Iodine-induced synthesis of sulfonate esters from sodium sulfinates and phenols under mild conditions

Abstract

An iodine-induced synthesis of sulfonate esters via cross-coupling reactions of sodium sulfinates with phenols is reported. This synthetic route is low-cost, facile, green and efficient, and could afford the target products with good to excellent yields under mild conditions.

---

Sulfonate esters are well-known ester compounds and crucial pharmaceutical ingredients which work as bridge structures or ligands and have presented particular biological activities (such as antitumor and monoamine oxidase inhibitory activities) in medicinal chemistry (Fig. 1).^1–4 Besides, sulfonate esters play a unique role in coupling reactions because sulfonate ester groups are removed easily.⁵ To date, many methods have been developed to synthesize sulfonate esters, mainly including the reaction of phenols with sulfonic acids,⁶ or with thiols using H₂O₂–POCl₃ system,⁷ and with sulfonyl chlorides in ionic liquids,⁸ or under microwave-assistance⁹ and catalyzed by copper oxide.¹⁰ Other routes have been also reported.¹¹ Nevertheless, most of these methods suffer from harsh reaction conditions. In addition, expensive and unstable sulfonyl chlorides as sulfonylating reagents would lead to some drawbacks. Hence, it is necessary to search for low-cost, green and efficient sulfonylating reagents (sulfonyl sources) for the synthesis of sulfonate esters.

Fig. 1 Selected examples for bioactive and pharmaceutical compounds containing sulfonate ester group.

In recent years, many chemists became interested in the direct sulfonylation reaction using various sulfonylation reagents.¹² Among various sulfonylation reagents, sodium sulfinates seem to be more attractive due to their stability, low price and convenience handling. Actually, sodium sulfinates have been widely applied in sulfonylations,¹³ C–H arylations¹⁴ and sulfenylations.¹⁵ In addition, iodine-mediated synthesis has attracted more and more attention because iodine is cheap, readily available and eco-friendly.¹⁶ Recently, some interesting reactions related phenols in organic chemistry have been also reported.¹⁷

Based on our research interest in iodine-mediated reactions,¹⁸ herein we reported an iodine-induced the synthesis of sulfonate esters from sodium sulfinates and phenols under mild conditions. To our knowledge, such a route for the synthesis of sulfonate esters has not been reported to date.

To optimize the reaction conditions, the reaction of 4-chlorophenol (1a) with sodium p-toluenesulfinate (2a) was selected as the model reaction, and the results were shown in Table 1. When the reaction of 1a and 2a was carried out in the presence of I₂ in CH₃CN for 5 h, the yield of 4-chlorophenyl 4-methylbenzenesulfonate (3a) was only 10% (entry 1). Pinhey's investigations indicated that base additives could efficiently promote the coupling reaction of phenols with aryllead triacetates.¹⁹ Based on this idea, we suppose that base may act as the similar role in the present system. Thus, we examined the effect of various inorganic and organic bases on the coupling reaction of 4-chlorophenol with sodium p-toluenesulfinate. In the presence of CH₃COONa, the yield of 3a was raised to 36% (entry 2). Very pleasedly, Cs₂CO₃, especially K₂CO₃, could dramatically improve the yield of 3a (entries 3 and 4). However, a strong inorganic base KOH and organic bases (Et₃N and pyridine) gave unsatisfactory results (entries 5–7). The effect of solvents were further investigated. Compared with other solvents (H₂O, DMF, EtOH and DMSO), CH₃CN or CH₃OH gave the better results (entries 8–12). Considering the toxicity of CH₃CN, we chose CH₃OH as the solvent for this transformation. When the temperature was elevated to 50 °C, the yield of 3a was not influenced (entry 13), so room temperature was found as the optimal temperature. In addition, the amount of I₂ and K₂CO₃ has a great influence on the reaction (see ESI†). When 1 equiv. of I₂ or K₂CO₃ was used in the present system, the best result could be obtained (entry 8). Moreover, when the reaction was performed on a 10.0 mmol scale (Table 1, entry 19), an excellent yield (88%) of 3a was obtained. This means that the reaction could be scalable and has a potential application for the preparation of more complex molecules.

