Metal-free direct construction of sulfenylated pyrazoles via the NaOH promoted sulfenylation of pyrazolones with aryl thiols

Abstract

A convenient and cost-effective NaOH-promoted direct sulfenylation of pyrazolones with aryl thiols has been developed under mild and metal-free conditions. In this transformation, a range of valuable sulfenylated pyrazoles can be easily achieved in moderate to excellent yields, with high atom efficiency and good functional group tolerance.

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Pyrazole and its derivatives, an important class of heterocyclic compounds, have been widely used in the medicinal and agrochemical industry due to their diverse pharmacological and biological activities.¹ For example, they have been recognized as an antibacterial agent,² histone deacetylase inhibitor,³ HIV-1 reverse transcriptase inhibitor (Fig. 1, compound I),⁴ the inhibitor of type 5 cGMP phosphodiesterase (Fig. 1, compound II),⁵ antidepressant zometapine (Fig. 1, compound III),⁶ the inhibitor of dipeptidyl peptidase IV (DPP-IV) (Fig. 1, compound IV),⁷ and many agrochemicals such as insecticides and herbicides.⁸ Consequently, substantial efforts have been devoted to the construction of various pyrazole derivatives.⁹ Particularly, the interest in sulfenylated pyrazoles has increased due to their proven usefulness as the herbicidal agents¹⁰ and antioxidants.¹¹ Generally, sulfenylated pyrazoles were prepared by the nucleophilic substitution reaction of sodium thiolate with bromopyrazolones, the cyclization reaction of methyl 3-oxo-2-(phenylthio)butanoate with phenylhydrazine,^11,12 and the sulphenylation of pyrazolones with preformed and unstable sulphenyl chlorides.¹² However, most of these reactions suffer from certain limitations, such as the need for prefunctionalized sulfenylating reagents, multiple-step operation, relatively harsh reaction conditions, and low atom economy. Therefore, the development of a simple, convenient and efficient strategy for the synthesis of sulfenylated pyrazoles is still highly desirable.

Fig. 1 Biologically active pyrazole derivatives.

In 2014, Zhao and Lu presented an elegant work for p-toluenesulphonic acid-promoted, I₂-catalysed sulphenylation of pyrazolones with aryl sulphonyl hydrazides for the synthesis of sulfenylated pyrazoles in i-PrOH at 120 °C (eqn (1)).¹³ Very recently, Purohit et al. have reported the palladium N-heterocyclic carbene catalyzed sulphenylation of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones with aryl thiols leading to sulfenylated pyrazoles (eqn (2)).¹⁴ Nevertheless, the above two well established methods still have some disadvantages of high reaction temperature, limited substrate scope, or the use of expensive and toxic transition metal catalysts, which may limit their wide applications in organic synthesis and medicinal chemistry. With our continuous efforts in the synthesis of sulfur-containing compounds,¹⁵ herein, we wish to report a new strategy for the facile and highly efficient synthesis of sulfenylated pyrazoles through the NaOH-promoted direct sulfenylation of pyrazolones with various commercial available aryl thiols under metal- and additive-free conditions at 60 °C (eqn (3)).

In an initial experiment, the sulfenylation reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 1a with 4-methylbenzenethiol 2a was investigated by using a variety of bases in CH₃CN at 50 °C (Table 1, entries 1–7). Among the various bases examined, NaOH was found to be the most effective one giving the desired product 3aa in 96% yield (Table 1, entry 4). Further screening of reaction temperature revealed that the best yield of 3aa (99%) was obtained when reaction was conducted at 60 °C and a lower reaction temperature led to a slightly lower yield of product (Table 1, entries 8–11). Next, to investigate the effects of solvent, the model reaction was performed in various polar and non-polar solvents at 60 °C using NaOH as the base. Among the solvents tested, CH₃CN was the most suitable solvent for the present transformation (Table 1, entry 10). In contrast, a moderate amount of 3aa was obtained when the reaction was performed in THF or EtOH (Table 1, entries 12 and 13). Moreover, none or only a trace amount of product was detected in 1,4-dioxane, DME, H₂O, DMF, DMSO, toluene, DCE, or EtOAc (Table 1, entries 14–21). Finally, the equivalent amounts of base were examined, 1.2 equiv. of NaOH was found the best choice (Table 1, entries 10, 22 and 23). In the absence of NaOH, no desired product was detected, which indicated that base was essential to this reaction (Table 1, entry 24).

