Electrochemically promoted defluorinative sulfoximination and fluorosulfonylation of non-activated aryl fluorides at room temperature

Abstract

Due to the high bond dissociation energy and kinetic inertness of the C–F bond, direct activation of inert aryl fluorides for new transformations under mild conditions remains a significant challenge. Although it has been known that single electron reduction can be applied for the activation of inert aryl fluorides at room temperature, the need for very strong reduction conditions along with the competitive side reactions during the reduction process limits the synthetic applications. Herein, by leveraging the advantages of electrosynthesis and the versatile transformation nature of aryl radicals, two types of challenging defluorinative transformations of non-activated aryl fluorides which include sulfoximination via cheap nickel catalysis and transition metal catalyst-free fluorosulfonylation at room temperature have been disclosed for the first time. These reactions show good functional group tolerance and can be applied for the late-stage modifications of bioactive derivatives. As for the practical nickel-catalyzed defluorinative sulfoximination, detailed mechanistic studies reveal that after the cathodic reduction of aryl fluorides to form the key aryl radical, subsequent nickel-promoted C–N bond formation via paired electrolysis is responsible for the success.

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Introduction

The ubiquity and importance of non-activated aryl fluorides in synthetic chemistry have continuously driven the development of efficient transformations under mild conditions.¹ However, their activation has long been a formidable challenge due to the high bond dissociation energy (126 kcal mol⁻¹) and kinetic inertness. While traditional methods typically rely on transition metals to activate the C–F bond via oxidative addition (Fig. 1A),² recent contributions from the groups of Shibata³ and Shi⁴ have demonstrated that the coordination of simple aryl fluorides with Ru or Rh could deliver η⁶-coordinated complexes, facilitating S_NAr substitutions with N- or O-nucleophiles. Nevertheless, the use of harsh conditions such as high temperatures or metallic reagents is often necessary for the above examples.

Fig. 1 State of the art for the activation of C–F bonds of inert ArF and our progress.

To develop more robust defluorinative examples under mild conditions, recent advances have uncovered the single electron activation models, enabling some interesting defluorinative transformations even in a catalytic way (Fig. 1A). For example, thanks to the moderate oxidation potential (E_ox = +2.2 V vs. SCE) of aryl fluorides, researchers such as Lambert,⁵ Nicewicz,⁶ and Jiang⁷ have demonstrated that aryl fluorides can be easily oxidized to form electrophilic aryl radical cations, facilitating S_NAr substitutions. Nevertheless, compared with the aforementioned single electron oxidation strategy, the development of a single electron reduction strategy for the defluorinative transformation of inert aryl fluorides lags behind. To date, only visible light-promoted borylation, phosphonylation, arylation, sulfuration and selenization have been reported by König,⁸ Jiao,⁹ Miyake and co-workers¹⁰ (with moderate yields in most cases) recently, in addition to hydrodefluorination.¹¹ The difficulty can be attributed to the need for very negative reduction conditions to effectively reduce PhF (E_red = −3.0 V vs. SCE), and the presence of very competitive side reactions such as hydrodefluorination and defluorinative dimerization (to form the corresponding arenes or biaryls) during the reduction process (Fig. 1B),^1g resulting in limited transformations with limited functional group tolerance.

