Alkylation of enolate anions

Enolate anions generated from ketones, esters, and nitriles can be used as nucleophiles in Sn2 reactions. This results in the attachment of an alkyl group to the a-carbon in a process termed alkylation. Aldehydes are too reactive and cannot usually be alkylated in this manner. Alkylation of cyclohexanone is illustrated in the following equation  

O A strong base must be used to ensure complete deprotonation in this step. The solvent must not have any acidic hydrogens. An ether (diethyl ether, DME, THF, dioxane) or DMF is commonly used. 

What reaction would occur if one attempted to use butyllithium to form the enolate anion of cyclohexanone  

To avoid the formation of two products, deprotonation of the ketone must produce a single enolate ion. Therefore, the ketone must be symmetrical, like cyclohexanone in the preceding example, or have a structure that favors the formation of the enolate ion at only one of the a-carbons, as is the case in the following example  

Esters and nitriles can also be alkylated by this procedure  

PROBLEM 18.17 Outline two ways in which 4-methyl-2-octanone can be prepared by conjugate addition of an organocuprate to an a,fj-unsaturated ketone. 

SAMPLE SOLUTION Mentally disconnect one of the bonds to the (3 carbon so as to identify the group that comes from the lithium dialkylcuprate. 

According to this disconnection, the butyl group is derived from lithium dibutyl-cuprate. A suitable preparation is 

3-Penten-2-one Lithium dibutylcuprate Now see if you can identify the second possibility. 

Like Other carbon-carbon bond-forming reactions, organocuprate addition to enones is a powerful tool in organic synthesis. 

Since enolate anions are sonrces of nncleophihc carbon, one potential use in organic synthesis is their reaction with alkyl halides to give a-alkyl derivatives of aldehydes and ketones  

Though this topic is treated here under a separate heading, alkylation of enolate anions is nothing other than enolate anions acting as carbanion nucleophiles in Sn2 reactions. We deferred this topic 

By treating the 1,3-dicarbonyl compound acety-lacetone with methyl iodide in the presence of potassium carbonate, one observes alkylation at the central carbon. 

Now for some interesting features of the reaction, though they become fairly obvious with a little thought. First, the central methylene contains the more acidic protons (pATa 9) since it is flanked by two carbonyls, so the enolate anion formed involves this carbon (see Section 4.3.5). In other words, alkylation occurs on the central carbon of acetylacetone, not on the terminal carbons. Second, it is possible to use carbonyl compounds such as acetone as a solvent without these reacting under the reaction conditions. Acetone will have similar acidity (pATa 19) to the acetyl groups of acetylacetone, so likewise will not 

Furthermore, the product formed still contains an acidic proton on a carbon flanked by two carbonyls, so it can form a new enolate anion and participate in a second Sn2 reaction. The nature of the product will thus depend on electrophile availability. With 1 mol of methyl iodide, a monomethylated compound will be the predominant product, whereas with 2 mol of methyl iodide the result will be mainly the dimethyl ated compound. 

Of course, minor products might be produced, including monoalkylated products and dialkylated products (in which the two alkyl groups are the 

---

The heats of reaction for O-alkylation and C-alkylation of enolate anions clearly show that the latter reactions lead to the thermodynamically more stable products 12). 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

Exercise 18-31 Arguing from the factors that appear to regulate the ratio of C- to O-alkylation of enolate anions (Section 17-4), show how you could decide whether the reaction of the sodium enolate salt of ethyl 3-oxobutanoate with a strong acid would give, as the initial product, mostly the enol form, mostly the keto form, or the equilibrium mixture. 

Click Coached Tutorial Problems to practice Alkylations of Enolate Anions. 

Alkylation and acylation of ketones and nitriles. DMSO greatly enhances the rate of alkylation of enolate anions. " Dialkylation of malononitrile and of pentane-2,4-... 

Piers, E., Abeysekera, B., and Scheffer, J.R., Preparation of, and alkylation of enolate anions with, dimethyl 3-bromo-2-ethoxypropenylphosphonate. An efficient, convergent synthesis of 2-cyclo-penten-l-ones, Tetrahedron Lett., 20, 3279, 1979. 

Alkylation of enolate anions usually gives C-alkylation and is therefore not suitable for the preparation of enol ethers. The exception is when triethyloxonium tetrafluoroborate is used as the alkylating agent in a dipolar aprotic solvent. 0-Alkylation can be regioselectiveiy achieved if the enolate anion is derived from acetoacetate or a similar compound. On the other hand, 0-acylation of enols or enolate anions is quite common. Enol esters can therefore be prepared readily from the parent carbonyl compounds. For... 

Much faster alkylation of enolate anions can often be achieved in dimethylfor-mamide (DMF), dimethylsulfoxide (DMSO) or 1,2-dimethoxyethane (DME) than in the usual protic solvents. The presence of hexamethylphosphoramide (HMPA) or a triamine or tetramine can also enhance the rate of alkylation. This is thought to be because of the fact that these solvents or additives solvate the cation, but not the enolate, thereby separating the cation-enolate ion pair. This leaves a relatively free enolate ion, which would be expected to be a more reactive nucleophile than the ion pair. Reactions with aqueous alkali as base are often improved in the presence of a phase-transfer catalyst such as a tetra-alkylammonium salt. ... 

Alkylation of enolate anions is achieved readily with alkyl halides or other alkylating agents. Both primary and secondary alkyl, allyl or benzyl halides may be used successfully, but with tertiary halides poor yields of alkylated product often result because of competing elimination. It is sometimes advantageous to proceed by way of the toluene-p-sulfonate, methanesulfonate or trifluoromethane-sulfonate rather than a halide. The sulfonates are excellent alkylating agents and can usually be obtained from the alcohol in a pure condition more readily than... 

The readily available 1-propyne reacts with HBr to obtain 29. Disconnection of the bond adjacent to the carbonyl in 27 (the functional group) leads to 30 and 31. Because 30 is the one-carbon fragment, it becomes the acceptor and the synthetic equivalent is iodomethane. This makes 31 the donor, and a reasonable synthetic equivalent is the enolate anion of acetaldehyde, 32 (see Chapter 22, Section 22.9, for alkylation of enolate anions). This leads to the overall synthesis shown, based on the retrosynthesis (see Figure 25.11). The ability to see the relationship between an alkene and an alkyne allowed identification of a logical disconnection and a reasonable synthesis. 

In some respects, the alkylation of enolate anions resembles nucleophilic substitution. We recall that many nucleophiles displace leaving groups from primary alkyl halides by an Sj 2 mechanism (Section 9.3). A similar reaction occurs with secondary alkyl halides, but competing elimination reactions also occur. Primary alkyl halides react with carbanions, such as the alkynide ion, by an Sj 2 mechanism. (Secondary alkyl halides react not only in displacement reactions but also in elimination reactions because the alkynide ion is a strong base.)... 

---