Ethyl pyruvate

ETHYL PYRUVATE (Pyruvic acid, ethyl ester) 

Checked by Charles C. Price, Kenneth N. Campbell, and John Warnke. 

Petroleum ether, b.p. 40-60°, was washed with concentrated sulfuric acid before use. The checkers used the hexane fraction of petroleum. 

The ethyl lactate should be of good quality, as its impurities tend to appear in the final product. The submitter used a good commercial grade supplied by British Industrial Solvents, Ltd. Its specification included an ester content of not less than 99% (calculated as ethyl lactate). 

The commercial 99% ethyl lactate available to the checkers did not give satisfactory results. It was purified by distillation through a fractionating column 8 by % in., packed with glass beads. The portion having the following properties was used b.p. 154-155°, no 1-4125, df 1.0302. 

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Amino-5-hydrazinopyrazole dihydrochloride 300 is a good source for the synthesis of this type of heterocyclic compound [78JCS(P1)885] and it was prepared by reaction of malononitrile with two equivalents of hydrazine. Reaction of 300 with ethyl pyruvate afforded 301. Unstable hydra-zone 302 formed when 300 was boiled with diacetyl rapidly cyclized to 303. Reaction of 300 with benzil gave 304 directly, which gave an acetyl derivative and resisted reductive deamination. On the other hand, a polymer was isolated from the reaction of 300 with glyoxal (Scheme 65). 

The synthesis has been described mainly by building the thiadiazole onto a triazine ring. However, one report has used thiadiazole 981 as starting material. Reaction of 981 with ethyl pyruvate gave 982 that was... 

In a related reaction, the Danishefsky diene 1434 cyclizes with ethyl pyruvate 1435 in the presence of catalytic amounts of the asymmetric Lewis acid catalyst 1436, at -72 °C in THF, to give the Diels-Alder adduct 1437, in 85% yield and 91% ee, and the ring-opened product 1438, which cyclizes, however, with triflic acid to give 1437 [11] (Scheme 9.9). 

An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

Not so long ago, the general opinion was that high enantioselectivity can only be achieved with natural, structurally unique, complex modifiers as the cinchona alkaloids. Our results obtained with simple chiral aminoalcohols and amines demonstrate the contrary. With enantiomeric excesses exceeding 80%, commercially available naphthylethylamine is the most effective chiral modifier for low-pressure hydrogenation of ethyl pyruvate reported to... 

Variety of a-keto esters, such as methyl and ethyl pyruvate, methyl mandalate, dihydro-4,4 - dimethyl-2,3 fiiranedione were used to calculate the shielded form of [CDdosed - a-keto ester] complexes leading to the formation of ( R) or (S) product, respectively. The details of these results will be a subject of a subsequent paper [17]. As emerges from these calculations the favourable directionality is maintained in complexes (R), even for dihydro-4,4 - dimethyl-2,3 fiiranedione. 

Hydrogenation of ethyl pyruvate in the presence of cinchonidine. In our previous studies [3, 4,14] variety of experimental data were obtained, which could not be explained by existing models [1,2] proposed earlier. These results are as follows [3,4,12] (i) the monotonic increase type behaviour of the optical yield - conversion dependencies, (ii) the complexity of the reaction kinetics, (iii) side reactions catalyzed by CD. It was also demonstrated that the enantio-differentiation can be induced if the modifier is injected into the reactor during racemic hydrogenation. 

One of the most interesting side reactions taking place during the enantioselective hydrogenation is the transesterification of the substrate or the reaction product. If the enantioselective hydrogenation of ethyl pyruvate was performed in methanol as a solvent the formation of methyl pyruvate and methyl lactate was observed. CD appeared to be an effective catalyst for the above transesterification reaction. 

Methyl pyruvate thiosemicarbazone in the presence of zinc chloride or acetate resulted in the formation of complexes with the ligand hydrolyzed or transesterified. The complexes with pyruvate thiosemicarbazone, ZnL2, or ethyl pyruvate thiosemicarbazone, ZnLCl2 were structurally characterized by single-crystal X-ray crystallography showing respectively a distorted octahedral and distorted square pyramidal geometry.874... 

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

Table 3 Ethyl Pyruvate (EtPy) hydrogenation data (60 bar).

Ethylphenyldichlorophosphine, 31, 89 Ethyl phenylpropiolate, 32, 75 Ethyl phosphite, 31, 111 Ethyl pyruvate, 31, 59 1,1 Eth vn ylene-6is-c yclohex ANOL, 32, 70... 

New modifiers have traditionally been discovered by the trial-and-error method. Many naturally occurring chiral compounds (the chiral pool38) have been screened as possible modifiers. Thus, the hydrogenation product of the synthetic drug vinpocetine was discovered to be a moderately effective modifier of Pt and Pd for the enantioselective hydrogenation of ethyl pyruvate and isophorone.39 Likewise, ephedrine, emetine, strychnine, brucine, sparteine, various amino acids and hydroxy acids, have been identified as chiral modifiers of heterogeneous catalysts.38... 

Torok B, Karoly F, Gerda S, Mihaly B (1997) Sonochemical enantioselective hydrogenation of ethyl pyruvate over platinum catalysts. Ultrason Sonochem 4(4) 301-304... 

The ring system in 541 was synthesized (76JHC1249) by interaction of 4-hydrazino-7-phenylpyrazolo[l,5-a][l,3,5]triazine 540 and ethyl pyruvate. The hydrazino derivative 540 was prepared on cyclocondensation of 5-amino-l-thioamido-3-phenylpyrazole 537 with triethyl ortho-formate to give the pyrazolotriazinethione 538 followed by methylation to give 539 and hydrazinolysis to give 540. 

Dehydrogenation of 566 gave 567 (77AP588). Ring closure of the hydrazine 568 with ethyl pyruvate gave methanoazepinotriazine 569 (86H907). 

Ethyl pyruvate Ethanol Horn 6 Ethyl lactate (100) 16.6... 

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