Methyl 3-oxobutanoate, reaction with

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]. 

In related studies, it has been shown that a-fluorobenzylphosphonates ArCHFPO(OEt)2 (38) will undergo Wadsworth-Emmons-type olefination reactions with aldehydes and ketones [57]. 39 was prepared from benzaldehydes and HP(0) (OEt)2, which was fluorinated using diethylaminosulfur tiifluoride for example, diethyl [(3,5-dimethylphenyl)(fluoro)methyl]phosphonate (38) was formed in 91%. An 82% yield of Me 2-[(fluoro)(4-fluorophenyl)methylene]butanoate (1 1 E Z) (40) was obtained from 38 and methyl 2-oxobutanoate (Scheme 13). 

No metalation is required for the / -fluorination of a-oxo esters.150 Ethyl 3-methyl-2-oxo-butanoate and 3-methyl-2-oxopentanoic acid give the corresponding /f-fluoro derivatives 30 a and 30 b, respectively, in quantitative yield on reaction with A-fluorobis(trifluoromethylsul-fonyl)amine (Id). 3-Fluoro-2-oxobutanoic acid (30c) is exclusively formed by treating 2-oxobutanoic acid with an equimolar amount of reagent Id.150... 

C7H10O3 Mr 142.15, has been found in, e.g., lovage and roast coffee. It has a bouillon-like, coffee and lovage aroma, depending on its concentration. It can be synthesized by condensation of 2-oxobutanoic acid (from acrylic aldehyde with acetic anhydride and sodium cyanide, followed by reaction with methanol/hydrochloric acid) with methanol/sodium methylate and subsequent decarbomethoxylation [200]. It is used for aromatization of food. 

By reaction with hydrazides. In these reactions, aliphatic, aromatic and heteroaromatic hydrazides 118 condense and cyclize with ethyl (or methyl) 3-oxobutanoate 1 to give pyrazol-3-ones 3 or 4 in one... 

Nucleophilic Ring-opening Reactions with Carbanions. The anion of methyl 3-oxobutanoate, generated by adding NaOH in MeOH, reacts with ethene oxide to yield a-acetyl-y-butanolactone (132). ... 

The Pd-catalyzed reaction of allylamines with active methylene compounds was first reported in 1970. A,A-Diethylallylamine undergoes reaction with 2,4-pentanedione in the presence of Pd(acac>2 (0.5 mol %) and PPhj (1.5 mol %) at 85 C to give 3-monoallylated and 3,3-bisallylated products in 70% and 20% yields, respectively (Scheme 2). Nickel(O) complexes are found to be a more active catalyst for aUyla-tion. Thus, more than 600 h of turnover frequency was achieved for the allylation of methyl 3-oxobutanoate with A,A-diethylallylamine in DMF at 80 C using Ni(dppb)2 catalyst,... 

The biosynthesis of 4 -phosphopantetheine is quite interesting. This transfer agent (also, of course, part of coenzyme A) is derived from the pathway leading to and from valine (Vat, V). As shown in the next figure and in Scheme 12.17, 3-methyl-2-oxobutanoate (2-ketoisovalerate) is the immediate precursor/ product (transamination, EC 2.6.1.42) to/from valine (Val, V). When 2-ketoisovalerate (3-methyl-2-oxobutanoate) abstracts the one-carbon unit from 5,10-methylenetetrahydrofolate (below and Scheme 12.9) in an aldol-type condensation, 2-dehydropantoate results (EC 2.1.2.11). Reduction of the latter (NADPH/H, EC 1.1.1.169) generates (R)-pantoate. After activation of the carboxylate by adenylation, reaction with P-alanine produces pantothenate (EC 6.3.2.1), which is phosphorylated at the 4-position... 

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). 

The product described here, 4-(4-chlorophenyl)butan-2-one, was previously prepared in the following ways a) by reduction of the corresponding benzalacetone, b) by catalyzed decarbonylation of 4-chlorophenylacetaldehyde by HFeiCO) in the presence of 2,4-pentanedione, - c) by reaction of 4-chlorobenzyl chloride with 2,4-pentanedione under basic catalysis (K2CO3 in EtOH), d) by reaction of 4-chlorobenzyl chloride with ethyl 3-oxobutanoate under basic catalysis (LiOH), - and e) by reaction of 3-(4-chlorophenyl )-propanoic acid with methyl lithium. - ... 

