腈類化合物是很多藥物的合成中間體，而腈的合成是有機合成中非常重要的一部分，它一般經由如下幾種方法制備：
1.?酰胺的脫水
2.?脂肪鹵代烴或磺酸酯的反應
3.芳香鹵代烴的氰基取代
4.其他羥基或肟到腈的轉化
今天分享一下通過酰胺脫水制備腈的方法。
本文內容整理自網絡
酰胺的脫水反應可在P2O5、POCl3、SOCl2、PCl5等脫水劑存在下進行脫水反應生成腈，此為實驗室合成腈的方法之一。
將酰胺與P2O5的混合物加熱，反應畢將生成的腈蒸出可得到良好的收率。SOCl2最適宜于處理高級的酰胺，這是由于副產物均為氣體，易于除去，因而減少精制腈的困難。
同時，以上這些脫水試劑多在酸性條件下反應，對于酸敏感的底物是不實用的，因此人們也開發了許多更加溫和的方法用于酰胺的脫水，如：Burgess reagent [Et3N+SO2N-COOMe]，三氟醋酸酐(TFAA)－三乙胺，(COCl)2-NEt3-DMSO等條件可以在低溫和幾乎中性的條件下反應。還有甲烷磺酰氯(CH3SO2Cl)，四氯化鈦(TiCl4) 等等。
用P2O5為脫水劑的反應實例
Asolution of 35g (0.16 mol) of 2-(2-ethyl-3-benzofuranyl)-propionamide in 500mlof toluene was refuxed for 18 hours in the presence of P2O5.? The organic phase was decanted off and theresidue 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 reducedpressure and the residue was fractionated to give 23.8g of2-(2-ethyl-3-benzofuranyl)-propionitrile (yield 74.4%, boiling point: 105.deg.C. at0.2 mmHg).
Reference:?US4124710? A1? (1978/11/07)
用POCl3為脫水劑的反應實例
A mixture of2-chloro-1,3,4-thiadiazole-5-carboxamide (1.4 g) in 17 ml of POCl3 is heated atreflux for 18 hours.? The reactionmixture is concentrated and the residue is suspended in 25 ml of ethyl acetate.? The suspension is cooled in an ice bath andneutralized with saturated, aqueous NaHCO3 (to pH 7).? The phases are separated and the aqueousphase is extracted with 20 ml of ethyl acetate.?The combined organic phases are dried over MgSO4, filteredand concentrated.? The residue ispurified by column chromatography (using 30 percent ethyl acetate / hexane aseluent) 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)
用SOCl2為脫水劑的反應實例
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?(4.20g, 0.013 mol) in dry DMF (25 ml) at room temperature.? The stirred mixture was heated at 120C for 3h and poured into ice–water. The product was extracted into ether (twice) and thecombined ethereal extracts were washed with water, saturated sodium hydrogencarbonate solution, water, and dried (MgSO4). ?The solvent was removedin vacuo?and the residue was purified by column chromatography (silicagel–light petroleum (bp 40–60 8C) with the gradual introduction ofdichloromethane) to yield a colourless solid. Yield 2.88 g (68%);
Reference:?J. Chem. Soc.,Perkin Trans. 1,?1998,3479–3484
用PCl5為脫水劑的反應實例
4-Oxo-4H-9-oxa-1,4a-diaza-fluorene-3-carboxylic acidamide (4.58 g, 20 mmol) wassuspended in 150 ml of anhydrous DMF, PC15 (5.0 g, 24 mmol) wasadded, and the mixture was stirred for 2 h at 40-50 oC. ?The reaction mixture was poured into 600 mlice-water to yield a solid, which was collected by filtration.? The solid was washed thoroughly (first withsaturated 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
用Bugess試劑為脫水劑的反應實例
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 ethylacetate.? ????? 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:
將無水甲醇19.2g (0.6 mol) 和無水苯40mL的混合物在30-40分鐘內，滴入ClSO2NCO 85g(52.3 mL, 0.6 mol)和無水苯200mL的混合物中，控溫10-15℃。加畢，室溫攪拌2小時。然后加入1000mL無水苯稀釋后，小心滴入190mL無水三乙胺和250mL無水苯的混合物中，控溫10-15℃，約40分鐘左右加完。加畢，室溫攪拌2小時，析出大量固體。反應畢，過濾，固體用無水苯200mL、無水THF200mL洗后，濾液濃縮后，（控溫<30℃），加入無水THF溶解后，重結晶得123g, 收率86%。注：整個操作溫度要低于30℃。
用TFAA-NEt3為脫水劑的反應實例
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).
用(COCl)2-NEt3-DMSO為脫水劑的反應實例
A solution of (COCl)2(67 μL, 0.77 mmol) in CH2Cl2 (0.5 mL) was addedto the solution of 3-carbamoyl-piperidine-1-carboxylic acid?tert-butylester (142.0 mmol) and DMSO (78 μL, 1.1 mol) in CH2Cl2(1.5 mL) at -78 oC.? Afterstirring for 15 min at -78 oC, Et3N (0.23 mL, 1.65 mmol)was added dropwise to the mixture.? Afterthe reaction mixture was stirred for 15 min. at -78 oC, the mixturewas quenched by addition of water (5 mL).?After this mixture was warmed to room temperature, the aqueous layer wasextracted with EtOAc (3×10 mL).? The combined organiclayers were washed with brine, dried and filtered.? Concentration after filtration in vaccuofollowed 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
用甲烷磺酰氯(CH3SO2Cl)為脫水劑的反應實例
6-(3-Methoxy-2-propyl-phenyl)-hexanoic acid amide (7.2g, 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 slowlywarming to 25 oC. ?Thereaction mixture was then poured into 3 volumes of ice water. ?The aqueous mixture was repeatedly extractedwith ethyl acetate. ?The combined organicextracts were washed with dilute HC1 and brine, then dried over MgSO4.? After evaporation of the solvent, a brownoily residue was obtained. ?The crudenitrile was purified by bulb-to-bulb distillation (bp 133-137″C (0.02mmHg)), which was pure enough for further transformation (5.50 g, 83 %).
Reference:?J. Med. Chem.?1988,?31, 172-175
用TiCl4為脫水劑的反應實例
Toa solution of CCl4 (110?μL, 1.17 mmol) and THF (6 mL) at 0 oC wasadded TiCl4 (58 μL, 0.52mmol).? 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 thisyellow heterogeneous solution, and stirring was continued at room temperature untilno starting material remained. ?Diethylether and water were added, and the organic layer was washed with brine, driedover 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
