Kinetic keto esters

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

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]. 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

Dynamic kinetic resolution of a-alkyl-P-keto ester was conducted successfully using biocatalysts. For example, baker s yeast gave selectively syn(2R, 3S)-product [29a] and the selectivity was enhanced by using selective inhibitor [29b] or heat treatment of the yeast [29c]. Organic solvent was used for stereochemical control of G. candidum [29d]. Plant cell cultures were used for reduction of 2-methyl-3-oxobu-tanoate and afforded antialcohol with Marchantia [29e,f] and syn-isomer with Glycine max [29f]. 

In earlier kinetic and computer modeling [1,2, 14] the open form of CD (CDopen) was used to illustrate the adsorbed [CD - a-keto ester] complex. In this complex the quinuclidine nitrogen was involved in the interaction with the substrate directly or via a proton bridge. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

A diastereoselective intramolecular thermal carbonyl-ene reaction of a single enantiomer of keto ester 7 afforded the C5-C14 fragment of the jatrophane skeleton (Scheme 3).11 The key reaction was performed under thermal conditions (180 °C, 3 days) to afford only the m-compounds 8 and 9 in a 5 1 diastereomeric ratio. The kinetic preference for the m-isomers was explained by the less strained m-annulated transition states. 

Kinetic resolution results of ketone and imine derivatives are indicated in Table 21.19. In the kinetic resolution of cyclic ketones or keto esters, ruthenium atrop-isomeric diphosphine catalysts 25 induced high enantiomer-discriminating ability, and high enantiopurity is realized at near 50% conversion [116, 117]. In the case of a bicyclic keto ester, the presence of hydrogen chloride in methanol served to raise the enantiomer-discriminating ability of the Ru-binap catalyst (entry 1) [116]. 

Scheme 21.9 Dynamic kinetic resolution of /7-keto ester.

The sense of diastereoselectivity in the dynamic kinetic resolution of 2-substi-tuted / -keto esters depends on the structure of the keto ester. The ruthenium catalyst with atropisomeric diphosphine ligands (binap, MeO-biphep, synphos, etc.) induced syn-products in high diastereomeric and enantiomeric selectivity in the dynamic kinetic resolution of / -keto esters with an a-amido or carbamate moiety (Table 21.21) [119-121, 123, 125-127]. In contrast to the above examples of a-amido-/ -keto esters, the TsOH or HC1 salt of /l-keto esters with an a-amino unit were hydrogenated with excellent cwti-selectivity using ruthenium-atropiso-... 

Fig. 32.26 Hydrogenation of acyclic a-substituted yfi-keto esters via dynamic kinetic resolution.

The anions of CDs may also function as simple basic catalysts towards acidic substrates included in their cavities. Such was observed by Daffe and Fastrez (1983) who studied the deprotonation and hydrolysis of oxazolones in basic media containing CDs. Also, in a paper dealing mainly with catalysis by amylose, it was noted that CDs catalyse the deprotonation of long chain /3-keto esters in basic aqueous DMSO (Cheng et al., 1985) no saturation kinetics were found for CDs, indicating weak substrate binding under the conditions used. 

The primary literature now contains a very large body of kinetic data for the catalysis of enolization and ketonization, not only of ketones and aldehydes but also of )3-diketones, )3-keto esters, and dienones, much of which could be treated by the Kurz approach. Also, data exist for third-order enolization, due to combined general acid and base catalysis, that could also be analysed. Such treatment is beyond the scope the present review. However, one study of metal ion catalysis of enolization is discussed later in this section. 

The kinetics of reactions between aroylpyruvic acids, ArC0CH2C0C02H, and arylamines in toluene show evidence of several mechanistic features intramolecular carboxyl catalysis, and catalysis by a second molecule of nucleophile, either on its own, or in concert with an (external) carboxylic acid. An extended solvent study shows an increase in the efficiency of the aforementioned intramolecular carboxyl catalysis with decreasing polarity of the solvent.Hydrolysis of the related /3-keto esters, methyl 4-aryl-2-arylamino-4-oxobut-2-enoates [ArC0CH=C(NHAr)C02Me] in aqueous dioxane is subject to general acid catalysis. " ... 

