腈水解制备酰胺
早在1989年，Alan R. Katritzky就报道了一种 H2O2-K2CO3-DMSO体系水解腈为伯酰胺的方法【Synthesis1989, 949 】，室温下，5-30分钟就能完成反应，是一种非常实用的水解腈制备酰胺的方法。
之前有小伙伴问此反应的机理是什么？H2O2为什么能够加速反应，小编查了一下，发现此反应的机理研究早有报道【 Bulletin of the Chemical Society of Japan , 1981, 54, 793-799】，下面对此反应的机理 分享给大家，以供大家学习交流。
反应机理
反应中加入催化量的碳酸钾，反应体系呈碱性，因此会生成HOO-（其亲核性大于HO-）, 其对腈进行亲核加成生成过氧亚胺酸，过氧亚胺酸是一种氧化性很强的氧化剂，其甚至可以氧化过氧化氢生成氧气。此反应的改进就是加入了DMSO作为还原剂可以迅速消耗生成的过氧亚胺酸，由于此步骤很快，而且不可逆，因此可以明显加速整个反应进程。
反应操作
To a stirred solution of 4-chlorobenzonitrile (1.37 g, 0.01 mol) in DMSO (3 ml), cooled in a ice bath, was added 30% H2O2 (1.2 ml) and K2CO3, the reaction was allowed to warm up to r.t. (strong exothermic effect was observed). After 5 min., distilled water (50 ml) was added, cooling applied, and the product was collected by filtration, yield 85%.
酰胺脱水制备腈
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，三聚氯氰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 solventwas 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).
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
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.
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
10. 三聚氯氰也是一种很好的酰胺脱水试剂，反应不用另外加碱，通常用DMF作为溶剂，室温下搅拌即可得到腈。
To a DMF solution of benzyl (S)-(1-amino-3-(2-nitrophenyl)-1-oxopropan-2-yl)carbamate (1.2 g, 3.5 mmol) was added cyanuric chloride (1.2 g, 6.5 mmol, 1.86 eq.) at 0°C and stirred overnight at RT. To this solution was added ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Recrystalization from acetone gave a pure target molecule as an off-white solid (1.6 g, quant.).
【 J. Am. Chem. Soc. 2020, 142, 25, 10899–10904 】
