Mechanochemical Oxidative Coupling of Sulfenamides with Phenols and Related Electron-Rich Aromatic Partners for the Synthesis of Sulfilimines

doi:10.6023/A26050173

Abstract

Sulfilimines are valuable tetravalent sulfur-nitrogen compounds with broad applications in synthetic chemistry, medicinal chemistry, and sulfur-containing functional molecules. Although sulfenamides have emerged as useful and readily accessible S(II) synthons for sulfur functionalization, most related transformations are still conducted under conventional solution-phase conditions, often with considerable solvent use, longer reaction times, and additional purification burden. Herein, we report an N-fluorobenzenesulfonimide (NFSI)-promoted mechanochemical oxidative coupling of sulfenamides with phenols and related electron-rich aromatic partners for the rapid synthesis of sulfilimines. In a typical procedure, a sulfenamide substrate (1.0 equiv.), an aromatic coupling partner (1.2 equiv.), and NFSI (1.2 equiv.) were charged into a stainless-steel milling jar and subjected to ball milling at 450 r•min^-1 under solvent-free and additive-free conditions. The milling program consisted of forward rotation for 5 min, a 2 min pause, and reverse rotation for 5 min, and this sequence was repeated twice to give a total effective milling time of 20 min. Under the optimized conditions, sulfenamides bearing diverse sulfur-side substituents and N-acyl groups were converted into the corresponding sulfilimines in generally good yields. The aromatic coupling partner scope covered substituted phenols, naphthol, indole, and 1,3,5-trimethoxybenzene, indicating that the reaction is applicable to different electron-rich aromatic systems. A representative 3 mmol-scale experiment afforded the desired product without flash column chromatography, and a modified scale-up protocol using 1.2 equiv. of NFSI, 2-MeTHF as a liquid-assisted grinding additive, and prolonged milling improved the yield to 81%. The resulting sulfilimines could be further derivatized through O- or N-alkylation, and selected alkylated products underwent subsequent sulfur-center oxidation. Preliminary radical-trapping and solvent-free stirring control experiments suggested that a radical-chain-dominated pathway is unlikely and that ball milling promotes the reaction beyond simple thermal activation. Comparisons with representative solution-phase procedures and green-metrics analysis revealed clear reaction-stage advantages in reaction time, solvent intensity, and material efficiency. This method provides a concise mechanochemical approach to sulfilimines from readily available sulfenamides.

Key words: mechanochemistry, sulfenamides, sulfilimines, oxidative coupling, solvent-free synthesis

Cite this article

Xunbo Lu, Zhenghao Huang, Juntao Ye, Shanyan Zhou, Shuting Zhou, Wanlin Zheng, Jiaqi Sun, Zhibo Zhao, Guoling Huang. Mechanochemical Oxidative Coupling of Sulfenamides with Phenols and Related Electron-Rich Aromatic Partners for the Synthesis of Sulfilimines[J]. Acta Chimica Sinica, 2026, 84(10): 1633-1640.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 8

Figure 1. Significance of S=N-containing sulfur compounds, previous S-functionalization of sulfenamides, and this work

Entry^a	X	Oxidant	Speed/(r•min^-1)	Additive	Yield/%
1	2.5	NBS	450	none	trace
2^b	2.5	TCCA	450	none	trace
3	2.5	NCS	450	none	22
4	2.5	Selectfluor	450	none	73
5	2.5	NFSI	450	none	96
6	2.5	NFSI	300	none	89
7	1.5	NFSI	450	none	95
8^c	1.5	NFSI	450	none	86
9^d	1.5	NFSI	450	Al₂O₃	41
10^e	1.5	NFSI	450	SiO₂	71
11^f	1.5	NFSI	450	4 Å MS	81
12^g	1.5	NFSI	450	Na₂CO₃	52
13^h	1.5	NFSI	450	none	89
14ⁱ^,^j^,^k	1.0	NFSI	450	none	91
15ⁱ^,^j^,^k	1.0	NFSI	450	MeCN	48
16ⁱ^,^j^,^k	1.0	NFSI	450	H₂O	40
17ⁱ^,^j^,^k	1.0	NFSI	450	EtOH	16
18ⁱ^,^j^,^k	1.0	NFSI	450	MTBE	72
19ⁱ^,^j	1.2	NFSI	450	none	94

Table 1. Optimization of the reaction conditions

Figure 2. Scope of sulfur-side substituents in the mechanochemical oxidative coupling with p-cresol Reaction conditions: N-pivaloyl sulfenamide 1 (0.1 mmol), p-cresol 2a (1.2 equiv.), NFSI (1.2 equiv.), ball milling at 450 r•min-1 for a total effective grinding time of 20 min. Each cycle consisted of forward rotation for 5 min, a 2 min pause, and reverse rotation for 5 min, and the sequence was repeated twice. Isolated yields are shown.

