Alkyl methyl ketone enolate

Ab initio through-space/bond interaction analysis was applied to 3 + 2-anulation based on Brook rearrangement using /i-phcnylthioacryloylsilanes with alkyl methyl ketone enolates (Scheme 103).150 The major product has the large substituents on the same side of the five-membered ring. Orbital interactions related to the carbanion... 

The butylated /3-ketoester C of Figure 10.23 is not the final synthetic target of the acetoacetic ester synthesis of methyl ketones. In that context the /3-ketoester C is converted into the corresponding /3-ketocarboxylic add via add-catalyzed hydrolysis (Figure 10.24 for the mechanism, see Figure 6.19). This /3-ketocarboxylic acid is then heated either in the same pot or after isolation to effect decarboxylation. The /3-ketocarboxylic add de-carboxylates via a cyclic six-membered transition state in which three valence electron pairs are shifted at the same time. The reaction product is an enol, which isomerizes immediately to a ketone in general and to phenyl methyl ketone in the specific example shown. In general, alkyl methyl ketones are obtained by such acetoacetic ester syntheses. 

Same measures of stereocontrol had previously been observed in approaches to pyrethroid acids involving intramolecular enolate alkylation. As outlined in Figure 3, workers at Sumitomo have investigated the cyclization of a methyl ketone enolate (5). They obtained a 9 1 ratio of cis trans products upon ring closure initiated by sodium hydroxide. The methyl ketone was subsequently converted to the corresponding carboxylic acid via the haloform reaction. 

The highly electrophilic cationic bis(8-quinolinolato)aluminum complex 407 enabled Yamamoto and coworkers to perform Mukaiyama-Michael additions of silyl enol ethers to crotonylphosphonates 406. The procedure was not only applicable to enol silanes derived from aryl methyl and alkyl methyl ketones (a-unsubstituted silicon enolates) but also to several cycfic a-disubstituted silyl enol ethers, as illustrated for the derivatives of a-methyl tetralone and indanone 405 in Scheme 5.105. Despite the steric demand of that substitution pattern, the reaction occurred in relatively high chemical yield with varying diastereoselectivity and excellent enantiomeric excess of the major diastereomer. The phosphonate residue was replaced in the course of the workup procedure to give the methyl esters 408. The protocol was extended inter alia to the silyl enol ether of 2,6,6-tetramethylcyclohexanone. The relative and absolute configuration of the products 408 was not elucidated [200]. 

Takeda, K., Nakajima, A., and Yoshii, E. (1997) Synthesis of clavulones (claviridenones) via [3+2] annulation using reaction of (P-(phenyllhio)actyloyl)silane with lithium enolate of alkyl methyl ketone. Synlett, 255—256. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

The equilibrium ratios of enolates for several ketone-enolate systems are also shown in Scheme 1.1. Equilibrium among the various enolates of a ketone can be established by the presence of an excess of ketone, which permits reversible proton transfer. Equilibration is also favored by the presence of dissociating additives such as HMPA. The composition of the equilibrium enolate mixture is usually more closely balanced than for kinetically controlled conditions. In general, the more highly substituted enolate is the preferred isomer, but if the alkyl groups are sufficiently branched as to interfere with solvation, there can be exceptions. This factor, along with CH3/CH3 steric repulsion, presumably accounts for the stability of the less-substituted enolate from 3-methyl-2-butanone (Entry 3). 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

FORMATION AND ALKYLATION OF SPECIFIC ENOLATE ANIONS FROM AN UNSYMMETRICAL KETONE 2-BENZYL-2-METHYL-CYCLOHEXANONE AND 2-BEN-ZYL-6-METHYLCYCLOHEXA-NONE 52 39... 

The metalation of vinyl ethers, the reaction of a-lithiated vinyl ethers obtained thereby with electrophiles and the subsequent hydrolysis represent a simple and efficient method for carbonyl umpolung. Thus, lithiated methyl vinyl ether 56 and ethyl vinyl ether 54, available by deprotonation with t- or n-butyllithium, readily react with aldehydes, ketones and alkyl halides. When the enol ether moiety of the adducts formed in this way is submitted to an acid hydrolysis, methyl ketones are obtained as shown in equations 72 and 73 . Thus, the lithiated ethers 56 and 54 function as an acetaldehyde d synthon 177. The reactivity of a-metalated vinyl ethers has been reviewed recently . 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

Regioselective alkylation of a methyl ketone Even though the kinetic enolate of 2-heptanone consists of a mixture of terminal and internal enolates in the ratio 87 13, benzylation in DME results in preferential internal alkylation. Regioselective benzylation at the terminal position can be enhanced by addition of various ligands such as benzo-14-crown-4 and DMF, but HMPT is the most effective ligand, resulting in a ratio of terminal to internal benzylation of 11 1. The three ligands also increase the rate of alkylation. The same effect, but less marked, is observed in alkylation with the less reactive electrophile butyl iodide. 

C-Carboxylation of enolates.1 Carboxylation of potassium enolates generated from silyl enol ethers is not regioselective because of extensive enolate equilibration. Regiospecific C-carboxylation of lithium enolates is possible with carbonyl sulfide in place of carbon dioxide. The product is isolated as the thiol methyl ester. If simple esters are desired, transesterification can be effected with Hg(OAc)2 (8, 444). Carboxylation of ketones in this way in the presence of NaH and DMSO is not satisfactory because of competing alkylation of the enolate.2 Example ... 

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