Ketone enolate ions

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

Aldol reactions occur in many biological pathways, but are particularly important in carbohydrate metabolism, where enzymes called aldolases catalyze the addition of a ketone enolate ion to an aldehvde. Aldolases occur in all organisms and are of two types. Type 1 aldolases occur primarily in animals and higher plants type II aldolases occur primarily in fungi and bacteria. Both types catalyze the same kind of reaction, but type 1 aldolases operate place through an enamine, while type II aldolases require a metal ion (usually 7n2+) as Lewis acid and operate through an enolate ion. 

The procedure reported here is based on a reaction discovered by Bunnett and Creary, and was first employed for preparative purposes by Bunnett and Traber.3 It is attractive because of the high yield obtained, the ease of work-up, and the cleanliness of the reaction. The reaction is believed to occur by the SRN1 mechanism, which involves radical and radical anion intermediates.2,4 The SRN1 arylation of other nucleophiles, especially ketone enolate ions,5 ester enolate ions,6 picolyl anions,7 and arenethiolate ions,8 has potential application in synthesis. 

When dihalobenzenes (Cl, Br, I) react with aliphatic ketone enolate ions, disubstitution products are furnished. On the other hand, mainly monosubstitution with retention of one halogen is obtained in the photostimulated reactions of o-iodohalobenzenes (X = I, Br, Cl) with the enolate ions of aromatic ketones, such as acetophenone, propiophenone, and l-(2-naphthyl)ethanone in DMSO. These results are explained in terms of the energetics of the intramolecular ET from the ArCO-7i system to the C-X a bond in the monosubstituted radical anions proposed as intermediates [81]. For example see Sch. 13. 

The dark reaction of pinacolone enolate ion and Phi in DMSO was described167. The same reaction is stimulated by light and inhibited by radical scavengers. This system was used to study the reactivity of different ketone enolate ions with Phi. In competition experiments, the following reactivity order was determined 2-acetylcyclohexanone (unreactive) < phenylacetone (0.39) < cyclohexanone (0.67) < pinacolone (1.00) < acetone (1.09) < 2-butanone (1.10) < 3-pentanone (1.40)168. 

The reaction of aryl and hetaryl halides with ketone enolate ions can also be initiated by sodium amalgam in liquid ammonia. In these reaction conditions, neither the carbonyl group nor the aromatic moiety are reduced, as was the case in the reaction initiated with solvated electrons. Thus, the ketones below have been synthesized, mostly in good yields175. 

The photostimulated reaction of ketone enolate ions with 6-iodo-9-ethylpurine (129) in liquid ammonia leads to the substitution product 130 as a mixture of the keto and enol... 

The anion of nitromethane (31) failed to react with Phi under irradiation in DMSO, as was the case with 1-AdI. However, when the reaction was carried out in the presence of acetone (27a) or pinacolone (27b) enolate ions, l-phenyl-2-nitroethane (161) was formed as major product, together with small amounts of benzene and toluene (equation 104). No products from the coupling with the ketone enolate ions were found169... 

It has been suggested that the ketone enolate ions 27 initiate the photostimulated cycle. The coupling reaction of the phenyl radical with 31 is faster than with 27, forming a radical anion that fragments to give benzyl radicals, which are reduced to toluene or react with 31 to afford a new radical anion (161) , responsible for forming the substitution product 161 (equation 105). 

This approach was used for the synthesis of furo[3,2-/z]quinolines (277). The reaction of 5-chloro-7-iodo-8-methoxyquinoline (229) with several ketone enolate ions gave the substitution product 276 (70-80 % yield, R = Me, t-Bu, 2-furyl,/>-anisyl) which, when treated with HBr at 100 °C, quantitatively led to 277 (equation 111)326. 

The photostimulated reaction of 2-bromo-3-f-propoxypyridine (278) and ketone enolate ions in liquid ammonia afforded the substitution products 279, which gave quantitatively the furo[3,2-6]pyridines (280) (equation 173). With 2-pentanone enolate ion, 278... 

The photostimulated reaction of benzylamines with an o-iodo (bromo) substituent (281) and ketone enolate ions gave the product 282 that cyclized spontaneously to give 283 (equation 174)327. 

Another S l reaction that leads to a substitution product that cyclized in a subsequent step is the reaction of (o-iodoaryl)acetic acid derivatives with ketone enolate ions. Thus, substrate 298 reacts under irradiation with ketone enolate ions to give 299 [R = Me (75-80%), R = z-Pr (75-80%), R = t-Bu (85-90%)] (equation 183)332. The substitution products 299 are the key intermediates for the synthesis of 3-benzazepines and 3-benzoxepines332. 

The formation of the bicyclic intermediate, VII/157, (Scheme VII/31) was achieved by nucleophilic conjugate addition of tributyltinlithium to cyclohexe-none, reaction of the intermediate ketone enolate ion with a small excess of ethyl vinyl ketone and, subsequently, with a large excess of formaldehyde. The mechanism is analogous to that presented in Scheme VII/9 of Chapter VII. 1. 

More remarkable are the reactions between ketone enolate ions and arynes generated by a complex base. Products derived using the aprotic solvent system differ considerably from those involving enolate ions in ammonia. In the protic solvent the aryl anion resulting from the addition of an enolate ion to an aryne is protonated and continued reaction is thereby prevented. Such protonation does not occur in the aprotic medium further reactions occur by intramolecular addition of the aryl anion to a carbonyl group, Scheme 5. Products obtained from acyclic ketones include... 

For the formation and reaction of ketone enolate ions, see Section 8.4.3... 

The photostimulated arylation of ketone enolate ions has been shown to be of fairly wide scope, although the reaction fails with the enolate ions of acetophenone and several -dicarbonyl compounds and is impeded by steric crowding. Coupled with new, mild methods for the regeneration of the carbonyl group (see Section 4), the chemistry of azomethine ketone derivatives has taken on new dimensions. The alkylation of such derivatives has been of particular interest recently. For example, two groups of workers have shown that only yn-dianions are formed on metalation of oximes. Furthermore, the dianions are configurationally stable, allowing alkylation and aldol condensation to be effected stereo-specifically (Scheme 22). - . 

Acidity of Aldehydes and Ketones Enolate Ions CHAPTER 18... 

The presence of high concentrations of K1 has been found to enhance the quantum yield of photosubstitution of chloride by sulfo groups on irradiation in the 313-365 nm band. The yields of aryl and heteroaryl products obtained by reactions of aryl and heteroaryl halides with a ketone enolate ion in MejSO are enhanced by catalysis with ferrous ion. Photo-Sja lAr reactions of chloro substituted N-methylpyridones with phenoxide have been reported. ... 

The S y.jl mechanism can be an excellent route to isoquinoHnes rings and derivatives by reaction of o-iodobenzylamines with ketone enolate ions under irradiation.The substitution products formed in their irradiated reactions spontaneously cyclize to give a non-isolable intermediate which affords iso-quinolines by Pd/C dehydrogenation (Eq. (47.35a)) or tetrahydroisoquinohnes by reduction with NaBH4 in approximately 100% yields (Eq. (47.35b)... 

Scamehorn, R. G. and Bunnett, J. R, Photostimulated reactions of halobenzenes with ketone enolate ions in dimethyl sulfoxide solution,/. Org. Chem., 42, 1457,1977. 

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