一般情况下,酸先转化为酰氯,一种方法是酰氯和重氮甲烷或TMS重氮甲烷反应得到重氮酮,用相应的卤化氢处理即可高产率得到α-卤代酮。第二种方法是
卤乙酰卤与N-甲氧基-N-甲基氯化铵反应得到weinreb酰胺,weinreb酰胺再和有机金属化物反应得到α-卤代酮。
一、重氮酮法
To 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%).
由于重氮甲烷制备比较危险(后附制备方法),可以直接买到相对稳定的TMS重氮甲烷用于反应,操作方便。
(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-oxopentanoate.
Ref. : J. Med. Chem.; EN; SIN48; 4; 2005; 926 - 934.
二、weinreb 酰胺法
Benzylmagnesium chloride (1.0 M in diethyl ether, 50.0 mL) was treated with
2-chloro-N-methoxy-N-methylacetamide (5.16 g, 37.5 mmol) in THF (200 mL) at -78℃ dropwise. The reaction was allowed to warm slowly to room temperature overnight and quenched with 1N hydrochloric acid. The layers were separated and the organic phase dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, elution with hexanes) to provide the title compound.
重氮甲烷的制备
A 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 of diazomethane (0.07 mol) is dissolved in ether distillate. The reagent should be used at once without storing it.
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