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 Aug 19;16(1):7731.
doi: 10.1038/s41467-025-62834-3.

Modular synthesis of CF2-containing compounds with PhSO2CF2H reagent through difluoromethylene radical anion synthon strategy

Shuo Sun #  1 , Rulong Jia #  1   2 , Xin Zhou  1 , Zhongyi Wang  1 , Jian Rong  1 , Chuanfa Ni  1 , Jinbo Hu  3   4
Affiliations

Modular synthesis of CF2-containing compounds with PhSO2CF2H reagent through difluoromethylene radical anion synthon strategy

Shuo Sun et al. Nat Commun. .

Abstract

Difluoromethylene moiety has gained widespread applications in pharmaceuticals, agrochemicals, and materials owing to its augmented lipophilicity and being bioisosteric to ethereal oxygen. Possessing two orthogonal reactivity modes for bridging an electrophile and a radical acceptor to give gem-difluorides (R1-CF2-R2), the efficient difluoromethylene radical anion synthon (diFRAS) has been long sought after. In this work, we successfully utilize the readily available difluoromethyl phenyl sulfone (PhSO2CF2H) to couple with electrophiles and radical acceptors, thereby enabling PhSO2CF2H to serve as a novel diFRAS in organic synthesis. The generation of radicals (•CF2R) via visible light-promoted homolytic cleavage of C-S bonds in (phenylsulfonyl)difluoromethylated derivatives (PhSO2CF2R) is the linchpin in the diFRAS strategy to construct gem-difluorides (R1-CF2-R2) with structural complexity.

PubMed Disclaimer

Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Synthesis of gem-difluorides.
a Synthetic route to gem-difluorides and its bioisostere. b Previously developed difluoromethylene synthon. c Challenges for difluoromethylene radical anion synthon (diFRAS). d This work: PhSO2CF2H as diFRAS for modular synthesis of gem-difluorides with chemical complexity. FG functional group, LG leaving group, PG protecting group.
Fig. 2
Fig. 2. Scope of gem-difluorides from sulfones generated via additions using alkenes as radical acceptors.
Reaction conditions: 2 (0.5 mmol, 1.0 equiv), 1 (2.0 equiv), 2-NpSH (20 mol%), HCO2K (3.0 equiv), DMSO (4 mL), white LED, room temperature, 18 h. All yields are isolated yields. a1 (0.5 mmol, 1.0 equiv), 2 (2.0 equiv).
Fig. 3
Fig. 3. Scope of gem-difluorides from sulfones generated via substitutions using alkenes as radical acceptors.
Reaction conditions: 2 (0.5 mmol, 1.0 equiv), 1 (2.0 equiv), 2-NpSH (20 mol%), HCO2K (3.0 equiv), DMSO (4 mL), white LED, room temperature, 18 h. All yields are isolated yields. aK2CO3 (1.0 equiv) as an additive. bThe reaction was conducted on 0.2 mmol scale.
Fig. 4
Fig. 4. Scope of gem-difluorides from sulfones with thiols as radical acceptors.
Reaction conditions: 2 (0.5 mmol, 1.0 equiv), 1 (2.0 equiv), DBU (2.0 equiv), DMSO (4 mL), white LED, room temperature, 18 h. All yields are isolated yields. a1 (0.5 mmol, 1.0 equiv), 2 (2.0 equiv). bfac-Ir(ppy)3 (0.2 mol%) as an additive, blue LED instead of white LED. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Fig. 5
Fig. 5. Scope of gem-difluorides from sulfones with hydrogen atom as radical acceptor.
Reaction conditions: 1 (0.5 mmol), 2-naphthalenethiol (10 mol%), HCO2K (3.0 equiv), DMSO (4 mL), white LED, room temperature, 18 h. All yields are isolated yields.
Fig. 6
Fig. 6. Scope of hydrodifluoromethylation of alkenes.
Reaction conditions: 2 (0.5 mmol, 1.0 equiv), 1 (2.0 equiv), 2-NpSH (20 mol%), HCO2K (3.0 equiv), DMSO (4 mL), white LED, room temperature, 18 h. All yields are isolated yields. aAdditional H2O (0.5 mL) was added. bFollowing conditions for construction of CF2-S bond in Fig. 4.
Fig. 7
Fig. 7. Applications and mechanistic studies.
a Radical clock reaction. b Radical cyclization of unconjugated dienes. c Sunshine-induced difluoroalkylation. d Gram-scale reaction. e UV-vis absorption spectra of species in the transformation and oxidative quenching cycle of 2-napthalenethiolate. f Proposed mechanism.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem.61, 5822–5880 (2018). - PubMed
    1. Ogawa, Y., Tokunaga, E., Kobayashi, O., Hirai, K. & Shibata, N. Current contributions of organofluorine compounds to the agrochemical industry. iScience23, 101467 (2020). - PMC - PubMed
    1. Blackburn, G. M., England, D. A. & Kolkmann, F. Monofluoro- and difluoro-methylenebisphosphonic acids: isopolar analogues of pyrophosphoric acid. J. Chem. Soc. Chem. Commun. 15, 930–932 (1981).
    1. Blackburn, G. M., Kent, D. E. & Kolkmann, F. The synthesis and metal binding characteristics of novel, isopolar phosphonate analogues of nucleotides. J. Chem. Soc. Perkin Trans.1, 1119–1125 (1984).
    1. Xu, Y. et al. Structure−activity relationships of fluorinated lysophosphatidic acid analogues. J. Med. Chem.48, 3319–3327 (2005). - PubMed

LinkOut - more resources