碘盐/过氧化物促进次磺酰胺自由基氧化活化实现硫亚胺酰胺和硫亚胺酯的N/O分流合成

doi:10.6023/A26050146

摘要/Abstract

硫亚胺酰胺和硫亚胺酯是重要的S(IV)高价硫氮化合物, 发展由易得次磺酰胺出发的模块化合成方法具有重要意义. 本工作报道了一种碘盐/过氧化物促进的次磺酰胺氧化转化反应, 实现了硫亚胺酰胺和硫亚胺酯的N/O分流合成. 在四正丁基碘化铵(TBAI)/过氧化叔丁醇(TBHP)条件下, 次磺酰胺可与多种胺类底物发生氧化胺化反应, 构建S—N键; 在四甲基碘化铵(TMAI)/过氧化氢异丙苯(CHP)或TMAI/TBHP条件下, 次磺酰胺可在甲醇中转化为相应硫亚胺酯, 构建S—O键. 该方法无需过渡金属, 条件温和, 操作简便, 对不同硫取代基、酰基片段及胺类底物具有较好的兼容性, 产物收率最高可达 96%. 机理实验表明, 该反应可能经历自由基氧化活化和碘代高价硫中间体亲核捕获并存的双重反应机制. 该研究为基于次磺酰胺平台构建高价硫氮化合物提供了新的氧化体系.

关键词: 次磺酰胺, 硫亚胺酰胺, 硫亚胺酯, 碘盐/过氧化物, N/O分流合成

Sulfinamidines and sulfinimidate esters are important S(IV) aza-sulfur compounds containing S(=N)—N and S(=N)—O motifs. Developing modular methods from readily available sulfenamides is valuable for expanding the chemistry of high-valent sulfur compounds. Herein, we report an iodide/peroxide-promoted oxidative transformation of sulfenamides for the N/O-divergent synthesis of sulfinamidines and sulfinimidate esters. For oxidative amination, sulfenamides were reacted with amines in the presence of tetrabutylammonium iodide (TBAI) and tert-butyl hydroperoxide (TBHP) in EtOAc at room temperature for 15 h, affording a series of N-acyl sulfinamidines through S—N bond formation. For esterification, sulfenamides were treated with tetramethylammonium iodide (TMAI) and cumene hydroperoxide (CHP) in MeOH at 60 ℃ for 5 h to give the corresponding sulfinimidate esters through S—O bond formation. In selected cases, TMAI/TBHP conditions also promoted the esterification efficiently. This transition-metal-free protocol is operationally simple and shows good compatibility with aryl, alkyl, naphthyl, heteroaryl, and acyl-substituted sulfenamides, as well as primary amines, cyclic secondary amines, acyclic secondary amines, and structurally complex amines. The desired products were obtained in up to 96% yield, and both the amination and esterification reactions could be performed on millimole scale, demonstrating the synthetic practicality of the method. Mechanistic studies were carried out to probe the reaction pathway. Addition of butylated hydroxytoluene (BHT) or 2,2,6,6-tetramethylpiperidinooxy (TEMPO) strongly inhibited both transformations and led to substantial recovery of the sulfenamide starting materials. HRMS analysis detected sulfilimidoyl-related, morpholine-related, and methoxy-related radical adducts, suggesting that both sulfenamides and the external N/O nucleophiles may participate in radical processes. In addition, N-iodosuccinimide (NIS)-mediated control reactions afforded both amination and esterification products, supporting the possible involvement of iodinated high-valent sulfur intermediates. These results indicate that the reaction may proceed through a dual radical/polar pathway involving radical oxidative activation, possible radical coupling, and nucleophilic trapping of electrophilic sulfur species. This work provides a new oxidative platform for the synthesis of high-valent aza-sulfur compounds from sulfenamides.

Key words: sulfenamides, sulfinamidines, sulfinimidate esters, iodide/peroxide, N/O-divergent synthesis

引用此文

黄国玲, 黄政豪, 孙嘉琦, 赵智博, 李鹏妍, 潘雅雯, 卢训博. 碘盐/过氧化物促进次磺酰胺自由基氧化活化实现硫亚胺酰胺和硫亚胺酯的N/O分流合成[J]. 化学学报, 2026, 84(8): 1318-1325.

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.

