Carboxylic acids dianions alkylation

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. 

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. 

A variation on a literature procedure draws attention to a useful method for the synthesis of tetrolic acid. Copper dienolates derived from a,jS-unsatur-ated acids undergo y-alkylation with a regioselectivity of 91%. A full paper has appeared from Mulzer and his co workers on the control of 1,2-/1,4-regioselectivity in the additions of carboxylic acid dianions to a,jS-unsaturated carbonyl compounds. The addition of phenyl acetate dianion (23) (Scheme 20) to a,/3-un aturated aldehydes leads to the f/ireo-unsaturated /S-hydroxy-carboxylic acid (24) the threo and erythro ratio of 5 examples was >9 1. 

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). 

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),... 

We have previously seen (10-106) that dianions of carboxylic acids can be alkylated in the a position. These ions can also be acylated on treatment with a carboxylic... 

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... 

Formally related reactions are observed when anthracene [210] or arylole-fines [211-213] are reduced in the presence of carboxylic acid derivatives such as anhydrides, esters, amides, or nitriles. Under these conditions, mono- or diacylated compounds are obtained. It is interesting to note that the yield of acylated products largely depends on the counterion of the reduced hydrocarbon species. It is especially high when lithium is used, which is supposed to prevent hydrodimerization of the carboxylic acid by ion-pair formation. In contrast to alkylation, acylation is assumed to prefer an Sn2 mechanism. However, it is not clear if the radical anion or the dianion are the reactive species. The addition of nitriles is usually followed by hydrolysis of the resulting ketimines [211-213]. 

Treating the dianion of a carboxylic acid with an alkyl nitrate leads to an a-nitrocarboxylic acid which readily undergoes decarboxylation to the corresponding nitroalkane. This method is particularly useful for the synthesis of arylnitromethanes containing electron-donating groups. ... 

We have previously seen (0-96) that dianions of carboxylic acids can be alkylated in the a position. These ions can also be acylated on treatment with a carboxylic ester1705 to give salts of p-keto acids. As in 0-96, the carboxylic acid can be of the form RCH2COOH or RR"CHCOOH. Since p-keto acids are so easily converted to ketones (2-40), this is also a method for the preparation of ketones R COCHiR and R COCHRR", where R can be primary, secondary, or tertiary alkyl, or aryl. If the ester is ethyl formate, an a-formyl carboxylate salt (R = H) is formed, which on acidification spontaneously de-carboxylates into an aldehyde.1706 This is a method, therefore, for achieving the conversion RCH2COOH — RCH2CHO, and as such is an alternative to the reduction methods discussed in 0-83. When the carboxylic acid is of the form RR CHCOOH. better yields are obtained by acylating with acyl halides rather than esters.1707... 

In this chemistry, pivotal final steps in the sequence are a dianion alkylation of the side-chain carboxylic acid, leading to erythro products only. Second, ozonolysis of this product is followed by silyl migration, hydrolysis to a hydroperoxyaldehyde, and, finally, after acidification, cyclization to product. 

A complementary access to alkoxy- and aminocarbene complexes ( Semmelhack-Hegedus route ) involves the addition of the pentacarbonylchromate dianion 18 (obtained from the reduction of hexacarbonylchromium with C8K) to carboxylic acid chlorides and amides [27] (Scheme 10). While alkylation of acyl chromate 19 leads to alkoxycarbene complexes 12, addition of chromate dianion 18 to carboxylic amides generates the tetrahedral intermediates 20, which are deoxygenated by trimethylsilyl chloride to give amino carbene complexes 14. 

Intramolecular acylation of alkylsilanes. Cyclopentanones can be prepared by ring closure of 5-(trimethylsilyl)alkanoyl chlorides mediated by AlCl,. The starting materials are readily available from alkylation of the dianion of a carboxylic acid with a 3-(trimethylsilyl)alkyl bromide or iodide (equation 1). 

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." " ... 

The dilithio dianions of carboxylic acids can be prepared in THF-HMPA solution using LDA as the base. These dianions are more stable than a-ester anions but can still be readily C-alkylated. " ... 

Although carboxylic acids and their derivatives are somewhat weaker carbon acids than aldehydes and ketones, it is generally possible to quantitatively convert them to the corresponding metal enolates with dialkylamide bases, the most popular of which is LDA. - - Thus, monoanions of saturated esters, lactones, nitriles, /VA -dialkylamides and V-alkyllactams and dianions of carboxylic acids and V-unsub-stituted amides and lactams are easily prepared in aprotic solvents such as THF and C-alkylated with a variety of simple and functionalized SN2-reactive alkylating agents at room temperature or below. When more-hindered systems are involved, the basicity of the metal dialkylamide and the reactivity of the metal enolate can be enhanced by the addition of HMPA. Of course, many of the indirect methods used for the generation of aldehyde and ketone enolates are also applicable to the preparation of enolates of carboxylic acid derivatives (Section 1.1.2.1). O-Alkylations or dialkylations at carbon generally are of minimal importance with metal enolates of carboxylic acid derivatives. 

Nearly all common mono- and disubstituted acetic acids, including several functionally substituted examples, have been reported to metalate. Unsaturated as well as saturated alicyclic carboxylic acids form dianions, but cyclopropane carboxylic acid is exceptional. Low yields of alkylated products are produced,14,20 suggesting incomplete dianion formation. 

Dianions derived from cc, P- or P, y-unsaturated carboxylic acids alkylate at the C carbon if the dianions are associated with alkali metal cations.22 24 However, high proportions of y-substitution are observed when Cu( i) dianions are employed.22 The preparation of dl-lanceol illustrates synthetic use of y-alkylation,22 and the preparation... 

Epoxides can serve as competent electrophiles in the alkylation of a variety of carbanions, as illustrated by the ring opening of cyclohexene oxide (64) with the dianion of phenylacetic acid (77) to produce the y-hydroxy carboxylic acid 78. In this protocol, the dianion is generated using K-butyllithium and a substoichiometric quantity of a secondary amine lithium chloride is also used as a Lewis acid additive to activate the secondary epoxide toward nucleophilic addition. Primary epoxides undergo addition without the use of catalyst—in these cases, the nucleophile attacks at the less substituted position <04EJOC2160>. 

---