Potassium enolates conjugate addition

The simplest amino acid, glycine, would be an ideal starting material for the synthesis of more complicated amino acids but it does not easily form enols or enoiates. The methyl ester of the ben-zaldehyde imine has two electro n-withdra wing groups to help stabilization of the enolate and conjugate addition of acrylonitrile is now possible. The base used was solid potassium carbonate with a quaternary ammonium chloride as phase transfer catalyst. Simple hydrolysis of the alkylated product leads to the extended amino acid. 

It is not essential to have two anion-stabilizing groups for successful conjugate addition and it is even possible with simple alkali metal (Li, Na, and K) enolates. Lithium enolates are not ideal nucleophiles for thermodynamically controlled conjugate addition. Better results are often observed with sodium or potassium enolates, which are more dissociated and thus more likely to revert. Lithium binds strongly to... 

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... 

The simplest products are formed when Nu=H, but this poses a problem of regioselectivity in the nucleophilic attack step a nucleophilic hydride equivalent that selectively undergoes conjugate addition to the enone is required. This is usually achieved with extremely bulky hydride reagents such as lithium or potassium tri(sec-butyl)borohydride (often known by the trade names of L- or K-Selectride, respectively). In this example, K-Selectride reduces the enone to an enolate that is alkylated by methyl iodide to give a single regioisomer. 

A Michael addition of the silyl enolate was employed in a short synthesis of ( )-methyl jasmonate from cyclopentenone (eqs 9 and 10). This convergent scheme was carried out in three steps conjugate addition of methyl Q -(methyldiphenylsilyl)lithioacetate to cyclopentenone, alkylation of the resulting enolate with (Z)-l-bromopent-2-ene, and desilylation with potassium fluoride ( )-ethyl jasmonate was prepared in a similar fashion. In the conjugate addition step, the Q -(methyldiphenylsilyl)ester gave superior results to those obtained with the a-trimethylsilyl esters. 

This principle can be extended to ketones whose enolates have less dramatic differences in stability. We said in Chapter 21 that, since enols and enolates are alkenes, the more substituents they carry the more stable they are. So, in principle, even additional alkyl groups can control enolate formation under thermodynamic control. Formation of the more stable enolate requires a mechanism for equilibration between the two enolates, and this must be proton transfer. If a proton source is available— and this can even be just excess ketone—an equilibrium mixture of the two enolates will form. The composition of this equilibium mixture depends very much on the ketone but, with 2-phenylcyclo-hexanone, conjugation ensures that only one enolate forms. The base is potassium hydride it s strong, but small, and can be used under conditions that permit enolate equilibration. 

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