Enolate anions, dianions

Under the conditions of the Birch reduction, IV-Boc amides such as 60 can be reductively alkylated in high yields, presumably via a dianion intermediate which is protonated by ammonia at C-5 leaving an enolate anion at C-2 <96JOC7664>. Quenching the reaction with alkyl halides or ammonium chloride then affords the 3-pyrrolines 61. 

The direct a-alkylation of monoketones normally employs reaction of an alkyl halide or sulfonate with the enolate anion produced using a strong base. This method can be satisfactorily used with symmetrical ketones, which are to be dialkylated with a dihalide, and with intramolecular cyclization reactions, where the formation of five- and six-membered rings is often favored over the formation of three-, four-, seven-, and eight-membered rings (M. Mous-seron, 1937 W.S. Johnson, 1963). Regioselective alkylation of dianions according to Hauser s rule (see p. 9f.) is usually also a satisfactory procedure (F.W. Sum, 1979). 

Alkynolate anions.2 Treatment of the enolate anion 1 of a-chloroacetophenone with t-butyllithium (1.5-2.1 equiv.)3 in THF involves deprotonation to the dianion a followed by loss of Cl" and migration of the group on carbon to give the alkynolate anion b. The rearrangement was established by use of 3C. The anion b reacts with benzaldehyde to form the /Mactone c, which can be isolated as such or as the product 2 of hydrolysis. Quenching b with methanol affords the ester C6H5CH2COOCH3 (57% yield). 

The mechanism for this reaction is slightly different from that presented previously for the reduction of benzene. First an electron is added to the pi antibonding MO to produce a radical anion. Because there is no alcohol to protonate this anion, a second electron is then added to produce a dianion. The dianion is a strong enough base to remove a proton from the ammonia solvent, producing an enolate anion. The enolate anion is stable to the reaction conditions until acid is added to work up the reaction. 

The reaction under these conditions is sometimes called the Knoevenagel reaction after its nine-leenth century inventor, and presumably uses the enolate anion of the monocarboxylate of the malonic acid. Though this enolate is dianion, its extensive delocalization and the intramolecular hydrogen bond make it really quite stable. 

Looking back on the history of ketone dianion chemistry, one soon notices that dianion species, derived from / -keto esters, have been in continuous steady use in organic synthesis3,4, as shown in Scheme 2. Thus, ethyl acetoacetate can be converted to the corresponding ketone o a -chainon via consecutive proton abstraction reactions. The resulting dienolate anion reacts with a variety of alkyl halides to give products, resulting from exclusive attack at the terminal enolate anions. 

Treating succinic anhydrides (64) with triethylamine, zinc chloride and trimethylchlorosilane in acetonitrile gives 2,5-bis(trimethylsiloxy)furans (65). ° The relative ease of silylation in these cases demonstrates one of the differences between enol silyl ether chemistry and classical enolate anion chemistry. It would have been quite difficult to generate the dianion of succinic anhydride. 

For lithium enolate anions, the tendency is for the enolate to occupy the concave face of the transition structure cf. Figure 6.4d and 6.5c) and therefore to prefer transition structures such as those illustrated in Figure 6.6b and c. Table 6.2 lists several examples of simple acyclic diastereoselection, which show a tendency for E -> syn and Z —> anti selectivity, in contrast to the tendency observed for hydrocarbon substituted carbanions (Table 6.1). Entries 1 and 2 involve dianions of crotyloxy acetates, and show E -> syn and Z —> anti selectivity. A more complex example involving extension of a steroid side chain (similar to Scheme 6.6a), is 100% anti selective from an -alkene, however [53]. 

A cyclic transition state model, that differs from the Zimmerman-Traxler and the related cyclic models inasmuch as it does not incorporate the metal in a chelate, has been proposed by Mulzer and coworkers [78] It has been developed as a rationale for the observation that, in the aldol addition of the dianion of phenylacetic acid 152, the high ti-selectivity is reached with naked enolate anions (e.g., with the additive 18-crown-6). Thus, it was postulated that the approach of the enolate to the aldehyde is dominated by an interaction of the enolate HOMO and the n orbital of the aldehyde that functions as the LUMO (Scheme 4.31), the phenyl substituents of the enolate (phenyl) and the residue R of the aldehyde being oriented in anti position at the forming carbon bond, so that the steric repulsion in the transition state 153 is minimized. Mulzer s frontier molecular orbital-inspired approach reminds of a 1,3-dipolar cycloaddition. However, the corresponding cycloadduct 154 does not form, because of the weakness of the oxygen-oxygen bond. Instead, the doubly metallated aldol adduct 155 results. Anh and coworkers also emphasized the frontier orbital interactions as being essential for the stereochemical outcome of the aldol reaction [79]. 

Carboxylic acids can be directly alkylated by conversion to dianions with two equivalents of LDA. The dianions are alkylated at the a-carbon, as would be expected, because the enolate carbon is a more strongly nucleophilic than the carboxylate anion.76... 

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