Table 1 Optimization of reaction conditions^a

Entry	Base	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), I2 (1 equiv.), base (1 equiv.), solvent (2 mL) and room temperature.b GC yield based on 1a.c At 50 °C.d Reaction in a dark background.e Adding TEMPO.f Adding BHT.g Using tosyl iodide (0.6 mmol) instead of 2a and I2.h Under N2 atmosphere.i Reaction on a 10 mmol scale.
1	No base	CH3CN	5	10
2	CH3COONa	CH3CN	5	36
3	Cs2CO3	CH3CN	5	80
4	K2CO3	CH3CN	5	98
5	KOH	CH3CN	5	19
6	Et3N	CH3CN	5	6
7	Pyridine	CH3CN	5	14
8	K2CO3	CH3OH	5	98
9	K2CO3	H2O	5	11
10	K2CO3	DMF	5	57
11	K2CO3	EtOH	5	75
12	K2CO3	DMSO	5	69
13^c	K2CO3	CH3OH	5	94
14^d	K2CO3	CH3OH	5	89
15^e	K2CO3	CH3OH	5	Trace
16^f	K2CO3	CH3OH	5	Trace
17^g	K2CO3	CH3OH	5	77
18^h	K2CO3	CH3OH	5	90
19^i	K2CO3	CH3OH	5	88

---

Under the optimized reaction conditions, the scope of synthesis of sulfonate esters by using various phenols with 2a was investigated (Table 2). A series of ortho and para-substituted phenols by electron-withdrawing groups (R = F, Br, I, NO₂, CN) all proceeded smoothly to afford the corresponding products (3d–3f, 3i–3k) in excellent yields. However, when some electron-donating groups (R = CH₃, isopropyl) substituted phenols were used, a long reaction time was needed, a lower yield was obtained, and some by-products substituted by iodine were observed (3c, 3g, 3h, 3l). This result may be attributed to the fact that the presence of electron-donating groups is not favourable for the conversion of phenols to aryloxy anion. In the present reaction system, the aryloxy anion may be one of key intermediates. To our delight, naphthol and quinolin-8-ol performed with good yields (3m–3o). Specially, aliphatic alcohols could react well with sodium p-toluenesulfinate (2a) in CH₃CN solvent to afford the target products (3p–3r) with good yields when K₂CO₃ was replaced by CH₃ONa. These results indicate that aliphatic alcohols are also suitable for this transformation in the presence of a strong base CH₃ONa.

Table 2 Synthesis of sulfonate esters with various phenols^a,b

a Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), I₂ (0.5 mmol), K₂CO₃ (1 equiv.), CH₃OH (2 mL), room temperature.b Isolated yield based on 1.c CH₃CN (2 mL) as the solvent.d Using CH₃ONa (0.5 mmol) instead of K₂CO₃.

---

On the other hand, the reactions of some sodium sulfinates with 1a were examined, and the result was summarized in Table 3. Various sodium sulfinates with 4-fluoro, 4-chloro, 4-bromo, 4-methoxyl and 4-ethyl groups substituted on aryl rings all proceeded smoothly to give good to excellent yields (3s–3x). In addition, 4-chlorophenylphenylmethane sulfonate (3y) was also obtained in a high yield.

Table 3 Scope of various sodium sulfonates^a,b

Sodium sulfinate	Product		Yield (%)
a Reaction conditions: 1a (0.5 mmol), sodium sulfinate (0.6 mmol), I2 (0.5 mmol), K2CO3 (1 equiv.), CH3OH (2 mL), 5 h and room temperature.b Isolated yield based on sodium sulfinate.
		3s	86
		3t	90
		3u	88
		3v	89
		3w	74
		3x	77
		3y	82

