Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jun 18;11(12):7383-7393.
doi: 10.1021/acscatal.1c00728. Epub 2021 Jun 7.

Near-Ambient-Temperature Dehydrogenative Synthesis of the Amide Bond: Mechanistic Insight and Applications

Sayan Kar  1 , Yinjun Xie  1 , Quan Quan Zhou  1 , Yael Diskin-Posner  2 , Yehoshoa Ben-David  1 , David Milstein  1
Affiliations

Near-Ambient-Temperature Dehydrogenative Synthesis of the Amide Bond: Mechanistic Insight and Applications

Sayan Kar et al. ACS Catal. .

Abstract

The current existing methods for the amide bond synthesis via acceptorless dehydrogenative coupling of amines and alcohols all require high reaction temperatures for effective catalysis, typically involving reflux in toluene, limiting their potential practical applications. Herein, we report a system for this reaction that proceeds under mild conditions (reflux in diethyl ether, boiling point 34.6 °C) using ruthenium PNNH complexes. The low-temperature activity stems from the ability of Ru-PNNH complexes to activate alcohol and hemiaminals at near-ambient temperatures through the assistance of the terminal N-H proton. Mechanistic studies reveal the presence of an unexpected aldehyde-bound ruthenium species during the reaction, which is also the catalytic resting state. We further utilize the low-temperature activity to synthesize several simple amide bond-containing commercially available pharmaceutical drugs from the corresponding amines and alcohols via the dehydrogenative coupling method.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected examples of amide synthesis via dehydrogenative coupling of amines and alcohols.
Scheme 1
Scheme 1. Amide Formation from Ester Catalyzed by 2
Scheme 2
Scheme 2. Pathway of Amide Formation
Scheme 3
Scheme 3. Reactivity of Ru Complexes with the Base, Alcohol, and Amine
Figure 2
Figure 2
ORTEP diagram of complex 1d.amide. Atoms are drawn with a probability level of 50%. Selected hydrogen atoms omitted for clarity. Tert-butyl groups displayed as a wireframe for clarity. Selected bond lengths (Å) and angles (o): Ru(1)–P(1) 2.2576(5), Ru(1)–O(2) 2.2380(15), Ru(1)–N(1) 2.0850(19), Ru(1)–N(2) 2.2010(17), Ru(1)–C(26) 1.818(2), O(2)–C(8) 1.394(3), C(7)–C(8) 1.570(3); P(1)–Ru(1)–H 81.5(11), O(2)–Ru(1)–P(1) 105.13(4), O(2)–Ru(1)–H 168.8(11), N(1)–Ru(1)–P(1) 81.81(5), N(1)–Ru(1)–O(2) 81.74(7), N(2)–Ru(1)–O(2) 72.92(6), C(8)–O(2)–Ru(1) 113.36(13), O(2)–C(8)–C(7) 109.38(18).
Scheme 4
Scheme 4. Plausible Mechanistic Cycle
Scheme 5
Scheme 5. Importance of the Terminal N–H Moiety
Energy values correspond to Gibbs free energies (kcal mol–1) with respect to the ethoxy complex + ethylamine at 298.15 K in a diethyl ether continuum. All reactant concentrations are 1 M, except for H2 which is at 1 atm. Mass balance is ensured throughout.
Scheme 6
Scheme 6. Synthesis of Various Pharmaceutical Drugs
Conditions A: alcohol (0.5 mmol), amine (0.6 mmol), 2 (0.005 mmol), t-BuOK (0.01 mmol), MTBE (2 mL, bp 55.2 °C), reflux (bath temp. 70 °C), 60 h. Conditions B: alcohol (0.5 mmol), amine (5 mmol), 1 (0.005 mmol), t-BuOK (0.01 mmol), K3PO4 (0.5 mmol), dioxane (2 mL), reflux in a closed tube for 60 h (see the Supporting Information for details). Yields in parentheses are isolated yields, and yields outside parentheses are 1H NMR yields.
See this image and copyright information in PMC

