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

药明康德内部保密资料

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

目 录

1．前言 ................................................................................................................. 4 2．由醇合成醛酮 ................................................................................................. 4

2.1铬（VI）试剂 .............................................................................................................. 4

2.1.1 Jones氧化（Cr2O3/H2SO4/acetone） .............................................................. 4 2.1.2 Collins氧化（Cr2O3·2Py） .............................................................................. 5 2.1.3 PCC（Pyrindium Chlorochromate）氧化 ..................................................... 7 2.1.4 PDC（Pyrindium Dichromate）氧化 ............................................................. 9 2.2 用活性MnO2氧化 .................................................................................................... 10

2.2.1 用活性MnO2氧化示例一: ............................................................................ 10 2.3用DMSO氧化 ........................................................................................................... 11

2.3.1 DMSO-(COCl)2氧化（Swern Oxidation） .................................................. 11 2.3.2 DMSO-SO3-Pyridine ....................................................................................... 12 2.4 用氧铵盐氧化 ............................................................................................................ 13

2.4.1 用氧铵盐氧化示例： .................................................................................... 13 2.5 用高价碘试剂氧化 .................................................................................................... 14

2.5 .1 Dess-Martin氧化反应示例： .................................................................... 14 2.5.2 IBX氧化反应示例： .................................................................................... 15 2.6 亚硝酸钠和醋酐氧化 ................................................................................................ 15

2.6.1 亚硝酸钠和醋酐氧化示例 ............................................................................ 15 2.6 TPAP-NMO 氧化 ...................................................................................................... 16

2.6.1 TPAP-NMO 氧化示例 .................................................................................... 16 2.7 1,2-二醇的氧化 ....................................................................................................... 16

2.7.1 1,2-二醇的氧化示例一： ............................................................................. 17 2.7.1 其他1,2-二醇的氧化相关文献： ................................................................ 18

3．由卤化物合成醛酮 ....................................................................................... 18

3.1 由伯卤甲基和仲卤甲基的氧化合成醛酮 ................................................................ 18

3.1.1 用DMSO氧化（Kornblum反应） ............................................................. 18 3.1.2用硝基化合物氧化（Hass反应） ................................................................. 20 3.1.3用乌洛托品氧化（Sommelet反应） ............................................................. 21 3.1.4用对亚硝基二甲苯胺氧化吡啶翁盐氧化（Kr?hnke反应） ...................... 22 3.1.5用胺氧化物氧化 ............................................................................................... 22 3.2 由二卤甲基或二卤亚甲基合成醛酮 ........................................................................ 22

3.2.1 由二卤甲基合成醛反应示例： .................................................................... 23 3.3 由有机金属化合物的酰化合成醛酮 ........................................................................ 24

3.3.1 由有机金属化合物的酰化合成醛酮示例 .................................................... 25 3.4 由Pd催化反应合成醛 ............................................................................................. 25

4．由活泼甲基或活泼亚甲基烷烃合成醛酮 .................................................. 25

4.1 用SeO2氧化合成醛酮 .............................................................................................. 26

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4.1.1 用SeO2氧化合成醛酮示例 ............................................................................ 26 4.2用空气氧化合成酮 ..................................................................................................... 26

4.2.1用空气氧化合成酮反应示例： ....................................................................... 27 4.3 用铬酸氧化合成酮 .................................................................................................... 27

4.3.1 用铬酸氧化合成酮示例 .................................................................................. 27 4.4用高锰酸盐氧化合成酮 ............................................................................................. 29 4.5 用醌氧化合成酮 ........................................................................................................ 29

5．由羧酸及其衍生物合成醛酮 ....................................................................... 30

5.1由羧酸合成醛 ............................................................................................................. 30

5.1.1用金属氢化物还原 ........................................................................................... 30 5.1.2由脱CO2合成醛 .............................................................................................. 31 5.1.3由羧酸合成酮 ................................................................................................... 31 5.2由酰氯及酸酐合成醛酮 ............................................................................................. 33

5.2.1用Rosenmund法合成 .................................................................................... 33 5.2.2用金属氢化物还原 ........................................................................................... 34 5.3由酯及内酯合成醛 ..................................................................................................... 35

