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

doi:10.6023/A26050173

摘要/Abstract

硫亚胺是一类重要的高价含硫氮化合物, 在有机合成、药物化学和功能分子构建中具有广泛应用. 次磺酰胺作为易得且结构可调的S(II)合成子, 已被用于多种硫官能团化反应, 但相关转化多依赖传统溶液相条件, 仍存在溶剂用量较大、反应时间较长和后处理负担较重等问题. 本工作发展了一种NFSI促进的次磺酰胺与酚及相关富电子芳香底物的机械化学氧化偶联反应. 该反应在无溶剂、无添加剂的球磨条件下进行, 20 min内即可完成, 并能兼容不同硫端取代基、N-酰基以及多种酚类和富电子芳香底物. 除酚类底物外, 萘酚、吲哚和1,3,5-三甲氧基苯等富电子芳香体系也可顺利参与反应. 代表性产物可在3 mmol规模下无需柱层析分离获得, 所得硫亚胺还可进一步发生烷基化、氧化衍生. 与代表性溶液相方法相比, 部分可比底物的反应时间可由1 h或10 h缩短至20 min. 对照实验表明, 球磨促进作用并不只是来源于热效应; 绿色指标分析显示, 该方法在反应阶段具有较低的过程质量强度(PMI)、环境因子(E-factor)和溶剂强度.

关键词: 机械化学, 次磺酰胺, 硫亚胺, 氧化偶联, 无溶剂合成

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

引用此文

卢训博, 黄政豪, 叶俊桃, 周善研, 周舒婷, 郑琬霖, 孙嘉琦, 赵智博, 黄国玲. 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[J]. 化学学报, 2026, 84(10): 1633-1640.

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.

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图/表 8

图1. 含S=N键硫化合物的意义、次磺酰胺S-官能团化研究进展及本工作设计

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

表1. 机械化学反应条件的优化

Table 1. Optimization of the reaction conditions

图2. 次磺酰胺硫端取代基与对甲基苯酚在机械化学氧化偶联反应中的适用范围

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.

图3. N-酰基片段在次磺酰胺与对甲酚机械化学氧化偶联反应中的适用范围

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.

图4. 酚及相关富电子芳香底物在次磺酰胺1a机械化学氧化偶联反应中的适用范围a

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.

图5. 放大实验、产物衍生化及初步机理研究

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

图6. 代表性产物在球磨条件和溶液相条件下的产率比较

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.

图7. 机械化学条件与溶液相条件下反应阶段绿色指标比较

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

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