Table 1 Optimization of the reaction conditions^a

Entry	Base	Solvent	T (°C)	Yield^b (%)
a Reaction conditions: 1a (0.25 mmol), 2a (0.375 mmol), base (0.3 mmol), solvent (2 mL), 25–70 °C, air, 2 h.b Isolated yields based on 1a.c NaOH (0.25 mmol).d NaOH (0.5 mmol).
1	KOH	CH3CN	50	77
2	K2CO3	CH3CN	50	80
3	Na2CO3	CH3CN	50	0
4	NaOH	CH3CN	50	96
5	Et3N	CH3CN	50	61
6	DBU	CH3CN	50	94
7	Pyridine	CH3CN	50	0
8	NaOH	CH3CN	25	67
9	NaOH	CH3CN	40	90
10	NaOH	CH3CN	60	99
11	NaOH	CH3CN	70	97
12	NaOH	THF	60	53
13	NaOH	EtOH	60	51
14	NaOH	DMF	60	0
15	NaOH	DMSO	60	0
16	NaOH	Toluene	60	0
17	NaOH	DCE	60	0
18	NaOH	EtOAc	60	0
19	NaOH	1,4-Dioxane	60	Trace
20	NaOH	DME	60	Trace
21	NaOH	H2O	60	Trace
22	NaOH	CH3CN	60	76^c
23	NaOH	CH3CN	60	99^d
24	—	CH3CN	60	0

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With the optimized conditions in hand, the scope of this sulfenylation reaction was examined by conducting a variety of pyrazolones and thiols. As shown in Table 2, aryl thiols which have electron-donating or withdrawing groups on the aryl rings were suitable for this reaction, and the products were obtained in good to excellent yields (3aa–3an). It was found that this transformation was not significantly affected by the steric effect, and the sterically congested ortho-substituted aryl thiols were compatible with this reaction to give products 3ae–3ah in good yields. Notably, diverse functional groups, such as amino, fluoro, chloro, bromo, and trifluoromethyl groups were compatible, giving access to the expected products in good to excellent yields (3ag–3an). Nevertheless, when alkyl thiols such as butane-1-thiol and 2-phenylethanethiol were employed in this reactions, none of the desired products were obtained. After the successful utilization of various aryl thiols, we next extended our investigation to the electronic and steric nature of substituents on 1 and 3 position of pyrazolone. Obviously, this sulfenylation reaction can tolerate structurally diverse pyrazolones with a different electronic nature and steric bulk. For the 1 position of pyrazolones, a series of aryl substrates were appropriate for the reaction to furnish the corresponding products (3ba–3ga) in good yields. For the 3 position of the pyrazolone, pyrazolone 1h bearing steric bulk tert-butyl groups produced the desired product in 90% yield.

Table 2 NaOH-promoted sulfenylation of pyrazolones with aryl thiols^a,b

a Reaction conditions: 1 (0.25 mmol), 2 (0.375 mmol), NaOH (0.3 mmol), CH₃CN (2 mL), 60 °C, air, 2–5 h.b Isolated yields based on 1.

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In order to gain further insight into the mechanism, two control experiments were conducted under the standard conditions. When thiophenol 2b was added independently in the absence of pyrazolone 1a under the standard conditions, the corresponding diphenyl disulfide (4b) was obtained in 95% yield at 2 h (eqn (4)).¹⁶ Moreover, the desired product 4ab was isolated in 97% when the reaction of pyrazolone 1a and the isolated diphenyl disulfide 4b was conducted under the standard conditions (eqn (5)). These results indicated that diphenyl disulfide as a key intermediate might be involved in this transformation.

Although the mechanism has not been completely understood yet, based on the above experimental results and previous reports,^13–17 a possible reaction pathway was proposed as described in Scheme 1. Initially, the hydrogen abstraction of pyrazolone 1 by NaOH would produce carbanion intermediate 5, which underwent the rapid tautomerization leading to the enolate anion intermediate 6.

Scheme 1 Possible reaction pathway.

Subsequently, the nucleophilic substitution of 6 with disulfide 4 that generated from thiol gave the corresponding sulfenylated pyrazolone 7. Finally, the rapid tautomerization of 7 would lead the generation of the desired product 3.

