卤代酮的合成-060123

经典化学合成反应标准操作α-卤代酮的合成目录1．前言 (2)2. 直接卤化 (2)3．经重氮酮制备 (4)4．从weinreb 酰胺制备 (6)5．傅克酰基化合成卤代酮 (7)6 其他合成α-卤代酮的方法 (9)1．前言α-卤代酮的合成广泛应用于现代有机合成中， 多用于溴的烷基化、合成咪唑及噻唑等杂环类化合物，其合成方法常用直接卤化、经重氮酮制备、经Weinreb 酰胺制备、傅克酰基化等方法合成。

2. 直接卤化酮的α-氢易被取代，可以直接合成α-卤代酮。

一般操作是将酮与卤素于醋酸、氯仿、DMF 或水中反应。

除卤素外， 硫酰氯、五卤化磷、过溴化吡啶氢溴酸盐（C5H5NH.Br 3）、三卤化三甲基苄基铵盐等也可以做卤化试剂。

对称酮或只有一个取代方向的酮卤代时，可以良好产率（80~90%）生成α-卤代酮。

不对称酮卤代，往往生成α-及α’-卤代酮的混合物。

由于酮卤代的决定步骤是酮的烯醇化，因此，易形成烯醇的方向优先卤代。

例 2-甲基环己酮与亚硫酰氯作用， 多取代的α-氢优先氯代1。

OCH 3OCH 3Cl 2485%若利用双（二甲基乙酰胺基）三溴化氢做溴化剂，可使不对称酮在少取代一边溴代2。

OOBr[(Me 2NCOCH 3)2H]Br 3384%若将不对称酮首先转变成为一定构型的烯醇盐，继而卤代，是区域定向卤代的新方法3。

OH 3COH 3CCl1. i -Pr 2NLi, THFPhCOOEtO CH 3PhOCH 3Br 1. NaH, DMSO另外，甲基酮可用甲基格式试剂与相应的Weinreb 酰胺来制备， 如下例即是先合成甲基酮，后溴化来合成α-溴代酮的4。

NBocO HONBocO NO NBocODCC, D MAP, N HMeOMe MeMgI , e t h er合成实例一 5OOOOOOBrBr 2, AcOH2B 2AA suspension of ketone 2A (700 mg, 2.17 mmol) in acetic acid (15 ml) was heated to 70℃, followed by addition of bromine (347 mg, 2.17 mmol). After the mixture was stirred at 70℃ for 3h, the solvent was evaporated and the residue was purified by column chromatography to give the compound 2B (591 mg, 68%).合成实例二6OMe MeOO Br OMeMeOOBr232C2DBromine (7.99 g, 50 mmol) in CHCl 3 (20 ml) was added in a dropwise manner to a stirred solution of 2, 5-dimethoxy-4-bromoacetophenone 2C (12.95 g, 40 mmol) in CHCl 3 (100 ml) at 5℃. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The mixture was poured onto crushed ice, the organic portion was separated and washed with water, saturated NaHCO 3 solution, and again with water. The solution was dried MgSO 4, and evaporated to dryness under reduced pressure to give a crude product. The product was recrystallized from MeOH to yield 14.70 g (87%) of the desired bromoacetophenone 2D as a white solid.ON NH 2NON NH 2NBr AcOH, 48% aq. HBr and Br 2To a solution of 1-(2-aminopyrimidin-4yl) ethanone (412 mg, 3 mmol) in glacial acetic acid (1 mL) and 48% aq. HBr (0.3 mL), bromine (0.153 mL) in acetic acid (0.4 mL) was added and the resulting orange solution was stirred at RT for1.5 hours. After diluting with ethyl acetate (15 mL), the precipitate was filtered and washed with ethl acetate thus affording the target compound as a whitish solid (580 mg, 65%).合成实例四8O OSiOOSi Br 2E 2FBenzyltrimethylammonium tribromide (4.17 g, 10.7 mmol) was added to a solution of Compound 2E (4.00 g, 10.7 mmol) in CH 2Cl 2-MeOH (5:2, 25 mL). The mixture was stirred at RT for 3 h. At this time the reaction mixture was concentrated in vacuo and H 2O (15 mL) was added. The mixture was extracted with diethyl ether (3 × 20 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexanes:EtOAc, 3:1) to afford to afford Compound 2F (3.97 g, 8.8 mmol, 82%) as a thick yellow oil.3．经重氮酮制备不对称酮卤代时，有时无法得到单卤代产物。

