this paper. The effects of the selection of cyanide source, the type of copper catalyst, the type of solvent, the reaction temperature, the time and the amount of each reactant on the reaction were investigated. The optimum reaction conditions were determined as follows: cyclopropanol substrate (0.2mmol), cuprous iodide (1Omol%), high iodide cyanide source (0.3mmol), and 1o 2-dichloroethane (0.5ml), which reacted at room temperature for 12 hours under nitrogen protection. On the basis of optimum reaction conditions, the reaction adaptability was studied. The results showed that the yield of cyclopropanol substrates for aromatic and aliphatic cyclopropanol was very high (40-79%). For the substrates containing ibuprofen, thiophene, cholic acid and other drugs, a good reaction effect was also obtained, which showed the potential value in drug synthesis. We expanded the scale of the reaction to the gram level, still achieved 60% yield, showing great potential for industrialization. In order to verify the application prospect of the reaction in the field of drug synthesis, we designed the reduction of carbonyl group and the ring reaction of carbonyl group and cyanyl group for 尾 -position cyanoketones, and obtained good results. The free radical trapping agent TEMPO,BHT and N- Tertiary Ding Ji-伪-phenylnitrone were used to control the reaction. It was proved that the reaction was possible through the free radical mechanism. Copper catalyzed cyclopropanol ring opening cyanation reaction is easy to obtain, the conditions are mild, the experimental operation is simple, and the functional group compatibility is good. The reaction extended the concept of C-C bond breaking rearrangement and C-C bond coupling strategy, enriched the content of ring opening group reaction of cyclopropanol, and provided a new method for the synthesis of 尾 -position cyanone.
【学位授予单位】：合肥工业大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O621.251
本文编号：2300982
[Abstract]:尾-substituted ketones are important pharmaceutical intermediates in the field of organic chemistry. They are precursors for the synthesis of enones, heterocyclic derivatives, cyclic compounds, dicarbonyl compounds and so on. In recent years, the selective synthesis of 尾-substituted ketones by transition metal catalyzed ring opening reaction of cyclopropanol has been widely reported. It has been proved that the cross-coupling reaction of 尾 -C-C bond after ring opening of cyclopropanol catalyzed by copper as catalyst has been proved to be very effective. Cyanide is an important organic functional group, which is widely used in the preparation of amines, amides, aldehydes, esters and carboxylic acids. It has important applications in pesticide, dye, biological probe and so on. Therefore, copper-catalyzed cyclization of cyclopropanol was studied in this paper. The effects of the selection of cyanide source, the type of copper catalyst, the type of solvent, the reaction temperature, the time and the amount of each reactant on the reaction were investigated. The optimum reaction conditions were determined as follows: cyclopropanol substrate (0.2mmol), cuprous iodide (1Omol%), high iodide cyanide source (0.3mmol), and 1o 2-dichloroethane (0.5ml), which reacted at room temperature for 12 hours under nitrogen protection. On the basis of optimum reaction conditions, the reaction adaptability was studied. The results showed that the yield of cyclopropanol substrates for aromatic and aliphatic cyclopropanol was very high (40-79%). For the substrates containing ibuprofen, thiophene, cholic acid and other drugs, a good reaction effect was also obtained, which showed the potential value in drug synthesis. We expanded the scale of the reaction to the gram level, still achieved 60% yield, showing great potential for industrialization. In order to verify the application prospect of the reaction in the field of drug synthesis, we designed the reduction of carbonyl group and the ring reaction of carbonyl group and cyanyl group for 尾 -position cyanoketones, and obtained good results. The free radical trapping agent TEMPO,BHT and N- Tertiary Ding Ji-伪-phenylnitrone were used to control the reaction. It was proved that the reaction was possible through the free radical mechanism. Copper catalyzed cyclopropanol ring opening cyanation reaction is easy to obtain, the conditions are mild, the experimental operation is simple, and the functional group compatibility is good. The reaction extended the concept of C-C bond breaking rearrangement and C-C bond coupling strategy, enriched the content of ring opening group reaction of cyclopropanol, and provided a new method for the synthesis of 尾 -position cyanone.
【学位授予单位】：合肥工业大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O621.251
【参考文献】
相关期刊论文 前1条
1 陶贤鉴,谭本祝;新农药AC303630的合成与应用[J];农药译丛;1998年05期
，本文编号：2300982
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