Enolates counter ion

Ambient nucleophiles ( S-diketones or jS-ketoesters) are known to attack always by the more basic y-carbon atom. A difficulty, frequently encountered in intramolecular alkylation of S-dicarbonyl compounds, is the concurrent formation of both C- and 0-alkylated products. It is, however, normally possible to direct the alkylation toward carbon or oxygen by proper selection of (1) the solvent, (2) the enolate counter ion, and (3) the leaving group. 

Detailed studies by Davis et al. [63] demonstrated that enolate oxidation, using (camphorsulfonyl)oxaziridine (lS)-(+)-52 or (li<)-(-)-52 (Fig. 7) as a chiral oxidizing agent, was highly enantioselective. However, the yields and ees of the hydroxylated products are strongly dependent on the structure of the substrate and oxaziridine as well as the reaction conditions (enolate counter-ion, solvent, temperature) [64]. 

Changing the enolate counter ion can also be beneficial. Reformatsky reagents 2.494 are zinc enolates, generated indirectly. These reagents can couple with aryl halides using either palladium or nickel catalysis (Scheme 2.141). This may also be considered as a variant of Negishi coupling (Section 2.3). 

The enolate counter-ion has an important effect on the rate of the reverse aldol reaction. Boron enolates usually undergo completely irreversible addition to aldehydes. The more ionic of the alkali metals, for example... 

Combination of achiral enolates vith achiral aldehydes mediated by chiral ligands at the enolate counter-ion opens another route to non-racemic aldol adducts. Again, this concept has been extremely fruitful for boron, tin, titanium, zirconium and other metal enolates. It has, ho vever not been applied very frequently to alkaline and earth alkaline metals. The main, inherent, dra vback in the use of these metals is that the reaction of the corresponding enolate, vhich is not complexed by the chiral ligand, competes vith that of the complexed enolate. Because the former reaction path vay inevitably leads to formation of the racemic product, the chiral ligand must be applied in at least stoichiometric amounts. Thus, any catalytic variant is excluded per se. Among the few approaches based on lithium enolates, early vork revealed that the aldol addition of a variety of lithium enolates in the presence of (S,S)-l,4-(bisdimethylamino)-2,3-dimethoxy butane or (S,S)-1,2,3,4-tetramethoxybutane provides only moderate induced stereoselectivity, typical ee values being 20% [177]. Chelation of the ketone enolate 104 by the chiral lithium amide 103 is more efficient - the j5-hydroxyl ketone syn-105 is obtained in 68% ee and no anti adduct is formed (Eq. (47)) [178]. 

The site of sulphonylation of ketone enolates by benzenesulphonyl fluoride is strongly influenced by the enolate counter-ion. Whilst lithium enolates give the a-sulphonyl-ketone, caesium or quatmiary ammonium salts give vinyl sulphonates via O-sulphonation. Benzenesulphonyl chloride gives the a-chloro-ketone. 

Pron et al.569) looked at polyacetylene treated from the gas phase with H2S04 which leads to HS04 counter-ions. They found that the conductivity drops in air with the appearance of C=O bands in the ir, although the rate of decay is much lower than would be expected for undoped samples. The polymer was more rapidly degraded by exposure to water but could be redoped with further acid treatment. Pron et al.570) have also reported hydrolytic instability in polyacetylene with A1C14 as the counterion. In both cases the proposed mechanism involves addition of OH" to the chain and keto-enol tautomerism to form carbonyl groups. 

The thermodynamic enolates are generally prepared at room temperature or even at reflux of a protic solvent. In these conditions the more stable enolate is obtained, and this tends to be the more substituted or more conjugated one when the counter ion is a potassium or sodium, but with notable exceptions for lithium which can favor the less substituted enolate3, as in the case of 2-methylpentan-3-one or 2-methylcyclopentanone64. 

The incoming monomer unit would then be forced, either because of steric interactions, or by the interaction of its carboxyl group with lithium at the chain-end, to add in a specific manner to re-form the same loose ring structure present initially. One variant of this mechanism [192] involves a covalently bonded six membered ring formed by enolization of the active chain end followed by alkoxide ion attack on the penultimate carboxyl group. In polar solvents, or in the presence of moderate amounts of them, competition for solvation of the counter-ion would be produced and the intramolecular solvation producing the stereospecificity would be reduced in effectiveness as the ether concentration is increased. Replacing the lithium counter-ion with sodium or other alkali metal would be... 

The capability of the highly oxygenated carbohydrate auxiliaries to coordinate the counter-ion of the enolate allows the formation of chiral chelate complexes with a restricted flexibility of the enolate moiety. The cation complexation also increases the tendency of the carbohydrate to react as a leaving group. It has been found [153] that the enolate 204 generated by deprotonation of the carbohydrate linked ester 203 with LDA underwent an elimination of the carbohydrate moiety generating the alcohol chelate complex 205 and the ketene 206 (Scheme 10.67). 

