Regioselective functionalization of sulfenamides: S-arylation with cyclic diaryl λ³-bromanes and λ³-chloranes

Abstract

We report an S-selective and meta-regioselective arylation of sulfenamides with cyclic diaryl λ³-bromanes and λ³-chloranes. This metal-free strategy proceeds under mild conditions, tolerates diverse functional groups, and delivers S-aryl sulfilimines in good to excellent yields with high regioselectivity. The method is scalable, enabling scale-up synthesis and further transformations, highlighting the potential for efficient late-stage functionalization.

---

Sulfur-containing compounds are widely distributed in natural products and pharmaceuticals, with approximately 10% of U.S. food and drug administration (FDA)-approved drugs featuring sulfur-based functional groups.¹ The remarkable structural diversity of these molecules largely stems from the variable oxidation states of sulfur atoms.² Among them, sulfoxides represent one of the most prominent sulfur(IV) frameworks, finding extensive applications in pharmaceuticals, agrochemicals, and materials science.³ As the aza-analogues of sulfoxides by replacement of the oxygen atom with the nitrogen atom, sulfilimines have attracted growing attention in medicinal chemistry due to their unique properties compared to sulfoxides (Scheme 1a).⁴ The cross-linking of collagen-IV via sulfilimine bonds marks the first identification of this group in biomolecules.⁵ Incorporating sulfilimine moieties into biomacromolecules can impart novel chemical and biological properties.⁶ In synthetic chemistry, sulfilimines serve as ligands and nitrogen-radical precursors for heterocycle synthesis.⁷ Moreover, they can be readily transformed into higher-oxidation-state N–S frameworks, such as sulfoximines and sulfondiimines. Owing to their broad utility and potential in drug discovery, sulfilimines have emerged as valuable synthetic building blocks, prompting considerable research efforts toward the development of efficient synthetic methodologies.

Scheme 1 Application of sulfilimines and their synthetic routes.

A traditional approach to sulfilimine synthesis involves the oxidative imidation of thioethers with electrophilic nitrogen reagents to form the characteristic S=N double bond.⁸ However, the oxidative conditions, reliance on potentially hazardous iminating reagents, and frequent use of transition-metal catalysts are drawbacks of this approach. [2,3]-sigmatropic rearrangement provides an alternative route, enabling the synthesis of ortho-sulfiliminyl phenols from oxyacetamides and electrophilic sulfenylation reagents, yet this method suffers from a narrow substrate scope.⁹ A consecutive addition of two Grignard reagents to sulfinylamines is feasible to afford the desired sulfilimines.¹⁰

Recently, elegant methods have been established for the synthesis of sulfilimines from sulfenamides through highly chemoselective sulfur functionalization pathways (Scheme 1b). Transition-metal-catalyzed approaches have enabled efficient coupling of sulfenamides with diverse partners such as boronic acids, sulfonylhydrazones, aryl iodides, diazonium salts, thianthrenium salts, and diazo compounds.¹¹ In line with the principles of green chemistry, transition-metal-free strategies have also emerged. For example, alkyl halides serve as effective reagents for the S-alkylation of sulfenamides under basic conditions,¹² while diaryliodonium salts enable S-arylation under metal-free conditions.¹³

Notably, in all these transformations, the reaction site is determined by the position directly bound to the functional group (e.g., boronic acid or halide). As highly reactive intermediates with two potential reactive sites, arynes have also been exploited for sulfilimine synthesis via S-arylation of sulfenamides.¹⁴ Although these reactions exhibit excellent efficiency, they are typically limited to symmetric arynes. The use of unsymmetric arynes often leads to mixtures of regioisomers in a 1 : 1 ratio. Given these limitations, the development of a regioselective S-arylation of sulfenamides would provide a valuable complementary pathway for the synthesis of S-aryl sulfilimines.

Hypervalent compounds are indispensable tools in organic synthesis, with diaryl iodonium salts being among the most powerful and widely used examples.¹⁵ Typically, cyclic diaryl λ³-iodanes undergo transition-metal-catalyzed cross-coupling reactions smoothly, involving rapid oxidative addition into the C–I(III) bond to achieve ortho-functionalizations (Scheme 1c).¹⁶ Owing to the steric congestion introduced by the substituents, cyclic diaryl λ³-iodanes have often been employed in the synthesis of axially chiral biaryls. In this scenario, Zhang's group reported the construction of biaryl sulfilimines bearing both axial and S-central chirality from cyclic diaryl λ³-iodanes and sulfenamides (Scheme 1b).^16b In sharp contrast, the chemistry of cyclic diaryl λ³-bromanes and λ³-chloranes has only recently attracted growing attention following Wencel–Delord's development of a general and efficient synthetic strategy.¹⁷ Due to the higher ionization potential and electronegativity of Br and Cl, hypervalent λ³-bromanes and λ³-chloranes display enhanced nucleofugality and reduced positive charge, enabling amplified reactivity under metal-free conditions.¹⁸ These features impart distinct reactivity profiles compared to their iodane counterparts, notably allowing their use as novel aryne precursors for selective C–C, C–O, and C–N bond formation at the meta-position.^17a,18 Building on these precedents, we envisioned that cyclic diaryl λ³-bromanes and λ³-chloranes could serve as a promising platform for the regioselective meta-arylation pathway for the synthesis of structurally diverse S-aryl sulfilimines (Scheme 1d).

