醛酮的经典合成
醛酮的合成
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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OHOOEtOOOEtJones 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
NO Page 11 of 72
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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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To a solution of (Z)-hex-3-enol (9.55 g, 9.55 mmol) in CH2Cl2 (100 mL) under argon was added at 0 °C the DMP (4.85 g, 11.46 mmol). After 5 min, the reaction mixture was allowed to warm to r.t. and stirred for 1 h. The mixture was cooled down to 0 °C and washed with a satarate solution (80 mL) of NaHCO3/Na2S2O3 (1:1). After decantation the organic layer was washed once again (20 mL). The combined aqueous layers were extracted with CH2Cl2 (30 mL). After drying over MgSO4 for 2 min, the organic phase was concentrated by slow distillation of CH2Cl2 at 760 mm Hg. Addition and distillation of anhydrous benzene allowed obtaining an anhydrous solution of hex-3-enal (Yield: 95%). Reference: Synthesis 2002, No. 3, 326–330
2.5.2 IBX氧化反应示例：
OHOIBXDMSOO76%O
General procedure oxidation of alcohols with IBX: A sample of 11 mmol of recrystallised IBX and 10 mmol of general alcohols were added to (27.5mL) DMSO to form 0.4 M of solution and this mixture was stirred at room temperature for 4 h. Water (20mL) was then added to the reaction mixture to precipitate 2-iodobenzoicacid crystals, and these crystals were decanted. The mother liquid was extracted with ether (3 x 25mL), washed with NaHCO3 solution, and dried over MgSO4 to obtain aldehydes or ketones. Reference: Turk. J. Chem. 2003, 27, 713-716
2.6 亚硝酸钠和醋酐氧化
一个较实用的合成醛的方法，反应一般在室温下进行，反应时间较短，可氧化大部分伯醇、烯丙醇和苄醇，而且产率较高，副反应较少。
2.6.1 亚硝酸钠和醋酐氧化示例
OHO2NNaNO2,Ac2OO2NO
A typical procedure for oxidation of 4-nitrobenzyl alcohol: a mixture of NaNO2 (1035 mg, 15
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mmol) and 4-nitrobenzyl alcohol (5 mmol) in acetic anhydride (2 mmol) was stirred. A spontaneous exothermic reaction took place which was controlled by cooling the mixture in ice. After completion of the reaction (TLC), the product was extracted with ether (2 × 10 ml). Removal of the solvent under reduced pressure a.orded crude 4-nitrobenzaldehyde which was further puri.ed by column chromatography (petroleum ether–ethyl acetate, 9 : 1). Reference: J. Chem. Soc., Perkin Trans. 1, 2000, 3559–3560
2.6 TPAP-NMO 氧化
TPAP ([n-Pr4N][RuO4])是比较温和的将醇氧化为醛酮的方法(Reviews: Ley, Synthesis, 1994, 639)，反应为均相，收率较高，常用于对复杂分子的氧化。
OHTPAP-NMOOSitBuMe2OSitBuMe2OSitBuMe2OSitBuMe2O
2.6.1 TPAP-NMO 氧化示例
Tetrapropylammonium perruthenate (16 mg, 0.0468 mmol), N-methylmorpholine -N-oxide (0.16 g, 1.4 mmol), and 3? molecular sieves (0.47 g) were added to a solution of alcohol (400 mg, 0.94 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 30 min then filtered through a Celite? pad and the solvent evaporated in vacuo. Flash chromatography of the residue using 10% diethylether - hexane as eluent afforded 2,8-Bis(tert-butyldimethylsilyloxy) undec-10-en-6-yn-5-one (385 mg, 98%) as colorless oil. Reference:ARKIVOC 2001 (i) 74-87
2.7 1,2-二醇的氧化
氧化1,2-二醇的氧化剂一般为过碘酸及四醋酸铅。用过碘酸氧化的反应虽然选择性好且有意义，但因氧化剂不溶于有机溶，应用受到了限制。为了弥补这个缺点，可用相转移催化剂的双相体系氧化的改良法或使用硅胶的非均相反应，二者都很有效。
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乙酸钴，硝酸铊也可氧化1,2-二醇类化合物。
2.7.1 1,2-二醇的氧化示例一：
OOOHOOOHNaIO4, NaHCO3OOCHO
A large, magnetic stir bar is added to the flask that contains the crude solid diacetonide from procedure A above and 700–800 mL of dichloromethane (10 mL/g of diacetonide) is added. The flask is equipped with a condenser and heating mantle, and the slurry is stirred vigorously and heated to reflux until the solids are digested to an even consistency. The mantle is removed, the slurry is allowed to cool below reflux, and Celite (10 g) is added with stirring. The contents are further cooled to room temperature and vacuum-filtered through a pad of Celite on a glass frit filter into a three-necked, 2-L vessel. The flask is rinsed with 50 mL of dichloromethane and the rinse is filtered through the funnel. The 2-L vessel is then equipped with an overhead stirrer, thermometer, and water bath, and stirring is begun at 300–350 rpm. A solution of 30–40 mL of saturated aqueous sodium bicarbonate (0.4 mL/g of diacetonide) is added with stirring, followed by 130–140 g of sodium metaperiodate (2.0 mol equiv), added portionwise over 2–3 min. The resulting mixture is stirred while the internal temperature is maintained below 35°C with water bath cooling. After the solution is stirred for 2 hr, 35–50 g of magnesium sulfate (0.5 g/g of diacetonide) is added and stirring is continued for 20 min. The slurry is vacuum-filtered through a glass frit filter into a 2-L, one-necked, round-bottomed flask. The filter cake is removed, transferred back into the three-necked vessel, 200 mL of dichloromethane is added, and the resulting slurry is stirred for 10 min. The slurry is vacuum-filtered and the filtrate is added to the one-necked flask.
The filtrate-containing flask is equipped with a 12\column, distillation head, receiver, and heating mantle, and dichloromethane is removed by distillation (head temperature to 40°C). The residual oil is cooled and transferred to a 250-mL, round-bottomed flask and the flask is equipped with a simple distillation head, cow receiver, and heating mantle. After a brief forerun (2–3 g), product is collected by distillation at 30 mm (65–120°C)
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into a chilled receiver (5°C) to afford 54–68 g (75–85%) of crude
2,3-O-isopropylidene-D-glyceraldehyde. The crude product is transferred to a 100-mL, round-bottomed flask equipped with a 6\and redistilled at 30 mm, collecting the fraction distilling at 67–73°C into a chilled receiver to afford 50–64 g of product (70–80%, 34–45% overall). Reference: Organic Syntheses, Coll. Vol. 9, p.450; Vol. 72, p.6
2.7.1 其他1,2-二醇的氧化相关文献： 1,2-二醇可以通过甲磺酰化然后碱消除合成酮。
COOCH3HOHO1.MsCl/Et3N2.EtONaOCOOCH3
Reference:Tetrahedron Letters，1990, Pages 463-464
DMDO(dimethyldioxirane)a，NaOCl/HACb可选择性氧化仲醇
OOHOHOOOH
Reference: a）Tetrahedron Letters 1994, 8477-8480
b）Tetrahedron Letters 1982, 4647-4650
3．由卤化物合成醛酮
3.1 由伯卤甲基和仲卤甲基的氧化合成醛酮
伯卤甲基和仲卤甲基可以通过多种方法的氧化成醛酮。通常所用的氧化剂有DMSO（Kornblum反应）、硝基化合物（Hass反应）、乌洛托品（Sommelet反应）、对亚硝基二甲苯胺氧化吡啶翁盐（Krohnke反应）、胺氧化物等。
3.1.1 用DMSO氧化（Kornblum反应）
将反应活性好的卤甲基化合物与DMSO反应，生成烷氧基锍基，然后起β-消除反
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应而得醛。
本法对于活性较高的卤甲基化合物收率很好，对于活性低的卤甲基化合物，可先将其变成碘化物，然后再进行反应可得较高收率。（N. Kornblum., J. Am. Chem. Soc., 1959, 81, 4113.）
OBrDMSO r.t.84%OO
对于仲卤代物经常发生消除反应，酮的收率低下。但对α-卤代酮或α-卤代酯等活性较高的仲卤代物而言，酮的收率也较高。（N. Kornblum., J. Am. Chem. Soc., 1957, 79, 6562.）
BrDMSOO150 oC95%OO
3.1.1 .1 Kornblum反应示例：
DMSO, 150 oCI
To a flask, protected from light, containing 11 g (0.0394 mol) of silver tosylate in 100 mL of acetonitrile at 0-5℃ is added 7.0 g (0.0309 mol) of 1-indoheptane. The product is allowed to come to room temperature overnight, added to ice water, and then extracted with ether. The dried ether solution is concentrated under reduced pressure to yield an aily residue which is added to a flask containing 150 mL of dimethyl sulfoxide and 20 g of sodium bicarbonate at 150℃. Nitrogen is bubbled through the mixture. After 3 min at 150℃ the reaction mixture is cooled rapidly to room temperature and the product, 6.9 g (70%), is isolated as the 2,4-dinitrophenylhydrazine, mp 106-107℃. For benzyl halides the same procedure is used except that tosylate is heated for 5 min at 100℃ in the DMSO-sodium bicarbonate mixture. For example, p-methylbenzyl bromide gives a 65% yield of p-tolualdehyde.
