Bromo acids

Amino acids may be prepared by the action of a large excess of concentrated ammonia solution upon a-chloro- or a-bromo-acids the presence of a considerable amount of ammonium carbonate often increases the yield of monoamino acid, for example ... 

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins with reaction of the carboxylic acid with PBr3 to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br2 in an cr-substitution reaction to give an cv-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the a-bromo carboxylic acid product. 

Amino acids can be synthesized in racemic form by several methods, including ammonolysis of an a-bromo acid, alkylation of diethyl acetamido-malonate, and reductive amination of an cv-keto acid. Alternatively, an enantio-selective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

Amino acid synthesis (Section 26.3) (a) From a-bromo acids... 

The intermediate o-bromo acid bromide undergoes a nucleophilic acyl substitution reaction with methanol to give an a-bromo ester. 

Diazotization of a-amino acids in the above solvent at room temperature gives a-fluoro carboxylic acids.If this reaction is run in the presence of excess KCl or KBr, the corresponding a-chloro or a-bromo acid is obtained instead. 

Procedures for enantioselective preparation of a-bromo acids based on reaction of NBS with enol derivatives 16A and 16B have been developed. Predict the absolute configuration of the halogenated compounds produced from both 16A and 16B. Explain the basis of your prediction. 

The use of phenylpiperidinols rather than the meperidine-related piperidines as the basic component in antidiarrheal compounds results in retention of activity. The fact that the base is not directly related to a narcotic presumably leads to greater selectivity of action on the gut. Ring scission of butyrolactone 98 (obtainable by alkylation of a diphenylacetate ester with ethylene oxide) with hydrogen bromide gives the bromo acid 99. This is then converted to the dimethylamide by successive treatment with thionyl chloride and dimethylamine. 

A simple two-step synthesis of 5H-alkyl-2-phenyloxazol-4-ones has been reported by Trost and coworkers (Scheme 6.209) [377]. a-Bromo acid halides were condensed with benzamide in the presence of pyridine base at 60 °C to form the corresponding imides. Microwave irradiation of the imide intermediates in N,N-dimethylacetamide (DMA) containing sodium fluoride at 180 °C for 10 min provided the desired 5H-alkyl-2-phenyloxazol-4-ones (oxalactims) in yields of 44—82%. This class of heterocycles served as excellent precursors for the asymmetric synthesis of a-hydroxycar-boxylic acid derivatives [377]. 

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 starting point for the 5-fluoropentanecarboxylic esters was cyclohexanone, which was oxidized to 5-hydroxypentane-carboxylic acid by a modification of Robinson and Smith s method.3 This was then converted into the bromo acid by means of hydrogen bromide and sulphuric acid.4... 

The checkers found that the product partially decomposed when stored for a day at ambient temperature. Therefore it is recommended that the bromo acid be used immediately in the next step. 

B) a-Bromo-fi-methoxypropionic Acid.—Eight hundred grams of the bromo ester and 11. of 0.5 N sodium hydroxide are placed in a 5-I. three-necked flask equipped with an efficient stirrer and a separatory funnel, and cooled with running tap water. The stirrer is started, and 800 cc. of 5 N sodium hydroxide is added during the course of two hours. After the addition is complete, the solution is stirred for one hour and then neutralized with an equivalent quantity of sulfuric acid (Note n). The neutralized solution is extracted once with a i-l. portion, and three times with 500-cc. portions, of ether. The ether extracts are combined, washed once with a cold saturated solution of sodium sulfate, and dried over anhydrous sodium sulfate the ether is removed by distillation (Note 12). There remains 700-750 g. of crude bromo acid which is used without purification in the preparation of serine (Note 13). 

The yield of crude bromo acids is 350-370 g. (88-93 Per cent of the theoretical amount based on the crotonic acid used in the first step). This material is used without purification in the preparation of aminomethoxybutyric acid. 

The crude bromo acid is placed in a 2-1. modified Claisen flask and distilled under reduced pressure. The low-boiling... 

Volhard, J. Justus Liebigs Ann. Chem. 1887, 242, 141. Jacob Volhard (1849-1909) was born in Darmstadt, Germany. He apprenticed under Liebig, WiU, Bunsen, Hofmann, Kolbe, and von Baeyer. He improved Hell s original procedure in preparing a-bromo-acid during his research in thiophenes. 

This procedure has been used to prepare a variety of substituted a-bromohydrocinnamic acids 2 p-acetyl-a-bromohydro-cinnamic acid was prepared for the first time by this method. The method illustrates a typical application of the Meerwein reaction for the arylation of unsaturated substrates.3 In this reaction a catalytic amount of a copper(I) salt is used to reduce an aryl diazonium salt forming an aryl radical and a copper(II) halide. Addition of the aryl radical to an unsaturated substrate forms an alkyl radical that is reoxidized by the copper(II) halide present forming an alkyl halide and regenerating the copper(I) salt catalyst. In this preparation, the product, an a-bromo acid, is formed in an acidic reaction mixture and dehydro-halogenation does not occur. However, dehydrohalogenation... 

