发布时间 : 星期一 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
OOONO2OH1. SOCl2/TolueneO2.OOOONO2OO
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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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
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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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
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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