Amides, carbamates, and ureas are ubiquitous functionalities in medicines, natural products, and pesticides. These amide-related compounds are useful protecting groups of amines in organic synthesis because of their high stability. Furthermore, they are key structural motifs in chiral auxiliaries and widely used for C–H functionalization reactions. Despite their utility, cleavage of simple unactivated amide-related compounds generally required strongly acidic/basic conditions with limited functional groups tolerance. To expand utility of them, development of direct cleavage of unactivated amide related compounds under mild conditions is in high demand. Recently, we reported cleavage of unactivated amides using a combination of ammonium salts and ethylenediamine. This reaction proceeds under milder conditions than commonly used strongly acidic/basic hydrolysis/alcoholysis conditions, because nitrogen nucleophiles are more nucleophilic than oxygen nucleophiles (e.g. H2O or alcohol). Here, we present two new reactions to cleave amide-related compounds under mild conditions: 1) cleavage of unactivated amides, 2) cleavage of unactivated carbamates and ureas. 1) Hydrazinolysis of unactivated amide was significantly accelerated by the addition of ammonium salts. This method expanded the substrate scope with high functional group tolerance, including acid-sensitive acetal, Boc, base-sensitive TBS, and t-butyl ester groups, which were not applicable in our previous method. Application to peptide and amino sugar derivatives was also demonstrated. 2) Diethylenetriamine was effective for the direct cleavage of unactivated carbamates and ureas without additional reagents, catalysts and consideration of air and moisture. This method was applicable to various carbamates and more stable ureas, including challenging substrates, such as N,N-disubstituted carbamates and ureas and carbamates bearing acid-sensitive THP group or base-sensitive TIPS group, affording the desired products in good yield. Unique chemoselective cleavage of carbamates and ureas in the presence of amides was also achieved.

Hydrazine and diethylenetriamine mediated direct cleavage of unactivated amides, carbamates, and ureas

254th National Meeting (2017)

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