Iodine-mediated thiolation of phenol/phenylamine derivatives and sodium arylsulfinates in neat water

Abstract

An efficient and convenient protocol for iodine-mediated thiolation of phenols/phenylamines with sodium benzene-sulfinates in water has been achieved. In this transformation, environment-friendly conditions (including metal-free and water as solvent) are employed under air conditions, and a series of valuable thioethers are easily obtained in moderate to good yields.

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The reactions for the construction of C–C and C–X (X = heteroatom) bonds via C–H functionalization have emerged as an important research trend in organic synthesis.¹ In recent decades, a good deal of novel and shortcut synthetic methods have been reported for the construction of C–C and C–X via C–H functionalization between two C–H/C–H and X–H centers. Among all C–H functionalization reactions, the formation of C–S bonds has drawn attention as an important field of research in contemporary synthetic organic chemistry.

Aryl sulfides are important compounds because they often appear in many natural products and are employed in total synthesis, in functional materials science, and in medicinal chemistry.² It is noteworthy that the diaryl sulfide are applied in numerous disease areas to cure HIV, allergies and cancer as well as Alzheimer's and Parkinson's diseases.³ Compounds containing 2-naphthalenol are still an important part in all sorts of sulfocompounds because of their presence in many bioactive relevant molecules, including glycine transporter-1 (GlyT-1) inhibitions, and 4-hydroxy-3-(arylthio)-2H-chromen-2-ones exhibiting antibacterial and analgesic activities.⁴ Over the past few decades, there are plenty of C–S cross-coupling reactions of aryl thiols and disulfides with aryl halides, boronic acids and triflates involving various transition metals, such as Pd,⁵ Cu,⁶ Ni,⁷ In,⁸ Fe,⁹ Co¹⁰ and so on. Nevertheless, many of these sulfur sources are often limited because of their expensiveness, instability and high-toxicity. Therefore, a new general and flexible approach under metal-free conditions and with increased efficiency and decreased energy and cost is still required. Sodium sulfinates as desirable sulfur source have been extensively used to construct the C–S bond because they are readily accessible and environment-friendly. We envisaged that sodium arylsulfinates might serve as feasible thiolating agents to couple with naphthols in the specified reaction conditions due to sodium arylsulfinates can be reduced to disulphides, which are classical sulfenylating agents. There is no doubt that many efficient methods have also made great progress, which have been reported by groups of Peddinti,¹¹ Huang,¹² Wang,¹³ and others.¹⁴ These urge us to report our own discovery. Herein we present a range of phenol/phenylamine derivatives readily experience thiolation with sodium arylsulfinates mediated by I₂–PPh₃ in water.¹⁵

Triphenylphosphine was often used as reducing agent in virtue of its inexpensiveness, wide material sources and application.¹⁶ Inspired by this result, we began our investigation with the reaction of sodium benzenesulfinate with 2-naphthalenol (2a) as a model reaction to obtain the optimal reaction conditions and the results are presented in Table 1. 2-Naphthalenol was treated with benzenesulfinic acid sodium salt (1a, 1.2 equiv.), iodine (1.0 equiv.) and triphenylphosphine (1.2 equiv.) in 2 mL of toluene at 100 °C for 10 h in the opening system. In a preliminary attempt, we were particularly pleased that the target product 1-(phenylthio)naphthalen-2-ol (3a) was obtained in 71% yield (Table 1, entry 1). Among the different solvents examined, water gave the best efficiency in terms of product yield (82% yield) and as an environment-friendly solvent (Table 1, entry 8). We further investigated the effect of the stoichiometry of I₂ and PPh₃. Unfortunately, obvious decreased yields of 3a were observed when reducing the loads of iodine and triphenylphosphine (from 82% yield to 17% yield) (Table 1, entries 9–12). Furthermore, when the reaction was performed at lower temperature, the yield of 3a was reduced as well (Table 1, entry 14). On the basis of the results shown in Table 1, the I₂/Ph₃P system at 100 °C in water for 10 h emerged as the optimized reaction conditions for follow-up studies.

