Other enolate-related reactions

A number of species, such as nitroalkanes and nitriles, have an acidic a-hydrogen atom. These compounds can lose a hydrogen ion to produce an anion that is analogous to and reacts like an enolate ion. 

A number of other reactions involve, directly or indirectly, enols or enolates. 

A crossed Cannizzaro reaction with excess formaldehyde. 

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The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Organometallic methods, with the possible exception of those involving the stoichiometric generation of enolates and other stabilized carbanionic species 140], have seldom been used in carbohydrate chemistry for the synthesis of cyclohexane and cyclopentane derivatives. The present discussion will not cover these areas. The earliest of the examples using a catalytic transition metal appears in the work of Trost and Runge [41], who reported the Pd-catalyzed transformation of the mannose-derived intermediate 22 to the functionalized cyclopentane 23 in 98% yield (Scheme 10). Under a different set of conditions, the same substrate gives a cycloheptenone 24. Other related reactions are the catalytic versions of the Ferrier protocol for the conversion of methylene sugars to cyclohexanones (see Chap. 26) [40,42,43]. 

Transition-metal mediated carbene transfer from 205 to benzaldehyde generates carbonyl ylides 211 which are transformed into oxiranes 216 by 1,3-cyclization, into tetrahydrofurans 212, 213 or dihydrofurans 214 by [3 + 2] cycloaddition with electron-deficient alkenes or alkynes, and 1,3-dioxolanes 215 by [3 + 2] cycloaddition with excess carbonyl compound120 (equation 67). Related carbonyl ylide reactions have been performed with crotonaldehyde, acetone and cyclohexanone (equation 68). However, the ylide generated from cyclohexanone could not be trapped with dimethyl fumarate. Rather, the enol ether 217, probably formed by 1,4-proton shift in the ylide intermediate, was isolated in low yield120. In this respect, the carbene transfer reaction with 205 is not different from that with ethyl diazoacetate121, whereas a close analogy to diazomalonates is observed for the other carbonyl ylide reactions. 

A related reaction is the oxidation of silyl enol ethers to enones. This requires stoichiometric pal-ladium(II), though reoxidation of Pd(0) with benzoquinone can cut that down to about half an equivalent, but does ensure that the alkene is on the right side of the ketone. The first step is again oxypalladation and p elimination puts the alkene in conjugation with the ketone chiefly because there are no P hydrogens on the other side. 

An organometallic equivalent that opens epoxides is a hydrosilane, for example, MeaSiH, and carbon monoxide, catalyzed by dicobalt octacarbonyl See 10-55 for other coupling reactions with organosilanes. Silyl enol ethers react with epoxides in a related reaction, but a Lewis acid, such as TiCl4, is required. ... 

A number of other reports relating to 02 chemistry have appeared. The discovery of a new monooxide of fullerene, a [5,6]-open oxidoannulene, and the suggestion that a careful re-examination of all product mixtures obtained by oxidizing [60]fullerene would show that this material was a standard product of such reactions, has led to a re-investigation of the photooxygenation of [60]-fullerene. HPLC and C-NMR analysis of the product obtained, however, failed to detect any trace of the new monooxide. The photo-oxidation of the enol ether (101) has been considered as part of a comparative study which also... 

Such reactions are normally base catalyzed. Scheme 76 illustrates the use of this reaction to provide both fused and bridged rings. Other techniques for synthesizing the keto ester from trimethylsilyl ethers are shown in Scheme 77. The diketones shown were usually isolated as a mixture of enols or enol ethers. Acid-catalyzed acylation also provides a route to diketones not readily obtained by other routes (Scheme 78). The acid catalysts included polyphosphoric acid and naphthalene-2-sulfonic acid. In the latter example continuous removal of water facilitated the reaction. A related reaction involved treatment of an acid chloride with silver perchlorate in nitromethane (equation 41), although the yield of diketone was low. ° ... 

Similarly, a qualitative relation between the chemical behavior and the distortion from ideal C2v symmetry was suggested for a series of lithium ester enolates (Scheme 6.13) [108]. Enolate 1, furthest along the reaction coordinate to ketene, had to be handled at temperatures below -50°C and decomposed rapidly at temperatures higher than -30°C. The two other enolates, 2 and 3, were found to survive in crystalline form at 0°C and at room temperature, respectively. The decomposition occurs most likely through a ketene-like intermediate, whose transient existence was demonstrated by cleaving the lithium enolate of 2,6-di-/ert-butyl-4-methylphenyl-2-methylpropanoate at room temperature in the presence of excess -BuLi. 

There are related reactions involving the addition to, or abstraction of protons from the organic group. Thus acetonyl and other oxoalkyl compounds give olefin-coordinated ions in which the enol forms, e.g., of acetone, are stabilized by bonding to the metal atom ... 

Reactions.—An intermediate (71) has been isolated from the bromina-tion of alcohols using triphenylphosphine dibromide in dimethylformamide (Scheme 12). This implies that these reactions are closely related to the Vilsmeier reaction, and further evidence for this view comes from the isolation of a formylated product (72) from the analogous reaction of cholest-5-ene-3)8,4jS-diol (73). The other product (74) appears to be the result of an enol-bromination of the 3-ketone. Two related reactions which substantiate this are the mild reaction between pentane-2,4-dione and triphenylphosphine dibromide in DMF, to give (75), and the formation of 1-chlorocyclohex-l-ene (76) from cyclohexanone and a solution of... 

The Dieckmann cyclization of diesters and related reactions has found an enormous amount of use in the synthesis of five-, six-, seven-, and even larger-memberedrings. In unsymmetrical systems, steric effects and the stability of the product enolates determine the regiochemistry of the reaction. As shown in eqs 14 and 15, t-BuOK is an effective base for these reactions when used in t-BuOH or other solvents such as benzene. In the former example, 40% of unchanged starting material is recovered when MeONa/PhH is used to effect the cyclization. 

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