Ethyl a-bromoacetate

The reaction of ethyl a-bromoacetate with 17-keto steroids such as estrone methyl ether or dehydroepiandrosterone acetate " under standard Reformatsky conditions is stereospecific, producing the 17 -ol in up to 80% yields. Ethyl a-bromopropionate reacts similarly but the yields are somewhat lower. 

The iron slurries react readily with ethyl a-bromoacetate. The resulting organoiron species adds readily to aldehydes and ketones to produce 3 -hydroxyesters in excellent yields. Addition of a mixture of an aryl aldehyde and an allylic halide to the iron slurry produced good yields of the cross-coupled alcohol. 

An appropriately functionalized isoquinoline (38) bearing a benzyl group is prepared from an aromatic aldehyde (37). The benzyl position is metalated with LDA and the resulting carbanion is reacted with a highly substituted methyl benzoate to produce a ketone (39). The isoquinoline nitrogen is alkylated with ethyl a-bromoacetate and the resulting quaternary salt is cyclized... 

Ishibashi and Iwao have reported [37] a novel route (Scheme 13) to lamellarin G trimethyl ether that utilizes a much different strategy than the one outlined in Scheme 8. The synthesis begins with the dialkylation of a phenethyl amine with ethyl a-bromoacetate to yield an aminodiester (67). 

This procedure is an adaptation of ones described by Dunna-vant and Hauser.2-4 Ethyl /3-hydroxy-/S,/3-diphenylpropionate has been prepared previously using the Reformatsky reaction by condensing ethyl a-bromoacetate with benzophenone by means of zinc metal.5... 

This strategy also provides a convenient method for amination of various ester enolates with DPH Ih (Scheme 14). The amination of lithium eniminate of phenyl acetonitrile, the silyl enolate of ethyl phenylacetate and the Reformatsky reagent derived from ethyl a-bromoacetate with DPH were found to be unsuccessful. A failure of DPH for the amination of sodium enolates of S-diketones and the lithium enolate of 3-methylbutanoic acid was also reported . 

Even unreactive alkenes undergo the Simmons-Smith reaction (cyclopropanation) in high yield with dibromomethane and this zinc powder. Almost quantitative yields are obtained in the Reformatsky reaction of ethyl a-bromoacetate and this zinc powder. Ethyl a-chloroacetate can also be used if the reaction is conducted at higher temperatures for a longer period. 

The site at which alkylation occurs depends on the alkylation reagent, the reaction conditions and the nature of the substituents on the azoloazine ring system. Thus, whereas alkylation of compound (114) by alkyl iodides in THF in the presence of sodium hydride gives the products (115), alkylation by ethyl a-bromoacetate or ethyl a-bromopropionate gives the products (116) (Scheme... 

The zinc-mediated Reformatsky reaction is one of the classical methods for carbon-carbon bond formation. To date, various main group metals and transition metals have been used for this reaction. Rieke s activated indium powder mediates readily the coupling of ethyl a-bromoacetate and a variety of carbonyl compounds yielding /3-hydroxy esters in good yields (Scheme 87).3 Later, commercially available indium powder has been found to be equally effective for the indium-based Reformatsky reaction in THF.28 This indium Reformatsky reaction is accelerated by ultrasound irradiation (Scheme 88).322,323 Indium(i) iodide also mediates the Reformatsky reaction of aldehydes and ketones to give /3-hydroxy esters, presumably via organoindium(m) diiodide (Scheme 89).27... 

SYNS ANTOL BROMOACETIC ACID, ETHYL ESTER ETHOXYCARBONYLMETHYL BROMIDE ETHYL BROMOACETATE ETHYL-a-BROMOACETATE ETHYL MONOBROMOACETATE... 

A new ring closure to quinazolines was found by allowing 2-benzoyl-5-nitroaniline to react with hexamine (hexamethylenetetramine), in the presence of ethyl a-bromoacetate, in a solvent. When the solvent was methanol,... 

Thieno[2,3-J]thiazoles (396) have been prepared from aryl isothiocyanates and thiocarbonates, through the alkylation of the thiolate intermediate with ethyl a-bromoacetate (Scheme 98) <90S62l>. 

The phosphonium ylid from ethyl a-bromoacetate reacts with the [Fp(ethylene)] complex to give a stable -alkyliron phosphonium salt, which reacts with base and benzaldehyde after the fashion of a normal reagent ... 

Excess ethyl a-bromoacetate followed by excess triethylamine added to a soln. of methyl 3-morpholinodithioacrylate in acetone 2-methylthio-5-carbethoxythio-phene. Y almost 100%. - The reaction is a general one with a-halogenocarbonyl compounds. F. e. s. E. J. Smutny, Am. Soc. 91, 208 (1969). 

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. 

When a 1 1 mixture of ethyl a-bromoacetate and ketone was reacted with the active zinc at -5°C, followed by refluxing for various times, yields of the P hydroxy ester on the order of 70-85% were obtained. It was then discovered that a superior solvent system was diethyl ether. In this case, the highly reactive zinc was generated in THF by the usual procedure, then the THF was removed, and freshly distilled dry diethyl ether is added to the black powder. A one-to-one mixture of ketone or aldehydes and a-bromoester is then added dropwise at ice-bath temperatures. Finally, the reaction mixture is stirred at room temperature for 1 h followed by normal workup procedures. The ability to use diethyl ether at ice bath or room temperatures would appear to make the activated zinc procedure highly desirable. 

Reaction of this activated indium metal with a-haloesters is rapid. For example, reaction of a mixture of ethyl-a-bromoacetate and cyclohexanone in xylene at 55°C for 2 h gives an almost quantitative yield of the corresponding P-hydroxyester. The activated indium will also react with ethyl-a-chloroace-tate. In this case reaction for 7 h at 55°C in xylene gave a 42% yield of the p-hydroxy ester. In contrast, commercial indium metal (325 mesh) was... 

Finally, the results of reactions of a variety of carbonyl compounds with the activated indium and ethyl-a-bromoacetate are summarized in Table 6.5. In general, the yields of p-hydroxy esters are good with ketones and also with benzaldehyde in xylene and diethyl ether. However, alkyl aldehydes give relatively low yields. In conclusion, highly activated indium has been prepared and some interesting new results have been reported. However, it is clear that much work remains to be done to fully explore the utility of this new material. 

The following is a representative procedure ethyl a-bromoacetate (60 mmol) and benzaldehyde (58 mmol) were weighed separately. To the black slurry of active manganese in THF (30 ml) was added the mixture of benzaldehyde and ethyl a-bromoacetate drop by drop over 25 min. The addition was conducted at 0°C, and the entire system was kept under argon. The reaction mixture was stirred at room temperature for about an hour after the addition was completed. The reaction was then quenched with 2 N hydrochloric acid... 

A soln. of benzylideneaniline in dry toluene heated to reflux with Zn-foil and a little iodine, ethyl a-bromoacetate added until an exothermic reaction starts... 

Alkylation of cyclohexane is expected to start with deprotonation of the a-C atom by a strong base. However, the more acidic a-C atom of ethyl a-bromoacetate will preferably be deprotonated. This deprotonation triggers the sequence of reactions presented in Scheme 5.42. 

Scheme 5.42 Base-promoted reaction between cyclohexanone and enolate of ethyl a-bromoacetate...

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