0 -dicarbonyl enolates

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

D. Reactions of Magnesium Dicarbonyl Enolates with Eiectrophiles... 

Similarly, ethynylation of / -dicarbonyl enolates via the tandem Michael-car-bene rearrangement (MCR) pathway occurs smoothly by the reaction with the parent ethynyl-A3-iodane 128. High migratory aptitude of a-hydrogens of alkylidene carbenes is responsible for this facile ethynylation [199]. 

Cyclopentenes are commonly formed in the reaction of the appropriate alkynyliodonium salts with enolate anions. Various alkynyliodonium tetrafluo-roborates interact with / -dicarbonyl enolates to give products of cyclopentene annulation in 50-90% yield [121]. Several examples of such annulations are shown in Scheme 59. The carbene cyclization can also occur when the long alkyl... 

Despite the synthetic possibilities suggested by this early study, the chemistry of the alkynyliodonium salts lay dormant until the mid-1980s. In 1986, Ochiai and his coworkers published an important communication which shaped much of the later thinking on the reactions of alkynyliodonium ions with nucleophiles28. When / -dicarbonyl enolates are treated with alkynyliodonium tetrafluoroborates containing a long (> three carbons) alkyl chain, derivatives of cyclopentene are produced. This is illustrated in equation 41 for the... 

When / -dicarbonyl enolates are allowed to react with alkynyliodonium salts, typically in ter/-butyl alcohol or THF, alkynyl- and/or cyclopentenyl- -dicarbonyl compounds are obtained. The product compositions are largely regulated by the migratory aptitude of R in the alkynyl moiety and the availability of alkyl side chains for the MC-insertion (MCI) pathway (equation 45). These divergent modes of reactivity are nicely illustrated by the reactions of the 2-phenyl-1,3-indandionate ion with ethynylfphenyl)- and 4-methyl-1-hexynyl(phenyl)iodonium tetrafluoroborates (equation 1 15)27 2. 

Because the hydrogen atom and phenyl group migrate so readily, the reactions of / -dicarbonyl enolates with ethynyl- and (phenylethynyl)iodonium salts can be expected to result in alkynylation. It has already been noted that the 2- -hexyl-l,3-indandionate ion undergoes alkynylation with (phenylethynyl)phenyliodonium tetrafluoroborate (equation 43), despite the availability of the -hexyl group for [2 + 3] annulation. Ethynylations of six / -dicarbonyl enolates and the anion of 2-nitrocyclohexane with ethynyl(phenyl)-iodonium tetrafluoroborate in THF have also been reported27. For example, admixture of the ethynyliodonium salt and the anion of ethyl 2-cyclopentanone-l-carboxylate in THF affords the 1-ethynyl derivative in 71% isolated yield (equation 124)27. 

Even when both enolates can form, the less substituted dicarbonyl enolate is preferred because it constrains fewer groups to lie in the hindered plane of the tetrasubstituted enolate double bond. 

In the lithium and cesium enolates of o-methoxyacetophenone, the methoxy oxygen coordinates with the smaller lithium cation but not with the cesium cation . Other examples of lithium enolate chemistry include a thermochemical analysis of the aldol reaction of lithiopinacolonate with pivalaldehyde and a comparison of the proton affinities and aggregation states of lithium alkoxides, phenolates, enolates, -dicarbonyl enolates, carboxylates and amidates. Although the lithium enolate of cyclopropanone itself remains unknown, derivatives (accompanied by their aUenoxide isomer) have been implicated in the reaction of a-(trimethylsilyl) vinyl lithium with CO. That both species are seemingly formed is surprising because cyclopropanone enolate is expected to be much less stable than its acyclic isomer cyclopropene is less stable than allene by almost 90 kJmol-. ... 

Initial, electrochemical reduction of /S-dicarbonyl enol phosphates linked to an ole-finic chain gives cleavage of the phosphate with formation of a vinylic radical [222-224]. Reduction in DMF takes place in the potential range —2.0 to —2.3 V and may lead to bicyclic products as illustrated in Scheme 23. 

