腈的合成-060303讲解

经典化学合成反应标准操作

腈的合成

编者： 江志赶

药明康德新药开发有限公司化学合成部

经典合成反应标准操作—腈的合成 药明康德新药开发有限公司

目 录

1． 前言………………………………………………………………4 2． 酰胺的脱水………………………………………………………4 2.1用P2O5为脱水剂的反应实例……………………………………………4 2.2用POCl3为脱水剂的反应实例……………………………………………5 2.3用SOCl2为脱水剂的反应实例……………………………………………5 2.4用PCl5为脱水剂的反应实例………………………………………………6 2.5用Bugess 试剂为脱水剂的反应实例…………………………………6 2.6用TFAA-NEt3为脱水剂的反应实例………………………………………7 2.7用(COCl) 2-NEt3-DMSO为脱水剂的反应实例……………………………7 2.8用CH3SO2Cl为脱水剂的反应实例…………………………………………8 2.9用TiCl4为脱水剂的反应实例……………………………………………8

2.10 叔丁酰胺脱水为腈 ………………………………………………………………9

3． 脂肪卤代烃或磺酸酯的反应 …………………………………10 3.1脂肪卤代烃的氰基取代的反应示例………………………………………11 3.2磺酸酯的氰基取代的反应示例……………………………………………11 4. 用TMSCN转化羟基到腈 ………………………………………12 4.1 TMSCN双芳基甲醇氰化反应示例……………………………………12 4.2 TMSCN单芳基甲醇氰化反应示例……………………………………12 5. 用TosMIC直接从酮转化为氰基 ………………………………13 6. 用2,4,6-三异丙基磺酰肼-KCN将酮转化为氰基…………………14 7.芳香卤代烃在金属催化作用下的腈化反应………………………14

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7.1 钯催化下芳香卤代烃或（TfO-）氰基取代反应 ……………………………14 7.2 Cu催化下芳香卤代烃或（TfO-）和K4[Fe(CN)6]反应氰基取代………16 7.3 微波反应芳卤氰基化………………………………………………16

8. 肟脱水生成腈………………………………………………………17

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经典合成反应标准操作—腈的合成 药明康德新药开发有限公司

1. 前言

腈类化合物是很多药物的合成中间体，而腈的合成是有机合成中非常重要的一部分，它一般经由如下几种方法制备： 1. 酰胺的脱水

2. 脂肪卤代烃或磺酸酯的反应 3．芳香卤代烃的氰基取代 4．其他羟基或肟到腈的转化 下面分别进行阐述。

2. 酰胺的脱水反应

酰胺的脱水反应可在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。

ORCNH2OHHRCN-H2ORCN

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。

2.1 用P2O5为脱水剂的反应实例

OH2NP2O5OON

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

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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)

2.2 用POCl3为脱水剂的反应实例

OH2NSNNClPOCl3NSNNCl

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)

2.3 用SOCl2为脱水剂的反应实例

H2NOOFBrSOCl2 DMFONFBr

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

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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) 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，

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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

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%).

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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

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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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

FFONO2HNOHNONNFONO2F

A 5 L round bottom flask was charged with N,N'-di-tert-butyl-5-(2,3-difluoro-6-nitro- phenoxy)-isophthalamide (21; 564 g) and 1.3 L of phosphorus oxychloride. The mixture was heated to between 90 deg C. ~ 100.deg. C. for 2 h, after which approximately 1/2 of the POCl3 was removed by distillation. Toluene was added (1 L) and additional liquid was

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distilled. After cooling the mixture overnight, a crude was obtained by filtration. Additional material was obtained by recovery from the mother liquid. The combined solids were stirred in MeOH (0.7 L) for between 1 and 3 h, filtered and dried in a vacuum oven between 50~80 degC. at 25 Torr with a nitrogen bleed to afford 339 g of 22 (90percent theory).

