Carboxylic acids, dianions reactions

G. Reactions of Carboxylic Acid Dianions with Electrophiles. 503... 

Fig. 13.10. Formation of carboxylate enolates ("carboxylic acid dianions") by reaction of carboxylic acid salts with strong bases.

Carboxylic acid dianions may be readily alkylated at the more reactive a-site to produce a-alkylated acids upon acidic work-up (equation 69)504,505. This reaction has been reviewed by Petragnani and Yonashiro506. The reaction is commonly followed by decarboxylation, which yields a ketone. 

Carboxylic acid dianions have also been alkylated by reaction with aziridines to give novel y-amino substituted acids in good yields508. Methoxybenzoic acids have also been alkylated in a reductive process by reaction with lithium in ammonia followed by treatment with an alkyl halide. The product formed in this one-pot reaction is an alkylated cyclohexa-2,5-diene carboxylic acid507. 

LDA prepared in tiis way is recommended for regiosclectivc preparation of the less thermodynamically stiible enol ether and for generation of dianions of carboxylic acids. The reaction of dianions prepared with this base with aldehydes provides a stereoselective route to 7,8-unsaturatpd 3-hydroxy carboxylic acids (equation II). 

Unsymmetrically substituted succinic acid derivatives can be prepared by reaction of carboxylic acid dianions with lithium a-iodocarboxylates (40-70% yield). 

B-alkyl-9-BBN derivatives (p. 1077). Since only the 9-alkyl group migrates, this method permits the conversion in high yield of an alkene to a primary alcohol or aldehyde containing one more carbon." When B-alkyl-9-BBN derivatives are treated with CO and lithium tri-ferf-butoxyaluminum hydride," other functional groups (e.g., CN and ester) can be present in the alkyl group without being reduced." Boranes can be directly converted to carboxylic acids by reaction with the dianion of phenoxyacetic acid." " ... 

A.V. The Noyori Open-Chain Model. In the Mukaiyama reaction, the Zimmerman-Traxler and Evans models are not satisfactory for predicting diastereoselectivity. Several open (nonchelated) transition states have been considered as useful models. The condensation reaction of carboxylic acid dianions with aldehydes indicated that anti selectivity increased with increasing dissociation of the gegenion (the cation, M+),224 When analyzing an aldol condensation that does not possess the bridging cation required for the Zimmerman-Traxler model, an aldehyde and enolate adapt an eclipsed orientation as they approach. Noyori reported syn selectivity for the reaction of a mixture of (Z)-silyl enol ether 389 and ( )-silyl enol ether 390 with benzaldehyde in the presence of the cationic tris-(diethylamino) sulfonium (TAS).225 xhis reaction is clearly a variation of the Mukaiyama reaction, which does not usually proceed with good diastereoselectivity... 

Diisopropylamine has a pK of 36, which makes lithium diisopropylamide (LDA) a strong enough base to convert acetic acid to its dianion. Other carboxylic acids behave similarly to give dianions that undergo typical carbanion reactions. Alkylation of carboxylic acid dianions provide a useful alternative to the malonic ester synthesis. 

A completely different approach to Y-keto-esters proceeds via Michael additions of carboxylic acid dianions to an a-anilino-acrylonitrile followed by alkylation of the resulting anion and finally acidic hydrolysis (Scheme 13). Overall yields are in the range 47-79% the method is also useful in the synthesis of r-keto-amides. An alternative anion-based route to y-keto-esters utilizes the homoenolate (166) as the interroediate which undergoes smooth acylation by a wide variety of acid chlorides.The homoenolate is obtained from the corresponding iodoester using Zn-Cu couple, and it seems likely that the method can be used to prepare more highly substituted keto-esters although such reactions have not yet been reported. 

Some interesting results have come out of a study of the variations in stereochemistry erythrojthreo ratio) of jS-hydroxy-acids produced by condensations between carboxylic acid dianions and aldehydes. The reactions seem not to be controlled by complexation between the metal counterions and the incoming aldehyde but rather by HOMO(dianion)-LUMO(aldehyde) interactions with changes in the metal counterion affecting the HOMO(dianion) level. ... 

Synthesis of Keto-acids.—a-Keto-acids are obtained in moderate to good yields by the reaction of carboxylic acid dianions with conjugated nitro-olefins at — 100°C, followed by acidic work-up. Another route to these compounds involves the C-silylation of butyrolactone enolate, followed by a Peterson-type olefination to give the vinylic ether (20), which is then oxidized to the y-keto-acid (Scheme 12). Eight examples, with yields of between 50 and 83%, along with one failure are reported. 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

Because hydride ion is a base as well as a nucleophile, the actual nucleophilic acyl substitution step takes place on the carboxylate ion rather than on the free carboxylic acid and gives a high-energy dianion intermediate. In this intermediate, the two oxygens are undoubtedly complexed to a Lewis acidic aluminum species. Thus, the reaction is relatively difficult, and acid reductions require higher temperatures and extended reaction times. 

A completely different dipolar cycloaddition model has been proposed39 in order to rationalize the stereochemical outcome of the addition of doubly deprotonated carboxylic acids to aldehydes, which is known as the Ivanov reaction. In the irreversible reaction of phenylacetic acid with 2,2-dimethylpropanal, metal chelation is completely unfavorable. Thus simple diastereoselectivity in favor of u f/-adducts is extremely low when chelating cations, e.g., Zn2 + or Mg- +, are used. Amazingly, the most naked dianions provide the highest anti/syn ratios as indicated by the results obtained with the potassium salt in the presence of a crown ether. 

The lithium dianions of carboxylic acids add to 1-nitrocyclohexene to give, after acid hydrolysis, a mixture of diastereomeric y-oxo acids. The diastereoselectivity of these reactions, however, was not reported7. 

These can be prepared in good yield by reaction of either the mono-anions of trimethylsilyl carboxylates or, preferably, the dianions of carboxylic acids with TMSCI. Acetic and propionic acids give mixtures of O- and C-silylated products. 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0")2 ] by treatment with a strong base such as LDA. The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCH2COOH and RR"CHCOOH. This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 458),... 

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