Hydroxides enolate formation with

Kimura and co-workers have synthesized a series of alkoxide complexes with the alcohol functionality as a pendent arm.447 674 737 A zinc complex of l-(4-bromophenacyl)-l, 4,7,10-tetraaza-cyclododecane was also synthesized by the same workers to mimic the active site of class II aldolases. The X-ray structure shows a six-coordinate zinc center with five donors from the ligand and a water molecule bound. The ketone is bound with a Zn—O distance of 2.159(3) A (Figure 12). Potentiometric titration indicated formation of a mixture of the hydroxide and the enolate. Enolate formation was also independently carried out by reaction with sodium methoxide, allowing full characterization.738... 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

The anion is a doubly stabilized enolate ion with the negative charge being spread over two oxygen atoms and one carbon atom. Because of the relatively high acidity of beta diketones, LDA is not required to irreversibly deprotonate these compounds. Rather, treatment with hydroxide or an alkoxide ion is sufficient to ensure nearly complete enolate formation. 

FIGURE 19.65 Two reactions of acetaldehyde with hydroxide ion addition (hydrate formation) and enolate formation. 

Oppolzer s camphor-based sultams 92 proved itself as an efficient, robust auxiliary for enolate amination with 1-chloro-l-nitroso cyclohexane 486 as an electrophile. Thus, sultams 92 were first deprotonated with NaHMDS, and to the sodium enolates thus formed was added a solution of the blue nitrosochloride 486. Decolorization occurred immediately, and the mixture was quenched with hydrochloric acid to give hydroxylamines 487, in all cases as essentially pure diastereomers. The reductive cleavage of the nitrogen-oxygen bond was achieved with zinc dust to yield a-aminoacyl sultams 488. By mild hydrolysis with lithium hydroxide, the chiral auxiliary 91 was removed and recovered under concomitant formation of a-amino acids 490. Any racemization was avoided by applying this procedure, even in the case of the labile substrates with R equals a phenyl or / r -methoxyphenyl substituent. On the other hand, the auxiliary could be cleaved at the stage of hydroxylamines 487, so that not only a-amino acids 490 but also a-hydroxyamino acids 489 became available with excellent enantiomeric purity (Scheme 4.103) [232]. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Addition of hydride ion from the catalyst gives the adsorbed dianion (15). The reaction is completed and product stereochemistry determined by protonation of these species from the solution prior to or concurrent with desorption. With the heteroannular enolate, (13a), both cis and trans adsorption can occur with nearly equal facility. When an angular methyl group is present trans adsorption (14b) predominates. Protonation of the latter species from the solution gives the cis product. Since the heteroannular enolate is formed by the reaction of A" -3-keto steroids with strong base " this mechanism satisfactorily accounts for the almost exclusive formation of the isomer on hydrogenation of these steroids in basic media. The optimum concentration of hydroxide ion in this reaction is about two to three times that of the substrate. 

As an example of enolate-ion reactivity, aldehydes and ketones undergo base-promoted o halogenation. Even relatively weak bases such as hydroxide ion are effective for halogenation because it s not necessary to convert the ketone completely into its enolate ion. As soon as a small amount of enolate is generated, it reacts immediately with the halogen, removing it from the reaction and driving the equilibrium for further enolate ion formation. 

When an enolate is forced to take the E configuration, e.g, the enolate derived from cyclohexanone, predominant formation of the anti-aldol might be expected. Surprisingly, early experiments gave more or less stereorandom results in that the reaction with benzaldehyde gave a ratio of. vvtt/ant/ -aldols of 48 521B 23, Contrarily, recent investigations24 reveal a substantial anti selectivity (16 84), which is lowered in a dramatic manner (50 50) by the presence of lithium salts. Thus, the low stereoselectivity in the early experiments may be attributed to impurities of lithium salts or lithium hydroxide. 

Crystalline, diastereomerieally pure syn-aIdols are also available from chiral A-acylsultams. lhe outcome of the induction can be controlled by appropriate choice of the counterion in the cnolate boron enolates lead, almost exclusively, to one adduct 27 (d.r. >97 3, major adduct/ sum of all other diastereomers) whereas mediation of the addition by lithium or tin leads to the predominant formation of adducts 28. Unfortunately, the latter reaction is plagued by lower induced stereoselectivity (d.r. 66 34 to 88 12, defined as above). In both cases, however, diastereomerieally pure adducts are available by recrystallizing the crude adducts. Esters can be liberated by treatment of the adducts with lithium hydroxide/hydrogen peroxide, whereby the chiral auxiliary reagent can be recovered106. 

An enolate anion generated from a carboxylic acid derivative may be used in the same sorts of nucleophilic reactions that we have seen with aldehyde and ketone systems. It should be noted, however, that the base used to generate the enolate anion must be chosen carefully. If sodium hydroxide were used, then hydrolysis of the carboxylic derivative to the acid (see Section 7.9.2) would compete with enolate anion formation. However, the problem is avoided by using the same base, e.g. ethoxide, as is present in the ester... 