---

To investigate the reaction mechanism, several controlled experiments were performed (Table 1, entries 14–18). Firstly, when radical scavenger TEMPO or BHT was added to this reaction system (Table 1, entries 15 and 16), no desired 3a was obtained, indicating that the reaction involves a radical pathway. Besides, when the reaction of tosyl iodide instead of molecule iodine with 2a was carried out (Table 1, entry 17), 3a was still obtained in a high yield, revealing that tosyl iodide may be an intermediate in this transformation. Even if the reaction was proceeded in a dark background or under N₂ atmosphere, the yield of 3a was almost unchanged (Table 1, entries 14 and 18). This means that visible light and oxygen were irrelevant for this transformation. As a result, a possible mechanism is proposed in Scheme 1. Sodium sulfinate firstly reacts with I₂ to form sulfonyl iodide (A),²⁰ which is easily subjected to homolysis to give a sulfonyl radical (E). At the same time, phenols is transformed to aryloxy anion (B) in alkaline medium. Then, the aryloxy anion B is combined with the radical E to generate the radical anion C, followed by the reaction with A to afford the desired sulfonate ester, together with radical anion D.²¹ The radical anion D could generate the radical E to enter into the next reaction cycle. In the present reaction system, molecular I₂ practically is a reactant or an inducer, which is delineated in Scheme 2. The total reaction equation (Scheme 2) could explain well why the full conversion of 0.5 mmol of 1a to 3a requires 0.5 mmol of I₂ (see ESI, Table S1,† entry 6).

Scheme 1 Proposed reaction mechanism.

Scheme 2 A total reaction equation for this transformation.

In conclusion, we have developed a simple, metal-free and eco-friendly synthesis of sulfonate esters from sodium sulfinates and phenols. Compared with the reported methods (such as using sulfonyl chlorides as starting materials), the present route appears to be more attractive and efficient for the synthesis of sulfonate esters. Further study on this reaction's application is ongoing currently in our laboratory.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (21172079) and the Science and Technology Planning Project of Guangdong Province (2011B090400031) for financial support.

