Lithium aluminum hydride, reaction with carboxylic acids

Lithium aluminum hydride, reaction with aldehydes, 610 reaction with carboxylic acids. 611-612... 

An important example of this type of reaction is the formation of esters, which was discussed previously in connection with the reactions of alcohols in Section 15-4D. Similar addition-elimination mechanisms occur in many reactions at the carbonyl groups of acid derivatives. A less obvious example of addition to carboxyl groups involves hydride ion (H 0) and takes place in lithium aluminum hydride reduction of carboxylic acids (Sections 16-4E and 18-3C). 

On the basis of what we have already learned about the reactions of lithium aluminum hydride with aldehydes and ketones (Chapter 18) and the mechanisms presented so far in this chapter, we can readily predict the product that results when hydride reacts with a carboxylic acid derivative. Consider, for example, the reaction of ethyl benzoate with lithium aluminum hydride. As with all of the reactions in this chapter, this reaction begins with attack of the nucleophile, hydride ion, at the carbon of the carbonyl group, displacing the pi electrons onto the oxygen (see Figure 19.7). Next, these electrons help displace ethoxide from the tetrahedral intermediate. The product of this step is an aldehyde. But recall from Chapter 18 that aldehydes also react with lithium aluminum hydride. Therefore, the product, after workup with acid, is a primary alcohol. 

A setup similar to the preceding one is used in this experiment except that provision should be made for heating the reaction vessel (steam bath, oil bath, or mantle). Lithium aluminum hydride (10 g, 0.26 mole) is dissolved in 200 ml of dry -butyl ether and heated with stirring to 100°. A solution of 9.1 g (0.05 mole) of ra j-9-decalin-carboxylic acid (Chapter 16, Section I) in 100 ml of dry -butyl ether is added dropwise over about 30 minutes. The stirring and heating are continued for 4 days, after which the mixture is cooled and water is slowly added to decompose excess hydride. Dilute hydrochloric acid is added to dissolve the salts, and the ether layer is separated, washed with bicarbonate solution then water, and dried. The solvent is removed by distillation, and the residue is recrystallized from aqueous ethanol, mp 77-78°, yield 80-95 %. 

Diclofenac Diclofenac, 2-[(2,6-dichlorophenyl)-amino]-phenylacetic acid (3.2.42), is synthesized from 2-chIorobenzoic acid and 2,6-dichloroaniline. The reaction of these in the presence of sodium hydroxide and copper gives iV-(2,6-dichlorophenyl)anthranyIic acid (3.2.38), the carboxylic group of which undergoes reduction by lithium aluminum hydride. The resulting 2-[(2,6-dicholorphenyl)-amino]-benzyl alcohol (3.2.39) undergoes further chlorination by thionyl chloride into 2-[(2,6-dichlorophenyl)-amino]-ben-zylchloride (3.2.40) and further, upon reaction with sodium cyanide converts into... 

A carboxylic acid group may be introduced into the 2-position of dibenzofuran by Friedel-Crafts reaction with 2,2-dichloro-l,3-benzodioxole (catechol dichloromethylene ether) and hydrolysis of the resultant ester. Similarly, reaction with methylphenylcarbamoyl chloride produces the 2-(N-methyl-yV-phenylcarboxamide) or the 2,8-disubstituted derivative under more stringent conditions. Controlled reduction of these amides with lithium aluminum hydride supplies the corresponding aldehydes. ... 

Hydroxjrmethylbenzof Jthiophenes are most conveniently prepared by reduction with lithium aluminum hydride of the corresponding carboxylic acid78,100 S37 485,486,521,528,540 or ester.77,87,336,337, 52i, 526 Lesg frequently, they are prepared by reduction of the corresponding aldehyde 100,487 or acid chloride,618 with sodium boro-hydride, or, in the case of 2-hydroxymethylbenzo[6]thiophenes, by reaction of the 2-lithium derivative with formaldehyde.90,628 3-Hydroxymethylbenzo[6]thiophene has been prepared from the corresponding aldehyde by means of a crossed Cannizzaro reaction... 

Esters, like carboxylic acids, are normally reduced with lithium aluminum hydride. In these reactions, two alcohols are formed. An example is the reduction of methyl benzoate to benzyl alcohol and methanol. 

In summary, reductions of carboxylic acid derivatives to primary alcohols are usually accomplished by reaction of esters or acids with lithium aluminum hydride. The following equations provide several examples ... 

Reactions of Nitriles Nitriles undergo acidic or basic hydrolysis to amides, which may be further hydrolyzed to carboxylic acids. Reduction of a nitrile by lithium aluminum hydride gives a primary amine, and the reaction with a Grignard reagent gives an imine that hydrolyzes to a ketone. 

When lithium aluminum hydride was applied, besides reduction of the C-4—N-5 double bond, the ester group was converted to a hydroxymethyl group. S By reaction with dry formic acid under reflux conditions, the pyrroloquinazoline-2-carboxylates 63 yielded the 6-formyl-5,6-dihydro derivatives 65. S The formyl group was transformed into a methyl group by diborane. S The NH group of the dihydro derivatives 64 was acylated by ethyl chloroformate. Reaction with ethyl acrylate and acrylonitrile involved a Michael addition.The ethoxycarbonyl moiety in position 2 and on the side chain in position 6 was hydrolyzed to a carboxylic group by the action of potassium hydroxide in aqueous methanol and was reduced to a hydroxymethyl group by lithium aluminum hydride in ether. 

Dihydro-1,4-benzothiazines are generally more reactive, and direct N-alkylation has been reported, but this reaction is not always straightforward.21 Funke et al. could not alkylate 2-phenyldihydro-l,4-benzothiazine with co-chloramines, even under forcing conditions.90 However, later work showed that this reaction was possible in toluene solution,37 and other workers have also reported direct alkylations.143 The l,4-benzothiazin-3-ones are, however, more easily alkylated, and reduction of the N-alkyl derivatives of these compounds, usually with lithium aluminum hydride, affords the corresponding N-alkyldihydro-1,4-benzothiazines.52,56 70 90,154 These products can also be prepared in one step from the corresponding 1,4-benzothiazines, e.g., Ill - 112, presumably via intermediate dihydro-1,4-benzothiazines, by sodium borohydride in the presence of a carboxylic acid. Boron derivatives, such as Na[(RCOO)3BH] and Na[(RCOO)4B] are suggested as the species responsible for N—C bond formation.155... 

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