Ethyl bromoacetate, Reformatsky reaction

The Reformatsky Reaction consists of the interaction of an ester of an a-halogeno-acid with an aldehyde, a ketone or another ester in the presence of zinc. For example, if a mixture of ethyl bromoacetate and benzaldehyde is heated with zinc, the latter undoubtedly first combines with the ethyl bromoacetate to form a Grignard-like reagent (reaction A), which then adds on to the benzaldehyde Just as a Grignard reagent would do (reaction B). The complex so formed, on acidification gives ethyl p-phenyl-p-hydroxy-propionate (reaction C). Note that reaction A could not satisfactorily be carried out using... 

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

Higher-molecular-weight normal 2-alkenoic acids have been prepared in poor yields by the Doebner condensation of aldehydes with malonic acid,5-7 and by the Reformatsky reaction of aldehydes with ethyl bromoacetate followed by dehydration.8 The a-iodo acid, prepared from the bromo acid, has been dehydrohalogenated with potassium hydroxide in ethanol,9 but large quantities of the a-hydroxy acid are formed as a by-product which is difficult to separate in some instances. The present procedure is an adaptation of a published method.6... 

The synthesis of (3S,4R)-4-(l-aminocycloprop-l-yl)-3-fluoropyrrolidine (28) is illustrated in Schemes 9 and 10. Namely, Reformatsky reaction of 1-acetylcyclopropanecarboxylate (32) [28] with ethyl bromoacetate yields the hydroxyester intermediate (33). Chlorination of this intermediate with... 

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... 

Carbohydrate lactones have been used as the carbonyl reagent in the Reformatsky reaction. Thus, 2,3 5,6-di-O-cyclohexylidene-D-mannono-1,4-lactone [44, obtained by oxidation of the mannofuranose derivative (49)] reacted with ethyl bromoacetate and zinc to give the protected 2-deoxy-3-octulosonic acid ethyl ester (45a) in 69% yield (50). Ketonic hydrolysis with potassium hydroxide in aqueous methanol, followed by acidification and heating, afforded the 1-deoxyheptulose derivative 45b. Similarly, starting from compound 44, the 1-C-substituted allyl and propar-gyl lactols were prepared on reaction with allyl or propaigyl bromides in the presence of zinc (51). 

Since the advent of the one step procedure for the preparation of various substituted thenaldehydes (44), the majority of the necessary starting materials were readily available. Consequently, the Reformatsky reaction was studied with these compounds. With the a-bromoesters the reaction was successfully carried out with four of the thenaldehydes and 2-acetothienone. The nature of the product seemed to depend on the degree of branching of the bromoester. In only one case, where ethyl bromoacetate was used, was a hydroxyester obtained. However, when the carbon atom adjacent to the carbethoxy group was substituted, the product usually contained a hydroxyl group. The dehydration by means of aqueous oxalic acid resulted in a nearly quantitative conversion to the unsaturated esters. 

As an example of the solid-state C-C bond forming reaction with a nucleophile, a Reformatsky-type reaction was conducted with Cgo- Thus, a mixture of Csoj ethyl bromoacetate, and zinc powder in a molar ratio of 1 5 20 was vigorously milled under the HSVM conditions for 20 min. After the mixture was treated with trifluoroacetic acid, the expected adduct 38 was obtained in 17%... 

On the way to fluorinated target molecules, a CF2 group may be also incorporated in the ketone framework in this case drastic conditions are required to promote the Reformatsky reaction with ethyl bromoacetate (lb). The example reported in equation 19 was carried out on 100 g scale and was directed to the synthesis of a fluoro analogue 23 of the anticancer drug chlorambucil94. 

A new preparation of the C g ketone, an important synthon for the synthesis of vitamin A had also been published by Valla et al. [71]. Hence p-ionone and acetonitrile were condensed in the presence of KOH, to afford the nitrile (80%, E/Z isomers 80/20). A Reformatsky reaction of ethyl bromoacetate with the nitrile provided the ethyl P-ionylideneacetoacetate in 70% yield. Subsequent reduction with NaBH4, followed by esterification (MeSC Cl) and desulfonation of the unstable... 

REFORMATSKY REACTION. Dating back to 1887, this reaction depends on interaction between a carbonyl compound, an a-halo ester, and activated zinc in the presence of anhydrous ether or ether-benzene, followed by hydrolysis. The halogen component for example ethyl bromoacetate, combines with zinc bo form an organozinc bromide that adds to the carbonyl group of the second component to give a complex readily hydrolyzed to carbinol. The reaction... 

In a Reformatsky reaction with ethyl bromoacetate, 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one affords a mixture of two esters [Eq. (10)].355 448 4,5,6,7-Tetrahydrobenzo[6]thiophen-7-one behaves analogously.363... 

Thioindoxyl and its 6-ethoxy derivative undergo the Reformatsky reaction with ethyl bromoacetate to give the corresponding 3-benzo-[6]thienylacetic acid, on alkaline hydrolysis of the reaction mixture.569... 

Benzo[6]thienylacetic acid and its 6-ethoxy derivative are obtained in low yield from the corresponding thioindoxyl by the Reformatsky reaction with ethyl bromoacetate.509 4-Benzo[6]thienylacetic acid is obtained by successive dehydrogenation and hydrolysis of the ester mixture shown in Eq. (10).355,448 7-Benzo[6]thienylacetic acid may be prepared similarly.303... 

