2- Methylcyclohexanone enolates formed from

The formation of lithium enolates using lithium diisopropylamide furnishes a useful way of alkylating ketones in a regioselective way. For example, the lithium enolate formed from 2-methylcyclohexanone can be methylated or benzylated at the less hindered a carbon by allowing it to react with LDA followed by methyl iodide or benzyl bromide, respectively ... 

An unsymmetrical ketone such as 2-methylcyclohexanone can form two possible enolates, arising by removal of an a hydrogen from one side or the other of the carbonyl group. Which enolate predominates in the reaction depends on whether the enolate is formed under conditions that favor an acid-base equilibrium. 

Simple aldehyde, ketone, and ester enolates are relatively basic, and their alkylation is limited to methyl and primary alkyl halides secondary and tertiary alkyl halides undergo elimination. Even when alkylation is possible, other factors intervene that can reduce its effectiveness as a synthetic tool. It is not always possible to limit the reaction to monoalkylation, and aldol addition can compete with alkylation. With unsymmetrical ketones, regioselectivity becomes a consideration. We saw in Section 20.2 that a strong, hindered base such as lithium diisopropylamide (LDA) exhibits a preference for abstracting a proton from the less-substituted a carbon of 2-methylcyclohexanone to form the kinetic enolate. Even under these conditions, however, regioisomeric products are formed on alkylation with benzyl bromide. 

High-boiling products found in this procedure and in similar experiments involving cyclohex-2-enone derivatives5 probably result from bimolecular reduction processes.15 3-Methylcyclohexanone, which arises by protonation rather than alkylation of the enolate (and which made up ca. 12% of the volatile products), is probably the result of reaction of allyl bromide with liquid ammonia to form the acidic species allyl ammonium bromide.5 10... 

An unsymmetrical ketone can form two different enolates. In some situations it is possible to distinguish between them by trapping the separate enolates as their silyl enol ethers. The anions may then be regenerated from the silyl enol ether in an aprotic solvent under non-equilibrating conditions using fluoride ion. The rapidly formed kinetic enol of 2-methylcyclohexanone may be trapped using lithium di-isopropylamide as the base (Scheme 3.77a). On the other hand, the thermodynamically more stable enol is trapped with a milder base such as triethylamine (Scheme 3.77b). ... 

With unsymmetrical ketones, a mixture of regioisomeric enolates may be formed, resulting in a mixture of Michael adducts. Deprotonation in a protic solvent is reversible and leads predominantly to the thermodynamically favoured, more-substituted enolate. Reaction with a Michael acceptor then gives the product from reaction at the more-substituted side of the ketone carbonyl group. The 1,5-dicarbonyl compound 24 is the major product from conjugate addition of 2-methylcyclohexanone to methyl acrylate using potassium tert-butoxide in the protic solvent tert-butanol (1.39). In contrast, the major product from Michael addition... 

Scheme 8.80. A representation of the pathway from the f-butyldimethylsilyl ether of the enol of cyclohexanone to 2-methylcyclohexanone via the addition of methylene from the Simmons-Smith reagent and rearrangement of the cyclopropane formed (see Simmons, H. E. Smith, R. D. J. Am. Chem. Soc., 1959,81,4256).

VI. ENEAMiNE-AssisTED ALKYLATION OF KETONES. As shown in Figure 9.13 (vide supra) the kinetic enolate of 2-methylcyclohexanone (formed at low temperature) is the enolate anion of the less substituted alkene and, reasonably, alkylation with, for example methyl iodide will yield 2,6-dimethylcyclohexanone. Regrettably, however, the yield of alkylated product from the kinetic enolate is difficult to maximize since even the smallest perturbation (e.g., rise in temperature and presence of excess ketone.) tends to drive the system toward equilibrium, resulting in the more highly substituted enolate anion. Enamines can be employed to overcome this tendency to produce alkylation on the more substituted side. 

The proposed catalytic cycle [42] is analogous to that shown in Scheme 5.6, except for the additional release of an enolate anion due to the fluoride-induced desilylation. Oxidative addition of allyl carbonates leads to the formation of the allyl complex 78, COj, and an alkoxide RO . The fluoride source and the alkoxide RO are capable of liberating an enolate anion by desilylation. This explains why substoichiometric amounts of Bu4NPhgSiF2 are sufficient to maintain the catalytic cycle that is displayed in Scheme 5.25 for the allylation of 2-methylcyclohexanone through the silyl enol ether. The carbon-carbon bond-forming step is assumed to occur by a collapse of the ion pair 79 consisting of the cationic allylpalladium complex and the enolate anion. Aside from these ionic species, covalently bound palladium enolates were also discussed. 

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