Alkylation of enolates

The alkylation of relatively acidic substances such as -diketones, j8-ketoesters, and esters of malonic acid can be carried out in alcohols as solvents using metal 

A general review of enolate alkylation is available D. Caine, in Carbon-Carbon Bond Formation, Vol. 1, R. L. Augustine (ed.), Marcel Dekker, New York, 1979, Chapter 2. 

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON. ENOLATES AND ENAMINES 

Methylene groups can be dialkylated if sufficient base and alkylating agent are used. Dialkylation can be an undesirable side reaction if the monoalkyl derivative 

PhjCHCN + KNH2 - Ph2CCN PhjCCN + PhCH2Cl Ph2CCN 

The reactivity of enolates is also affected by the metal counterion. For the most commonly used ions the order of reactivity is Mg2+ Li+ Na+ K+. The factors that are responsible for this order are closely related to those described for solvents. The smaller, harder Mg2+ and Li+ cations are more tightly associated with the enolate than are the Na+ and K+ ions. The tighter coordination decreases the reactivity of the enolate and gives rise to more highly associated species. 

Thought is needed to ensure that the carbonyl compound exhibits the right sort of reactivity. In particular, the carbonyl compound must not act as an electrophile when it is intended to he a nucleophile. If it does, it may react with itself to give some sort of dimer—or even a polymer—rather than neatly attacking the desired electrophile. This chapter will consider ways of avoiding unwanted nucleophilic attack at the carbonyl C=0 bond. 

Fortunately, over the last four decades lots of thought has already gone into the problem of controUing the reactions of enolates with carbon electrophiles. This means that there are many excellent solutions to the problem our task in this chapter is to help you understand which to use, and when to use them, in order to design useful reactions. 

Some important considerations that affect all alkylations 

The alkylations in this chapter will each consist of two steps. The first is the formation of a stabilized anion— usually (but not always) an enolate—by deprotonation with base. 

Online support. The icon in the margin indicates that accompanying interactive resources are provided online to help your understanding just type www.chemtube3d.com/clayden/123 into your browser, replacing 123 with the number of 

Write an equation for the carbon-carbon bond-fornning step in the cyclization just cited. Show clearly the structure of the enolate ion, and use curved arrows to represent its nucleophilic addition to the appropriate carbonyl group. Write a second equation showing dissociation of the tetrahedral internnediate fornned in the carbon-carbon bond-forming step. 

Even though ketones have the potential to react with themselves by aldol addition, recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 20.3). On the other hand, acylation of ketone enolates gives products (P-keto esters or P-diketones) that are converted to stabilized anions under the reaction conditions. Consequently, ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base in the presence of esters. 

As sources of nucleophilic carbon, enolates can be alkylated at the a carbon by reaction with alkyl halides. 

Alkylation occurs by an 8 2 mechanism. The alkyl halide should be methyl or primary, and preferably allylic or benzylic. Secondary and tertiary alkyl halides undergo elimination under these conditions. 

Enolate alkylation can be difficult to carry out with simple aldehydes and ketones. It is not always possible to limit the reaction to monoalkylation, and aldol condensation competes with alkylation, especially with aldehydes. The formation of regioisomeric alkylation products is an issue with unsymmetrical ketones but can be minimized by selecting reaction conditions that favor either kinetic or thermodynamic control of enolate formation. The kinetic enolate of 2-methylcyclohexanone, for example, was prepared by deprotonation with lithium diisopropylamide then treated with benzyl bromide to give predominantly 2-benzyl-6-methylcyclohexanone, 

Answer The reactant is a methyl ketone and the reagents wiU convert a methyl ketone into a carboxylic acid (with a by-product of bromoform)  

PROBLEMS Predict the products for each of the following reactions O 

27 On a separate piece of paper, draw a mechanism for the transformation in the previous 

In this section, we will continue to explore reactions between enolates and electrophiles. Specifically, we will learn how to install an alkyl group at an alpha position  

In order to alkylate the alpha position, it makes sense to use an enolate to attack an alkyl halide, for example  

Chapters 26-29 continue the theme of synthesis that started with Chapter 24 and will end with Chapter 30. This group of four chapters introduces the main C-C bond-forming reactions of enols and enolates. We develop the chemistry of Chapter 21 with a discussion of enols and enolates attacking to alkylating agents (Chapter 26), aldehydes and ketones (Chapter 27), acylating agents (Chapter 28), and electrophilic alkenes (Chapter 29). 

Much of this chapter will concern that phrase, thoughtfully devised . 

Fortunately, over the last three decades lots of thought has already into the problem of con- 

Regioselective silylation of ketones by in situ enolate trapping 

This example illustrates the synthesis of cyclic compounds by intramolecular alkylation reactions. The relative rates of cyclization for ca-haloalkyl malonate esters are 650,000 1 6500 5 for formation of three-, four-, five-, and six-membered rings, respectively.28 (See Section 3.9 of Part A to review the effect of ring size on Sn2 reactions.) 

Similarly, the dilithium salt of monoethyl malonic dianion is easily alkylated and the product decarboxylates on acidification.30 

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the 

---

Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 

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. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

The rate of alkylation of enolate ions is strongly dependent on the solvent in which the reaction is carried out.41 The relative rates of reaction of the sodium enolate of diethyl n-butylmalonate with n-butyl bromide are shown in Table 1.3. Dimethyl sulfoxide (DMSO) and iV,Ai-dimethylformamide (DMF) are particularly effective in enhancing the reactivity of enolate ions. Both of these are polar aprotic solvents. Other... 

Scheme 1.3. Alkylation of Enolates Stabilized by Two Functional Groups...

---