醛酮的合成060331.docx

1、醛酮的合成060331经典化学合成反应标准操作醛酮的经典合成编者： 雷耀辉，周盛峰药明康德新药开发有限公司化学合成部目 录1前言 42由醇合成醛酮 42.1铬（VI）试剂 42.1.1 Jones氧化（Cr2O3/H2SO4/acetone） 42.1.2 Collins氧化（Cr2O32Py） 52.1.3 PCC（Pyrindium Chlorochromate）氧化 72.1.4 PDC（Pyrindium Dichromate）氧化 92.2 用活性MnO2氧化 102.2.1 用活性MnO2氧化示例一: 102.3用DMSO氧化 112.3.1 DMSO-(COCl)2氧化（Swer

2、n Oxidation） 112.3.2 DMSO-SO3-Pyridine 122.4 用氧铵盐氧化 132.4.1 用氧铵盐氧化示例： 132.5 用高价碘试剂氧化 142.5 .1 Dess-Martin氧化反应示例： 142.5.2 IBX氧化反应示例： 152.6 亚硝酸钠和醋酐氧化 152.6.1 亚硝酸钠和醋酐氧化示例 152.6 TPAP-NMO 氧化 162.6.1 TPAP-NMO 氧化示例 162.7 1,2-二醇的氧化 162.7.1 1,2-二醇的氧化示例一： 172.7.1 其他1,2-二醇的氧化相关文献： 183由卤化物合成醛酮 183.1 由伯卤甲基和仲卤甲基的

3、氧化合成醛酮 183.1.1 用DMSO氧化（Kornblum反应） 183.1.2用硝基化合物氧化（Hass反应） 203.1.3用乌洛托品氧化（Sommelet反应） 213.1.4用对亚硝基二甲苯胺氧化吡啶翁盐氧化（Krhnke反应） 223.1.5用胺氧化物氧化 223.2 由二卤甲基或二卤亚甲基合成醛酮 223.2.1 由二卤甲基合成醛反应示例： 233.3 由有机金属化合物的酰化合成醛酮 243.3.1 由有机金属化合物的酰化合成醛酮示例 253.4 由Pd催化反应合成醛 254由活泼甲基或活泼亚甲基烷烃合成醛酮 254.1 用SeO2氧化合成醛酮 264.1.1 用SeO2氧化合

4、成醛酮示例 264.2用空气氧化合成酮 264.2.1用空气氧化合成酮反应示例： 274.3 用铬酸氧化合成酮 274.3.1 用铬酸氧化合成酮示例 274.4用高锰酸盐氧化合成酮 294.5 用醌氧化合成酮 295由羧酸及其衍生物合成醛酮 305.1由羧酸合成醛 305.1.1用金属氢化物还原 305.1.2由脱CO2合成醛 315.1.3由羧酸合成酮 315.2由酰氯及酸酐合成醛酮 335.2.1用Rosenmund法合成 335.2.2用金属氢化物还原 345.3由酯及内酯合成醛 355.3.1 酯通过DIBAL还原为醛示例： 355.4由酰胺合成醛酮 365.4.1 由酰胺合成醛酮 3

5、75.4.2 McFadyen-Stevens Reaction 385.5由酯或酰氯经Weinreb酰胺合成醛酮 395.5.1 由Weinreb酰胺还原合成醛反应示例一 405.5.2由Weinreb酰胺还原合成酮反应示例: 415.6由氰合成醛酮 415.6.1DIBAL 还原腈到醛示例 （最重要的方法） 425.6.2Li(EtO)3AlH 还原腈到醛示例 （较重要的方法） 425.6.3Ranney Ni 加氢还原氰到合成醛示例 435.6.4有机金属试剂对腈加成合成酮示例 446. 由烯烃、芳环合成醛酮 456.1 由烯烃臭氧氧化合成醛 456.2 烯烃用OsO4/NaIO4氧化合

6、成醛 466.3 烯烃经由有机硼化合物中间体的烯烃甲酰化合成醛 466.5 由烯烃的甲酰化合成醛 476.5.1 Vilsmeyer 反应 476.5.2 Duffs 甲酰化 506.5.3 Reimer-Tiemann 甲酰化 516.5.4 Gattermann甲酰化 526.5.5 多聚甲醛/甲醇镁 苯酚甲酰化 526.5.6氯化锡/多聚甲醛 苯酚甲酰化 536.5.7重氮化后甲酰化 536.6烯烃经加成-氧化反应合成酮 556.6.1 烯烃经加成-氧化反应合成酮示例 557. 由炔烃合成醛酮 567.1 由加成-氧化反应合成醛酮 567.2 由氧化反应合成酮 567.3 由加成-水解反

