Visible-light-promoted photoredox synthesis of thioacetylenes by dehydrogenation coupling of thiophenols and alkynes

Abstract

Herein, by applying visible-light photoredox catalysis, we achieved the first example of catalytic dehydrogenative coupling of thiophenols and alkynes for the synthesis of thioacetylenes at room temperature under mild reaction conditions. The advantages of our catalytic system mainly lie in the use of air instead of atmospheric oxygen with photoredox catalysis at room temperature.

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Introduction

Aromatic sulfur-containing compounds are commonly found in natural products, bioactive molecules,¹ pharmaceutical molecules,^2,3 organic materials⁴ and polymers.⁵ Therefore, constructing C–S bonds using environmentally friendly and atomically economical synthetic methods is of great significance.^6–8 In traditional transition metal catalyzed cross-coupling reactions, a cross coupling reaction involving thiols and aryl halides is one of the effective methods for C–S bond formation.⁹ However, traditional methods have shortcomings such as the use of strong bases (such as ^tBuONa), complex ligands that are sensitive to air and high-temperature reaction conditions as well as substrate applicability limitations such as narrow scope and poor compatibility with functional groups.^10–13 Besides, the toxicity of sulfides towards transition metals often hinders catalytic recycling, which is also a disadvantage. Correspondingly, developing a new catalytic system for C–S bond formation has become a priority for synthetic chemists, as it addresses the disadvantages of traditional methods.

Over the past decades, visible-light photoredox catalysis has emerged as a powerful synthetic approach, providing numerous possibilities for organic synthesis.^14–20 These reactions mainly focus on C–C and C–E (E = N, S, Cl, Br, Si, B, and Se) bond formation.^21–27 It should be emphasized that in the research on C–S bond formation, these methods mainly focus on C(sp³)–S^28–33 and C(sp²)–S bond formation,^34–38 while the C(sp)–S bond formation has been less reported.³⁹ Besides, in the literature on C(sp)–S bond formation for the direct synthesis of thioalkynes with thiophenols and phenylacetylenes, to the best of our knowledge, only one example using 1 atm of oxygen at 70 °C (Scheme 1A) has been reported, requiring heating conditions and strict conditions of atmospheric oxygen.⁴⁰ Consequently, the development of a milder and more convenient approach for the direct synthesis of thioalkynes with thiophenols and alkynes remains underdeveloped. Herein, we report the first example of a general dehydrocoupling of thiophenols with alkynes enabled by photoredox catalysis under visible-light irradiation to produce a series of thioalkynes (Scheme 1B).

Scheme 1 (A): Synthesis of thioalkynes using a catalyst of CuI and base of K₂CO₃ with 1 atm of oxygen at 70 °C; (B): our current work using a photocatalyst of CuBr and base of Cs₂CO₃ under visible light conditions at room temperature and air atmosphere.

Results and discussion

We chose ethynylbenzene (1a) (0.2 mmol) coupled with 4-methylbenzenethiol (2a) (0.4 mmol) as reactants, MeCN (1 mL) as solvent and CuBr (10 mol%) as the photoredox catalyst (see Table 1, entry 1–6 for base screening), under air conditions, with a 25 W white LED plate as the light source at room temperature. The results of our initial investigations revealed that in reactions screened using organic bases (such as TEA, DBU and DIPEA, Table 1, entries 1–3), the yields are approximately close with the product containing no more than 60% of 3a. When it turned to Cs₂CO₃, 85% of 3a was obtained with a relatively satisfactory yield (Table 1, entry 4), slightly higher than the K₂CO₃ with 82% yield of 3a (Table 1, entry 5). It should be pointed out that we only got a trace amount of 3a without base (Table 1, entry 6). With Cs₂CO₃ as the best base in hand, we turned to optimizing photocatalysts(Table 1, entry 4 and entry 7–10). With CuCl as the photocatalyst, we obtained a 75% yield of 3a (Table 1, entry 7). Coincidentally, CuI and Cu(OAc)₂·H₂O had an equal catalytic effect with 60% yield of 3a (Table 1, entry 8–9). Only 56% yield of 3a was obtained when CuCl₂ was used as the photocatalyst (Table 1, entry 10). Finally, the economic viability of the catalyst was under consideration, and we turned to reduce the amount of catalyst (CuBr) used (Table 1, entry 11–13), when the amount of CuBr were reduced to 1%, 2% and 5%, we obtained the yield of 3a as 43%, 44% and 47% respectively, which were far less than 10 mol% CuBr was used, while it is worth to mention that 20 mol% CuBr as the catalyst also gave a lower result with 65% yield of 3a (Table 1, entry 14).

