A-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 ... 

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... 

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. 

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]. 

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... 

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. 

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... 

This is a general method for preparing a-bromo acids. By using exactly analogous directions -bromo- -caproic acid may be obtained in 65-70 per cent yields from w-butylmalonic ester a-bromo-isocaproic acid in 65-70 per cent yields from isobutylmalonic ester and a-bromo-/3-methyl valeric acid in 75-80 per cent yields from sec.-butylmalonic ester. 

The final step is the formation of the a-bromo acid by bromine exchange between the a-bromoacyl bromide and the parent acid the acyl bromide, which is necessary for continued reaction, is thus regenerated ... 

Examples of the formation of a range of a-bromo acids are given in Expt 5.164. An alternative method, which has the advantage of being applicable to the... 

When it is required to prepare an a-bromo acid from a carboxylic acid which is not particularly readily available commercially, but which can be synthesised by the malonic acid route (Section 5.11.6, p. 680), advantage may be taken of the ease of bromination in the a-position of the intermediate alkylmalonic acid. The substituted bromomalonic acid undergoes ready decarboxylation on heating to yield the a-bromo acid (e.g. 2-bromo-3-methylpentanoic acid, Expt 5.166). 

This type of expansion very frequently occurs among long-chain aliphatic compounds. All the fatty acids show it, and the expansion is very similar with the a-bromo-acids, the nitriles, alcohols, amides, ureas, oximes, amines, and acetamides. In all these series the expanded film is probably liquid, with a definite surface-vapour pressure, and the area is about 48 sq. A. at the lowest compression. Some other substances form similar films but of different areas the p-alkyl phenols tend to 39 sq. A. (j), and the a-monoglycerides (j) and the a-glyceryl ethers1 of long-chain alcohols,... 

HVZ reaction) Reaction of a carboxylic acid with Br2 and PBr3 to give an a-bromo acyl bromide, often hydrolyzed to an a-bromo acid. (p. 1059)... 

The Hell-Volhard-Zelinsky reaction (Section 22-6) is an effective method for introducing bromine at the a position of a carboxylic acid. The racemic a-bromo acid is converted to a racemic a-amino acid by direct amination, using a large excess of ammonia. 

A-Methylaminoaromatic acids have been prepared by a variety of methods by the reaction between methylamine and an a-bromo acid 4 by condensing methylhydantoin with aromatic aldehydes 8 by condensation of creatinine6 or benzoylmethyl-sarcosine with aromatic aldehydes 7 by methylation of the tol-uenesulfonyl derivative of the amino acid 8 and by substituting methylamine for ammonia in the Strecker synthesis.9... 

It is curious that under thermal conditions a-bromo acids preferentially undergo oxidative decarboxylation rather than oxidation to the a-keto acid (equation 29). ... 

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