On the other hand, by borrowing the advantages of electrosynthesis such as tunable and wide redox potential with robust catalytic models under mild conditions, many excellent synthetic methodologies focusing on the use of electrosynthesis to activate and transform inert molecules have been developed recently.¹² Nevertheless, while the reduction of simple fluorobenzenes at the cathode has been observed for more than 50 years,^11b the potential for using such a convenient activation strategy for defluorative transformations of non-activated aryl fluorides remains underexplored.¹³ Herein, coupled with our continuing interest in electrochemically promoted transformations with the involvement of aryl radicals,¹⁴ we envisioned that the exquisite control of cathodic reduction conditions might realize the selective single electron reduction of inert aryl fluorides at first, which could deliver the key aryl radical via fragmentation.^1g After this, by borrowing the versatile chemical transformations of aryl radicals,¹⁵ it might provide an opportunity for developing new defluorinative transformations of inert aryl fluorides at room temperature by overcoming the typically undesired side reactions (vide anta). Specifically, the following two kinds of useful yet unknown reactions have been tentatively designed. (1) First of all, guided by known nickel-promoted radical transformations,¹⁶ we thought that the trapping of the aryl radical by nickel species¹⁷ followed by interaction with suitable nucleophiles might constitute a new and efficient solution for achieving the novel defluorination coupling of fluoroarenes at room temperature. Guided by pioneering studies related to the success of nickel-catalyzed C–N bond construction,^17c,18 we have focused our attention on the N-arylation of NH-sulfoximines since N-aryl sulfoximines have found wide applications in organic synthesis, drug discovery, and other fields,¹⁹ as well as the use of non-activated aryl fluorides as the arylation source for the purpose remains elusive.²⁰ (2) Second, to further demonstrate the synthetic usefulness of such a cathodic reduction strategy, it was further postulated that the trapping of in situ formed aryl radicals with stoichiometric amounts of SO₂, followed by fluorination²¹ might be able to achieve the unprecedented transition metal catalyst-free defluorinative fluorosulfonylation of inert aryl fluorides at room temperature. Herein, we wish to report these preliminary results. The substrate scope, synthetic applications and the mechanistic studies of these two transformations have been carefully disclosed.

Results and discussion

Condition optimization for N-arylation of NH-sulfoximines with unactivated aryl fluorides was performed. To explore the feasibility of the designed Ni-catalyzed arylation with aryl fluorides enabled by electrosynthesis, NH-sulfoximine 1a and 1-fluoro-4-methylbenzene 2a have been chosen as model substrates. After careful screening of various parameters such as nickel source, electrodes, electrolyte, solvent or base, we are pleased to notice that the desired 3a could be facilely isolated with 83% isolated yield under the optimal mild reaction conditions (Table 1). Both toluene (trace) and 4,4′-dimethyl-1,1′-biphenyl (16%) have been detected as the main byproducts, indicating the involvement of aryl radical species in our system, as well as the challenge in achieving the desired transformation. The following five points should be highlighted. (1) First, the use of the simple and cheap NiCl₂·6H₂O as a catalyst is essential, as the change to others, such as NiCl₂, NiBr₂ led to inferior results, and the use of NiI₂ or Ni(COD)₂ inhibits the reactivity (entry 2). More interestingly, the addition of bidentate nitrogen-containing ligands, which are commonly used in nickel-catalyzed radical reactions such as L₁–L₅, gave only trace 3a in this system (entry 3). Notably, DMA can serve as a good ligand for NiCl₂, which could bind to the nickel center in our case, thereby benefiting the efficiency.²² Noteworthily, although sulfoximines have been reported as ligands for nickel catalysis,²³ and we also obtained the X-ray structure of the NiCl₂(1a)₂(H₂O)₂ complex (CCDC: 2433423†), UV-visible absorption spectra experiments indicate the complete dissociation of the crystal upon mixing with DMA (for details, please see the ESI†). (2) The reactivity diminished significantly when electrodes such as C(+), RVC(+), Ni foam (+), C(−), RVC(−), or Pt(−) were used (entries 4 and 5). (3) Additionally, other solvents (DMF, DMSO, MeCN, HFIP, and CH₂Cl₂), base (Na₂CO₃, K₂CO₃ or KOAc), or electrolyte (ⁿBu₄NPF₆ or ⁿBu₄NBr) proved ineffective (entries 6–8). (4) Control experiments indicated that the nickel catalyst, electric current, electrolyte and additive ⁱPr₂NEt are all essential for the transformation (entries 9 and 10). (5) Notably, the use of Mn or Zn instead of electricity as a reductant led to the shutdown of the reactivity (entry 11), indicating the importance of electrosynthesis.

