Enolates 1.3- dicarbonyl compounds

The equilibrium constants, measured by NMR spectroscopy, of ethyl acetoacetate and acetylacetone [47, 48, 134] (Table 4-2) indicate a higher enol content for these czx-enolizing 1,3-dicarbonyl compounds in apolar aprotic than in dipolar protic or dipolar aprotic solvents. 

In contrast to the m-enolizing 1,3-dicarbonyl compounds, the tran -enolizing cycloalkane-l,3-diones with four- to six-membered rings show exactly the opposite dependence on solvent polarity [46]. In these compounds, intramolecular hydrogen bonding is excluded on steric grounds. For example, 5,5-dimethyl cyclohexane-1,3-dione (5a,b) is 95% enolized in aqueous solution [51], However, in dilute solution in toluene, an apolar solvent, it is only 7% enolized [52, 134] x(enol) = 7 cmol/mol cf. Table 4-2. 

In addition to the carboxylates, other anions can be dimerized at the anode, presumably via radicals. Anionized or enolized 1,3-dicarbonyl compounds and heteroanalogs of CH acids couple in satisfactory yields (Table 10, numbers 1-3). 

Yoshioka, M., Nishioka, T, and Hasegawa, T., Dye-sensitized photooxygenation of 6-acyl- and 6-carbalkoxybenzocycloalken-5-ones reaction of singlet oxygen with enolic 1,3-dicarbonyl compounds,/. Org. Chem., 58, 278, 1993. 

A few years after Knoevenagel proposed his mechanism for the reaction that came to bear his name, Hann and Lapworth showed that primary or secondary amines were not required for the transformation to take place, as Knoevenagel had claimed, but that tertiary amines could indeed promote the reaction between menthylacetoacetate 15 and aldehydes (although they were less efficient)." The use of a tertiary amine obviously precludes the possibility of an aminal or imine intermediate, therefore Hann and Lapworth proposed direct reaction between the enolized dicarbonyl compound and the aldehyde (Hann-Lapworth mechanism). This mechanism would proceed similarly to that proposed by Knoevenagel, but without aminal formation, and proceeding through a P-hydroxy dicarbonyl compound such as 18, rather than a P-amino dicarbonyl compound (e.g., 13). 

Treatment of O-silyl enols with silver oxide leads to radical coupling via silver enolates. If the carbon atom bears no substituents, two such r -synthons recombine to symmetrical 1,4-dicarbonyl compounds in good vield (Y. Ito, 1975). 

The two most important structural features that stabilize the enol of a (3 dicarbonyl compound are... 

Enolate ions of p dicarbonyl compounds are useful intermediates m organic synthesis We shall see some examples of how they are employed m this way later m the chapter... 

Most of the reactions of ester enolates described so far have centered on stabilized eno lates derived from 1 3 dicarbonyl compounds such as diethyl malonate and ethyl ace toacetate Although the synthetic value of these and related stabilized enolates is clear chemists have long been interested m extending the usefulness of nonstabilized enolates derived from simple esters Consider the deprotonation of an ester as represented by the acid—base reaction... 

Formation o( oleltns by coupling or cross coupling of ketones, mediated by low valent titanium Also coupling ol enol ethers of 1,3-dicarbonyl compounds. 

The carbonyl group forms a number of other very stable derivatives. They are less used as protective groups because of the greater difficulty involved in their removal. Such derivatives include cyanohydrins, hydrazones, imines, oximes, and semicarbazones. Enol ethers are used to protect one carbonyl group in a 1,2- or 1,3-dicarbonyl compound. 

The procedure described illustrates a general method for the preparation of o ,j3-unsaturated aldehydes and ketones from the enol ethers of 3-dicarbonyl compounds. 

Af-Fluorobis(trifluoromethanesulfonyl)imide is also effective in the mono-fluonnation of ester and amide enolates, and of neutral dicarbonyl compounds. Excellent stereoselectivity is observed [48, 80, 81] (equations 39-41)... 