Table 1 Condition optimizations^a

Entry	Cat.(mol%)	Base	Yield(%)^b
a Reaction conditions: the reactions were performed in 25 mL vials with 1a (0.2 mmol), 2a (0.4 mmol), MeCN 1.0 mL and the vial was placed under air conditions with irradiation for 12 h at room temperature.b Yields were determined by isolation.
1	CuBr (10 mol%)	TEA	60
2	CuBr (10 mol%)	DBU	55
3	CuBr (10 mol%)	DIPEA	58
4	CuBr (10 mol%)	Cs2CO3	85
5	CuBr (10 mol%)	K2CO3	82
6	CuBr (10 mol%)	None	Trace
7	CuCl (10 mol%)	Cs2CO3	75
8	CuI (10 mol%)	Cs2CO3	60
9	Cu(OAc)2^.H2O (10 mol%)	Cs2CO3	60
10	CuCl2 (10 mol%)	Cs2CO3	56
11	CuBr (1 mol%)	Cs2CO3	43
12	CuBr (2 mol%)	Cs2CO3	44
13	CuBr (5 mol%)	Cs2CO3	47
14	CuBr (20 mol%)	Cs2CO3	65

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With the optimized reaction conditions in hand (Table 1, entry 4), we evaluated the generality of our methodology for the synthesis of various thioacetylenes. First, thiophenols with different substituents on the phenyl ring were applied in the reaction with ethynylbenzene (1a) (Scheme 2). In general, good to excellent yields were obtained except 3l and 3m with 0% yield. For example, thiophenols with 4-Me, 4-OMe, 2-OMe and naphthalene ring reacted smoothly with 1a and afforded the corresponding thioacetylenes 3a–3d in yields ranging from 75% to 94%, thiophenols with –OH, –NO₂, –CN in the para position and –NH₂ in the meta position of the phenyl ring, we obtained 3e–3i in yields ranging from 70% to 98%. With an acetamide group in the para position and methylate in the ortho position of the phenyl ring, we got 85% yield of 3j and 94% yield of 3k, respectively. It should be pointed out that only trace amounts of 3n and 3o were obtained when phenylacetylene reacted with n-butanethiol and cyclohexanethiol, which is similar to the results for 3l and 3m.

Scheme 2 Dehydrogenative coupling of ethynylbenzene with various thiophenols under visible-light irradiation: the reactions were performed in 25 mL vials with 1a (0.2 mmol), 2 (0.4 mmol), CuBr (10 mol%), Cs₂CO₃ (0.4 mmol), MeCN 1.0 mL and the vial were placed under air conditions with irradiation for 12 h at room temperature, yields were determined by isolation.

We then turned our attention to the dehydrogenative coupling of different alkynes with various thiophenols under visible-light irradiation. Firstly, –Me, –Et and –^tBu of alkyl substituents on the phenyl rings at different positions of the acetylenes reacted with thiophenols, we obtained products 4a–4k in yields ranging from 73% to 95% (Scheme 3). Subsequently, we reacted 2-ethynylnaphthalene with –OMe on the para position and ortho position of the phenyl ring at the thiophenols, we got 4l and 4m with yields of 98% and 82% respectively. Two-substituted benzyl acetylenes of –OMe with thiophenols, the yields of product 4n–4r ranged from 75% to 98% with relatively satisfactory results. Next, we got 97% 4s from the reaction of 1-chloro-4-ethynylbenzene with 4-methylbenzenethiol. Finally, we have expanded the reaction between different substituted alkyl alkynes and p-methoxyphenylthiophenol, product 4t, 4u and 4v were obtained with excellent yields: 94%, 97% and 85% yield, respectively. The reactions with 2-fluorophenylthiophenol (2w) and 4-cyanophenylthiophenol (2x) led to the desired products 4w and 4x in 94% and 92% yields. Regretfully and imagined, we still cannot obtain the desired product from the reaction of alkanethiol with acetylene in 0% yield of product 4y.

Scheme 3 Dehydrogenative coupling of alkynes with various thiophenols under visible-light irradiation: the reactions were performed in a 25 mL vial with 1 (0.2 mmol), 2 (0.4 mmol), CuBr (10 mol%), Cs₂CO₃ (0.4 mmol), and MeCN 1.0 mL, and the vial were placed under air conditions with irradiation for 12 h at room temperature, yields were determined by isolation.

