P-Ketoesters

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

For example, ot-anilino-P-ketoesters photocyclize to indole-2-carboxylate csters[2]. 

The Japp-Klingeraann coupling of aryidiazonium ions with enolates and other nucleophilic alkenes provides an alternative route to arylhydrazones. The reaction has most frequently been applied to P-ketoesters, in which deacylation follow S coupling and the indolization affords an indole-2-carboxylate ester. 

In addition to formation from a ketone, the hydra2ones can be obtained from dicarbonyl compounds by a Japp-Klingemann reaction. This is especially useful for P-ketoesters and P-ketoacids, which undergo either deacylation or decarboxylation. 

Reaction of a P-ketoestei witii gaseous ammonia (/) gives an enamine, which on treatment with methylhydiazine (2) yields an 85 15 mistuie of 3-hydioxy- and 5-hydioxy-l-substituted pyrazoles (36) (eq. 5). Previously P-ketoesters furnished mainly the 5-hydroxy isomer. 

Substitution of some of the alkoxy groups on the polytitanoxanes with glycols, P-diketones or P-ketoesters, fatty acids, diester phosphates or pyrophosphates, and sulfonic acids gives a group of products that are very effective surface-treating agents for carbon black, graphite, or fibers (32). 

P-Ketoester Chelates. p-Ketoesters react in a fashion similar to the p-diketones. TYZOR DC [27858-32-8] is the hght-yeUow Hquid from TYZOR TPT and two moles of ethyl acetoacetate (eaa) after removal of the isopropyl alcohol. TYZOR BEAT, the bis-ethylacetoacetate [20753-28-0] derived from the tetra- -butyl titanate, and TYZOR IBAY [83877-91-2] the isobutoxy analogue, perform similarly to TYZOR DC. Both, however, have better cold-storage stabiHty. 

All lation of Garbanions. Concentrated N a OH—hen syl triethyl amm onium chloride is the base/catalyst system normally used for this type of process (20). Classes of compounds alkylated in this way include phenylacetonitriles, ben2ylketones, simple aUphatic ketones, certain aldehydes, aryl sulfones, P-ketosulfones, P-ketoesters, malonic esters and nitriles, phenylacetic esters, indene, and fluorene (see Alkylation). 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

The most convenient synthesis of 6-hydroxy-2-pyridones is by the condensation of a P-ketoester, eg, ethyl acetoacetate, with an active methylene compound, eg, malonic ester, cyanoacetic ester, and an amine. The amine can be omitted if an acetamide is used and in some cases this modification results in a higher yield. 

Dlmethyl-3-carboxyethyl-5 p-methoxyphenyl)-4,5 dlhydrofuran (3).3 A mixture of syn and anti cyclopropyl-p ketoesters 1 and 2 was left in contact with neutral akjmina activity I in CHCI3 for 24 h The starting materials 1 and 2 disappeared and 3, homogeneous by HPLC and NMR in quantitative yield, was isolated... 

S I M O N I S Benzopyrone synthesis Benzopyrene synthesis Irem phenols and p ketoesters... 

The fluorination of P-diketones and p-ketoesters with N-/luorobis(trifluo-romethanesulfonyl)imide (Table 3a, B) can be controlled to give either mono-fluorination or difluorination. Monofluorination occurs when the strong acid, bis(trifluoromethanesulfonyl)imide, a reaction product, is removed by addition of water, which prevents further enolization and fluormation of the monofluoro adduct [83] (equation 38)... 

A significant number of examples exist in which 1,3-dicarbonyl derivatives undergo reaction with thioglycolates to produce thiophenes. ° Such reactions are particularly effective when used in conjunction with P-ketoesters, as demonstrated by the preparation of 27. ... 

The reaction is generally performed between 0 and 100 °C with the majority of the reactions being mn at reflux. Polar protic solvents such as methanol, ethanol, isopropanol, and water are commonly used as solvents. Addition of acid or use of acetic acid as solvent generally helps push sluggish reactions. The use of P-ketoesters as the dicarbonyl partner occasionally requires added base for cyclization to occur to form the pyrazolone. When using alkyl hydrazine salts, base may be required to deprotonate the hydrazine for the reaction to take place. 

A limitation of this approach was the fact that the cyclization could not be accomplished on the resin. This would preclude further functionalization of the core. Therefore an alternate approach was to link the resin to the core via an aminoalcohol spacer as in 93. Furthermore, since linkage was conducted through the P-ketoester component rather than through the nitrogen atom, dihydropyridines 94 could now be formed on the solid support. When the 4-aryl substituent of 94 was nitro, on-resin reduction to the corresponding amine was possible. This allowed for further addition of diversity elements to the core scaffold before cleavage from the resin. 