此时，从酰氯或活泼酯经重氮酮合成α-卤代酮可以顺利得到单卤代产物。

重氮酮常用重氮甲烷的醚溶液加到相应的酰氯或活波酯中制得，也可以用三甲基硅重氮甲烷处理相应的酰氯制得。

重氮酮用相应的卤化氢处理即可高产率得到α-卤代酮。

COOH COClO Br(COCl)1. CH2N2/Et2O3A3BTo a solution of compound 3A (0.7 g, 4.3 mmol) in DCM (15 ml, 2 drops of DMF) was added oxalyl chloride (0.55 ml, 6.47 mmol). The reaction mixture was stirred at RT for 10 min, at reflux for 1 h. Then the solvent was removed in vacuo. The residue was dissolved in THF (8 ml), then the mixture was cooled to 0℃. Diazomethane in ether (42 ml, 21 mmol) was then added slowly, the reaction solution was stirred at 0℃for 1 h, followed by 2 h at RT. The reaction mixture was cooled to 0℃again, and 1.2 ml of 35% of HBr in acetic acid was added slowly. The reaction mixture was stirred at RT overnight. The reaction solution was poured into cooled water, and extracted with EtOAc. The organic layer was washed with water, saturated ammonium chloride and brine, dried over sodium sulfate. The solvent was concentrated under reduced pressure to afford 1 g of α-bromoketone 3B (yield 80%).Note: Preparation of diazomethaneSO2NO+ ROH CH2N2+SO2OR+H2OKOHA reaction and distillation apparatus is assembled by connecting an addition funnel and condensor to a 100 ml long-neck distillation flask. Two in series receiving flasks are connected to the apparatus with the second flask containing an induction tube. A solution containing 6 g potassium hydroxide in 10 ml water, and a solution containing 35 ml Carbitol (diethylene glycol monoethyl ether) and 10 ml of ether are placed in the distillation flask. 20~30 ml ether is placed in the second receiving flask makin gsure the induction tube is immersed into the ether. Both receiving flasks are cooled to 0℃. A solution containing p-toluenesulfonyl-N-methyl-N-nitosamide (21.5 g, 0.1 mol) in 140 ml ether is placed in the addition funnel. Heat the distillation flask to 70℃in a warm water bath. As the ether begins to boil, start adding the p-toluenesulfonyl-N-methyl –N-nitrosamide solution dropwise over a 20 minute period. Swirl distillation flask from time to time. About 3 g ofwithout storing it.合成实例二9OOOOOO Cl1. (trimethylsilyl-diazomethane(Trimethylsilyl ）-diazomethane (34 ml, 67 mmol, 20 M solution in hexanes) was added dropwise to a solution of ethyl succinyl chloride (5 g, 303 mmol) in acetonitrile (60 ml) over a period of 30 min after the mixture was stirred for 2 h, hydrogen bromide (14 ml, 30% solution in acetic acid) was slowly added over 15 min after the reaction was stirred for an additional 1 h, the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate and washed with 1 N NaOH and brine. The organic layer was dried with sodium sulfate, filtered, and evaporated under vacuum to yield 4.3 g (64%) of ethyl 5-bromo-4-oxopentanoate4．从weinreb 酰胺制备N -甲氧基-N -甲基酰胺做为易离去基团，可因与有机金属试剂在温和的条件下反应，以良好的收率生成酮。