A Discriminating Protecting Group Strategy for Alcohols and Amines

The protection of alcohols and amines as O‐ and N‐benzyl derivatives has long played a central role in organic synthesis. For cases where the conventional method of benzylation under strongly basic conditions is not applicable, we now describe an alternate method using phenyldiazomethane that proceeds under near‐neutral conditions with HBF 4 as a catalyst. O‐Benzylation occurs at −40 °C and works well on primary, secondary, and tertiary alcohols. The technique is compatible with ester, acetal, and reactive halide functionalities. Under the same conditions PhCHN 2 also N‐benzylates primary and secondary amines, albeit more slowly. However S‐benzylation is only marginally successful. As a consequence aminoalcohols like 2‐hydroxymethylpiperidine can be O‐benzylated cleanly and in good yield. Thus HBF 4 ‐mediated benzylations using PhCHN 2 achieve a kinetic selectivity not customarily possible in the standard Williamson ether synthesis. Preliminary experiments with other, substituted phenyldiazomethanes indicate the method can be extended to the production of substituted benzyl ethers and amines.