In summary, we have successfully developed a facile and atom economical method for the construction of sulfenylated pyrazoles via the NaOH promoted direct sulfenylation of pyrazolones with the commercial available aryl thiols. A series of biologically important sulfenylated pyrazoles could be efficiently obtained in good to excellent yields under mild and transition metal-free conditions with high atom efficiency and good functional group tolerance. The developed synthesis route holds great promise of the potential applications for sulfenylated pyrazoles in synthetic and pharmaceutical chemistry. The detailed scope, mechanism, and synthetic application of this reaction are under investigation.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 21302109, 21302110, and 21375075), the Taishan Scholar Foundation of Shandong Province, the Natural Science Foundation of Shandong Province (ZR2015JL004), and National Training Programs of Innovation and Entrepreneurship for Undergraduates (201410446018).

References

1. Selective examples see: (a) J. Elguero, Comprehensive Heterocyclic Chemistry, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon, Oxford, UK, 1996, vol. 5; (b) X. H. Liu, P. Cui, B. A. Song, P. S. Bhadury, H. L. Zhu and S. F. Wang, Bioorg. Med. Chem., 2008, 16, 4075; (c) S. Velaparthi, M. Brunsteiner, R. Uddin, B. Wan, S. G. Franzblau and P. A. Petukhov, J. Med. Chem., 2008, 51, 1999; (d) I. V. Magedov, M. Manpadi, S. Van slambrouck, W. F. A. Steelant, E. Rozhkova, N. M. Przheval'skii, S. Rogelj and A. Kornienko, J. Med. Chem., 2007, 50, 5183; (e) C. B. Vicentini, C. Romagnoli, E. Reotti and D. Mares, J. Agric. Food Chem., 2007, 55, 10331; (f) C. B. Vicentini, S. Guccione, L. Giurato, R. Ciaccio, D. Mares and G. Forlani, J. Agric. Food Chem., 2005, 53, 3848.
2. H. Azami, D. Barrett, A. Tanaka, H. Sasaki, K. Matsuda, M. Sakurai, T. Terasawa, F. Shirai, T. Chiba, Y. Matsumoto and S. Tawara, Bioorg. Med. Chem., 2001, 9, 961.
3. S. Sidique, S. A. Shiryaev, B. I. Ratnikov, A. Herath, Y. Su, A. Y. Strongin and N. D. P. Cosford, Bioorg. Med. Chem. Lett., 2009, 19, 5773.
4. M. J. Genin, C. Biles, B. J. Keiser, S. M. Poppe, S. M. Swaney, W. G. Tarpley, Y. Yagi and D. L. Romero, J. Med. Chem., 2000, 43, 1034.
5. N. K. Terret, A. S. Bell, D. Brown and P. Ellis, Bioorg. Med. Chem. Lett., 1996, 6, 1819.
6. H. A. De Wald, S. Lobbestael and B. P. H. Poschel, J. Med. Chem., 1981, 24, 982.
7. W. T. Ashton, R. M. Sisco, H. Dong, K. A. Lyons, H. He, G. A. Doss, B. Leiting, R. A. Patel, J. K. Wu, F. Marsilio, N. A. Thornberry and A. E. Weber, Bioorg. Med. Chem. Lett., 2005, 15, 2253.
8. (a) D. N. Gandhale, A. S. Patil, B. G. Awate and L. M. Naik, Pesticides, 1982, 16, 27; (b) H. S. Chen, Z. M. Li and Y. F. Han, J. Agric. Food Chem., 2000, 48, 5312; (c) C. B. Vicentini, D. Mares, A. Tartari, M. Manfrini and G. Forlani, J. Agric. Food Chem., 2004, 52, 1898; (d) T. W. Waldrep, J. R. Beck, M. P. Lynch and F. L. Wright, J. Agric. Food Chem., 1990, 38, 541; (e) R. D. Clark, J. Agric. Food Chem., 1996, 44, 3643.
