Bench-stable azidodifluoromethyl imidazolium reagents unlock the synthetic potential of carbonimidic difluorides

Abstract

N-fluoroalkyl compounds are highly valuable in medicinal chemistry. While carbonimidic difluorides have been recognized as valuable intermediates for N-CF₃ compounds synthesis, their broader synthetic potential remains largely unexplored due to the limitations of current methodologies, particularly in expanding the scope of N-fluoroalkyl derivatives. Herein, we report the design and synthesis of azidodifluoromethyl imidazolium reagents that enable the in situ generation of carbonimidic difluorides. These intermediates undergo a series of controlled transformations, including chlorination, fluorination, monodefluorination, didefluorination, and subsequent derivatization of N-chlorodifluoromethyl compounds, providing an efficient strategy for the synthesis of structurally diverse N-fluoroalkane and amine derivatives.

Here, the authors report the design and synthesis of azidodifluoromethyl imidazolium reagents that enable the in situ generation of carbonimidic difluorides. These intermediates undergo a series of controlled transformations, including chlorination, fluorination, monodefluorination, didefluorination, and subsequent derivatization of N-chlorodifluoromethyl compounds, providing an efficient strategy for the synthesis of structurally diverse N-fluoroalkane and amine derivatives.

Introduction

The N-fluoroalkyl compounds have garnered increasing attention due to their distinctive physicochemical properties and broad applicability across pharmaceutical chemistry, agrochemicals, and materials science^1–6. Notably, N-CF₃ and N-CF₂H motifs play a crucial role in the design of bioactive molecules, often enhancing metabolic stability, lipophilicity, and bioavailability. As illustrated in Fig. 1a, numerous bioactive molecules incorporate N-fluoroalkyl functionalities^7–11, underscoring their significance in drug discovery and development.

Fig. 1. The importance of carbonimidic difluorides in synthesis and our design strategy.

a Selective bioactive molecules with N-fluoroalkyl groups. b Conventional synthetic methods to access carbonimidic difluoride derivatives. c Pathways to access difluoromethylenimino radicals. d Synthesis and applications of azidodifluoromethyl imidazolium reagents.

Carbonimidic difluorides play a pivotal role in current strategies for synthesizing N-CF₃ compounds^12–18. However, existing approaches^19–28 for their synthesis and modification fail to fully exploit their synthetic potential. Typically, carbonimidic difluorides are prepared either by oxidation of isothiocyanates or isocyanides (Fig. 1, b)^29–33, or through chlorine-to-fluorine substitution from carbonimidic dichlorides^19,34–38. The pioneering work of Schoenebeck^20–25, Wilson²⁶, Yi²⁷, and Tlili²⁸ has significantly advanced the application of carbonimidic difluorides in the synthesis of N-CF₃ compounds, introducing a series of one-pot transformations from isothiocyanates and AgF. Additionally, carbonimidic difluorides can be generated through defluorination of N-CF₃ compounds, which is often regarded as a side reaction^19,27. Despite these advances, current methodologies predominantly rely on substituted amines as starting materials for functional group interconversion, often requiring harsh reaction conditions, highly toxic reagents, or excessive fluorine sources, thereby limiting their scope for broader and more versatile applications.

Notably, in 1967, the Ogden group reported a reaction that generated difluoromethylenimino radicals by reacting tetrafluoro-2,3-diaza-1,3-butadiene with hexafluoropropylene (Fig. 1, c)³⁹. This process enables radical amination with polyfluoro-olefins to yield carbonimidic difluorides, offering a route to these compounds without requiring excess fluorine sources. However, limited by unstable difluoromethylenimino radical precursors and harsh activation conditions, the substrate scope of the reaction and related derivatization have not been fully explored. Follow-up studies on difluoromethylenimino radicals have not resolved these issues^40–42. Thus, we aim to design a bench-stable reagent that can generate difluoromethylenimino radicals, synthesize carbonimidic difluorides under mild conditions, and produce a variety of N-fluoroalkyl derivatives in a one-pot process.