5.3.1 酯通过DIBAL还原为醛示例： ................................................................... 35 5.4由酰胺合成醛酮 ......................................................................................................... 36

5.4.1 由酰胺合成醛酮 .............................................................................................. 37 5.4.2 McFadyen-Stevens Reaction........................................................................... 38 5.5由酯或酰氯经Weinreb酰胺合成醛酮 .................................................................... 39

5.5.1 由Weinreb酰胺还原合成醛反应示例一 ..................................................... 40 5.5.2由Weinreb酰胺还原合成酮反应示例: ......................................................... 41 5.6由氰合成醛酮 ............................................................................................................. 41

5.6.1DIBAL 还原腈到醛示例 （最重要的方法） ............................................... 42 5.6.2Li(EtO)3AlH 还原腈到醛示例 （较重要的方法） ...................................... 42 5.6.3Ranney Ni 加氢还原氰到合成醛示例 ............................................................ 43 5.6.4有机金属试剂对腈加成合成酮示例 ............................................................... 44

6. 由烯烃、芳环合成醛酮 ................................................................................ 45

6.1 由烯烃臭氧氧化合成醛 ............................................................................................ 45 6.2 烯烃用OsO4/NaIO4氧化合成醛 ............................................................................. 46 6.3 烯烃经由有机硼化合物中间体的烯烃甲酰化合成醛............................................ 46 6.5 由烯烃的甲酰化合成醛 ............................................................................................ 47

6.5.1 Vilsmeyer 反应 ................................................................................................ 47 6.5.2 Duff’s 甲酰化 .................................................................................................. 50 6.5.3 Reimer-Tiemann 甲酰化 ................................................................................ 51 6.5.4 Gattermann甲酰化 ......................................................................................... 52 6.5.5 多聚甲醛/甲醇镁 苯酚甲酰化 ....................................................................... 52 6.5.6氯化锡/多聚甲醛 苯酚甲酰化 ........................................................................ 53 6.5.7重氮化后甲酰化 ............................................................................................... 53 6.6烯烃经加成-氧化反应合成酮 ................................................................................... 55

6.6.1 烯烃经加成-氧化反应合成酮示例 .............................................................. 55

7. 由炔烃合成醛酮 ............................................................................................ 56

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7.1 由加成-氧化反应合成醛酮 ...................................................................................... 56 7.2 由氧化反应合成酮 .................................................................................................... 56 7.3 由加成-水解反应合成酮 .......................................................................................... 57 7.4 由加成-还原反应合成酮 .......................................................................................... 58 7.5 由加成-烷基化，酰化等反应合成酮 ...................................................................... 58

8. 由醚及环氧化合物合成醛酮 ........................................................................ 58

8.1 Claisen重排 ............................................................................................................... 58

8.2酸催化下环氧化物重排 ............................................................................................. 60

8.2.1 酸催化下环氧化物重排合成醛酮示例一 .................................................... 60 8.3氧化法 ......................................................................................................................... 60 8.4 水解法缩醛或酮合成醛酮 ........................................................................................ 60

9. 由胺合成醛 .................................................................................................... 61

9.1胺的氧化 ..................................................................................................................... 61

9.1.1 胺的氧化合成醛反应示例： .......................................................................... 62 9.2 由胺经由西佛碱的方法 ............................................................................................ 63

9.2.1 由胺经由西佛碱合成醛示例 .......................................................................... 63 9.3 自苯胺衍生物合成 .................................................................................................... 63

10. 由硝基化合物合成醛酮 .............................................................................. 63 11. 由Friedel-Crafts反应合成芳基酮 ........................................................... 64

11.1 由Friedel-Crafts反应合成芳基酮示例 ............................................................. 66

12. Dieckmann 缩合脱酸 ................................................................................. 68 13. 由合成子合成醛酮 ...................................................................................... 70 14. 由砜合成醛酮 .............................................................................................. 70 15. Michael 反应 和类似反应(Addition, Condensation) ............................. 70

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1．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）、Collins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

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经典合成反应标准操作— 醛酮的合成

OHOOEt 药明康德新药开发有限公司

OOOEtJones reagentsacetone, 0oC to rt A 1-L, round-bottomed flask equipped with a magnetic stirring 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 30–40 min). When addition of the Jones reagent is complete, the reaction mixture is allowed to warm slowly to room temperature and is stirred overnight (10–20 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 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 Kugelrohr distillation at 0.60 mm (oven temp 45°C) with a 250-mL receiving 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 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.236

