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
. 2020 Aug 3;59(32):13484-13489.
doi: 10.1002/anie.202002271. Epub 2020 Jun 5.

Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids

Jiang Wang  1 , Megan E Hoerrner  2 , Mary P Watson  2 , Daniel J Weix  1
Affiliations

Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids

Jiang Wang et al. Angew Chem Int Ed Engl. .

Abstract

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low-abundance starting materials. In contrast, amide formation is the most-used bond-construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N-alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2-pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.

Keywords: acyl fluorides; cross-coupling; ketone synthesis; nickel; pyridinium Salts.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors declare no conflict of interest.

Figures

Scheme 1.
Scheme 1.
How to make ketones from amine and carboxylic acid derivatives.
See this image and copyright information in PMC

References

    1. Lawrence NJ, J. Chem. Soc, Perkin Trans 1 1998, 1739–1750.
    2. Dieter RK, Tetrahedron 1999, 55, 4177–4236.
    3. Blangetti M, Rosso H, Prandi C, Deagostino A, Venturello P, Molecules 2013, 18, 1188–1213. - PMC - PubMed
    1. Nahm S, Weinreb SM, Tetrahedron Lett. 1981, 22, 3815–3818.
    2. Balasubramaniam S, Aidhen IS, Synthesis 2008, 3707–3738.
    3. Senatore R, Ielo L, Monticelli S, Castoldi L, Pace V, Synthesis 2019, 51, 2792–2808.
    4. Martín R, Romea P, Tey C, Urpí F, Vilarrasa J, Synlett 1997, 1414–1416.
    5. Kurosu M, Kishi Y, Tetrahedron Lett. 1998, 39, 4793–4796.
    1. Tokuyama H, Yokoshima S, Yamashita T, Fukuyama T, Tetrahedron Lett. 1998, 39, 3189–3192.
    2. Hirschbeck V, Gehrtz PH, Fleischer I, Chem. Eur. J 2018, 24, 7092–7107. - PubMed
    3. Liebeskind LS, Srogl J, J. Am. Chem. Soc 2000, 122, 11260–11261.
    4. Prokopcová H, Kappe CO, Angew. Chem. Int. Ed 2009, 48, 2276–2286. - PubMed
    1. Cooper TWJ, Campbell IB, Macdonald SJF, Angew. Chem., Int. Ed 2010, 49, 8082–8091. - PubMed
    2. Roughley SD, Jordan AM, J. Med. Chem 2011, 54, 3451–3479. - PubMed
    3. Brown DG, Boström J, J. Med. Chem 2016, 59, 4443–4458. - PubMed
    4. Schneider N, Lowe DM, Sayle RA, Tarselli MA, Landrum GA, J. Med. Chem 2016, 59, 4385–4402. - PubMed
    5. b). Boström J, Brown DG, Young RJ, Keserü GM, Nat. Rev 2018, 17, 709–727. - PubMed

    1. For alkyl-X: X = [ZnX], 443 compounds; X = [B], 4225; X = I, 8621; X = Br, 193284; X = CO2H (1°, 2° and 3°), 1385384; X = NH2 (1° and 2°), 1237920; Data from eMolecules Database accessed via REAXYS (April 8, 2019).

Publication types

LinkOut - more resources