Notes and references

1. P. J. Stang, Acc. Chem. Res., 1991, 24, 304.
2. D. P. Elder, E. Delaney, A. Teasdale, S. Eyley, V. D. Reif, K. Jacq, K. L. Facchine, R. S. Oestrich, P. Sandra and F. David, J. Pharm. Sci., 2010, 99, 2948.
3. (a) L. Pisani, M. Bareletta, R. Soto-Otero, O. Nicolotti, E. Mendez-Alvarez, M. Catto, A. Introcaso, A. Stefanachi, S. Cellamare, C. Altomare and A. Carotti, J. Med. Chem., 2013, 56, 2651; (b) L. Yan and C. E. Müller, J. Med. Chem., 2004, 47, 1031; (c) P. Wang, J. Min, J. C. Nwachukwu, V. Cavett, K. E. Carlson, P. Guo, M. Zhu, Y. Zheng, C. Dong, J. A. Katzenellenbogen, K. W. Nettles and H. Zhou, J. Med. Chem., 2012, 55, 2324; (d) H. Zhou, J. S. Comninos, F. Stossi, B. S. Katzenellenbogen and J. A. Katzenellenbogen, J. Med. Chem., 2005, 48, 7261.
4. P. J. Stang and W. L. Treptow, J. Med. Chem., 1981, 24, 468.
5. (a) P. Y. Yeung, C. M. So, C. P. Lau and F. Y. Kwong, Angew. Chem., 2010, 122, 9102; (b) H. N. Nguyen, X. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 11818; (c) Z. Tang and Q. Hu, J. Am. Chem. Soc., 2004, 126, 3058; (d) L. J. Gooβen, N. Rodrígue, P. P. Lange and C. Linder, Angew. Chem., Int. Ed., 2010, 49, 1111; (e) C. Cai, N. R. Rivera, J. Balsells, R. R. Sidler, J. C. McWilliams, C. S. Shultz and Y. Sun, Org. Lett., 2006, 8, 5161; (f) C. H. Cho, H. S. Yun and K. Park, J. Org. Chem., 2003, 68, 3017; (g) S. C. Miller, J. Org. Chem., 2010, 75, 4632.
6. (a) S. Caddick, J. D. Wilden and D. B. Judd, J. Am. Chem. Soc., 2004, 126, 1024; (b) Y. Nitta and Y. Arakawa, Chem. Pharm. Bull., 1985, 33, 1380.
7. K. Bahrami, M. M. Khodaei and J. Abbasi, Tetrahedron, 2012, 68, 5095.
8. G. Song, Y. Cai and Y. Peng, J. Comb. Chem., 2005, 7, 561.
9. (a) M. Oliverio, P. Costanzo, R. Paonessa, M. Nardi and A. Procopio, RSC Adv., 2013, 3, 2548; (b) S. Lakrout, H. K'tir, A. Amira, M. Berredjem and N. Aouf, RSC Adv., 2014, 4, 16027; (c) N. Zhao, Y. Li, Y. Wang and J. Wang, J. Sulfur Chem., 2006, 27, 427; (d) L. Xu and C. Xia, Synth. Commun., 2004, 34, 1199.
10. G. A. Meshram and V. D. Patil, Tetrahedron Lett., 2009, 50, 1117.
11. (a) M. J. Maritinelli, R. Vaidyanthan, J. M. Pawlak, N. K. Nayyar, U. P. Dhokte, C. W. Doecke, L. M. H. Zollars, E. D. Moher, V. V. Khau and B. Košmrlj, J. Am. Chem. Soc., 2002, 124, 3578; (b) M. J. Martinelli, N. K. Nayyar, E. D. Moher, U. P. Dhokte, J. M. Pawlak and R. Vaidyanathan, Org. Lett., 1999, 1, 447; (c) K. Yuasa, K. Enomoto, Y. Maekawa, J. Kato, T. Yamashita and M. Yoshida, J. Photopolym. Sci. Technol., 2004, 17, 21; (d) Z. Quan, F. Jing, Z. Zhang, Y. Da and X. Wang, Chin. J. Chem., 2013, 31, 1495.
12. For selected examples on various sulfonyl sources, see: (a) W. Wei, C. Li, D. Yang, J. Wen, J. You, Y. Suo and H. Wang, Chem. Commun., 2013, 49, 10239; (b) X. Li, Y. Xu, W. Wu, C. Jiamg, C. Qi and H. Jiang, Chem.–Eur. J., 2014, 20, 7911; (c) X. Zhao, E. Dimitrijević and V. M. Dong, J. Am. Chem. Soc., 2009, 131, 3466; (d) Z. Wu, H. Song, X. Cui, C. Pi, W. Du and Y. Wu, Org. Lett., 2013, 15, 1270; (e) H. Li and G. Liu, J. Org. Chem., 2014, 79, 509.
13. For selected examples, see: (a) F. Xiao, S. Chen, Y. Chen, H. Huang and G. Deng, Chem. Commun., 2015, 51, 652; (b) Q. Jiang, B. Xu, A. Zhao, Y. Zhao, Y. Li, N. He and C. Guo, J. Org. Chem., 2014, 79, 7372; (c) Y. Gao, W. Wu, Y. Huang, K. Huang and H. Jiang, Org. Chem. Front., 2014, 1, 361; (d) Y. Xu, X. Tang, W. Hu, W. Wu and H. Jiang, Green Chem., 2014, 16, 3720; (e) X. Tang, L. Huang, Y. Xu, J. Yang, W. Wu and H. Jiang, Angew. Chem., Int. Ed., 2014, 53, 4205; (f) X. Tang, L. Huang, C. Qi, X. Wu, W. Wu and H. Jiang, Chem. Commun., 2013, 49, 6102.
