【摘要】：β位取代酮是有機化學領域一種重要的醫(yī)藥中間體,是合成烯酮、雜環(huán)衍生物、環(huán)化合物、二羰基化合物等的前體。近年來利用過渡金屬催化環(huán)丙醇開環(huán)反應區(qū)域選擇性合成β位取代酮已經被廣泛報道。已經有前人工作證明銅作為催化劑催化環(huán)丙醇開環(huán)后β位C-C鍵構建的交叉偶聯反應很有效。而氰基是一種重要的有機官能團,被廣泛用于制備胺、酰胺、醛、酯和羧酸。在農藥、染料、生物探針等方面均有重要的應用。因此本文致力于銅催化環(huán)丙醇開環(huán)氰基化反應的研究。以苯丁基環(huán)丙醇為模型底物,主要考察了氰基源的選擇、銅催化劑的種類、溶劑的種類、反應溫度、時間、各反應物的投料量等因素對反應的影響。最后確定了反應的最優(yōu)條件為:環(huán)丙醇底物(0.2mmol),碘化亞銅(1Omol%),高碘氰基源(0.3mmol), 1,2-二氯乙烷(0.5ml),在氮氣保護下室溫反應12小時。在最優(yōu)化反應條件基礎上,研究反應適應性,結果顯示對于芳香族和脂肪族環(huán)丙醇底物均有很高的收率(40%-79%)。對于含布洛芬、噻吩、石膽酸等藥物分子結構的底物也取得了較好的反應效果,顯示了在藥物合成中的潛在價值。我們擴大反應規(guī)模到克級,仍然獲得了 60%的收率,顯示了巨大的工業(yè)化潛能。為了驗證反應在藥物合成領域的應用前景,我們對β位氰基代酮設計了羰基的還原以及羰基和氰基的合環(huán)反應,均取得了不錯的結果。利用自由基捕捉劑TEMPO、BHT和N-叔丁基-α-苯基硝酮參與的控制反應,驗證了反應可能是通過自由基機理進行的。銅催化環(huán)丙醇開環(huán)氰基化反應原料易得,條件溫和,實驗操作簡便,官能團兼容性好。反應拓展了 C-C鍵斷裂重排和C-C鍵偶聯策略的概念,豐富了環(huán)丙醇開環(huán)官能團化反應的內容,為合成β位氰基酮提供了一種新的方法。
[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-偽-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.
【學位授予單位】：合肥工業(yè)大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：O621.251

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本文編號：2300982