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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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3.3.1 由有机金属化合物的酰化合成醛酮示例
BrFn-BuLi/DMFFCHO
n-BuLi (2.6M in hexane, 57 mL, 143 mmol) was added over 15 minutes to a THF solution (200 mL) of 2-methyl-4-fluorophenylbromide (24.5 g, 130 mmol), cooled to -78.deg. C. and allowed to stir 1 hour at -78 oC. DMF (26.61 gm, 364 mmol) was then added over 2 minutes, and the solution was allowed to stir another hour. The reaction was quenched with NH4Cl and warmed to room temperature. 10% HCl was added until the solution became acidic. The mixture was diluted with ether and the organic layer washed with water and brine, then dried over MgSO4, filtered and concentrated to give an orange oil. The oil was purified by distillation (bp=69 oC. at 7 mm Hg) to afford aldehyde 4-fluoro-2-methylbenzaldehyde as a clear liquid (13.3 g, 74%). TLC: Rf 0.30 (10% EtOAc in hexane) Reference:
3.4 由Pd催化反应合成醛
芳基卤化物及乙烯基卤化物在Pd催化剂的存在下与H2及CO反应则生成醛。
Pd(PPH3)2X2ArX + CO + H2 + R3N ArCHO125-150 oC, 1200psi
该法为高压反应，如用Si-H或Sn-H为还原剂，则也可在低压下进行甲酰化。
CH3Pd(PPh3)4 (1%)C6H5-I + CO + CSiO6H5CHOHn96%
Reference:V. P. Baillargeon, J.Am Chem Soc., 1986, 108, 452
4．由活泼甲基或活泼亚甲基烷烃合成醛酮
甲基可被许多氧化剂如SeO2、铬酸、次卤酸等氧化为醛，特别是与羰基及芳香环
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相邻的活性甲基更易氧化。其中SeO2的选择性较好，是最常用的氧化方法之一。相比之下，由亚甲基氧化合成酮的方法较多。主要有用SeO2氧化、用空气氧化、用铬酸氧化、用高锰酸盐氧化、用醌氧化等方法。
4.1 用SeO2氧化合成醛酮
羰基及与芳香环相邻的活泼甲基、亚甲基很容易被SeO2氧化为相应的醛酮。反应操作简单，选择性、重复性良好。 4.1.1 用SeO2氧化合成醛酮示例
OSeO2, H2Odioxane, heatOO
In a 1-l. three-necked, round-bottomed flask, fitted with a liquid-sealed stirrer and a reflux condenser, are placed 600 cc. of dioxane, 111 g. (1 mole) of selenium dioxide, and 20 cc. of water. The mixture is heated to 50–55° and stirred until the solid has gone into solution, 120 g. (1 mole) of acetophenone is added in one lot, and the resulting mixture is refluxed with continued stirring for four hours. The hot solution is decanted from the precipitated selenium, and the dioxane and water are removed by distillation through a short column. The phenylglyoxal is distilled at diminished pressure from a 250-cc. Claisen flask, and the fraction boiling at 95–97°/25 mm. collected. The yield is 93–96 g. (69–72 per cent of the theoretical amount).
The aldehyde sets to a stiff gel on standing, probably as the result of polymerization. It may be recovered without appreciable loss by distillation. Phenylglyoxal may be preserved also in the form of the hydrate, which is conveniently prepared by dissolving the yellow liquid in 3.5–4 volumes of hot water and allowing crystallization to take place. Reference: Organic Syntheses, Coll. Vol. 2, p.509; Vol. 15, p.67
4.2用空气氧化合成酮
二芳基甲烷衍生物比较容易氧化，由于产物酮是稳定的，所以各种氧化均能有良好
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收率。比如芴或二芳基甲烷在Co2O的存在下，空气氧化可以定量地得到相应的酮。
Co2O3, O2C6H6, reflux99%O
二芳基甲烷衍生物在叔丁醇钾、Triton B、KOH等碱存在下，用氧气使之氧化，酮的收率很高。
4.2.1用空气氧化合成酮反应示例：
MeOSSCHOO2, 50% KOH 95% ethanol 88%MeOSOSCHO
8 g of 5-((5-methoxythiophen-2-yl)methyl)thiophene-2-carbaldehyde (0.0303 mol) was dissolved in 1250 mL of 95% ethanol. 0.8 g of 50% KOH solution was added under vigorous stirring. The solution changed to deep blue. O2 was bubled to the solution for 30 min untill blue color of the solution dissapeared. Precipitate was filtered and crystallized in acetic acid for 2 times to give 7.3 g (Yield :88%) of ketone as needles. mp 262-263℃. Reference: T. L. Cairns, J. Am. Chem. Soc., 1951, 73, 1270
4.3 用铬酸氧化合成酮
烯丙位或苄位的亚甲基易被铬酸氧化成酮。用过量的氧化剂且在激烈的反应条件下进行反应时，生成的酮会进一步氧化开裂而生成羧酸。用大过量的Collins试剂或PCC在DCM中回流；或在硅藻土或分子筛存在下使用PCC；以及用PCC时使用3，5-二甲基吡啶， 则能高收率地将亚甲基变成酮。
4.3.1 用铬酸氧化合成酮示例
OClClOCrO3/HOAcOClClO
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6,7-Dichloro-5-methoxy-2,3-dihydro-1H-inden-1-one.
4,5-Dichloro-6-methoxy-2,3-dihydro-1H-indene (21 g, 0.097 mole) is dissolved in acetic acid (280 mL) and chromium trioxide (14 g, 0.14 mol) in a mixture of water (15 mL) and acetic acid (40 mL) is added dropwise with stirring over a period of one hour.. The mixture is poured, with stirring into cold water (1200 mL) and the solid that separates is removed by filtration, washed with water and dried. The product is subjected to column chromatographic separation using 225 g of silica gel and chloroform is used for elution. Evaporation of the solvent gives 6,7-dichloro-5-methoxy- 2,3-dihydro-1H- inden-1-one, 5.2 g, m.p. 154-156 oC Reference:US4316043
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4.4用高锰酸盐氧化合成酮
使用高锰酸钾，在温和的条件下，能合成酮。
OKMnO4, H2ON 70-80oCN
4.5 用醌氧化合成酮
用2，3-二氯-5，6-二氰基对苯醌（DDQ）氧化富电子的芳环苄位，能生成酮。
ODDQ (2 eq)NHEthanol83%NH
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5．由羧酸及其衍生物合成醛酮 5.1由羧酸合成醛 5.1.1用金属氢化物还原
一般不用金属氢化物直接部分还原羧酸得醛，而是先将羧酸还原至醇后再氧化比较可靠。但化学家也开发出了一些比较有用的直接还原方法，如用有机硼氢化物2，3-二甲基-2-丁基甲硼烷、1，1，2-三甲基丙基卤代甲硼烷、9-BBN及叔丁基锂等还原羧酸为醛。这些方法用于脂肪羧酸还原时非常有效。对于含有氨基、硝基及卤素等取代基的芳族羧酸，也可得到很高的收率。
虽然有报道用氢化二异丁基铝（DIBAL）在低温下还原羧酸可得到醛，但并不适用于合成。但氢化氨基铝是一种很好的羧酸还原试剂，可高收率地得到醛。氢化氨基铝可由LAH与N-甲基哌嗪制取。
5.1.1用金属氢化物还原羧酸为醛示例：
A.
N,N-Dimethylchloromethylenammonium
chloride.
A
500-mL,
three-necked,
round-bottomed flask is equipped with a magnetic stirring bar, a thermometer, and a three-way stopcock fitted with a drying tube containing anhydrous calcium chloride and a rubber septum. The flask is charged with 50 mL of dichloromethane and 3.07 (0.042 mol) of N,N-dimethylformamide added through the septum from a syringe, and cooled in an ice bath. To the cooled mixture is slowly added 5.23 mL (0.06 mol) of oxalyl chloride by means of a syringe. The addition is accompanied by gas evolution and formation of a white precipitate. The reaction mixture is stirred for an additional hour at 0°C. Excess oxalyl chloride and solvent are removed under reduced pressure by first using a water aspirator and then a rotary pump at room temperature through the drying tube. The white solid remaining in the flask is N,N-dimethylchloromethylenammonium chloride, which is used directly in Part B.