Although nitrosation of (l-dicarbonyl compounds becomes increasingly more facile upon successive replacement of the a alkyl groups with perfluoroalkyl groups because of the increased ionization of the perfluorinated enolate (equation 7), the stability of the nitrosodiketone tautomers decreases Thus, 1,1,1-trifluoro pentane-2,4-dione and 1,1,1,5,5,5-hexafluoropentane 2,4 dione mtrosate much faster than penta-2,4 dione but yield ketoximes, which decompose upon workup... 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

The enolate anion 1 may in principle be generated from any enolizable carbonyl compound 4 by treatment with base the reaction works especially well with /3-dicarbonyl compounds. The enolate 1 adds to the a ,/3-unsaturated compound 2 to give an intermediate new enolate 5, which yields the 1,5-dicarbonyl compound 3 upon hydrolytic workup ... 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced even more. Table 22.1 thus shows that compounds such as 1,3-dikotoncs (/3-diketoncs). 3-oxo esters (/3-keto esters), and 1,3-diesters are more acidic than water. This enhanced acidity of jS-dicarbonyl compounds is due to the stabilization of the resultant enolate ions by delocalization of the negative charge over both carbonyl groups. The enolate ion of 2,4-pentanedione, for instance,... 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

It becomes clear that in all these compounds it is the conjugate base that takes part in the substitution proper. For mono- and particularly 1,3-dicarbonyl compounds this result actually removes the problem of whether it is the keto or the enol form which enters into an electrophilic substitution by diazonium ions, halogenating agents, and many other reagents. The keto and the enol form are distinct species, but they have one (common) conjugate base This was made clear quite early, but even today there are many chemists who seem not to be aware of it. 

Conjugate addition of enolate anions to a, jS-unsaturated sulphoxides followed by a sulphoxide- ketone transformation were used for the preparation of 1,4-dicarbonyl compounds and cyclopentenone derivatives (equation 355)648. 

The enolized form of 2-acetyl-2-cyclohexen-l-one has been synthesized in low yield by dehydrochlorination of 2-acetyl-2-chlorocyclohexanone in collidine at 180° and by elimination of acetamide from 3-acetamido-2-acetylcyclohexanone at 120-140°. The preparation of other a,/3-unsaturated /3-dicarbonyl compounds has been attempted with varying degrees of success. The... 

Because of the equilibrium between silylated alcohols and free carbonyl compounds, the reaction between silylated alcohols ROSiMe3 13 and free enolized 1,2-dicarbonyl compounds such as 403 in the presence of 1% CF3SO3H results, at... 

Normal yS-dicarbonyl compounds such as ethyl acetoacetate 723 a or acetylace-tone 723 b are converted, as the free yS-dicarbonyl compounds or as their sodium salts, by TCS 14, 14/pyridine, or HMDS 2/TCS 14 into their enol silyl ethers 724a [216, 217, 219] and 724b [218]. Yet treatment of / -triketones such as 2-acetyl-dimedone 725 with HMDS 2 results, via the corresponding 2-enol trimethylsilyl... 

Ketones such as methyl cyclohexyl ketone 1284 react with DMSO/TCS 14, via their enol form, to give 21% of the chloroketone 1285 a and 63% of the a-methyl mercaptoketone 1286 [70]. Reaction of 1284 with DMSO/MesSiBr (TBS) 16 affords 85% of the bromo compound 1285 b and 12% hexahydrophenacyl bromide 1287 but no 1286 [71]. Whereas reaction of tra s-4-phenyl-3-buten-2-one (benzalacetone) 1288 with DMSO/TCS 14 gives 81% of the sulfonium salt 1289 [70], the y9-dicar-bonyl compound ethyl acetoacetate furnishes 69% of 1290 [70]. In contrast with DMSO/TCS 14, the combination DMSO/TBS 16 effects selective monobromina-tion of y9-dicarbonyl compounds [71] (Scheme 8.28). 

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