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 Apr 18;140(15):5057-5060.
doi: 10.1021/jacs.8b02568. Epub 2018 Apr 6.

Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and Pyridazines without Preactivation of the Heterocycle or Nucleophile

Michael W Gribble Jr  1 , Sheng Guo  1 , Stephen L Buchwald  1
Affiliations

Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and Pyridazines without Preactivation of the Heterocycle or Nucleophile

Michael W Gribble Jr et al. J Am Chem Soc. .

Abstract

We show that a chiral copper hydride (CuH) complex catalyzes C-C bond-forming dearomatization of pyridines and pyridazines at room temperature. The catalytic reaction operates directly on free heterocycles and generates the nucleophiles in situ, eliminating the need for stoichiometric preactivation of either reaction partner; further, it is one of very few methods available for the enantioselective 1,4-dearomatization of heteroarenes. Combining the dearomatization with facile derivatization steps enables one-pot syntheses of enantioenriched pyridines and piperidines.

PubMed Disclaimer

Conflict of interest statement

Notes

No competing financial interests have been declared

Figures

Figure 1
Figure 1
Methods for stereocontrolled 1,4-dearomatization; (A) with chiral auxiliaries; (B) with chiral nucleophiles; (C) using asymmetric catalysis; (D) this work: asymmetric direct catalytic dearomatization.
Figure 2
Figure 2
Plausible Mechanism for the Direct Dearomatization.
See this image and copyright information in PMC

References

    1. Vitaku E, Smith DT, Njardson JT. J Med Chem. 2014;57:10257–10274. - PubMed

    1. For reviews on pyridine dearomatization and dihydropyridine chemistry, see:

    2. Lavilla R. J Chem Soc, Perkin Trans. 2002;1:1141–1156.
    3. Ahamed M, Todd MH. Eur J Org Chem. 2010;2010:5935–5942.
    4. Bull JA, Mousseau JJ, Pelletier G, Charette AB. Chem Rev. 2012;112:2642–2713. - PubMed
    5. Zhuo CX, Zhang W, You SL. Angew Chem, Int Ed. 2012;51:12662–12686. - PubMed
    6. Ding Q, Zhou X, Fan R. Org Biomol Chem. 2014;12:4807–4815. - PubMed

    1. For examples of 1,4-dearomatizations using copper, see:

    2. Piers E, Soucy M. Can J Chem. 1974;52:3563–3564.
    3. Comins DL, Abdullah AH. J Org Chem. 1982;47:4315–4319.
    4. Akiba KY, Iseki Y, Wada M. Bull Chem Soc Jpn. 1984;57:1994–1999.

    1. For examples of asymmetric catalysis using activated substrates, see:

    2. Sun Z, Yu S, Ding Z, Ma D. J Am Chem Soc. 2007;129:9300–9301. - PubMed
    3. Black DA, Beveridge RE, Arndtsen BA. J Org Chem. 2008;73:1906–1910. - PubMed
    4. Fernández-Ibáñez MA, Maciá B, Pizzuti MG, Minnaard AJ, Feringa BL. Angew Chem, Int Ed. 2009;48:9339–9341. - PubMed
    5. Lutz JP, Chau ST, Doyle AG. Chem Sci. 2016;7:4105–4109. - PMC - PubMed
    1. Mohiti M, Rampalakos C, Feeney K, Leonori D, Aggarwal VK. Chem Sci. 2014;5:602–607.

Publication types

LinkOut - more resources