English

• Over the past decade, the strategic development of introducing fluorine-containing groups into organic molecules has emerged as a prominent field of research [1–9]. Trifluoromethyl (CF₃), for instance, exhibits a strong electron-withdrawing effect and can significantly enhance key molecular properties, including lipophilicity, metabolic stability, and bioavailability [10–12]. Pyridines and their derivatives are prevalent nitrogen-containing heterocycles in pharmaceuticals, materials, and agrochemicals [13–18], and also serve as prominent ligands [19]. Due to the beneficial effects conferred by CF₃ group introduction, CF₃-containing pyridine cores feature in numerous drugs and agrochemicals (Fig. 1A) [20–24]. A prominent example is Tipranavir, a non-peptidic anti-HIV drug featuring a trifluoromethylated pyridine scaffold, which exhibits approximately 10–fold higher antiviral activity than its phenyl-based counterpart [25]. Traditional methods for pyridine functionalization rely on prefunctionalized substrates [26–35]. However, the step economy and ready availability of C–H bonds as substrates make direct trifluoromethylation of pyridine C–H bonds a highly attractive strategy [36–38]. This approach is particularly valuable for the late-stage functionalization of existing bioactive molecules, a capability crucial for accelerating drug candidate screening.

  Figure 1

  

  Figure 1.  meta-C-H trifluoromethylation of pyridines. (A) Examples of pharmaceuticals with meta-trifluoromethylated pyridines. (B) Dearomatization through Huisgen 1,4-dipolar cycloaddition for meta-trifluoromethylation of pyridines. (C) This work: Selective meta-C-H trifluoromethylation of pyridines via 1,4-dihydropyridinephosphonate.

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  The nitrogen atom in pyridine possesses a lone pair of electrons, enabling protonation or coordination with Lewis acids, which significantly reduces the electron density of the heteroaromatic ring, particularly at the ortho- and para-positions [39]. Consequently, current C-H functionalization of pyridines, including C-H trifluoromethylation, predominantly targets at the ortho- and para-positions [40–49]. However, the direct meta-C-H functionalization of pyridines remains highly challenging. In recent years, a number of ingenious strategies have been developed for the meta-C-H functionalization of pyridines, including the use of directing groups [50–52], non-directed metalation [53–57], temporary dearomatization strategies [38,58–77] and ring-opening, functionalization, then ring-closing strategies [78–82]. Nevertheless, to the best of our knowledge, most of the direct C-H-trifluoromethylation methods have substrate dependence as well as low yields and poor selectivity, Studer and his co-workers conducted a dedicated study on meta-C-H trifluoromethylation of pyridines [37]. In 2022, Studer group employed a dearomatized oxazino-pyridine intermediate, which was produced by 1,4-Huisgen cycloaddition with pyridines [70], for regioselective trifluoromethylation under light conditions, followed by acid-promoted rearomatization to obtain meta-trifluoromethylated pyridines with high selectivity (Fig. 1B).

  Herein, based on temporary dearomatization strategy, we disclose a method to create a 1,4-dihydropyridinephosphonate that undergoes regioselective trifluoromethylation, followed by base-promoted rearomatization to afford meta-trifluoromethylated pyridines in one-pot process (Fig. 1C). This method tolerates a variety of functional groups and is applicable for late-stage meta-C-H trifluoromethylation of pharmaceutical molecules containing pyridine motifs, while at the same time, it offers a complementary scope to the Studer approach.