Table 1 Optimization of reaction conditions for I₂–PPh₃ mediated C1 thiolation reaction of 2-naphthalenol (2a)^a

Entry	I2 (equiv.)	PPh3 (equiv.)	Solvent	Temp (°C)	Yield^b (%)
a Reaction conditions: 1a (0.36 mmol) and 2a (0.30 mmol) in 2 mL of solvent reflux for 10 h in air.b Yield of isolated product.
1	1	1.2	Toluene	100	71
2	1	1.2	CH2Cl2	100	58
3	1	1.2	THF	100	23
4	1	1.2	Dioxane	100	41
5	1	1.2	DMSO	100	Trace
6	1	1.2	DMF	100	42
7	1	1.2	EtOH	100	18
8	1	1.2	H2O	100	82
9	1	1.5	H2O	100	79
10	1	1	H2O	100	65
11	0.5	1.2	H2O	100	17
12	1.5	1.2	H2O	100	80
13	1	1.2	H2O	80	47
14	1	1.2	H2O	rt	Trace

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With the optimized conditions in hand, we next investigated the substrate scope of the sulfenylation of 2-naphthalenol (2) with various sulfinic acid sodium salts (1). The results were clarified in Table 2. It was exhilarating to find that a range of substituted sodium benzenesulfinates reacted with 2-naphthalenol to provide the corresponding products in good to excellent yields. It was important to note that both electron-withdrawing and electron-donating groups were introduced into the thiolation products by employing sodium benzenesulfinates bearing such groups on the aromatic ring. However, it was found that the effect of sodium benzenesulfinate with electron-withdrawing groups on the yield of target products were higher than that of naphthols on it. Obviously, when sodium 4-nitrobenzene sulfinate was employed under the standard conditions, only a trace amount of 3g was detected by TLC. What interesting is that 2-methoxynaphthalene and 2-ethoxynaphthalene can be tolerated in this transformation, but 2 equiv. of I₂ and 1 equiv. of PPh₃ were needed, and the corresponding compounds were isolated in 71% and 75% yields, respectively.

Table 2 C-1 sulfenylation of 2-naphthalenol derivatives with sodium sulfinates mediated by I₂–PPh₃ system^a

Entry	R^1	R^2	R^3	Product, yield^b (%)
a Conditions: 1 (0.36 mmol), 2 (0.30 mmol), I2 (1.0 equiv.), and PPh3 (1.2 equiv.) in 2 mL of water reflux for 10 h in air.b Isolated yield after column chromatography (SiO2).c The reaction of 1a (0.30 mmol) with 2i (0.36 mmol) under the standard conditions.d 2 equiv. of I2 and 1 equiv. of PPh3 were added in water (2 mL).
1	C6H̲5	H	H	3a, 82
2	4-MeC6H4	H	H	3b, 89
3	2-MeC6H4	H	H	3c, 83
4	4-ClC6H4	H	H	3d, 85
5	4-BrC6H4	H	H	3e, 87
6	4-MeOC6H4	H	H	3f, 81
7	4-O2NC6H4	H	H	3g, trace
8	C6H̲5	6-Br	H	3h, 91
9^c	C6H̲5	7-OH	H	3i, 88
10^d	C6H̲5	H	CH3	3j, 71
11^d	C6H̲5	H	C2H5	3k, 75

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It's worth mentioning that when 5,6,7,8-tetrahydro-2-naphthol (2l) was subjected to the transformation under the optimal reaction conditions, the isolated yield of the corresponding product 3l can reach 52% (Scheme 1).

Scheme 1 Reaction of 2l with sodium benzenesulfinate.