To understand the reaction mechanism, we carried out several control experiments. First, we observed that the omission of light yielded a lower amount of 3a at 32%, without CuBr or Cs₂CO₃, product 3a was not detected, hence indicating the crucial role of light, photocatalyst and base in the reaction (Scheme 4A). In the study of the atmosphere of the reaction, when air was replaced with oxygen, we got 3a with a similar yield, Ar instead of air; however, the product 3a was not detected, and this indicated the key role of oxygen or oxygen in the air (Scheme 4A). Second, the addition of 5 equiv. of TEMPO to the reaction largely suppressed the reaction, with only 24% of 3a obtained (Scheme 4B). In addition, disulfide reacted with phenylacetylene to produce 3a in 76% yield, with a similar result compared with “standard conditions” (Scheme 4C). It should be pointed out that, no product of 3a were detected from 1,4-diphenylbutadiyne 6 reacted with thiophenol 2a and disulfide 5 under “standard conditions” severally (Schemes 4D and E). This might already indicated the cyclic pathway of this catalytic reaction.

Scheme 4 Mechanism study reactions.

Based on the above control experiments and previous reports,^20,41,42 a plausible mechanism is proposed in Scheme 5. The photo irradiation of in situ generated copper(I)-phenylacetylide A generates a long-lived triplet photoexcited copper(I)-phenylacetylide B. The electron donor behavior of photoexcited B has undergone the SET process with O₂ and results in the intermediate super oxide radical anion as well as electron-deficient copper(II) phenylacetylide C. [CuBr] was excited under visible light to yield its excited state species, [CuBr]*, which then undergoes a single electron transfer with benzaldehyde to yield [CuBr]⁺ and super oxide radical anion. Then, [CuBr]⁺ was reduced by thiophenol to regenerate [CuBr] and produce the radical cation of thiophenol D, which produced the S-based radical after deprotonation. Coupling of S-based radical generated ArS–SAr, which reacted with copper(II) phenylacetylide C and H⁺ to generate Cu(I)-amino thiophenol complex E and thiophenol. Finally, complex E reacted with Br⁻ and O₂ to give the C(sp)–S coupling product thioacetylenes and regeneration of CuBr (Scheme 5).

Scheme 5 Plausible reaction mechanism for photoredox dehydrocoupling of thiophenols and alkynes.

In conclusion, we have developed the first visible-light-promoted photoredox dehydrogenative coupling of alkynes with thiophenols. Our system offers the milder conditions (without atmospheric O₂ and at room temperature) for the dehydrogenative coupling of thiophenols and alkynes. Moreover, a series of thioacetylenes was successfully synthesized with excellent yields (up to 98%) and excellent tolerance of functional groups.

Author contributions

Xianya Wang, administration of the funding project and writing the manuscript; Xun Wu, conducting the experiments; Yong Zhu and Yaowu Liu, analysis of the experimental results. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

The authors declare no competing interests.

Data availability

The data supporting this article have been included as part of the SI. Supplementary information: all experimental procedures, characterization data and NMR spectra for all new compounds. See DOI: https://doi.org/10.1039/d5ra05631d.

Acknowledgements

This work was fnancially supported by the funding program of Key R&D Program Project of Bozhou of Anhui Province (bzzc2023037) and the Project of Huatuo Institute of Traditional Chinese Medicine (YLFW2311).