2.1.2 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 (1953).）

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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 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 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 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 the 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 ether. 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 150–160 g. (85–91%) of dipyridine chromium (VI) oxide as red crystals. 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.5

2.1.2.2 Collins氧化标准操作

A sufficient quantity of a 5% solution of dipyridine chromium (VI) oxide in anhydrous dichloromethane is prepared to provide a sixfold molar ratio of complex to alcohol, an excess

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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 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 unhindered primary (and secondary) alcohols proceeds to completion within 5 to 15 minutes at 25 °C with deposition of brownish-black, polymeric, reduced chromium–pyridine products. When deposition of reduced chromium compounds is complete (monitoring the reaction by GC or TLC is helpful), the supernatant 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 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，且随着碱性部分碱性的增强，氧化的选择性也提高。其中，DMAP·HCrO3Cl为适用于烯丙醇类及苄醇类的选择性氧化试剂。

OHHODMAP, HCrO3ClOHO

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:

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Preparation of 1,2:4,5-Di-O-isopropylidene-D-erythro-2,3-hexodiulo-2,6-pyranose

A 500-mL, round-bottomed flask equipped with a 4.5-cm, egg-shaped 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 temperature 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 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 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 ketone 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 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 (CrO3) in aqueous HCl and crystallization. Reference:Organic Syntheses, Vol. 80, p.1

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PCC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 and 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。

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2.2 用活性MnO2氧化

活性MnO2广泛用于氧化α,β-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:

TBSOOHMnO2, CH2Cl2TBSOO

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 vigorously stirred solution is treated with 33 g of active manganese dioxide (380 mmol). Additional 2–5 g lots of the oxidant are added every 2–3 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 dichloromethane. 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 8.43–8.71 g (87–90%) of enone as a pale yellow oil that solidifies when cooled below 15°C. Crystallization of the crude product from pentane at ?70 °C gives (4S)-(?)-tert-butyldimethylsiloxy-2-cyclopenten-1-one as colorless needles having mp 32–33 °C, [α]D23 ?65.1° (CH3OH, c 0.94). Reference: Organic Syntheses, Coll. Vol. 9, p.136; Vol. 73, p.44

2.2.2 用活性MnO2氧化示例二:

HOMnO2NNO A 100-mL, one-necked, round-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 over 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

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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 washed with about 200–300 mL of dichloromethane. Evaporation of solvent from the combined filtrates leaves 1.4–1.6 g of a light yellow oil. Bulb-to-bulb distillation at 100°C/0.1 mm gives 1.27–1.40 g (8.4–9.3 mmol, 64–71% yield) of an oil 3-Butyroyl-1-methylpyrrole. Reference: Organic Syntheses, Coll. Vol. 7, p.102; Vol. 62, p.111

2.3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。

SO + ESOER1R2CHOHSOR1R2S+OR2 R1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, 788 (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

BocOHDMSO, (COCl)2i-Pr2NEtOBocNCHO

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A 250-mL, three-necked, round-bottomed flask, containing a magnetic stirring bar is equipped with a 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 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 temperature 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 portions 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 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 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 purity of > 95%.

Reference: Organic Syntheses, Coll. Vol. 10, p.320; Vol. 77, p.64

2.3.2 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 , ?-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。

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Preparation of 1,2,3,4-tetramethoxy-5-methyl-6-(3-formylpropyl)-benzene

OOOOOHSO3.pyridine complexOOOOO

In 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 trioxide 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 ether (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-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：

OHCH2Cl2, aq. NaOCl, pH 9.5KBr (cat.)0-15oCONO

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 44.05 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

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stirred and cooled to ?10°C with a salt–ice bath, then 550 mL (0.55 mol) of 1 M aqueous sodium hypochlorite at pH 9.5 is added over 15–20 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 of 10% aqueous sodium thiosulfate, and 60 mL of water. The organic phase is dried over anhydrous magnesium sulfate and then distilled at atmospheric pressure through a 20-cm Vigreux distilling column to give 35.3–36.3 g (82–84%) of (S)-(+)-2-methylbutanal as a colorless oil, bp 90–92°C (GC purity >99%), [α]D22 +36.8° (acetone, c 2.5).

