Tautomerization of Ketones

The tautomerism of ketones is discussed in Section 4.05.4.5 and such compounds are considered under the aromatic tautomer. 

The a-hydioxypyiioles, which exist piimadly in the tautomeric pyiiolin-2-one form, can be synthesized either by oxidation of pyrroles that ate unsubstituted in the a-position or by ting synthesis. P-Hydtoxypyttoles also exist primarily in the keto form but do not display the ordinary reactions of ketones because of the contributions of the polar form (25). They can be teaddy O-alkylated and -acylated (41). 

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C N bond to give an imine anion in a process similar to nucleophilic addition to a polar C=0 bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes (Section 8.4) to an amide in a step similar to the tautomerization of an enol to a ketone. The mechanism is shown in Figure 20.4. 

Tautomerization of the hydroxyimine yields an amide in a reaction analgous to the tautomerization of an enol to give a ketone. 

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. If a full mole of base per mole of ketone is used, the enolate ion (10) is formed and can be isolated (see, e.g., 10-105). When enol ethers or esters are hydrolyzed, the enols initially formed immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to an asymmetric carbon a to a carbonyl group (as in 11) is treated with acid or base, racemization results. If there is another asymmetric center in the molecule. 

The reaction shows a first-order dependence on substrate concentration but, except at very low concentration, is zero-order with respect to oxidant moreover, the zero-order rate coefficient is the same as that observed with oxidations by iodine, cupric chloride and silver nitrate. The reaction is acid-catalysed. The oxidation is completely analogous to the halogenation of ketones and involves a slow tautomeric equilibrium followed by rapid oxidation, viz. 

After succeeding in the asymmetric reductive acylation of ketones, we ventured to see if enol acetates can be used as acyl donors and precursors of ketones at the same time through deacylation and keto-enol tautomerization (Scheme 8). The overall reaction thus corresponds to the asymmetric reduction of enol acetate. For example, 1-phenylvinyl acetate was transformed to (f )-l-phenylethyl acetate by CALB and diruthenium complex 1 in the presence of 2,6-dimethyl-4-heptanol with 89% yield and 98% ee. Molecular hydrogen (1 atm) was almost equally effective for the transformation. A broad range of enol acetates were prepared from ketones and were successfully transformed into their corresponding (7 )-acetates under 1 atm H2 (Table 19). From unsymmetrical aliphatic ketones, enol acetates were obtained as the mixtures of regio- and geometrical isomers. Notably, however, the efficiency of the process was little affected by the isomeric composition of the enol acetates. 

In one of the earliest applications of this type of process to complex molecule synthesis, Corey and Hortmann, in their synthesis of dihydrocostunolide 38, found that photolysis of 36 afforded a photostationary state of 36 and 37 (Scheme 9)19. Hydrogenation of this mixture then gave 38. A recent modification of this synthesis, which avoids the photostationary equilibrium between eudesmane (36) and germacrane (37) forms, was realized using a modified substrate, 3920. Irradiation of 39 provided a 77% yield of a mixture of diastereomeric ketones 41 these are produced via tautomerization of the intially produced trienol 40. Dienone 41 was then easily converted to 38 via a series of conventional steps (Scheme 9). 

The tautomerism of the aliphatic nitro-compounds is very closely allied to that of the ketones and aldehydes. Here also there are two ... 

An investigation of keto-enol tautomerism for perfluorinated keto-enol systems was undertaken. N-methylpyrrolidone (NMP) catalyzes equilibration of the keto and enol forms, but if used in more than trace amounts, it drives the equilibrium strongly toward enol because of hydrogen bonding to the amide. The enol is much more thermodynamically stable than its ketone, and it was found that in mildly Lewis basic solvents, such as ether, THE, acetonitrile, and NMP, the enohzation equilibrium lies too far right to allow detection of ketone (Correa et al., 1994). 

Lutz, R. E., J. A. Freek, and R. S. Miirphey Secondary and tertiary amino ketones and alcohols derived from desoxybenzoin and 1,2-di-phenylethanol. Ring-chain tautomerism of the a-(p-hydroxyethyl-amino)-ketones. J. Amer. chem. Soc. 70, 2015 (1948). 