7、应合成酮 577.4 由加成-还原反应合成酮 587.5 由加成-烷基化，酰化等反应合成酮 588. 由醚及环氧化合物合成醛酮 588.1 Claisen重排 588.2酸催化下环氧化物重排 608.2.1 酸催化下环氧化物重排合成醛酮示例一 608.3氧化法 608.4 水解法缩醛或酮合成醛酮 609. 由胺合成醛 619.1胺的氧化 619.1.1 胺的氧化合成醛反应示例： 629.2 由胺经由西佛碱的方法 639.2.1 由胺经由西佛碱合成醛示例 639.3 自苯胺衍生物合成 6310. 由硝基化合物合成醛酮 6311. 由Friedel-Crafts反应合成芳基酮 6411.1 由Fr

8、iedel-Crafts反应合成芳基酮示例 6612. Dieckmann 缩合脱酸 6813. 由合成子合成醛酮 7014. 由砜合成醛酮 7015. Michael 反应 和类似反应(Addition, Condensation) 701前言醛和酮是一类重要的有机化合物，其合成在有机合成中占有非常重要的地位。醛和酮的合成方法繁多，新合成途径也层出不穷。本部分主要以官能团的转换为主线，依次讨论了由醇、卤化物，甲基、亚甲基、羧酸及其衍生物、烯烃、炔烃、醚及环氧化合物、胺、硝基化合物等转换为醛酮的一些非常实用的方法，一些少用或罕见的反应并没有收录进去。2由醇合成醛酮由醇合成醛酮是有机合成中的一类

9、非常重要的反应。由伯醇的氧化可以得到醛。由于醛处于醇与羧酸的中间氧化状态，就必须选择适当的氧化剂加以控制，不致氧化过度而生成羧酸。由仲醇的氧化可以得到酮。但仲醇过度氧化可以导致分子开裂。由叔醇的氧化开裂、转位等反应也能合成酮，但实用范围不大。由此可见，要讨论由醇的氧化就必须从所使用氧化剂氧化性的强弱、醇分子的结构以及反应条件等多个方面入手。本部分由讨论最常用的铬（VI）氧化剂开始，依次讨论了活性MnO2，DMSO试剂，氧铵盐，高价碘化物等氧化剂在醇氧化合成醛酮反应中的应用。2.1铬（VI）试剂常用的铬（VI）试剂主要有三氧化铬（CrO3）、重铬酸、铬酸酯CrO2(OCOR)2、铬酰氯（CrO2

10、Cl2）等。为了控制醇不被过度氧化，化学家已经开发了种种氧化方法，最常用的方法有Jones氧化法（Cr2O3/H2SO4/acetone）、Collins氧化法（Cr2O32Py）、PCC（Pyrindium Chlorochromate）及PDC（Pyrindium Dichromate）氧化法等。2.1.1 Jones氧化（Cr2O3/H2SO4/acetone）Jones试剂通常可以将伯醇氧化成酸，把仲醇氧化成酮2.1.1.1（Cr2O3/H2SO4/acetone）合成方法示例A 1-L, round-bottomed flask equipped with a magnetic st

11、irring bar and pressure-equalizing dropping funnel is charged with ethyl 3-hydroxy-4-pentenoate and 400 mL of acetone. The mixture is cooled in an ice bath and Jones reagent (175 mL) is added dropwise via the dropping funnel (addition time is approximately 3040 min). When addition of the Jones reage

12、nt is complete, the reaction mixture is allowed to warm slowly to room temperature and is stirred overnight (1020 hr). Methanol (20 mL) is added to quench excess Jones reagent and the reaction mixture is poured into a 2-L separatory funnel containing diethyl ether (800 mL). After thorough mixing, th

13、e layers are separated and the aqueous layer is extracted with diethyl ether (three 200-mL portions). The combined organic layers are washed with brine (two 200-mL portions), dried over MgSO4, filtered, and the solvent is removed by simple distillation. Final purification is accomplished by Kugelroh

14、r distillation at 0.60 mm (oven temp 45C) with a 250-mL receiving bulb cooled to 78C using a dry ice/isopropyl alcohol cold bath. The purified product (14.9 g, 52%) can be stored at 20C for several months without decomposition. Notes： Jones reagent is prepared by dissolving chromium oxide (CrO3) (23

15、.5 g) in con. sulfuric acid (21 mL) with cooling and then diluting with distilled water to give a total volume of 175 mL. Reference: Organic Syntheses, Coll. Vol. 9, p.432; Vol. 71, p.2362.1.2 Collins氧化（Cr2O32Py）Collins氧化法是利用CrO3-pyridine配合物将伯醇和仲醇依次氧化成醛（和/或酸）和酮的方法。（G. I. Poos, G. E. Arth, R. E. Beyl

16、er, L. H. Sarett, J. Am. Chem. Soc. 75, 422 (1953).）Collins氧化法是在Sarett氧化法（以吡啶为溶剂）基础上的改进，以二氯甲烷为溶剂氧化伯醇为醛（J. C. Collins, Tetrahedron Letters 1968, 3363; J. C. Collins, W. W. Hess, Org. Syn. 52, 5 (1972); R. W. Ratcliffe, ibid. 55, 84 (1976).）.2.1.2.1 Dipyridine chromium(VI) oxide的制备方法A dry, 1-l., three

