Thermodynamic control enolate formation

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

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... 

In the case of 3-pentanone, evidence has been presented27-28 for thermodynamic control during formation of the (Z)-enolates and for kinetic control during formation of the ( )-eno-lates in the presence or absence of HMPA. Ester enolates are preferentially ( ), when prepared with LDA (THF), and (Z) when prepared with LDA in the presence of HMPA. In contrast, dialkylamides are deprotonated (LDA/THF) preferentially to give the (Z)-enolates. The role of HMPA in the above case is still not quite clear6-29. 

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. 

There is a lot to explain here. It looks very odd that syn-66 is preferred and even more so that alkylation of the enolate 67 occurs on the same face as the undoubtedly large /-butyl group. Both these issues matter as the original chiral centre in proline is destroyed in 67 and only the newly introduced chiral centre in 66 retains the stereochemical information from proline. This centre acts as a relay for the stereochemical information. Others call this a memory effect. The acid-catalysed formation of the N, O-acetal 66 is under thermodynamic control (acetal formation is reversible) and the conformation 66a shows that the molecule folds about the necessarily cis ring junction and the /-butyl group prefers to be on the outside (or exo- face).8 The enolate 67 has a flattened conformation 67a (probably more flattened than this ) and its alkylation is under kinetic control. Attack is preferred on the outside, exo-face. Note that this happens to restore the original configuration at the ex-proline chiral centre. 

In base, as in acid, a./ -unsaturated ketones are hydrogenated in preference to the saturation of isolated double bonds. In basic solutions the product configuration obtained is markedly dependent on the amount of base present, particularly in very dilute systems. This indicates that the reaction proceeds by way of kinetically and thermodynamically controlled cnolatc formation. It is proposed that these enolates are very strongly or irreversibly adsorbed onto the catalyst surface and that the product configuration can best be explained by way of a hydride ion transfer from the catalyst, followed by protonation of the adsorbed species 7 by the solution28. 

The last two ketones have two different a-positions so there is a good chance of controlling enol formation from the parent ketone. But the first ketone has two primary a-positions and the difference appears only in the two p-positions. The obvious solution is conjugate addition and trapping (described in the textbook on p. 603). The thermodynamic enol is needed from the second ketone and direct silylation is a good bet. The third requires kinetic enolate formation and LD A is a good way to do that. 

Kinetic Versus Thermodynamic Control in Formation of Enolates... 

By adjusting the conditions under which an enolate mixture is formed from a ketone, it is possible to establish either kinetic or thermodynamic control. Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative, and irreversible, This ideal is approached experimentally by using a very strong base such as lithium diisopropylamide or hexamethyldisilylamide in an aprotic solvent in the absence of excess ketone. Lithium as the counterion is better than sodium or potassium for regioselective generation of the kinetic enolate. Aprotic solvents are required because protic solvents permit enolate equilibration by allowing reversible protonation-deprotonation, which gives rise to the thermodynamically controlled enolate composition. Excess ketone also catalyzes the equilibration. 

Under thermodynamic control, the formation of cis-enolates is generally favored, except for the 4- to 10-membered rings of cyclic ketones, lactones, and lactams that necessarily form fcraws-enolates for geometrical reasons. It is obvious that a twofold deprotonation of carboxylic acids does not give rise to diastereomeric enolates. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

Addition of the chelated enolate of the S-oxo ester moiety of a 2,8-dioxo-6-alkenoate 1 under thermodynamic control at 25 °C using stoichiometric or catalytic amounts of sodium hydride in benzene results in the formation of tram-2-oxo-5-(2-oxoalkyl)-l-cyclopentane-carboxylate 2 exclusively. 

The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pK data summarized in Table 6.7 in Part A. These pK data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between kinetic or thermodynamic control of enolate formation by deprotonation (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of Sw2 alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

The intramolecular version of ester condensation is called the Dieckmann condensation.217 It is an important method for the formation of five- and six-membered rings and has occasionally been used for formation of larger rings. As ester condensation is reversible, product structure is governed by thermodynamic control, and in situations where more than one product can be formed, the product is derived from the most stable enolate. An example of this effect is the cyclization of the diester 25.218 Only 27 is formed, because 26 cannot be converted to a stable enolate. If 26, synthesized by another method, is subjected to the conditions of the cyclization, it is isomerized to 27 by the reversible condensation mechanism. 

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are [Tdicarbonyl compounds, which are rather acidic and can be alkylated by the procedures described in Section 1.2. Reaction of ketone enolates with formate esters gives a P-ketoaldehyde. As these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Entries 1 and 2 in Scheme 2.16 are examples. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. 

By adjusting the conditions under which an enolate mixture is formed from a ketone, it is possible to establish either kinetic or thermodynamic control. Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative,... 

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