Photoredox-catalyzed cascade annulation of methyl(2-(phenylethynyl)phenyl)sulfanes and methyl(2-(phenylethynyl)phenyl)selanes with sulfonyl chlorides: synthesis of benzothiophenes and benzoselenophenes

Jianxiang Yana, Jian Xua, Yao Zhoua, Jinglong Chenb and Qiuling Song*a
aInstitute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, 668 Jimei Blvd, Xiamen, Fujian 361021, P. R. China. E-mail:; Fax: +86-592-6162990
bQuanzhou Jersey Biosciences, Quanzhou, Fujian, China 362200

Received 7th February 2018 , Accepted 8th March 2018

First published on 9th March 2018

A photoredox-catalyzed cascade annulation of methyl(2-(phenylethynyl)phenyl)sulfanes and methyl(2-(phenylethynyl)phenyl)selanes with sulfonyl chlorides was developed. A variety of benzothiophenes and benzoselenophenes were obtained in moderate to good yields at ambient temperature.

Benzothiophene and its derivatives have attracted tremendous attention due to their wide application in pharmaceuticals, materials science, catalysis and biology.1 As a consequence, a myriad of reports have been developed for the preparation of substituted benzothiophenes.2 In recent years, radical cascade reactions have been predominant for the synthesis of benzothiophenes, since they offer a simple and efficient approach to build these skeletons.3 For instance, Zanardi's3a and McDonald's3b group independently reported a radical-involving cascade approach for the construction of benzothiophenes from o-methylthioarene diazonium salts and alkynes. Similarly, Schiesser and coworkers described a method for the preparation of benzoselenophenes by employing an analogous tandem radical addition strategy in 2011.3c However, the involvement of stoichiometric amounts of transition metals was essential in these approaches, which limited their further applications in both academia and industry. To overcome this drawback, Köning developed a metal-free protocol for the synthesis of benzothiophene derivatives via visible-light photoredox catalysis using aryl diazonium salts as aryl radicals.3d In addition to the radical cyclization, electrophilic cyclization of o-(1-alkynyl)thioanisoles is another common and robust strategy to obtain benzothiophenes.4 For instance, the construction of 3-halosubstituted benzothiophenes with I2 and Br2 as electrophilic reagents was developed by Larock and co-workers.4a,b Very recently, Ingleson and Blum groups independently disclosed the preparation of borylated benzothiophenes via BCl3 or ClBcat-induced borylative cyclization of 2-alkynyl thioanisoles.4c,d Later on, Yamamoto and co-workers designed a novel Au-catalyzed 1,3-shift of the migrating groups to afford 3-substituted benzothiophenes.5 Despite the above advances in the synthesis of substituted benzothiophenes, efficient and facile tactics for the construction of 3-sulfonyl benzothiophenes are relatively scarce. Owing to the significance of 3-sulfonyl benzothiophenes, which are the prevalent core scaffolds in bioactive species and pharmaceutical candidates6 (see Fig. 1), very recently, our group disclosed a novel approach to synthesize 3-sulfonyl benzothiophenes via TBHP-initiated radical cyclization of 2-alkynyl thioanisoles with sulfinic acid7 (Scheme 1d). Nevertheless, the reaction was performed at a high temperature (100 °C) and the radical precursor sulfinic acids are easy to decompose, which might restrict their potential application in organic synthesis. Therefore, the development of an efficient and facile method to construct 3-sulfonyl benzothiophenes is still highly desirable.
image file: c8qo00147b-f1.tif
Fig. 1 Representative drugs and biologically active molecules containing a benzothiophene motif.

image file: c8qo00147b-s1.tif
Scheme 1 The synthesis of substituted benzothiophenes from 2-alkynyl thioanisoles.