References

    1. Cupido T.; Tulla-Puche J.; Spengler J.; Albericio F. The synthesis of naturally occurring peptides and their analogs. Curr. Opin. Drug Discovery Dev. 2007, 10, 768–783. - PubMed
    2. Hu P.; Ben-David Y.; Milstein D. Rechargeable Hydrogen Storage System Based on the Dehydrogenative Coupling of Ethylenediamine with Ethanol. Angew. Chem., Int. Ed. 2016, 55, 1061–1064. 10.1002/anie.201505704. - DOI - PubMed
    3. Hu P.; Fogler E.; Diskin-Posner Y.; Iron M. A.; Milstein D. A novel liquid organic hydrogen carrier system based on catalytic peptide formation and hydrogenation. Nat. Commun. 2015, 6, 6859. 10.1038/ncomms7859. - DOI - PMC - PubMed
    4. Xie Y.; Hu P.; Ben-David Y.; Milstein D. A Reversible Liquid Organic Hydrogen Carrier System Based on Methanol-Ethylenediamine and Ethylene Urea. Angew. Chem., Int. Ed. 2019, 58, 5105–5109. 10.1002/anie.201901695. - DOI - PubMed
    1. Carey J. S.; Laffan D.; Thomson C.; Williams M. T. Analysis of the reactions used for the preparation of drug candidate molecules. Org. Biomol. Chem. 2006, 4, 2337–2347. 10.1039/b602413k. - DOI - PubMed
    2. Dunetz J. R.; Magano J.; Weisenburger G. A. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Dev. 2016, 20, 140–177. 10.1021/op500305s. - DOI
    1. Han S.-Y.; Kim Y.-A. Recent development of peptide coupling reagents in organic synthesis. Tetrahedron 2004, 60, 2447–2467. 10.1016/j.tet.2004.01.020. - DOI
    2. Valeur E.; Bradley M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 2009, 38, 606–631. 10.1039/b701677h. - DOI - PubMed
    3. de Figueiredo R. M.; Suppo J.-S.; Campagne J.-M. Nonclassical Routes for Amide Bond Formation. Chem. Rev. 2016, 116, 12029–12122. 10.1021/acs.chemrev.6b00237. - DOI - PubMed
    4. Montalbetti C. A. G. N.; Falque V. Amide bond formation and peptide coupling. Tetrahedron 2005, 61, 10827–10852. 10.1016/j.tet.2005.08.031. - DOI
    5. Sabatini M. T.; Boulton L. T.; Sneddon H. F.; Sheppard T. D. A green chemistry perspective on catalytic amide bond formation. Nat. Catal. 2019, 2, 10–17. 10.1038/s41929-018-0211-5. - DOI
    1. Constable D. J. C.; Dunn P. J.; Hayler J. D.; Humphrey G. R.; Leazer J. L.; Linderman R. J.; Lorenz K.; Manley J.; Pearlman B. A.; Wells A.; Zaks A.; Zhang T. Y. Key green chemistry research areas—a perspective from pharmaceutical manufacturers. Green Chem. 2007, 9, 411–420. 10.1039/b703488c. - DOI
    2. Bandichhor R.; Bhattacharya A.; Diorazio L.; Dunn P.; Fraunhoffer K.; Gallou F.; Hayler J.; Hickey M.; Hinkley B.; Hughes D.; Humphreys L.; Kaptein B.; Mathew S.; Oh L.; Richardson P.; White T.; Wuyts S. Green Chemistry Articles of Interest to the Pharmaceutical Industry. Org. Process Res. Dev. 2013, 17, 1394–1405. 10.1021/op400263a. - DOI
    1. Gunanathan C.; Ben-David Y.; Milstein D. Direct Synthesis of Amides from Alcohols and Amines with Liberation of H2. Science 2007, 317, 790. 10.1126/science.1145295. - DOI - PubMed