Nitriles acid-induced hydrolysis

FIGURE 18.45 The acid-induced hydrolysis of a nitrile to a carboxylic acid. The nitrile is the Lewis base (nucleophile) in the first step. 

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. 

The acid-induced nucleophilic addition of a nitrile to a carbenium ion, followed by hydrolysis to the corresponding amide. 

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. 

In the second case, a nonnatural amino acid of commercial value was synthesized in a Strecker reaction using a chiral amine to help induce chirality in the product. In this case, the authors were interested in the synthesis of 3-ethyl-L-norvaline. So, as shown in Scheme 12.33, a mixture of (5)-(-)-a-methylbenzylamine, potassium cyanide (KCN), and 2-ethylbutyraldehyde in dilute aqueous methanolic HCI was allowed to stir for several days at room temperature. During this time, the hydrochloride salt of the Strecker adduct precipitated and, under these conditions, the precipitate was found to be enriched in the levorotatory isomer (>30 1 by chromatographic separation of the diastereomers). Hydrolysis of the appropriate amino nitrile with cold concentrated sulfuric acid produced 3-ethyl-N -[(lS)-phenylethyl]-L-norvalinamide and debenzylation was accomplished by hydrogenation at lOOpsi of hydrogen (H2) over a 5% Pd/C catalyst. Finally, the amide was hydrolyzed in concentrated HCI to produce 3-ethyl-L-norvaline hydrochloride. 

Aliphatic nitriles react slowly with phenols and phenyl ethers in the presence of trifluoromethanesulphonic acid to give ketones after hydrolysis, in a variation of the Houben-Hoesch reaction. The crystalline complex of copper(i) triflate and benzene induces the acylation of aromatic substrates with selenol esters, affording a transition-metal mediated version of the Friedel-Crafts reaction. Aromatic carboxylic acids can be converted into symmetrical diaryl ketones in good yield by treatment of their 5-(2-pyridyl)thioesters with bis-(l,5-cyclo-octadiene)nickel [equation (15)]. In contrast to other methods for preparing symmetrical aromatic ketones, this method allows their preparation from a single starting material. 

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