Bromoacetate, ethyl, reaction

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]. 

A number of methods are available for the preparation of phosphonate reagents. For example, treatment of triethylphosphite with ethyl bromoacetate Arbuzov reaction) produces the phosphonoacetate A. Its reaction with a suitable base such as NaH gives the carbanion B, which, on treatment with cyclohexanone, furnishes cyclo-hexylideneacetate C in 70% yield. This compares favorably to the 25% yield obtained when using the triphenylphosphorane Ph3P=CHC02Et. 

The best results are obtained with the use of alkali metal hydrides (NaH, KH) in THF, DME, or DMF. The reaction works well in THF or DME with activated halides such as ethyl bromoac-etate, ten-butyl bromoacetate, - ethyl 2-bromobutyratc, ethyl T-broniobulyrale.- (iodom-ethyl)trimethylstannane, " (iodomethyl)trimethylsilane, benzoyl bromide,- benzyl bro-mide, - farnesyl bromide,- " alkyl 4-bromocrotonates, l-(bromomethyl)naphtalene,- andN-bromomethylphthalimide but gives poor results with primary alkyl halides.- Primary and secondary alkyl halides, bromides and iodides (Scheme 8.16), react satisfactorily in dMF or DMSO, although bulky electrophiles give poor results. In DMSO the expected product is frequently contaminated by the dialkylation product. ... 

Ethyl diallylaminoacetate (XIII) was obtained from ethyl-bromoacetate by reaction with diallylamine as before. 1,6-Diallylaminohexane (XVI) was obtained from ICI Australia Ltd. and purified by vacuum distillation. 

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... 

The reaction can be applied to allyl malonates. Alkylation of diallyl mal-onate (734) with bromoacetate and acetoxymethylation afford the mixed triester 735. Treatment of the tricster 735 with Pd catalyst affords allyl ethyl itaconate (736). In a similar way, a-methylene lactone and the lactam 737 can be prepared[462]. 

Bromoacetic acid [79-08-3] (BrCH2COOH), mol wt 138.96, C2H3Br02, occurs as hexagonal or rhomboidal hygroscopic crystals, mp 49°C, bp 208°C, 1.9335, 1-4804. It is soluble in water, methanol, and ethyl ether. Bromoacetic acid undergoes many of the same reactions as chloroacetic acid under... 

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). 

Medium Boiling Esters. Esterificatioa of ethyl and propyl alcohols, ethylene glycol, and glycerol with various acids, eg, chloro- or bromoacetic, or pymvic, by the use of a third component such as bensene, toluene, hexane, cyclohexane, or carbon tetrachloride to remove the water produced is quite common. Bensene has been used as a co-solvent ia the preparatioa of methyl pymvate from pymvic acid (101). The preparatioa of ethyl lactate is described as an example of the general procedure (102). A mixture of 1 mol 80% lactic acid and 2.3 mol 95% ethyl alcohol is added to a volume of benzene equal to half that of the alcohol (ca 43 mL), and the resulting mixture is refluxed for several hours. When distilled, the overhead condensate separates iato layers. The lower layer is extracted to recover the benzene and alcohol, and the water is discarded. The upper layer is returned to the column for reflux. After all the water is removed from the reaction mixture, the excess of alcohol and benzene is removed by distillation, and the ester is fractionated to isolate the pure ester. 

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 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. 

Reaction of pyridinium-A -(2-pyridyl)amidine (402) and alkyl haloace-tates in the presence of K2CO3 afforded a mixture of 4-oxo-4/f-pyrido[l, 2-u]pyrimidine-2-carboxylates 407 and 2-aminopyridine derivatives 406 through intermediers 403- 05, as depicted in Scheme 15 (00TL5837). Compound 406 could be cyclized on the action of heat or silica gel into 407. The best yield was achieved in the case of ethyl bromoacetate. 

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. 

In semiindustrial synthesis, to achieve better yields, it is possible to omit (A), by directly preparing the ester (B) by reaction of p-hydroxy acetophenone on ethyl 2-bromoacetate in the presence of potassium carbonate in butanone. The yield of ester is 90%, and elimination of excess of p-hydroxyacetophenone is effected by washing with sodium hydroxide. 

NaH should serve as an efficient template ion to yield cone conformers. Conformer distribution for the reaction of p-tert-h Wy calix[4]arene and ethyl bromoacetate is given in Table I. 

Table 1 Conformer Distribution for the Reaction of p-Zerz-Butyl Calix[4]arene and Ethyl Bromoacetate [16]...

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). 

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