The amide bond is one of the most important linkages in organic chemistry and constitutes the key functional group in peptides, polymers, and many natural products and pharmaceuticals. Amides are usually prepared by coupling of carboxylic acids and amines by the use of either a coupling reagent or by prior conversion of the carboxylic acid into a derivative. Alternative procedures include the Staudinger ligation, aminocarbonylation of aryl halides, and oxidative amidation of aldehydes. However, all these methods require stoichiometric amounts of various reagents and lead to equimolar amounts of byproducts. In special cases, amides can be formed by catalytic procedures as shown for the Schmidt reaction between ketones and azides, the Beckmann rearrangement, and the amidation of thioacids with azides.
A more environmentally friendly protocol for amide synthesis is the direct amidation of amines with alcohols where two molecules of dihydrogen are liberated. This unique transformation has been described before where a ruthenium pincer complex was used for the direct coupling of sterically unhindered primary amines and alcohols.1 Recently, Madsen et al. reported the synthesis of amides from alcohols and amines by the extrusion of dihyrdogen using a ruthenium catalyst, an N-heterocyclic carbene (NHC), and a phosphine ligand (Scheme 1).2
Scheme 1:Catalytic amide bond formation
Special Hazards: Corrosives, Irritants, and Flammables (Note: For a comprehensive understanding of all associated hazards, refer to each component’s SDS by MatNo).
The first experiment was carried out with 2-phenylethanol and hexylamine to validate the literature method (Scheme 2).
Scheme 2:Amidation of 2-phenylethanol with hexylamine
N-Hexyl-2-phenylacetamide: [Ru(COD)Cl2]n, PCyp3·HBF4, 1,3-diisopropylimidazolium chloride, and tBuOK were placed in an oven dried Schlenk tube. Vacuum was applied and the tube was then filled with argon (repeated twice). Toluene was added and the mixture was heated to reflux under an argon atmosphere for 20 min in an oil bath. The flask was removed from the oil bath, and the alcohol and the amine were added. The mixture was heated at reflux under an argon atmosphere in the oil bath for 24 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc 8:2 to 7:3) to afford the amide.
With the optimized conditions in hand, we then applied this methodology to aliphatic alcohols (Scheme 3) containing nitrogen heterocycles (eq. 1) and protected amines (eq. 2) to study the scope and limitations of this method.
Scheme 3:Amidation of amines and alcohols.