酰胺脫水制備腈

酰胺可在P2O5、POCl3、SOCl2、PCl5等脫水劑存在下進(jìn)行脫水反應(yīng)生成腈，此為實(shí)驗(yàn)室合成腈的方法之一。

將酰胺與P2O5的混合物加熱，反應(yīng)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(jí)的酰胺，這是由于副產(chǎn)物均為氣體，易于除去，因而減少精制腈的困難。

同時(shí)，以上這些脫水試劑多在酸性條件下反應(yīng)，對(duì)于酸敏感的底物是不實(shí)用的，因此人們也開(kāi)發(fā)了許多更加溫和的方法用于酰胺的脫水，如： [Et3N+SO2N-COOMe]，三氟醋酸酐(TFAA)－三乙胺，(COCl)2-NEt3-DMSO，三聚氯氰等條件可以在低溫和幾乎中性的條件下反應(yīng)。還有甲烷磺酰氯(CH3SO2Cl)，四氯化鈦(TiCl4)等等。

反應(yīng)實(shí)例

1.用P2O5為脫水劑的反應(yīng)實(shí)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).

Reference: US4124710 A1 (1978/11/07)

2. 用POCl3為脫水劑的反應(yīng)實(shí)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為脫水劑的反應(yīng)實(shí)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為脫水劑的反應(yīng)實(shí)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試劑為脫水劑的反應(yīng)實(shí)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:

將無(wú)水甲醇19.2g (0.6 mol) 和無(wú)水苯40mL的混合物在30-40分鐘內(nèi)，滴入ClSO2NCO85g (52.3 mL, 0.6 mol)和無(wú)水苯200mL的混合物中，控溫10-15℃。加畢，室溫?cái)嚢?小時(shí)。然后加入1000mL無(wú)水苯稀釋后，小心滴入190mL無(wú)水三乙胺和250mL無(wú)水苯的混合物中，控溫10-15℃，約40分鐘左右加完。加畢，室溫?cái)嚢?小時(shí)，析出大量固體。反應(yīng)畢，過(guò)濾，固體用無(wú)水苯200mL、無(wú)水THF200mL洗后，濾液濃縮后，（控溫<30℃），加入無(wú)水THF溶解后，重結(jié)晶得123g, 收率86%。注：整個(gè)操作溫度要低于30℃。

6.用TFAA-NEt3為脫水劑的反應(yīng)實(shí)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為脫水劑的反應(yīng)實(shí)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)為脫水劑的反應(yīng)實(shí)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為脫水劑的反應(yīng)實(shí)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. 三聚氯氰也是一種很好的酰胺脫水試劑，反應(yīng)不用另外加堿，通常用DMF作為溶劑，室溫下攪拌即可得到腈。

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】

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