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
. 2018 Sep 17;57(38):12543-12548.
doi: 10.1002/anie.201807629. Epub 2018 Aug 28.

Metallaphotoredox Difluoromethylation of Aryl Bromides

Vlad Bacauanu  1 , Sébastien Cardinal  1 , Motoshi Yamauchi  1 , Masaru Kondo  1 , David F Fernández  1 , Richard Remy  1 , David W C MacMillan  1
Affiliations

Metallaphotoredox Difluoromethylation of Aryl Bromides

Vlad Bacauanu et al. Angew Chem Int Ed Engl. .

Abstract

Herein, we report a convenient and broadly applicable strategy for the difluoromethylation of aryl bromides by metallaphotoredox catalysis. Bromodifluoromethane, a simple and commercially available alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl-radical-mediated halogen abstraction. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late-stage functionalization of several drug analogues.

Keywords: difluoromethylation; fluorine; heterocycles; nickel; photoredox catalysis.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Silane-mediated difluoromethylation of aryl bromides.[10]
Scheme 1.
Scheme 1.
Proposed mechanism for metallaphotoredox difluoromethylation.
Scheme 2.
Scheme 2.
Application of difluoromethylation: late-stage functionalization for the expedient synthesis of difluoromethyl analogues of pharmaceutical agents.
See this image and copyright information in PMC

References

    1. a) Hagmann WK, J. Med. Chem 2008, 51, 4359. - PubMed
    2. b) Purser S, Moore PR, Swallow S, Gouverneur V, Chem. Soc. Rev 2008, 37, 320. - PubMed
    3. c) Zhuo Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H, Chem. Rev 2016, 116, 422. - PubMed
    1. a) Liang T, Neumann CN, Ritter T, Angew. Chem. Int. Ed 2013, 52, 8214 - PubMed
    2. b) Campbell MG, Ritter T, Chem. Rev 2015, 115, 612. - PubMed
    3. c) Tomashenko OA, Grushin VV, Chem. Rev 2011, 111, 4475. - PubMed
    4. d) Alonso C, de Marigorta EM, Rubiales G, Palacios F, Chem. Rev 2015, 115, 1847. - PubMed
    1. a) Erickson JA, McLoughlin JI, J. Org. Chem 1995, 60, 1626
    2. b) Zafrani Y, Yeffet D, Sod-Moriah G, Berliner A, Amir D, Marciano D, Gershonov E, Saphier S, J. Med. Chem 2017, 60, 797. - PubMed
    3. c) Sessler CD, Rahm M, Becker S, Goldberg JM, Wang F, Lippard SJ, J. Am. Chem. Soc 2017, 139, 9325. - PMC - PubMed
    1. a) Meanwell NA, J. Med. Chem 2011, 54, 2529. - PubMed
    2. b) Meanwell NA, J. Med. Chem 2018. Article ASAP. DOI: 10.1021/acs.jmedchem.7b01788. - DOI - PubMed
    1. For recent reviews on difluoromethylation reactions, see: a) Chen B, Vicic DA, Top. Organomet. Chem 2015, 52, 113
    2. b) Yerien DE, Barata-Vallejo S, Postigo A, Chem. Eur. J 2017, 23, 14676. - PubMed
    3. c) Rong J, Ni C, Hu J, Asian J Org. Chem 2017, 6, 139.

Publication types