Oxetanes can be formed by intramolecular reaction between a carbonyl group and an alkene, and this has been used (4.74) in making analogues of thromboxane A, (one of the compounds responsible for the control of blood clotting), albeit usually as the minor product. A special case of intramolecular reaction is seen for a,p-unsaturated carboxylic acids 14.75), where the product is an oxete that is tautomeric with a p-lactone. Oxetes may also be formed by photocycloaddition of ketones or aldehydes with alkynes the oxete normally ring-opens at room temperature to give an a,p-unsaturated carbonyl compound (4.76), but at lower temperatures its spectral... 

Equilibrium and rate constants for the keto-enol tautomerization of 3-hydroxy-indoles and -pyrroles are collected in Table 32 (86TL3275). The pyrroles ketonize substantially (103-104 times) faster than their sulfur or oxygen analogues, and faster still than the benzo-fused systems, indole, benzofuran, and benzothiophene. The rate of ketonization of the hydroxy-thiophenes and -benzothiophenes in acetonitrile-water (9 1) is as follows 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[/ Jthiophene > 3-hydroxythiophene. 3-Hydroxythiophene does not ketonize readily in the above solvent system, but in 1 1 acetonitrile-water, it ketonizes 6.5 times slower than 2-hydroxythiophene (87PAC1577). 

Thus, phosphogluconate dehydratase yields 2-oxo-3-deoxyphosphogluconate as the product. When the reaction is carried out in 2HzO the 2H is incorporated with a random configuration at C-3, indicating that the enzyme catalyzes only the dehydration and that the tautomerization of the enol to the ketone is nonen-zymatic. 

Flash photolysis has provided a wealth of kinetic and thermodynamic data for tautomerization reactions. Equilibrium constants of enolization, KE, spanning a range of 30 orders of magnitude, have thereby been determined accurately as the ratio of the rate constants of enolization, kE, and of ketonization, kK. Nowadays, tautomerization constants KE can be predicted with useful... 

Magnesium bis(hexamethyldisilazide), Mg(HMDS)2, catalyses the enolization of ketones.287 On addition to propiophenone in toluene at ambient temperature, a ca 3 1 E Z mixture of enolates (103, R=SiMe3) is formed. These enolates, and an initial ketone complex, have been characterized by NMR, X-ray, IR, and UV-visible spectroscopy and computational studies. Kinetics of tautomerization have been measured, with proton transfer confirmed as rate determining ( hAd = 18.9 at 295 K). The significant temperature dependence of the primary isotope effect is indicative of tunnelling. 

Secondary (3-bromo alcohol (70) can be transformed to ketone (71) in good yield via the following radical pathway with DBPO [78]. The reaction involves the abstraction of an hydrogen atom at the a-position of the HO group, followed by p-elimination of the bromine atom, and then the tautomerization of the formed enol to the ketone (eq. 2.34). 

In the presence of an electrophile, tautomerization of a substrate with a C=0 double bond to its enol only takes place when catalyzed by either a Bronsted- or a Lewis acid. The proton-catalyzed mechanism is shown for the ketone — enol conversion B — iso-B (Figure 12.4), the carboxylic acid —> enol conversion A — E (Figure 12.6), the carboxylic acid bromide — enol conversion E —> G (Figure 12.7) and the carboxylic acid ester — enol conversion diethyl-malonate —> E (Figure 12.9). Each of these enol formations is a two-step process consisting of the protonation to a carboxonium ion and the latter s deprotonation. The mechanism of a Lewis acid-catalyzed enolization is illustrated in Figure 12.5, exemplified by the ketone —> enol conversion A —> iso-A. Again, a protonation to a carboxonium ion and the latter s deprotonation are involved the Lewis acid-complexed ketone acts as a proton source (see below). 

The enol formed by irradiation of a-disubstituted indanones and tetralones bearing at least one hydrogen in the y-position undergoes enantioselective tautomerization to ketone in the presence of catalytic amounts of optically active aminoalcohols [74]. 

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