NFBrSOCl2 DMFOFBr

H2NOOA 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

2.4 用PCl5为脱水剂的反应实例

ONON PCl5 DMFCONH2ONONCN

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

2.5 用Bugess试剂为脱水剂的反应实例

NNNONH2NNNNNNBugess reagent THF

To a solution of 2-tetrazol-1-yl-benzamide (1.5 g, 7.9 mmol) in tetrahydrofuran (50 ml)

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was added Et3N+SO2N-COOMe (2.8 g, 11.8 mmol) in three portions over 1.5 h. added and the reaction mixture was extracted with ethyl acetate.

Water was

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℃。

2.6 用TFAA-NEt3为脱水剂的反应实例

EtOOCNNNH2OTFAA, Et3NDCMEtOOCNNCN

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).

2.7 用(COCl)2-NEt3-DMSO为脱水剂的反应实例

ONH2NBoc(COCl)2, NEt3, DMSOCH2Cl2NBocCN

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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

2.8 用甲烷磺酰氯(CH3SO2Cl)为脱水剂的反应实例

OCH3SO2ClO(CH2)4CONH2(CH2)4CN

6-(3-Methoxy-2-propyl-phenyl)-hexanoic acid amide (7.2 g, 27.2 mmol) was cooled to 0

o

C 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\(0.02 mmHg)), which was pure enough for further transformation (5.50 g, 83 %). Reference: J. Med. Chem. 1988, 31, 172-175

2.9 用TiCl4为脱水剂的反应实例

OH2NTiCl4NOO

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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 2.10 叔丁酰胺脱水为腈

叔丁酰胺也可当作伯酰胺的替代品，在二氯亚砜，三氯氧磷或草酰氯作用下脱叔丁基脱水为腈，因此有时在制备伯酰胺不容易时，做成相应的叔丁酰胺转化为腈也不失为一个好的方法。

2.10.1叔丁酰胺脱水为腈示例一

NHON

A solution of 1.240 mmol of N-tert-butyl-4-(6,7-dihydro-5H-[2]pyridin-7-yl)benzamide

NNand 1.0 ml of thionyl chloride in 30 ml of chloroform is stirred under reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. The residue is taken up in dichloromethane and mixed with saturated aqueous sodium bicarbonate solution. The organic phase is separated and the aqueous phase is extracted with dichloromethane (2x). The combined organic phases are dried with sodium sulphate and concentrated. The residue is dissolved in diethyl ether and the title compound is converted into the hydrochloride salt by adding ethereal HCI solution (2N). The solid is stirred in diethyl ether/acetone (1: 1), filtered and dried. The title compound is obtained as a dark grey solid. Rf (free base) = 0.36 (EtOAc)

Reference: WO2005/118540

2.10.2叔丁酰胺脱水为腈示例二

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