14. (a) J. Aziz, S. Messaoudi, M. Alami and A. Hamze, Org. Biomol. Chem., 2014, 12, 9743; (b) B. Rao, W. Zhang, L. Hu and M. Luo, Green Chem., 2012, 14, 3436; (c) D. H. Ortgies, F. Chen and P. Forgione, Eur. J. Org. Chem., 2014, 3917.
15. (a) P. Katrun, S. Hongthong, S. Hlekhlai, M. Pohmakotr, V. Reutrakul, D. Soorukram, T. Jaipetch and C. Kuhakarn, RSC Adv., 2014, 4, 18933; (b) S. Liu, L. Tang, H. Chen, F. Zhao and G. Deng, Org. Biomol. Chem., 2014, 12, 6076.
16. (a) H. Togo and S. Iida, Synlett, 2006, 2159; (b) S. Das, R. Borah, R. R. Devi and A. J. Thakur, Synlett, 2008, 2741; (c) B. Alcaide, P. Almendros, G. Cabrero, R. Callejo, M. P. Ruiz, M. Arnó and L. R. Domingo, Adv. Synth. Catal., 2010, 352, 1688; (d) C. Chen, S. Yang and M. Wu, J. Org. Chem., 2011, 76, 10269; (e) K. Xu, Y. Hu, S. Zhang, Z. Zha and Z. Wang, Chem.–Eur. J., 2012, 18, 9793; (f) U. T. Sunil, S. K. Sushma, A. D. Satish, R. S. Swapnil and P. P. Rajendra, Curr. Org. Chem., 2012, 16, 1485; (g) P. T. Parvatkar, P. S. Parameswaran and S. G. Tilve, Chem.–Eur. J., 2012, 18, 5460; (h) W. Lee, H. Shen, W. Hu, W. Lo, C. Murali, J. K. Vandavasi and J. Wang, Adv. Synth. Catal., 2012, 354, 2218.
17. (a) K. Seth, S. R. Roy, B. V. Pipaliya and A. K. Chakraborti, Chem. Commun., 2013, 49, 5886; (b) B. Alcaide, P. Almendros, M. T. Quirós, R. López, M. I. Menéndez and A. S. Ćwikla, J. Am. Chem. Soc., 2013, 135, 898; (c) J. Hu, E. A. Adogla, Y. Ju, D. Fan and Q. Wang, Chem. Commun., 2012, 48, 11256; (d) Z. Wu, F. Luo, S. Chen, Z. Li, H. Xiang and X. Zhou, Chem. Commun., 2013, 49, 7653; (e) W. Sun, H. Lin, W. Zhou and Z. Li, RSC Adv., 2014, 4, 7491; (f) Y. E. Lee, T. Cao, C. Torruellas and M. C. Kozlowski, J. Am. Chem. Soc., 2014, 136, 6782; (g) W. Chen, J. Li, D. Fang, C. Feng and C. Zhang, Org. Lett., 2008, 10, 4565; (h) D. Lee, K. Kwon and C. S. Yi, J. Am. Chem. Soc., 2012, 134, 7325.
18. (a) X. Gao, X. Pan, J. Gao, H. Huang, G. Yuan and Y. Li, Chem. Commun., 2015, 51, 210; (b) G. Yuan, Z. Chen, X. Gao and H. Jiang, RSC Adv., 2014, 4, 24300; (c) H. Huang, G. Yuan, X. Li and H. Jiang, Tetrahedron Lett., 2013, 54, 7165; (d) X. Pan, J. Gao, J. Liu, J. Lai, H. Jiang and G. Yuan, Green Chem., 2015, 17, 1400.
19. (a) H. C. Bell, J. T. Pinhey and S. Sternhell, Aust. J. Chem., 1979, 32, 1551; (b) J. T. Pinhey, Aust. J. Chem., 1991, 44, 1353; (c) J. T. Pinhey, Pure Appl. Chem., 1996, 68, 819.
20. (a) W. E. Truce and G. C. Wolf, J. Org. Chem., 1971, 36, 1727; (b) P. Katrun, C. Mueangkaew, M. Pohmakotr, V. Reutrakul, T. Jaipetch, D. Soorukram and C. Kuhakarn, J. Org. Chem., 2014, 79, 1778; (c) E. Truce, D. L. Heuring and G. C. Wolf, J. Org. Chem., 1980, 45, 406; (d) L. M. Harwood, M. Julia and G. L. Thuiller, Tetrahedron, 1980, 36, 2483; (e) D. C. Craig, G. L. Edwards and C. A. Muldoon, Synlett, 1977, 1441; (f) J. Barluenga, J. M. Martínez-Gallo, C. Nájera, M. Yus and F. J. Fananas, J. Chem. Soc., Perkin Trans. 1, 1987, 2605; (g) C. Nájera, B. Baldó and M. Yus, J. Chem. Soc., Perkin Trans. 1, 1988, 1029.
21. (a) M. T. Baumgartner, G. A. Blanco and A. B. Pierini, New J. Chem., 2008, 32, 464; (b) J. M. Savéant, J. Phys. Chem., 1994, 98, 3716.

---

Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, characterization of products, and NMR spectral charts. See DOI: 10.1039/c5ra00724k

---