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
. 2023 Dec 4;62(49):e202312331.
doi: 10.1002/anie.202312331. Epub 2023 Oct 31.

Ligand-Enabled Double γ-C(sp3 )-H Functionalization of Aliphatic Acids: One-Step Synthesis of γ-Arylated γ-Lactones

Md Emdadul Hoque  1 , Jin-Quan Yu  1
Affiliations

Ligand-Enabled Double γ-C(sp3 )-H Functionalization of Aliphatic Acids: One-Step Synthesis of γ-Arylated γ-Lactones

Md Emdadul Hoque et al. Angew Chem Int Ed Engl. .

Abstract

γ-methylene C(sp3 )-H functionalization of linear free carboxylic acids remains a significant challenge. Here in we report a Pd(II)-catalyzed tandem γ-arylation and γ-lactonization of aliphatic acids enabled by a L,X-type CarboxPyridone ligand. A wide range of γ-arylated γ-lactones are synthesized in a single step from aliphatic acids in moderate to good yield. Arylated lactones can readily be converted into disubstituted tetrahydrofurans, a prominent scaffold amongst bioactive molecules.

Keywords: Arylation; Carboxylic Acids; C−H Activation; Lactonization; Palladium.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Scheme 1.
Scheme 1.
Pd(II)-Catalyzed γ-Methylene C─H functionalization of Aliphatic Acids
Scheme 2.
Scheme 2.
1.0 mmol Scale Synthesis and Further Transformation to Tetrahydrofuran. Step-1: Conditions: 1a (1.0 mmol), 2a (2.5 equiv.), Pd(OAc)2 (10 mol %), ligand L14 (15 mol%), K2HPO4 (2.0 equiv.), Ag3PO4 (1.0 equiv.), HFIP (1.0 mL), 80 °C, under air, 36 h. Step-2: 3a (0.5 mmol), LAH (1.5 equiv.), THF, 0 °C - rt, 6h.
Scheme 3.
Scheme 3.
Control Experiments with Possible Intermediate. [a] Standard conditions: 1a (0.1 mmol), 4-Iodobiphenyl (2.5 equiv.), Pd(OAc)2 (10 mol %), L14 (15 mol%), K2HPO4 (2.0 equiv.), Ag3PO4 (1.0 equiv.), 4-Iodobiphenyl (2.5 equiv.), HFIP (1.0 mL), 80 °C, under air, 36 h. Here, Ar means 4-biphenyl group.
Scheme 4.
Scheme 4.
H/D Exchange Experiments.
See this image and copyright information in PMC

References

    1. Kang EJ, Lee E, Chem. Rev 2005, 105, 4348–4378. - PubMed
    2. Janecka A, Wyrębska A, Gach K, Fichna J, Janecki T, T. Drug Discovery Today 2012, 17, 561–572. - PubMed
    3. Geske GD, O’Neill JC, Blackwell HE, Chem. Soc. Rev 2008, 37, 1432–1447. - PMC - PubMed
    4. Kitson RRA, Millemaggi A, Taylor RJK, Angew. Chem., Int. Ed 2009, 48, 9426–9451. - PubMed
    5. Corkery JM, Loi B, Claridge H, Goodair C, Corazza O, Elliott S, Schifano F, Neurosci. Biobehav. Rev 2015, 53, 52–78. - PubMed
    1. Chamorro G, Vega F, Madrigal E, Salazar M, Arzneim.-Forsch 2002, 52, 524–528; - PubMed
    2. Chamorro G, Vega F, Madrigal E, Mercado EN, Salazar MA, Toxicol. Lett 2003, 142, 37–43; - PubMed
    3. Rasgado LAV, Villanueva I, Diaz FV, Acta Pharmaceutica 2017, 67, 215–226. - PubMed
    1. Wang T-C, Lee K-H, Chen Y-L, Liou S-S, Tzeng C-C, Bioorg. Med. Chem. Lett 1998, 8, 2773–2776; - PubMed
    2. Tzeng C-C, Lee K-H, Wang T-C, Han C-H, Chen Y-L, Pharm. Res 2000, 17, 715–719; - PubMed
    3. Lee K-H, Huang B-R, Eur. J. Med. Chem 2002, 37, 333–338; - PubMed
    4. Huang P-J, Lee K-H, Med. Chem. Res 2011, 20, 1081–1090.
    1. Mulholland DA, McFarland K, Randrianarivelojosia M, Biochem. Syst. Ecol 2006, 34, 365–369.
    1. Dowle MD, Davies DI, Chem. Soc. Rev 1979, 8, 171–197.

LinkOut - more resources