A Mild Synthesis of Aryl Triflates Enabling the Late‐Stage Modification of Drug Analogs and Complex Peptides

We report the discovery of a straightforward protocol to convert phenols into the corresponding aryl triflates using 1‐methyl‐3‐((trifluoromethyl)sulfonyl)‐1,3‐dihydro‐2H‐benzo[d]imidazol‐2‐one in the presence of a fluoride source. This novel reagent can be handled without any precautions to exclude air or moisture making this method highly convenient. The reactions generally show very clean conversions within only a few minutes at room temperature. The mild conditions allow the so far unprecedented O‐triflation of tyrosine in peptides bearing challenging side chains present for example in arginine and histidine including the late‐stage triflation of complex bioactive peptides. We show how aryl triflates – an interesting but so far underutilized group – can be used to optimize physicochemical and in vitro properties of compound series in medicinal chemistry. We believe that this method is highly attractive for applications in peptide functionalization as well as automated and medicinal chemistry. We report a highly convenient strategy to convert phenols into the corresponding aryl triflates using a newly discovered reagent in presence of a fluoride source. The reactions are generally complete within a few minutes at room temperature. The mild conditions allow the late‐stage O‐triflation of complex peptides bearing challenging side chains like arginine and histidine. We show that aryl triflates can be an interesting moiety for medicinal chemistry.