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图/表 9

图1. 硫亚胺酰胺和硫亚胺酯分流合成的研究背景与策略

Figure 1. Background and strategy for the N/O-divergent synthesis of sulfinamidines and sulfinimidate esters

Entry^a	Cat.	Oxidant	Temp.	Yield/%
1	TBAI	TBHP	60 ℃	80
2^b	TBAI	TBHP	60 ℃	79
3	TBAI	CHP	60 ℃	75
4	TBAI	H₂O₂	60 ℃	Trace
5	TBAI	BPO	60 ℃	46
6	TBAI	DTBP	60 ℃	15
7	TBAI	TBPB	60 ℃	38
8	TBAI	TBHP	50 ℃	77
9	TBAI	TBHP	40 ℃	75
10	TBAI	TBHP	r.t.	73
11	I₂	TBHP	r.t.	67
12	KI	TBHP	r.t.	65
13	TPeAI	TBHP	r.t.	68
14	THexAI	TBHP	r.t.	36
15	TMAI	TBHP	r.t.	38
16^c	TBAI	TBHP	r.t.	41
17^d	TBAI	TBHP	r.t.	61
18^e	TBAI	TBHP	r.t.	95 (71)^f
19^g	TBAI	TBHP	r.t.	42
20^h	TBAI	TBHP	r.t.	68
21ⁱ	TBAI	TBHP	r.t.	23
22	TBAB	TBHP	r.t.	15

表1. 次磺酰胺氧化胺化反应条件的优化

Table 1. Optimization of the reaction conditions for the oxidative amination of sulfenamides

图2. 不同硫酚或硫醇衍生次磺酰胺与吗啉反应的底物范围

Figure 2. Substrate scope of the reaction of morpholine with sulfenamides derived from different thiophenols and thiols Unless otherwise noted, sulfenamide 1 (0.05 mmol, 1.0 equiv.), morpholine 2a (1.5 equiv.), TBAI (0.01 mmol), and TBHP (2.5 equiv.) were stirred in EtOAc (1.0 mL) at room temperature for 15 h. Isolated yields are shown

图3. 不同酰基取代次磺酰胺与吗啉反应的底物范围

Figure 3. Substrate scope of N-acyl sulfenamides in the reaction with morpholine Unless otherwise noted, sulfenamide 1 (0.05 mmol, 1.0 equiv.), morpholine 2a (1.5 equiv.), TBAI (0.01 mmol), and TBHP (2.5 equiv.) were stirred in EtOAc (1.0 mL) at room temperature for 15 h. Isolated yields are shown

图4. 不同胺与次磺酰胺反应的底物范围

Figure 4. Substrate scope of amines in the reaction with sulfenamides Unless otherwise noted, sulfenamide 1a (0.05 mmol, 1.0 equiv.), amine 2 (1.5 equiv.), TBAI (0.01 mmol), and TBHP (2.5 equiv.) were stirred in EtOAc (1.0 mL) at room temperature for 15 h. Isolated yields are shown. Np=neopentyl.

Entry ^a	Cat.	Oxidant	Yield/%
1^b	TBAI	TBHP	46
2^c	TBAI	TBHP	43
3	TBAI	TBHP	57
4^d	TBAI	TBHP	58
5^e	TBAI	TBHP	41
6	I₂	TBHP	30
7	KI	TBHP	44
8	TPeAI	TBHP	50
9	THexAI	TBHP	66
10	TMAI	TBHP	80 (64)^f
11	TMAI	H₂O₂	Trace
12	TMAI	BPO	20
13	TMAI	CHP	79
14	TMAI	DTBP	Trace
15	TMAI	TBPB	20
16^g	TMAI	CHP	23
17^h	TMAI	CHP	41
18ⁱ	TMAI	CHP	53
19^j	TMAI	CHP	70
20^k	TMAI	CHP	81
21^g,k	TMAI	CHP	29

表2. 次磺酰胺氧化酯化反应条件的优化

Table 2. Optimization of the reaction conditions for the synthesis of sulfinimidate esters

图5. 次磺酰胺酯化的底物范围a

Figure 5. Substrate scope for the synthesis of sulfinimidate estersa a Reaction conditions: unless otherwise noted, 1 (0.05 mmol), TMAI (0.01 mmol), and CHP (2.5 equiv.) in MeOH at 60 ℃ for 5 h. Isolated yields are shown. b TBHP was used as oxidant. c 3.0 equiv. CHP was used. d r.t., 24 h.

图6. 自由基捕获、HRMS分析及NIS对照实验

Figure 6. Radical trapping experiments, HRMS analysis, and NIS-mediated control reactions

图7. 碘盐/过氧化物促进的次磺酰胺胺化及醇氧化酯化反应可能的机理

Figure 7. Proposed mechanism for the iodide/peroxide-mediated amination and alkoxylation of sulfenamides

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