Reaction with enols or enolates as intermediates

You may think it a crazy idea to want to racemize an amino acid. Supposing, however, that you are preparing pure (S)-amino acid by resolution. Half your material ends up as the wrong (K)-enan-tiomer and you don t want just to throw it away. If you racemize it you can put it back into the next resolution and convert half of it into the (S)-acid. Then you can racemize what remains and so on. 

Some compounds may be racemized inside the human body. Bacterial cell walls are built partly from unnatural (K)-amino-acids and we can t digest these. Instead, we use enzymes designed to racemize them. These also work by enolization, though it is the imine-enamine type from p. 528. 

We discussed resolution, the separation of enantiomers by the formation of dfaster ofeomers with en optically active resolving agent, in Chapter 16. 

We have already seen that exchange of hydrogen for deuterium, movement of double bonds into conjugation, and racemization can occur with enols or enolates as intermediates. These are chemical reactions of a sort, but it is time to look at some reactions that make significant changes to the carbonyl compound. 

Carbonyl compounds can be halogenated in the a position by halogens (such as bromine, Br2) in acidic or basic solutions. We shall look at the acid-catalysed reaction first because it is simpler. Ketones can usually be cleanly brominated in acetic acid as solvent. 

The first step is acid-catalysed enolization and the electrophilic bromine molecule then attacks the nucleophilic carbon of the enol. The arrows show why this particular carbon is the one attacked. 

Notice that the acid catalyst is regenerated at the end of the reaction. The reaction need not be carried out in an acidic solvent, or even with a protic acid at all. Lewis acids make excellent catalysts for the bromination of ketones. This example with an unsymmetrical ketone gives 100% yield of the bromoketone with catalytic AICI3 in ether as solvent, 

Interactive mechanism for acid-catalysed ketone bromlnation 

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Heterocycles.—The phosphonium salt (59) is an effective three-carbon synthon, as demonstrated by its reaction with enolates of /9-keto-esters (Scheme 20) to give cyclopentenyl sulphides via an intramolecular Wittig reaction.63 Ylides are also intermediates in the synthesis of dihydrofurans (60) from the cyclopropylphos-phonium salt (61) and sodium carboxylates (Scheme 21).64 Cumulated ylides are very useful for the synthesis of heterocyclic compounds, e.g. (62), from molecules which contain both an acidic Y—H bond and a carbonyl or nitroso-function, as shown in Scheme 22.65... 

Photostimulated, S r k 1 reactions of carbanion nucleophiles in DMSO have been used to advantage in C—C bond formation (Scheme 1).25-27 Thus, good yields of substitution products have been obtained from neopentyl iodide on reaction with enolates of acetophenone and anthrone, but not with the conjugate base of acetone or nitromethane (unless used in conjunction, whereby the former acts as an entrainment agent).25 1,3-Diiodoadamantane forms an intermediate 1-iodo mono substitution product on reaction with potassium enolates of acetophenone and pinacolone and with the anion of nitromethane subsequent fragmentation of the intermediate gives derivatives of 7-methylidenebicyclo[3.3.1]nonene. Reactions of 1,3-dibromo- and 1-bromo-3-chloro-adamantane are less effective.26... 

In both schemes, the upper pathway represents the formation of an unstable intermediate that is then trapped by reaction with ATP. By contrast, the lower pathways represent activation of a carbonyl group by ATP, followed by loss of a proton (to form enol pyruvate eq. 9) or reaction with ammonia (to yield an intermediate for the formation of CTP eq. 10). ATP has long been known to drive metabolic processes if it phosphorylates carbonyl groups, it will prove to serve a catalytic role as well. 

Besides its use as a mechanistic probe, deuteriation of anions under kinetically controlled conditions is a potentially promising way to access deuteriated molecules in a regio- and stereo- controlled manner, in opposition to the thermodynamic equilibration in the presence of an excess of deuterium donor. Thus, treatment of the lithium anion of 2-methyltetralone (p E = 7.31, pfsfEa = 10.8, pKkr = 18.1 in water)335, by one equivalent of a solution of deuterium chloride in deuterium oxide, generates the intermediate O-deuteriated enol whose reaction with water or with an excess of deuterium chloride in deuterium oxide conducts to, respectively, the tetralone or the deuteriated tetralone (Scheme 69)336. 

Ester enolates react with imines to give, as intermediates, metallo-P-amino esters (Scheme 18). Depending on the particular substitution pattern and reaction conditions, these species either undergo spontaneous cyclization or can be isolated as their proto forms and then cyclized, usually according to Breckpot procedure [67]. 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

As noted previously, conjugate addition of a nucleophile to the j3 carbon of an cr,/3-unsaturated aldehyde or ketone leads to an enolate ion intermediate, which is protonated on the a carbon to give the saturated product (Figure 19.16). The net effect is addition of the nucleophile to the C=C bond, with the carbonyl group itself unchanged. In fact, of course, the carbonyl group is crucial to the success of the reaction. The C=C bond would not be activated for addition, and no reaction would occur, without the carbonyl group. 

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