Inspired by the work of Schoenebeck²⁴ and Beier^14,43, we envisioned that an azidodifluoromethyl reagent containing a leaving group could undergo single-electron transfer (SET) upon photoexcitation (Fig. 1, d). This process would release difluoromethylenimino radicals, which then react with radical acceptors to generate carbonimidic difluorides in situ. Since this process does not require an excess fluorine source, the carbonimidic difluorides can undergo further transformations such as chlorination (the AgF system is not compatible with chloride ions^20,26), fluorination, monodefluorination, and didefluorination reactions, yielding the corresponding N-fluoroalkyl and amine compounds. Our previous work has established that imidazolium salts exhibit significant reactivity in the generation of fluorinated radicals^44–47. In this work, we report the synthesis and application of bench-stable azidodifluoromethyl imidazolium reagents (IMADFs), with the aim of enabling the efficient synthesis of diverse N-fluoroalkyl compounds.

Results

Synthesis and reactivity study of IMADFs

Starting from CF₂Br₂, the compound undergoes two or three nucleophilic substitutions⁴⁸, yielding a series of IMADFs. In order to test the reactivity of these reagents, we designed a radical cyclization reaction using phenylvinylbenzoyl chloride for N-fluoroalkyl pyridone synthesis. The 2-pyridone scaffold is commonly found in pharmaceuticals and natural products^49–52. N-fluoroalkyl-substituted 2-pyridones have been shown to enhance the biological activity of molecules^10,11. In parallel, chlorodifluoromethyl groups are also widely used in bioactive molecules^53,54 and can be further modified to synthesize a variety of difluoromethylene derivatives^55–57. We began our study with the reaction of 2-(1-phenylvinyl)benzoyl chloride (1a) and IMADF-1 in anhydrous dichloromethane catalyzed by fac-Ir(ppy)₃ under 30 W blue LED irradiation. To our delight, the 2-(chlorodifluoromethyl)−4-phenylisoquinolin-1(2H)-one product (2a) was produced after 12 hours in a 30% yield (Table 1, entry 1). Next, we explored the use of different photocatalysts (entries 2-5) and found that Ir(piq)₃ improved the yield. Other IMADFs were also tested (entries 6-8), with IMADF-1 being the most effective. Considering that high concentrations might lead to the formation of various byproducts^20,35, we reduced the concentration, which significantly improved the yield (entries 9–12). Additionally, we observed that the yield varied with light intensity (entries 13–14), with the 90 W blue light source providing the best results, achieving a 78% GC yield and a 72% isolated yield for the target product. Control experiments confirmed that both the light source and the photocatalyst were essential for these transformations (entries 15 and 16).

Table 1.

Optimization of the Reaction Conditions

Entry	PC (3%)	Solvent	Light intensity	Reagent	Yielda (isolated)
1	fac-Ir(ppy)3	DCM (0.1 M)	30 W	IMADF-1	30%
s2	Ir(piq)3	DCM (0.1 M)	30 W	IMADF-1	40%
3	Ir[dF(CF3)ppy]2(dtbpy)PF6	DCM (0.1 M)	30 W	IMADF-1	<5%
4	Ir(Fppy)3	DCM (0.1 M)	30 W	IMADF-1	26%
5	4CzIPN	DCM (0.1 M)	30 W	IMADF-1	13%
6	Ir(piq)3	DCM (0.1 M)	30 W	IMADF-2	24%
7	Ir(piq)3	DCM (0.1 M)	30 W	IMADF-3	13%
8	Ir(piq)3	DCM (0.1 M)	30 W	IMADF-4	trace
9	Ir(piq)3	DCM (0.05 M)	30 W	IMADF-1	55%
10	Ir(piq)3	DCM (0.033 M)	30 W	IMADF-1	60%
11b	Ir(piq)3	DCM (0.033 M)	30 W	IMADF-1	61%
12b	Ir(piq)3	DCM (0.05 M)	30 W	IMADF-1	61%
13b	Ir(piq)3	DCM (0.05 M)	60 W	IMADF-1	72%
14b	Ir(piq)3	DCM (0.05 M)	90 W	IMADF-1	78% (72%)
15b	Ir(piq)3	DCM (0.05 M)	–	IMADF-1	0%
16b	–	DCM (0.05 M)	90 W	IMADF-1	trace

Reaction conditions: 1a (0.1 mmol), IMADF (0.15 mmol), PC (0.003 mmol), solvent, blue LED, 12 h under Ar.

