A-Keto acid oximes

The starting semicarbazones were most often prepared directly from the a-keto acids. Godfrin proceeded from a-alkyl acetoacetates, which were converted by oxidation with nitrosylsulfuric acid to a-keto-acid oximes and the latter transformed to semicarbazones or thioseraicarbazones by applying semicarbazide or thiosemicarbazide. For glyoxylic acid semicarbazone a very convenient procedure was employed, making use of the hydrolysis of nonisolated chloral semicarbazone. ... 

Incorporation of natural amino acids (114, 115,116, 117, 118) and homologs (119,120,121) without further chain lengthening (VII to XVI) proceeds with retention of the a-amino nitrogen (119, 120, 122). An enzyme catalyzing the oxidation and decarboxylation of the N-hydroxyamino acid VIII to the aldoxime XI (123,124) has been purified 1400-fold (125). It is stimulated by FMN, O2 uptake is observed, and the a-keto acid oxime V is not used as a substrate (124,125). Decarboxylation may occur via the a-nitroso acid IX. Incorporation of the nitro compound XIII (126) presumably occurs via the acf-nitro compound XII which was suggested by Ettlinger and Kjaer (72) as an intermediate. The addition of thiols to... 

The hydrolysis of nitriles (58) formed in this way is usually difficult (Scheme 19). In the presence of cone, sulfuric acid mainly amides of a-keto acid oximes (59) were obtained (1), Concentrated hydrochloric acid yields amides of N-hydroxyamino acids (60) (130) while in dilute acid the desired products (1) are formed (1, 79). Taking into account the instability of N-hydroxyamino nitrile (58) and the possibility of its polymerization, the first stage of hydrolysis is carried out at lower temperature (79). The Strecker method has also been applied to the synthesis of several cyclic N-hydroxyamino acids (70, 71) (134). 

Spenser, I.D., and A. Ahmad a-Amino Acids and a-Keto Acid Oximes from a-Hydroxylamino Acids a New Disproportionation Reaction. Proc. Chem. Soc. (London) 1961, 375. 

Ahmad, A., and I.D. Spenser The Conversion of a-Keto Acids and of a-Keto Acid Oximes to Nitriles in Aqueous Solution. Canad. J. Chem. 39, 1340 (1961). 

It yields a monobromide melting at 41°, a semi-carbazone melting at 220° to 221 °, and an oxime melting at 106°. When reduced with sodium and alcohol it yields a secondary alcohol, which forms large crystals melting at 51°. On oxidation by cold 3 per cent, solution of potassium permanganate it yields geronic acid, a keto-acid of the constitution—... 

Certain ketoximes can be converted to nitriles by the action of proton or Lewis acids. Among these are oximes of a-diketones (illustrated above), a-keto acids, a-dialkylamino ketones, a-hydroxy ketones, p-keto ethers, and similar compounds. These are fragmentation reactions, analogous to 17-25 and 17-26. For example, ot-dialkylamino ketoximes also give amines and aldehydes or ketones besides nitriles. 

The enantioselective reduction of a C=N double bond is an interesting alternative for the production of chiral amines by hydrogenation of enamides. Required imines or oximes can be prepared by reaction of ketones with amines or hydroxylamines. However, to date, trials to reduce these substrates with ethyl-DuPHOS catalysts gave no satisfying results. Therefore, transformation of ketones or a-keto acids into acylhydrazones and subsequent enantioselective hydrogenation has proven advantageous (eq 12, Table 5). ... 

Numerous asymmetric catalytic hydrogenations of carbon-nitrogen double bonds have been carried out. Some of the substrates used are oximes and hydrazones, but most of the reactions were carried out using Schiff s bases of ketones. a-Keto acids are precursors of a-amino acids in biosynthesis, and therefore a-keto acids have been used for the asymmetric syntheses of a-amino acids. ... 

Certain ketoximes can be converted to nitriles by the action of proton or Lewis acids. " Among these are oximes of a-diketones (illustrated above), a-keto acids,... 

An attempt to pre )are the oxime of the dibenzyl ketone (26.6) by heating it with hydroxylamine hydrochloride-sodium acetate gave the A -hydroxyisoquinoline as the only product [2120]. In a similar cyclization of a keto acid, ammonium acetate provides the nitrogen atom [2140]. Ammonium carbonate in acetic acid may also be used [2257]. 

This reaction was initially reported by Granacher in 1922. It is the preparation of thionic acid by the treatment of Aldol Condensation product from an aldehyde and rhodanine with a base (e.g., NaOH). Therefore, this reaction is known as the Granacher synthesis or Granacher reaction." The prepared thionic acid in this reaction can be further converted into a variety of derivatives under different conditions. For example, it can be transformed into a-thiol acid under a basic sodium amalgam reduction, whereas aliphatic acid is formed under an acidic zinc amalgam reduction. In addition, when the thionic acid is treated with ammonia, a-keto acid is generated, and the thionic acid can be converted into af-carboxyl oxime in reaction with hydroxylamine, from which either cy-amino acid or aliphatic nitrile forms via the treatment of sodium amalgam reduction or acetic anhydride, respectively. 

Reduction of Oximes of a-Keto Acids and Substituted Aldoximes. . . 227... 

