Ethyl bromoacetate, reaction with

Homologation via a-Haloenolates. Organoboranes can also be used to construct carbon-carbon bonds by several other types of reactions that involve migration of a boron substituent to carbon. One such reaction involves a-halocarbonyl compounds.19 For example, ethyl bromoacetate reacts with trialkylboranes in the presence of base to give alkylated acetic acid derivatives in excellent yield. The reaction is most efficiently carried out with a 9-BBN derivative. These reactions can also be effected with B-alkenyl derivatives of 9-BBN to give /i,y-unsaturatcd esters.20... 

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... 

The next stage requires formation of an extended enolate 118 and its reaction with ethyl bromoacetate. Reactions of enolates with a-bromoesters are not normally recommended as the basic enolates may remove the rather acidic proton between the ester and the bromine atom. The extra conjugation in the extended enolate makes it significantly less basic and this reaction goes... 

Wittig reactions. Ethylene oxide can be used as the base for generation of Wittig reagents from phosphonium salts. It is often not necessary to prepare the salts thus a mixture of ethylene oxide, triphenylphosphine, and ethyl bromoacetate reacts with benzaldehyde at 25° to give ethyl cinnamate (91% yield, trans.cis = 93 7).3... 

This reaction is sensitive to steric hindrance22-24. Moderately hindered alkyl groups, e.g., 1-methyl-1-propyl, 3-methyl-2-butyl, 3-hexyl, 2-c.vo-norbornyl and tm .s-2-methylcyclopentyl. are transferred, whereas the /rimv-2-mcthylcyclohcxyl group is not. As the substrate, chloroace-tonitrile is more reactive than ethyl bromoacetate. Reaction yields are in the range 45-66% (see Table 3). T he procedure also works with a mixture of 9-alkyl-9-borabicyclo[3.3.1]nonane and 9-alkyl-9-borabicyclo[4.2.1]nonane since these initial hydroboration products can be thermally isomerized solely to 9-alkyl-9-borabicyclo[3.3.1]nonane. 

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... 

A 1500 ml. flask is fitted (preferably by means of a three-necked adaptor) with a rubber-sleeved or mercury-sealed stirrer (Fig. 20, p. 39), a reflux water-condenser, and a dropping-funnel cf. Fig. 23(c), p. 45, in which only a two-necked adaptor is shown or Fig. 23(G)). The dried zinc powder (20 g.) is placed in the flask, and a solution of 28 ml. of ethyl bromoacetate and 32 ml. of benzaldehyde in 40 ml. of dry benzene containing 5 ml. of dry ether is placed in the dropping-funnel. Approximately 10 ml. of this solution is run on to the zinc powder, and the mixture allowed to remain unstirred until (usually within a few minutes) a vigorous reaction occurs. (If no reaction occurs, warm the mixture on the water-bath until the reaction starts.) The stirrer is now started, and the rest of the solution allowed to run in drop-wise over a period of about 30 minutes so that the initial reaction is steadily maintained. The flask is then heated on a water-bath for 30 minutes with continuous stirring, and is then cooled in an ice-water bath. The well-stirred product is then hydrolysed by the addition of 120 ml. of 10% sulphuric acid. The mixture is transferred to a separating-funnel, the lower aqueous layer discarded, and the upper benzene layer then... 

There are several laboratory methods useful for the preparation of suberic acid. One starting material is 1,6-hexanediol which can be converted to the dibromide with HBr. Reaction of the dibromide with NaCN gives the dinitrile which can be hydrolyzed to suberic acid. The overall yield is 76% (42). Another laboratory method is the condensation of 1,3-cyclohexanedione with ethyl bromoacetate foUowed by reductive cleavage to give suberic acid in 50% yield (43). 

Thiazolines and thiazolidines may also be prepared in this fashion, the structure of the final product determining the substitution pattern to be chosen in the reaction components. Reaction of ethyl bromoacetate with the substituted thioamide (71) resulted in formation of the thiazolidin-4-one (72) (70KGS1621). 

The ring-contracted analog of alphaprodine is prepared by a variation of the scheme above. Alkylation of 109 with ethyl bromoacetate affords the lower homolog diester (115). Dieckmann cyclization followed by saponification-decarboxylation yields the pyrrolidine (116). Reaction with phenylmagnesium bromide leads to the condensation product (117) acylation with propionic anhydride gives the analgesic agent prolidine (118)... 

Substitution of somewhat more complex side chains on the imidazole nitrogen of the purines leads to CNS stimulant drugs that have also been used as vasodilators and antispasmodic agents. Thus, alkylation of theophyline (2) with ethyl bromoacetate followed by saponification of the product gives acephylline (9). Alkylation with l-bromo-2-chloroethane gives the 2-chloroethyl derivative (10). Reaction of that intermediate with amphetamine yields fenethylline (11). ... 

Trialkylboranes react with ethyl bromoacetate to give ethyl alkylacetates in good yields (6). As in other reactions of boranes, only one of the three alkyl groups is utilized... 