References

1. M. Feng, B. Tang, H. Liang and X. Jiang, Curr. Top. Med. Chem., 2016, 16, 1200–1216.
2. G. A. Patani and E. LaVoie, J. Chem. Rev., 1996, 96, 3147–3176.
3. E. A. Ilardi, E. Vitaku and J. T. Njardarson, J. Med. Chem., 2014, 57, 2832–2842.
4. D. A. Boyd, Angew. Chem., Int. Ed., 2016, 55, 1521–3773.
5. A. S. Rahate, K. R. Nemade and S. A. Waghuley, Rev. Chem. Eng., 2013, 29, 471–489.
6. J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534–1544.
7. I. P. Beletskaya and V. P. Ananikov, Chem. Rev., 2011, 111, 1596–1636.
8. S. Song, Y. Zhang, A. Yeerlan, B. Zhu, J. Liu and N. Jiao, Angew. Chem., Int. Ed., 2017, 56, 2487–2491.
9. D. X. Geyang Song, Chin. J. Org. Chem., 2022, 42, 2275–2299.
10. F. Y. Kwong and S. L. Buchwald, Org. Lett., 2002, 4, 3517–3520.
11. M. A. Fernández-Rodríguez, Q. Shen and J. F. Hartwig, J. Am. Chem. Soc., 2006, 128, 2180–2181.
12. E. Alvaro and J. F. Hartwig, J. Am. Chem. Soc., 2009, 131, 7858–7868.
13. P. Gogoia, S. Hazarikaa, M. J. Sarmab, K. Sarmaa and P. J. T. Barman, Tetrahedron, 2015, 46, 7484–7489.
14. D. A. Nicewicz and D. W. C. MacMillan, Science, 2008, 322, 77–80.
15. T. P. Yoon, M. A. Ischay and J. Du, Nat. Chem., 2010, 2, 527–532.
16. J. M. R. Narayanam and C. R. Stephenson, J. Chem. Soc. Rev., 2011, 40, 102–113.
17. J.-R. Chen, X.-Q. Hu, L.-Q. Lu and W.-J. Xiao, Chem. Soc. Rev., 2016, 45, 2044–2056.
18. N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016, 116, 10075–10166.
19. X. Wang, X. Wang, C. Xia and L. Wu, Green Chem., 2019, 21, 4189–4193.
20. X. Wang, C. Xia and L. Wu, Org. Lett., 2020, 22, 7373–7377.
21. M. Jiang, H. Yang and H. Fu, Org. Lett., 2016, 18, 5248–5251.
22. Q.-B. Zhang, Y.-L. Ban, P.-F. Yuan, S.-J. Peng, J.-G. Fang, L.-Z. Wu and Q. Liu, Green Chem., 2017, 19, 5559–5563.
23. P. Chakrasali, K. Kim, Y.-S. Jung, H. Kim and S. B. Han, Org. Lett., 2018, 20, 7509–7513.
24. R. Alam and G. A. Molander, Org. Lett., 2018, 20, 2680–2684.
25. L. Blank, M. Fagnoni, S. Protti and M. J. S. Rueping, Synthesis, 2019, 51, A–J.
26. H.-Y. Song, F. Xiao, J. Jiang, C. Wu, H.-T. Ji, Y.-H. Lu, K.-L. Wang and W.-M. He, Chin. Chem. Lett., 2023, 34, 108509.
27. W. Wang, Y. Liu, G. Qiu, I. B. Krylov, A. O. Terent’ev, S. Cao, K. Sun, X. Chen, L. Qu and B. Yu, Chin. J. Chem., 2025, 43, 1664–1672.
28. F. Penteado, C. S. Gomes, L. I. Monzon, G. Perin, C. C. Silveira and E. J. Lenardão, Eur. J. Org. Chem., 2020, 14, 2110–2115.
29. E. L. Tyson, M. S. Ament and T. P. Yoon, J. Org. Chem., 2013, 78, 2046–2050.
30. G. Zhao, S. Kaur and T. Wang, Org. Lett., 2017, 19, 3291–3294.
31. N. Sundaravelu, A. Nandy and G. Sekar, Org. Lett., 2021, 23, 3115–3119.
32. F. Liang, D. Lou, R. Wang, Q. Fu, J. Yuan, B. Liu and M. Wu, Chin. J. Org. Chem., 2023, 43, 2269–2292.
33. L. Zuo, Z. Zhang, X.-Y. Yuan, K. Sun and B. Yu, New J. Chem., 2024, 48, 9000–9003.
34. Y. Li, T. Miao, P. Li and L. Wang, Org. Lett., 2018, 20, 1735–1739.
35. H. E. Ho, A. Pagano, J. A. Rossi-Ashton, J. R. Donald, R. G. Epton, J. C. Churchill, M. J. James, P. O’Brien, R. J. K. Taylor and W. P. Unsworth, Chem. Sci., 2020, 11, 1353–1360.
36. Z. Chen, W. Jin, Y. Xia, Y. Zhang, M. Xie, S. Ma and C. Liu, Org. Lett., 2020, 22, 8261–8266.
37. X. Liang, Y. Li, Q. Xia, L. Cheng, J. Guo, P. Zhang, W. Zhang and Q. Wang, Green Chem., 2021, 23, 8865–8870.
38. W. Xie, P. Ma, Y. Zhang, L. Xi, S. Qiu, X. Huang, B. Yang, Y. Gao and J. Zhang, Org. Lett., 2022, 24, 6099–6104.
39. J. Santandrea, C. Minozzi, C. Cruché and S. K. Collins, Angew. Chem., Int. Ed., 2017, 56, 12255–12259.
40. Y. Yang, W. Dong, Y. Guo and R. M. Rioux, Green Chem., 2013, 15, 3170–3175.
41. X. Zhu, P. Li, Q. Shi and L. Wang, Green Chem., 2016, 18, 6373–6379.
42. W. Guo, K. Tao, W. Tan, M. Zhao, L. Zheng and X. Fan, Org. Chem. Front., 2019, 6, 2048–2066.

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