Reference: Organic Syntheses, Coll. Vol. 8, p.367; Vol. 69, p.212 2.5 用高价碘试剂氧化

高价碘氧化剂可以在中性或接近中性的条件下，在室温很温和的将伯醇和仲醇氧化为醛酮。一般用二氯甲烷作溶剂。

常用的高价碘氧化剂有三种，即 (Diacetoxyiodo)benzene (DIB)， o-iodoxybenzoic acid (IBX) 和Dess-Martin periodinane (DMP)。

DMP可由邻碘苯甲酸通过两步反应制得。(Dess, D. B.; Martin J.C., J. Org. Chem., 1983, 48, 4188)

ICOOHKBrO3H2SO4 93%OH-+IOOOAcOH, Ac2O 100 oC 93?OOAcIOAcOODMP

2.5 .1 Dess-Martin氧化反应示例：

OHDMPO

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Reference: J. Am. Chem. Soc. 1959, 4113

3.1.2用硝基化合物氧化（Hass反应）

将卤甲基化合物与硝基烷烃的钠盐反应，可得相应的醛。

25-80oCArCH2X + (CH3)2C=NO2-Na+ ArCH2ON=C(CH3)2 ArCHOabs. EtOH70-80%OAr = C6H5, C6H4CH3, C6H4COCH3, C6H4COOCH3, C6H4CF3, C6H4CN, C6H4Br X = Cl, Br, I

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3.1.3用乌洛托品氧化（Sommelet反应）

将卤甲基化合物与乌洛托品（六甲基四胺，HMT）反应，然后用酸水解可得相应的醛。这是将芳香族甲基变成醛的一个有效方法。

M. Sommelet, Compt. Rend. 157, 852 (1913); Bull. Soc. Chim. France [4] 23, 95 (1918). Early reviews: S. J. Angyal, Org. React. 8, 197-217 (1954); Bayer, Houben-Weyl 7/1, 194 (1954). Synthetic applications: S. Miyano et al., Bull. Chem. Soc. Japan 59, 3285 (1986); D. Evans et al., Heterocycles 26, 1569 (1987).

3.1.3用乌洛托品氧化（Sommelet反应）反应示例：

A. 2-Thienylmethylhexamethylenetetrammonium chloride. In a 1-l. round-bottomed flask are placed 67 g. (0.5 mole) of 2-chloromethylthiophene, 400 mL. of chloroform, and 70 g. (0.5 mole) of hexamethylenetetramine. The flask is fitted with a reflux condenser, and the mixture is boiled gently for 30 minutes. The mixture is cooled, and filtered on a Büchner funnel. The precipitate is washed with 100 mL. of cold chloroform, drained thoroughly, and air-dried. The yield is 128–136 g. (94–99%) of a white powder.

B. 2-Thiophenealdehyde. The hexamethylenetetrammonium salt is placed in a 2-l. round-bottomed flask containing 400 mL. of warm water. The flask is fitted for steam

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distillation, and steam is passed in until all the aldehyde has distilled. The distillate is cooled, 10 mL. of 6 N acetic acid is added, and the aldehyde is extracted with two 100-mL. portions of ether. The ether solution is dried over anhydrous calcium chloride, and the ether is evaporated on a steam bath until the volume of the solution has decreased to about 50 mL. The solution is placed in a 100-mL. Claisen flask, the ether is removed by distillation, and the aldehyde distilling at 89–91°/21 mm., n25D 1.5880, is collected. The yield is 27–30 g. (48–53%) of a colorless oily liquid which darkens slowly on standing. Reference: Organic Syntheses, CV 3, 811

3.1.4用对亚硝基二甲苯胺氧化吡啶翁盐氧化（Kr?hnke反应） F. Kr?hnke et al., Ber. 69, 2006 (1936); 71, 2583 (1938); 72, 440 (1939).

A. A. Goldberg, H. A. Walker, J. Chem. Soc. 1954, 2540; F. Kr?hnke, Angew. Chem. Int. Ed. 2, 380 (1963); A. Markovac et al., Heterocyclic Chem. 14, 19 (1977); I. Maeba et al., J. Chem. Soc. Perkin Trans. I 1991, 939; S. N. Kilenyi, Comp. Org. Syn. 7, 657-659 (1991).

