The metal- and column-free synthesis of pyridin-2-yl ureas carrying cyclic secondary amine substituents and establishing the mechanism of the reactions through a computational study†
Abstract
A protocol for the synthesis of unsymmetrical ureas bearing 2-pyridyl units has been developed, relying on metal- and column-free one-pot ammonolysis by using a wide range of aryl and alkyl amines, resulting in nearly quantitative conversions. The reaction is not hindered by either donor or acceptor groups on secondary amine rings containing sp2C, sp3C, O, S, and N atoms, as well as diverse functionalities including variant ring strain and chiral substrates, and could be easily scaled up to yield bulk amounts of triazole attaching pyridyl ureas as potential ASK1 inhibitors. Theoretical DFT computational studies were compared to the initial experimental data supporting a plausible mechanism for the process, from which the relative merits of different mechanistic schemes for direct urea formation could be assessed. This reaction initiates through the in situ pyridinolysis of phenyl chloroformate followed by inner molecular rearrangement to phenyl carbamate hydrochloride. On the basis of calculated energies, a pathway involving a concerted mechanism was speculated to be more accessible and may explain how direct aminolysis occurs through benign base catalysis. Such a mechanism is inconsistent with traditional kinetic modelling of zwitterionic intermediates and neutral ortho-pyridinyl isocyanate during the procedure, which is perhaps more likely applicable for similar meta- and para-pyridinyl fragments with intermolecular rearrangements.