Enolates condensation with ethyl formate

The direct condensation of pentan-3-one with ethyl formate failed to give 3,5-dimethyl-pyran-4-one. Instead, the diketone was produced, the enolate of which is apparently of insufficient reactivity to undergo condensation with a second molecule of ester. However, the isopropyl derivative (407) of the enol condensed with ethyl formate, and the potential triketone cyclized to the pyran-4-one (408) under acid conditions (Scheme 133) (64JOC2678). 

Geminal alkylation of ketones. Coates and Sowerby2 have reported a new method for site-selective geminal alkylation of ketones which involves reduction of the n-butyl-thiomethylene derivative of the ketone by lithium-ammonia to give a methyl-substituted enolate anion which can be alkylated in situ. The ketone, for example cyclohexanone (1), is condensed with ethyl formate and then transformed into the n-butyl-thiomethylene derivative (2) by reaction with n-butyl mercaptan (2, 53-54). This is then reduced with excess lithium in liquid ammonia at -33° with 2 eq. of a proton donor (water is usually used to avoid overalkylation). The lithium enolate is then... 

An Illinois group has described a method of selective geminal alkylation of aaa -trisubstituted ketones the corresponding n-butylthiomethylene derivatives of such ketones undergo a process of double reduction with lithium in ammonia, affording a methyl-substituted enolate anion at the original methylene position, which can be alkylated in situ. This permits the introduction of a methyl group and a second, variable substituent at that ketone flank which condenses with ethyl formate (Scheme 81). 

The 12-step synthesis of imatinib mesylate (1) in the manufacturing process was accomplished by Novartis in an astonishingly short time. The synthesis began with a condensation reaction between 6 and ethyl formate. Deprotonation of the methyl group on 3-acetylpyndine (6) using freshly prepared sodium methoxide afforded an enolate. Condensation of the enolate with ethyl formate was followed by exchange with to produce 3-dimethylamino-l-(3-pyridyl)-2-propen-l-one (7). could be prepared from the condensation of 6 and N,N-... 

The keto-aldehyde can be made by a simple Claisen ester condensation (Chapter 28) using the enolate of the methyl ketone with ethyl formate (HCC Et) as the electrophile. It actually exists as a stable enol, like so many 1,3-dicarbonyl compounds (Chapter 21). 

If one of the carbonyl partners is much more acidic than the other and is easily tranaformed into its etiolate ion, then a mixed aldol reaction is likely to be successful. Ethyl acetoaoetate, for inetarKe, is completely converted into its enolate hm ii preference to enolate oti formation from other carbonyl pcondensations with ethyl acetoacetate occur preferentially to give the mixed product. 

In many reactions there is an equilibrium between reactants and products so that only the more stable of the two alkenes is produced. In the Claisen ester condensation of cyclohexanone 8 with ethyl formate, the true product under the conditions of the reaction is the stable enolate 9 and this is reversibly protonated on workup to give the more stable H-bonded enol of the ketoaldehyde Z-10. In the aldol reaction between the same ketone and benzaldehyde, the initial product 7 gives the enolate 6 and dehydration is reversible only the more sterically favourable E isomer of 5 is formed. Note that it is irrelevant that the aldol 7 is a mixture of diastereoisomers all stereochemistry is lost in the formation of the enolate 6. In later parts of this chapter a more specific relationship between 3D and 2D stereochemistry will be established. 

Another 1,3-dicarbonyl equivalent is keto-enol. Treatment of the ketone with ethyl formate in the presence of NaH afforded the keto-enol as the 2-hydroxy-methylene ketone. Condensation of the keto-enol with hydrazines provided the corresponding pyrazole fused bile acid methyl ester... 

In a situation where severe steric hindrance e.g., 16,16-dimethyl-20-keto-pregnanes) prevents enol acetate formation, an alternate scheme has been devised. Condensation of ethyl oxalate at C-21 produces, after hydrolysis, the 21-glyoxylic acid this on treatment with acetic anhydride and a strong acid catalyst such as perchloric acid gives both lactone acetates. 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

The succinct synthesis of warfarin starts with condensation of ort/zo-hydroxy-acetophenone (1-2) with ethyl carbonate to give the (3-ketoester (1-3) as the presumed intermediate shown in the enol form. Attack of the phenoxide on the ester grouping will lead to cyclization and the formation of the coumarin (1-4). Conjugate addition of the anion from that product to methyl styryl ketone (1-5) gives the corresponding Michael adduct and thus warfarin (1-6) [1]. 

Among other reactions proceeding through aldol-like intermediates, the formation of 2 hydroxymethylene-3-ketones (20) and similar derivatives deserves comment. The condensation occurs when ethyl formate reacts with the A2>4 enolate anion (ig), the product separating from non-polar solvents as an enolate salt (21) [xg6]. Similar condensations occur with ethyl oxalate [igy] 5a-3-Ketones naturally react at C 2>, through their stable enolates, but A -g-ketones and 5j5-3 ... 

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