Then we explored the scope of the reaction with respect to a variety of sodium arylsulfinates with other phenols/phenylates (Table 3, entries 1–10). These compounds participated well to afford aryl sulfides in good to excellent yields under the optimized conditions (Table 3). Various sodium arylsulfinates having electron-withdrawing and electron-donating halo-groups at the 4-position were able to react with phenols/phenylates to give the desired products 5aa–5eb in a few hours in moderate to high yields. Besides, we further tested this protocol with the carbon nucleophile N,N-dimethylaniline bearing an amino functionality providing the corresponding aryl sulfides 5ac–5ec in good yields. In general, for substituted sodium benzenesulfinates, the substrates containing electron-donating groups showed higher reactivity than those with electron-withdrawing groups.

Table 3 C-4 sulfenylation of X^a–X^c with sodium sulfinates mediated by I₂–PPh₃ system^a

Entry	R^1	X^n	Time (h)	Product yield^b (%)
a Conditions: 1 (0.3 mmol), 4 (0.36 mmol), I2 (1.0 equiv.), and PPh3 (1.2 equiv.) in 2 mL of water reflux for 10 h in air.b Isolated yield.
1	C6H5	a	8	5aa, 80
2	4-MeC6H4	a	8	5ba, 86
3	4-ClC6H4	a	8	5ca, 82
4	4-BrC6H4	a	8	5da, 80
5	4-OMeC6H4	a	8	5ea, 82
6	4-O2NC6H4	a	12	5fa, 78
7	C6H5	b	8	5ab, 90
8	4-MeC6H4	b	8	5bb, 92
9	4-BrC6H4	b	8	5db, 88
10	4-OMeC6H4	b	8	5eb, 87
11	C6H5	c	10	5ac, 83
12	4-MeC6H4	c	10	5bc, 87
13	4-BrC6H4	c	10	5dc, 84
14	4-OMeC6H4	c	10	5ec, 82

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Inspired by these satisfactory results, we tried to probe the synthetic adaptability of the present method. The gram-scale reaction was completed between 1a and 2a, and the reaction afforded 3a in 80% yield (Scheme 2). Consequently, this expedient protocol could be served as an efficient method for the synthesis of various thioether derivatives with hydroxy/amidogen/methoxyl groups.

Scheme 2 Synthesis of 3a on gram scale.

In order to gain further insight into the plausible reaction pathway of I₂-mediated thiolation of substituted phenols, several control experiments were conducted under various reaction conditions, as showed in Scheme 3. No reaction occurred upon treatment of benzenesulfinic acid sodium salt 1a with 2-naphthalenol 2a in the absence of iodine (Scheme 3, a). Only phenyl disulfide was produced in the standard conditions without 2-naphthalenol (Scheme 3, b). In the optimized conditions, 2-naphthalenol 2a stably reacted with diphenyldisulfane 6 to give the desired product 3a in 95% yield (Scheme 3, c).

Scheme 3 Control experiments.

On the basis of the experimental results described above and together with previous relevant mechanistic studies,¹⁷ we proposed a plausible reaction pathway depicted in Scheme 4. Initially, sodium benzenesulfinate was reduced to diphenyldisulfane (6) in the presence of I₂ and PPh₃. Then, 6 reacts with I₂ to form 2 equiv. of an electrophilic species PhSI (7), which is attacked by 2 to yield the desirable product 3 and HI.

Scheme 4 The plausible mechanism.

Conclusions

In conclusion, a metal-free and convenient way for the synthesis of diaryl sulfide derivatives via the I₂–PPh₃ system mediated thiolation of substituted naphthols/phenylamines in water under air condition has been described. The thiolation of naphthols/phenylamines and sodium benzene-sulfinate undergoes S–S bond formation, S–S bond cleavage, and C–S bond formation. In this program, using a range of arylsulfinic acid salts as sulfur source, structurally diversed naphthol/aniline thioethers can be smoothly produced in moderate to good yields. It is believed that this method would offer an efficient approach to thioethers containing hydroxy/amino/alkoxy groups.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (21302084).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra24351c

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