Enolate kinetic

Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions. 

Advantages mono-alkylation, usually gives product from kinetic enolization... 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

Potassium Amides. The strong, extremely soluble, stable, and nonnucleophilic potassium amide base (42), potassium hexamethyldisilazane [40949-94-8] (KHMDS), KN [Si(CH2]2, pX = 28, has been developed and commercialized. KHMDS, ideal for regio/stereospecific deprotonation and enolization reactions for less acidic compounds, is available in both THF and toluene solutions. It has demonstrated benefits for reactions involving kinetic enolates (43), alkylation and acylation (44), Wittig reaction (45), epoxidation (46), Ireland-Claison rearrangement (47,48), isomerization (49,50), Darzen reaction (51), Dieckmann condensation (52), cyclization (53), chain and ring expansion (54,55), and elimination (56). 

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. 

In general bromination of 20-ketones is directed to the introduction of functionality at C-21. However, on occasion 17-bromo compounds are required for dehydrobromination to A -20-ketones, although these are generally obtained in other ways. Kinetic enolization of a 20-ketone gives the A °-enol, whereas the thermodynamic product is the A kjsomer. An interesting enolate trapping reaction has been used recently to prepare 16-methyl-A -20-ketones ... 

Halogenation of steroid 3-ketones can lead to complicated mixtures by virtue of the fact that the kinetic enol leads to 3 halo products, whereas the thermodynamic product is that halogenated at the 4 position. Carefully controlled reaction of the 5a-androstanolone with chlorine thus leads to the 2a-chloro derivative (29). Reaction of that intermediate with O(p-nitrophenyl)-hydroxylamine affords the androgenic agent ni stremine acetate (30). ... 

The key step in a short and efficient synthesis of pleraplysillin-1 (127) is the palladium-catalyzed cross-coupling of vinylstannane 125 with vinyl triflate 126 (see Scheme 33). This synthesis is noteworthy in two respects. First, vinyl triflate 126 is generated regio-specifically from the kinetic enolate arising from a conjugate reduction of enone 124 the conjugate reduction of an enone is, in fact, a... 

The syn TS is favored by about 1 kcal/mol, owing to reduced eclipsing, as illustrated in Figure 1.4. An experimental study using the kinetic enolate of 3-(/-butyl)-2-methylcyclopentanone in an alkylation reaction with benzyl iodide gave an 85 15 preference for the predicted cis-2,5-dimethyl derivative. 

Fig. 1.4. Transition structures for syn and anti attack on the kinetic enolate of trans-2,3-dimethylcyclopentanone showing the staggered versus eclipsed nature of the newly forming bond. Reproduced from J. Am. Chem. Soc., 121, 5334 (1999), by permission of the American Chemical Society. 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allyl and benzyl halides, a-halo esters, a-halo ethers, and a-halo ketones are the most successful alkylating agents. The use of enamines for selective alkylation has largely been supplanted by the methods for kinetic enolate formation described in Section 1.2. 

Kinetic enolates. Alkyllithium reagents have the advantage over lithium amides for deprotonation of ketones in that the co-product is a neutral alkane rather than an amine. This bulky lithium reagent is useful for selective abstraction of the less-hindered a-proton of ketones with generation of the less-stable enolate, as shown previously for a hindered lithium dialkylamide (LOBA,12,285). Thus reaction of benzyl methyl ketone (2) with 1 and ClSifCH,), at - 50° results mainly in the less-stable enolate (3), even though the benzylic protons are much more acidic than those of the methyl group, the less hindered ones. Mesityllithium shows... 

The kinetic enolization of esters with amide bases such as lithium diisopropylamide (LDA) and the resultant aldol condensations with representative aldehydes have been investigated by several groups (2,32,33). The enolate stereochemical assignments were determined by silylation in direct analogy to studies reported by Ireland (34). The preponderance of (E )-enolate observed with LDA (THF) in these... 

Detailed investigations indicate that the enolization process (LDA, THF) affords enolates 37 and 38 with at/east 97% (Z)-stereoselection. Related observations have recently been reported on the stereoselective enolization of dialkylthioamides (38). In this latter study, the Ireland-Claisen strategy (34) was employed to assign enolate geometry. Table 10 summarizes the enolization stereo selection that has been observed for both esters and amides with LDA. Complementary kinetic enolization ratios for ketonic substrates are included in Table 7. Recent studies on the role of base structure and solvent are now beginning to appear in the literature (39,40), and the Ireland enolization model for lithium amide bases has been widely accepted, A tabular survey of the influence of the ester moiety (ORj) on a range of aldol condensations via the lithium enolates is provided in Table 11 (eq. [24]). Enolate ratios for some of the condensations illustrated may be found in Table 10. It is apparent from these data that ( )-enolates derived from alkyl propionates (Rj = CH3, t-C4H9) exhibit low aldol stereoselectivity. In contrast, the enolates derived from alkoxyalkyl esters (Rj = CHjOR ) exhibit 10 1 threo diastereo-... 

Kinetic Enolization of Carboxylic Acid Esters and Amides (Scheme 7)... 

It is important to perform both the Birch reduction of 5 and the alkylation of enolate 6 at —78 °C. Enolate 6 obtained directly from 5 at low temperatures is considered to be a kinetic enolate . A thermodynamic enolate obtained from 6 by equilibration techniques has been shown to give an opposite sense of stereoselection on alkylation. Although a comprehensive study of this modification has not been carried out, diastereoselectivities for formation of 8 were found to be greater than 99 1 for alkylations with Mel, EtI, and PhCH2Br. Thus, it should be possible to obtain both enantiomers of a target structure by utilization of a single chiral benzamide. SE... 

The E Z ratio can be modified by the precise conditions for formation of the enolate. For example, the E Z ratio can be increased for 3-pentanone and 2-methyl-3-pentanone by use of a 1 1 lithium tetramethylpiperidide (LiTMP)-LiBr mixture for kinetic enolization.6 The precise mechanism of this effect is not clear, but it probably is due to an aggregate... 

Simple synthetic routes to bisabolol-3-one (35) (a-bisabololone) (c/. Vol. 6, p. 58) and ar-turmerone (36) have been achieved by condensing the kinetic enolate... 

A striking reversal of the stereoselectivity has been observed when hexamethylphosphoric triamide is added as a cosolvent in kinetic enolate formation7. This effect can be attributed to a disruption of the pericyclic transition-state model1. 

In the reaction of a simple ketone enolate with a chiral aldehyde, the use of a zinc enolate may offer advantages in terms of facial selectivity with respect to the use of a lithium enolate. This is exactly the result recorded in the condensation of the kinetic enolate of 2-undecanone 140 with 141, the key step in a total synthesis of (-l-)-preussin 142, a fermentation product with antifungal and antibacterial activity (equation 77)169. While 2-undecanone Li enolate did not display stereocontrol when added to 141, an acceptable syn diastereoselectivity was displayed by the Zn enolate 140. 

A strong, sterically demanding, base useful for preparation of kinetic enolates. Soluble in THF, ether and toluene. 

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