发布时间 : 星期日 文章醛酮的合成-060331更新完毕开始阅读cae2ef5ca98271fe900ef918
经典合成反应标准操作— 醛酮的合成 药明康德新药开发有限公司
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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经典合成反应标准操作— 醛酮的合成
药明康德新药开发有限公司
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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经典合成反应标准操作— 醛酮的合成 药明康德新药开发有限公司
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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经典合成反应标准操作— 醛酮的合成 药明康德新药开发有限公司
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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