Enolate Formation by Deprotonation

The deprotonation in a-position of a carbonyl group induced by treatment with strong, nonnucleophUic bases is the most important, most convenient, and most frequently applied procedure for the preparation of preformed enolates of alkaU metals and magnesium (Equation 2.1) [2]. A sufficient thermodynamic acidity, prerequisite to an efficient quantitative formation of an enolate 3, requires the difference between the pA value of the conjugate acid 4 of the base 2 and the corresponding carbonyl compound 1 (at least) to reach or to surpass the value of 2 [P a (4) P a (1) — 2] [3] Even if this thermodynamic condition is met, an efficient 

Modern Enolate Chemistry From Preparation to Applications in Asymmetric Synthesis, First Edition. Manfred Braun. 

Among alkali metal enolates, those derived from ketones are the most robust one they are stable in etheric solutions at 0 C. The formation of aldehyde enolates by deprotonation is difficult because of the very fast occurring aldol addition. Whereas LDA has been reported to be definitely unsuitable for the generation preformed aldehyde enolates [15], potassium amide in Hquid ammonia, potassium hydride in THE, and super active lithium hydride seem to be appropriate bases forthe metallation of aldehydes [16]. In general, preformed alkali metal enolates of aldehydes did not find wide application in stereoselective synthesis. Ester enolates are very frequently used, although they are more capricious than ketone enolates. They have to be formed fast and quantitatively, because otherwise a Claisen condensation readily occurs between enolate and ester. A complication with ester enolates originates from their inherent tendency to form ketene under elimination 

Under nitrogen, a solution of LDA was prepared from diisopropylamine (28.0 ml, 20.2 g, 200 mmol) in 150 ml of absolute THF and 160 ml of a 1.25 M solution of -butyllithium in hexane (200 mmol). To this mixture was added under stirring at -30 °C a solution of the carboxylic acid (100 mmol) in 100 ml of THF. In most cases, a colorless voluminous precipitate formed during the addition. In order to complete the deprotonation, the mixture was stirred at 50 °C for 1 h. Then, all volatile material was removed by evacuation and collected in a cooling trap. The enolates 13 formed white solid materials or had a glassy consistence. They were dissolved in THF and used immediately for subsequent reactions. 

3000 upon addition of triethylamine (and the ratio of regioisomers 14a 15a was found to surpass 95 5). The observation of triethylamine participation in the deprotonation step had serious implications on the rationale of enolate formation by means of lithium amide bases (vide infra). Under kinetic control, the potassium enolate 14b of 2-methylcyclohexanone is accessible in a regioselective manner by using KHMDS. Here again, the ketone is added to an excess of the base. The regioisomer ratio 14b 15b amounts to 95 5, as determined after quenching as silyl enol ethers 16/17 [26]. 

---

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. 

The selection of transition-state models suitable for rationalizing enolate formation by deprotonation, shown in this overview, give an impression of the complexity of a process that looked simple and convincing in Ireland s intuitive model. Nevertheless - despite all the differences in the deprotonation mechanisms of the various aggregates - its key idea, the cyclic arrangement, seems to be confirmed by the more recent studies. 

It is also possible to achieve enantioselective enolate formation by using chiral bases. Enantioselective deprotonation requires discrimination between two enantiotopic hydrogens, such as in d.v-2,6-dimethylcyclohexanone or 4-(/-butyl)cyclohcxanonc. Among the bases that have been studied are chiral lithium amides such as A to D.22... 

Enolates prepared by deprotonation of carboxylic acid derivatives can also undergo elimination to yield ketenes. This is rarely seen with amides, but esters, thiolesters, imides, or N-acylsulfonamides can readily decompose to ketenes if left to warm to room temperature (Scheme 5.58). At -78 °C, however, even aryl esters can be converted into enolates stoichiometrically without ketene formation [462, 463],... 

Finally, the alkylation of the hexameric di-solvated lithium enolate of methyl 3-amino-butyrate with benzyl bromide in THF shows a conversion-dependent deceleration attributed to the formation of LiBr (this is relevant for NMR results). Interestingly, the side dibenzylated product results from the alkylation of the enolate formed by deprotonation of the syn isomer (km/kan,i = 7)288. Kinetic studies performed under pseudo-first-order conditions reveal approximate first-order dependencies in THF (n = 1.3) and enolate. The idealized rate law implicates a direct alkylation of the hexamer without deaggregation. Moreover, the hypothesis of an anti alkylation taking place at either end of the open form of the hexamer (Scheme 81), although unusual, was not excluded by MNDO calculations. 

