酰胺可在P₂O₅、POCl₃、SOCl₂、PCl₅等脱水剂存在下进行脱水反应生成腈，此为实验室合成腈的方法之一。

将酰胺与P₂O₅的混合物加热，反应毕将生成的腈蒸出可得到良好的收率。SOCl₂最适宜于处理高级的酰胺，这是由于副产物均为气体，易于除去，因而减少精制腈的困难。

同时，以上这些脱水试剂多在酸性条件下反应，对于酸敏感的底物是不实用的，因此人们也开发了许多更加温和的方法用于酰胺的脱水，如：Burgess reagent [Et₃N⁺SO₂N^-COOMe]，三氟醋酸酐(TFAA)－三乙胺，(COCl)2-NEt3-DMSO等条件可以在低温和几乎中性的条件下反应。还有甲烷磺酰氯(CH₃SO₂Cl)，四氯化钛(TiCl₄) 等等。

反应实例

1.用P₂O₅为脱水剂的反应实例

A solution of 35g (0.16 mol) of 2-(2-ethyl-3-benzofuranyl)-propionamide in 500ml of toluene was refuxed for 18 hours in the presence of P₂O₅.  The organic phase was decanted off and the residue was carefully decomposed with ice-water and extracted with ether.  The organic phase was washed with water, dried over sodium sulphate and added to the toluenic phase.  The solvent was evaporated off under reduced pressure and the residue was fractionated to give 23.8g of 2-(2-ethyl-3-benzofuranyl)-propionitrile (yield 74.4%, boiling point: 105.deg. C. at0.2 mmHg).

Reference: US4124710  A1  (1978/11/07)

2.用POCl3为脱水剂的反应实例

A mixture of 2-chloro-1,3,4-thiadiazole-5-carboxamide (1.4 g) in 17 ml of POCl3 is heated at reflux for 18 hours.  The reaction mixture is concentrated and the residue is suspended in 25 ml of ethyl acetate.  The suspension is cooled in an ice bath and neutralized with saturated, aqueous NaHCO3 (to pH 7).  The phases are separated and the aqueous phase is extracted with 20 ml of ethyl acetate.  The combined organic phases are dried over MgSO₄, filtered and concentrated.  The residue is purified by column chromatography (using 30 percent ethyl acetate / hexane as eluent) to afford 0.832 g of 2-cyano-5-chloro-1,3,4-thiadiazole. MP: 65-67. deg.C

Reference: Patent; EP883611  B1  (2002/07/31) 

3.用SOCl₂为脱水剂的反应实例

A solution of thionyl chloride (7.70 g, 0.065 mol) in dry DMF (10 ml) was added dropwise to a stirred solution of compound 13 (4.20 g, 0.013 mol) in dry DMF (25 ml) at room temperature.  The stirred mixture was heated at 120C for 3 h and poured into ice–water. The product was extracted into ether (twice) and the combined ethereal extracts were washed with water, saturated sodium hydrogen carbonate solution, water, and dried (MgSO4).  The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel–light petroleum (bp 40–60 8C) with the gradual introduction of dichloromethane) to yield a colourless solid. Yield 2.88 g (68%);

Reference: J. Chem. Soc., Perkin Trans. 1, 1998, 3479–3484

4.用PCl₅为脱水剂的反应实例

4-Oxo-4H-9-oxa-1,4a-diaza-fluorene-3-carboxylic acid amide (4.58 g, 20 mmol) was suspended in 150 ml of anhydrous DMF, PC1₅ (5.0 g, 24 mmol) was added, and the mixture was stirred for 2 h at 40-50 ^oC.  The reaction mixture was poured into 600 ml ice-water to yield a solid, which was collected by filtration.  The solid was washed thoroughly (first with saturated aqueous NaHCO₃, then with water) and dried to give 4-oxo-4H-9-oxa-1,4a-diaza- fluorene-3-carbonitrile.

Ref: J . Med. Chem. 1983, 26, 608-611

5.用Bugess试剂为脱水剂的反应实例

To a solution of 2-tetrazol-1-yl-benzamide (1.5 g, 7.9 mmol) in tetrahydrofuran (50 ml) was added Et₃N⁺SO₂N^-COOMe (2.8 g, 11.8 mmol) in three portions over 1.5 h.Water was added and the reaction mixture was extracted with ethyl acetate.  The combined organic layers were washed with brine and water. After drying and filtration, the solvent was evaporated to give 2-tetrazol-1-yl-benzonitrile.

