1,3-Dicarbonyl compounds, keto/enol

Reactions of unsymmetrical methylene 1,3-dicarbonyl compounds with enol ethers have been investigated by Yamauchi et al. [137]. As we have mentioned earlier, the a,/ -unsaturated ketone moiety in alkylidene-/ -ketoesters reacts exclusively as the oxabutadiene. However, high regioselectivity is also observed with mixed alkyl-phenyl-1,3-diketones with exclusive reaction of the aliphatic carbonyl group, whereas in alkylidene-1,3-dicarbonyl compounds bearing an aldehyde and a keto-moiety, the a,/J-unsaturated aldehyde reacts preferentially as oxabutadiene, but not exclusively [130a]. 

Malonate esters and acetoacetate esters are more acidic than water or alcohols (Table 22.2). Thus, the hydroxide ion or an alkoxide ion is sufficiently basic to produce the conjugate base of either of these P dicarbonyl compounds. The enolates of simple esters and P-keto esters are nucleophiles, and they undergo the condensation reactions we will discuss below. 

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. 

Like reaction rates, the effect of solvent polarity on equilibria may be rationalized by consideration of the relative polarities of the species on each side of the equilibrium. A polar solvent will therefore favour polar species. A good example is the keto-enol tautomerization of ethyl acetoacetate, in which the 1,3-dicarbonyl, or keto, form is more polar than the enol form, which is stabilized by an intramolecular H-bond. The equilibrium is shown in Scheme 1.3. In cyclohexane, the enol form is slightly more abundant. Increasing the polarity of the solvent moves the equilibrium towards the keto form [28], In this example, H-bonding solvents will compete with the intramolecular H-bond, destabilizing the enol form of the compound. 

On the other hand, the use of [Rh(CO)2Cl]2 as a catalyst results in ring opening of the siloxycyclopropanes 13 to the silyl enol ethers 14 with high stereoselectivity [10]. The 2-siloxyrhodacyclobutane 15a is proposed to undergo j8-elimination to give jr-allylrhodium 16a followed by reductive elimination to the silyl enol ether 14a. 1-Trimethylsiloxybicyclo[n.l.0]alkanes serve as / -metallo-carbonyl compounds via desilylation with a variety of transition metals [11]. The palladium-catalyzed reaction of the siloxycyclopropanes 17 under carbon monoxide in chloroform provides a route to the 4-keto pimelates 18. In the presence of aryl triflates, the 1,4-dicarbonyl compounds 19 are... 

A mechanistic study of acetophenone keto-enol tautomerism has been reported, and intramolecular and external factors determining the enol-enol equilibria in the cw-enol forms of 1,3-dicarbonyl compounds have been analysed. The effects of substituents, solvents, concentration, and temperature on the tautomerization of ethyl 3-oxobutyrate and its 2-alkyl derivatives have been studied, and the keto-enol tautomerism of mono-substituted phenylpyruvic acids has been investigated. Equilibrium constants have been measured for the keto-enol tautomers of 2-, 3- and 4-phenylacetylpyridines in aqueous solution. A procedure has been developed for the acylation of phosphoryl- and thiophosphoryl-acetonitriles under phase-transfer catalysis conditions, and the keto-enol tautomerism of the resulting phosphoryl(thiophosphoryl)-substituted acylacetonitriles has been studied. The equilibrium (388) (389) has been catalysed by acid, base and by iron(III). Whereas... 

In addition to preparation of arylhydrazones from the carbonyl compounds and an arylhydrazine, the Japp-Klingemann reaction of arenediazonium ions with enolates and enamines is an important method for preparation of arylhydrazones. This method provides a route to monoarylhydrazones of a-dicarbonyl compounds from /3-keto acids and to the hydrazones of pyruvate esters from / -keto esters. Enamines also give rise to monoarylhydrazones of a-diketones. Indolization of these arylhydrazones provides the expected 2-acyI-or 2-alkoxycarbonyl-indoles (equations 95-97). 

Keto-enol equilibrium constants for simple /i-dicarbonyl compounds, RCOCH2COX (R = X = Me R = Me, Ph for X = OEt) have been measured in water1423 by a micelle perturbation method previously reported for benzoylacetone142b (R = Ph, X = Me). The results have been combined with kinetic data for nitrosation by NO+, C1NO, BrNO, and SCNNO in all cases, reaction with the enol was found to be rate limiting. 

When we come to 1,3-dicarbonyl compounds 4 the principle is the same but we now have a choice the keto-ester 35 could be disconnected 35b to the enolate 36 of acetone and diethyl carbonate 37 and this synthesis would work but we prefer 35a as that gives us the enolate of ethyl acetate 34 and ethyl acetate itself 33—another self condensation. 