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. 

The addition of vinylmagnesium bromide to methyl (S)-3-benzyloxy-4-oxobutanoate (5) in tetrahydrofuran proceeded with a slight preference for the nonchelation-controlled reaction product (40 60)5°. A reversal of the diastereoselectivity (80 20) could be observed when the Grignard reagent, as a solution in tetrahydrofuran, was added to a dichloromethane solution of the aldehyde which had been precomplexed with one equivalent of magnesium bromide. The almost exclusive formation of the chelation-controlled reaction product 6 was achieved when tetrahydrofuran was completely substituted by dichloromethane the presence of tetrahydrofuran interferes with the formation of the chelate complex, which is a prerequisite for high chelation-controlled diastereoselection. 

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%. 

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. ... 

This enzyme complex [EC 1.2.4.4], also known as 3-methyl-2-oxobutanoate dehydrogenase (lipoamide) and 2-oxoisovalerate dehydrogenase, catalyzes the reaction of 3-methyl-2-oxobutanoate with lipoamide to produce S-(2-methylpropanoyl)dihydrolipoamide and carbon dioxide. Thiamin pyrophosphate is a required cofactor. The complex also can utilize (5)-3-methyl-2-oxopenta-noate and 4-methyl-2-oxopentanoate as substrates. The complex contains branched-cham a-keto acid decarboxylase, dihydrolipoyl acyltransferase, and dihydrolipoa-mide dehydrogenase [EC 1.8.1.4]. 

This enzyme [EC 4.1.3.12] catalyzes the reaction of 3-carboxy-3-hydroxy-4-methylpentanoate with coenzyme A to produce acetyl-CoA, 3-methyl-2-oxobutanoate, and water. This enzyme has a potassium-ion requirement. 

Keto esters are the best functionalized ketone substrates for enan-tioselective hydrogenation. Esters of methyl, primary, secondary, and tertiary alcohols can be used to produce hydroxy esters in high yields, with up to 100% enantioselectivity (Scheme 49) (95). The fact that methyl 2, 2-dimethyl-3-oxobutanoate is hydrogenated in high chemical and optical yields with normal asymmetric orientation implies that the reaction does not necessarily involve the enol. 

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. 

The reaction of succinic acid anhydride 111 with 2-methyl-2,4-diphenyl-2,3-dihydroli/-benzo[Z ][l,4]diazepine 112 in toluene in the presence of potassium carbonate leads to 4-(2-methyl-2,4-diphenyl-2,5-dihydro-l/f-l,5-benzodiazepin-5-yl)-4-oxobutanoic acid 113 in 70% yield [110], while its treatment with 2,4-diphenyl-2,3-dihydro-l//-l,5-benzodiazepine 104 follows with chalcone elimination and yields 3-(benzimidazol-2-yl)propionic acid 114 [115] (Scheme 4.36). 

In another study, screening was carried out for reduction of substituted benzazepin-2,3-dione 23 to a 3-hydroxy derivative 24 (Scheme 19.14). This was accomplished by a bacterial strain of Rhodococcus fascians ATCC 12975 (Norcardia salmonicolor SC 6310) with a conversion of 97% and an optical purity of >99.9%. This reaction product 24 is a key intermediate in the synthesis of the calcium antagonist SQ 31,765 (25).104 105 The Bristol-Myers Squibb group has also shown the selective reduction of the (3-keto ester, methyl-4-chloro-3-oxobutanoate, by the fungus Geotrichum candidum SC 5469 to the corresponding (,S )-hydroxy ester.106... 

The reactions of methyl 3-oxobutanoate or its 2-alkyl-substituted derivatives with thiobenzhydrazide lead to the 1,3,4-thiadiazolines 85B (R1 = Me R2 = H, Me, Et, t -Pr) (83KGS1048). An increase in the steric demands of the substituent R2 destabilizes the cyclic tautomer and when R2 = t-Pr, the equilibrium mixture 85A 85B (R1 = Me) appears in (CD3)2SO solution. This mixture contains ca. 10% of the open-chain tautomer 85A,... 

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