Catalytic Amide Bond Formation Protocol

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).

General experimental procedure:

1. Assemble a 500 mL 4-neck reaction flask in a heating mantle with condenser topped with a large bore stopcock leading to argon bubbler and thermometer.
2. Flush the flask with argon for 30 minutes.
3. Charge the [Ru(COD)Cl₂]_n, PCyp₃^.HBF₄, 1,3-diisopropyl imidazolium chloride and tBuOK into the reaction flask using a powder funnel under argon pressure.
4. Degas the solids by evacuating and backfilling with argon for a total of three cycles; afterwards, place the reaction flask under a slight positive pressure of argon.
5. Charge toluene using a cannula under argon pressure.
6. Reflux the reaction mixture for 30 minutes. A dark or black solution is observed.
7. Cool the reaction mixture to room temperature.
8. Charge alcohol and amine under argon pressure.
9. Reflux the reaction mixture under an argon atmosphere in the heating mantle for 24 hours.
10. Cool the reaction mixture to room temperature and remove the solvent in vacuo.
11. Adsorb the residue onto silica gel and purify by column chromatography (eluent: hexane/EtOAc 8:2 to 7:3) to afford the amide.

Representative example:

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.

Chemical	FW	Dens	MatNo	Qty	Moles(x10-3)	Ratio
2-Phenylethanol	122.16	1.020	77861	7.3296 g	60	1
Hexylamine	101.19	0.766	219703	6.0714 g	60	1
[Ru(COD)Cl2]n	280.16	1.00	337331	0.8404 g	3	0.05
PCyp3.HBF4	326.16	1.00	673951	03913 g	3	0.05
1,3-diisopropyl imidazolium chloride	188.70	1.00	656577	0.2264 g	3	0.05
tBuOK	112.21	1.00	156671	1.3465 g	12	0.2
Toluene	92.14	0.865	244511	120 mL	1126	18.76

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.

References

1. Gunanathan C, Ben-David Y, Milstein D. 2007. Direct Synthesis of Amides from Alcohols and Amines with Liberation of H2. Science. 317(5839):790-792. https://doi.org/10.1126/science.1145295

2. Nordstrøm LU, Vogt H, Madsen R. 2008. Amide Synthesis from Alcohols and Amines by the Extrusion of Dihydrogen. J. Am. Chem. Soc.. 130(52):17672-17673. https://doi.org/10.1021/ja808129p