The furo[2,3-b]quinoxalines 20 are formed only in cases where the keto group in the intermediate quinoxalinyl ketone 19 is enolizable. If enolization is not possible, the reaction is completed by the formation of product 19 (Scheme 15) (72YZ736). Therefore, it is not surprising that / -dicarbonyl compounds, which are considerably enolized, undergo a very smooth cyclization with tetrachloropyrazine with ethyl acetoacetate, furo [2,3-b] pyrazine is obtained in good yield (Scheme 15) (83JHC365). 

The 1,3-dicarbonyl compound need not be symmetrical and if it is not two different enol forms will interconvert by proton transfer. Here is a cyclic keto-alde-hyde as an example. It exists as the rapidly equilibrating enol. The proportions of the three species can be measured by NMR there is 0% keto-aldehyde, 76% of the first enol, and 24% of the second. 

Each of our two much simpler starting materials needs to be made. The keto-ester is a 1,5-dicarbonyl compound so it can be made by a conjugate addition of an enolate, a process greatly assisted by the addition of a second ester group (Chapter 29). 

The keto-aldehyde can be made by a simple Claisen ester condensation (Chapter 28) using the enolate of the methyl ketone with ethyl formate (HCC Et) as the electrophile. It actually exists as a stable enol, like so many 1,3-dicarbonyl compounds (Chapter 21). 

The abbreviations which refer to /3-dicarbonyl compounds are meant to refer to all those species which comprise the /3-dicarbonyl system, i.e. the keto and the various enol tautomers. 

Which conformers of Fig. 2 are important depends upon the type of /3-dicarbonyl compound. For/3-diketones two predominate to the virtual exclusion of the others these are the cis diketo and the cis enol. Each has a sufficiently distinguished set of proton signals in the H NMR spectrum to make integration a reliable measure of molar proportions, and hence K, [enol]/[keto], can be easily obtained. 

The influence of solvents on chemical equilibria was discovered in 1896, simultaneously with the discovery of keto-enol tautomerism in 1,3-dicarbonyl compounds (Claisen [14] acetyldibenzoylmethane and tribenzoylmethane Wislicenus [15] methyl and ethyl formylphenylacetate Knorr [16] ethyl dibenzoylsuccinate and ethyl diacetylsuccinate) and the nitro-isonitro tautomerism of primary and secondary nitro compounds (Hantzsch [17] phenylnitromethane). Thus, Claisen wrote Es gibt... 

Open-chain 1,3-dicarbonyl compounds are observed in the tran -enolic form only in rare cases [41] (for examples, see references [44, 45]). When the trans -enolic form is excluded, the keto/enol equilibrium constant Ki is given by Eq. (4-23). 

In solution, open-chain 1,3-dicarbonyl compounds enolize practically exclusively to the czls-enolic form (4b), which is stabilized by intramolecular hydrogen bonding. In contrast, cyclic 1,3-dicarbonyl compounds e.g. cycloalkane-1,3-diones [46]), can give either trans-Qnols (for small rings) or czk-enols (for large rings). As the diketo form is usually more dipolar than the chelated cu-enolic form, the keto/enol ratio often depends on solvent polarity. This will be discussed in more detail for the cases of ethyl acetoacetate and acetylacetone [47-50, 134, 135]. 

The first attempt to introduce an empirical relationship between an equilibrium constant and solvent polarity was made in 1914 by K. H. Meyer [24]. Studying the solvent-dependent keto-enol tautomerism of 1,3-dicarbonyl compounds, he found a proportionality between the equilibrium constants of various tautomeric compounds in the same set of different solvents cf. Table 4-2 in Section 4.3.1). He therefore split the tautomeric equilibrium constant Ky into two independent factors according to Eq. (7-9). 

Initial attempts at the direct fluorination of carbonyl compounds such as acetone, bulan-2-one, and butyric acid with elemental fluorine resulted in the formation of complex mixtures, with only low yields of a-monofluorinated carbonyl compounds formed. However, more recently, methyl 3-phenylpyruvate. and other pyruvate derivatives, e.g. 1," are reported to be selectively monofluorinated with dilute elemental fluorine at — lO C in moderate yield. The success of this reaction is attributed to the fact that the substrate predominantly exists in the enol form and not the keto form." Direct fluorination of acyclic 1,3-dicarbonyl compounds in formic acid or acetonitrile at room temperatures results in the formation of 2-fluoro-... 

Clerici A, Pastori N, Porta O (2001) Mild acetalisation of mono and dicarbonyl compounds catalysed by titanium tetrachloride. Eacile synthesis of (3-keto enol ethers. Tetrahedron 57 217-225... 

Pentanedione (acac) and related jS-dicarbonyl compounds are an extremely important class of hgands that have been studied widely for many years. In general, jS-dicarbonyl compounds exist as mixtures of tautomeric keto and enol forms (equation 15). These compounds are usually easily deprotonated to form monoanions, which form the basis for a large class of coordination compounds, encompassing vir-tuaUy every element. In addition, coordination compounds of the dianions and trianions of jS-diketones have been observed, as well as complexes of the neutral molecules. ... 

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