  The choice of pyridine N-activating groups and nucleophiles is crucial for the process and directly impacts the selectivity and yield of dearomatization, the efficiency of trifluoromethylation and the ease of rearomatization. Based on Akiba's method [83] for the synthesis of 1,4-dihydropyridinephosphonates, we implemented several optimizations to the procedure. We began our investigation with 3-(4-fluorophenyl)pyridine (1a) as the model substrate with three electrophiles potentially suited as N-activating reagents (Ⅰ–Ⅲ, Table 1) and three phosphites as nucleophiles (Ⅳ–Ⅵ, Table 1). It indicated that P(OEt)₃ was superior to P(OMe)₃ and P(OⁱPr)₃ in forming 1,4-dihydropyridinylphonate from 1a when methyl chloroformate served as N-activating reagent (entries 1–3). Comparable yields were obtained with ethyl chloroformate as the N-activating reagent and P(OEt)₃ or P(OⁱPr)₃ as the nucleophiles, both of which performed better than P(OMe)₃ (entries 4–6). Notably, N-Tf-dihydropyridinylphosphonate remained inaccessible through this strategy using P(OEt)₃, P(OMe)₃, or P(OⁱPr)₃ (entries 7–9). The reaction performed in DCM provided lower yields (entry 10). Only 23% yield of the reaction was observed at 0℃ with methyl chloroformate, leaving substantial unreacted starting material (entry 11), while room-temperature conditions failed to initiate effective pyridine activation (entry 12).

  Table 1

  

  Table 1.  Optimization for pyridine dearomatization.

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  Entry	N-Activating reagents	Phosphites	Yield (%)a
  1	Ⅰ	Ⅳ	96
  2	Ⅰ	Ⅴ	70
  3	Ⅰ	Ⅵ	93
  4	Ⅱ	Ⅳ	91
  5	Ⅱ	Ⅴ	63
  6	Ⅱ	Ⅵ	91
  7	Ⅲ	Ⅳ	N.D.
  8	Ⅲ	Ⅴ	N.D.
  9	Ⅲ	Ⅵ	N.D.
  10b	Ⅰ	Ⅳ	83
  11c	Ⅰ	Ⅳ	23
  12d	Ⅰ	Ⅳ	N.D.
  a Yields were determined by crude 1H NMR spectra using 1,3,5-trimethylbenzene as internal standard. b Using DCM as solvent. c Activation at 0 ℃. d Activation at room temperature.

  Based on the results in Table 1, methyl chloroformate was selected as the N-activating reagent, and the 1,4-dihydropyridinephosphonate 2a derived from triethyl phosphite served as the model substrate for subsequent regioselective CF₃ introduction under copper catalysis, using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni Ⅱ) as the CF₃ source. Through systematic experimentation, we achieved a 71% yield of the trifluoromethylation product 3a using catalytic CuBr(PPh₃)₃ (10 mol%) and 1.2 equiv. Togni Ⅱ (entry 1, Table 2). Togni Ⅱ was found to be essential for activating substrate 2a to afford 3a. When alternative trifluoromethylation reagents (such as Togni I and Umemoto reagents) were employed, no significant associated trifluoromethylated products were detected (see Supporting information for further details). Given the critical role of copper salts play in enamine trifluoromethylation, systematic screening of copper catalysts was conducted, identifying CuBr(PPh₃)₃ as the optimal catalyst due to its superior efficacy (entries 2 and 3, Table 2). Notably, no product formation was observed in the absence of copper catalyst (entry 4, Table 2). In the testing of other solvents including 1,2-dichloroethane (DCE), acetonitrile (ACN), and dimethyl sulfoxide (DMSO), significantly decreased the conversion of 2a (entries 5–7, Table 2). Subsequently, the rearomatization of 3a was optimized (Table 3). In the presence of base, 3a was converted to product 4a, with 1,4-diazabicyclo[2.2.2]octane (DABCO) proving more efficient than t-BuONa or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (entries 2 and 3, Table 3). The reaction proceeds optimally in DMSO (entries 4 and 5, Table 3). Additionally, a one-pot, two-step procedure was attempted, affording 4a in 60% yield from 2a (entry 6, Table 3). This yield proved comparable to that achieved through sequential reactions, while significantly streamlining the synthetic process.