Table 1 Condition optimization for arylation

Entry^a	Deviation	GC yield of 3a (%)
a Standard conditions: Pt anode (1 cm × 0.2 cm) and Ni foam cathode (0.8 cm × 0.2 cm), 1a (0.30 mmol), 2a (0.75 mmol), NiCl2·6H2O (10 mol%), Cs2CO3 (2.0 equiv.), ^iPr2NEt (1.5 equiv.), ^nBu4NBF4 (1.0 equiv.), DMA (4 mL) in an undivided cell, 20 mA, 6 h, and argon. b Isolated yield.
1	None	81^b
2	NiCl2, NiBr2, NiI2 or Ni(COD)2 instead of NiCl2·6H2O	52/25/trace/trace
3	With L1–L5 (12 mol%)	All trace
4	C(+), RVC(+), Ni foam (+) instead of Pt(+)	Trace/trace/trace
5	C(−), RVC(−) or Pt(−) instead of Ni foam (−)	8/13/trace
6	DMF, DMSO, MeCN, HFIP, CH2Cl2 instead of DMA	43/32/0/0/0
7	Na2CO3, K2CO3 or KOAc instead of Cs2CO3	32/23/trace
8	^nBu4NPF6 or ^nBu4NBr instead of ^nBu4NBF4	25/16
9	No electrolyte, NiCl2·6H2O or ^iPr2NEt	0/0/64
10	0, 15 or 25 mA instead of 20 mA	0/61/trace
11	Mn, Zn instead of electricity	0/0

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Substrate scope evaluation for N-arylation

With the optimal conditions in hand, the substrate scope was first evaluated with respect to various aryl fluorides 2 and NH-sulfoximines 1. As shown in Fig. 2, our protocol shows good functional group tolerance, as the introduction of phenyl (3c), alkoxyl (3d–3e, 3m, 3n, and 3t), phenoxyl (3f), ester group (3g, 3r, and 3s), alkylhydroxyl (3h) and Bpin (3i) at the para- or meta-position of fluorobenzene delivered products with 54–86% yields. Noteworthily, the utilization of (S)-NH-sulfoximine 1b as the substrate enables the delivery of (S)-3b without erosion of enantioselectivity. The use of 1,4-, 1,3-difluorobenzene or 1,3,5-trifluorobenzene as substrates enables selective production of the mono-substituted sulfoximines 3j, 3p and 3o with moderate yields (58–71%). Moreover, fluoroarenes bearing substituents at the ortho-position are also suitable for the reaction, and the desired 3u–3aa was obtained with 49–62% yield. In addition, our system is compatible with polyaromatic fluorides, as naphthyl, O- or N-containing products 3ab–3af could be easily isolated with 62–79% yields. Next, the scope of sulfoximines with different substituents has been evaluated, as the introduction of methyl, aryl, diaryl or dialkyl groups has a marginal effect on the yields (3ag–3an). Although the full conversion of aryl fluorides for products 3y and 3aa has been observed, the low yields for these substrates can be partially attributed to the formation of defluorinative byproducts (58% and 51%, respectively) with the remaining 1a untouched. As for methyl 4-fluorobenzoate, low conversion (60%) was observed under standard conditions, along with the formation of 18% of methyl benzoate as the main byproduct.

Fig. 2 Ni-catalyzed electrochemical N-arylation with versatile aryl electrophiles. Reaction conditions: 1 (0.30 mmol), 2 (0.75 mmol) or 4 (0.60 mmol), NiCl₂·6H₂O (5–10 mol%), Cs₂CO₃ (2.0 equiv.), ⁱPr₂NEt (1.5 equiv.), ⁿBu₄NBF₄ (1.0 equiv.), DMA (4 mL) in an undivided cell, 10–20 mA, 6 h, argon. ^a10-Dicyanoanthracene (40 mol%) was added. For details, please see the ESI.†

Encouraged by the above success achieved through the formation of a postulated aryl radical via cathodic reduction, we envisioned that the use of other aryl electrophiles with appropriate reduction potential should work similarly in principle. With this in mind, attention was turned to sulfoximination using simple PhCl, PhI, PhN₂BF₄, and PhNMe₃OTf as arylating sources. To our delight, as shown at the bottom of Fig. 2, slightly modified reaction conditions (5 mol% NiCl₂·6H₂O) enabled the formation of the desired 3b with 54–82% yield across the above electrophiles. Moreover, our system demonstrates superior reactivity for certain substrates compared to existing methods. For instance, while Mei and colleagues reported a yield of only 31% with sterically hindered 1-bromo-2-methylbenzene under their electrochemical conditions,^20f our system achieved a significantly improved yield of 52% for 3ao. Similarly, while Bolm and co-workers found that using a phenol-derived electrophile under the catalysis of Ni(COD)₂/BINAP (10 mol%) at 110 °C resulted in only a 35% yield,^20b our approach with phenol-derived PhOTf led to a 53% yield of the same product (3ap). In addition, for 6-bromo-4-chloroquinoline, the system preferentially coupled at the bromo moiety, delivering 3aq in 55% yield.