Reference:  J. Med. Chem. 47, 12, 2004, 2995-3008.

Preparation of Bugess reagent:

将无水甲醇19.2g (0.6 mol) 和无水苯40mL的混合物在30-40分钟内，滴入ClSO2NCO85g (52.3 mL, 0.6 mol)和无水苯200mL的混合物中，控温10-15℃。加毕，室温搅拌2小时。然后加入1000mL无水苯稀释后，小心滴入190mL无水三乙胺和250mL无水苯的混合物中，控温10-15℃，约40分钟左右加完。加毕，室温搅拌2小时，析出大量固体。反应毕，过滤，固体用无水苯200mL、无水THF200mL洗后，滤液浓缩后，（控温<30℃），加入无水THF溶解后，重结晶得123g, 收率86%。注：整个操作温度要低于30℃。

6.用TFAA-NEt₃为脱水剂的反应实例 

To a mixture of compound amide (287 mg, 1 mmol), Et₃N (470 mg, 4.5 mmol) in anhydrous DCM (4 mL) was added TFAA (0.44 g, 2 mmol) at 0℃ with stirring.  The resulting mixture was warmed to room temperature and stirred for 12 h.  The reaction was monitored by TLC (Hexane:AcOEt = 1:1) until its completion.  The organic layer was washed with brine and water, dried and concentrated to give the desired product (~80% yield).

7.用(COCl)₂-NEt₃-DMSO为脱水剂的反应实例

A solution of (COCl)₂ (67 μL, 0.77 mmol) in CH₂Cl₂ (0.5 mL) was added to the solution of 3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (142.0 mmol) and DMSO (78 μL, 1.1 mol) in CH₂Cl₂ (1.5 mL) at -78 ^oC.  After stirring for 15 min at -78 ^oC, Et₃N (0.23 mL, 1.65 mmol) was added dropwise to the mixture.  After the reaction mixture was stirred for 15 min. at -78 ^oC, the mixture was quenched by addition of water (5 mL).  After this mixture was warmed to room temperature, the aqueous layer was extracted with EtOAc (3×10 mL).  The combined organic layers were washed with brine, dried and filtered.  Concentration after filtration in vaccuo followed by purification by column gave 3-cyano-piperidine-1-carboxylic acid tert-butyl ester (123.3 mg, 93%).

Reference: T. L. 38, 12, 1997, 2099-2102

8.用甲烷磺酰氯(CH₃SO₂Cl)为脱水剂的反应实例

6-(3-Methoxy-2-propyl-phenyl)-hexanoic acid amide (7.2 g, 27.2 mmol) was cooled to 0 ^oC and added methane-sulfonyl chloride (18.5 mL, 239 mmol) dropwise over 5 min.  The mixture was stirred overnight while slowly warming to 25 ^oC.  The reaction mixture was then poured into 3 volumes of ice water.  The aqueous mixture was repeatedly extracted with ethyl acetate.  The combined organic extracts were washed with dilute HC1 and brine, then dried over MgSO₄.  After evaporation of the solvent, a brown oily residue was obtained.  The crude nitrile was purified by bulb-to-bulb distillation (bp 133-137"C (0.02 mmHg)), which was pure enough for further transformation (5.50 g, 83 %).

Reference: J. Med. Chem. 1988, 31, 172-175

9.用TiCl4为脱水剂的反应实例

To a solution of CCl₄ (110 μL, 1.17 mmol) and THF (6 mL) at 0 ^oC was added TiCl₄ (58 μL, 0.52 mmol).  After 5 min, 5,11-diethyl-8-methoxy-5,6,11,12-tetrahydro-chrysene- 2-carboxylic acid amide (47 mg, 0.13 mmol) in THF (14 mL) and Et₃N (72μL, 0.52 mmol) was added to this yellow heterogeneous solution, and stirring was continued at room temperature until no starting material remained.  Diethyl ether and water were added, and the organic layer was washed with brine, dried over MgSO₄, and concentrated.  Repeated recrystallization from diethyl ether gave 5,11-diethyl-8-methoxy-5,6,11,12-tetrahydro- chrysene-2-carbonitrile (45 mg, 99%).

Reference: J. Org. Chem. 1992, 1262-1271

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