Reference: US2005/234236

2.10.3叔丁酰胺脱水为腈示例三

OONNONHNOONN

At ice-water bath, oxalyl chloride (0.345 ml) was added dropwise to a solution of 1.0 g of ethyl

1-{4-[2-(t-butylaminocarbonyl)phenyl]phenyl}methyl-4-(1-hydroxy-1-methylethyl)-

2-propylimidazole-5-carboxylate in 10 ml of methylene chloride. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using 1:1 EtOAc/hex (v/v) as the eluent, to give 0.69 g of the title compound as crystals. Reference: US5616599

3. 脂肪卤代烃或磺酸酯与金属氰化物的亲核取代反应

脂肪体系中的亲核取代反应是最受有机化学家注意的单元反应之一，其中脂肪卤代烃或磺酸酯与金属氰化物的亲核取代合成腈得到了广泛的应用：

R-X+CN-R-CN+X-X is I- Br- Cl- or MsO- or TsO-

在转化合成过程中最有用的是在直接取代机理方面有反应活性的底物。即伯类及未受阻碍的仲类脂肪卤代烷或磺酸酯。在叔烷基体系中发生消去反应的倾向是相当显著的，从而在涉及这些体系的转化合成方面限制了亲核取代反应的应用。有时侯，当非碘

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代的卤代烃反应活性不够时，需要在反应体系中加入KI或NaI 增加卤代烃反应活性，或者假如氧离子络合剂，如18冠6等; 有不少文献报道用相转移催化方法完成这一取代。

脂肪卤代烃可由相应醇经卤代反应制备，而磺酸酯可由相应醇经与甲烷磺酰氯或对甲苯磺酰氯反应得来。

3.1 烷基卤代物的氰基取代反应示例

NaCNBr KIN

To a stirring solution of sodium cyanide (1.62 g, 33 mmol) and potassium iodide (66 mg, 0.4 mmol) in dimethyl sulfoxide (20 ml) at 40 deg C., was slowly added 1-bromo-2-ethylbutane over 30 min. The reaction mixture was stirred at 80 deg C for 12 h, then at 110 deg C for 4 h. The reaction mixture was cooled and partitioned between Et2O and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield 2.9 g (87percent yield) of 1-cyano-2-ethylbutane as an amber oil.

1

H NMR (300 MHz, CDCl3): ?2.34 (d, 2 H), 1.58(m, 1 H), 1.46(m, 4 H), 0.92(t, 6 H).

Reference: : Bioorg. Med. Chem. 11, 18, 2003, 4093-4102.

3.2 磺酸酯的氰基取代反应示例

ClClNNHOOOSONaCNNDMFNHON

A mixture of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-

[(methylsulfonyl)oxyl]-hexyl]urea (2.0 g) in a few mL of DMF was added to a cooled stirring suspension of anhydrous sodium cyanide (0.50 g) in 3 mL of dry DMSO. The mixture was heated overnight at 80 oC. Then it was poured into water (100 mL) and the product was extracted with dichloromethane. The combined extracts were washed water, dried (MgSO4)

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and concentrated to give 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-

1-(6-cyanohexyl)urea. Ref: US 4623662 A1

4. 用TMSCN转化羟基到腈

对于芳基苄位的羟基，可以用TMSCN直接转化为腈，反应的好坏与邻位的碳上是否有烷基的氢质子有关。

4.1 TMSCN双芳基甲醇氰化反应示例一

OHTMSCNFFFF

NThionyl chloride (50 ml) was added to bis(4-fluorophenyl)methanol (24.2 g) at 0 deg C and after stirring for 30 min, the mixture was poured into 2N hydrochloric acid (500 ml). The mixture was extracted with ethyl acetate and the organic layer was dried over calcium chloride and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (200 ml) and after addition of trimethylsilylcyanide (16.4 ml), titanium tetrachloride (13.4 ml) was added dropwise at 0 degC. The mixture was stirred for 50 min. Methanol (5 ml) was added to the reaction mixture and the mixture was poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (21.8 g) oil. Ref: EP1219294 A1 (2002/07/03)

4.2 TMSCN单芳基苄醇氰化反应示例二

OHNN TMSCNSnCl2 / CH2Cl2CNNEtOOCNEtOOC To solution of 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexane carboxylic acid ethyl ester (13.5 g, 33.9 mmol) in CH2Cl2 (135 mL) cooled to 0 °C was

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added trimethylsilyl cyanide (22.6 mL, 169 mmol) followed by a slow addition of SnCl4 (13.6 mL of a 1.0 M solution in CH2Cl2, 13.6 mmol). The reaction mixture was allowed to warm to room temperature overnight. K2CO3 (18.7 g, 136 mmol) and KFa2H2O (12.8 g, 136 mmol) were added, followed by dropwise addition of H2O (4.30 mL, 239 mmol). The reaction mixture was stirred vigorously for 90 min, after which silica gel (25 g) was added. The mixture was filtered and washed thoroughly with CH2Cl2. The filtrate was washed with saturated aqueous NaHCO3 (250 mL), dried over MgSO4, filtered, and concentrated to yield 13.2 g oily product of (96% recovery) cyano-4-(1-cyclohexyl-3-ethyl- 1H-indazol-6-yl)cyclohexanecarboxylic acid ethyl ester as a mixture of diastereoisomers. For characterization purposes, a sample of each diastereoisomer was obtained by chromatographic purification on silica gel eluting with 4:1 hexanes/EtOAc. Reference: : Organic Process Research & Development 2001, 5, 587-592