Substrate scope evaluation for fluorosulfonation

The success of the above defluorinative N-arylation prompted us to explore other transformations, leading us to investigate the previously unreported yet synthetically valuable fluorosulfonation of unactivated aryl fluorides. Building on prior work²¹ from others and our group, we quickly screened electrochemical conditions and established an optimized protocol (using 0.5 equivalents of DABSO as the SO₂ source, without an added nickel catalyst or base). As shown in Fig. 3, the reaction tolerated a range of para- or meta-substituted aryl fluorides bearing methyl, methoxy, hydroxyl, fluoro, or 4-fluorophenyl groups, with minimal impact on yield. The desired products 6a–6f were isolated in 65–81% yield; however, the ester-containing substrate 6g gave a moderate yield. Notably, ortho-substituted aryl fluorides with fluoro, methyl, or methoxy groups (6h–6j) also reacted efficiently, albeit in slightly lower yields (58–64%). Additionally, the protocol proved compatible with O- or N-substituted heterocycles, affording 6k and 6l in good yields. Furthermore, the use of 1.0 equivalent of DABSO with prolonged reaction time allows the delivery of the bisfluorosulfonylation products 6m and 6n with moderate yield (see the bottom of Fig. 3). Different from known methods which rely on regioselective bis-sulfonylation under harsh conditions, followed by bis-chlorination and fluorination, our one-pot protocol at room temperature makes it very attractive.²⁴

Fig. 3 Fluorosulfonylation with aryl fluorides. Reaction conditions: 2 (0.3 mmol), DABSO (0.15 mmol), ⁿBu₄NBF₄ (1.0 equiv.), DMA (4 mL) in an undivided cell, 20 mA, 6 h, argon. For details, please see the ESI.†

Synthetic applications

To further demonstrate the synthetic utility of our method, we conducted gram-scale reactions and late-stage modifications of bioactive molecules. As shown in Fig. 4A, the N-arylation reaction proceeded efficiently on a gram scale without yield erosion. Moreover, the protocol proved compatible with structurally complex substrates, including those bearing ester and ketone functional groups. Using functionalized aryl fluorides or NH-sulfoximines, we successfully obtained derivatives 3ar–3au in moderate to good yields (Fig. 4B). Furthermore, the current method can be applied for the facile synthesis of 6o, a key intermediate for the preparation of serine protease inhibitors (Fig. 4C).²⁵

Fig. 4 Synthetic applications. Reaction conditions for late-stage modification: 1 (0.30 mmol), 2 (0.75 mmol), NiCl₂·6H₂O (10 mol%), Cs₂CO₃ (2.0 equiv.), ⁱPr₂NEt (1.5 equiv.), ⁿBu₄NBF₄ (1.0 equiv.), DMA (4 mL) in an undivided cell at rt under an argon atmosphere. For details, please see the ESI.†