To initiate our study, we selected diaryl λ³-bromane 1a and sulfenamide 2a as model substrates for the regioselective meta-arylation. In the presence of Cs₂CO₃, no desired product was observed (Table 1, entry 1). A screening of bases, including NaOH, ^tBuOK, ^tBuONa, and NaH, revealed that NaH was uniquely effective, affording the S-aryl sulfilimine 3aa in 86% yield (Table 1, entries 2–5). Solvent optimization further identified THF as the most suitable medium, outperforming DCM, 1,4-dioxane, and toluene (Table 1, entries 6–8). Notably, both sulfenamide and base loadings significantly affected the reaction outcome, with a reduced loading delivering an improved yield of 94% (Table 1, entries 9 and 10). Time monitoring indicated that a reaction duration of 2 hours was sufficient to achieve the optimal yield (Table 1, entry 11).

Table 1 Condition optimization^a

Entry	Base (equiv.)	Solvent	Yield of 3aa^b (%)
a Reaction conditions: cyclic diaryl λ^3-bromane 1a (0.1 mmol), sulfenamide 2a (0.2 mmol), base, solvent (1.5 mL), −78 °C to rt, 3 h. b Isolated yield. c 1.5 equiv. of 2a was used. d 1.0 equiv. of 2a was used. e 2 hours.
1	Cs2CO3 (5)	THF	Trace
2	NaOH (5)	THF	44
3	^tBuOK (5)	THF	73
4	^tBuONa (5)	THF	50
5	NaH (5)	THF	86
6	NaH (5)	DCM	47
7	NaH (5)	1,4-Dioxane	34
8	NaH (5)	Toluene	25
9^c	NaH (3)	THF	93
10^d	NaH (2)	THF	94
11^d^e	NaH (2)	THF	99

---

With the optimal conditions established, we next examined the generality of this strategy for S-selective and meta-regioselective arylation of sulfenamides with diaryl λ³-bromanes (Scheme 2). For aryl-substituted sulfenamides, halogen substituents were well tolerated, affording the desired products in good to excellent yields (3aa–3ac), with only a slight steric effect observed (86%, 3ac). In contrast, electron-donating groups reduced the yields due to decreased reactivity (43–47%, 3ad–3af). Extended conjugated systems also performed well, delivering the product in a good yield (82%, 3ag). We then evaluated the influence of acyl protecting groups. Alkanoyl- and methacryloyl-protected sulfenamides gave the corresponding sulfilimines in 82% and 89% yield, respectively (3ah–3ai). Benzoyl-protected substrates were highly reactive, affording 3aj in 89% yield. Benzoyl derivatives bearing Br, Cl, or F at different positions also reacted smoothly, producing 3ak–3am in 82–94% yield. Even the sterically hindered 2-bromo derivative was well tolerated (89%, 3an). Electron-rich benzoyl groups, such as methyl and methoxy, yielded 3ao (93%) and 3ap (82%), respectively, while CF₃-substituted benzoyl sulfenamide afforded 3aq in 83% yield. A range of cross-substituted sulfenamides produced the corresponding sulfilimines in 74–88% yield (3ar–3aw). Pyridyl-substituted sulfenamide proved to be a competent candidate for this transformation, producing 3ax in 46% yield, and alkylated sulfenamides remained highly reactive, providing 3ay–3aa′ in 77–93% yield. The structure of 3aw has been further confirmed by single-crystal X-ray diffraction.

Scheme 2 Scope of sulfenamides and cyclic diaryl λ³-bromanes/λ³-chloranes.

