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
. 2025 May 20;16(1):4702.
doi: 10.1038/s41467-025-60011-0.

Modular access to alkylfluorides via radical decarboxylative-desulfonylative gem-difunctionalization

Xianjin Wang #  1 , Haotian Li #  2 , Yasu Chen  1 , Ziqiang Wang  1   2 , Xinxin Wu  2 , Chen Zhu  3   4
Affiliations

Modular access to alkylfluorides via radical decarboxylative-desulfonylative gem-difunctionalization

Xianjin Wang et al. Nat Commun. .

Abstract

Fluorine-containing compounds hold pivotal importance in life sciences. Recent decades have witnessed significant research efforts toward developing practical fluorination methods. Radical-mediated decarboxylative fluorination has proven to be a robust approach for incorporating diverse monofluoroalkyl groups. Here we show a radical-mediated modular synthesis of alkyl fluorides through a decarboxylative-desulfonylative gem-difunctionalization under mild photochemical conditions. The multi-component reaction proceeds in a controlled sequence of radical decarboxylation and heteroaryl migration, governed by radical polarity and kinetic effects, resulting in a wide range of valuable alkyl fluorides. Two C-C bonds and one C-F bond are concurrently formed throughout the process. Both styrenes and aliphatic alkenes serve as suitable substrates for this transformation. Furthermore, this method can be applied to the incorporation of a monofluoroalkyl moiety into complex alkene molecules at a late stage.

PubMed Disclaimer

Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The importance of monofluoroalkyl moiety and its incorporation by radical approaches.
a The importance of monofluoroalkyl moiety in bioactive molecules. b Classic decarboxylative fluorination. c Fluorination via decarboxylation-desulfonylation.
Fig. 2
Fig. 2. Generality assessment of the reaction.
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (2 mol %), Selectfluor (0.6 mmol), and KHCO3 (0.6 mmol) in DCM (2 mL), irradiated with 30 W blue LEDs at 20 oC under N2 for 48 h.
Fig. 3
Fig. 3. Product transformations.
a The synthesis of 4. Reaction conditions: (1) 3a (0.1 mmol), 4 Å molecular sieves powders (150 mg), Me3OBF4 (0.5 mmol), CH2Cl2, 10 min; (2) MeOH (1 mL), 0 °C, NaBH4 (0.25 mmol); (3) AgNO3 (0.3 mmol), CH3CN (1.5 mL)/H2O(0.18 mL). Further transformations of 4. Reaction conditions: 4 (0.1 mmol). b DAST (1.2 equiv), rt, 4 h; c Na2HPO4 (1.2 equiv), m-CPBA (3 equiv), 0 oC, 12 h; d (1) NaBH4 (1.2 equiv), MeOH, rt, 4 h; (2) DAST (1.2 equiv), CH2Cl2, rt, 8 h; e MoO2Cl2 (5 mol %), N2CHCOOEt (1.2 equiv), CH2Cl2, 30 °C. Isolated yields are shown.
Fig. 4
Fig. 4. Mechanistic studies and proposed mechanism.
a Light on/off experiment. b Cyclic voltammogram of the potassium salt of 2a in MeCN. c Stern-Volmer Studies. d Proposed reaction mechanism.
See this image and copyright information in PMC

References

    1. Dolbier, W. R. Structure, reactivity, and chemistry of fluoroalkyl radicals. Chem. Rev.96, 1557–1584 (1996). - PubMed
    1. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science317, 1881–1886 (2007). - PubMed
    1. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev.37, 320–330 (2008). - PubMed
    1. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem.54, 2529–2591 (2011). - PubMed
    1. Wang, J. et al. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade. Chem. Rev.114, 2432–2506 (2014). - PubMed

LinkOut - more resources