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B. 6-Oxodecanal. The drying tube is removed and the flask is flushed with nitrogen. A nitrogen atmosphere is maintained throughout the subsequent reaction. A dropping funnel is attached and charged with 7.45 g (0.04 mol) of 6-oxodecanoic acid, 3.32 g of pyridine, and 80 mL of tetrahydrofuran, which are mixed well by shaking. The flask is charged with 45 mL of acetonitrile and 80 mL of tetrahydrofuran and cooled (methanol–liquid nitrogen) to ?30°C. The contents of the funnel are added to the flask at ?30°C over 30 min. The reaction mixture is stirred at ?30°C for an additional hour and at ?20°C for 30 min. After the mixture is cooled to ?90°C, 34 mL (0.046 mol) of a 1.35 M solution of lithium tri(tert-butoxy)aluminum hydride in tetrahydrofuran is injected through the septum by means of a syringe over 30 min, while the internal temperature is kept below ?85°C. Stirring is continued for an additional 30 min at ?90°C. To the flask is added 50 mL of 2 M hydrochloric acid solution, and the cooling bath is immediately removed. The organic layer is separated and the aqueous layer is extracted with three 50-mL portions of ether. The combined organic extracts are washed with two 50-mL portions of saturated sodium hydrogen carbonate solution and 50 mL of brine, dried over anhydrous sodium sulfate, and filtered. The solvent is removed with a rotary evaporator and the residual liquid is distilled under reduced pressure to yield 5.78–6.35 g (85–93%) of 6-oxodecanal as a fragrant liquid, bp 85–90°C (1.4 mm). Reference: Organic Syntheses, Coll. Vol. 8, p.498; Vol. 66, p.121
5.1.2由脱CO2合成醛
α-酮酸及α，β-环氧酸（缩水甘油酸）加热时易脱羧成醛。如为α-酮酸，则加入苯胺或吗啉，脱羧后以亚胺或烯胺形式存在，难发生副反应。反应停止后用酸处理即可高收率的得到醛。
ORCOOHOH+BenzeneNRCOOH-CO2RNOH+84-100%RO
5.1.3由羧酸合成酮
Preparation of Methyl (5-methoxy-2-nitrophenylacetyl)acetoacetate
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OOONO22.OH1. SOCl2/TolueneOOOOONO2OO
A 2-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, inert gas inlet, and two stoppers is flame dried and cooled to room temperature under an atmosphere of argon. The flask is charged with 42.5 g (0.20 mol) of (5-methoxy-2-nitro-phenyl)-acetic acid in 480 mL of anhydrous toluene. To the resulting suspension is added 15.3 mL (0.21 mol) of thionyl chloride followed by 2 mL of anhydrous N,N-dimethylformamide (DMF). As soon as the DMF is added the color of the mixture turns light red. The mixture is stirred at room temperature overnight. A 1-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, 250-mL pressure-equalizing funnel, and an inert gas inlet is flame dried and allowed to cool to room temperature under argon. The flask is charged with 10.1 g (0.49 mol) of 97% sodium hydride in 280 mL of dry tetrahydrofuran (THF) and then cooled to 0°C in an ice bath. A solution of 45.3 mL (0.42 mol) of methyl acetoacetate in 160 mL of dry THF is placed in the addition funnel and added dropwise to the reaction flask over a period of 45–50 min. After the addition is complete the light gray-colored solution is quickly transferred to a dried, 500-mL addition funnel. The funnel is mounted on the flask containing the acid chloride solution. The solution of methyl acetoacetate anion is added to the crude acid chloride solution over 5 min and the resulting mixture is stirred overnight at room temperature. Water (350 mL) is added to the reaction mixture and the mixture is stirred for 15 min before being poured into a 2-L separatory funnel. The layers are separated and the aqueous layer is extracted with ether (2 × 150 mL). The combined organic layers are washed with brine and dried over sodium sulfate. The filtered organic layer is concentrated under reduced pressure and the residue is dissolved in 100 mL of methanol. After cooling in the freezer overnight, the yellow crystals that separate are collected and dried to give 34.8–37.3 g (56–60%) of methyl (5-methoxy-2- nitrophenylacetyl)acetoacetate, suitable for use in the next step.
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5.2由酰氯及酸酐合成醛酮 5.2.1用Rosenmund法合成
酰氯经催化氢化还原为醛称为Rosenmund法。通常在酰氯的二甲苯或甲苯溶液中，加入喹啉-S或硫尿等催化剂钝化剂，加热通氢并使生成的HCl脱离反应体系。如果甲硅烷或甲锡烷替代氢，收率可进一步提高。
K. W. Rosenmund, Ber. 51, 585 (1918); K. W. Rosenmund, F. Zetzsche, ibid. 54, 425 (1921).
Reviews: E. Mosettig, R. Mozingo, Org. React. 4, 362 (1948); A. Rachlin et al., Org. Syn. 51, 8 (1971); J. A. Peters, H. Van Bekkum, Rec. Trav. Chim. 100, 21 (1981). Investigation of reaction parameters: W. F. Maier et al., J. Am. Chem. Soc. 108, 2608 (1986). Modified procedure applied to the synthesis of esters: V. V. Grushin, H. Alper, J. Org. Chem. 56, 5159 (1991).
5.2.1.1 用Rosenmund法合成醛反应示例：
MeOOMeOClMeOH2 (50 psi), Pd/C, Quinoline SNaOAc, tolueneMeOOMeOHMeO
A pressure vessel is charged in order with 600 mL of dry toluene, 25 g. (0.30 mole) of anhydrous sodium acetate, 3 g. of dry, 10% palladium-on-carbon catalyst, 23 g. (0.10 mole) of 3,4,5-trimethoxybenzoyl chloride, and 1 mL of Quinoline S. The pressure vessel is flushed with nitrogen, sealed, evacuated briefly, and pressured to 50 p.s.i. with hydrogen. The mixture is shaken with 50 p.s.i. of hydrogen for 1 hour at room temperature, then heated at 35–40° for 2 hours. Agitation is continued overnight while the reaction mixture cools to room temperature. The pressure on the vessel is released, the vessel is opened, and the mixture is filtered through 10 g of Celite filter aid, and the insoluble material is washed with 25 mL of toluene. The combined filtrates are washed successively with 25 mL of 5% sodium carbonate solution and 25 mL of water. The toluene solution is dried over 5 g of anhydrous sodium sulfate and filtered. The filtrate is concentrated by distillation at reduced pressure using a
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water aspirator. The residue is distilled through a 10-cm. Vigreux column with warm water circulating through the condenser, to prevent crystallization of the distillate, yielding 12.5–16.2 g (64–83%) of 3,4,5-trimethoxybenzaldehyde, b.p. 158–161°C (7–8 mmHg.), m.p. 74–75°C.
Reference: Organic Syntheses, Coll. Vol. 6, p.1007; Vol. 51, p.8
5.2.2用金属氢化物还原
最常用的还原剂为氢化三叔丁氧基铝锂（LTBA），反应在等当量乙二醇二甲醚或其与THF的溶液中进行，反应温度尽量低为好。芳香醛的收率较脂肪醛好。
5.2.2.1 用金属氢化物还原酰氯合成醛反应示例
O2NOClO2NLiAlH(OtBu)3diglyme, -78oCO2NO2NOH
A 3-l., three-necked, round-bottomed flask is equipped with an efficient stirrer, a pressure-equalizing dropping funnel with a nitrogen inlet, and a Y-tube fitted with a low temperature thermometer and a nitrogen outlet. The outlet is vented through a bubbler tube, maintaining a slight positive pressure. The flask and dropping funnel are flamed in a stream of dry nitrogen. To the flask is added 115.0 g (0.4989 mol) of 3,5-dinitrobenzoyl chloride followed by 500 mL of dry diglyme. The solution is stirred vigorously, and the flask is immersed in a cooling bath at ?78°. A diglyme solution of lithium aluminum tri-tert-butoxyhydride is prepared in the following manner. Dry diglyme (450 mL) is added with vigorous stirring to an Erlenmeyer flask containing 140.0 g. (0.5512 mol) of lithium aluminum tri-tert-butoxyhydride. After standing overnight, the resulting suspension is filtered under a blanket of dry nitrogen through a thick layer of Celite packed tightly on a Büchner funnel. The flask containing the filtrate is kept stoppered until the reducing agent is transferred to the dropping funnel. Dropwise addition of this solution is started when the contents of the reaction flask reach ?72°. There is a color change and a temperature rise of a few degrees. The rate of addition is adjusted, maintaining the temperature of the mixture
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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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AlONHOOONOHOXORNR'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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配合物水解则得到酮。
5.5.1 由Weinreb酰胺还原合成醛反应示例一
OOSHNONOLAH/THFOOSHNO
4-[4-(methanesulfonamido)phenyl]butyraldehyde
A mixture of 4.20 g (14 mmol) of 4-[4-(methanesulfonamido)phenyl]butyric acid,
N-methoxy-N-methylamide and 100 mL of anhydrous tetrahydrofuran was stirred under nitrogen with cooling in an ice bath as 17.5 mL (17.5 mmol) of 1M lithium aluminum hydride in tetrahydrofuran was added gradually by syringe. After 0.75 hours, 70 mL of 5percent potassium hydrogen sulfate solution (aqueous) was added cautiously by syringe. The mixture was then removed from the ice bath, diluted with 150 ML of water, and shaken with 150 mL of ethyl acetate. The milky aqueous phase was extracted with an additional 50 mL of ethyl acetate. The combined organic fractions were washed successively with 2*100 mL of 1N hydrochloric acid, then 50 ML of saturated aqueous sodium bicarbonate solution, and finally 50 ML of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 3:2 hexane-EtOAc) yielded 2.47 g (73%) of an oil; homogeneous by TLC in 1:1 hexane-EtOAc).Upon storage in the freezer, solidification occurred (mp 41~44
o
C.).