Then, we evaluated the scope of diaryl λ³-bromanes under the optimized conditions. A range of substrates bearing diverse substituents, including halogens, CF₃, and methyl groups at various positions, proved compatible. Unsymmetric diaryl λ³-bromanes underwent smooth S-arylation, affording the desired products (3ba–3ga) in good yields. Notably, high regioselectivity was observed with 2-substituted diaryl λ³-bromanes, yielding S-aryl sulfilimines 3ba and 3ca exclusively. In contrast, regioisomers were obtained for 2-methyl substituted diaryl λ³-bromane (3da). Furthermore, 3-substituted analogues gave mixtures of regioisomers (3ea–3ga) due to competing arylation at different sites, likely a consequence of steric hindrance from adjacent substituents and the electrical properties of the aryl rings, which also led to diminished yields. In addition, we further explored the meta-arylation of sulfenamides with diaryl λ³-chloranes. Symmetric λ³-chloranes offered sulfilimines 3ha and 3ja in good yields (80% and 82%, respectively), whereas unsymmetric variants exhibited outstanding regioselectivity, providing 3ka and 3la efficiently. In addition, pyridyl- and alkyl-substituted sulfenamides were also successfully transformed to the desired sulfilimines in good yields (3ma–3na). Notably, a dramatic decrease of yield was observed for cyclic diaryl λ³-iodane under such conditions (3ia), underscoring the distinct reactivity of diaryl λ³-bromanes and λ³-chloranes.

To further demonstrate the practicality and efficiency of this strategy, a scale-up reaction was carried out under the optimized conditions. As shown in Scheme 3a, the reaction proceeded smoothly to afford product 3aa in 92% yield, which is comparable to the yield obtained in the scope study, thereby highlighting the excellent scalability of this protocol and its potential for practical applications. We next explored divergent transformations of the sulfilimine products (Scheme 3b). Sulfilimines 3ay and 3aa′ underwent efficient dealkylation under mild conditions to furnish the corresponding sulfenamides 4a and 4b in good yields, providing a straightforward route to structurally diverse sulfenamides and enabling late-stage functionalization of sulfenamide-based molecules. In addition, sulfilimine 3aa was oxidized to sulfoximine 5 in excellent yield, which was readily deprotected to afford sulfoximine 6 in almost quantitative yield (Scheme 3c). Furthermore, treatment of 3aa with LiAlH₄ delivered thioether 7 in good yield, further demonstrating the synthetic versatility of this methodology.

Scheme 3 Scale-up synthesis and further transformations.

To gain further insight into the mechanism, a deuterated labelling experiment has been conducted (Scheme 4a). Product 3aa was obtained in 90% yield with 70% deuterium incorporation at the ortho-position, indicating the formation of an aryne intermediate. Based on the results and previous reports,^17,18 a plausible reaction mechanism is outlined in Scheme 4b. In the presence of NaH, deprotonation of bromane 1a initiates the process, followed by C–Br bond cleavage to generate the aryne intermediate I. Concurrently, NaH deprotonates sulfenamide 2a to form the nucleophilic intermediate III. Given that N-functionalization of sulfenamides is often disfavored compared to the higher reactivity at the sulfur atom,^11–14 nucleophilic attack occurs preferentially at the sulfur center of the deprotonated sulfenamide, which has an anionic character as represented in the resonance structure III, generating the anion intermediate II. An autocatalytic process may then occur,^17a implying the attack of II on 1a to realize the protonation of II and the generation of aryne intermediate I, providing the desired S-selective and meta-regioselective arylation product 3aa.

Scheme 4 Proposed mechanism.

In conclusion, we have developed an S-selective and meta-regioselective arylation of sulfenamides with cyclic diaryl λ³-bromanes and λ³-chloranes, enabling efficient synthesis of S-aryl sulfilimines. This protocol features a broad substrate scope, delivering products in good to excellent yields with outstanding selectivity, even for sterically hindered substrates. The method offers rapid access to structurally diverse sulfilimines and demonstrates excellent scalability, with scale-up synthesis providing comparable efficiency to that obtained in the scope study. Moreover, the obtained sulfilimines can be readily further transformed, underscoring the broad synthetic utility and application potential of this strategy in various fields.

We are grateful to the financial support from the National Natural Science Foundation of China (Grant No. 22201144).

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental procedures, characterization data, X-ray crystallographic data, and NMR spectra. See DOI: https://doi.org/10.1039/d5cc05327g.

