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 May 16;26(10):2957.
doi: 10.3390/molecules26102957.

Cu-Catalyzed Arylation of Bromo-Difluoro-Acetamides by Aryl Boronic Acids, Aryl Trialkoxysilanes and Dimethyl-Aryl-Sulfonium Salts: New Entries to Aromatic Amides

Satenik Mkrtchyan  1 , Michał Jakubczyk  1   2 , Suneel Lanka  1   3 , Michael Pittelkow  4 , Viktor O Iaroshenko  1   5   6
Affiliations

Cu-Catalyzed Arylation of Bromo-Difluoro-Acetamides by Aryl Boronic Acids, Aryl Trialkoxysilanes and Dimethyl-Aryl-Sulfonium Salts: New Entries to Aromatic Amides

Satenik Mkrtchyan et al. Molecules. .

Abstract

We describe a mechanism-guided discovery of a synthetic methodology that enables the preparation of aromatic amides from 2-bromo-2,2-difluoroacetamides utilizing a copper-catalyzed direct arylation. Readily available and structurally simple aryl precursors such as aryl boronic acids, aryl trialkoxysilanes and dimethyl-aryl-sulfonium salts were used as the source for the aryl substituents. The scope of the reactions was tested, and the reactions were insensitive to the electronic nature of the aryl groups, as both electron-rich and electron-deficient aryls were successfully introduced. A wide range of 2-bromo-2,2-difluoroacetamides as either aliphatic or aromatic secondary or tertiary amides were also reactive under the developed conditions. The described synthetic protocols displayed excellent efficiency and were successfully utilized for the expeditious preparation of diverse aromatic amides in good-to-excellent yields. The reactions were scaled up to gram quantities.

Keywords: C-C-coupling; amides; aryl trialkoxysilanes; boronic acids; catalysis; copper; dimethyl-aryl-sulfonium salts; fluorine.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
(a) Synthetic scenario, (b,c) Proposed reaction mechanisms.
Scheme 2
Scheme 2
Model reactions for reaction conditions optimization: (a) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with (4-(trifluoromethyl)phenyl)boronic acid, (b) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with trimethoxy(4-(trifluoromethyl)phenyl)silane, (c) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with dimethyl(4-(trifluoromethyl)phenyl)sulfonium triflate.
Scheme 3
Scheme 3
(a) Reactions of 2-bromo-2,2-difluoro-acetamides with aryl boronic acid, (b) Reactions of 2-bromo-2,2-difluoro-acetamides with aryl trialkoxysilanes, (c) Reactions of 2-bromo-2,2-difluoro-acetamides with dimethyl-aryl-sulfonium triflates. Product scope of amides using developed synthetic protocols.
See this image and copyright information in PMC

References

    1. Harrington A., Tal-Gan Y. The Importance of Amide Protons in Peptide Drug Development. [(accessed on 8 November 2019)]; Available online: https://www.future-science.com/doi/abs/10.4155/fmc-2019-0238?journalCode.... - DOI - PubMed
    1. Allen C.L., Williams J.M. Metal-Catalysed Approaches to Amide Bond Formation. Chem. Soc. Rev. 2011;40:3405–3415. doi: 10.1039/c0cs00196a. - DOI - PubMed
    1. de Figueiredo R.M., Suppo J.S., Campagne J.M. Nonclassical Routes for Amide Bond Formation. Chem. Rev. 2016;116:12029–12122. doi: 10.1021/acs.chemrev.6b00237. - DOI - PubMed
    1. Valeur E., Bradley M. Amide Bond Formation: Beyond the Myth of Coupling Reagents. Chem. Soc. Rev. 2009;38:606–631. doi: 10.1039/B701677H. - DOI - PubMed
    1. Pattabiraman V.R., Bode J.W. Rethinking Amide Bond Synthesis. Nature. 2011;480:471–479. doi: 10.1038/nature10702. - DOI - PubMed

LinkOut - more resources