  Table 2

  

  Table 2.  Optimization for trifluoromethylation of pyridine dearomatization intermediates.^a

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  Entry	Deviation from standard conditions	3a Yield (%)b
  1	None	71
  2	CuI instead of CuBr(PPh3)3	46
  3	Cu(MeCN)4PF6 instead of CuBr(PPh3)3	55
  4	w/o Cu catalyst	N.D.
  5	DCE instead of DCM	69
  6	ACN instead of DCM	60
  7	DMSO instead of DCM	23
  a Reaction conditions: 2a (0.1 mmol, 1.0 equiv.), Togni Ⅱ (1.2 equiv.), CuBr(PPh3)3 (10 mol%), DCM (0.2 mol/L), 60 ℃, 22 h, Ar. b Determined by 19F NMR spectroscopy using PhCF3 as internal standard.

  Table 3

  

  Table 3.  Optimization for rearomatization.^a

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  Entry	Deviation from standard conditions	4a Yield (%)b
  1	None	88
  2	t-BuONa instead of DABCO	69
  3	DBU instead of DABCO	11
  4	DCE instead of DMSO	N.D.
  5	DCM instead of DMSO	N.D.
  6c	One-pot procedure from 2a	60
  a Reaction conditions: 3a (0.05 mmol, 1.0 equiv.), DABCO (2.0 equiv.), DMSO (0.05 mol/L), 80 ℃. DABCO: 1,4-diazabicyclo[2.2.2]octane; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene. b Determined by 19F NMR spectroscopy using PhOCF3 as internal standard. c One-pot procedure, yield based on dearomatized intermediate 2a.

  Under the optimized conditions, the scope of the trifluoromethylation reaction was evaluated with various substrates (Fig. 2). The method proved applicable to a range of functionalized pyridine derivatives. Replacement of the fluorine substituent on the aromatic ring with electron-donating groups (e.g., methyl, methoxy, tert-butyl) in mono- and disubstituted derivatives also provided the trifluoromethylated products 4c–4g and 4m–4p in moderate yields. Electron-withdrawing groups such as cyano and trifluoromethyl were also compatible, providing products 4h–4i. Furthermore, carbon–halogen bonds remained intact under the reaction conditions, delivering products 4j–4l with preserved halogen atoms in moderate yields. These halogenated derivatives serve as versatile synthetic building blocks for further coupling transformations. Notably, when an electron-rich thiophene ring occupied the meta-position of pyridine, the reaction exclusively delivered meta-selective trifluoromethylation on the pyridine ring (4q). Our approach was also successful in achieving meta-selective trifluoromethylation of pyridine derivatives containing heteroaromatic substituents (4s–4z), such as pyrimidine, pyrazine, and pyridazine, despite the significant electron deficiency caused by these heterocycles. Additionally, the protocol also tolerated functional groups such as esters and amides (4aa–4ac). Given the multifaceted roles of pyridines in drug development, the late-stage functionalization of pyridines could rapidly optimize a candidate's pharmacokinetic and pharmacodynamic (PK/PD) properties and facilitate the discovery of new drugs. This method was extended to bioactive molecule-derived substrates (4ad–4ag), including l-menthol, loratadine, estrone, and vonoprazan, underscoring its utility in medicinal chemistry. Unfortunately, this approach is restricted mostly to meta-substituted pyridines, the yield of 2,3-disubstituted pyridine derivatives was relatively low (4ah), sometimes with no product formed (4ai). For the ortho-aryl-substituted pyridines, significant steric hindrance prevented dearomatization (4aj). Finally, a gram-scale reaction of 2b afforded compound 4b in 42% yield.

  Figure 2

  

  Figure 2.  Substrate scope of meta-C-H trifluoromethylation of pyridines. Reaction conditions: 2a (1.0 equiv.), Togni Ⅱ (1.2 equiv.), CuBr(PPh₃)₃ (10 mol%), DCM (0.2 mol/L), 60 ℃, Ar, 22 h, then remove the solvent under vacuum, DABCO (2.0 equiv.), DMSO (0.05 mol/L), 80 ℃, Ar, 20 h. The yields based on dearomatized intermediate 2 were determined via ¹⁹F NMR with PhOCF₃ as internal standard, the yields in parentheses were isolated yields. ^a DABCO (4.0 equiv.). ^b The intermediate 3aa was isolated prior to rearomatization.