Reference: US5756507
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5.5.2由Weinreb酰胺还原合成酮反应示例:
F3CF3CNOOHMgClNF3CF3CONOOH
1-(Methyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)-pentan-2-one
To a solution of [N-1--methoxy-N-1-N-2-dimethyl-N-2-- {4- [2,] 2,2- trifluoro-1-hydroxy- 1-(trifluoromethyl)ethyl]phenyl}glycinamide (240 mg, 0.64 mmol) in CH2Cl2 (3.5 mL) at 0
o
C under a nitrogen atmosphere was slowly added a solution of propylmagnesium chloride
(1.6 mL, 2M in Et2O). After stirring 3 hours, the reaction mixture was poured into 1 M HCI and extracted twice with EtOAc. The organic layer was washed with brine, dried (NA2SO4), filtered, and concentrated. Purification by flash chromatography (2: 1 EtOAc/hexanes) afforded the title compound as a dark yellow waxy solid (110 mg, 48%). Reference:WO2003/99769
5.6由氰合成醛酮
腈与金属氢化物反应生成醛亚胺的金属盐，由于亚胺的碳氮双键极化比较小，难以被第二个负氢进攻，则可让反应停于此阶段而得醛。Stephen 醛合成法（H. Stephen, J. Chem. Soc. 127, 1874 (1925); T. Stephen, H. Stephen, ibid. 1956, 4695）是用SnCl2/HCl将腈转化为醛亚胺的盐酸盐然后水解便得醛。此法只用于芳香醛的合成。
L. N. Ferguson, Chem. Rev. 38, 243 (1946); E. Mosettig, Org. React. 8, 246 (1954); O. Bayer, Houben-Weyl 7/1, 299 (1954); E. N. Zilberman, P. S. Pyryalova, J. Gen. Chem. U.S.S.R. (Engl. trans.) 33, 3348 (1963); C. G. Stuckwisch, J. Org. Chem. 37, 318 (1972).
低温下，加入氢化铝锂至腈中，随可得到一定收率（40-70%）的醛。但最好的方法还是向腈化物中加入等当量至稍过量的DIBAL，0℃以下进行反应。该法对缩醛及卤化物不反应，但除羧酸外会先与其它羰基化合物作用，所以通常要保护这些羰基后再进行反应。
Raney Ni 的活性作适当调节，可以催化还原腈到醛。通常用亚磷酸钠和甲酸钝化
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Raney Ni。也有在N，N-二苯基乙二胺或氨基脲共存下制得醛衍生物的方法。
腈与Grignard试剂反应，可以将腈变为酮。由于反应中形成了活性低的酮亚胺盐，当反应停于此阶段，则经水解便能以较好的收率得到酮。因为Grignard试剂有些碱性，它可以在连接吸电子基氰基的邻位碳上夺取一个质子，所以本法用于脂肪族腈时，收率低了些，相反自芳香腈制芳酮时，便是个高收率的优良合成法。
5.6.1DIBAL 还原腈到醛示例 （最重要的方法）
ClNCDIBAlOHC
ClPreparation of 2-chloro-6-methylbenzaldehyde
To a stirred solution of 2-chloro-6-methylbenzonitrile (1 g, 6.6 mmol) in THF (15 mL)
under argon at 0 oC a solution of DIBAL (1 M in THF, 7 ML, 7 mmol) was added dropwise over 5 minutes. After 3 hr at 0 oC, the reaction mixture was brought to room temperature and further stirred overnight. The reaction mixture was quenched with 5percent sulfuric acid at 0 oC, extracted with ether, washed with brine and dried (MgSO4). Concentration provided 2-chloro-6-methylbenzaldehyde (0.92 g) which was used without further purification.
Reference:: US6506747
5.6.2Li(EtO)3AlH 还原腈到醛示例 （较重要的方法）
CN1. Li(C2H5O)3AlH2. H3O+CHO
In a 1-liter flask equipped with a stirrer, condenser, dropping funnel, and thermometer is placed 10.2 g (0.3 mol) of lithium aluminum hydride in 300 mL of ether. The flask contains a nitrogen atmosphere throughout the reaction period. To the stirred solution is added 39.6 g (0.45 mol) of ethyl acetate over a period of 1.25 h at 3-7℃. The reaction mixture is stirred for an additional 0.5 h and then 24.9 g (0.30 mol) of trimethylacetonitrile is added over a period of 5 min. The temperature rise to 10℃, with the formation of a highly visous solution. The reaction mixture is stirred for 1 h at 0℃ and then the solution is decomposed
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cautiously with 300 mL of 5 N H2SO4. The ether layer is separated and the layer is extracted three times with 50 mL portions of ether. The ether extracts are washed with saturated sodium bicarbonate solution followed by ether washings with 30 mL portions of cold water in order to remove ethanol. The ether extracts are dried over sodium sulfate and distilled to yield 25.8 g (74%) of pivalaldehyde, bp 70-72.5℃ (747 mm), n20D 1.3794.
Reference: H. Stephen, J. Chem. Soc., 1925, 127, 1874
5.6.3Ranney Ni 加氢还原氰到合成醛示例
CNRaney nickelHCO2H, heatSO2NH2SO2NH2 CHOA 2-l., two-necked, round-bottomed flask fitted with a mechanical stirrer and a reflux condenser is charged with 40.0 g. (0.232 mole) of 4-cyanobenzenesulfonamide, 600 mL of 75% (v/v) formic acid, and 40 g. of Raney nickel alloy. The stirred mixture is heated under reflux for 1 hour. The mixture is filtered with suction through a Büchner funnel coated with a filter aid, and the residue is washed with two 160-mL portions of 95% ethanol. The combined filtrates are evaporated with a rotary evaporator. The solid residue is dissolved in 400 mL of boiling water and freed from a small amount of insoluble material by decantation through a plug of glass wool placed in a filter funnel. The filtrate is chilled in an ice bath, and the precipitate is collected by filtration with suction, washed with a small amount of cold water, and dried at 50° under vacuum, yielding about 32 g. of crude product, m.p. 112–114°C. The product is dissolved in 800 mL of hot 95% ethanol, 15.5 g. of activated carbon is added, and the mixture is swirled periodically while it is allowed to cool for 1 hour. The activated carbon is removed by filtration with suction through a bed of filter aid, the filter cake is washed with 50 mL of 95% ethanol, and the combined filtrates are evaporated with a rotary evaporator. The residue is dissolved in 225 mL of boiling water, and the hot solution is decanted through glass wool placed in a filter funnel. The filtrate is cooled to 0°, the product is collected by filtration with suction, washed with a small amount of cold water, and dried in
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a vacuum oven at 50°C, yielding 25.6–28.0 g. (62.9–68.8%) of 4-formylbenzenesulfonamide, m.p. 117–118°C.
Reference: Organic Syntheses, Coll. Vol. 6, p.631; Vol. 51, p.20
5.6.4有机金属试剂对腈加成合成酮示例
CN1. MeMgI2. H+O
To a flask containing 0.11 mol of methyl magnesium iodide (prepared from 7 mL of methyl iodide in 30 mL of ether containing 2.7 g of magnesium) is added 25 mL of benzene followed by 15 g (0.074 mol) of 9-cyanophenanthrene. The reaction mixture is refluxed for 3 h, cooled, and hydrolyzed with cold ammonium chloride solution. The benzene-ether layer is separated, shaken with cold dilute hydrochloric acid, and then refluxed for 1 h in order to hydrolyze the ketimine hydrochloride to the ketone. The ketone, which precipitates as an oil, is seperated, distilled under pressure, and then recrystallized from ethanol to yield 9.5 g (58%), mp 73-74℃.
Reference: E. Bachman, J. Am Chem. Soc., 1936, 58, 2098
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6. 由烯烃、芳环合成醛酮
烯烃及芳环的C=C双键经臭氧、氧化锇等作用而氧化断裂生成醛，是醛的重要合成法之一。此外，将烯烃变为醛的方法尚有用在Rh及Co催化下与氢及一氧化碳起反应的加氢甲酰化，硼氢化反应以及将芳环上的C-H直接转化为Li而起甲酰化反应等。
烯烃经加成-氧化、加成-还原、加成-水解、加成异构化以及一氧化碳插入反应等则能合成酮。
6.1 由烯烃臭氧氧化合成醛
烯烃及芳香环等与臭氧反应，先生成过氧化物，由于有爆炸危险不予分离，直接将其还原为醛。还原可用催化氢化、锌、碘化钠、磷化氢类化合物、亚磷酸、甲硫醚等方法。要是不予还原则经氧化分解得酸。
(CH3O)3PO3-50~ -70oCOOOCH3CO3HCHOCHO85%COOHCOOH90%
有多个双键共存时，臭氧化的选择性一般在电子密度高而位阻小的双键。芳香环的反应较迟钝，有不饱和侧链存在时优先选择氧化侧链双键。含杂原子的芳环对臭氧的稳定性大于苯环。
6.1.1由烯烃臭氧氧化合成醛示例： 5-formylvaleraldehyde
O3OO
To a stirred -78 oC solution of cyclohexene (15 mL) in 100 mL of dichloromethane was bubbled in ozone until light blue color appeared. Excessive ozone was removed by a nitrogen flow, then 60 mL of dimethyl sulfide was added. The mixture was left overnight, dried over sodium sulfate. The solvent and DMS were removed under low vacuum to afford 5-formylvaleraldehyde. The crude product could be used in other reactions without further purification.