Figure 3. Scope of the N-acyl moiety in the mechanochemical oxidative coupling of sulfenamides with p-cresol Reaction conditions: sulfenamide 1 (0.10 mmol), p-cresol 2a (1.2 equiv.), NFSI (1.2 equiv.), ball milling at 450 r•min-1 for a total effective grinding time of 20 min. Each cycle consisted of forward rotation for 5 min, a 2 min pause, and reverse rotation for 5 min, and the sequence was repeated twice. Isolated yields are shown.

Figure 4. Scope of phenols and related electron-rich aromatic partners in the mechanochemical oxidative coupling of sulfenamide 1aa a Reaction conditions: sulfenamide 1a (0.15 mmol), phenol 2 (1.2 equiv.), NFSI (1.2 equiv.), ball milling at 450 r•min-1 for a total effective grinding time of 20 min. Each cycle consisted of forward rotation for 5 min, a 2 min pause, and reverse rotation for 5 min, and the sequence was repeated twice. Isolated yields are shown; regioisomeric ratios are indicated where applicable. b 2-MeTHF (20 μL) was used as a liquid-assisted grinding (LAG) additive. c p-Tolyl sulfenamide was used instead of 1a.

Figure 5. Scale-up reaction, product derivatization, and preliminary mechanistic studies

Figure 6. Comparison of yields for representative products under ball-milling and solution-phase conditions The solution-phase yields shown for 3a were obtained from our preliminary solution-phase optimization studies, including conditions using NFSI in CH2Cl2 and Selectfluor in CH2Cl2 or MeCN (see the SI for details). The solution-phase yields shown for 3b, 3x', and 3y' were taken from literature- reported solution-phase procedures.

Figure 7. Comparison of reaction-stage green metrics for the mechanochemical and solution-phase protocols

