Hydrogenolysis of Benzyl-Nitrogen Bonds

Palladium catalysts, mostly palladium on carbon and Pearlman s catalyst, are used for the hydrogenolysis of the benzyl—nitrogen bond. However, in some cases, platinum, nickel, and copper chromite catalysts have also been used. 

The benzyl—nitrogen bond is not so easily cleaved as the benzyl—oxygen bond, unless the O-benzyl group is sterically hindered. This difference in activity allows the selective removal of the O-benzyl function in a molecule containing both N-benzyl and O-benzyl protecting groups. The selectivity can be reversed if the amine is protected by the Cbz group. If a small amount of amine (e g., butylamine) is added, then the selective removal of N-benzyl amines can be achieved.292 

It was found in the case of O-benzyl systems that palladium oxide is much more effective than palladium metal. No such effect was observed with the N-benzyl system.8 It is possible that the N-compounds can poison the electrophile metal ions, and the hydrogenolysis of the N-benzyl bond can take place only by the hydrogenolytic cleavage instead of the insertion mechanism. This is supported by the experimental finding that the product amine can inhibit the catalyst, and this can be minimized by buffering at a pH less than 4. 

Catalyst Solvent Pressure Time Temperature Citation 

Sulfuric acid in ethanol and Pd(OH)2/C was used for removing the benzyl group from compound 12, whereas Pd/C was used in the case of compound 13 (Fig. 4.3).311 

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Palladium catalysts, usually Pearlman s catalyst [42] and Pd/C are used for the hydrogenolysis of benzyl-nitrogen bonds. Acetic acid, ethyl acetate, ethanol, or methanol are frequently used as solvents. Sometimes a small amount of a strong acid is added to the reaction mixture [54-56]. The bond rupture needs the adsorption of carbon [57]. The hydrogenolysis of C-N bonds occurs with inversion on both Pd and Ni [2,58]. 

Palladium hydroxide on C, typically 20 wt% Pd (dry basis), is commonly called Pearl-man s catalystJ It has been reported to be particularly active for hydrogenolysis of benzyl-nitrogen bonds and effective even in cases where other Pd/C catalysts are not. 

Cleavage of the carbon-nitrogen bond occurs in benzyloxycarbon amino compounds as a result of decarboxylation of the corresponding free carbamic acids resulting from hydrogenolysis of benzyl residues [725, 729, 7S0] (p. 151). 

It is widely accepted that a benzyl-nitrogen bond is not as readily cleaved as a benzyl-oxygen bond. The presence of nitrogen can, however, influence the hydrogenolysis of C-O bonds. It has been reported that butylamine completely prevented the hydrogenolysis of the benzylic C-O bond [62]. The same effect was observed for molecules containing both benzylic C-O and C-N bonds [62,63]. In a mixture of A-benzylcyclohexylamine and benzyl cyclohexyl ether only the C-N bond was hydrogenolyzed on Pd/C, whereas in the presence of HCl the... 

Both benzyl-oxygen and nitrogen-oxygen bonds undergo hydrogenolysis readily in the presence of a benzyloxy-nitrogen bond but it appears that the benzyl-oxygen bond can be made to cleave selec-... 

Ester enolates which contain the chiral information in the acid moiety have been widely used in alkylations (see Section D.1.1.1,3.) as well as in additions to carbon-nitrogen double bonds (sec Section D.1.4.2.). Below are examples of the reaction of this type of enolate with aldehydes720. The (Z)-enolate generated from benzyl cinnamate (benzyl 3-phenylpropcnoate) and lithium (dimethylphenylsilyl)cuprate affords the /h/-carboxylic acid on addition to acetaldehyde and subsequent hydrogenolysis, The diastereoselectivity is 90 10. 

Because of the need for initial coordination with the catalyst, only benzylic or allylic C-X bonds can be reduced, but the X can be oxygen as well as nitrogen. We will come back to benzyl groups, and their hydrogenolysis, as a means for temporary protection of amines and alcohols later in the chapter. For the moment, though, we should take a broader look at catalytic hydrogenation as our second (after hydride reduction) important class of reductions. 

The same was found for nitrogen-containing compounds protected by benzyl-oxymethyl groups. These compounds have two reactive bonds. The regioselectivity of the hydrogenolysis depends on the catalyst used. The carbon-oxygen bond was ruptured by use of Pd/C as catalyst whereas the rupture of the C-N bond occurred when hydrogenolysis was performed with Pd(OH)2 in MeOH (Scheme 8) [65]. 

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