As the last example of C-C bond-formation reactions catalyzed by alkaline earth hydroxides, we mention the recently reported a-arylation of diethyl malonate in the presence of a palladium catalyst and a base in a separate phase 299). The arylation of carbonyl compounds is a carbon-carbon coupling reaction between an aryl halide and an enolate, which is usually catalyzed by palladium salts in the presence of an appropriate base (300,301). The arylation of diethyl malonate with bromobenzene (Scheme 48) was performed with tetrachloropalladate as the... 

Studies of relative rates, activation parameters, kinetic isotope, and solvent isotope effects, and correlation of rates with an acidity function, have elucidated the mechanisms of cyclization of diacetyl aromatics (23-26) promoted by tetramethyl-ammonium hydroxide in DMSO.32 Rate-determining base-catalysed enolate anion formation from (24-26) is followed by relatively rigid intramolecular nucleophilic attack and dehydration whereas the cyclization step is rate determining for (23). 

The optimal reaction conditions for reactions involving catalyst 33 and substrates 16a-c or 34 were investigated, and it was found that best results were obtained at room temperature [36] with toluene as the solvent [37] and with sodium hydroxide or sodium hydride as the base. In particular, the use of potassium hydroxide always gave lower enantioselectivities than sodium hydroxide, and lithium hydroxide was not effective in these reactions. Attempts to use aqueous sodium hydroxide as the base under liquid-liquid phase-transfer conditions resulted in the formation of a negligible amount of product [33,34]. An important finding of these optimization studies was the presence of a significant background reaction [38], Hence, one role of catalyst 33 must be to enhance the reactivity of an enolate when it is coordinated to the catalyst relative to the uncoordinated enolate. 

The mechanisms used for reaction of hydroxide with monocarbonyl and dicarbonyl compounds differed because for the more reactive dicarbonyl compounds the desolvation cost of bringing hydroxide into direct contact with the acidic CH became large relative to the overall kinetic barrier instead the reaction involved a bridging water that lost a proton to hydroxide as it abstracted a proton from carbon, thus avoiding the unfavorable contact species. An analogous mechanism was needed for water reaction with dicarbonyl compounds with two waters being involved so that formation of a direct complex of hydronium ion with the enolate carbon could be avoided. Thus, the mechanisms for the monocarbonyl compounds were two-dimensional and for the dicarbonyl compounds were three-dimensional. These mechanisms are illustrated in Fig. 11. 

Stacey and Turton61 objected to Isbell s mechanism on two counts first, that he did not specify that a proton acceptor must be used to promote the reaction and second, that the orthoacetate intermediate would not be applicable in the conversion which they demonstrated (by absorption spectra data) to take place on treatment with dilute, aqueous sodium hydroxide. (The presence of the proton acceptor seems implicit in Isbell s general description of the process of enolization.) The mechanism of Stacey and Turton is shown in Formulas XXIV to XXVIII it calls for the donation of electrons by pyridine to the incipient, ionic proton at C2 and elimination of acetic acid between C2 and C3 with the formation of the partially acetylated enediol-pyridinium complex. The pyridinium ion is removed by acetic acid. Electronic readjustment results in the elimination of acetic acid from positions 4 and 5. The final step, conversion of XXVII to XXVIII, was not explained. Stacey and Turton considered that with sodium hydroxide the reaction proceeds after deacetylation by a similar mechanism except that hydroxyl groups take the place of acetyl groups. Neither mechanism requires a free hydroxyl group at Cl, a condition considered by Maurer to be essential to kojic acid formation. 

We began the last chapter with the treatment of acetaldehyde with base. This led initially to the formation of an enolate anion and then to the aldol reaction. We are going to start this chapter with the treatment of ethyl acetate with base, To start with, there is hardly any difference. We shall use ethoxide as base rather than hydroxide as hydroxide would hydrolyse the ester, but otherwise the first steps are very similar. Here they are, one above the other. 

Reaction Mechanism The mechanism of the sodium hydroxide-catalyzed elimination of hexamethyldisiloxane may easily be understood when the reaction is compared to the well-known Peterson olefination in organic chemistry [24], Provided that an enolate anion is formed as an intermediate, either directly or via a proceeding hydrolysis of the 0-Si bond with traces of water which are always present on the hot surface of the crude catalyst, trimethylsilanolate splits off readily and thus the PsC triple bond is introduced into the molecule (Eq. 5). Subsequent attack of trimethylsilanolate at the trimethylsiloxy group of the starting compound results in a formation of hexamethyldisiloxane and the initial enolate anion so that the reaction circle is closed. 

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