Compounds Derived from Bromoacetic Acids

Monhaloacetic acids are compounds derived from acetic acid with the substitution of a halogen to replace one of the hydrogens. Chloroacetate, fluoroac-etate, iodoacetate, and bromoacetate are compounds that vary in toxicity and mode of action although they are closely related. Sodium fluoroacetate was a widely used mammalian pesticide known as compound 1080. Chloroacetic acid is used as a feedstock and is manufactured in large quantities. 

All four isomeric selenolopyridines which can be derived from benzoselenophene (423— 426 Scheme 123) have been described. Ethyl 3-hydroxyselenolo[2,3-fe]pyridine-2-carboxy-late (429) has been prepared as shown in Scheme 124 (73BSF704). Treatment of ethyl 2-chloropyridine-3-carboxylate with methaneselenol yields (427). Nucleophilic displacement of bromine in bromoacetic acid with subsequent loss of methyl bromide yields (428), which after esterification is cyclized under Dieckmann conditions to give (429). The parent compound (423 colorless oil with b.p. 92 °C/1 mmHg) is prepared either by cyclization of compound (430) and subsequent decarboxylation of the intermediate acid (equation 57) or by reduction of 2-nitroselenophene and subsequent condensation of the amino compound with malonaldehyde bis(diethyl acetal) in the presence of zinc chloride (equation 58) (76BSF883). Selenolo[3,2-6]pyridine (426 b.p. 127-129°C/10 mmHg m.p. 35.5-37.0°C) has been obtained in an analogous manner. 

Treatment of the diaminopyrazole 29 with bromoacetic acid and zinc results in cyclization to the oxo compound 30 identical with that obtained unambiguously from compound 32. Apparently none of the 5-oxo isomer 31 was isolated. Reaction of the nitrosopyrazole 32 with acetic anhydride provided the 6-acetoxy derivative 34. Various substituted analogues were also made by this approach, alkaline hydrolysis providing the... 

Bromoacetyl-p-aminobemylsuccinic Acid. Bromoacetic acid, 1.5 mmoles, and 1.5 mmoles of AT-hydroxysuccinimide dissolved in 6 ml of dioxane are coupled with 1.5 mmoles of dicyclohexylcarbodiimide for 2 hr at 0°. The urea derivative is removed by filtration, and the active ester in the dioxane solution is coupled with 1.2 mmoles of p-aminobenzyl-succinic acid dissolved in 4 ml of 80% dioxane. The reaction mixture is kept at room temperature for 6 hr and then evaporated to dryness. The oily residue is dissolved in ethyl acetate. The organic phase is washed twice with H2O, dried over NagSO, and evaporated to dryness. The compound crystallizes from ethyl acetate-petroleum ether m.p. 126°. 

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). 

The analogous transients of acetophenone and fluorenone have been observed (Adams et al., 1964,1967b) as well as that formed from thiobar-bituric acid (Gordon, 1964). The negative-ion derivatives of acrylamide, methacrylamide and acrylonitrile may be considered as further examples of (R1.CO.R2)- (Dainton, 1967). The electron transfer from (CH3. CO. CH3) to acetophenone has been found to proceed at a rate of 8 x 108 m" sec-1 (Adams et al., 1967a). The same species has been found to react efficiently with bromoacetate and bromopropionate ions, and this reaction, which is probably an electron-transfer process, results in a quantitative debromination of the bromaliphatic compounds (Anbar and Neta, 1967c). The electron adduct of benzoquinone was found to react very rapidly with water to form the semiquinone (Adams and Michael, 1967). 

M-Acetylsaccharinyl acid derivatives 408, which are structurally related to COX-2 inhibitor celecoxib, were designed and synthesised [133] from M-saccharinyl acetate 407a, prepared via the reaction of ethyl bromoacetate with sodium saccharin by heating the reactants in DMF (see [133]). Its transformation into the corresponding hydrazide 407b and subsequent reaction with ethyl acetoacetate, /3-diketones and maleic anhydride, afforded the heterocyclic compounds 408 [134] (Scheme 97). 

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