Disulfides as efficient thiolating reagents enabling selective bis-sulfenylation of aryl dihalides under mild copper-catalyzed conditions

Abstract

Selective bis-sulfenylation reactions of aryl dihalides have been achieved by copper-catalyzed C–S coupling reactions under mild conditions of refluxing EtOH (80 °C). Employment of disulfides as thiolating reagents enables the production of various bis(phenylthio)benzenes with excellent selectivity, and no products from mono C–S coupling are isolated.

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Introduction

The formation of C–S bonds is one of the fundamental transformations of organic synthesis. Owing to the prevalent presence of the C–S bond in biologically relevant compounds, natural products, argrochemicals and organic materials, the research on the construction of C–S bonds, especially sp² C–S bonds that involving the transformation of inactive sp² C–X (X = halide, H, etc.) bonds has become an issue of widespread interest.^1–7 Presently, transition metal-catalyzed C–S coupling reactions between thiol nucleophiles and aryl/vinyl halides are amongst the most practical approach for the generation of sp² C–S bonds.^8,9 Originally, this kind of reaction has been dominantly performed in the presence of a transition metal catalyst and high temperature in polar solvents such as DMSO, DMF or NMP.^10–12 Among the different transition metal species which have been used in the C–S cross-coupling reactions, copper catalysts have attracted tremendous attention because of their low cost as well as low toxicity.^13–30

While spectacular progress has been witnessed in the field of C–S coupling chemistry during the past decade, interestingly, few attentions have been paid to the chemo-selective C–S coupling reactions of dihalide substrates. These kind of selective reactions providing mono- and bis-sulfenylated aryls, however, are crucial in expanding the application scope of C–S coupling chemistry by affording structurally diverse S-containing products. In 2011, Mao and coworkers reported the ligand-free bis-sulfenylation of diiodoaryls using thiols as S-nucleophiles in the presence of iron–copper mixed catalysts at 140 °C.³¹ In addition, Bagley and coworkers reported the microwave irradiated, copper-catalyzed protocol which has also been found selectively promote the bis-sulfenylation of dihalobenzenes.²⁶ While these methods rely on the tough reaction conditions to achieve bis-sulfenylation, developing new methodologies enabling selective bis-sulfenylation reactions under milder conditions is highly demanding.

Following our previous work on copper-catalyzed selective mono-sulfenylation (Scheme 1)³² as well as other related copper-catalyzed coupling chemistry,^33–37 we report herein the copper-catalyzed selective bis-sulfenylation of dihaloaryls under mild and clean conditions by using disulfides as bis-thiolating agents³⁸ (Scheme 1).

Scheme 1 Tunable mono- and bis-sulfenylation of dihaloaryls.

Results and discussion

Since we previously discovered that using thiols in the coupling reactions with diiodobenzenes led to selective mono-sulfenylation,³² in order to achieve the tunable selective bis-sulfenylation, we tentatively chosen disulfides as thiolating reagents in the reactions. Firstly, a class of aryl and alkyl disulfides were synthesized following a simple and clean method developed in our lab.³⁹ The reaction of 1,2-diiodobenzene 1a and phenyl disulfide 2a was then employed as model reaction for optimizing investigation. In the presence of CuI, Cs₂CO₃ at 120 °C in DMSO, a series of different ligands were firstly screened. It was found that the bis-sulfenylation could be achieved in the presence of CuI and different types of ligands. Among the examined ligands, including 1,10-phenanthroline (L1), 8-hydroxylquinoline (L2), L-proline (L3), D-glucose (L4) and two enaminone-based ligands (L5 and L6), 2-hydroxylphenyl functionalized enaminone ligand L5 (ref. 40) displayed the best effect in assisting the bis-sulfenylation reaction with 93% yield of product 3a (Fig. 1).

Fig. 1 Different ligands for bis-sulfenylation of 1,2-diiodobenze; conditions: 1a (0.15 mmol), 2a (0.15 mmol), Cs₂CO₃ (0.30 mmol), CuI (0.03 mmol) and ligand (0.03 mmol) in DMSO (1 mL), 120 °C, 15 h (TLC).

Subsequently, other parameters of the model reaction were investigated. The experiments employing different copper catalysts, including cupric, cuprous salts and copper dust, suggested that CuI was the most efficient catalyst (entries 1–6, Table 1). Examination on the effect of different organic and inorganic bases found no better alternative to Cs₂CO₃ (entries 7–10, Table 1). Experiments in different solvents implied that DMF, toluene or dioxane were not able to provide improved yield over DMSO, however, it has been found that ethanol as the solvent allowed smooth bis-sulfenylation reaction with excellent yield of 3a at reflux and open air conditions (entries 11–14, Table 1). Other low boiling point solvent such as acetonitrile was not able to mediate the reaction effectively (entry 15, Table 1), demonstrating the unique advantage of ethanol in this selective bis-sulfenylation process. Finally, reducing the amount of CuI to 10 mol% loading gave 3a with equally excellent yield (entry 16, Table 1). Further decreasing the catalyst loading, however, was not favored (entry 17, Table 1).