Visible light induced photoredox catalyzed transformation has emerged as a powerful strategy in synthetic chemistry, due to the remarkable features it possesses, such as safety, mild conditions, environmental friendliness and great functional group tolerance. Very recently, we developed a visible-light-induced thiotrifluoromethylation of terminal alkenes via an unconventional reductive quenching cycle8 and a photoredox-catalyzed decarboxylative alkylation of silyl enol ethers to synthesize functionalized aryl alkyl ketones.9 As part of our ongoing interest in photoredox catalysis promoted radical reactions, we report herein the visible light induced synthesis of 3-sulfonyl benzothiophenes from methyl(2-(phenylethynyl)phenyl)sulfane via a radical annulation process under ambient conditions, with the commercially available benzenesulfonyl chloride as a radical precursor (Scheme 1e).

Initially, we commenced the reaction by employing methyl(2-(phenylethynyl)phenyl)sulfane (1a) and 4-methylbenzenesulfonyl chloride (2a) as model substrates to optimize the reaction conditions. To our delight, when the reaction was irradiated by using 5 W blue LED light using eosin Y as a photocatalyst and K2CO3 as a base at room temperature for 24 h, the desired product (3a) was obtained in 69% yield (Table 1, entry 1). Subsequently, we investigated various photoredox catalysts and it turned out that [IrdF(CF3)(ppy)2(dtbbpy)]-PF6 was the most effective one (entries 1–4). When the reaction was performed in the absence of the base, no reaction occurred (entry 5). In view of the importance of the base, a series of bases were examined (entry 6–9) and K2CO3 demonstrated itself to be the best choice (entry 3) among the bases tested. Furthermore, the solvent effect on this transformation was investigated as well and CH3CN was the optimal one (entry 3). The control experiments revealed that a photoredox catalyst and visible light were essential for the reaction. When the reaction was carried out in the absence of a photoredox catalyst or visible light, the starting materials 1a and 2a were intact (entries 15 and 16). Consequently, the desired product 3a was obtained in the optimal 83% yield when the reaction was performed in the presence of [IrdF(CF3) (ppy)2(dtbbpy)]PF6 (2 mol%) and K2CO3 (2 equiv.) in CH3CN at room temperature.

Table 1 Optimizing the reaction conditions

image file: c8qo00147b-u1.tif

Entrya Photocatalyst Base Solvent Yieldb (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), base (0.4 mmol), photocatalyst (2 mol%), solvent (2 mL),5W blue LED light, 24 h, rt.b Isolated yield.c In the dark.
1 Eosin Y K2CO3 CH3CN 69
2 fac-Ir(ppy)3 K2CO3 CH3CN 50
3 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K2CO3 CH3CN 83
4 [Ru(bpy)3]PF6 K2CO3 CH3CN 55
5 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 CH3CN 0
6 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K3PO4 CH3CN 69
7 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 KOAc CH3CN 53
8 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 Na2CO3 CH3CN 37
9 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K2HPO4 CH3CN 76
10 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K2CO3 DMF 71
11 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K2CO3 DCM 56
12 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K2CO3 DMSO 38
13 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K2CO3 THF 53
14 [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K2CO3 Toluene 58
15 K2CO3 CH3CN 0
16c [IrdF(CF3)(ppy)2(dtbbpy)]PF6 K2CO3 CH3CN 0

With the optimal reaction conditions in hand, we next explored the efficiency and generality of this reaction. To our delight, when a variety of sulfonyl chlorides were used as radical precursors, the corresponding products were obtained in good to excellent yields. As described in Scheme 2, the sulfonyl chlorides which bear electron-donating or electron-withdrawing substituents at the para- position of the benzene ring were good candidates, affording the desired benzothiophenes (3a–3f) in moderate to high yields. Halo-substituted sulfonyl chlorides were well compatible in this reaction as well, providing the targeted products (3g–3i) in 87%, 68% and 76% yields, respectively. In addition to the substituents at the para-position, the ortho-position and the meta-position substituted sulfonyl chlorides (1j–1n) were also amenable for this transformation and delivered the corresponding benzothiophenes (3j–3n) in 63% to 84% yields.

image file: c8qo00147b-s2.tif
Scheme 2 Scope of sulfonyl chlorides. The reaction was carried out with 1 (0.2 mmol), 2 (0.4 mmol), K2CO3 (0.4 mmol), and [IrdF(CF3)(ppy)2(dtbbpy)]PF6 (2 mol%) in CH3CN (2 mL) at room temperature, 5 W blue LEDs, 24 h.