References 9

[1]	(a) Gilchrist, T. L.; Moody, C. J. Chem. Rev. 1977, 77, 409.
	(b) Greenwood, N. S.; Boyer, Z. W.; Ellman, J. A.; Gnamm, C. J. Med. Chem. 2025, 68, 4079.
[2]	(a) Vanacore, R.; Ham, A.-J. L.; Voehler, M.; Sanders, C. R.; Conrads, T. P.; Veenstra, T. D.; Sharpless, K. B.; Dawson, P. E.; Hudson, B. G. Science 2009, 325, 1230.
	(b) Miyazaki, I.; Simizu, S.; Okumura, H.; Takagi, S.; Osada, H. Nat. Chem. Biol. 2010, 6, 667.
	(c) Bizet, V.; Hendriks, C. M. M.; Bolm, C. Chem. Soc. Rev. 2015, 44, 3378.
	(d) Zhou, S.; Jia, Z. H.; Xiong, L. X.; Yan, T.; Yang, N.; Wu, G. P.; Song, H. B.; Li, Z. M. J. Agric. Food Chem. 2014, 62, 6269.
	(e) Passia, M. T.; Schöbel, J.-H.; Bolm, C. Chem. Soc. Rev. 2022, 51, 4890.
	(f) Liu, Z.; Wu, H.; Zhang, H.; Wang, F.; Liu, X.; Dong, S.; Hong, X.; Feng, X. J. Am. Chem. Soc. 2024, 146, 18050.
[3]	(a) Greenwood, N. S.; Champlin, A. T.; Ellman, J. A. J. Am. Chem. Soc. 2022, 144, 17808.
	(b) Champlin, A. T.; Ellman, J. A. J. Org. Chem. 2023, 88, 7607.
[4]	(a) Huang, G. L.; Lu, X. B.; Yang, K. Y.; Xu, X. Y. Org. Lett. 2023, 25, 3173.
	(b) Chen, Y.; Fang, D.-M.; Huang, H.-S.; Nie, X.-K.; Zhang, S.-Q.; Cui, X.; Tang, Z.; Li, G.-X. Org. Lett. 2023, 25, 2134.
	(c) Huang, G.; Huang, Z.; Zhou, S.; Ye, J.; Sun, J.; Lu, X. Asian J. Org. Chem. 2026, 15, e00616.
	(d) Han, Y.; Yuan, Y.; Qi, S.; Zhang, Z.-K.; Kong, X.; Yang, J.; Zhang, J. Org. Lett. 2024, 26, 3906.
	(e) Zhang, M.; Tan, Y.; Yang, H.; Fu, X.; Liu, Y.; Wang, Z.; Wang, Q. ACS Catal. 2025, 15, 4007.
	(f) Huang, G.; Zhao, Z.; Huang, Z.; Zhu, H.; Lu, X. J. Org. Chem. 2026, 91, 4581.
	(g) Lu, X.; Huang, G. L.; Ye, J. L.; Bashir, M. A.; Su, J. F.; Yang, K. Y.; Liang, F. P.; Xu, X. Y. Org. Lett. 2023, 25, 2151.
	(h) Huang, G. L.; Ye, J. L.; Bashir, M. A.; Chen, Y. T.; Chen, W. J.; Lu, X. B. J. Org. Chem. 2023, 88, 11728.
	(i) Yang, G.-F.; Huang, H.-S.; Nie, X.-K.; Zhang, S.-Q.; Cui, X.; Tang, Z.; Li, G.-X. J. Org. Chem. 2023, 88, 4581.
	(j) Huang, G.; Ye, J.; Tan, M.; Chen, Y.; Lu, X. J. Org. Chem. 2023, 88, 16116.
	(k) Huang, G. L.; Zhu, H. R.; Zhou, S. T.; Zheng, W. L.; Liang, F. P.; Zhao, Z. B.; Chen, Y. F.; Lu, X. B. Beilstein J. Org. Chem. 2026, 22, 158.
	(l) Zhang, T.; Pan, S.; Bolm, C. Org. Lett. 2026, 28, 316.
	(m) Greenwood, N. S.; Ellman, J. A. Org. Lett. 2023, 25, 2830.
	(n) Jian, C.; Huang, X.; Long, H.; Liao, M.; Wu, X. Org. Lett. 2025, 27, 5464.
	(o) Huang, G.; Lu, X.; Liang, F. Org. Lett. 2023, 25, 3179.
	(p) Guo, Y.; Zhuang, Z.; Feng, X.; Ma, Q.; Li, N.; Jin, C.; Yoshida, H.; Tan, J. Org. Lett. 2023, 25, 7192.
	(q) Liang, Q.; Wells, L. A.; Han, K.; Chen, S.; Kozlowski, M. C.; Jia, T. J. Am. Chem. Soc. 2023, 145, 6310.
	(r) Yuan, Y.; Han, Y.; Zhang, Z.-K.; Sun, S.; Wu, K.; Yang, J.; Zhang, J. Angew. Chem. Int. Ed. 2024, 63, e202409541.
	(s) Zhuang, X.; Li, H.; Feng, Z.; Wang, H. Org. Lett. 2025, 27, 4886.
	(t) Dong, F.; Liu, H.; Xiong, X. Org. Biomol. Chem. 2026, 24, 1515.
	(u) Wang, Y.; Mu, Y.; Han, X.; Xiao, J.; Huang, G.; Wang, F.; Li, X.-X.; Li, X. J. Am. Chem. Soc. 2025, 147, 38931.
	(v) He, M.; Zhang, R.; Wang, T.; Xue, X.-S.; Ma, D. Nat. Commun. 2025, 16, 2310.
	(w) Liang, Q.; Zhang, X.; Rotella, M. E.; Xu, Z.; Kozlowski, M. C.; Jia, T. Nat. Catal. 2024, 7, 1010.
	(x) Jiang, H.-J.; Tu, X.-Q.; Kong, X.-Y.; Wang, J.-Y.; Liu, Y.-Y.; Shen, M.-L.; Yao, C.-Z.; Li, Q.; Yu, J. Nat. Commun. 2025, 16, 6988.
	(y) Priya, V. R. P.; Sugapriya, S.; Nandi, G. C. Eur. J. Org. Chem. 2025, 28, e202500026.
	(z) Liu, H.; Liu, Y.; Wang, X.; He, F.-S.; Wu, J. Acta Chim. Sinica 2026, 84, 287 (in Chinese).
	刘洪昤, 刘艺婷, 王新华, 何福生, 吴劼, 化学学报, 2026, 84, 287).
	(a') Huang, G.; Huang, Z.; Sun, J.; Zhao, Z.; Li, P.; Pan, Y.; Lu, X. Acta Chim. Sinica 2026, 84, 1318 (in Chinese).
	黄国玲, 黄政豪, 孙嘉琦, 赵智博, 李鹏妍, 潘雅雯, 卢训博, 化学学报, 2026, 84, 1318).
[5]	James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friščić T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C. Chem. Soc. Rev. 2012, 41, 413.
[6]	(a) Chatterjee, T.; Saha, D.; Ranu, C. J. Org. Chem. 2021, 86, 13895.
	(b) Boldyreva, E. Chem. Soc. Rev. 2013, 42, 7719.
	(c) Reynes, J. F.; Brunet, V.; Bantreil, X.; Lamaty, F. ACS Org. Inorg. Au 2024, 4, 432.
	(d) Hernández, J. G.; Bolm, C. J. Org. Chem. 2017, 82, 4007.
	(e) Lu, X.; Bai, Y.; Qin, J.; Wang, N.; Wu, Y.; Zhong, F. ACS Sustain. Chem. Eng. 2021, 9, 1684.
	(f) Howard, J. L.; Cao, Q.; Browne, D. L. Chem. Sci. 2018, 9, 3080.
[7]	Pan, S.; Wu, P.; Hu, Y.; Bolm, C. Green Synth. Catal. 2025, DOI: 10.1016/j.gresc.2025.03.016.
[8]	Zhu, H.; Zhou, S.; Zheng, W.; Ye, J.; Huang, Z.; Zhou, S.; Huang, G.; Lu, X. J. Org. Chem. 2026, 91, 10197.
[9]	(a) Jiménez-González, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Org. Process Res. Dev. 2011, 15, 912.
	(b) Sheldon, R. A. Green Chem. 2023, 25, 1704.
	(c) Becker, J.; Manske, C.; Randl, S. Curr. Opin. Green Sustain. Chem. 2022, 33, 100562.
	(d) Benison, C. H.; Payne, P. R. Curr. Res. Green Sustain. Chem. 2022, 5, 100229.