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  To gain a deeper understanding of the mechanism, some preliminary studies were conducted. The addition of 2.0 equiv. 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2.0 equiv. butylated hydroxytoluene (BHT) as radical inhibitors completely inhibited the reaction. When TEMPO was reduced to 1.2 equiv., the yield of 3a decreased to 21%, while the TEMPO-CF₃ adduct was detected with a yield of 45% by ¹⁹F NMR (Fig. 3A). Moreover, the structure of intermediate 3ac derived from 2ac was confirmed by single-crystal X-ray diffraction (SC-XRD) analysis (Fig. 3B). Furthermore, monitoring the rearomatization process by ¹⁹F NMR spectroscopy revealed that the concentrations of two intermediates (δ -70.76 and -60.50) changed as the reaction proceeded (Fig. 3C). By comparing them with the signals of the starting material 3a (δ -70.47) and the product 4a (δ -62.42), in combination with the molecular weights of 5 monitored by HRMS, we surmised that the two intermediates were D (δ -70.76) and E (δ -60.50), respectively. According to the above experimental results and related literature studies [84–94], a plausible reaction mechanism is proposed (Fig. 3D): (ⅰ) The Togni Ⅱ reagent undergoes copper-catalyzed single-electron transfer (SET) to generate a trifluoromethyl radical and a Cu(Ⅱ) specie B; (ⅱ) This radical adds to the 1,4-dihydropyridinephosphonate 2a to give the radical intermediate C; (ⅲ) Intermediate C reacts with B to yield intermediate 3a while regenerating the Cu(I) catalyst; (iv) Finally, 3a undergoes DABCO-mediated aromatization via intermediates D and E to afford the meta-trifluoromethylated pyridine product 4a.

  Figure 3

  

  Figure 3.  Mechanistic studies. (A) Radical inhibition experiments. (B) X-ray of 3ac. (C) ¹⁹F NMR monitoring of the rearomatization experiment reaction at different reaction times. (D) Proposed mechanism.

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  In summary, we developed a novel dearomatization-rearomatization strategy based on 1,4-dihydropyridinephosphonate intermediates, which undergo copper-catalyzed regioselective C–CF₃ bond formation with Togni Ⅱ reagent followed by DABCO-promoted rearomatization, achieving meta-C-H trifluoromethylation of pyridine derivatives. A variety of pyridines bearing either electron-donating or electron-withdrawing (hetero)aryl substituents were converted to their corresponding trifluoromethylated products. The reaction proceeded with high regioselectivity, and meta-trifluoromethylated products were obtained as the sole regioisomer. Carbon-halogen bonds, esters, aryl ethers, and amides were tolerated under the reaction conditions. This activation paradigm overcomes the inherent site-selectivity constraints of traditional aromatic systems, demonstrating broad applicability to various pyridine-containing heterocyclic substrates and successful implementation in late-stage trifluoromethylation of pharmaceutical molecules. We anticipate this work will contribute to the development of robust methods for meta-selective transformations of pyridines.

  CRediT authorship contribution statement

  Wanqiu Zhao: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. Aijia Zhang: Formal analysis, Data curation. Qingyun Huang: Writing – review & editing, Writing – original draft, Project administration, Investigation, Formal analysis, Conceptualization. Pingping Tang: Writing – review & editing, Writing – original draft, Supervision, Project administration, Funding acquisition, Conceptualization.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  Acknowledgments

  This work was financially supported by the National Key Research and Development Program of China (No. 2021YFF0701700), the National Natural Science Foundation of China (NFSC, Nos. 21925105 and 92156001), the Natural Science Foundation of Tianjin (No. 24JCZDJC00700), the Haihe Laboratory of Sustainable Chemical Transformations, and the Fundamental Research Funds for the Central Universities.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.112133.

