Enols ketonization

In a reaction related to the mixed Claisen condensation nonenolizable esters are used as acylatmg agents for ketone enolates Ketones (via their enolates) are converted to p keto esters by reaction with diethyl carbonate... 

It has been reported by Burgada (I09a) that highly enolized ketones form enamines when they are treated with tris[dimethylamino]phosphine. Only condensation products are formed when slightly enolized ketones are treated with this reagent. 

Due to their tendency to form (Z)-enolates, ketones usually provide syn-aldols, and anti-se ec-tive chiral ketone enolates are rare. When, however, (S)-5,5-dimethyl-4-trimethylsiloxy-3-hex-anone is deprotonated with (V-(bromomagnesio)-2,2,6,6-tetramethylpiperidine, the (E)-enolate la is assumed to be formed. Subsequent addition to aldehydes delivers anh-aldols 2a and 3a in ratios of between 92 8 and 95 5 and yields of 75-85%53b. 

Section 4.2.1 will be devoted to heterocycles, section 4.2.2 will cover other kinds of protomeric tautomeric equilibria (e.g., enol/ketone, formic acid, formamidine, etc.), and section 4.2.3 will discuss an example of a ring/chain tautomeric equilibrium. The order of presentation will be approximately by increasing molecular weight within each section. A review by Kwiatkowski et al. [267] covers work on formamide, pyridines, pyrimidines, purines, and nucleic... 

The stereo- and regioselectivity of deprotonation can be kinetically or thermodynamically (equilibrium) controlled. Equilibrium between enolates occurs when a proton donor is present. The proton donor can be the solvent or an excess of the ketone in relation to the strong base present for generation of the enolate. Ketone enolate equilibration can also proceed via an aldol-rever-... 

It is interesting to note that the diene system of the diene-ketene (Formula 118) contains an enolic ketone which must be maintained as the enol by the chelate ring formed with the adjacent acetyl group. 

The isomerization of cyclic allyl alcohols to produce ketones proceeds more cleanly [17]. Effective kinetic resolution of racemic cyclic allylic alcohols has been reported [18]. The isomerization of racemic 4-hydroxy-2-cyclopentanone (29) in the presence of 0.5 mol % of [Rh[(/ )-BlNAP](MeOH)2 + in THF proceeded with 5 1 enantiomeric discrimination at 0°C to give 1,3-cyclopentadione (31) via enol ketone 30, leaving the /(-starting allylic alcohol (91% ee and 27% recovery yield) at 72% conversion after 14 days (eq 3.12). (R)-4-Hydroxy-2-cy-clopentenone is a key building block for prostaglandin synthesis [19]. 

Enolates are important nucleophiles which react nicely with a variety of carbonyl compounds. In this case, the nucleophilic reactivity of the enolate and the electrophilic reactivity of the carbonyl group are well matched and a wide variety of products can be made. The type of enolate (ketone, ester, etc.) and the type of carbonyl electrophile (aldehyde, ketone, ester, etc.) determine the structure of the final product. Furthermore these reactions are often named according to the two partners that are reacted and the type of product produced from them. 

Ester enolate Ester enolate Ketone enolate Ketone enolate... 

Summing up the rates of these competing reaction paths, Equations (5-7), one obtains the total rate of enol ketonization, Equation (8). Note that vK refers exclusively to the forward reaction E —> K. 

Thus the approach to equilibrium always follows a first-order rate law, Equation (14), with the pH-dependent rate constant kobs = kE + kK. Figure 1 shows the concentration changes in time starting from a 1m solution of pure enol (full line) and of pure ketone (dashed line). The individual, unidirectional rate constants kE and kK can be determined as follows For most ketones the equilibrium enol concentration is quite small, i.e., tE = cE(oo)/ ck(oo)<<1. Hence kE kK [Equation (1)], so that enol ketonization is practically irreversible and kE may be neglected, kobskK. The rate constant of enolization kE, on the other hand, is equal to the observed rate constant of reactions for which enolization is rate-determining, such as ketone bromination (Scheme 2). 

Fig. 9 Variation of the Bronsted parameter a for general acid catalysis of enol ketonization with the free energy change AG° for carbon protonation of enols (o) and enolates ( ). The data are taken from Table 2.

Treatment of isogarryfoline (59) with 10% DC1 in D20 gave (60). The n.m.r. spectra of (60) revealed deuterium substitution at C-16 and C-17. The mechanism outlined in Scheme 2 accounts for this observation and explains the stereochemistry observed i.e., D+ is transferred from the less-hindered exo side during ketonization. When (60) was treated with dilute HC1, no deuterium exchange by hydrogen was observed in 24 hours. However, after 96 hours, (61) was obtained. This result further supports an enol-ketone mechanism. 

Acetic Anhydride, Carbon Tetrachloride, and 2-Methylcyclohexanone. During acetylation of the enolized ketone, the 70% perchloric acid must be added last.6... 

Cyclopentanedione and 1,3-cyclohexanedione are highly enolized ketones. Will they give the same proportions of O- and C-alkylations under the same reaction conditions (of solvent, cation, etc.) ... 