In the case of carbon nucleophiles, the behaviour depends on the nature of the substrate. P-Dicarbonyl enolates react with alkynyliodonium salts to afford a transient carbene, which evolves either by migration towards alkynyl-substituted product, or by insertion towards cyclopentene... 

It is important to distinguish this synthesis from the alkylation of a 1,3-dicarbonyl enolate with a 2-halo-ketone, with displacement of halide, producing a 1,4-dicarbonyl unit for subsequent ring closure " presumably the difference lies in the greater reactivity of the carbonyl group (aldehyde in the example) in the Feist-Benary sequence. 

Similarly, the simple lithium enolate 4.143 reacts with cyclohexenone at -78 °C to give the product 4.142 of direct attack, but warming the reaction mixture to room temperature allows this step to revert to the starting materials, and they then form the thermodynamically more stable product 4.144 of conjugate attack.374 /3-Dicarbonyl enolates, commonly used in Michael reactions, usually do not allow the isolation of the product of direct attack, since the first step is even more easily reversible in such cases. 

Moving to a,3-unsaturated esters, hydroxide ion and alkoxide ion (hard nucleophiles) react with ethyl acrylate 4.145 by direct attack at the carbonyl group to give ester hydrolysis and ester exchange, respectively, whereas the /3-dicarbonyl enolate ion 4.146 (a softer nucleophile) undergoes a Michael reaction.381 There is no certainty in this latter reaction that the attack of the enolate anion on the carbonyl group, in a Claisen-like condensation, is not a more rapid (and reversible) process.382... 

Noting the greater reactivity of the newly formed dicarbonyl products for the Corey-Kim reagent present in excess, the authors propose the following mechanism in which the C-2 of the dicarbonyl enol ether tautomer attacks the electrophilic sulfonium... 

Scheme 3-4 Products of reaction of p-dicarbonyl enolates with HCsCiPh BF, t-BuOK in t-BuOH or THF [28].

More complex nucleophiles can be reacted with alkynyl(phenyl)iodonium salts as well. For example, protected aminomalonates (50) and 18 give the corresponding alkynylmalonates 51 in 30-90% isolated yields (equation 19). Likewise, a variety of dicarbonyl enolates 52-54 react with 55 to give alkynyl products 56-58 (equations 20-22). These reactions may be looked upon as alkynylations or, in other words, the triple-bond analogs of the well-established alkylation reactions. Unfortunately, they only work with soft nucleophiles such as 52-54 (OTs, PhC02 PhsP, etc.). Nucleophiles such as RO, or simple enolates, do not seem to work. 

We can account for the greater acidity of j8-dicarbonyl systems, as compared to single carbonyl systems, by delocalization of the negative charge to two oxygen atoms instead of one. We can represent this delocalization by drawing contributing resonance structures for a jS-dicarbonyl enolate and its resonance hybrid ... 

Ethylphenol and 1 eq. KOBu-r in benzene kept at 25° for 1 h, 2-acetoxymethyl-phenol added, and the mixture kept at 25° for 3 h product. Y 63%. F.e. and nucleophiles (MeOH, amines, NaNj, (3-dicarbonyl enolates), also syntheses via p-quinone methids and vinylogs thereof, s. B. Loubinoux et al.. Tetrahedron Letters 30, 1939-42 (1989). 

The a-position of the p-dicarbonyl enolate is the most nucleophilic (here labelled C-1) and lodobutane is the only electrophile. 

The nickel-catalyzed reductive coupling reaction of methyl vinyl ketone with enyne 43 bearing a P-dicarbonyl moiety proceeds with liberation of the P-dicarbonyl enolate (Scheme 5.56) [39]. Reductive coupling of 43 with enone would afford nickelaoxacyclooctadiene 44. Transmetalation is accompanied by carbonickelation to yield 45. Intermediate 45 engages in P-carbon elimination through a six-membered cyclic transition state to liberate nickel enolate 46, which should be transformed to the corresponding zinc enolate to complete the catalytic cycle, and zinc enolate 47, which is eventually protonated upon hydrolysis. 

The obvious diseonnection on a 1,4-dicarbonyl compoimd gives us a logieal nucleophilie synthon (an enolate anion) A but an illogieal electrophilic synthon B ... 

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