The Knorr quinoline synthesis refers to the formation of a-hydroxyquinolines 4 from P-ketoesters 2 and aryl amines 1. The reaction usually requires heating well above 100°C. However, some cases do exist when the cyclization takes place in the presence of a catalytic amount of mineral acid at temperatures as low as -10 °C. The intermediate anilide 3 undergoes cyclization by dehydration with concentrated sulfuric acid. The reaction is conceptually close to the Doebner-Miller and Gould-Jacobs reactions. ... 

The Knorr quinoline synthesis has been nicely extended by Hodgkinson and Staskun to include P-ketoesters that do not have protons at the 2 position of the starting keto-ester. 2,2 -dichloroanilides of type 14 can cyclize to provide quinolines such as 15 and 16 in good respective yields. ... 

Suitably stabilized end forms also behave as oxygen nueleophiles, e.g., phenyl diphenylmethyl ketone 21, p-diketones 23 (R = = alkyl), or p-ketoesters 23... 

The progress of the reaction was followed by HPLC (Zorbax RX-C8 column, 1.5 mL/min, 50 50 CH3CN 0.01M H3P04 in water, room temperature, detection at 200 nm retention times methyl ester 2 2.343 min, P-ketoester 3 3.987 min. After 30 min, less than 0.5 area% methyl ester was found to be remaining. 

The Claisen condensation of t-butyl acetate with a methyl ester is a general route for the preparation of complex P-ketoesters.4 The reaction requires an excess of the enolate of t-butyl acetate to rapidly deprotonate the product and prevent tertiary alcohol formation. Some workers have also used excess LDA or t-butoxide for this purpose. 

A divergent synthesis of tropane alkaloid ferruginine was reported by Node and coworkers [59]. The P-ketoester intermediate was prepared by a novel PLE-catalyzed asymmetric dealkoxycarbonylation (hydrolysis followed by a decarboxylation) of a symmetric tropinone-type diester (Figure 6.12). Dimethyl sulfoxide was added to the phosphate buffer pH 8 (1 9) to reduce the activity of PLE and prevent over-deal-koxycarbonylation leading to tropinone. 

The first step is the preparation of the P-ketoester easily accessible by condensation of methylisopropylketone with dimethylcarbonate in benzene in the presence of sodium hydride. Chlorination of this 3-ketoester with sulfiiryl chloride in dichloromethane occurred smoothly at room temperature affording the methyl 2-chloro-3-oxoalkanoate free from side products. The acidic splitting of the latter with 50 % sulfuric acid under reflux gives a yield of 70 % pure product, free from the isomeric form (eqn. 3). 

Reaction of 1,3-dicarbonyl compounds with IVJV-dimethylformamide dimethyl acetal followed by malonamide in the presence of sodium hydride gives 5,6-disubstituted 1,2-dihydro-2-oxopyridine-3-carboxamides, whereas reaction of the intermediate enamines with cyanothioacetamide or cyanoacetamide in the presence of piperidine provides 2-thioxopyridine-3-carboxamides and 4,5-disubstituted l,2-dihydro-2-oxopyridine-3-carboxamides, respectively <95S923>. P-Enaminonitriles 14 react with p-ketoesters and alkyl malonates, in the presence of stoichiometric amounts of tin(IV) chloride, to afford 4-aminopyiidines 15 and 4-amino-2-pyridones 16 <95T(51)12277>. 

Among the various strategies [34] used for designing enantioselective heterogeneous catalysts, the modification of metal surfaces by chiral auxiliaries (modifiers) is an attractive concept. However, only two efficient and technically relevant enantioselective processes based on this principle have been reported so far the hydrogenation of functionalized p-ketoesters and 2-alkanons with nickel catalysts modified by tartaric acid [35], and the hydrogenation of a-ketoesters on platinum using cinchona alk oids [36] as chiral modifiers (scheme 1). 

Two further methods for the preparation of p-ketoesters consist of the Reformatsky reaction of pyrazolides[67] (a) and the magnesium bromide-induced Claisen condensation of pyrazolides[68] (b). 

Surface faceting may be particularly significant in chiral heterogeneous catalysis, particularly in the N i/P-ketoester system. The adsorption of tartaric add and glutamic acid onto Ni is known to be corrosive and it is also established that modifiers are leached into solution during both the modification and the catalytic reaction [28]. The preferential formation of chiral step-kink arrangements by corrosive adsorption could lead to catalytically active and enantioselective sites at step-kinks with no requirement for the chiral modifier to be present on the surface. 

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