Table 1 Experiments on optimizing reaction conditions^a

Entry	Cat.	Base	Solvent	T (°C)	Yield^b (%)
a General conditions: 1a (0.15 mmol), 2a (0.15 mmol), Cu cat. (20 mol%), L5 (20 mol%) and base (0.3 mmol) in solvent (1 mL), stirred for 15 h (TLC).b Yield of isolated product.c CuI in 10 mol%.d CuI in 5 mol%.
1	CuCl2·2H2O	Cs2CO3	DMSO	120	64
2	CuBr	Cs2CO3	DMSO	120	79
3	CuBr2	Cs2CO3	DMSO	120	67
4	CuO	Cs2CO3	DMSO	120	59
5	Cu (dust)	Cs2CO3	DMSO	120	76
6	Cu(OAc)2·H2O	Cs2CO3	DMSO	120	62
7	CuI	NaOH	DMSO	120	36
8	CuI	Et3N	DMSO	120	67
9	CuI	t-BuOK	DMSO	120	Trace
10	CuI	K2CO3	DMSO	120	87
11	CuI	Cs2CO3	DMF	120	89
12	CuI	Cs2CO3	Toluene	Reflux	69
13	CuI	Cs2CO3	Dioxane	Reflux	59
14	CuI	Cs2CO3	Ethanol	Reflux	95
15	CuI	Cs2CO3	MeCN	Reflux	46
16^c	CuI	Cs2CO3	Ethanol	90	95
17^d	CuI	Cs2CO3	Ethanol	90	59

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Under the optimal conditions, the application scope of this catalytic method has been investigated by subjecting different diiodoaryls and disulfides. As outlined in Table 2, this method has been found with excellent applicability for the synthesis of various bis(phenylthio)benzenes. 4-Substituted phenyl disulfides such as alkyl, halide substituted phenyl disulfides reacted with different diiodobenzenes 2a–c with generally excellent yields (3a–f, 3n–r and 3u–y, Table 2). Similarly, 2- and 3-substituted phenyl disulfides also displayed excellent tolerance to this synthetic method by providing corresponding products with satisfactory yields (3g–i, 3s–t and 3z, Table 2). More importantly, other aryl disulfides such as naphthyl disulfide and heteroaryl disulfides also acted as double thiolating reagents to yield structurally divergent bis-thiolated benzenes 3j–l (Table 2).

Table 2 Application scope of the copper-catalyzed, EtOH mediated bis-sulfenylation of diiodoaryls^a

R	Diiodobenzene	Product	Yield^b (%)
a General conditions: 1 (0.5 mmol), 2 (0.5 mmol), CuI (0.05 mmol), L5 (0.1 mmol) and Cs2CO3 (1.0 mmol) in alcohol (2 mL), reflux for 15 h.b Yield of isolated product.
Ph	2a	3a	94
4-CH3C6H4	2a	3b	91
4-i-PrC6H4	2a	3c	86
4-FC6H4	2a	3d	86
4-ClC6H4	2a	3e	85
4-BrC6H4	2a	3f	79
2-ClC6H4	2a	3g	82
2-CH3C6H4	2a	3h	83
3-CH3C6H4	2a	3i	94
Naphth-2-yl	2a	3j	92
Pyridine-2-yl	2a	3k	84
Benzothiazol-2-yl	2a	3l	81
sec-Butyl	2a	3m	72
Ph	2b	3n	91
4-CH3C6H4	2b	3o	85
4-i-PrC6H4	2b	3p	82
4-FC6H4	2b	3q	82
4-ClC6H4	2b	3r	86
2-CH3C6H4	2b	3s	81
2-ClC6H4	2b	3t	83
Ph	2c	3u	92
4-CH3C6H4	2c	3v	94
4-i-PrC6H4	2c	3w	86
4-FC6H4	2c	3x	87
4-ClC6H4	2c	3y	87
3-CH3C6H4	2c	3z	91
2-NH2C6H4	—	—	—
2-NO2C6H4	—	—	—

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Finally, it is noteworthy that alkyl disulfide was also able to incorporate diiodobenzene to give corresponding bis(alkylthio)benzene 3m, albeit with lower yield than equivalent entries using aryl disulfides. Further attempts on running the bis-sulfenylation with amino and nitro functionalized phenyl disulfides revealed the intolerance of these groups to the present protocol (Table 2).

Based on the known conditions for bis-sulfenylation, the cross bis-sulfenylation using two different disulfides to incorporate 1,2-diiodobenzene was attempted. As outlined in Scheme 2, the reaction employing simultaneously tolyldisulfide and p-bromophenyl disulfide led to the production of three mixed products, including the products 3b, 3f from homo-bis-sulfenylation as well as product 3bf from cross bis-sulfenylation.

Scheme 2 Bis-sulfenylation with 2 different disulfides.

Following the good results provided the reactions of diiodobenzenes, the entries using 1,2-dibromobenzene have also been investigated. However, the expect products could only be obtained with low to fair yields from these experiments, although harsher conditions (sealed tube, 110 °C) were employed (Scheme 3).

Scheme 3 Bis-sulfenylation reactions of 1,2-dibromobenzene.

Conclusions

The selective bis-sulfenylation reactions of aryl dihalides have been achieved with excellent efficiency by employing the disulfides as double thiolating reagent. The present method provided a highly useful methodology for the synthesis of bis(phenylthio)benzenes of type 3. This method also possessed notable advantages such as green reaction medium, mild conditions and full utility of thiolating reagents.

Acknowledgements

This work is financially supported by NSFC of China (no. 21202064), a research project of the Jiangxi Provincial Department of Education (no. GJJ12211), a Sponsored Program for Cultivating Youths of Outstanding Ability in Jiangxi Normal University (Y. Liu), a program Sponsored by Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents (C. Wen) as well as a program of Graduate Student Innovative Research from Jiangxi Province (no. YC2013-S104).

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data of all products, ¹H and ¹³C NMR spectra of all products. See DOI: 10.1039/c4ra02935f

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