Carboxylic acids reductive amination

The nitro group must be reduced to an amino group and cyclized onto the ketone or the carboxylic acid. Reductive amination (pp. 234-7 in the textbook) allows the amine to cyclize onto the more electrophilic ketone. 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

This lactamization process can be promoted by enzymes such as pancreatic porcine lipase. Reduction of co-azido carboxylic acids leads to macrocyclic lactams. Although treatment of carboxylic acids with amines does not directly give amides, the reaction can be made to proceed in good yield at room temperature or... 

Aldehydes themselves are of little commercial interest, but they open a way to alcohols via hydrogenation, to carboxylic acids via oxidation, and to amines via reductive amination. Aldolization is the starting point for branched alcohols, carboxylic acids, and amines with a double carbon number. As an example of co-aldolization, the route to polyols is shown. All... 

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. 

Cleavage of p-nitrobenzyl group. Protection of carboxylic acids and amines as the esters and carbamates can take advantage of the selective reduction-induced fragmentation by zinc dust, as C=C bonds, S-N bonds, benzyloxycarbonyl, and diphenylmethyl groups are not affected during the operation. 

The partial hydrolysis of 4a with methanolic potassium hydroxide followed by selective carboxylic acid reduction with excess borane and treatment of the resulting monoalcohol with methanesulfonyl chloride affords methyl 4-0-methanesulfonyl-2,3-0-isopropylidene-L-threonate (43). Facile displacement of the mesylate with azide followed by ester hydrolysis and catalytic reduction to an amine provides 4-amino-4-deoxy-2,3-0-isopropylidene-L-threonic acid (44). Mild acidic deprotection and ion-exchange desalting of 44 yields (2i ,3 S)-4-amino-4-deoxy-L-threonic acid (45), which has been utilized for the preparation of anthopleurine 46, the alarm pheromone of the sea anemone Anthopleura elegantissima [4] (Scheme 11). 

Reduction of aldehydes and ketones allylic alcohols from a, 3-unsaturated aldehydes and ketones alcohols from carboxylic acid chlorides amines from aliphatic azides.21 ... 

Aldehydes and ketones are converted to amines by a handful of methods. The most common is reductive amination. When a keto-acid or keto-ester molecule is utilized and the carbonyl is not in conjugation, reductive amination leads to an amino acid or an amino-ester. When the carbonyl of an aldehyde or ketone is P- to the carboxyl moiety, reductive amination is unnecessary for preparing amino acids and alkenyl amino acids are possible (specifically, 3-aminopropenoic acid derivatives). There are several methods that can be applied to keto-acid derivatives, largely dependent on whether the aldehyde or ketone carbonyl is in or out of conjugation with the carboxyl moiety. The first part of this section will focus on reductive amination procedures, and the latter part of the section will focus on p-keto acids and esters. A few other specialized methods for converting aldehydes and ketones to amino acids will be mentioned at the end of this section. l.l.C.1. Reductive Amination... 

The less hindered f/ans-olefins may be obtained by reduction with lithium or sodium metal in liquid ammonia or amine solvents (Birch reduction). This reagent, however, attacks most polar functional groups (except for carboxylic acids R.E.A. Dear, 1963 J. Fried, 1968), and their protection is necessary (see section 2.6). 

Converting aldehydes and ketones to cyanohydrins is of synthetic value for two reasons (1) a new carbon-carbon bond is formed and (2) the cyano group in the prod uct can be converted to a carboxylic acid function (CO2H) by hydrolysis (to be discussed in Section 19 12) or to an amine of the type CH2NH2 by reduction (to be discussed m Section 22 9)... 

The zwitterion (6) can react with protic solvents to produce a variety of products. Reaction with water yields a transient hydroperoxy alcohol (10) that can dehydrate to a carboxyUc acid or spHt out H2O2 to form a carbonyl compound (aldehyde or ketone, R2CO). In alcohoHc media, the product is an isolable hydroperoxy ether (11) that can be hydrolyzed or reduced (with (CH O) or (CH2)2S) to a carbonyl compound. Reductive amination of (11) over Raney nickel produces amides and amines (64). Reaction of the zwitterion with a carboxyUc acid to form a hydroperoxy ester (12) is commercially important because it can be oxidized to other acids, RCOOH and R COOH. Reaction of zwitterion with HCN produces a-hydroxy nitriles that can be hydrolyzed to a-hydroxy carboxyUc acids. Carboxylates are obtained with H2O2/OH (65). The zwitterion can be reduced during the course of the reaction by tetracyanoethylene to produce its epoxide (66). 

Reduction of Carboxylic Acids to Alcohols. In addition to the nonsupported catalysts mentioned for the hydrogenation of amides to amines, mthenium and rhenium on alumina can be used to reduce carboxyHc acids to alcohols. The conditions for this reduction are somewhat more severe than for most other hydrogenation reactions and require higher temperatures, >150° C, and pressures, >5 MPa (725 psi) (55). Various solvents can be used including water. 

Among the most useful reactions of nitriles are hydrolysis to yield first an amide and then a carboxylic acid plus ammonia, reduction to yield an amine, and Grignard reaction to yield a ketone (Figure 20.3). 

Conversion of Amides into Amines Reduction Like other carboxylic acid derivatives, amides can be reduced by LiAlH.4. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction reaction is thus the conversion of the amide carbonyl group into a methylene group (C=0 —> CTbV This kind of reaction is specific for amides and does not occur with other carboxylic acid derivatives. 

The most common reactions of carboxylic acid derivatives are substitution by water (hydrolysis) to yield an acid, by an alcohol (alcoholysis) to yield an ester, by an amine (aminolysis) to yield an amide, by hydride ion to yield an alcohol (reduction), and by an organometallic reagent to yield an alcohol (Grignard reaction). 

We ve already seen in Sections 20.7 and 21.7 how amines can be prepared by reduction of nitriles and amides with LiAlH4. The two-step sequence of 5 2 displacement with C followed by reduction thus converts an alkyl halide into a primary alkylamine having one more carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms. 

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