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
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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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
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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经典合成反应标准操作— 醛酮的合成
AlON 药明康德新药开发有限公司
OHOONOHOXORNR'R'XAlORONR'R'RONR'OROHAlNR'O
5.4.1 由酰胺合成醛酮
ONOHLiAlH(OEt)3Hexanes/THF, -78 to 0oCHO
A flame-dried, 1-L, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar is charged with 2.95 g (73.9 mmol) of 95% lithium aluminum hydride under a nitrogen atmosphere. The flask is sealed with a rubber septum containing a needle adapter to an argon-filled balloon and is charged with 170 mL of hexanes. The septum is removed and the flask is equipped with an oven-dried, 25-mL, pressure-equalizing addition funnel sealed with a rubber septum containing a needle adapter to an argon-filled balloon. The reaction flask is cooled to 0°C in an ice-water bath, the addition funnel is charged with 10.7 mL (109 mmol) of ethyl acetate, and slow, dropwise addition of ethyl acetate is initiated and completed within 1.25 hr. Upon completion of the addition, the addition funnel is removed, the reaction vessel is sealed with a rubber septum containing a needle adapter to an argon-filled balloon, and the reaction flask is cooled to ?78°C in a dry ice-acetone bath. A solution of 10.0 g (32.1 mmol) of (1S,2S)-pseudoephedrine-(R)-2-methylhydrocinnamamide in 110 mL of tetrahydrofuran is added to the cold suspension of lithium triethoxyaluminum hydride [LiAlH(OEt)3] via cannula over 5 min. Upon completion of the addition, the dry ice-acetone bath is removed and the reaction mixture is warmed to 0°C in an ice-water bath. During the
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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
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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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
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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