The formation of a-allylated ketones through allylation of selenium-stabilized enolates, generated by deprotonation of a-selanylated ketones, can be explained by three general postulated mechanisms depending on the nature of the RSe substituent and the allyl halide used [37] (Scheme 29). The first ex-... 

Formation of enolate ions by deprotonation (Eq. 18.3) involves the use of a base, and the strength of the base required will depend on the pfC of the hydrogen atom attached to the a-carbon atom. The pK is defined as the negative log of K, the equilibrium constant for the ionization shown in Equation 18.9. Thus, pKg = -log fCg. Water is the usual reference solvent for reporting values of pK, which are known to be solvent-dependent. Experimentally, the pfC values of aldehydes and ketones are in the range of 18-20. This is a remarkably low value when compared to those for saturated hydrocarbons, which are in excess of 50 ... 

Whereas carboxylic esters had been considered to be inert under the conditions of boron enolate formation by enolization [2c], Corey s group elaborated protocols that allowed for the generation of boron enolates from esters. Thus, trans-boron enolates 100 result from simple carboxylic esters by deprotonation, while 5-phenyl thiopropionate formed cis-enolate 101 - in accordance with Masamune s observation. In both cases, the C2-symmetric diazaborolidine 99 served as the Lewis acid for enolization (Scheme 2.28) [112]. The stereochemical divergence of ester and thioester has been rationalized by postulating an E2-type elimination mechanism starting from the complex 102 that loses bromide in a... 

The Claisen condensation is initiated by deprotonation of an ester molecule by sodium ethanolate to give a carbanion that is stabilized, mostly by resonance, as an enolate. This carbanion makes a nucleophilic attack at the partially positively charged carbon atom of the e.ster group, leading to the formation of a C-C bond and the elimination ofan ethanolate ion, This Claisen condensation only proceeds in strongly basic conditions with a pH of about 14. 

There have been numerous studies of the rates of deprotonation of carbonyl compounds. These data are of interest not only because they define the relationship between thermodynamic and kinetic acidity for these compounds, but also because they are necessary for understanding mechanisms of reactions in which enolates are involved as intermediates. Rates of enolate formation can be measured conveniently by following isotopic exchange using either deuterium or tritium ... 

The methyl group of a methyl ketone is converted into an a ,a ,a -trihalomethyl group by three subsequent analogous halogenation steps, that involve formation of an intermediate enolate anion (4-6) by deprotonation in alkaline solution, and introduction of one halogen atom in each step by reaction with the halogen. A... 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

The lithium enolate 2a (M = Li ) prepared from the iron propanoyl complex 1 reacts with symmetrical ketones to produce the diastercomers 3 and 4 with moderate selectivity for diastereomer 3. The yields of the aldol adducts are poor deprotonation of the substrate ketone is reported to be the dominant reaction pathway45. However, transmetalation of the lithium enolate 2a by treatment with one equivalent of copper cyanide at —40 C generates the copper enolate 2b (M = Cu ) which reacts with symmetrical ketones at — 78 °C to selectively produce diastereomer 3 in good yield. Diastereomeric ratios in excess of 92 8 are reported with efficient stereoselection requiring the addition of exactly one equivalent of copper cyanide at the transmetalation step45. Small amounts of triphcnylphosphane, a common trace impurity remaining from the preparation of these iron-acyl complexes, appear to suppress formation of the copper enolate. Thus, the starting iron complex must be carefully purified. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Scheme 1.1 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor formation of the less-substituted enolate, especially for methyl ketones. The main reason for this result is that removal of a less hindered hydrogen is faster, for steric reasons, than removal of a more hindered hydrogen. Steric factors in ketone deprotonation are accentuated by using bulky bases. The most widely used bases are LDA, LiHMDS, and NaHMDS. Still more hindered disilylamides such as hexaethyldisilylamide9 and bis-(dimethylphenylsilyl)amide10 may be useful for specific cases. 

Scheme 1.5 gives some examples of alkylation of ketone enolates. Entries 1 and 2 involve formation of the enolates by deprotonation with LDA. In Entry 2, equilibration... 

A complementary method was reported 3 years later by Hino, in which a readily enolizable diketopiperazine 48 was directly converted to the epidisulfide by deprotonation with sodium hydride and exposure to sulfur monochloride [38]. As with the Trown method, this method was limited to a specific class of substrates, namely, ones possessing a 1,3-dicarbonyl motif at each of the reactive centers, yet it has also seen subsequent applications in total synthesis [39, 40]. In 1972, Schmidt was able to significantly broaden the scope of the enolate thiolation method by introducing elemental sulfur as the electrophilic agent [41]. In contrast to Hino s method in which formation of a highly reactive, unstable adduct requires readily... 

---