5. 用TosMIC直接从酮转化为氰基

ONOO tosylmethylisocyanideNNOO

To a 250 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 4.34 g (23.49 mmol) N-carboethoxyperhydroazepin-4-one (prepared according to the procedure given by Z. G. Finney and T. N. Riley, J. Med. Chem., 23, 895, 1980), 10.53 g (54.02 mmol) tosylmethylisocyanide and 117 mL 1,2-dimethoxyethane. The solution was cooled to 0 deg C and 2.48 mL (54.02 mmol) ethanol and 9.21 g (82.2 mmol) potassium t-butoxide were added.

The mixture was heated at 60 deg C for 18 hours, cooled and

concentrated. The residue was taken up in ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to give an oil. The oil was purified by chromatography on silica gel using hexane/ethyl acetate as eluent to afford 4.6 g (100percent) of oil. Reference: 72800; Patent; Pfizer Inc.; Publ.: US5373003 A1 (1994/12/13),

6. 用2,4,6-三异丙基磺酰肼-KCN将酮转化为氰基

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NO2,4,6-triisopropylbenzenesulphonohydrazineKCNNCN

3-Quinuclidinone (24.2 g, 0.19 mol) and 2,4,6-triisopropylbenzenesulphonohydrazide (72 g, 0.24 mol) were stirred together in anhydrous MeOH (250 mL) for 3 h. Potassium cyanide (33.8 g, 0.51 mol) was added and the mixture was heated under reflux for 5 h. The residue after evaporation of the solvent was partitioned between water and CH2C12. The organic phase was dried and evaporated and the residue was fractionally distilled under reduced pressure to give 3-cyanoquinuclidine (32, 6.1 g). Reference: J. Med. Chem. 1990, 33, 1128-1138

7. 芳香卤代烃在金属催化作用下的腈化反应

芳腈化合物在有机合成中占据非常重要的地位，尤其是在染料，除草剂，农用化学品，药物及自然产品中应用非常广泛。传统方法合成芳腈化合物主要通过苯胺的重氮化接着Sandmeyer反应制得，对不是复杂的苯腈可由甲苯类化合物在NH3作用下直接氧化制备。但这些方法有较大局限性：反应条件较剧烈，底物要比较简单取代基较少，毒性很大。以下介绍的是实验室常用方法。

7.1a 芳香卤代烃与氰化亚酮作用可用来制备相应芳腈化合物

ClBrCuCNOOODMFOOOClCN

About 14.7 g (0.05 mol) of 5-bromo-4-chloro-2-methoxybenzoic acid ethyl ester, 5.4 g (0.06 mol) of copper (I) cyanide and 8 ml of dimethylformamide are heated at 190 deg for three hours while stirring under nitrogen atmosphere. After cooling, the reaction mixture is stirred well with 250 ml of methylene chloride and 250 ml of 2N hydrochloric acid. The insoluble portions are filtered off with suction filtration and the layers are separated in a separating funnel. The methylene chloride solution is washed neutral with water and then concentrated by evaporation. The obtained residue was re-crystallized from methylene chloride/hexane to give pure 4-chloro-5-cyano-2-methoxybenzoic acid ethyl ester. Ref.: Frontpage/Claim: 59938; Patent; Ciba Geigy Corporation; Publ.: US4559349 A1

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(1985/12/17), Appl.: US1984-586493 (1984/03/05)

7.1b 芳香卤代烃与KCN或 Zn(CN)2在钯催化剂作用下可以实现氰基取代反应。 这类反应常用的催化剂及配体有：Pd(PPh3)4, Pd(OAc)2/PPh3, Pd2dba3等。DMF或NMP为常用溶剂。 实例1

BrNNNOZn(CN)2OPd(PPh3)4NNCNNOO

In a similar fashion, a mixture of 3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4- oxadiazole (33.2 mg, 0.1 mmol), zinc cyanide (17.6 mg, 0.15 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in N,N-dimethylformamide (1 ML) was heated under an argon atmosphere at 80 deg C for 16 hours. After cooling the reaction mixture was poured into water and the crude product was extracted with dichloromethane. Silica gel chromatography using 50 percent ethyl acetate in hexane afforded of 3-(2-pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4- oxadiazole.

