Diethyl ether, Reformatsky

Highly reactive zinc can be prepared by reduction of anhydrous ZnC with potassium/THF or sodium/DME(l 7,29). This zinc has been shown to undergo rapid oxidative additions with alkyl bromides to produce near quantitative yields of the corresponding dialkylzinc. It also underwent oxidative addition with phenyl iodide and bromide. Moreover, the zinc was found to be useful in the Reformatsky reaction. Reactions could be carried out in diethyl ether at room temperature to generate near quantitative yields of the 3-hydroxyester. 

The Reformatsky reactions of ethyl a-bromopropionate and related esters with N-substituted 6-bromo-2-oxochromene-3-carboxamides in a mixed diethyl ether-benzene-HMPA-THF solvent system give substituted 9-bromo-2,3,4,4a,5,10b-hexahydro-l//-chromeno[3,4-f]pyridine-2,4,5-triones (HMPA = hexamethylphosphoramide Scheme 45) <2004RJ0892>. Without the THF present in the mixed-solvent system, the reaction stops at the intermediate Wbenzyl-6-bromo-4-(l-alkoxycarbonylalkyl)-2-oxochroman-3-carboxamide stage. 

The synthesis of the fluoroketone that combines the retroamide type bond (76) is shown in Scheme 5. The 2,2-difluoro-3-hydroxyester 11 from a Reformatsky reaction was converted to the primary amide 12 by treatment with ammonia in diethyl ether. Reduction of the amide with borane dimethyl sulfide and protection of the resulting amine gave the protected intermediate 13. For the preparation of peptides XIV and XV, the hydroxy function was oxidized to the corresponding ketone using pyridinium dichromate. 

Single-stage procedures are most commonly used for the Reformatsky reaction with aldehydes and ketones. A mixture of a-halo ester and carbonyl substrate is added to a suspension of zinc at a rate sufficient to maintain the reaction. In the original procedure of Reformatsky, no solvent was used but modem practice is to use benzene or an ether solvent such as diethyl ether, THF, glyme or dimethoxymethane. The reaction is often conducted at reflux temperature, probably to avoid surges from the highly exothermic nature of the reaction. However, in a comparison with a number of aldehydes and ketones, much higher yields were obtained at room temperature than at reflux in benzene (equation 11). ... 

After the successful application of Zn/TMSCl in the Reformatsky reaction [82] (see also more recent work in this field [83-85]), the same combination was applied in Zn-Barbier reactions with allylic bromides in diethyl ether [86] ... 

We have found that Rieke zinc is especially attractive for the generation of the Reformatsky reagent [79-81]. The unusual reactivity of Rieke zinc is further demonstrated by its reaction with ethyl a-bromoacetate, which proceeds rapidly in THF or diethyl ether at -5°C. The reaction was completed in 0.5 h, which was confirmed by GPC analysis. Furthermore, the active zinc reacted with ethyl a-chloroacetate rapidly in ether solvents at room temperature. 

The activated zinc will also react rapidly with a-chloroesters in THF. However, the yields are not as high and generally are in the 70-80% range. The Reformatsky reagent can be prepared separately and then added dropwise to the carbonyl compound at room temperature. In addition, the Reformatsky reagent in THF or diethyl ether can be purchased from Rieke Metals, LLC. The shelf life of the Reformatsky reagent is limited and slowly decomposes over a period of 10-20 days even if it is stored in a refrigerator. The best results are obtained if it is used as soon as possible. 

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