DCM dichloromethane, IMADF azidodifluoromethyl imidazolium reagent, PC photocatalyst.

^aGC-MS yield with n-dodecane as the internal standard.

^b1a (0.2 mmol), IMADF (0.3 mmol), PC (0.006 mmol), solvent, blue LED, 12 h under Ar. Isolated yield in parentheses.

With the optimal conditions established, the substrate scope of chlorodifluoromethylamination was examined (Fig. 2). A broad range of benzoyl chlorides (1) with electron-withdrawing and electron-donating substituents smoothly underwent these transformations to afford the corresponding products (2b-2f) in 53-84% yields. Other aromatic rings, such as naphthalene afforded the corresponding product (2g) in 68% yield. Heteroaromatic acyl chlorides also participated in the reaction, affording the corresponding N-chlorodifluoromethyl-2-pyridone in moderate to good yields, examples include substrates derived from thiophene (2 h), furan (2i), oxazole (2j), imidazole (2k), thiazole (2 l), pyridine (2 m). Other disubstituted and trisubstituted phenylvinylbenzoyl chlorides also demonstrated the feasibility of the reaction (2n and 2o). Notably, monosubstituted alkenylbenzoyl chlorides also successfully yielded the target products in synthetically useful yields (2p-2s). To further demonstrate the potential of this protocol in medicinal chemistry, we synthesized 2-chlorodifluoromethyl-1(2H)-isoquinolone derivatives (2t and 2u), which may function as bioisosteric building blocks for some drugs. Trotabresib, an oral potent inhibitor of bromodomain and extraterminal (BET) proteins, is used for the treatment of high-grade glioma⁵⁸. Using our strategy, its N-CF₂Cl bioisostere was synthesized in 65% yield (2v). The mild conditions tolerated many functional groups, including halides (2b, 2m, 2t, 2u), ethers (2f), nitriles (2c), trifluoromethyl groups (2d, 2s), and sulfonyl groups (2 v). Through the employment of phenylvinylbenzoyl fluorides in the reaction, the corresponding N-CF₃ compounds were successfully synthesized. While the yield was less than ideal, the products were still obtained in synthetically useful quantities (3a-3e, 3v).

Fig. 2. Substrate scope of chlorodifluoromethylamination^a,b and trifluoromethylamination^c.

Reaction conditions: ^a1a (0.2 mmol in DCM), IMADF-1 (0.3 mmol), Ir(piq)₃ (0.006 mmol), 90 W blue LED, 12 h under Ar. ^bAdditional NaCl (0.2 mmol) was added to the reaction. ^c1’a (0.2 mmol in DCM), IMADF-1 (0.3 mmol), Ir(piq)₃ (0.006 mmol), 4-pyrrolidinopyridine (0.02 mmol), 90 W blue LED, 12 h under Ar.

Carbonimidic difluorides not only underwent chlorination and fluorination reactions, but also tunable defluorination reactions (Fig. 3). When styrene was used as radical acceptor, the intermediate imine was stable enough to be detected in the reaction system (see SI for details). Subsequently, secondary amines were used as nucleophiles. The radical addition followed by selective defluorination of carbonimidic difluorides led to the corresponding fluoroformamidines. Such types of moieties have been less studied due to their limited approaches⁵⁹. We applied our protocol to various styrene derivatives—including electron-withdrawing (6b), electron-donating (6c), disubstituted (6a-6d), trisubstituted (6e), and monosubstituted (6f)—affording the corresponding fluoroformamidines in 36%-83% yields. Besides morpholine, various nitrogen nucleophiles were evaluated in the monodefluorination reaction. Pyrrolidine (6g) and acyclic secondary amines (6h, 6i) underwent smooth transformation, affording fluoroformamidines in moderate to good yields. Additionally, azoles such as imidazole (6j), pyrazole (6k), pyrrole (6l) and 1,2,3-triazole (6 m) showed reactivity under the conditions, yielding analogous products in comparable yields. The defluorination could proceed further to produce isocyanate (7a), isothiocyanate (7b), and isoselenocyanate (7c), which are important synthons for amine derivatives.

