Methyl 3-oxobutanoate

Carbon is alkylated ia the form of enolates or as carbanions. The enolates are ambident ia activity and can react at an oxygen or a carbon. For example, refluxing equimolar amounts of dimethyl sulfate and ethyl acetoacetate with potassium carbonate gives a 36% yield of the 0-methylation product, ie, ethyl 3-methoxy-2-butenoate, and 30% of the C-methylation product, ie, ethyl 2-methyl-3-oxobutanoate (26). Generally, only one alkyl group of the sulfate reacts with beta-diketones, beta-ketoesters, or malonates (27). Factors affecting the 0 C alkylation ratio have been extensively studied (28). Reaction ia the presence of soHd Al O results mosdy ia C-alkylation of ethyl acetoacetate (29). 

To a solution of methyl 3-oxobutanoate 127 (580 mg, 5 mmol) and l-methyl-2-methylthio-l//-imidazole-5-carboxaldehye 128 (390 mg, 2.5 mmol) in 5 mL of absolute methanol was added a solution of ammonium hydroxide (25%, 0.4 mL). The reaction was heated at reflux overnight before cooling to room temperature and removing the solvent. The crude product was purified by preparative TLC to afford 526 mg of dimethyl l,4-dihydro-2,6-dimethyl-4-(l-methyl-2-methylthio-5-imidazolyl)-3,5-pyridine-dicarboxylate 129 (60%) as a solid, mp = 200-201 °C (MeOH). 

Katritzky and co-workers studied the mechanism of this reaction in detail. His work involved a NMR study of 16 reactions of methyl-, phenyl-, 1,2-dimethyl-, and l-methyl-2-phenylhydrazine with /3-keto esters. In many cases starting materials, intermediates, and products were detected simultaneously. Most reactions proceed by nucleophilic addition of the less hindered hydrazine nitrogen atom to the keto carbon of the keto ester. For example, the pathway given in Scheme 3 for the reaction of methyl 3-oxobutanoate 9 with methyl- or phenyUiydrazine 2 (R = Me or Ph) was found to be dominant. The initially formed addition product 10 dehydrates to hydrazone 11, which then isomerizes to hydrazone 12. Intermediate 12 then cyclizes to pyrazol-3-one 13, which tautomerizes to the kinetically more stable pyrazol-3-otie 14 [87JCS(P2)969]. 

Tetraphenyl-3//-azepine (2) is formed by the action of sodium hydride on 1-benzyl-2,4,6-triphenylpyridinium tetrafluoroborate (1) in refluxing toluene.37 The 3//-azepine. which arises by attack of the carbanion, generated at the benzylic carbon, at the 2-position of the pyridine ring, is also formed, unexpectedly, in the reaction of the pyridinium tetrafluoroborate with the enolate of ethyl 2-methyl-3-oxobutanoate. 

Cas/liquid reaction 5 [CL 5] Fluorination of ethyl 2-methyl-3-oxobutanoate (ethyl-2-methylacetoacetate) [16]... 

Methyl 3-oxobutanoate, available from Nakaral Chemicals (the checkers used ester purchased from Aldrich Chemical Company, Inc.), Is distilled over molecular sieves 4A under argon and stored in a 200-mL Schlenk tube. It is degassed by three treeze-thaw cycles before use. 

Gas chromatographic analysis indicates that the yield of methyl 3-hydroxybutanoate is 98% column, PEG-20M on Chromosorb WAW (Stainless steel 3 m x 31, Gasukuro Kogyo) column temperature, 120°C injector temperature, 160°C, carrier nitrogen pressure, 1.2 kg/cm tn of methyl 3-oxobutanoate, methyl 3,3-dimethoxybutanoate, and methyl 3-hydroxybutanoate are 31.5, 34.0 and 41.7 min, respectively. 

The Ru-BINAP diacetate complex, which gives good results in the enantio-selective hydrogenation of various ketones, is ineffective in the hydrogenation of methyl 3-oxobutanoate. Reactivity in methanol is low, and the enantioselectivity is discouragingly poor. As the carboxylate ligands in Ru complexes may also be replaced by other anions, it is possible to introduce a strong acid anion by... 

TABLE 6-7. Ru-BINAP-Catalyzed Enantioselective Hydrogenation Reactions of Methyl 3-Oxobutanoate... 

Scheme 6-30 shows that the halogen-containing complexes RuX2 (BINAP) are excellent catalysts With an S/C of over 103 or even 104, the enantioselective hydrogenation of methyl 3-oxobutanoate can still proceed well in methanol. The yield of the enantioselective reaction is almost 100%. 

Catalytic hydrogenation of ethyl a-methyl- 3-oxobutanoate (1) catalyzed by RuBr2[(R)-BINAP] gives a 1 1 mixture to two (3-hydroxy esters, both of which have the (3R)-configuration (equation I). 

A NMR study of reactions of methyl 2-(bromomethyl)-but-2-enoate with the sodium enolate of methyl 2-methyl-3-oxobutanoate has been carried out to rationalize the observed solvent-dependent regioselectivity in terms of addition-eiimination sequences. ... 

Alkylation of 2-methoxycarbonyl-l-oxoindane with these sugar-substituted sulfonium salts gives the (/f)-2-alkyl derivatives with enantiomeric excesses up to 12%, while alkylation of ethyl 2-methyl-3-oxobutanoate with allyl or benzyl(aryl)sulfonium perchlorates gives 2-allyl-(or benzyl)-substituted ethyl 2-methyl-3-oxobutanoates 5 with enantiomeric excess up to 25%12. 

Formamido-5-methoxy-2-(methoxycarbonyl) Methyl 2-methyl-3-oxobutanoate HCO,H 72 [6]... 

SCHEME 46. BINAP-Ru(II)-catalyzed enantioselective hydrogenation of methyl 3-oxobutanoate. 

SCHEME 51. Diastereomeric complexes of RuHCl[(/ )-binap] and methyl 3-oxobutanoate (top views naphthalene rings are omitted). 

A soln of methyl 3-oxobutanoate (4.38 g, 37.8 mmol) and 4-acetamidobenzenesulfonyl azide17 1 (10.0 g, 41.6 mmol) in MeCN was cooled to 0°C and treated with a dropwise addition of TEA (15.8 mL, 113.4 mmol). After stirring at rt for 16 h the mixture was concentrated and the resultant solid was triturated (Et20/petroleum ether). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, Et20/petroleum ether 1 4) to yield the desired product as a light oil yield 91%. 

Exercise 18-42 Write a mechanism based on analogy with other reactions in this chapter that will account for the strong alkali-induced cleavage of ethyl 2-methyl-3-oxobutanoate in accord with Equation 18-21. 

K Nakamura, T Miyai, K Nozaki, K Ushio, S Oka, A Ohno. Diastereo- and enantio-selective reduction of 2-methyl-3-oxobutanoate by baker s yeast. Tetrahedron Lett 3155-3156, 1986. 

---