Debenzylation, ethers

Debenzylation of benzylamines and benzyl ethers is carried out with ammonium formate[l 13,l 14]. Hydrosilanes are also used for debenzylation[l I5. ... 

Figure 3 Debenzylation of a pharmaceutical intermediate containing benzyl ether and aromatic chlorine.

Other examples of debenzylation of benzyl ethers on the frequently used Pd/C catalysts are summarized in Table 4.2. 

In some cases the hydrogenation of the double bond in an unsaturated benzyl ether is necessary without debenzylation. To hydrogenate the carbon-carbon double bond 5% Pd/C in AcOEt was used for 1.5 hours (Scheme 4.40).136 The benzyl ether-protecting group was removed over Pd(OH)2 in AcOEt for 1 hour. 

Benzyl esters of carboxylic acids are frequently used in organic synthesis for the protection of carboxyl groups. The C-O bond in benzyl esters can be cleaved more easily than the corresponding benzyl ether bond. The hydrogenolysis of an ester leads to carboxylic acid and toluene. Examples of debenzylation of benzyl esters of carboxylic acids on Pd/C catalysts are summarized in Table 4.4. 

Hydroxythiadiazole and neat trimethyl orthoacetate showed a 20 80 ratio of N- versus O-alkylation products by H NMR <2002EJ01763>. The acidic hydroxyl group of thiadiazole 130 can be selectively protected as the benzyl ether 113 (Equation 22) <2004TL5441>. Nonhydrogenative debenzylation of the bisbenzyl thiadiazole 116 was achieved with boron tribromide to afford the bis-l,2,5-thiadiazole 131 (Equation 23) <2004TL5441>. 

A similar process can be efficiently used for the deallylation or debenzylation of the corresponding ethers 52 and 53, just using water as the quenching reagent after the lithiation process. Some examples giving alcohols or phenols 54 are included in Scheme 17 . 

With the nitrogen atom well protected as the cyclic carbamate 105, all attempts to open the 1,6-anhydro ring under acidic conditions failed owing to the lability of the two allylic benzyl ethers present in the molecule. However, it was possible to debenzylate 105 with lithium in ammonia to form the new cyclic carbamate 108 and acetylation then gave 109. 

Most of the early syntheses of psilocin and psilocybin employ the O-benzyl ether as a protecting group. This provides more stability to the chemical intermediates, but also requires the additional step of reductive debenzylation. The flow chart of this process is conversion of 4-hydroxyindole to 4-benzyloxyindole via the sodium salt, with benzyl chloride the conversion of this with oxalyl chloride to 4-benzyloxyindole-3-glyoxylchloride the conversion of this to 4-benzyloxy-3-(N,N-dimethyl-glyoxamide with anhydrous dimethylamine the conversion of this to... 

Confirmation of these results was provided by a different laboratory67 in studies with allyl a-L-fucopyranoside. Partial benzylation of this compound, under conditions similar to those described previously,66 also gave the 2,4- and 3,4-dibenzyl ethers in the ratio of 3 2. In both publications, the structures assigned were primarily confirmed by methylation of unreacted hydroxyl groups with methyl iodide-sodium hydride in dimethyl sulfoxide,68 followed by catalytic debenzylation, and isolation and characterization of the known methyl ethers. 

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