N-Hydroxyamino acids, just like N-hydroxyamines, are strong reducing agents. At room temperature they reduce solutions of salts of such metals as silver, copper, mercury and lead (1). They also reduce Fehling s reagent (1) and decolorize iodine solutions in neutral or alkaline but not acidic media (36). As the result of the above reactions compounds of type (1) are oxidized to the oximes of a-keto acids (31). Esters of N-hydroxyamino acids (90), like N-alkylhydroxylamines, undergo oxidation to dimers of cw-nitroso compounds with a characteristic absorbance at 264 nm, this being analytically important (91). 

Already in the last century Hantzsch (155) observed that reaction of a-halo acids (127) with excess hydroxylamine leads to oximes of a-keto acids (31) as the result of an oxidation-reduction process (Scheme 28). This process, as a method of synthesis of (31), was later thoroughly studied by Barry and Hartung (156). The oxidation-reduction reaction is responsible for the fact that later attempts to obtain the title compounds (1) from (127) by this route were never efficient (81,100) although sometimes they were patented (157). 

Hutterer, F., and Gaul, G. Determination of a-Keto Acids as Silylated Oximes in Urine and Serum by Combined Gas Chromatography-Mass Spectrometry Clin. Chim. Acta 47(3) 371-379 (1973) CA 80 12013w... 

Catalytic reduction of oximes and phenylhydrazones of a-keto acids. 

Arylacetonitriles also can be prepared from the a-keto acids obtained from azlactones. The a-keto acids are isolated from the hydrolysis mixture and converted into the oximes, from which the nitriles are ob-... 

Lancaster, G., Lamm, P., Scriver, C.R., Tjoa, S.S. and Mamer, O.A. (1973), Quantitative analysis of branched-chain a-keto acids as their trimethylsilated oximes. Clin. Chim. Actay 48,279. 

Sternowsky, H.J., Roboz, J., Hutterer, F. and Gaull, G. (1973), Determination of a-keto acids as silylated oximes in urine and serum by combined gas chromatography-mass spectrometry. Clin. Chim. Acta, 47,371. 

When cedrene was oxidised with permanganate, there were chiefly formed products of an acid nature, from which a cedrene keto acid, CjjHj Oa, was isolated, which boiled at 215° to 222° (11 mm. press.). Its semicarbazone melts at 245° and its oxime at 60°. 

Catalytic asymmetric hydrogenation is a relatively developed process compared to other asymmetric processes practised today. Efforts in this direction have already been made. The first report in this respect is the use of Pd on natural silk for hydrogenating oximes and oxazolones with optical yields of about 36%. Izumi and Sachtler have shown that a Ni catalyst modified with (i ,.R)-tartaric acid can be used for the hydrogenation of methylacetoacetate to methyl-3-hydroxybutyrate. The group of Orito in Japan (1979) and Blaser and co-workers at Ciba-Geigy (1988) have reported the use of a cinchona alkaloid modified Pt/AlaO.i catalyst for the enantioselective hydrogenation of a-keto-esters such as methylpyruvate and ethylpyruvate to optically active (/f)-methylacetate and (7 )-ethylacetate. 

The GC-MS methods described here reflect the practice in the laboratory of the author. Organic acids are extracted from biological fluids by liquid-liquid extraction after mixing the specimen with an internal standard solution and a small amount of mineral acid (HC1) to bring the pH to < 2. Oximation of 2-keto acids with hy-droxylamine hydrochloride is not performed routinely, but only as a repeat analysis when the primary analysis reveals an abnormal excretion of 2-keto acids (e.g., lactic acidemia, ketonuria) and the potential presence of other compounds (e.g., glyoxylic acid, succinylacetone). 

Reaction with alcohols is general for diazo compounds, but it is most often performed with diazomethane to produce methyl ethers or with diazo ketones to produce a-keto ethers, since these kinds of diazo compounds are most readily available. With diazomethane593 the method is expensive and requires great caution. It is used chiefly to methylate alcohols and phenols that are expensive or available in small amounts, since the conditions are mild and high yields are obtained. Hydroxy compounds react better as their acidity increases ordinary alcohols do not react at all unless a catalyst such as HBF4594 or silica gel595 is present. The more acidic phenols react very well in the absence of a catalyst. Oximes, and ketones that... 

Reaction of benzo[6]thiophene-2-carboxaldehyde with pyruvic acid yields the keto acid (321), the oxime of which gives a-amino-y-(2-benzo[6]thienyl)butyric acid (322) on catalytic hydrogenation, and j9-(2-benzo[6]thienyl)acrylonitrile on treatment with acetic anhydride the latter yields 8-(2-benzo[6]thienyl)acrylic acid on hydro-... 

This is the case, e.g., with TMS derivatives of Krebs cycle acids, containing keto groups. These derivatives do not provide a simple peak, probably owing to on-column decomposition and, therefore, if keto acids are present in the sample conversion into an oxime [159] is recommended. A 10-mg amount of acids and 10 mg of hydroxylammo-nium chloride are placed in a 5-ml test-tube fitted with a ground-glass stopper and are dissolved in 1 ml of dry pyridine. After standing for 10 min at room temperature 0.1 ml of TMCS and 0.1 ml of HMDS are added. The reaction is completed within a few minutes... 

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