CCDC 2465288 contains the supplementary crystallographic data for this paper.¹⁹

Notes and references

1. (a) K. A. Scott and J. T. Njardarson, Top. Curr. Chem., 2018, 376, 5; (b) E. A. Ilardi, E. Vitaku and J. T. Njardarson, J. Med. Chem., 2013, 57, 2832–2842.
2. (a) A. Kausar, S. Zulfiqar and M. I. Sarwar, Polym. Rev., 2014, 54, 185; (b) J. J. Petkowski, W. Bains and S. Seager, J. Nat. Prod., 2018, 81, 423–446.
3. (a) V. V. Chaban, Phys. Chem. Chem. Phys., 2016, 18, 10507–10515; (b) C. Jacob, Nat. Prod. Rep., 2006, 23, 851–863.
4. (a) T. L. Gilchrist and C. J. Moody, Chem. Rev., 1977, 77, 409–435; (b) N. Furukawa and S. Oae, Ind. Eng. Chem. Prod. Res. Dev., 1981, 20, 260–270; (c) H. Takada, M. Oda, A. Oyamada, K. Ohe and S. Uemura, Chirality, 2000, 12, 299–312.
5. R. Vanacore, A.-J. L. Ham, M. Voehler, C. R. Sanders, T. P. Conrads, T. D. Veenstra, K. B. Sharpless, P. E. Dawson and B. G. Hudson, Science, 2009, 325, 1230–1234.
6. S. Lin, X. Yang, S. Jia, A. Weeks, M. Hornsby, P. S. Lee, R. V. Nichiporuk, A. T. Iavarone, J. A. Wells, F. D. Toste and C. J. Chang, Science, 2017, 355, 597–602.
7. (a) V. V. Thakur, N. S. C. Ramesh Kumar and A. Sudalai, Tetrahedron Lett., 2004, 45, 2915–2918; (b) Q. Cheng, Z. Bai, S. Tewari and T. Ritter, Nat. Chem., 2022, 14, 898–904.
8. (a) F. Collet, R. H. Dodd and P. Dauban, Org. Lett., 2008, 10, 5473–5476; (b) J. Wang, M. Frings and C. Bolm, Angew. Chem., Int. Ed., 2013, 52, 8661–8665; (c) M. Yoshitake, H. Hayashi and T. Uchida, Org. Lett., 2020, 22, 4021–4025; (d) Z. Liu, H. Wu, H. Zhang, F. Wang, X. Liu, S. Dong, X. Hong and X. Feng, J. Am. Chem. Soc., 2024, 146, 18050–18060.
9. (a) F. Xiong, L. Lu, T.-Y. Sun, Q. Wu, D. Yan, Y. Chen, X. Zhang, W. Wei, Y. Lu, W.-Y. Sun, J. J. Li and J. Zhao, Nat. Commun., 2017, 8, 15912; (b) Z. Xiao, M. Pu, Y. Li, W. Yang, F. Wang, X. Feng and X. Liu, Angew. Chem., Int. Ed., 2025, 64, e202414712.
10. Z.-X. Zhang, T. Q. Davies and M. C. Willis, J. Am. Chem. Soc., 2019, 141, 13022–13027.
11. (a) N. S. Greenwood, A. T. Champlin and J. A. Ellman, J. Am. Chem. Soc., 2022, 144, 17808–17814; (b) N. S. Greenwood, N. P. Cerny, A. P. Deziel and J. A. Ellman, Angew. Chem., Int. Ed., 2024, 63, e202315701; (c) N. S. Greenwood and J. A. Ellman, Org. Lett., 2023, 25, 2830–2834; (d) N. S. Greenwood and J. A. Ellman, Org. Lett., 2023, 25, 4759–4764; (e) Q. Liang, L. A. Wells, K. Han, S. Chen, M. C. Kozlowski and T. Jia, J. Am. Chem. Soc., 2023, 145, 6310–6318; (f) X. Wu, M. Chen, F.-S. He and J. Wu, Green Chem., 2023, 25, 9092–9096; (g) Y. Han, Y. Yuan, S. Qi, Z.-K. Zhang, X. Kong, J. Yang and J. Zhang, Org. Lett., 2024, 26, 3906–3910; (h) Y. Yuan, Y. Han, Z. K. Zhang, S. Sun, K. Wu, J. Yang and J. Zhang, Angew. Chem., Int. Ed., 2024, 63, e202409541; (i) X. Zhuang, H. Li, Z. Feng and H. Wang, Org. Lett., 2025, 27, 4886–4892.