3.1.5用胺氧化物氧化

胺氧化物与卤化氧化物盐，将该盐用碱处理或热分解变可得醛。

ONCH2Br+CH2ON+NaOH95%CHO

3.2 由二卤甲基或二卤亚甲基合成醛酮

将二卤甲基或二卤亚甲基化合物在酸性或碱性条件下水解，则生成相应的醛酮。比如9，9-二溴芴在醋酸中，于醋酸钠存在下加热回流即可以良好的收率生成芴酮。

NaOAc/HOAc refluxBrBr90%O

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3.2.1 由二卤甲基合成醛反应示例：

Cl2, PCl5, light, heatClClCHCl2H2SO4, H2OClCHO

p-Clorobenzal cloride was added to a 4-l. wide-mouthed bottle containing 400 cc. of concentrated sulfuric acid, and stirred vigorously (Hood) for five hours. The viscous mixture is then transferred to a separatory funnel and allowed to stand overnight, after which the lower layer is run slowly, with stirring, into a 3-l. beaker three-quarters filled with cracked ice. The cream-colored solid obtained when the ice has melted is filtered by suction, washed with water, pressed dry on the funnel, and divided into three equal parts. Each portion is dissolved in a minimum of ether, and the ether solution is repeatedly shaken with 2 per cent sodium hydroxide solution until acidification of the washings gives no precipitate of p-chlorobenzoic acid. After removal of the ether by distillation on a steam bath, the residue is distilled under diminished pressure from a Claisen flask. The yield of p-chlorobenzaldehyde distilling at 108–111°/25 mm. and melting at 46–47° is 76–84 g. (54–60 per cent of the theoretical amount).

Reference: Organic Syntheses, Coll. Vol. 2, p.133; Vol. 12, p.12

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3.3 由有机金属化合物的酰化合成醛酮

有机金属化合物（有机镁、有机锂化合物）可与过量的原甲酸脂反应，首先生成缩醛，继而用硫酸水解成醛，广泛用于脂醛及芳醛的合成，产率达55%-90%。

原甲酸脂外，甲酰胺、乙氧亚甲基苯胺（ethoxymethyleneaniline,C6H5N=CHOC2H5）等均为常用的甲酰化试剂。其中以甲酰胺的应用最为常见，常称为Bouveault反应。芳卤或乙烯卤化物与丁基锂发生金属化反应，生成芳基锂或乙烯基锂，后者与二甲基甲酰胺反应，高产率地生成相应的醛。醛或酚醚的邻位氢比较活泼，可与丁基锂直接进行金属化反应，继而甲酰化和水解，是邻羟基或邻烷氧基苯甲醛的良好合成方法。

将卤化物变为镁（Grignard试剂）或锂化物等，进行酰化可以合成醛酮。由镁（Grignard试剂）或锂化物等进行酮的合成将在由羧酸极其衍生物合成醛酮部分详细讨论，本部分只对有机金属化合物的甲酰化合成醛作一全面阐述。由有机金属化合物合成醛的甲酰化试剂以甲酸酯类、甲酰胺类用得较普遍，以DMF或N-甲酰哌啶使用较为方便。常用的甲酰化试剂有：FCHO，（HCO）HCOOCOCH3，CH（OCH3）HCO2C2H5，2O，3，

NNCHONCHOHCO2Li，PhN=CHOC2H5，Ph-N（CH3）-CHO，DMF，LM（CO）x，

ONCHOCH3，，

等。

BrMg, etherMgBrCHO1. BuLi2. DMF3. H+DMF87?%NCHOO92%NCHOCHO

G. A. Olah, Synthesis, 1984, 228;

G. A. Olah, Angew. Chem., Int. Ed. Engl., 20,878, 1981; Org. Synthesis., 64, 114, 1985; M. Bogavac, Tetrahedron Lett., 1984, 1843 E. A. Evans, Chem. Ind., 1957, 1596