Ref.: Patent; Wagenen, Bradford Van; Publ.: US2003/55085 A1 (2003/03/20), Appl.: US2002-76618 (2002/02/19) 实例2

FFNHOOBrZn(CN)2Pd2dba3FNHOOFCNClCl

A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (14) (3.01 g, 7.99 mmol), 1,1'-bis(diphenylphosphino) ferrocene (dppf) (93 mg, 0.162 mmol), Pd2dba3 (73 mg, 0.080 mmol) and Zn(CN)2 (573 mg, 4.78 mmol) in 1-methyl-2-pyrrolidin one (NMP: 4.5 ml) was heated in a sealed tube reactor. After 20 hours the reaction mixture was cooled to room temperature, quenched by the addition of 8 ml 4:1:4 (volume) mixture of

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saturated NHCl, concentrated NHOH and water. The solution was extracted with a

44mixture of EtOAc/THF. The combined organic extracts were washed with 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water, and then brine. The organic layer was dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (twice:100 percent hexanes to 35percent CH2Cl2 in hexanes, then 30 percent CH2Cl2 in hexanes) provided 1.33 g (52 percent) of the desired product. Ref: Patent; Wallace, Eli; Publ.: US2005/54701 A1 (2005/03/10), Appl: US2004-929295 (2004/08/30)

7.2 Cu催化下芳香卤代烃或（TfO-）和K4[Fe(CN)6]反应氰基取代

最近，Thornds Schdreind, Alexander zapf 报道了一种在Cu催化下芳香卤代烃或（TfO-）和K4[Fe(CN)6]反应高收率生成氰基化合物的方法。作者经过一系列实验，使用不同的铜催化剂，以及不同的配体与溶剂，从而得到了最好的实验条件。即：Cu(BF4)2.6H2O为催化剂，DMEDA为配体，DMAc为溶剂。

BrF3CK4[Fe(CN)6]Cu(BF4)2.6H2OF3CCN

No condition details were available in this literature. The general reaction conditions that the author gave were: 2.0 mmol aryl halide, Cu(BF4)2.6H2O(0.1 eq), 20 mol% dry K4[Fe(CN)6], 2 mL DMAc, 20 mol% KI, 20 mol % Na2CO3, 100 mol % DMEDA. Reference: Tetrahedron Letters. 46 (2005) 2585-2588

7.3 微波反应芳卤氰基化

在7.1反应实例中，这些直接取代大多用高温反应，最近有人开发了使用微波反应做这一取代。

BrNZn(CN)2Pd(PPh3)4NCN

A dried heavy-walled pyrex tube was charged with organo-bromide (0.2 mmol), Zn(CN)2 (23.5 mg, 0.2 mmol) and Pd(PPh3)4 (6.9 mg, 6.0 ímol) in DMF (1 ml). The reaction mixture

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was flushed with nitrogen and the screw cap tightened thoroughly before mixing with a Whirlimixer. The reaction mixture was exposed to microwave irradiation (60 W) for 2 min (for 2g 2.5 min). The reaction tube was allowed to reach room temperature before the reaction mixture was diluted in EtOAc (60 mL) and washed with water. The organic phase was dried and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give the pure nitrile. Reference: : J. Org. Chem. 2000, 65, 7984-7989.

8. 肟脱水生成腈

芳香或烷基的醛可以通过转变成肟脱水成相应的腈.

FFOHNHONOFthionyl chlorideOOFOHNNOFFOO

A solution of the powder (0.49 g) of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6- hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate and thionyl chloride (1.5 ml) in dry diethyl ether (1.5 ml) was stirred at room temperature for 30 minutes. After the resultant solution was evaporated to dryness, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give brown oil (0.39 g). The oil was purified by column chromatography on silica gel with eluent of 5:1 benzene:ethyl acetate and crystallized with n-hexane to give a yellow powder (50 mg). The powder was further recrystallized from diethyl ether / n-hexane to give crystals of diethyl 2-methyl-4- (2-trifluoromethyl-phenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate. Reference: Chem Pharm Bull. 1991, 89-3201.

The End

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