Thus alkylation and silylation of 231 i could be brought about with methyl iodide and chlorotrimethylsilane in 61 and 66% yield, respectively [108]. In these tricyclic keto esters 231, the carbonyl group at C-6 exerts its usual electron withdrawing effect and thereby increases the kinetic acidity of the adjacent cy-clopropylic proton. Equally important, however, is the effect of the alkoxy group... 

Pirrang, Liu, and Morehead [22] have elegandy demonstrated the application of saturation kinetics (Michaehs-Menten) to the rhodium(II)-mediated insertion reactions of a-diazo /9-keto esters and a-diazo /9-diketones. Their method used the Eadie-Hofstee plot of reaction velocity (v) versus v/[S] to give and K, the equilibrium constants for the catalytic process. However, they were unable to measure the Michaelis constant (fC ) for the insertion reactions of a-diazo esters because they proved to be too rapid. 

Paquette and coworkers have demonstrated that monoalkylation of dianion 860 proceeds with a kinetic preference for electrophilic capture at the ester enolate site. Thus, addition of. limited amounts of methyl iodide to 860 affords %8 in 46 % isolated yield With this keto ester in hand, it proved an easy matter to elaborate... 

Quinolones are obtained in the Conrad-Limpach-Knorr synthesis, which is subject to either kinetic or thermodynamic control, when aniline is reacted with a 3-keto ester (Scheme 3.11a). At room temperature the more reactive keto group combines with the aniline nitrogen atom, leading to an enamino ester the kinetic product. Cyclization of this product to a 4-quinolone requires heating at 250 C. 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

At the time this work was carried out, the mechanistic basis for the conversion of acyl Meldrum s acid adducts to corresponding P-keto esters/amides such as 25 was not well understood [16] . The IR method used to determine the nature of the protonation state of 24 presented an excellent opportunity to perform kinetic studies. These studies [17] showed that the reaction of 24 with amine nucleophile 3 was pseudo zero order in the anionic form 24. The reaction kobs was almost the same in the one-pot process as when the isolated 24 was used. This was consistent with the rate-determining step being the formation of the a-oxoketene intermediate 26 (Scheme 5.15). 

SCHEME 62. Dynamic kinetic resolution of a-substituted /3-keto esters. 

Highly stereoselective hydrogenation of racemic a-substituted P-keto esters via dynamic kinetic resolution [14,17] has been reported. Hydrogenation of a racemic a-amidomethyl substrate with the (-)-DTBM-SEGPHOS/Ru catalyst resulted in the 2S,3R alcohol in 99.4% ee (syn anti=99.3 0.7) (Scheme 22) [36]. The product was a key compound for an industrial synthesis of carbapenem antibi-... 

Dynamic kinetic resolution of a-alkyl- 3-keto ester was conducted successfully using biocatalysts (Figure 28(b)). 290 For the reduction of ethyl... 

Carbapenem antibiotics (29) can be manufactured from intermediates obtained by Ru(BINAP)-catalyzed reduction of a-substituted P-keto esters by a dynamic kinetic resolution (Scheme 12.8). 4-Acetoxy azetidinone (30) is prepared by a regioselective RuCl3-catalyzed acetoxylation reaction of 31 with peracetic acid 46 This process has been successful in the industrial preparation of the azetidinone 30 in a scale of 120 tons per year.47 The current process has changed ligands to 3,5-Xyl-BINAP (3c), and 31 is obtained in 98% ee and >94% de (substrate-to-catalyst ratio, or S/C ratio = 1,000).23... 

Dynamic kinetic resolution can occur for a-substituted P-keto esters with epimerizable substituents provided that racemization of the antipodes 32 and 33 is rapid with respect to the Ru(BINAP)-catalyzed reduction, thereby potentially allowing the formation of a single diastereo-isomer (Scheme 12.9). Deuterium labeling experiments have confirmed the rapid equilibrium of... 

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