Fig. 3. Substrate scope in the synthesis of carbonimidic difluorides and their defluorination reactions.

Reaction conditions: ^a4 (0.2 mmol), IMADF-1 (0.3 mmol), fac-Ir(ppy)₃ (0.006 mmol), 30 W blue LED, 2 h under Ar, then added secondary amine (0.3 mmol), triethylamine (0.3 mmol). ^bThe ratio of E/Z isomers was determined by NMR. ^c0.5 mmol IMADF-1 was used and stirred for 5 h. ^d The ratio of E/Z isomers was determined through isolated yield. ^epyrrole sodium salt as nucleophile. ^f The ratio of p1/p2 isomers was determined by NMR. ^gsilica gel (200 mg) as nucleophile and corresponding urea 7a’ was isolated. ^hNa₂S (0.4 mmol) as nucleophile. ⁱNa₂Se (0.4 mmol) as nucleophile.

Synthetic applications of 2a

To demonstrate the practical utility of this chlorodifluoromethylamination, a series of derivatizations were carried out (Fig. 4). A rapid chlorine-to-fluorine substitution was successfully achieved. Within 15 min, N-CF₂Cl (2a) was converted to N-CF₃ (3a) using KF as the fluorine source. The corresponding difluoromethyl (8) and difluoromethylene (9) compounds were also obtained via radical dechlorination in the presence of AIBN. These results demonstrate the potential of this protocol for late-stage diversification of fluorinated bioactive compounds.

Fig. 4. Synthetic applications.

a Synthesis of 3a via chlorine-to-fluorine substitution from 2a. b Dechlorination followed by hydrogenation of 2a. c Dechlorination followed by allylation of 2a. AIBN: Azobisisobutyronitrile.

Mechanistic studies

Based on our experimental results and precedents in the literature²⁴, a plausible mechanism for the chlorodifluoromethylamination reaction is proposed (Fig. 5). Initially, photoexcitation of Ir^III generates Ir^III*. This is followed by a single-electron transfer (SET) reduction of IMADF-1 (E_1/2^red = -1.05 V vs SCE; see SI for details) with Ir^III*, leading to the formation of radical Int-1 and Ir^IV [Ir(piq)₃, E_1/2^IV/III* = -1.42 V vs SCE, see SI for details]. Subsequently, the radical Int-1 undergoes N-N bond cleavage to produce the radical Int-2. Next, the imidazole derivative is removed from Int-2 yields Int-3 (difluoromethylenimino radical), which then attacks styrene to furnish the radical Int-4. This intermediate could undergo an intramolecular ring closure reaction and be oxidized by Ir^IV to generate the cationic intermediate Int-5. Finally, deprotonation of Int-5 results in the formation of N-CF₂Cl isoquinolone 2.

Fig. 5. Proposed mechanism.

Mechanistic proposal involving an SET pathway for the chlorodifluoromethylamination reaction.

