醛酮的合成-060331

1、经典合成反应标准操作 醛酮的合成 药明康德新药开发有限公司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（Cr2O3·2Py）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-

2、(COCl)2氧化（Swern Oxidation）112.3.2 DMSO-SO3-Pyridine122.4 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氧

3、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（Kröhnke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氧化合成醛酮示例264

4、.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375.4.2 McFadyen-Stevens Rea

5、ction385.5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

6、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

7、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Friedel-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701

8、5. 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

9、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（CrO2Cl2）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）、Colli

10、ns氧化法（Cr2O3·2Py）、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 stirring bar and pressure-equalizing dropping funnel is charged with et

11、hyl 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 reagent is complete, the reaction mixture is allowed to warm slowly to roo

12、m 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, the layers are separated and the aqueous layer is extracted with diethy

13、l 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 Kugelrohr distillation at 0.60 mm (oven temp 45°C) with a 250-mL receivi

14、ng bulb cooled to 78°C using a dry ice/isopropyl alcohol cold bath. The purified product (14.9 g, 52%) can be stored at 20°C for several months without decomposition. Notes： Jones reagent is prepared by dissolving chromium oxide (CrO3) (23.5 g) in con. sulfuric acid (21 mL) with cooling an

15、d 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（Cr2O3·2Py）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. Beyler, L. H. Sarett, J. Am. Chem. Soc. 75, 422 (

16、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-necked flask fitted with a sealed mechanical

17、 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 is added in portions through the neck of

18、 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 trioxide is added, an intensely y

19、ellow, 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 the initially yellow product change

20、s 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 ether. The product is collected by

21、 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 crystals. The product is extremely h

22、ygroscopic; 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 chromium (VI) oxide in anhyd

23、rous 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 red solution, but so

24、lutions 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 unhindered primary (an

25、d 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 supernatant liquid is de

26、canted 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 a chromatograph

27、ic 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，且随着碱性部分碱性的增强，氧化的选择

28、性也提高。其中，DMAP·HCrO3Cl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-shaped Teflon-

29、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 Å molecular sieves. Pyridinium chlorochromate (21.5 g, 100 mmol) is added portionwise over 10 min and the resulting mixture is stirred at room temperatur

30、e 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 re

31、sulting 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 Å (230-400 mesh) silica gel packed in a 4

32、-cm diameter 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 keto

33、ne is eluted using 500 mL of 1:1 ether:hexane and the eluent is concentrated by rotary evaporation to afford the crude ketone as a white solid. This material is dissolved in 40-45 mL of boiling hexane. Upon cooling the solution to room temperature, the ketone begins to crystallize. The flask is then

34、 cooled to 25 °C for 2 hr. The resulting solids are collected by filtration, washed with three 25-mL portions of cold (25 °C) hexane, and dried to afford 8.84-9.08 g, (86-88%) of the ketone as a white solid. Notes： PCC is prepared by addition of pyridine to a solution of chromium trioxide

35、(CrO3) in aqueous HCl and crystallization. Reference:Organic Syntheses, Vol. 80, p.1PCC的合成方法100 g of Chromium trioxide (CrO3) was dissolved in 100 ml of water and 80.6 ml of pyridine was added (keep the temperature under 30 oC), followed by 400 ml of acetone. Reaction mixture was cooled to -20 oC an

36、d yellow crystall was collected and washed with acetone and dried to give 127.2 g of PCC. Yield: 68%.2.1.4 PDC（Pyrindium Dichromate）氧化PDC的氧化能力较PCC强，其氧化作用一般在中性条件下进行，而PCC则需在酸性中进行。因此，对酸不稳定的化合物用PCC氧化时，必须在醋酸钠存在下进行。PDC的氧化一般在二氯甲烷中进行，如在DMF中进行时，氧化性增强，能将伯醇最终氧化成酸。PDC的氧化操作基本和PCC相同，这里不再举例说明。2.2 用活性MnO2氧化活性MnO2广泛