  
  
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  Figure 1  meta-C-H trifluoromethylation of pyridines. (A) Examples of pharmaceuticals with meta-trifluoromethylated pyridines. (B) Dearomatization through Huisgen 1,4-dipolar cycloaddition for meta-trifluoromethylation of pyridines. (C) This work: Selective meta-C-H trifluoromethylation of pyridines via 1,4-dihydropyridinephosphonate.

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  Figure 2  Substrate scope of meta-C-H trifluoromethylation of pyridines. Reaction conditions: 2a (1.0 equiv.), Togni Ⅱ (1.2 equiv.), CuBr(PPh₃)₃ (10 mol%), DCM (0.2 mol/L), 60 ℃, Ar, 22 h, then remove the solvent under vacuum, DABCO (2.0 equiv.), DMSO (0.05 mol/L), 80 ℃, Ar, 20 h. The yields based on dearomatized intermediate 2 were determined via ¹⁹F NMR with PhOCF₃ as internal standard, the yields in parentheses were isolated yields. ^a DABCO (4.0 equiv.). ^b The intermediate 3aa was isolated prior to rearomatization.

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  Figure 3  Mechanistic studies. (A) Radical inhibition experiments. (B) X-ray of 3ac. (C) ¹⁹F NMR monitoring of the rearomatization experiment reaction at different reaction times. (D) Proposed mechanism.

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  Table 1.  Optimization for pyridine dearomatization.

  Entry	N-Activating reagents	Phosphites	Yield (%)a
  1	Ⅰ	Ⅳ	96
  2	Ⅰ	Ⅴ	70
  3	Ⅰ	Ⅵ	93
  4	Ⅱ	Ⅳ	91
  5	Ⅱ	Ⅴ	63
  6	Ⅱ	Ⅵ	91
  7	Ⅲ	Ⅳ	N.D.
  8	Ⅲ	Ⅴ	N.D.
  9	Ⅲ	Ⅵ	N.D.
  10b	Ⅰ	Ⅳ	83
  11c	Ⅰ	Ⅳ	23
  12d	Ⅰ	Ⅳ	N.D.
  a Yields were determined by crude 1H NMR spectra using 1,3,5-trimethylbenzene as internal standard. b Using DCM as solvent. c Activation at 0 ℃. d Activation at room temperature.

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  Table 2.  Optimization for trifluoromethylation of pyridine dearomatization intermediates.^a

  Entry	Deviation from standard conditions	3a Yield (%)b
  1	None	71
  2	CuI instead of CuBr(PPh3)3	46
  3	Cu(MeCN)4PF6 instead of CuBr(PPh3)3	55
  4	w/o Cu catalyst	N.D.
  5	DCE instead of DCM	69
  6	ACN instead of DCM	60
  7	DMSO instead of DCM	23
  a Reaction conditions: 2a (0.1 mmol, 1.0 equiv.), Togni Ⅱ (1.2 equiv.), CuBr(PPh3)3 (10 mol%), DCM (0.2 mol/L), 60 ℃, 22 h, Ar. b Determined by 19F NMR spectroscopy using PhCF3 as internal standard.

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  Table 3.  Optimization for rearomatization.^a

  Entry	Deviation from standard conditions	4a Yield (%)b
  1	None	88
  2	t-BuONa instead of DABCO	69
  3	DBU instead of DABCO	11
  4	DCE instead of DMSO	N.D.
  5	DCM instead of DMSO	N.D.
  6c	One-pot procedure from 2a	60
  a Reaction conditions: 3a (0.05 mmol, 1.0 equiv.), DABCO (2.0 equiv.), DMSO (0.05 mol/L), 80 ℃. DABCO: 1,4-diazabicyclo[2.2.2]octane; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene. b Determined by 19F NMR spectroscopy using PhOCF3 as internal standard. c One-pot procedure, yield based on dearomatized intermediate 2a.

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