12. (a) Y. Chen, D.-m Fang, H.-S. Huang, X.-K. Nie, S.-Q. Zhang, X. Cui, Z. Tang and G.-X. Li, Org. Lett., 2023, 25, 2134–2138; (b) G. Huang, X. Lu, K. Yang and X. Xu, Org. Lett., 2023, 25, 3173–3178.
13. (a) G. Huang, X. Lu and F. Liang, Org. Lett., 2023, 25, 3179–3183; (b) X. Wu, Y. Li, M. Chen, F.-S. He and J. Wu, J. Org. Chem., 2023, 88, 9352–9359; (c) Q. Zhou, J. Li, T. Wang and X. Yang, Org. Lett., 2023, 25, 4335–4339.
14. (a) Y. Guo, Z. Zhuang, X. Feng, Q. Ma, N. Li, C. Jin, H. Yoshida and J. Tan, Org. Lett., 2023, 25, 7192–7197; (b) X. Wu, M. Chen, F.-S. He and J. Wu, Org. Lett., 2023, 25, 5157–5161.
15. (a) Y.-X. Xu, Y.-Q. Liang, W.-M. Liu, H.-K. Fang, H.-K. Li, S.-J. Ji and Z.-J. Cai, Org. Lett., 2024, 26, 9005–9010; (b) W.-M. Liu, Y.-J. Hao, Y. Zhang, X.-G. Li, S.-J. Ji and Z.-J. Cai, Org. Lett., 2024, 27, 363–368; (c) B. Kang, L. Wang, X. Sun, H. Liu, Z. Wen, Y. Ren, C. Qi and H. Jiang, Org. Chem. Front., 2023, 10, 5231–5241; (d) K. Zhao, S. Yang, Q. Gong, L. Duan and Z. Gu, Angew. Chem., Int. Ed., 2021, 60, 5788–5793; (e) L. Duan, K. Zhao, Z. Wang, F.-L. Zhang and Z. Gu, ACS Catal., 2019, 9, 9852–9858; (f) F. Heinen, E. Engelage, A. Dreger, R. Weiss and S. M. Huber, Angew. Chem., Int. Ed., 2018, 57, 3830–3833.
16. (a) W. Fang, Y. D. Meng, S. Y. Ding, J. Y. Wang, Z. H. Pei, M. L. Shen, C. Z. Yao, Q. Li, Z. Gu, J. Yu and H. J. Jiang, Angew. Chem., Int. Ed., 2024, 64, e202419596; (b) X. Liu, Z. Ye, J. Liu, Y. Wu and F. Zhang, Org. Lett., 2025, 27, 6695–6701; (c) L. Duan, Z. Wang, K. Zhao and Z. Gu, Chem. Commun., 2021, 57, 3881–3884; (d) K. Zhu, Y. Wang, Q. Fang, Z. Song and F. Zhang, Org. Lett., 2020, 22, 1709–1713; (e) K. Zhu, Z. Song, Y. Wang and F. Zhang, Org. Lett., 2020, 22, 9356–9359; (f) H. Xie, S. Yang, C. Zhang, M. Ding, M. Liu, J. Guo and F. Zhang, J. Org. Chem., 2017, 82, 5250–5262; (g) M. Ding, W. Hua, M. Liu and F. Zhang, Org. Lett., 2020, 22, 7419–7423.
17. (a) M. Lanzi, Q. Dherbassy and J. Wencel-Delord, Angew. Chem., Int. Ed., 2021, 60, 14852–14857; (b) M. Lanzi, R. A. Ali Abdine, M. De Abreu and J. Wencel-Delord, Org. Lett., 2021, 23, 9047–9052.
18. (a) M. Lanzi, T. Rogge, T. S. Truong, K. N. Houk and J. Wencel-Delord, J. Am. Chem. Soc., 2022, 145, 345–358; (b) Y. Wang, Y.-N. Tian, S. Ren, R. Zhu, B. Huang, Y. Wen and S. Li, Org. Chem. Front., 2023, 10, 793–798; (c) D. Carter Martos, M. de Abreu, P. Hauk, P. Fackler and J. Wencel-Delord, Chem. Sci., 2024, 15, 6770–6776; (d) M. De Abreu, T. Rogge, M. Lanzi, T. J. Saiegh, K. N. Houk and J. Wencel-Delord, Angew. Chem., Int. Ed., 2024, 63, e202319960; (e) K. Patra, M. P. Dey and M. Baidya, Chem. Sci., 2024, 15, 16605–16611; (f) B. Kang, W. Li, H. Jiang and C. Qi, Chem. Commun., 2025, 61, 3395–3398; (g) J.-Y. Shou and F.-L. Qing, Org. Lett., 2025, 27, 2815–2820; (h) J.-Y. Fan, M.-C. Wang, J.-F. Zhou, T.-Q. Gan, W.-X. Zhang, L. Wei and B.-J. Li, Org. Chem. Front., 2025, 12, 1212–1216.
19. CCDC 2465288: Experimental Crystal Structure Determination, 2025 DOI:10.5517/ccdc.csd.cc2nrbf6.

---