37、用于氧化,-不饱和基团（三键，双键、芳香环）的醇，可选择性氧化烯丙式醇，条件温和，不会引起双键的异构化MnO2的活性及溶剂的选择对反应至关重要，常用的溶剂有二氯甲烷、乙醚、石油醚、己烷、丙酮等。2.2.1 用活性MnO2氧化示例一:A 500-mL, round-bottomed flask, equipped with a Teflon-coated magnetic stirring bar, is charged with the 11.2 g of allylic alcohol and 300 mL of dichloromethane, and the resulting vigo

38、rously stirred solution is treated with 33 g of active manganese dioxide (380 mmol). Additional 25 g lots of the oxidant are added every 23 hr until the reaction is complete. The reaction mixture is vacuum-filtered through a pad of diatomaceous earth, and the pad is washed with 200 mL of dichloromet

39、hane. The resulting clear filtrate is concentrated carefully using a rotary evaporator, and the residual oil is purified by bulb-to-bulb distillation at 0.3 mm (pot temperature 100 °C) affording 8.438.71 g (8790%) of enone as a pale yellow oil that solidifies when cooled below 15°C. Crysta

40、llization of the crude product from pentane at 70 °C gives (4S)-()-tert-butyldimethylsiloxy-2-cyclopenten-1-one as colorless needles having mp 3233 °C, D23 65.1° (CH3OH, c 0.94). Reference: Organic Syntheses, Coll. Vol. 9, p.136; Vol. 73, p.442.2.2 用活性MnO2氧化示例二:A 100-mL, one-necked, r

41、ound-bottomed flask is fitted with an efficient reflux condenser and arranged for magnetic stirring and heating. The flask is charged with 50 mL of pentane and 2.0 g (13 mmol) of alcohol. To the rapidly stirred solution is added 16 g (180 mmol) of activated manganese (IV) oxide in small portions ove

42、r 5 min. The solution is heated at reflux for 18 hr and then an additional 8 g (90 mmol) of activated manganese (IV) oxide is added in portions. After being heated at reflux for 24 hr, the reaction mixture is filtered through a 2-cm Celite filter pad. The filtered manganese oxides are thoroughly was

43、hed with about 200300 mL of dichloromethane. Evaporation of solvent from the combined filtrates leaves 1.41.6 g of a light yellow oil. Bulb-to-bulb distillation at 100°C/0.1 mm gives 1.271.40 g (8.49.3 mmol, 6471% yield) of an oil 3-Butyroyl-1-methylpyrrole. Reference: Organic Syntheses, Coll.

44、Vol. 7, p.102; Vol. 62, p.1112.3用DMSO氧化DMSO可由各种亲电试剂（E）活化后与醇反应，生成烷氧基硫盐，接着发生消除，生成醛或酮。亲电试剂有DCC，(CH3CO)2O， (CF3CO)2O， SOCl2，(COCl)2等.2.3.1 DMSO-(COCl)2氧化（Swern Oxidation）Reference: K. Omura, D. Swern, Tetrahedron 34, 1651 (1978).Reactivity/selectivity studies: M. Marx, T. T. Tidwell, J. Org. Chem. 49, 7

45、88 (1984). Reviews: A. J. Mancuso, D. Swern, Synthesis 1981, 165-185 passim; T. T. Tidwell, Org. React. 39, 297-572 passim (1990). 各种酰氯及亚硫酰氯作为DMSO的活化剂是有效的，而由草酰氯活化的DMSO对醇的氧化最为合适。2.3.1.1 DMSO-(COCl)2氧化示例A 250-mL, three-necked, round-bottomed flask, containing a magnetic stirring bar is equipped with a

46、 low-temperature thermometer and two equalizing dropping funnels. One of these is connected to a nitrogen flow line and is charged with a solution of N-Boc-L-serinol (8.0 g, 34.6 mmol) in methylene chloride (60 mL), the other is charged with a solution of dimethyl sulfoxide (8.10 g, 103.71 mmol) in

47、10 mL of dried methylene chloride. The flask is charged with a solution of oxalyl chloride (6.58 g, 51.9 mmol) in 80 mL of methylene chloride, then cooled to 78°C in a CryoCool bath. When the solution in the flask is at 78°C, dimethyl sulfoxide is added dropwise over 25 min, while the temp