17、-necked flask fitted with a sealed mechanical stirrer, a thermometer, and a drying tube, is charged with 500 ml. of anhydrous pyridine, which is stirred and cooled to approximately 15 C with an ice bath. The drying tube is periodically removed and 68 g. (0.68 mole) of anhydrous chromium (VI) oxide i

18、s added in portions through the neck of the flask over a 30-minute period. The chromium trioxide should be added at such a rate that the temperature does not exceed 20 C and in such a manner that the oxide mixes rapidly with the pyridine and does not adhere to the side of the flask. As the chromium

19、trioxide is added, an intensely yellow, flocculent precipitate separates from the pyridine and the viscosity of the mixture increases. When the addition is complete, the mixture is allowed to warm slowly to room temperature with stirring. Within one hour the viscosity of the mixture decreases and th

20、e initially yellow product changes to a deep red, macrocrystalline form that settles to the bottom of the flask when stirring is discontinued. The supernatant pyridine is decanted from the complex and the crystals are washed several times by decantation with 250-ml. portions of anhydrous petroleum e

21、ther. The product is collected by filtration on a sintered glass funnel and washed with anhydrous petroleum ether, avoiding contact with the atmosphere as much as possible. The complex is dried at 10 mm. until it is free-flowing, leaving 150160 g. (8591%) of dipyridine chromium (VI) oxide as red cry

22、stals. The product is extremely hygroscopic; contact with moisture converts it rapidly to the yellow dipyridinium dichromate. It is stored at 0 in a brown bottle.Reference: Organic Syntheses, Coll. Vol. 6, p.644; Vol. 52, p.52.1.2.2 Collins氧化标准操作A sufficient quantity of a 5% solution of dipyridine c

23、hromium (VI) oxide in anhydrous dichloromethane is prepared to provide a sixfold molar ratio of complex to alcohol, an excess usually required for complete oxidation to the aldehyde. The freshly prepared, pure complex dissolves completely in dichloromethane at 25 C at 5% concentration, giving a deep

24、 red solution, but solutions usually contain small amounts of brown, insoluble material when prepared from crude complex. The alcohol, either pure or as a solution in anhydrous dichloromethane, is added to the red solution in one portion with stirring at room temperature or lower. The oxidation of u

25、nhindered primary (and secondary) alcohols proceeds to completion within 5 to 15 minutes at 25 C with deposition of brownish-black, polymeric, reduced chromiumpyridine products. When deposition of reduced chromium compounds is complete (monitoring the reaction by GC or TLC is helpful), the supernata

26、nt liquid is decanted from the (usually tarry) precipitate, which is rinsed thoroughly with dichloromethane.The combined dichloromethane solutions may be washed with dilute hydrochloric acid, sodium hydrogen carbonate solution, and water, or filtered directly through a filter aid, or passed through

27、a chromatographic column to remove traces of pyridine and chromium salts. The product is obtained by removal of dichloromethane; any pyridine that remains can often be removed under reduced pressure.2.1.3 PCC（Pyrindium Chlorochromate）氧化PCC易于合成和保存，操作简单，是将伯醇和仲醇氧化成醛和酮的应用最广的氧化方法。PCC中所用的碱除吡啶外，也可以是其它碱，且随着

28、碱性部分碱性的增强，氧化的选择性也提高。其中，DMAPHCrO3Cl为适用于烯丙醇类及苄醇类的选择性氧化试剂。PCC的氧化以均相反应为主，但有的方法是将催化剂吸附于硅胶、氧化铝等无机载体或离子交换树脂等有机高分子载体上，对醇作非均相催化氧化。后处理简单并可控制反应的选择性。2.1.3.1 PCC氧化合成方法示例:Preparation of 1,2:4,5-Di-O-isopropylidene-D-erythro-2,3-hexodiulo-2,6-pyranoseA 500-mL, round-bottomed flask equipped with a 4.5-cm, egg-shape

29、d Teflon-coated magnetic stir bar is charged with 130 mL of CH2Cl2, the alcohol prepared in Step A (10.4 g, 40.0 mmol), and 15 g of freshly powdered 3 molecular sieves. Pyridinium chlorochromate (21.5 g, 100 mmol) is added portionwise over 10 min and the resulting mixture is stirred at room temperat

30、ure for 15 hr. Ether (200 mL) is added slowly with vigorous stirring and the solution is filtered under vacuum through a pad of 35 g of Celite. The solids remaining in the reaction flask are transferred to the Celite pad by scraping with a spatula and washing with three 50-mL portions of ether. The

31、resulting cloudy brown filtrate is concentrated by rotary evaporation at room temperature to give a brown solid. To this solid is added 25 mL of 1:1 ether:hexane and the solids are scraped with a spatula. The mixture is then poured onto 60 g of Whatman 60 (230-400 mesh) silica gel packed in a 4-cm d

32、iameter chromatography column and the liquid is adsorbed onto the silica gel by gravity. The material remaining in the flask is further washed with 1:1 ether:hexane and transferred onto the silica gel; this process is repeated until all the material has been loaded onto the silica gel. The ketone is eluted using 500 mL of 1:1 ether:hexane and the eluent is concentrat