Metal-Free Carbamoylation/Annulation Cascade of Aryl Alkynoates: Synthesis of Carbamoylated Coumarins, Coumarin-Decorated Unnatural Amino Acids, and Peptides

An efficient and sustainable approach for the synthesis of pharmaceutically important carbamoylated coumarins has been developed via a metal-free radical cascade cyclization of aryl alkynoates. Readily available, inexpensive, and nontoxic oxamic acids are used as a carbamoyl radical source. Additionally, wide substrate scope, tolerance to air and water, operational simplicity, good to excellent yields, and scalability enhance the practicality of the current method. The synthetic utility of this mild and environmentally friendly method is further demonstrated by the assembly of structurally diverse unnatural amino acids with a bioactive coumarin scaffold and late-stage modification of tyrosine-containing peptides and a drug molecule. Mechanistic studies reveal that cascade cyclization is triggered by a carbamoyl radical generated from oxamic acids using cheap and environmentally friendly ammonium persulfate as a radical initiator.