[1]	Guoling Huang, Zhenghao Huang, Jiaqi Sun, Zhibo Zhao, Pengyan Li, Yawen Pan, Xunbo Lu. Iodide/Peroxide-Promoted Radical Oxidative Activation of Sulfenamides for the N/O-Divergent Synthesis of Sulfinamidines and Sulfinimidate Esters [J]. Acta Chimica Sinica, 2026, 84(8): 1318-1325.
[2]	Liu Hongling, Liu Yiting, Wang Xinhua, He Fu-Sheng, Wu Jie. Base-Mediated S-Fluoroalkylation of Sulfenamides with Iodine(III) Salts [J]. Acta Chimica Sinica, 2026, 84(3): 287-292.
[3]	Yichun Lou, Chengli He, Linrui Wang, Xiaoli Cui. Mechanochemical Urea Synthesis Using Nitrogen, Water and Carbon Dioxide with TiO₂ under Mild Conditions: An Experimental and Theoretical Study [J]. Acta Chimica Sinica, 2026, 84(1): 73-85.
[4]	Yuqi Zhang, Jinze Liu, Dongxu Xue, Yuxiang Shi, Weixian Zhang. Mechanochemistry: Pollutant Transformation Mechanism and Environmental Applications [J]. Acta Chimica Sinica, 2025, 83(9): 1055-1071.
[5]	Yuhan Liu, Pan Gao. Direct Borylation of Organohalides Using Mechanochemically Generated Calcium-Based Heavy Grignard Reagents (R-CaX) [J]. Acta Chimica Sinica, 2024, 82(11): 1114-1119.
[6]	Chuwen Luo, Chaoying Kong, Zhaohui Tang. Research Progress in Sonochemistry for Biomedical Applications^★ [J]. Acta Chimica Sinica, 2023, 81(7): 836-842.
[7]	Wenjun Wu, Yuting Li, Xi Feng, Wenxing Ding. Perovskite Dual-function Passivator: Room Temperature Ionic Liquid Obtained from Mechanochemical Preparation [J]. Acta Chimica Sinica, 2022, 80(11): 1469-1475.
[8]	Zhou Baolong, Chen Long. New Strategies for the Synthesis of Covalent Organic Porous Polymers [J]. Acta Chim. Sinica, 2015, 73(6): 487-497.
[9]	Shang Xiaojie, Liu Zhongquan. Recent Advances in Free-Radical-Promoted Selective Activation of Alcohol/Ether α-O-C(sp³)-H Bond [J]. Acta Chimica Sinica, 2015, 73(12): 1275-1282.
[10]	Lu Qingquan, Yi Hong, Lei Aiwen. Autoxidative Coupling and Its Applications to C-H Functionalization [J]. Acta Chim. Sinica, 2015, 73(12): 1245-1249.
[11]	Zhang Dan, Qin Yong. Oxidative Coupling Strategy in the Total Syntheses of Complex Indole Alkaloids [J]. Acta Chimica Sinica, 2013, 71(02): 147-150.
[12]	LI Yu-Chuan, LI Sheng-Hua, QI Cai, ZHANG Hui-Juan, ZHU Meng-Yu, PANG Si-Ping. Synthesis and Performance of A Novel Poly-nitrogen Compound 1,1-Azobis-1,2,3-triazole [J]. Acta Chimica Sinica, 2011, 69(18): 2159-2165.
[13]	LI Wen-Ling,HE Kan-Kan,LI Ying,HOU Zi-Jie*. Total Synthesis of (±)-Shegansu B, Gnetuhainin F, (±)-Maackin A and (±)-Cassigarol E [J]. Acta Chimica Sinica, 2005, 63(17): 1607-1612.

机械化学促进的次磺酰胺与酚及富电子芳烃氧化偶联合成硫亚胺