由酸制備α-鹵代酮

一般情況下，酸先轉化為酰氯，一種方法是酰氯和重氮甲烷或TMS重氮甲烷反應得到重氮酮，用相應的鹵化氫處理即可高產率得到α-鹵代酮。第二種方法是

鹵乙酰鹵與N-甲氧基-N-甲基氯化銨反應得到weinreb酰胺，weinreb酰胺再和有機金屬化物反應得到α-鹵代酮。

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%).

由于重氮甲烷制備比較危險（后附制備方法），可以直接買到相對穩定的TMS重氮甲烷用于反應，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.

重氮甲烷的制備

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.

制備操作

A 0.6 M stock solution of diazomethane in Et2O was prepared by treating a solution of N-nitroso-N-methylurea[10] (1.0 M in Et2O) with an aqueous KOH solution (40%, 5 equiv) at 5 °C for 15 min. The ethereal diazomethane phase was removed, dried on KOH pellets and used directly. The diazomethane solution was titrated by adding a known volume of this diazomethane solution to a know excess of benzoic acid. The residual acid was back-titrated with NaOH (0.5 M). The usual yields were 60 to 70%.

【Chemistry - A European Journal (2009), 15(12), 2923-2931】