To support the above mechanistic hypothesis, the control experiments were performed. Using diphenylethylene 4a as a trapping agent, the difluoromethylenimino radical was captured, and the formation of adduct 5a was confirmed by ¹⁹F-NMR [δ -47.29 and δ -60.29 ppm], GC-MS (m/z = 243.1), HRMS [ESI (m/z) calcd for C₁₅H₁₂F₂N (M + H)⁺ 244.0932, found 244.0931] and IR (C = N: 1805.62 cm⁻¹) (Fig. 6a, see SI for details). Radical clock experiment using cyclopropane 10 and 2 equivalents of KF under the standard chlorodifluoromethylamination conditions resulted in the ring-opening product 11 (28% yield, Fig. 6b). When Ir[dF(CF₃)ppy]₂(dtbpy)PF₆ (E_1/2^IV/III* = -0.89 V vs SCE)⁶⁰ was employed as the photocatalyst, intramolecular cyclization product 12 was predominantly formed, with only trace amounts of the SET product 5a. These results demonstrate that under photoexcitation conditions with weak reducing capacity, nitrene species are generated from cationic IMADF-1 via an energy transfer (EnT) process (Fig. 6c)^24,61. The consistently low yields (<5%) observed in both Table 1 (entry 3) and Supplementary Table 2 (entries 4-6) further support this mechanistic pathway. Additional experimental results demonstrate that the neutral IMADF-4 can also undergo the EnT process, yielding the cyclized product 13 instead of 5a (Fig. 6c). These results indicate that the SET process serves as the primary pathway for the chlorodifluoromethylamination reaction. Furthermore, the SET process exhibits a faster reaction rate compared to the EnT process. Luminescence quenching experiments reveal that the excited state photocatalyst (PC*) is quenched by IMADF-1, involving an oxidative quenching catalytic cycle (Fig. 6d). Moreover, difluoromethylenimino radical was confirmed in the photolysis of IMADF-1 via the Electron Paramagnetic Resonance (EPR) spectrum of PBN − NCF₂ (Fig. 6e, hyperfine coupling constants: A_Nα = 7.30 G, A_Hβ = 5.67 G, A_Nγ = 3.04 G, A_F1δ = A_F2δ = 5.67 G, g = 2.0066, see SI for details).

Fig. 6. Mechanistic experiments.

a Radical trapping experiment. b Radical clock experiment. c Control experiments. d Luminescence quenching experiments. e EPR experiments.

Discussion

In summary, we have successfully developed a highly reactive, bench-stable solid reagent capable of generating difluoromethylenimino radicals under visible-light catalysis. These radicals can then react with radical acceptors to form the corresponding carbonimidic difluorides. Through strategic substrate design, we programmed the synthesis of these compounds, enabling the subsequent preparation of various N-fluoroalkyl compounds and amine derivatives via chlorination, fluorination, and defluorination reactions (mono- and di-). We believe that this protocol will serve as a powerful tool for the preparation of valuable fluorinated amines. Ongoing studies of these reagents are underway in our laboratory.

Methods

General Procedure for Photocatalytic Chlorodifluoromethylamination, Trifluoromethylamination. Unless otherwise specified, all products were obtained using the following methods.

General procedure

Under argon, to an 8 mL flask was added Ir(piq)₃ (3 mol%), IMADF-1 (0.3 mmol, 1.5 equiv.), 4 mL 0.05 M acyl chloride or acyl fluoride (in DCM) at room temperature. After that, the tube was exposed to a 90 W blue LED and stirred for 12 h until the reaction was completed as monitored by GC-MS analysis. The reaction mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel or preparative TLC to give the desired product 2 and 3.

General Procedure for the Synthesis of Carbonimidic Difluorides and Their Defluorination.

General procedure

Under argon, fac-Ir(ppy)₃ (3 mol%) and IMADF-1 (0.3–0.5 mmol, 1.5–2.5 equivalents) were added to an 8 mL flask. If 4 was solid, it was also added to the flask. A mixture of DCE and AcOiPr (1 mL each) was then added. If 4 was liquid, it was added directly to the flask at room temperature. The reaction mixture was exposed to a 30 W blue LED for 2–5 h, until completion, as monitored by GC-MS analysis. Next, the CH₃CN or THF solution of the nucleophile, along with TEA (triethylamine), was added to the reaction tube. The mixture was stirred at room temperature until the intermediate was fully consumed. Finally, the reaction mixture was evaporated under vacuum, and the residue was purified by column chromatography on silica gel or preparative TLC to yield the desired product.

Author contributions

Y.W., W.Z., and Z.W. (王震) designed this project and analyzed the experiments. Z.W. (王震); Z.W. (王桢); J. L. and L.Y. carried out the experiments. X. G. conducted EPR experiments and data analysis. Z. W. (王震) and W.Z. wrote the manuscript. Y. P. and Y.W. directed the whole project.

Peer review

Peer review information

Nature Communications thanks Petr Beier, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.

Data availability

The authors declare that the main data supporting the findings of this study, including experimental procedures and compound characterization, are available within the article and its Supplementary Information files, or from the corresponding author upon request. The X-ray structural data of IMADF-1 is deposited in CCDC (No. 2333867 see Supplementary Table 1 for details). These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-025-66605-y.