Nitriles base-induced hydrolysis

An alternate route to substituted tetrahydrobenzazepines (Scheme 33) commenced with the Michael addition of the ester 351 to acrylonitrile in the presence of Triton B, and the intermediate cyanoester was converted to 352 by reduction of the ester function with lithium borohydride and O-benzylation (168). Base-induced hydrolysis of the nitrile group of 352 delivered the corresponding acid, which was transformed to 353 via a Curtius rearrangement. Subjection of 353 to a modified two-step Tschemiac-Einhom reaction involving AMiydroxymethyla-tion and subsequent acid-catalyzed cyclization gave 354. 

Both acid- and base-induced hydrolysis of a nitrile gives the amide, but rather severe conditions are required for the reactions, and further hydrolysis of the intermediate amides gives the carboxylic acids (p. 902). In acid, the first step is protonation of the nitrile nitrogen to give a strong Lewis acid (A, Fig. 18.45), which is attacked by water. A series of proton shifts then gives an amide that is hydrolyzed to the carboxylic acid. 

FIGURE 18.46 The base-induced hydrolysis of a nitrile to give a carboxylate anion. The nitrile is the Lewis acid (electrophile) in the first step. 

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