Enolates also alkylation

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and applied synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One reason is that aldehydes are rapidly converted to aldol addition products by base. (See Chapter 2 for a discussion of this reaction.) Only when the enolate can be rapidly and quantitatively formed is aldol formation avoided. Success has been reported using potassium amide in liquid ammonia67 and potassium hydride in tetrahydrofuran.68 Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions are discussed in Section 1.3. 

Use of TMSCl in combination with HMPA, DMAP, or TMEDA all favored 1,2-addition over 1,4-addition. Sequential a-alkoxyalkylcuprate conjugate addition, enolate trapping with TMSCl, and silyl enol ether alkylation provides a one-pot synthesis of tetrahydrofurans (Scheme 3.35) [129]. Cyclic enones afford as-fused tetrahydrofurans, while acyclic systems give complex mixtures of diastereomers. a-Alkoxyalkylcopper reagents also participate in allylic substitution reactions with ammonium salts [127]. 

Since enolates also add via a ligand attack process, the regioselectivity that they exhibit is quite comparable to soft caibon nucleophiles. Alkyl or aiyl substituents at the allyl termini direct attack to the less substituted terminus (equations 228-232) functional groups such as COaMe and halogen at one allyl terminus direct attack to the remote terminus (equations 233 and 234). Remote functionalities such as —OR also direct addition to the allyl terminus more removed from the substituent (equations 23S and 236). 

Ester-substituted ketone enolates are stabilized, and these enolates can be alkylated (ace-toacetic ester synthesis). Alkylation is, however, also possible for enolates that are not stabilized. In the case of the stabilized enolates, the alkylated ketones are formed in two or three steps, while the nonstabilized enolates afford the alkylated ketones in one step. However, the preparation of nonstabilized ketone enolates requires more aggressive reagents than the ones employed in the acetoacetic ester synthesis. 

Typical bases such as sodium hydroxide or an alkoxide ion cannot be used to form enolates for alkylation because at equilibrium a large quantity of the hydroxide or alkoxide base is still present. These strongly nucleophilic bases give side reactions with the alkyl halide or tosylate. Problem 22-4 shows an example of these side reactions. Lithium diisopropylamide (LDA) avoids these side reactions. Because it is a much stronger base, LDA converts the ketone entirely to its enolate. All the LDA is consumed in forming the enolate, leaving the enolate to react without interference from the LDA. Also, LDA is a very bulky base and thus a poor nucleophile, so it generally does not react with the alkyl halide or tosylate. 

The superior nucleophilicity and excellent thermal stability of pseudoephedrine amide enolates make possible alkylation reactions with substrates that are ordinarily unreactive with the corresponding ester and imide-derived enolates, such as (3-branched primary alkyl iodides. Also, alkylation reactions of pseudoephedrine amide enolates with chiral (J-branched primary alkyl iodides proceed with high diastereoselectivity for both the matched and mismatched cases (Table 3). ... 

Ester enolates and carbanions derived from nitriles are also alkylated under these conditions. 

Metal enolate solutions consist of molecular aggregates (6) such as dimers, trimers and tetramers in equilibrium with monomeric covalently bonded species (7), contact ion pairs (8) and solvent-separated ion pairs (9), as shown in Scheme 1. The nature of the metal cation, the solvent and, to a degree, the structure of the enolate anion itself may significantly influence the extent of association between the anion and the metal cation. In general, the factors that favor loose association, e.g. solvent-separated ion pairs, lead to an increase in the nucleophilicity of the enolate toward alkylating agents and also its ability to function as a base, i.e. to participate in proton transfer reactions. 

Alkylations of the enolate also occurred syn to the oxygen bridge, thus allowing the sequential functionalization of 94 to be achieved, Eq. 76 [59]. 

Compared with other synthetic intermediates, enolates show a decreased reactivity. The differences in reactivity are most striking in reactions with alkylating agents [1] and epoxides [6]. The reactivities of the various types of enolates towards alkyl halides decrease in the order C=C(0 )NR2 (amide-enolate) C=C(0 )0R (ester enolate) C=CO (ketone-enolate). Metallated nitriles, imines, and S,S-acetals are, in general, much better nucleophiles than enolates in alkylations and ft-hydroxyalkylations [1], Furthermore, the alkylation of aldehyde and ketone enolates usually does not stop after the mono-functionalization [12]. The decreased reactivity of (especially) aldehyde and ketone enolates also appears in thiolations with disulfides [2]. A solution of lithiated cyclohexanone in THF does not react at 20°C with CH3SSCH3 [1,2]. 

Delivery of an electrophile to the less hindered face of an enolate also occurs in intramolecular alkylation reactions. When 500 was treated with potassium fert-butoxide, a mixture of (E) and (Z) enolates (501 and 502. respectively) was obtained. Intramolecular displacement of bromide generated a single isomer (503). In this case, the electrophile can approach the enolate from only one face (the bottom or a face). Because of this conformational constraint, both (E) and (Z) enolates lead to the same product. In cyclopentanone and cyclohexanone enolates. an increase in the size of a facial blocking group increases selectivity. When that group was small, the selectivity decreased. 

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