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Reference:WO2004/94371
6.2 烯烃用OsO4/NaIO4氧化合成醛
与臭氧化法相比，OsO4/NaIO4是一种温和的烯烃氧化开裂法，在天然产物合成中很有用。烯烃先与OsO4反应生成锇酸酯，再用过碘酸钠氧化，发生开裂，在生成羰基化合物的同时，OsO4再生，所以OsO4用催化量即可。当生成的醛易于分子内缩合时，反应最好在两相系统中进行。
6.2.1 烯烃用OsO4/NaIO4氧化合成醛反应示例：
OAcOOAcONHNHOOAcCHOOAcO1ONHOAcCHOOAc3OsO4, NaIO42NHO
To a solution of 1 (1.8 mg) in THF (1 mL) was added OsO4 (excess) and then a solution of NaIO4, (excess) in H2O (1 mL). After a period of 1 hr, H2O (5 mL) was added and the aq. solution was extracted with three 5ml portions of CHCl3. The combined CHCl3 layers were dried over Na2SO4, and concentrated to give a residue, which was separated by preparation TLC (SiO2, 5% MeOH-CHCl3). Compounds 2 and 3 were obtained. Reference: Tetrahedron; 41; 6; 1985; 1007-1018.
6.3 烯烃经由有机硼化合物中间体的烯烃甲酰化合成醛
烯烃与甲硼烷反应所得的有机硼化合物能用各种方法转变为醛。用铬酸氧化时，所得醛的碳原子数不变。如与一氧化碳反应再进行氧化便得多一个碳原子的醛。要是与重氮乙醛反应，即可得增长二个碳原子的醛。通过与丙烯醛的加成，碳原子数可增加三个。
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PCC1. CO, MH2. H2O2RCH=CH2BH3(RCH2CH2)3BN2CHCHOCH2=CHCHORCH2CHORCH2CH2CHORCH2CH2CH2CHORCH2CH2CH2CH2CHO
6.5 由烯烃的甲酰化合成醛 6.5.1 Vilsmeyer 反应
此方法广泛应用于活性芳环，杂环，不饱和脂肪上（富电子）引入甲醛，-OH,-OR,-NR1R2,CH(OR)不影响反应，可用二氯甲烷，二氯乙烷或二氯苯作溶剂，也可不用反应溶剂。（A. Vilsmeier and A. Haack, Ber. 1937 119)
6.5.1.1 Vilsmeyer 反应示例一
POCl3,DMFNHCHO
In a 1-l. round-bottomed, three-necked flask fitted with an efficient mechanical stirrer, a drying tube containing drierite and a 125 mL dropping funnel is placed 288 mL (274g, 3.74 moles) of freshly distilled dimethylformamide. The flask and its contents are cooled in an ice-salt bath for about 0.5 hour, and 86 mL (144g, 0.94 moles) of freshly distilled phosphorous oxychloride is subsequently added with stirring to the dimethylformamide over a period of 0.5 hour. The pinkish color of the formylation complex may be observed during this step. The 125-mL dropping funnel is replaced with a 200 mL dropping funnel, and a solution of 100g (0.85 mole) of indole in 100 mL of dimethylformamide is added to the yellow solution over a period of 1 hour during which time the temperature should not rise above 10 ℃. Once the solution is well mixed, the dropping funnel is replaced with a thermometer, and the temperature of the viscous solution is brought to 35 ℃. The syrup is stirred efficiently at this temperature for 1 hour, or for 15 minutes longer than is necessary for the clear yellow solution to become opaque, canary-yellow paste. At the end of the reaction
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period, 300 g of crushed ice is added to the paste with careful stirring, producing a clear, cherry-red aqueous solution.
This solution is transferred with 100 mL of water to a 3-l. three-necked flask containing 200 g of crushed ice and fitted with an efficient mechanical stirrer and a separatory funnel containing a solution of 375 g. (9.4 mole) of sodium hydroxide in 1L of water The aqueous base is added. The remaining two-thirds is added rapidly with efficient stirring until about one-third of it has been added. The remaining two thirds is added rapidly with efficient stirring, and the resulting suspension is heated rapidly to the boiling point and allowed to cool to room temperature, after which it is placed in a refrigerator overnight. The precipitate is collected on a filter and resuspended in 1L of water. Most of the inorganic material dissolves, and the product is then collected on a filter, washed with three 300-mL portions of water and air-dried, yielding about 120 g (97%) of indole-3-aldehyde, mp 196-197 ℃. The indole-3-aldehyde resulting from this procedure is sufficiently pure for most purposes, but it may be recrystallized from ethanol if desired. Reference: Org. Syn., Vol 4, pp 539-541.
6.5.1.2 Vilsmeyer 反应示例二
OPOCl3,DMFAOCHOOO
Pyrophosphoryl chloride (1.889g, 7.5 mmol) was added dropwise to a stirred mixture of cold (ice bath) N,N-dimethylformamide (0.731g, 10.0 mmol) and p-dimethoxybenzene (0.691g, 5.0 mmol). The resulting syrup was then heated at 100 ℃ for 48 hours. The cold product was basified with an aqueous solution of 2M sodium hydroxide and extracted with dichloromethane and dried (MgSO4) and concentrated. Short-path distillation gave 2,5-dimethoxybenzaldehyde (0.332g 40%), mp 50-51 ℃. bp 80 ℃ at 0.1 mmHg. Reference: Tetrahedron 49(19) 4015-4034 (1993)
6.5.1.3草酰氯-DMF 体系Vilsmeyer 反应示例
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CHODMF, (COCl)2OHOHOHOH
A 1-L 3-neck flask equipped with a temperature thermocouple and an efficient overhead stirrer is charged with DMF (46.37 g, 0.63 mole) and acetonitrile (350 mL). The reaction is treated dropwise with a solution of oxalyl chloride (66.12 g, 0.521 mole) in actionitrile dropwise over 20 min so that the temperature is maintained at 20~26℃ with a water bath. Gas evolution is noted and a thick precipitate forms. The reaction is stirred at ambient temperature for 1 h to insure complete conversion to the Vilsmeier reagent. The reaction is cooled in a dry-ice bath to -14?to -17?C and a solution of resorcinol (26.87 g, 0.244 mole) in acetonitrile (75 mL) is added over 20 min. The Vilsmeier reagent dissolves as the reaction with resorcinol occurs, and soon afterward the precipitation of chloride salt 4--Scheme 4 begins. The reaction is stirred at -15?C. for 35 min, then at 28~32 oC. for 2 h. The HPLC of the reaction solution shows <6% of the starting material. After cooling to 3~5℃ for 2 h, the reaction is filtered and washed with cold acetonitrile (70 mL). The solid is washed with hexane (30-40 mL) and the product dried. The Vilsmeier formamidinium chloride is dried at 30~35 oC at 0.05 mm of Hg for 24 h. The recovery is 42.3 g; the yield corrected for purity is 79%; it is a single component by HPLC, mp 170~173 ℃. Hydrolysis:
To water (250 mL) stirred at 40 oC is added the above salt (42.3 g, 0.209 mole) in three portions. The reaction is heated to 50 oC for 0.5 h, and the reaction is cooled. When the temperature had reached 35 oC, sodium thiosulfate solution (0.09M, 1-2 mL) is added to discharge the resulting pink color. The reaction is cooled to 5 oC., and stirred for 2 h. The mixture is filtered, the solid is washed with cold water, and air dried at <35 oC for 24 h giving 2,4-dimethoxybenzaldehyde (24.4 g, wt/wt assay by HPLC 97%; corrected yield: 69% from resorcinol) an off-white solid, mp 134~136oC. Reference:US5599988
6.5.1.4 二氯亚砜用于Vilsmeyer 反应示例
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ON-methylformanilide, SOCl2OOOCHO
