Science · 2007 · 1.3K citations · 21 references
Natural SciencesBiochemistryChemistryCatalysisOrganic ChemistryOrganometallic ChemistryCatalytic MaterialsCatalytic MechanismsOrganic SynthesisReaction PathwaysAmide Bond FormationCatalytic AcylationCatalytic Reaction MechanismsDirect SynthesisMolecular Hydrogen FormationRuthenium-catalyzed Coupling
Amides are widely used, yet conventional syntheses rely on stoichiometric reagents or harsh conditions, so an efficient, waste‑free method is desirable. A ruthenium PNN‑ligand complex catalyzes the reaction without external base or acid, proceeding via dehydrogenation of hemiaminal intermediates derived from an aldehyde‑amine adduct. Primary amines are directly acylated by alcohols to give amides and H₂ in high yields and turnover numbers; primary diamines afford bis‑amides, and mixed primary‑secondary amines undergo chemoselective acylation of the primary site.
Given the widespread importance of amides in biochemical and chemical systems, an efficient synthesis that avoids wasteful use of stoichiometric coupling reagents or corrosive acidic and basic media is highly desirable. We report a reaction in which primary amines are directly acylated by equimolar amounts of alcohols to produce amides and molecular hydrogen (the only products) in high yields and high turnover numbers. This reaction is catalyzed by a ruthenium complex based on a dearomatized PNN-type ligand [where PNN is 2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine], and no base or acid promoters are required. Use of primary diamines in the reaction leads to bis-amides, whereas with a mixed primary-secondary amine substrate, chemoselective acylation of the primary amine group takes place. The proposed mechanism involves dehydrogenation of hemiaminal intermediates formed by the reaction of an aldehyde intermediate with the amine.
21