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between ?78° and ?68°. After addition is complete the mixture is stirred at ?78° for 30 minutes longer. The cold reaction mixture is poured slowly with stirring into a 3-l. beaker containing 150 mL of concentrated hydrochloric acid, 300 mL of saturated aqueous sodium chloride, and 150 g. of ice. A white precipitate starts to separate. An additional 150 mL of saturated aqueous sodium chloride is added to the beaker and, after a minute, an upper layer begins to appear. The contents are transferred to a 2-l. separatory funnel and allowed to stand for 15 to 30 minutes while an upper brown layer separates. The upper layer is reserved while the lower layer is extracted with several portions of benzene, totalling 900 mL. The upper layer and the benzene extracts are combined and washed with seven 1-l. portions of water containing 10 mL. of concentrated hydrochloric acid. The benzene layer is washed successively with 100-mL. portions of aqueous 2% sodium hydrogen carbonate until the washings are basic, dried over 100 g. of anhydrous sodium sulfate, treated with 1 g. of charcoal, and filtered. The filtrate is concentrated at reduced pressure, yielding 59–62 g. (60–63%) of crude 3,5-dinitrobenzaldehyde, as a tan solid, m.p. 76–80°. Trituration in an ice bath with cold dry diethyl ether (ca. 0.3 mL/g) gives a spongy solid, m.p. 85–87° (lit.3 85°), with losses of 5–10%, sufficiently pure for most uses. Further purification may be effected by recrystallization from toluene-hexane.

Reference: Organic Syntheses, Coll. Vol. 6, p.529; Vol. 53, p.52

5.3由酯及内酯合成醛

将酯部分还原为醛常用的试剂有DIBAL及双（2-甲氧基乙氧基）氢化铝钠（SBMEA）。DIBAL对官能团的选择性高，即使分子内存在缩醛基，卤素、环氧基、氨基甲酰基几叔丁基硅醚基团时，也可将酯及内酯转化为醛及邻位羟基内醚，所以可用于许多天然物的合成。SBMEA的选择性更高，如在-70℃以下温度，对酰胺、腈及叔丁酯均无影响。

5.3.1 酯通过DIBAL还原为醛示例：

OOEtOBnOHOBnDIBAH, Et2O, -78C1.5h, then 4N HClo

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A flame-dried, 500-mL Schlenk flask equipped with a magnetic stirring bar, dropping funnel sealed with a rubber septum, and an argon balloon is loaded under an atmosphere of argon with 18.7 g (90 mmol) of (?)-(S)-ethyl 2-(benzyloxy)propanoate and the compound is dissolved in anhydrous diethyl ether (180 mL). The reaction mixture is cooled to ?78°C by means of a cooling bath (dry ice/ethanol). A 1 M solution of diisobutylaluminum hydride (DIBAH) in hexane (126 mL, 126 mmol) is added very slowly dropwise to the solution of the ester and stirring is continued for at least 1 hr after the complete addition of the DIBAH solution. Upon complete consumption of the ester, the crude reaction mixture is poured directly with vigorous stirring into 360 mL of ice cold 4 N hydrochloric acid. The aqueous phase is extracted with diethyl ether (4 × 180 mL) and the combined organic extracts are washed with 50 mL of aqueous saturated NaCl solution. After drying over MgSO4, filtration and removal of the solvents under reduced pressure by means of a rotary evaporator, 14.4 g (98%) of the crude aldehyde is obtained.

Note: 这一反应关键是要控制反应的温度，和滴加速度，否则很容易被还原为醇

Reference: Organic Syntheses, Coll. Vol. 10, p.66; Vol. 78, p.177

5.4由酰胺合成醛酮

用LAH等金属氢化物还原N，N-二取代酰胺，中间经历的半缩醛比较稳定，反应能停于此阶段而最终的醛。DIBAL和SBMEA因其操作简单，活性适中，经常用来还原酰胺为醛。

用LAH等金属氢化物还原N，N-二取代酰胺，中间经历的半缩醛比较稳定并不是因为N，N-二取代酰胺，而是分子内一定有配位键的存在，使得中间体缩醛稳定，例如：?-烷氧基的双取代酰胺，Weinreb Type 酰胺原理都是一样的。

