Polyalkylation enolates

The methyl y-oxoalkanoates shown are not available by alternative methods with similar efficiency and flexibility. Although the reaction of enamines with alkyl ot-bromoacetates proceeds well in some cases, yields are only moderate in many examples.8 A further drawback is that the methods for enamine generation lack the high degree of selectivity and mildness that is characteristic of the preparation of silyl enol ethers. Related alkylations of lithium enolates often afford low yields or polyalkylated products, and are in general very inefficient when aldehydes are utilized as the starting materials.9... 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Under the same conditions simple etiolates react vigorously with alkyl halides (which must be primary) to give mono- and polyalkylated products. The reactivity of the simple enolate is greater and cannot be controlled at room temperature. However, if the alkylation is carried out at low temperature, the reaction can be controlled and smooth monoalkylation of simple enolates can be achieved. The same is true for the alkylation of acetylide anions, which must be carried out at low temperature for successful alkylation. 

In particular the synthesis of an a-alkylaldehyde or branched chain ketone by this overall strategy is of considerable merit since some of the problems associated with the a-alkylation of an enolate ion are largely avoided (e.g. competing aldol condensation in the case of an aldehyde, or polyalkylation and low regio-selective alkylation in the case of a ketone). 

Alkylation of fl-aryleyclopentanones. Addition of 10 mole% of CuCN to the lithium enolate prepared from /3-arylcyclopentanones and LDA increases the amount of the less stable product of alkylation. Polyalkylation is also suppressed. Similar results are obtained when methyl- or phenylcopper is added to the enolate prepared by alkyUithium cleavage of trimethylsilyl enol ethers. The mechanism by which Cu(I) influences these alkylations is not as yet understood. The regiospecificity of enolate formation in the example Illustrated in equation (I) has been attributed to a directing efiect of the proximate phenyl group. This effect is also observed in the deprotonation of -arylcyclohexanones. Quantitative, but not qualitative, differences exist between five- and six-membered rings, probably because of conformational differences. ... 

If di- or polyalkylation is a problem, the addition of triethanolamine borate to the reaction mixture will suppress overalkylation. Likewise, enolates formed in the presence of EtjB react smoothly to form mono-alkylation products, as illustrated in the following examples. ... 

Enolate equilibration and di- and poly-alkylation are the major side reactions, which lead to reduced yields of desired products in ketone alkylations. These processes occur as a result of equilibration of the starting enolate (or enolate mixture) with the neutral monoalkylation product(s) via proton transfer reactions. Polyalkylation may also occur when bases, in addition to the starting enolate, which are capable of deprotonating the monoalkylated ketone are present in the medium. With symmetrical ketones, e.g. cyclopentanone and cyclohexanone, the problem of regioselectivity does not arise. However, except under special conditions, polyalkylation occurs to a significant extent during enolate alkylations of more kinetically acidic ketones such as cyclobutanone, cyclopentanone and acyclic ketones, particularly methyl ketones. Polyalkylation is also a troublesome side reaction with less acidic ketones such as cyclohexanone. 

As shown in Scheme 3 conversion of the lithium enolate (10) to its complex lithium triethylaluminum enolate prior to alkylation in DME-HMPA at room temperature also significantly reduced the amount of polyalkylation. 5 However, the most dramatic results were obtained by addition of dimethylzinc to the... 

Lithiumlithium triethylaluminum, sodium triethylboron, sodium triethanolamine borate,- potassium triethylboron and tri-n-butyltin cyclohexanone enolates have been successfully monoalkyl-ated. In Scheme 6 the behavior of the lithium enolate of cyclohexanone (11) and the lithium triethylaluminum enolate upon reaction with methyl iodide is compared. The latter enolate gives better results since no dimethylation products were detected, but clearly the cyclohexanone enolate (11) is much less prone to dialkylation than the cyclopentanone enolate (10). Scheme 6 also provides a comparison of the results of alkylation of the potassium enolate of cyclohexanone, where almost equal amounts of mono- and di-alkylation occurred, with the alkylation of the potassium tiiethylboron enolate where no polyalkylation occurred. The employment of more covalently bonded enolates offers an advantage in cyclohexanone monoalkylations but not nearly as much as in the cyclopentanone case. 

Prior to the discoveries that lithium and other less electropositive metal cations were valuable counterions for enolate alkylations, the Stork enamine reaction was introduced to overcome problems such as loss of regioselectivity and polyalkylation that plagued attempts to alkylate sodium or potassium enolates of ketones or aldehydes.Methods of synthesis of enamines by reactions of ketones and aldehydes with secondary amines have been thoroughly reviewed.Enamine alkylations are usually conducted in methanol, dioxane or acetonitrile. Enamines are ambident nucleophiles and C- and V-alkylations are usually competitive. Subsequent hydrolysis of the C-alkylated product (an iminium salt) yields an... 

Finally like methyllithium (ref. 121) ammonium fluoride (ref. 122), tris-(dialkylamino)sulfonium salts (ref. 123) or alkali alkoxides (ref. 124), alkali amides in liquid ammonia are able to cleave the silicium-oxygen bond of silyl enol ethers (refs. 125, 126) leading to enolates. The sodium enolate obtained (Fig. 27) by treatment of a silyl enol ether with NaNH2 can be equilibrated in the medium, leading to two alkylated products, nevertheless no polyalkylated species is detected. With the use of LiNH2 only the expected reaction product is prepared but the use of KNH2 leads to a mixture of C-mono and dialkylated and O-alkylted products (ref. 125). 

Regioselective enolization. The kinetic ketone enolates are formed with manganese amides. Polyalkylation with such enolater is not observed. 

The procedure described here illustrates a general and very convenient method to carry out the regioselective monoalkylation of ketones via their Mn-enolates. A comparison with the classical procedure previously reported by House in Organic Syntheses to prepare the 2-benzyl-6-methylcyclohexanone via the corresponding Li-enolates clearly shows that the Mn-enolate gives a higher yield of desired product since the regioselectivity is better and the formation of polyalkylated products is not observed. 

Monoalkylation of ketones. Polyalkylated products are usually obtained as by-products of attempted monoalkylation of lithium ketone enolates. Polyalkylation can be suppressed by addition of triethylboron, but this substance is spontaneously flammable. The safer boron derivative 1 is also effective, but since it is sparingly soluble in THF, DMSO is also added to the reaction. The position of alkylation can be controlled also by use of the kinetically generated enolate or the more stable equilibrium enolate. ... 

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