9. For selected examples; see: (a) Y. H. Liao, W. B. Chen, Z. J. Wu, X. L. Du, L. R. Cun, X. M. Zhang and W. C. Yuan, Adv. Synth. Catal., 2010, 352, 827; (b) A. Zea, A. R. Alba, A. Mazzanti, A. Moyano and R. Rios, Org. Biomol. Chem., 2011, 9, 6519; (c) Z. G. Yang, Z. Wang, S. Bai, X. H. Liu, L. L. Lin and X. M. Feng, Org. Lett., 2011, 13, 596; (d) Z. Wang, Z. G. Yang, D. H. Chen, X. H. Liu, L. L. Lin and X. M. Feng, Angew. Chem., Int. Ed., 2011, 50, 4928; (e) J. W. Wu, F. Li, Y. Zheng and J. Nie, Tetrahedron Lett., 2012, 53, 4828; (f) Z. Wang, Z. L. Chen, S. Bai, W. Li, X. H. Liu, L. L. Lin and X. M. Feng, Angew. Chem., Int. Ed., 2012, 51, 2776; (g) B. S. Kuarmand and B. Rajitha, Synth. Commun., 2012, 42, 2382; (h) F. Li, L. Sun, Y. Teng, P. Yu, J. C.-G. Zhao and J.-A. Ma, Chem.–Eur. J., 2012, 18, 14255; (i) A. Mazzanti, T. Calbet, M. Font-Bardia, A. Moyano and R. Rios, Org. Biomol. Chem., 2012, 10, 1645.
10. K. Kawakubo, M. Shindo and T. Konotsune, Plant Physiol., 1979, 64, 774.
11. K. Watanabe, Y. Morinaka, K. Iseki, T. Watanabe, S. Yuki and H. Nishi, Redox Rep., 2003, 8, 151.
12. (a) R. T. Coutts, K. W. Hindmarsh and N. J. Pound, Can. J. Chem., 1966, 44, 2105; (b) H. Wilde, G. Mann, U. Burkhardt, G. Weber, D. Labus and W. Schindler, J. Prakt. Chem., 1979, 321, 495.
13. X. Zhao, L. Zhang, T. Li, G. Liu, H. Wang and K. Lu, Chem. Commun., 2014, 50, 13121.
14. V. B. Purohit, S. C. Karad, K. H. Patel and D. K. Raval, Tetrahedron, 2016, 72, 1114.
15. (a) H. Cui, X. Liu, W. Wei, D. Yang, C. He, T. Zhang and H. Wang, J. Org. Chem., 2016, 81, 2252; (b) H. Cui, W. Wei, D. Yang, J. Zhang, Z. Xu, J. Wen and H. Wang, RSC Adv., 2015, 5, 84657; (c) W. Wei, J. Wen, D. Yang, M. Guo, Y. Wang, J. You and H. Wang, Chem. Commun., 2015, 51, 768; (d) W. Wei, J. Wen, D. Yang, H. Jing, J. You and H. Wang, RSC Adv., 2015, 5, 4416; (e) W. Wei, X. Liu, D. Yang, R. Dong, Y. Cui, F. Yuan and H. Wang, Tetrahedron Lett., 2015, 56, 1808; (f) W. Wei, J. Wen, D. Yang, J. Du, J. You and H. Wang, Green Chem., 2014, 16, 2988; (g) W. Wei, J. Li, D. Yang, J. Wen, Y. Jiao, J. You and H. Wang, Org. Biomol. Chem., 2014, 12, 1861; (h) W. Wei, J. Wen, D. Yang, M. Wu, J. You and H. Wang, Org. Biomol. Chem., 2014, 12, 7678; (i) W. Wei, C. Liu, D. Yang, J. Wen, J. You, Y. Suo and H. Wang, Chem. Commun., 2013, 49, 10239.
16. (a) M. S. Abaee, M. M. Mojtahedi and S. Navidipoor, Synth. Commun., 2011, 41, 170; (b) W. L. Donga, G. Y. Huanga, Z. M. Lia and W. G. Zhao, Phosphorus Sulfur Relat. Elem., 2009, 184, 2058; (c) K. T. Liu and Y. C. Tong, Synthesis, 1978, 669; (d) A. V. Joshi, S. Bhusare, M. Baidossi, N. Qafisheha and Y. Sassona, Tetrahedron Lett., 2005, 46, 3583.
17. (a) H. Nakagawa, R. Ohyama, A. Kimata, T. Suzuki and N. Miyata, Bioorg. Med. Chem. Lett., 2006, 16, 5939; (b) F. Caruso, C. Pettinari, F. Marchetti, M. Rossi, C. Opazo, S. Kumar, S. Balwani and B. Ghosh, Bioorg. Med. Chem., 2009, 17, 6166; (c) A. Kimata, H. Nakagawa, R. Ohyama, T. Fukuuchi, S. Ohta, T. Suzuki and N. Miyata, J. Med. Chem., 2007, 50, 5053.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra09739a

‡ Authors with equal contribution.

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