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AlON 药明康德新药开发有限公司

OHOONOHOXORNR'R'XAlORONR'R'RONR'OROHAlNR'O

5.4.1 由酰胺合成醛酮

ONOHLiAlH(OEt)3Hexanes/THF, -78 to 0oCHO

A flame-dried, 1-L, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar is charged with 2.95 g (73.9 mmol) of 95% lithium aluminum hydride under a nitrogen atmosphere. The flask is sealed with a rubber septum containing a needle adapter to an argon-filled balloon and is charged with 170 mL of hexanes. The septum is removed and the flask is equipped with an oven-dried, 25-mL, pressure-equalizing addition funnel sealed with a rubber septum containing a needle adapter to an argon-filled balloon. The reaction flask is cooled to 0°C in an ice-water bath, the addition funnel is charged with 10.7 mL (109 mmol) of ethyl acetate, and slow, dropwise addition of ethyl acetate is initiated and completed within 1.25 hr. Upon completion of the addition, the addition funnel is removed, the reaction vessel is sealed with a rubber septum containing a needle adapter to an argon-filled balloon, and the reaction flask is cooled to ?78°C in a dry ice-acetone bath. A solution of 10.0 g (32.1 mmol) of (1S,2S)-pseudoephedrine-(R)-2-methylhydrocinnamamide in 110 mL of tetrahydrofuran is added to the cold suspension of lithium triethoxyaluminum hydride [LiAlH(OEt)3] via cannula over 5 min. Upon completion of the addition, the dry ice-acetone bath is removed and the reaction mixture is warmed to 0°C in an ice-water bath. During the

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course of warming, substantial gas evolution is observed and vented using a needle as necessary. The reaction mixture is stirred at 0°C for 1 hr, then transferred via a wide-bore cannula into a vigorously stirring solution of 400 mL of 1 N aqueous hydrochloric acid solution and 25 mL (325 mmol) of trifluoroacetic acid in an argon-purged, three-necked, 2-L, round-bottomed flask equipped with a mechanical stirrer and two rubber septa on the side-arms, one containing a needle adapter to an argon-filled balloon. A quantitative transfer is effected with 10 mL of tetrahydrofuran, and the biphasic hydrolysis mixture is stirred vigorously for 5 min at 23°C, then is poured into a 2-L separatory funnel containing 700 mL of 1 N aqueous hydrochloric acid solution. After the layers are shaken vigorously, they are separated and the aqueous layer is further extracted with three 150-mL portions of ethyl acetate. The combined organic layers are extracted with 250 mL of saturated aqueous sodium bicarbonate solution with care to avoid excessive build-up of pressure in the separatory funnel. The aqueous phase is separated and extracted with 100 mL of ethyl acetate. This ethyl acetate extract is combined with the other organic extracts, and the resulting solution is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by flash column chromatography (230-400 mesh silica gel, 270 g , packed with hexanes and eluted with 7.5% ethyl acetate-hexanes ) to afford 3.64 g (76%) of (R)-α-methylbenzenepropanal as an oil. The enantiomeric excess (ee) of this product is determined to be 95%.

Reference: Organic Syntheses, Coll. Vol. 10, p.509; Vol. 77, p.29

5.4.2 McFadyen-Stevens Reaction

Reference:J. S. McFadyen, T. S. Stevens, J. Chem. Soc. 1936, 584.

Base-catalyzed thermal decomposition of acylbenzenesulfonylhydrazines to aldehydes:

E. Mosettig, Org. React. 8, 232-240 (1954); S. Siddappa, G. A. Bhat, J. Chem. Soc. C 1971, 178; S. B. Matin et al., J. Org. Chem. 39, 2285 (1974); M. Nair, H. Shechter, Chem. Commun.

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1978, 793. Alternative hydrazide reagent: C. C. Dudman et al., Tetrahedron Letters 1980, 4645. Synthetic applications: H. Graboyes et al., J. Heterocyclic Chem. 12, 1225 (1975); R. K. Manna et al., Synth. Commun. 28, 9 (1998).

5.5由酯或酰氯经Weinreb酰胺合成醛酮

酯和酰氯与有机锂试剂、格氏试剂反应，产生的酮活性较高继续反应最终得醇。

如果将酯和酰氯变为相应的Weinreb酰胺再与有机锂试剂、格氏试剂反应则能将反应停止到醛或酮的阶段。

Weinreb酰胺和有机金属试剂的加成物形成了稳定的配合物使反应不再继续。

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