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1、经典化学合成反应标准操作目录1前言2 2氰基转化为酯2 3氰基转化为酰胺2 3.1丙稀酰胺的合成2 3.2苯乙酰胺的合成3 经典合成反应标准操作 Mitsunobu 反应Page 1 of 6 6. 从氰基合成酰胺6.1氰基水解腈加水可以分解为伯酰胺。 由于伯酰胺会继续水解为羧酸， 一般要控制水解的条件。目前有许多方法报道，有时需要根据底物的特性选择酸性，碱性或中性的水解条件。作为中性的条件，也有文献报道使用镍或钯催化剂的方法。在酸性条件下与饱和碳相连的氰基，可以在酸中很方便的水解转化为酰胺，并在条件较为剧烈时，很容易进一步水解成酸。 但乙烯基或芳基腈的水解条件则要求剧烈得多，一般需要强酸条件
2、，而且一般不会进一步水解。在碱性条件下，利用过氧化氢氧化的方法可在室温下短时间内水解腈为伯酰胺，这是一个较为可靠的方法。 利用 NaOH(aq.)-CH2Cl2相转移催化体系， DMSO-K2CO3体系2可以用于各种腈水解为伯酰胺。6.1.1 盐酸水解腈为伯酰胺示例3CNCONH2HCl, H2OIn a 3-l. three-necked round-bottomed flask equipped with glass joints are placed 200 g. (1.71 moles) of benzyl cyanide and 800 ml. of 35% hydrochloric
3、 acid. The flask is fitted with a reflux condenser, a thermometer, and an efficient mechanical stirrer. At a bath temperature of about 40 the mixture is stirred vigorously. Within a period of 20 40 minutes the benzyl cyanide goes into solution. During this time, the temperature of the reaction mixtu
4、re rises about 10 above that of the bath. The homogeneous solution is kept in the bath with, or without, stirring for an additional 20 30 minutes. The warm water in the bath is replaced by tap water at about 15 20 , and the thermometer is replaced by a dropping funnel from which 800 ml. of cold dist
5、illed water is added with stirring. After the addition of about 100 150 ml., crystals begin to separate. When the total amount of water has been added, the mixture is cooled externally with ice water for about 30 minutes. The cooled mixture is filtered by suction. Crude phenylacetamide remains on th
6、e filter and is washed with two 100-ml. portions of water. The crystals are then dried at 50 80 . The yield of crude phenylacetamide is 190 200 g. (82 86%). 经典合成反应标准操作 Mitsunobu 反应Page 2 of 6 6.1.2 浓硫酸水解不饱和腈为伯酰胺示例4CNCONH21. H2SO42. NH3To 106 g of 84 % sulfuric acid, was added 50 g of acrylonitrile.
7、After stirring for 30 min at r.t., the resulting mixture was heated to 95 , and stirred for 2 h. After cooling, the solid was collected by suction, and the filter cake was transferred into a beaker. To the ice-cooled solid, was added aq. ammonia with the speed that keep the temperature less than 50.
8、The precipitated ammonium sulphate was filtered off, and the filtrate was cooled. The precipitate was collected by filtration, and the filter cake was washed by water, dried in vacuum to give the desired product. 6.1.3 H2O2-K2CO3-DMSO 体系水解腈为伯酰胺示例1ClCN30% H2O2, K2CO3DMSO, rt, 5 minClONH2To a stirred
9、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
10、collected by filtration, yield 85%. 6.1.4NaOH( aq.)-CH2Cl2相转移催化体系水解腈为伯酰胺2CN(n-C 4H9)N+HSO 4-30 % H2O2, CH2Cl220% NaOH, 20-25 NH2OTo a magnetically stirred dichloromethane solution (1.5 ml) of o-tolunitrile (0.5 g, 4.27 mmol) cooled in an ice bath, are added 30% hydrogen peroxide (2.0 ml), tetrabutyl
11、ammonium hydrogen sulfate (0.290 g, 0.85 mmol), and a 20% aqueous solution of sodium hydroxide (1.6 ml). The 经典合成反应标准操作 Mitsunobu 反应Page 3 of 6 reaction mixture is allowed to warm up to r.t. and maintained under stirring. After 1.6 h, dichloromethane is added, the organic layer is separated, washed
12、with brine, and dried with sodium sulphate. The solvent is removed under reduced pressure to leave a white solid from which pure o-toluamide is obtained by chromatography on silica gel. Yield 0.485 g (97%). 6.2 Ritter 反应碳正离子加成到腈基的氮原子上生成的腈盐加水分解得到相应的酰胺加水可以分解为酰胺。一般能产生碳正离子化合物都可以发生这类反应。由于醇或烯烃在浓硫酸或其他强酸加热条
13、件下反应，一般在次条件下稳定的腈都可用于该类反应。这类反应通过腈和酸在溶剂中反应，但对于乙腈来说，直接用乙腈中反应即可，对于其他较为复杂，沸点较高的底物，一般用冰醋酸稀释。CH3CN,H2SO4AcOH, 20oC, overnightCH3CN NCH3CH2OON H85%一般卤代物用于这一反应比烯烃和醇要差，但用亚硝基四氟硼酸盐（NOBF4）和亚硝基六氟磷酸盐 (NOPF6)可以室温以下反应5。这两个试剂也可直接拔除三取代碳上的氢生成碳正离子。BrNOBF4, CH3CN0oC-rt, 1hN HO当使用醇作反应物时，则可以得到相应的N-烃基酰胺6。CNMeOH (1.5eq), PPA
14、 (3.eq.)150oC, 10hON H而通过卤素或有机硒等对烯烃加成，得到的碳正性的中间体也可用于对乙腈的加成7。如果所用的是环状烯烃，则为反式加成。PhSeCl, TfOH, H2OCH3CN, reflux, 1 hSePhNHAc经典合成反应标准操作 Mitsunobu 反应Page 4 of 6 6.2.1 Ritter 反应示例一8OH+CNH2SO4, AcOH 40oC, 1 hH NOA solution of 5.3 g (0.1 mol ) of acrylonitrile, 50 ml of acetic acid and 7.4 g of tbutylalcoho
15、l in an ice-bath was treated with conc. sulfuric acid (10.1 g, 0.1 mol) with stirring so as to keep the temperature below 40 during the addition and subsequent reaction (an hour), the reaction mixture was poured onto 200 g of ice, the product filtered and air dried, yield 10 g (yield 80 %). The prod
16、uct could be recrystallized from benzene. 6.2.2 Ritter 反应示例二9PhHOOCOHPh rt, 18 hTMSCN, H2SO4PhCOOHNHCHOPhTo a mixture of alcohol (10 mmol) and trimethylsilyl cyanide (20 mmnol), cooled to - 15C in an ice-salt bath, under nitrogen, is added concentrated sulfuric acid (30 mmol) dropwise with vigorous stirring (caution: highly exothermic). A