To 108 g (0.80 mole) of N-methylformanilide cooled in an ice-water bath, 95.2 g (0.80 mole) of thionyl chloride was added drop by drop with stirring. After completion of the addition, the mixture was allowed to stand at room temperature for 2 hours and then heated at 40~50 ℃ for 1 hour under a reduced pressure of 60-80 mmHg. To the resulting yellow mixture, 97.6 g (0.80 mole) of 1,2-methylenedioxybenzene was added and kept at 15 ℃. After completion of the addition, the reaction mixture was kept at 90 ℃ for 30 minutes, poured into ice water, and allowed to stand for 1 hour. Then, the resulting mixture was extracted with toluene. By vacuum distillation, the toluene was removed and the distillate at 84~85℃/30 mmHg was then collected to recover unreacted 1,2-methylenedioxybenzene. Subsequently, the distillate at 131~134℃/10 mmHg was collected to obtain piperonal. The yield (expressed in terms of mole percentage based on the amount of N-methylformanilide used) and selectivity (expressed in terms of mole percentage based on the amount of 1,2-methylenedioxybenzene having reacted) of piperonal were 55.6% and 95.1%, respectively. Reference: US4157333
6.5.2 Duff’s 甲酰化
活泼的芳香族化合物（如酚）与六亚甲四胺反应生成亚胺中间体，继而水解成醛。反应具有简便而迅速的特点，但这一经典方法往往产率不高，限制了它的应用。利芳香族化合物在三氟乙酸存在下与六亚甲基四胺反应，可以得到高产率的芳醛。改良方法不仅适用于活泼的芳香族化合物，亦可应用于简单的芳烃甲酰化。
Preparation of 3,5-dimethyl-4-hydroxy-benzaldehyde
OHOHHMTA,TFACHO
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A mixture of 12.2 g of 2,6-xylenol (100 mmol), 14.0 g of HMTA (aka urotropine, hexamine or hexamethylenetetramine) (100 mmol) and 150 mL of trifluoroacetic acid was heated at reflux (83-90 oC) for 12 hrs. The products were concentrated and combined with 600 mL of ice water; the resulting mixture was stirred 15 min, made basic with Na2CO3 and extracted with ether. Evaporation of the ether solution left a yellow solid which was recryst. from CHCl3-pentane to afford 14.3 g of 3,5-dimethyl-4-hydroxy-benzaldehyde mp 113 ℃ Reference: J. Org. Chem. 1972, 37, 3972
6.5.3 Reimer-Tiemann 甲酰化
活性高的芳香环碱性条件下上醛的方法（主要是苯酚），但产率一般不高，有时副反应较多，会产生焦油状物，后处理复杂，所以运用不广。
Preparation of 2-hydroxy-5-methoxy-benzaldehyde
OHNaOH,CHCl3OHCHOOO
Into a 2000mL three neck flask was placed 125g (1 mol) 4-Methoxyphenol and a still hot solution of 320g (8 mol) NaOH in 400mL H2O (Addition while hot helps the phenol to dissolve and avoid carbonate formation). The flask was set with a reflux condenser, dropping funnel and thermometer (using a Claisen adaptor) and mechanical stirrer then heated to ~70 ℃ on the oil bath. When this temperature had been reached, chloroform (160mL, 2 mol) was added dropwise (and portionwise) over the course of 4 hrs while maintaining the stirring and temperature, over this time the reaction became a very dark brown with a yellow green froth and a heavy brown precipitate (the sodium phenolate product). The reaction was allowed to stir for a further hour at the same temperature, allowed to cool and then transferred to a 5000mL flask with the aid of some hot water and subsequently acidified with H2SO4 (150-200 mL 0 N). Acidification causes the product to rise to the top as a black oil. The black oil was transferred into a flask with some clean water and steam distilled (collect ~5000mL distillate). Quite a volume of black tar remains after this distillation. The yellow oil in the distillate was
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extracted with DCM and evaporated to yield 112g (74%) 2-hydroxy-5-methoxy-benzaldehyde, can be further purified by vacuum distillation under nitrogen (bp 133 ℃/15mmHg). Note: The alkali salts of this salicylaldehyde are quite prone to atmospheric oxidation. Reference:Org. React. Vol 28 p16
6.5.4 Gattermann甲酰化
活性高的芳香环酸性条件下上醛的方法（主要是苯酚，苯醚），产率较高，但氰化锌毒性较大，操作要求高。
Zn(CN)2,HClHOOHHOCHOOH
6.5.5 多聚甲醛/甲醇镁 苯酚甲酰化
这是形成邻位苯酚甲酰化较好的方法，一般产率较高，特别适用于对甲氧基苯酚的甲醛化。有些专利上报道，加入吡啶有利于提高产率。
Preparation of 2-Hydroxy-4-methyl-benzaldehyde
OHCHOMg(OH)2OH
Phenol (37.6 g, 0.4 mol) was added to magnesium methoxide (259 g of 8 wt% solution in methanol; 20.7 g, 0.24 mol) and the mixture was heated to reflux. Approximately half the methanol was distilled off and toluene (300 g) was added to the residue. The azeotropic mixture of toluene and methanol was removed by fractional distillation, until the temperature of the reaction mixture rose to 95 ℃. A slurry of paraformaldehyde powder (43.2 g, 1.44 mol) in toluene (75 g) was added in small portions over 1 h to the reaction mixture at 95 ℃ with concurrent removal of volatile materials by distillation. Stirring was continued at 95 ℃ for 1 h, after which the mixture was cooled to 25 ℃ and added slowly to 10% sulfuric acid (450 g). The resulting mixture was stirred at 30-40 ℃ for 2 h, after which the aqueous layer was separated and extracted with toluene (2x100 g). The combined organic layers and extracts
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were washed with 10% sulfuric acid (50 g) and water (50 g) and evaporated under pressure to give the aldehyde as a pale yellow oil (48.35 g, 84% w/w by GC and 1H NMR comparison against a reference standard and against a commercial sample of known purity; 83% yield). Reference: Journal of the Chemical Society Perkins Transactions I, 1823-1831 (1994)
6.5.6氯化锡/多聚甲醛 苯酚甲酰化
在氯化锡或者氯化亚锡条件下，用多聚甲醛可在苯酚邻位上醛，反应收率较高。 Preparation of p-methoxy-phenol
OHSnCl4,tributylamine(HCHO)nOOOHCHO
To a four-neck RB flask (2.5 l) eq. with a reflux condenser, mech. stirrer, thermometer, and N2 source was added anhydrous toluene (200 mL) an appr. phenol (1 mol) tributylamine (54 g, 0.4 mol) and SnCl4 (26 g, 0.1 mol). The mixture was stirred 20 min at RT, then paraform was added (66 g, 2.2 mol). The resulting yellow solution was heated at 99~101 oC at 8 hrs. After cooling the RM was poured into water (5 L) acidified to pH 2 with 2N HCl and extracted with ether. The ether extract was washed with satur. brine, dried over Na2SO4 and conc. to leave crude aldehyde. Product was purified by steam distillation and if nesessary, by subseq. distillation and recryst. from pet. ether. Yields, f.e. from p-methoxy-phenol, 85%, mp 51-52C. Reference: JCS Perkins I, (1980) 1862-1865
6.5.7重氮化后甲酰化
在硫酸铜、亚硫酸钠的催化下，在乙酸钠的缓冲溶液中重氮盐甚与甲醛肟生成芳醛肟，酸性水解或用硫酸铁铵处理既得芳醛，提供了由芳胺转换成芳醛的方法，产率一般不超过50%。苯环上有卤素、硝基均无影响。但重氮基的邻位有氰基、烷氧基、羰基时，不能顺利地进行反应。本合成反应历程是重氮盐水首先形成芳基正离子，再对甲醛肟进行亲核进攻。见9.3苯胺衍生物合成
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6.6烯烃经加成-氧化反应合成酮
末端烯烃可通过使用二价钯的Wacker法氧化成甲基酮。催化剂有PdCl2、Pd（CH3CO2）2、Na2PdCl4等的钯盐。再氧化剂为CuCl2，CuCl， Cu（NO3）2，酞花菁铁。氧化剂除了用氧气外，还可用H2O2，t-BuOOH，苯醌电解氧化。
OC8H17PdCl2, CuCl, O2DMF, H2O65-73èH17
1，2-二取代烯或环状烯可用KMnO4氧化，在中性~pH9时生成2-羟基酮，在醋酐中则生成1，2-而酮。
OC8H17C7H14CO2HKMnO4, (CH3CO)2O46èH17OC7H14CO2H
6.6.1 烯烃经加成-氧化反应合成酮示例
HCO2HH2O2OHOCHO7% H2SO4O
In a 2-l. three-necked flask fitted with stirrer, dropping funnel, and thermometer are placed 700 mL. of formic acid (88%) and 140 mL. of hydrogen peroxide (30%, 1.37 moles). While the temperature is kept at 35–40°, 116.2 g. (117.3 mL., 1.00 mole) of indene (98%) is added dropwise, with stirring, over a period of 2 hours. An additional 100 mL. of formic acid is used to rinse the last of the indene from the dropping funnel into the reaction flask. The reaction solution is stirred at room temperature for 7 hours to ensure complete reaction. The solution is transferred to a 2- or 3-l. Claisen flask, and the formic acid is removed under aspirator pressure (b.p. 35–40°/20–30 mm.), care being taken to maintain the boiler temperature below 60°. The residue, after being cooled to room temperature, is a yellowish brown crystalline solid, the color being due to contamination by a small amount of brownish oil.