Mechanistic studies

To elucidate the reaction mechanism for the NH-sulfoximination of 1-fluoro-4-methylbenzene 2a, we conducted comprehensive experimental investigations (Fig. 5). (1) First, to determine whether the reaction proceeds via paired electrolysis, we performed the model reaction in a divided cell, observing a dramatic decrease in yield (16% for 3a, Fig. 5A). This result confirms that both cathodic and anodic processes are essential for efficient transformation. (2) Second, real-time monitoring of the cathode potential during the course of the reaction revealed values ranging from −15 to −20 V vs. Ag/AgCl. This significantly exceeds the reduction potential of 2a (−2.44 V vs. Ag/AgCl, Fig. 5D, curve a), confirming facile electrochemical reduction of the substrate under the reaction conditions. Further evidence was obtained through exhaustive electrolysis of 2a in the absence of both 1a and NiCl₂·6H₂O, which generated toluene (8%) and 4,4′-dimethylbiphenyl (23%) as characteristic reduction byproducts (Fig. 5B). (3) To obtain direct evidence for aryl radical intermediates, we performed a control experiment by using 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) as the radical scavenger. As shown in Fig. 5A, high resolution mass spectrometry (HRMS) indicates the formation of 2,2,6,6-tetramethyl-1-(p-tolyloxy)piperidine. Furthermore, by conducting EPR spectroscopy using PBN (N-tert-butyl-α-phenylnitrone) as a spin trap, characteristic radical adduct signals were observed during electrolysis of 2a, unambiguously confirming the generation of aryl radical species under reaction conditions (Fig. 5C).²⁶ (4) Additional cyclic voltammetry studies (vs. Ag/AgCl, Fig. 5D) provided further mechanistic insights. NiCl₂·6H₂O displayed a well-defined reduction wave at −2.16 V in DMA (curve b), corresponding to the Ni(II)/Ni(I) redox couple.²⁷ Upon addition of 1a to the 2a solution, the catalytic current decreased significantly at −2.64 V (curve c). Subsequent introduction of NiCl₂·6H₂O shifted this reduction wave to −2.42 V while substantially increasing the current intensity (curve d). Combining these CV studies with the observed complete loss of reactivity when using Ni(COD)₂ as a catalyst (Table 1, entry 2), we propose that a Ni(I) species serves as the active catalytic intermediate. Based on our experimental results and literature precedents,^16,18,20f,g we propose the catalytic cycle shown in Fig. 5E. Cathodic reduction of both the aryl fluoride substrate and L_nNi(II) generates the key aryl radical intermediate A along with the fluoride anion and L_nNi(I) species B. Radical trapping by B forms the ArNi(II)L_n complex C. Subsequent coordination with NH-sulfoximine 1, facilitated by Cs₂CO₃, yields intermediate D. Anodic oxidation of D produces intermediate E. Final reductive elimination affords the desired product 3 while regenerating the active Ni(I) catalyst B.

Fig. 5 Mechanistic studies and a plausible mechanism (for details, please see the ESI†).

As for the mechanism for defluorinative fluorosulfonylation, based on control experiments (for details, please see the ESI†) and previous studies,²¹ we envisioned that after the formation of the aryl radical via cathodic reduction, it can be efficiently trapped by SO₂ to form at first. The combination of with the radical cation of DABCO formed via anodic oxidation followed by nucleophilic substitution with fluoride could deliver the desired product 6.

Conclusions

In summary, we have developed an electrochemical strategy for the selective cleavage of inert C–F bonds in unactivated aryl fluorides through cathodic reduction at room temperature. This approach, combined with nickel catalysis, has enabled the first successful implementation of direct sulfoximination using aryl fluorides as coupling partners. The protocol demonstrates good substrate scope, accommodating various common aryl electrophiles while exhibiting better reactivity for some challenging substrates compared to existing methods. Furthermore, we have extended this strategy to achieve defluorinative fluorosulfonylation of inert aryl fluorides. The synthetic utility of this methodology has been highlighted through efficient late-stage functionalization of biorelated molecules. Current efforts in our laboratory are focused on expanding this platform to other valuable transformations via selective activation of inert electrophiles.

Data availability

ESI is available and includes the experimental procedures, characterization data and crystallographic data for NiCl₂(1a)₂(H₂O)₂. Deposition number 2433423 (for NiCl₂(1a)₂(H₂O)₂) contains the supplementary crystallographic data for this paper.†

Author contributions

X. K. and Z. C. conceived and directed the project. Y. C., S. Z., K. F., and X. C. discovered and developed the reaction. S. Z., K. F. and L. D. performed the experiments and collected the data. M. L. and Y. X. recorded the X-ray and UV spectra. All authors discussed and analyzed the data. X . K. and Z. C. wrote the manuscript with contribution from other authors.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This project was sponsored by the Natural Science Foundation of Henan (252300421183) and the National Natural Science Foundation of China (22102012, 22202021, 22272011, 22201062, and 22372015). This project was also funded by the China Postdoctoral Science Foundation (2024T170222) and the Postdoctoral Research Grant in Henan Province (HN2024001). This research was sponsored by the Qinglan Project of Jiangsu Province, China, under the leadership of Prof. X. Kong.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2433423. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5sc03674g

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