Carboxylic acid derivatives lithium aluminum hydride

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 ... 

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

One of the more difficult partial reductions to accomplish is the conversion of a carboxylic acid derivative to an aldehyde without over-reduction to the alcohol. Aldehydes are inherently more reactive than acids or esters so the challenge is to stop the reduction at the aldehyde stage. Several approaches have been used to achieve this objective. One is to replace some of the hydrogens in a group III hydride with more bulky groups, thus modifying reactivity by steric factors. Lithium tr i - / - b u to x y a I u m i n u m hydride is an example of this approach.42 Sodium tri-t-butoxyaluminum hydride can also be used to reduce acyl chlorides to aldehydes without over-reduction to the alcohol.43 The excellent solubility of sodium bis(2-methoxyethoxy)aluminum hydride makes it a useful reagent for selective... 

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. ... 

Lithium aluminum hydride usually reduces carbonyl groups without affecting carbon-carbon double bonds. It is, in addition, a good reducing agent for carbonyl groups of carboxylic acids, esters, and other acid derivatives, as will be described in Chapter 18. 

Metal hydrides, such as lithium aluminum hydride, also can be used to reduce derivatives of carboxylic acids (such as amides and nitriles see Table 16-6) to aldehydes. An example follows ... 

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). 

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... 

Alcohols are at a fairly low oxidation level compared to other oxygen-containing functional groups and consequently are readily prepared by reduction. Large numbers of reductive methods have been reported for the preparation of alcohols. Carboxylic acids and esters react vigorously with lithium aluminum hydride (LAH) to produce primary alcohols. Carboxylic acids, but not esters, are also reduced easily by borane, which is die only reducing agent diat reacts faster widi carboxylic acids dian widi esters or odier acid derivatives. 

Carboxylic acids, acid halides, esters, and amides are easily reduced by strong reducing agents, such as lithium aluminum hydride (LiAlH4). The carboxylic acids, acid halides, and esters are reduced to alcohols, while the amide derivative is reduced to an amine. 

Like other carboxylic acid derivatives, amides can be reduced by lithium aluminum hydride. The product of this reduction is an amine. 

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. 

As illustrated in Figure 19.7, the reduction of an acid derivative, such as an ester, with lithium aluminum hydride produces an aldehyde as an intermediate. Reduction of the aldehyde gives a primary alcohol as the ultimate product. It would be useful to be able to stop such a reduction at the aldehyde stage so that an aldehyde could be prepared directly from a carboxylic acid derivative. 

Carboxylic acids and their derivatives can be reduced to alcohols, aldehydes, and amines. Because they are relatively difficult to reduce, acid derivatives generally require a strong reducing agent such as lithium aluminum hydride (LiAlH4). 

Lithium aluminum hydride reduction of pleiocarpinilam (CXLVI-D) and kopsinilam (CXLII-D) gave, respectively, N-methylkopsinyl alcohol (CXLVI-F) and kopsinyl alcohol (CXLII-F) and thus there was every likelihood that these alkaloids were the E-ring lactams derived from pleiocarpinine and kopsinine, respectively. The correctness of this view was shown by synthesis. Pleiocarpinilam was obtained by the direct permanganate oxidation of pleiocarpinine (CXLVI-A) in acetone, while kopsinilam could be prepared, in a similar manner, from N-acetyl-kopsinine (CXLIV-A) followed by acid hydrolysis of the acetyl group, or from pleiocarpine lactam A (CXLV-D) by hydrolysis and simultaneous decarboxylation of the X-carbomethoxyl followed by reesterification of the C-3 carboxylic acid. 

The usual range of carboxylic acid derivatives can be prepared and interconverted. Both carboxylic acid and ester functions are capable of reduction by lithium aluminum hydride to alcohols, or by controlled potential reduction to aldehydes. Attempts to form the anhydride from imidazole-4,5-dicarboxylic acid by heating with acetic anhydride failed. Instead, compound (199) is formed. This product forms the monoester (200) when heated with methanol and the hydrazide (201) when treated similarly with hydrazine (Scheme 107) (75S162). The corresponding l-methyl-4,5-dicarboxylic acid loses the 4-carboxyl group when heated with acetic anhydride, but in boiling aniline it is transformed into the 1-methyl-4-carboxanilide (79H(12)186). 

The parent system (99) has been obtained by lithium aluminum hydride reduction of perhydro-imidazo[l,5-a]pyridine-l,3-dione (from ethyl 2-piperidine carboxylate and cyanic acid) and by ring closure of 2-aminomethylpiperidine with formaldehyde. 3-Substituted derivatives have also been described. The 3-phenyl- and 3-/-butyl derivatives (but not the propyl and benzyl derivatives) show ring-chain tautomerism (70JHC355). 

Preparation of Derivatives. Enoate derivatives are prepared from the corresponding chiral alcohol by treatment with acry-loyl chloride in the presence of Triethylamine and catalytic 4-Dimethylaminopyridine or the appropriate carboxylic acid chloride and Silveril) Cyanide. Alkynyl ethers are readily available from the potassium alkoxide by treating with Trichloroethylene, in situ dechlorination with n-Butyllithium, and electrophilic trapping. Trapping the intermediate anion with a proton source or lodomethane followed by Lindlar reduction of the alkynyl ether affords the corresponding vinyl and l-(Z)-propenyl ether, respectively, while reduction of the alkynyl ether with Lithium Aluminum Hydride affords the l-( )-propenyl ether. 

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