Ethyl 1-hydroxycyclohexylacetate has been prepared by the Reformatsky reaction of cyclohexanone with zinc and ethyl bromoacetate (56-71 %)3 and by the condensation of ethyl acetate with cyclohexanone in liquid ammonia using two equivalents of lithium amide (69%).4... 

The 3-hydroxytetradecanoic acid required in the next step was obtained as the racemic mixture from n-dodecan-al and ethyl bromoacetate in a Reformatsky condensation (12), and saponification of the ester formed with potassium hydroxide. The enantiomers were then separated as their dehydroabietylamine salts according to Demary et al. (12). All reactions described below were carried out using first the racemic mixture of the acid,and, when reaction conditions were established, with pure (3R)-3-hydroxytetradecanoic acid. 

Methyl 4-bromobut-2-enoate (BrCH2-CH=CH,C02Me, a vinyl analogue of ethyl bromoacetate, Expt 5.69) can also be used in the Reformatsky reaction, and its use permits an analogous four-carbon atom chain extension process. 

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. 

A number of azetidinones have been prepared, with ferrocene attached to carbon (56) and to nitrogen (57).51 These azetidinones were prepared by a Reformatsky-type reaction of aldimines with zinc and ethyl bromoacetate. 

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... 

The indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates with ketones or aldehydes gives di-, tri-, and tetrasubstituted /3-lactones (Table 21).327-329 A similar reaction of imines with ethyl bromoacetate gives 3-unsubstituted /3-lactams (Equation (83)).330 331... 

The Reformatsky reactions of methyl or ethyl bromoacetate with 4-acetoxy-,2,24 4-benzyloxy-,2 4-tetrahydropyranyloxy-,2 4-chloro-,8 and 4,4-dimethoxy-2-butanone1418 have been carried out. The adducts were converted to mevalonolactone by hydrolysis and, in the case of the acetal reactant, by appropriate reduction and oxidation procedures. The same Reformatsky-type syntheses of mevalonolactone have also been performed using the lithium and magnesium carbanions of acetate esters5,19 25 26 and the dianion of acetic acid28,27 instead of the usual zinc reagent. The intramolecular Reformatsky reaction of 4-(bromoacetoxy)-2-butanone gives mevalonolactone directly.28 A related route to mevalonolactone involves boron trifluoride-catalyzed cycloaddition of ketene to 4-acetoxy-2-butanone followed by hydrolysis.183... 

Many of the procedures given above have been utilized for the preparation of mevalonolactone labeled with isotopes of carbon, hydrogen, and oxygen.7-9 Mevalonolactone-14C has been prepared with the label at all six positions l-,7 29 2-,7 143 24 3-,llb 3 -, 203,30 4-,7,183 and 5-14C.19 Preparations of singly and doubly labeled meva-lonolactone-13C have been reported recently 2-,26,31 3-,32 4-,33 3, 4-,7,183 3,4-,26,33b and 4,5-13C.34 The procedure described here26 for the preparation of mevalonolactone-2-13C is both convenient and economical compared to the usual Reformatsky methods since acetic acid-2-13C is utilized directly in the condensation reaction, rather than methyl or ethyl bromoacetate. The overall yield of mevalonolactone-2-13C is 46-52% based on acetic acid-2-13C. 

Chiral Modification of Achiral Organometallic Reagents. The addition of n-Butyllithium or Ethylmagne-sium Bromide to aldehydes or ketones in the presence of (—)-sparteine resulted in the formation of optically active secondary or tertiary alcohols with 20% ee or lower. Optically active acyl sulfoxides (<15% ee) were obtained by acylation of p-Tolylsulfinylmethyllithium. The asymmetric Reformatsky reaction of ethyl bromoacetate with benzaldehyde proceeds with 95% ee, in an exceptional case (eq 1). ... 

The ketone (XXVI) was condensed with ethyl bromoacetate in a Reformatsky reaction, and the resulting unsaturated ester (XXXIV) was catalytically reduced and then saponified to give the endo acid (XXXV). Its configuration follows from its mode of formation and is confirmed by its cyclization in the presence of trifiuoroacetic anhydride to the bridge ketone (XXXVI). 

Treatment of the aromatic aldehydes (21a-e) with ethyl bromoacetate (22) and Zn-NHaCl gave the corresponding Reformatsky reaction products 23a-e in the yields shown in Table 15-6. The yield, for example, of 23a obtained in the solvent-free reaction (91%) is much higher than that obtained by the reaction in dry benzene-ether solution (61-64%) [11, 12]. The nonsolvent Reformatsky reaction, which does not require the use of an anhydrous solvent, is thus advantageous. 

For the Reformatsky reaction of benzuldehyde with ethyl bromoacetate to form ethyl /3-phenyl-/l-hydmxypropionate, Hauser and Hreslow" purified zinc dust by wtuihing It rapidly with dilute Hodium hydroxide solution, water, dilute acetic acid, water, ethanol, acetone, and ether. 11 was then dried in a vacuum over at 100°. 

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