Ethylthieno[2,3-6]thiophene-2-carboxylic acid with bromine in acetic acid gave the 4-bromo acid. ... 

Fronchimont Reaction. By the action of f CN on a-bromo acids or esters, a-cyano-a,j8-dicarboxylic acid derivatives are formed which on hydrolysis and decarboxylation yield a,/8 dicarboxylic acids ... 

In fact, even in such a low acidic medium, fluoride is not reactive enough to compete with strong nucleophiles and, for example, a-chloro or a-bromo acids can be obtained by halodediazoniation of a-amino acids with sodium nitrite/potassium chloride (or bromide) in 48% hydrogen fluoride/pyridine mixture.311... 

Reformatsky reaction. Tetrahydropyranyl esters are recommended for use in Rcformatsky reactions. They are formed from a-bromo acids in quantitative yield In dry benzene without need of an acid catalyst and they arc readily hydrolyzed by dilute hydrochloric acid. The Reformatsky reaction is generally conducted in THF at a temperature below 10". The reaction is more rapid if the zinc is activated with a trace of HgCI2. Yields of -hydroxy acids arc generally 70-90% when aldehydes are used, hul usually somewhat lower with ketones. 

The ether layer containing the bromomalonic acid is separated from the aqueous layer and the ether removed by distillation from a steam cone. The residual liquid is decarboxylated by refluxing for five hours in a 500-cc. round-bottomed flask on an oil bath heated to 130°. The bromo acid is then separated from the small amount of water and distilled. The material distilling at i25-i4o°/i8-2o mm. is a-bromo- -methylvaleric acid (Note 8). The yield is 150.5 g. (66.7 per cent of the theoretical amount). 

C) dl-Phenylalanitte.—The crude bromo acid is divided into four portions and each portion is added to 2 1. of technical ammonium hydroxide (sp. gr. 0.90) in a 3-I. round-bottomed flask. The flask is well shaken, a rubber stopper is wired in, and the mixture is allowed to stand for a week. The contents of the four amination flasks (Note 5) are then combined in a 12-I. flask, 20 g. of Norite is added, and the flasks are heated on a steam cone overnight. The ammonia which is evolved is conducted into a gas-absorption trap or merely led into water by a tube from the flask. The solution is filtered while still hot on cooling most of the phenylalanine precipitates. This is filtered, washed with 250 cc. of methanol, and the filtrate evaporated under the pressure of a water pump until more crystals form. The solution is then cooled and an additional crop of phenylalanine obtained, which is also washed with methanol. The yield of crude product is 500 g., but it is slightly wet if it is dried overnight in an oven at about 8o°, it will weigh 460 g. This need not be done, however, as the yield of pure product is the same whether or not the crude product is dried. 

In some cases the N-terminal component can be converted into a thiol [NH2-CH(R)-CH2SH] which is then used to displace the halogen of an a-bromo acid. This approach was used to prepare Boc-Ser t t[CFI2-S]Leu analogues by a role-reversal of the side-chain/acid group of Cys, once the amino acid was converted into an amino alcohol (Scheme 7).[38]... 

In this approach cysteine (19) was reduced to Cys(ol) (20) which was isolated as the triacetyl derivative 21. This compound was hydrolyzed with hydrochloric acid, the resulting hydrochloride 22 treated with 3 equivalents of NaOEt followed by addition of the a-bromo acid 24 derived from D-leucine (23). The resulting product 25 can then be /V-Boc-protected to yield the pseudodipeptide in a form suitable for solid-phase chain elongation. 

A report involving the solid-phase preparation of Fmoc-protected t t[CH2—S] pseudodipeptides revealed that the expected stereochemical patterns did not hold.147 It is known that the conversion of an a-bromo acid into the a-thioacid does not always occur with quantitative inversion of chirality, since it is side-chain dependent.146] With side chains such as benzyl (Phe) or butyl (Leu, lie), exceptions are not expected. But when the Fmoc-protected amino thiol 26 was condensed to a support-bound bromo acid 27, as shown in Scheme 8, the (S,R)-product 28 was obtained instead of the expected (S,S)-isomer. 

The Curtius rearrangement provides a route to carbamates of a-amino sulfonamides (Scheme 25). 108 Reaction of the ethyl ester of an a-bromo acid 52 with Na2S03 yielded the sodium salt of the corresponding sulfonic acid 53. Treatment of 53 with PQ5 afforded the sulfonyl chloride 54 which on reaction with an amine gave the sulfonamide 55. The latter... 

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