It should be noted that PCMU based on cross-linked macroligands possess a relatively high chemical and thermal stability. The stability of poly(enol-ketonate) chelates obtained by oxidation of thin polyvinylacetate films increases in the series of mono-, di- and trivalent ions [122], the oxidation promoting the penetration of the metal ions into the deep film layers. The weight loss of Co and Mn polychelates based on the condensation products of stoichiometric amounts of 5,5 -methylene-bis-salicylaldehyde and 4,4 -diaminophenyl ether at 300, 500, and 600 °C is 2.1, and 0.5 8.0 and 9.8 25.0 and 27.5%, respectively [14b]. The stability, in the range between 275 and 640 °C, of chelates formed by the transition metals and condensation products of p-hydroxybenzoic acid, urea and formaldehyde follow the series [123] Fe(III)>Co(II)>Cu(II)>Ni(II)>V02(II)> Zn(II) Mn(II) > CML. 

Aldehydes, ketones, carboxylic esters, carboxylic amides, imines and iV,jV-disubstituted hydrazones react as electrophiles at their sp2-hybridized carbon atoms. These compounds also become nucleophiles, if they contain an H atom in the a position relative to their C=0 or C=N bonds. This is because they are C,H-acidic at that position, that is, the H atom in the a position can be removed with a base (Figure 10.1). The deprotonation forms the conjugate bases of these substrates, which are called enolates. Depending on the origins of these enolates, they may be called aldehyde enolates, ketone enolates, ester enolates, or amide enolates. The conjugate bases of imines and hydra-zones are called aza-enolates. The reactions discussed in this chapter all proceed via enolates. 

Hence, the first clearcut evidence for the involvement of enol radical cations in ketone oxidation reactions was provided by Henry [109] and Littler [110,112]. From kinetic results and product studies it was concluded that in the oxidation of cyclohexanone using the outer-sphere one-electron oxidants, tris-substituted 2,2 -bipyridyl or 1,10-phenanthroline complexes of iron(III) and ruthenium(III) or sodium hexachloroiridate(IV) (IrCI), the cyclohexenol radical cation (65" ) is formed, which rapidly deprotonates to the a-carbonyl radical 66. An upper limit for the deuterium isotope effect in the oxidation step (k /kjy < 2) suggests that electron transfer from the enol to the metal complex occurs prior to the loss of the proton [109]. In the reaction with the ruthenium(III) salt, four main products were formed 2-hydroxycyclohexanone (67), cyclohexenone, cyclopen tanecarboxylic acid and 1,2-cyclohexanedione, whereas oxidation with IrCl afforded 2-chlorocyclohexanone in almost quantitative yield. Similarly, enol radical cations can be invoked in the oxidation reactions of aliphatic ketones with the substitution inert dodecatungstocobaltate(III), CoW,20 o complex [169]. Unfortunately, these results have never been linked to the general concept of inversion of stability order of enol/ketone systems (Sect. 2) and thus have never received wide attention. 

Cp 2La CH(SiMe3)2 reacts with 3-pentanone to form the solvated enolate, Cp 2La —O—C(Et)=CHMe Et2CO (equation 9a), while with acetone it forms a chelate (equation 9b) after intramolecular aldol condensation. The reaction of the precursor bistrimethylsi-lyhnethyl organometallic with hydroxyketone, preformed from the pentanone, yields the enolate ketone solvate. This difference between acetone and 3-pentanone presumably reflects the difference in strain in the condensation product because the ethyl groups in 3-pentanone are rather much bigger than the methyl groups in acetone. 

Enol/ketone and thiol/thione prototropic tautomerism in 2-imidazolone and 2-thioimidazolone has been investigated by ab initio methods in terms of thermodynamic stability (Scheme 4) <2003JP047>. Semiempirical methods (AMI, PM3, and MNDO) have been used to evaluate the tautomerism of 2-, 4-, and 5-imidazolones and their thio- or azo-analogues in the gas phase <1996JMT(366)227>. 

Enolized ketone Acceptor carbonyl compound Reagent Yield %) Threo erythro... 

Unsymmetrical alkenes can be prepared by mixed intermolecular reactions if one of the components, commonly acetone, is used in excess (equation 83). As the isopropyl group is a common subunit of many terpenes this method provides a valuable route for its introduction. Pattenden and Robertson used such a reaction followed by a Grob-type fragmentation in their preparation of the daucenone (42) from the readily enolized ketone (43). The bicycle (42) was used as an intermediate for the synthesis of the diterpene ( )-isoamijiol (44 equation 84). Mixed couplings are not restricted to acetone, and almost any carbonyl may be used. For example, Paquette et al. employed the aldehyde (45) in a synthesis of ( )-a-vetispirene (46 equation 85). More complex mixed couplings are also possible. For example, the aldehydes (47) and (48) are coupled efficiently to the stilbene (49), which in turn is converted to phenan-threne alkaloids such as atherosperminine and thalictuberine (equation 86). ... 

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