Grignard reagents nitrile reduction

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

Enantiomerically pure alkylboranes arc known to be excellent reagents for asymmetric reduction but they can also be used to generate enantiomerically pure /V-borylimines by partial reduction of nitriles. Addition of organolithium and Grignard reagents to these compounds affords secondary carbinamines in moderate to good yield but low enantioselectivity13,14. The best results reported so far are shown below. 

Addition of RMgBr to nitriles. Grignard reagents react with nitriles slowly if at all, but even r-butylmagnesium chloride will add to nitriles in refluxing THF when catalyzed by a copper(I) salt. The adduct can be converted to a ketimine by anhydrous protonation, to a primary amine by reduction (Li/NH,), or to a ketone by hydrolysis. The actual reagent may be a cuprate such as R3Cu(MgX)2. 

The furoxan ring is more susceptible to nucleophilic attack and reduction than it is to reaction with electrophiles or oxidation. Grignard reagents react with disubstituted furoxans primarily at C-3 and, in most cases, the resulting adduct fragments to a nitrile and a nitronate salt which affords a ketone on workup. 

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

After exchange of the protecting group, the Weinreb amide 111 (an alternative to nitriles for the formation of ketones discussed in detail in Strategy and Control) reacted with the aryl Grignard reagent to give, after reduction, 112—the protected version of the alcohol 106 required for cyclisation. 

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. 

Base-Catalyzed Hydrolysis of a Nitrile 1014 Hydride Reduction of an Ester 1015 Reduction of an Amide to an Amine 1016 Reaction of an Ester with Two Moles of a Grignard Reagent 1018... 

Isoxazolines 54, prepared by stereoselective 1,3-DC of nitrile oxides and enantiopure allylic alcohols, were converted into p-amino acids 56 eind 58 by nucleophilic addition to the C=N bond followed by reductive cleavage of the N-0 bond and oxidative cleavage of the diol moiety. The facial selectivity in the nucleophilic addition was dictated by the C-5 substituent in either a directed (hydride addition) or a sterically (Grignard reagents addition) controlled manner <03JA6846>. 

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. 

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