A dry 5(X)-mI flask equipped with a thermometer, pressure-equalizing dropping funnel, and magnetic stirrer is flushed with nitrogen and then maintained under a static pressure of the gas. The flask is charged with 50 ml of tetrahydrofuran and 13.3 ml (0.15 mole) of cyclopentene, and then is cooled in an ice bath. Conversion to tricyclo-pentylborane is achieved by dropwise addition of 25 ml of a 1 M solution of diborane (0.15 mole of hydride see Chapter 4, Section 1 for preparation) in tetrahydrofuran. The solution is stirred for 1 hour at 25° and again cooled in an ice bath, and 25 ml of dry t-butyl alcohol is added, followed by 5.5 ml (0.05 mole) of ethyl bromoacetate. Potassium t-butoxide in /-butyl alcohol (50 ml of a 1 M solution) is added over a period of 10 minutes. There is an immediate precipitation of potassium bromide. The reaction mixture is filtered from the potassium bromide and distilled. Ethyl cyclopentylacetate, bp 101730 mm, 1.4398, is obtained in about 75% yield. Similarly, the reaction can be applied to a variety of olefins including 2-butene, cyclohexene, and norbornene. 

A mixture of 274 g of methyl isonicotinate, 367 g of ethyl bromoacetate and 125 cc of ethyl alcohol was stirred without heating for 4 hours in a flask equipped with a reflux condenser. (The reaction was exothermic and precautions were taken to keep the temperature below 70°C.) The reaction mixture was then left for 15 hours at room temperature. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

The monothione 2 (vide supra) is converted into the (methylsulfanyl)benzoxazepinone 3a by sodium hydride/iodomethane an analogous reaction with ethyl bromoacetate gives the ester 3b.37... 

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. 

Another AMPA-derived procedure took advantage of the neat reaction between the N-carbamoyl-HHT 59 and diethyl phosphite catalyzed by boron trifluoride etherate to generate the AMPA carbamate 60. Subsequent alkylation with ethyl bromoacetate and base produced the glyphosate triester carbamate 61, which was hydrolyzed to GLYH3 (59). 

The Menschutkin reaction was carried out as a test reaction to show the feasibility of such novel micro flow concepts that allow to process fouling-sensitive reactions (see also Section 4.2.6 here another test reaction is decribed for the same purpose) [78]. The reaction of alkyl bromide with ternary bases such as pyridine or triethylamine gives quaternary salts insoluble in most solvents. Often, fairly rapid precipitation of this salt occurs, hence ideally serving as a test reaction for fouling sensitivity of micro-channel devices. The reaction of 4,4 -bipyridyl and ethyl bromoacetate [78] belongs to the category of fast-predpitating Menschutkin reactions, as the halide function is activated by the carbonyl fimction. 

P 5] Layers of 4,4 -bipyridyl (0.3 mol 1 in dichloromethane), ethyl bromoacetate (0.3 mol in dichloromethane) and a separation layer of dichloromethane were fitted into each other by means of a concentric separation mixer (three-fluid nozzle with three tubes having diameters of 1.5, 3 and 4 mm, slotted into each other) [78]. Thereby, two circular liquid layers of a thickness of 200 pm and a center stream of 1.5 mm diameter were generated. The reaction temperature was 22 °C. The reaction solution was inserted as droplets or a continuous stream either directly or via... 

Correlation analyses of this type have also been carried out in connection with the kinetics of the reaction of arfha-substituted benzoate ions with para-substituted phenacyl bromides and of ortho-substituted benzoate ions with ethyl bromoacetate. In all cases it is possible to include o-S02Me among the basic set of well-behaved substituents. 

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. 

Thus, the reaction of alkyl halides and a-halo esters with sodium nitrite provides a very useful synthetic method for nitroalkanes and a-nitro esters. However, ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate on treatment with sodium nitrite.93 This is due to the acidic hydrogen of the ethyl nitroacetate, which undergoes a further reaction with sodium nitrite to give the oxidized products (see Section 6.1, which discusses the Nef reaction). In a similar way, the reaction of benzyl bromide with sodium nitrite at 25 °C gives benzoic acid predominantly. To get phenylnitromethane, the reaction must be carried out at low temperature (-16 °C) (Eq. 2.48).93... 

A rich family of 2-alkoxycarbonyl-l,3,2-oxazaphospholidine-2-oxides 179-181 was prepared from the reaction of camphor derived aminoalcohols 177 and 178 with either methoxycarbonyl phosphonic dichloride or ethyl dichlorophosphite followed by the reaction with methyl bromoacetate. The reaction with aminoalcohol 177a afforded the phosphorus epimers 179 and 180, in ratios from 1/1 to 12/1 depending on the iV-substituent which could be separated easily by column chromatography. The reaction with aminoalcohols 178a-c, however, gave a single epimer 181a-c in each case (Scheme 50) [81]. 

The quinolizine derivative 276 was obtained through a Friedel-Crafts acylation reaction onto the C-3 indole position of 275. This precursor was obtained by a sequence comprising a Fischer cyclization leading to 5-methyl-2-(2-pyridyl)indole 274, catalytic hydrogenation, N-alkylation with ethyl bromoacetate, and hydrolysis of the ester group (Scheme 59) <1999FA479>. 

Reaction of the hydrazinoquinoline derivative 148 with ethyl bromoacetate or diethyl oxalate gave the cyclized product 149 in high yield upon microwave irradiation (Equation 22) <1998IJB174>. 

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