In a 5-l. flask fitted with a long condenser (about 40 cm.) connected to an ice-cooled
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receiver is placed 2 l. of 7% (by volume) sulfuric acid. The solution is heated to boiling, and the crude monoformate of 1,2-indanediol is added. Steam is introduced and the mixture is steam distilled, while external heat is applied with a flame in order to maintain the boiler contents at a constant volume of 2 l. The steam distillation is carried out at the rate of about 1 l. per hour until 5–6 l. of distillate have been collected and the 2-indanone has stopped distilling. The dark-brown oily residue becomes semisolid at room temperature.
The cold distillate is filtered with suction, and the white crystalline solid is sucked thoroughly dry on the filter. The crystals are dried further in a vacuum desiccator (at about 1 mm.) at room temperature or below for about 12 hours. The melting point of the 2-indanone is 57–58°. The yield is 90–107 g. (69–81%).
Reference: Organic Syntheses, Coll. Vol. 5, p.647; Vol. 41, p.53
7. 由炔烃合成醛酮
从炔烃出发合成醛的反应主要有加成-氧化反应。相对来说从炔烃出发合成酮的反应较多，具有适用价值的反应主要有氧化反应（包括加成-氧化反应）、加成-水解反应、加成-还原反应、加成-烷基化，酰化等反应。
7.1 由加成-氧化反应合成醛酮
炔烃通过硼氢化作用，继经氧化，可以得到相应的醛酮。
BHSia2R1R2BSia2H2O2-NaOHR1R2O
R1R27.2 由氧化反应合成酮
炔烃可以通过氧化反应合成1，2-二酮，氧化剂主要有RuO2?H2O-NaIO4，KMnO4，OsO4-KClO3，RuCl2（PPh3）3-PhIO，RuO2-NaClO，Ti（NO3）3-HClO4，Hg（CH3CO2）
2-H2O2-Na2WO4，O3-Ph3P
等。
CH3RuO2.H2O-NaIO480%OOCH3
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7.3 由加成-水解反应合成酮
由炔的加成-水解反应合成酮HgO-H2SO4法、HgO-NaFion-H法、C6H5HgOH法等。另外将α-炔醇和85%甲酸，固体超强酸，H2SO4进行反应，可得乙烯基酮。
HOCHH3CCH3HgO, H2SO480%HOOH3CCH3CH3
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7.4 由加成-还原反应合成酮
炔烃和腈氧化物或硝酮反应，生成异恶唑或异恶唑啉，再瑞尼镍或H2/PtO3还原得烯胺基酮。
OOCNO80%OONOH2, PtO2100%OONH2O
7.5 由加成-烷基化，酰化等反应合成酮
利用硼氢化和随后的转位反应，向烯烃或炔烃骨架引入相当于羰基的取代基，再经氧化或水解反应即可合成酮。
O9-BBNBheat, 16 hBH2O2, NaOH89%O
8. 由醚及环氧化合物合成醛酮 8.1 Claisen重排
Claisen Rearrangement; Eschenmoser-Claisen Rearrangement; Johnson-Claisen Rearrangement; Ireland-Claisen Rearrangement
L. Claisen, Ber. 45, 3157 (1912); L. Claisen, E. Tietze, ibid. 58, 275 (1925); 59, 2344 (1926).
将烯丙基乙烯基醚类加热，则发生[3,3]重排，高立体选择性的得γ,δ-不饱和醛。
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8.1.1 Claisen重排法合成醛反应示例：
C8H17220-225oCHOCHOHHHC8H17 A 50-mL., round-bottomed flask equipped with a magnetic stirring bar and a 20-mL. calibration mark is charged with 970 mg. (2.51 mmoles) of cholest-4-en-3β-ol. Ethyl vinyl ether is distilled into the flask to the 20-mL. mark. The mixture is stirred to effect solution before 820 mg. (2.55 mmoles) of mercury(II) acetate is added to the reaction mixture. The flask is fitted with a reflux condenser connected to a gas-inlet tube and flushed with argon. The reaction mixture is then stirred and heated at reflux under a positive argon pressure for 17 hours. After the solution has cooled to room temperature, 0.062 mL. (1.1 mmoles) of glacial acetic acid is added, and stirring is continued for 3 hours. The reaction mixture is poured into a preshaken mixture of 150 mL. of petroleum ether and 50 mL. of 5% aqueous potassium hydroxide. The aqueous phase is extracted with 50 mL. of petroleum ether, and the combined extracts are washed with three 50-mL. portions of a 20% aqueous sodium chloride, dried over anhydrous sodium carbonate, filtered and evaporated at reduced pressure, giving 1.11 g. of an oil which, upon filtration through 5 g. of silica gel with 200 mL. of petroleum ether, affords 0.81 g. of the cholestenyl vinyl ether as a clear, colorless oil. If desired, crystallization of this oil from 10 mL. of acetone will give 0.74 g. (71%) of the vinyl ether as colorless prisms, m.p. 55–56.5°. Alternatively, the crude vinyl ether (0.81 g.) is transferred with petroleum ether into a 50-mL., round-bottomed flask fitted with a long gas-inlet tube. After the petroleum ether is removed at reduced pressure, the flask is filled with argon and heated under a positive argon pressure at 220–225° for 5 hours; little or no bubbling should occur. After cooling, the oil is chromatographed on 75 g. of silica gel using 10% diethyl ether in petroleum ether as the
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elution solvent The first 175 mL. of eluant contains side products and is discarded; elution with another 175 mL. of the solvent gives 0.45–0.55 g. (50–53% overall yield from cholest-4-en-3β-ol) of 5β-cholest-3-ene-5-acetaldehyde as white prisms, m.p. 66.5–68°. Reference: Organic Syntheses, Coll. Vol. 6, p.298; Vol. 54, p.71
8.2酸催化下环氧化物重排
将环氧化物用酸处理则在开环时而发生重排得羰基化合物。
8.2.1 酸催化下环氧化物重排合成醛酮示例一
PhOPhBF3.OEt2benzenePhPhOH
In a 1-l. separatory funnel is placed a solution of 39.2 g. (0.2 mole) of trans-stilbene oxide in 450 mL. of reagent benzene. To the solution is added 13.2 mL. (0.1 mole) of boron trifluoride etherate. The solution is swirled, allowed to stand for 1 minute, and then washed with two 300-mL. portions of water. The organic layer is separated, and the benzene is removed by distillation. The residual crude aldehyde is purified by distillation under reduced pressure. The product, collected at 115–117°/0.6 mm., amounts to 29–32 g. (74–82%), nD25 1.5875–1.5877.
Reference: Organic Syntheses, Coll. Vol. 4, p.375; Vol. 38, p.26
8.3氧化法
醚的α-位易接受游离基反应，所以可因过氧化物、四醋酸铅、NBS等氧化开裂得醛。
8.4 水解法缩醛或酮合成醛酮
Preparation of (S)-2-[2-(p-Tolylsulfinyl)phenyl]acetaldehyde
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OSTolHCO2HOSTolOOO
A solution of the acetal (0.83 mmol) in formic acid (41.57 mmol) was stirred for 1 h at room temperature. Then, the mixture was diluted with dichloromethane, washed (NaHCO3 saturated aqueous solution) and the solvents evaporated under reduced pressure. The residue was purified by flash chromatography using as the eluent hexane–ethyl acetate 2:1. Yield: 99%; yellow oil;
J. L. Garc?′a Ruano et al. Tetrahedron 60 (2004) 10067–10075
Preparation of 3-[trans-4-(p-cyanophenyl)cyclohexyl]propionaldehyde
NCHClOONC
A solution of 10.5 g of p-[trans-4-(3-methoxy-2-propenyl)cyclohexyl]benzonitrile in 200 mL of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 45 minutes while stirring..; The mixture was then partitioned three times in diethyl ether/water..; The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated.; Chromatographic separation of the white, crystalline residue (9.9 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90 and 30:70) finally gave 9.4 g (95percent) of 3-[trans-4-(p-cyanophenyl)cyclohexyl]propionaldehyde as white crystals. Reference: US4565425
9. 由胺合成醛 9.1胺的氧化
胺甲基化合物与六次甲基四胺在弱酸性溶液中加热可得醛（Sommelt反应），收率在60-70%左右。苄胺在DMSO溶液中与亚硝酸钠及三氟醋酸100℃加热可得苯甲醛。
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9.1.1 胺的氧化合成醛反应示例：
NH2NNNNH2NCHOHCl, aq. HOAcCHO
A solution of 272 g. (261 mL, 2.00 moles) of α,α'-diamino-m-xylene, 1.00 kg (7.1 moles) of hexamethylenetetramine, 480 mL of concentrated hydrochloric acid, and 3.2 L of 50% aqueous acetic acid in a 12 L flask is stirred and heated at the reflux temperature for 2.5 hours. The hot amber reaction mixture is then poured into a large battery jar in a well-ventilated hood, and a solution prepared from 298 g of sodium hydroxide and 3.85 L of water is added slowly with stirring. The mixture is covered and allowed to stand overnight at about 5°C. The product, which separates as long needles, is collected, washed on a Buchner funnel with 100 mL of cold water, and then dried to constant weight under vacuum over calcium chloride. There is obtained 158–166 g. (59–62%) of almost colorless needles of isophthalaldehyde, m.p. 88–90°C
Reference: Organic Syntheses, Coll. Vol. 5, p.668; Vol. 47, p.76
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9.2 由胺经由西佛碱的方法
将胺与4-吡啶甲醛反应成西佛碱后在强碱作用下使不饱和键异构化，再予水解，即可得醛。
OHCNH2NNCHNDBUH2NCNH+O
9.2.1 由胺经由西佛碱合成醛示例
NH2+ClNCHO1. DBU2. H+ClCHO
1.77 g (12 mmol) of 4-chlorobenzylamine and 2.78 g (26 mmol) of isonicotinaldehyde were dissolved in 24 mL of DMF. 1.83 g (12 mmol) of DBU was added. The mixture was stirred overnight and acidified by 5% HCl, extracted with ehter. Organic phase was washed with water, dried over Na2SO4 and concentrated to give 1.40 g of 4-chlorobenzaldehyde. Yield: 83%. mp 42~46℃.