The most widely used application of sulfonyl azides is in the azidation of enolates and other stabilized carbanions. The main challenge here is the avoidance of the diazo transfer reaction, which leads to diazo compounds and thus makes a diastereoselective animation impossible. Addition of the enolates to the sulfonyl azide proceeds rapidly at low temperatures (—78° or lower) to give the mesomeric ion 42 (Eq. 30).318 Reagents 41, the counter ion M+, the solvent, and the quenching reagent all influence the subsequent partition between azide and diazo compound. For enolates of esters (39) and N-acyloxazolidinoncs (40) the preferred reagent is trisyl azide (41a) 4-nitrobenzenesulfonyl azide (41c) promotes diazo transfer, and tosyl azide (41b) usually leads to mixtures of the two types of products. For ester enolates 39, either lithium or potassium as the... 

Thus Liebeskind " studied the stereoselective aldol condensation with iron acyl enolates and showed that the choice of counter ion had a dramatic effect on the stereoselectivity of the two diastereomers 3.30 and 3.31. With i-Bu2Al adducts of the enolate, diastereomer 3.30 predominated with 3.30 and 3.31 in a ratio as high as 8.2 1. When SnCl" " is used instead, the stereoselectivity switched completely to favour the disatereomer 3.30 in a ratio of 1 11 (Scheme 3.8). " ... 

Davies examined the same reaction.He found that when using an excess of Et2Al adducts of the enolate, the diastereoselectivity ratio became > 100 1. Further, if Cu(I) was used as counter ion the opposite stereochemistry was obtained.Moreover both Davies and Liebsekind used this chiral iron auxiliary in a stereoselective synthesis of S-lactams. " " Liebeskind reported that chiral iron enolate complex condensed with imines in the presence of Et2Al counter ion to give two isomers with a ratio up to 20 1. Oxidation with I2/R3N produced the racemic jS-lacatms (Scheme 3.9)... 

Under these conditions the ester 81 was obtained in 90% yield with recovery of the starting material 80 in 10% yield. Obviously the less polar solvent toluene favors the formation of a chelated enolate, and the higher selectivity obtained with the bulkier potassium counter ion is explained by an additional chelation with the oxygen of the sUyl ether, which can reinforce the stability of the chelated transition state 80 (Figure 5.2.2). Metathesis with the Grubbs catalyst [34] afforded in nearly quantitative yield the anticipated cyclohexene derivate 83, which was reduced and dihydroxylated to provide the key structures of fumagiUin. 

Clearly, the electrostatic stabilization of the enolate by the sodium counter-ion, in the low-dielectric solvent THF, decreases the reactivity of the anion. Were it possible to withdraw, even if very slightly, both partners of this ion pair from one another, i.e. lengthen d somewhat, and the anion reactivity will be increased. 

We were able to envision a reasonable catalytic cycle for the use of silyl enol ethers in the asymmetric alkylation reaction, but there were several complications that could potentially lead to lower enantioinduction in the silyl enol ether reactions (Scheme 6). The generation of the enolate independent of the palladium(II) 7t-allyl complex and the presence of a tetrabutylammonium counter ion could shift the mechanism of the reaction. We had very httle proof at the time, but our working hypothesis was that the C-C bond-forming step occurred in the inner sphere of the palladium atom. We considered the possibihty that the conditions used in the silyl enol ether reactions might facilitate an outer sphere pathway resulting in lower ee products. In the event, we found that the ketone products generated from silyl enol ethers did not significantly differ in ee from the equivalent products of allyl enol carbonate reactions (e.g., Table 8 vs. Table 2). 

Even if a particular enolate vith a distinct geometry is reacted vith an aldehyde, the question vhether the transition state is closed or open cannot be ans vered by simple either-or . More recent discussions have, instead, led to an as vell as , because the role of the counter-ion becomes more evident. Thus, ab-initio calculations of Houk and co vorkers [92] predict an open-transition-state structure for metal-free, naked enoiates and closed transition states for lithium enoiates. For addition of acetaldehyde lithium enolate to formaldehyde, the lo vest-energy reaction path vay (sho vn in Scheme 1.13) has been studied on the basis of on ab-initio (3-21 G) calculations [93]. 

The influence of further counter-ions like ammonium, magnesium and zinc on the reversibility has been studied [65, 71]. Another influence comes from the stability of the enolate. As a rule, the rate of the retroaldol reaction correlates vith the stability of the enolate. In stereoselective aldol addition, the reversibility is, in general, rather considered as a complication than a tool to obtain high selectivity. In particular, thermodynamically controlled aldol additions are usually not suitable to obtain non-racemic aldols. 

Remarkably high stereoselectivity is obtained by means of the sodium enolate of a-N,N-dibenzylamino-substituted ketone 51, a counter-ion not very frequently used in stereoselective aldol additions. In this instance, however, the sodium enolate turned out to be more efficient than the lithium analog. The predominant formation of the main diastereomeric product 52a rather than 52b is explained by an open transition state, assumed to be strongly favored over the cyclic transition state, when the more ionic sodium enolate is used rather than the corresponding lithium reagent (Eq. (24)) [103]. 

---