Amino-aliphatic carboxylic acids, reactions

Unsubstituted aliphatic carboxylic acids are only very slowly further oxidized to the lower homologous acid in the oxidation of primary alkanols less than 2% of this acid are found. However, with substituted carboxylic acids the cleavage can become the main reaction. Thus anodic oxidation of phenylacetic acid at the nickel hydroxide electrode leads to 87% benzoic acid . Cleavages of similar to a lesser extent are observed with amino acids (Chapter 3.1) or P-alkoxy substituted acids (Chapter 2.4). 

Thiamine is another key sulphur precursor used for meat-like process flavours. Bid-mead and co-workers [95] used thiamine as precursor in combination with an aliphatic carboxylic acid to obtain roasted meat flavours. The reaction can be carried out in presence or absence of a carbohydrate. For example, refluxing thiamine, cysteine hydrochloride and a carbohydrate-free HVP (hydrolysed vegetable protein) for 4 hours results in a product with beef flavour. Giacino [69] proposes the reaction of thiamine with a cysteine-containing peptide, e.g. glutathione or an amino acid mixture containing cysteine, and adding aldehydes and ketones after the reaction. The reaction is preferably carried out in fat. 

The simple primary amines of the aliphatic series, then, do not form diazo-compounds because the reaction which would le, d to their formation only occurs at a temperature at which they are destroyed. The reactivity of the NH2-group can, however, be increased by a neighbouring carbonyl group. Thus we come to the case of the esters of the a-amino-carboxylic acids and of the a-amino-ketones. The ethyl ester of glycine can be diazotised even in the cold the diazo-compound which does not decompose under these conditions undergoes stabilisation by elimination of water and change into ethyl diazoacetate ... 

In the reactions of 4-amino-l-azadienes 295 with esters of glyoxylic acid, chemoselective cyclization occurred with displacement of the amino group NHR, and 2/7-1,3-oxazine-2-carboxylic acid derivatives 296 were formed in high yields instead of the corresponding 1,2-dihydropyrimidines usually obtained in the reactions of 295 with aliphatic or aromatic aldehydes (Equation 28) <1996T3095>. 

The best preventive measure against racemization in critical synthetic steps (e.g. fragment condensation, see p. 239) is to use glycine (which is achiral) or proline (no azlactone) as the activated carboxylic acid component. The next best choice is an aliphatic monoamino monocarboxylic acid, especially with large alkyl substituents (valine, leucine). Aromatic amino acids (phenylalanine, tyrosine, tryptophan) and those having electronegative substituents in the /7-position (serine, threonine, cysteine) are, on the other hand, most prone to racemization. Reaction conditions that inhibit azlactone formation and racemization are non-polar solvents, a minimum amount of base, and low temperature. If all precautions are taken, one still has to reckon with an average inversion of 1 % per condensation reaction. This means, for example, that a synthetic hectapeptide contains only 0.99100 x 100% = 37% of the fully correct diastereomer (see p. 233 f.). 

Recently, Sames and co-workers showed an interesting application, in which it was demonstrated that the Shilov chemistry permits heteroatom-directed functionalization of polyfunctional molecules [16]. The amino acid valine (10) was allowed to react in an aqueous solution of the oxidation catalyst PtCU and Cu(ii) chloride as stoichiometric oxidant (Scheme 3). At temperatures >130 °C a catalytic reaction was observed, and a regioselective C-H functionalization delivered the hydroxyvaline lactone 11 as a 3 1 mixture of anti/syn isomers. It was noted that the hydroxylation of amino acid substrates occurred with a regioselectivity different from those for simple aliphatic amines and carboxylic acids. The authors therefore proposed that the amino acid functionalization proceeded through a chelate-directed C-H activation. 

A one-pot synthesis of 3,5-disubstituted 7-hydroxy-3//-l,2,3-triazolo[4,5-d]pyrimidines (130) has been carried out by using benzyl azide, cyano-acetamide, ethyl or methyl esters of the appropriate carboxylic acid, and sodium ethoxide as catalyst. The reaction proceeds via a 5-amino-l-benzyltriazole-4-carboxamide intermediate (85JHC1607). 7-Amino-3H-l,2,3-triazolo[4,5-d]pyrimidines 133 (R2 = H) were prepared starting from benzyl azide, malononitrile, and an aliphatic or aromatic nitrile, or by reaction of 130 with phosphorus oxychloride followed by amination. Compound 132 was formed in most reactions from two molecules of the 5-amino-4-cyano-l-benzyltriazole intermediate by an intermolecular nucleophilic at-... 

The classical method for making tert-butyl esters involves mineral acid-catalysed addition of the carboxylic acid to isobutene but it is a rather harsh procedure for use in any but the most insensitive of substrates [Scheme 6.33].80-82 Moreover, the method is hazardous because a sealed apparatus is needed to prevent evaporation of the volatile isobutene. A simpler procedure [Scheme 6.34] involves use of tert-butyl alcohol in the presence of a heterogeneous acid catalyst — concentrated sulfuric acid dispersed on powdered anhydrous magnesium sulfate. 3 No interna] pressure is developed during the reaction and the method is successful for various aromatic, aliphatic, olefinic, heteroaromatic, and protected amino acids. Also primary and secondary alcohols can be converted into the corresponding /erf-butyl ethers using essentially the same procedure (with the exception of alcohols particularly prone to carbonium ion formation (e.g. p-... 

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