Reference: K. Ohta, Synthesis, 1982, 756
9.3 自苯胺衍生物合成
将苯胺制成重氮盐，然后在二价铜盐存在下与甲醛肟作用，生成肟后再水解得醛。此法收率虽不一定高，但由于可将苯胺类化合物直接转变为醛，因而很重要。
NH2ONO2H2SO4/NaNO2ON2NO2CH2=NOHOCHONO2Total yield: 63%
10. 由硝基化合物合成醛酮
用碱处理脂肪族硝基化合物，使其成为氮酸盐，然后在酸性条件下进行水解，可得醛或酮，这就是Nef反应。其缺点是不常用于带有抗酸或抗碱能力弱的基团的化合物。
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Modified conditions: W. Adam et al., Synlett 1998, 1335; P. Ceccherelli et al., Synth. Commun. 28, 3057 (1998). Application to spiroketals: T. Capecchi et al., Tetrahedron Letters 39, 5429 (1998). Reviews: P. Salomaa in The Chemistry of the Carbonyl Group, S. Patai, Ed. (Interscience, N.Y., 1966) pp 177-210; H. W. Pinnick, Org. React. 38, 655-792 (1990); D. S. Grierson, H.-P. Husson, Comp. Org. Syn. 6, 937-944 (1991).
对Nef反应的改进则是在比较缓和的情况下使用各种氧化剂，常用于酮的合成。所用的氧化剂有KmnO4，TiCl3， NaNO2-nPrONO， O3， t-BuOOHV（acac）2，MoO5等。收率均很高。
11. 由Friedel-Crafts反应合成芳基酮
Friedel-Crafts 反应是在芳环上引入酮基的非常好的方法。傅-克酰基化反应
(Friedel-Crafts acylation)的反应机制和烷基化是类似的，也是在催化剂的作用下，首先生成酰基正离子，然后和芳环发生亲电取代。
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常用的酰基化试剂是酰卤(主要是酰氯和酰溴)和酸酐。常用的催化剂是三氯化铝。由于AlCl3能与羰基络合，因此酰化反应的催化剂用量比烷基化反应多，含一个羰基的酰卤为酰化试剂时，催化剂用量要多于1mol，反应时，酰卤先与催化剂生成络合物，少许过量的催化剂再发生催化作用使反应进行。如用含两个羰基的酸酐为酰基化试剂，因同样的原因，催化剂用量要多于2mol，络合物的结构如下：
酰基是一个间位定位基，当一个酰基取代苯环的H后，苯环的活性就降低了，反应即行停止，不会生成多元取代物的混合物，因此芳烃的酰基化反应产率一般较好。例如：
傅-克酰基化反应是不可逆的，不会发生取代基的转移反应。鉴于以上两个特点，傅-克酰基化反应在制备上很有价值，工业生产及实验室常用它来制备芳香酮，例如：
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这不但是合成芳香酮的重要方法之一，同时也是芳环烷基化的一个重要方法，因生成的酮可以用克莱门森(Clemmensen，E.)还原法将羰基还原成亚甲基而得到烃。
与傅-克烷基化反应类似，有间位定位基的芳烃极难发生傅-克酰基化反应，因此在强酸性条件下苯胺的傅-克酰基化反应很难进行，因为氨基会与酸成盐而转变为间位定位基，可通过乙酰化将氨基保护起来，反应结束后，再水解除去乙酰基。例如邻氨基苯乙酮可采用如下合成路线制备：
酚类和芳香醚类化合物都有强活性的邻对位定位基，反应时可以选用比较弱的催化剂如ZnCl2、多磷酸(PPA)等。例如：
由于在邻位位阻较对位大，如对位无取代基主要进入对位。 Reference:C. Friedel, J. M. Crafts, Compt. Rend. 84, 1392, 1450 (1877).
11.1 由Friedel-Crafts反应合成芳基酮示例
AlCl3, CH3COCl, CCl4COCH3
To a 5 L three necked flask equipped with a stirrer, dropping funnel, condenser, and dry
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tube is added 1.5 L of dry, freshly distilled carbon tetrachloride. To this is added 454 g (3.3 mol) of reagent grade granular aluminum chloride and the mixture is cooled to about 5℃ by means of an ice-water bath. Acetyl chlorides (275 g, 3.5 mol) are added dropwise to the cooled mixture over a 5-10 min interval. This addition is then followed with the dropwise addition of the appropriate xylene isomer [o-xylene, 300mL (2.5 mol), m-xylene 300mL (2.5 mol), or p-xylene 275 mL (2.3 mol)] at 10-15℃, which takes about 1-2 h. The mixture is stirred at room temperature for 2 h and then allowed to stand overnight at room temperature. The mixture is poured into a mixture of 5 kg of ice and 700mL of concentrated HCl. The lower carbon tetrachloride layer is separated, washed twice with 250 mL portions of water, once with 500 mL of 2% NaOH solution, and then several times with water until the washings are neutral. The carbon tetrachloride is distilled off at atmospheric pressure and the residue is fractionally distilled to give 280 g (75%) of 3,4-dimethylacetophenone, bp 103℃ (6 mm), 140 g (43%) of 2,5-dimethylacetophenone, bp 85-86℃ (3 mm) and 225 g (61%) of 2,4-dimethylacetophenone, bp 90℃ (6 mmHg).
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12. Dieckmann 缩合脱酸
Dieckmann 缩和实质上是分子内的Claisen 缩和反应。 二元羧酸酯类在金属钠或醇钠、氢化钠等碱性缩和剂作用下发生分子内酯缩和反应，生成环状的β－酮酸酯。反应通常在苯、甲苯、乙醚、无水乙醇等溶剂中进行，缩和产物经水解、脱羧可得脂环酮。
.
12.2 Mechanism
EtO2CEtOOHOEtOCO2EtOEtEtOOOOEt
OHCO2EtOOEtCO2Et+H??CO2Et?CO2Et
12.3 General procedure
BnOHMeO2C1OTBSTMS2NNaTHF, -78oCCO2MeOMeO2C2HNOBnOTBS
Compound 1 (0.07g, 0.15 mmol) in dry THF (2 mL) under nitrogen was cooled to -78oC and treated with sodium bis-trimethylsilylamide (TMS2NNa; 180?L, 1 M in THF, 0.18 mmol). After 1 h the mixture was poured into saturated aq. NaHCO3 and extracted with CH2Cl2 (3 x 10 mL). The extract was washed, dried, evaporated and purified by chromatography using hexane-ethyl acetate 6:1 v/v as an eluant to give 2 (0.04 g, 58%), syrup.
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Reference:Rabiczko, J. et al. Tetrahedron 2002, 58, 1433.
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13. 由合成子合成醛酮
将甲酰基以适当形式保护后，变易产生负离子，与亲电试剂反应后可重新产生甲酰基。如用1，3-二噻烷合成醛的反应：
BuLiSSEERE = RX, C=O, , etc.OSSSSSSECHO
SSNR2常用的甲酰负离子的等价物有：
H3CH3CNNR2SSH3COSO，
S，，
H3CO，
OOSONC，H3CSS+CH3，PhSCH
2OCH3 等。
14. 由砜合成醛酮
烷基，烯炳基，苄基和环烷基砜在n-BuLi 和 Me3SiOOSiMe3的条件下可直接转化成醛或酮，而且收率非常高.
n-BuLi/(Me3SiO)2OSO2PhO
Reference:Jih Ru Hwu J. Org. Chem. 1983, 48, 4432-4433
15. Michael 反应 和类似反应(Addition, Condensation)
详见Michael 反应综述。
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Reference:Michael, J. Prakt. Chem.
35,
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[2] 349 (1887).