Nitrile Grignard reaction

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). 

The alcohol product can be formed by reduction of a carboxylic acid with UAIH4. The carboxylic acid can be synthesized either by Grignard carboxylation or by nitrile hydrolysis. The product can also be formed by a Grignard reaction between benzyl bromide and formaldehyde. 

Once you realize that the product results from a Grignard reaction with a nitrile, this synthesis is easy. 

The product results from two Grignard reactions. As in (a), nitrile hydrolysis is not a route to this compound. 

Synthesis of i-Keto-, 2,3,4 -tetrahydroisoquinolines These ketones have been prepared by four different routes a Dieck-mann condensation [Eq. (22)], ring closure of benzylglycine derivatives [Eq. (23)], ring closure of substituted nitriles [Eq. (24)], and a Grignard reaction on 4-hydroxy-JV-alkylisoquinolinium salts [Eq. (25)]. Earlier unsuccessful attempts at their synthesis have been summarized.52,58... 

A few 6- and 8-cyanopurines have been prepared and undergo characteristic nitrile addition reactions rather readily. Thus, alkaline hydrolysis produces carboxamides, then carboxylic acids, alcoholysis leads to imidates, ammonolysis to amidines, hydrazinolysis to amidhydrazines, hydroxylamine to amidoximes, and hydrogen sulfide to thioamides. Acid hydrolysis tends to give the decarboxylated acid derivative. Reduction either by sodium-ethanol or, preferably, by catalytic hydrogenation affords aminoalkylpurines and addition of Grignard reagents produces, in the first place, acylpurines. As with aldehydes, most of the compounds examined have been relatively non-polar derivatives. Table 28 lists some reactions and relevant literature. 

In the synthesis of imines and enamines by this method, the water produced in the reaction must be removed azeotropically to drive the reaction to the right. In aqueous acid, equilibrium conditions favor the ketone rather than the imine. This relationship is the reason why Grignard reaction of a nitrile provides a good route to the synthesis of ketones. The intermediate imine formed is hydrolyzed easily to the corresponding ketone (e.g., the transformation of 3-3 to 3-4 in Example 3.13). 

The stereoselective total synthesis of ( )-lepadiformine was accomplished in the laboratory of S.M. Weinreb. The introduction of the hexyl chain in a stereoselective fashion was achieved by a Grignard reaction to an iminium salt during the last steps of the synthetic sequence. The iminium salt was generated in situ from an a-amino nitrile with boron trifluoride etherate, and the addition of hexylmagnesium bromide gave a 3 1 mixture of alkylated products favoring the desired stereoisomer. Removal of the benzyl group completed the total synthesis. 

Tetrachloropyridine may be prepared from pentachloropentadiene nitrile by Grignard reaction, followed by oxidation with KMnO and decarboxylation according to the following reaction scheme ... 

Vnsaturated nitriles from 1-nitrocycloalkenes. Treatment of the conjugate adducts from the Grignard reactions with PCI3 triggers desilylative fragmentation. 

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