48、erature of the reaction mixture rises to 70°C. At the end of the addition the reaction solution is warmed to 60°C over a period of 20 min, then the N-Boc-L-serinol is added dropwise over 50 min and the reaction temperature rises to 55°C. The dropping funnel is washed with two 5-mL por

49、tions of methylene chloride, then charged with a solution of N,N-diisopropylethylamine (36 mL, 200 mmol) in 5 mL of methylene chloride and the reaction solution is warmed to 45°C over a period of 30 min. N,N-Diisopropylethylamine is added over 5 min, then the reaction flask is removed from the

50、CryoCool bath and allowed to warm to 0°C over 10 min. The reaction solution is transferred to a 500-mL separatory funnel charged with 130 mL of ice-cold 1 M hydrochloric acid solution. The two phases are separated, the aqueous phase is extracted with methylene chloride (3 × 30 mL), and the

51、 combined organic phases are washed with pH 7 aqueous phosphate buffer (4 × 80 mL), then dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 7.89 g (99% crude yield) of the aldehyde as a clear yellow oil. Analysis of crude aldehyde by 1H NMR indicates a chemical

52、purity of > 95%. Reference: Organic Syntheses, Coll. Vol. 10, p.320; Vol. 77, p.642.3.2 DMSO-SO3-Pyridine在常温条件下，DMSO 和 SO3-pyridine 混合，和有机碱（如三乙胺和吡啶）反应生成的中间体可以快速氧化伯醇和仲醇生成醛或酮，且收率较高。可有效的氧化烯丙醇类化合物为 a , ß-不饱和羰基化合物。还可以用来氧化生物碱类的醇化合物为酮类化合物。DMSO-SO3-pyridine试剂还用来氧化部分乙酰化的糖类化合物，得到新的不饱和的糖类化合物。 Preparati

53、on of 1,2,3,4-tetramethoxy-5-methyl-6-(3-formylpropyl)-benzeneIn anhydrous dimethyl sulfoxide (75 ml) were dissolved, 1,2,3,4-tetramethoxy-5-methyl-6- (4-hydroxybutyl)benzene (14.2 g, 50 mmole) and triethylamine (56.0 ml), and the solution was stirred at room temperature. A solution of sulfur trioxi

54、de pyridine complex (31.8 g, 200 mmole) in anhydrous dimethyl sulfoxide (75 ml) was added dropwise to the solution over a 25-minute period, followed by stirring at room temperature for 35 minutes. The reaction solution was poured into ice-water (300 g), and the product was extracted with isopropyl e

55、ther (500 ml). The isopropyl ether layer was washed with 10percent aqueous phosphoric acid solution and aqueous sodium chloride solution, successively, and dried (over MgSO4), and the solvent was distilled off. The residue was distilled under reduced pressure, thereby yielding 1,2,3,4-tetramethoxy-5

56、-methyl-6-(3-formylpropyl)-benzene (11.3 g, 80%, bp 137 to 140oC 0.7mmHg).Reference: US4393075;2.4 用氧铵盐氧化用氧铵盐氧化醇即可得到相应的醛酮。2.4.1 用氧铵盐氧化示例：A 1-L, three-necked, round-bottomed flask is fitted with a mechanical stirrer, pressure-equalizing dropping funnel, and a thermometer. The flask is charged with 44

57、.05 g (0.50 mol) of (S)-()-2-methyl-1-butanol, 0.78 g (5 mmol) of 2,2,6,6-tetramethylpiperidin-1-oxyl, 170 mL of dichloromethane, and a solution of 5.95 g (0.050 mol) of potassium bromide in 25 mL of water. The reaction mixture is vigorously stirred and cooled to 10°C with a saltice bath, then

58、550 mL (0.55 mol) of 1 M aqueous sodium hypochlorite at pH 9.5 is added over 1520 min, keeping the temperature of the reaction mixture between 10 and 15°C. The mixture is stirred for a further 3 min. The orange organic phase is separated and the aqueous phase is extracted with 50 mL of dichloromethane. The combined organic extracts are washed with 100 mL of 10% aqueous hydrochloric acid containing 1.6 g (0.010 mol) of potassium iodide, 60 mL