Next, we inspected the influence of the substitution pattern on the aromatic ring of 2-phenylethynyl. The results are summarized in Scheme 3; as we can see, the substrates bearing both electron-donating and electron-withdrawing groups (1o–1v) on the aryl ring of 2-phenylethynyl could be engaged in this transformation and produced the corresponding products (3o–3v) in good to excellent yields (68%–88%). Then different substituents on the aromatic ring of o-methylthio-aryl alkyne were studied. To our delight, the electronic effects of these groups have no significant influence on the yields of the products and the targeted benzothiophenes (3w–3aa) were generated in 79%–83% yields.

image file: c8qo00147b-s3.tif
Scheme 3 Scope of methyl(2-(phenylethynyl)phenyl)sulfane benzothiophenes. The reaction was carried out with 1 (0.2 mmol), 2 (0.4 mmol), K2CO3 (0.4 mmol), and [IrdF(CF3)(ppy)2(dtbbpy)]PF6 (2 mol%) in CH3CN (2 mL) at room temperature, 5 W blue LEDs, 24 h.

Benzoselenophenes have also attracted tremendous attention owing to their wide application in organic synthesis, medicinal chemistry, and materials science.4c,10 In light of this importance, subsequently, we commenced to prepare benzoselenophenes stemming from methyl(2-(phenylethynyl)phenyl)selane 4 and sulfonyl chloride 2 under optimal reaction conditions. As shown in Scheme 4, substituted 2-alkynyl selenoanisoles 5 which carry electron-donating (methyl) or electron-withdrawing (halides) groups on the aromatic rings could proceed smoothly and gave the corresponding products (5ab–5ad) in good yields. Sulfonyl chlorides were also compatible under the standard conditions; the desired benzoselenophenes 5ae and 5af were afforded in moderate yields.

image file: c8qo00147b-s4.tif
Scheme 4 Scope for the synthesis of benzoselenophenes. The reaction was carried out with 4 (0.2 mmol), 2 (0.4 mmol), K2CO3 (0.4 mmol), and [IrdF(CF3)(ppy)2(dtbbpy)]PF6 (2 mol%) in CH3CN (2 mL) at room temperature, 5 W blue LEDs, 24 h.

To gain insight into the detailed mechanism of this reaction, several control experiments were carried out, demonstrated in Scheme 5. Firstly, it was found that the reaction was absolutely controlled, when TEMPO or BHT as a scavenger was added. Next when ethene-1,1-diyldibenzene was added to the reaction under the standard conditions, we received the radical addition elimination product 6 in 70% yield. The results suggested that a SET pathway was implied in this transformation. Finally, when we changed the group on the sulfur atom from methyl to ethyl, phenyl and benzyl, all of the substrates delivered 3a in moderate yields. Notably, in the latter two examples, the corresponding by-products chlorobenzene and benzyl chloride were detected by GC-MS; these results provide solid evidence for the mechanism of this transformation.

image file: c8qo00147b-s5.tif
Scheme 5 Control experiments.

On the basis of the above control experiments and previous reports,11,12 a possible reaction mechanism is depicted in Scheme 6. Firstly, the Ir(III) photoredox catalyst is converted to the excited state *Ir(III) transition through a metal-to-ligand charge-transfer (MLCT) with the irradiation of visible light. The sulfonyl radical A is generated in situ from sulfonyl chloride 2a through a single electron transfer (SET) pathway and at the same time Ir(III) is oxidized to Ir(IV). Subsequently, the addition of the sulfonyl radical A to the alkynyl moiety of 1a takes place to give the vinyl radical intermediate B, which further undergoes intramolecular attack by the methylthio moiety to yield the desired product 3a along with the release of the methyl radical. Notably, this methyl radical is oxidized to a methyl cation by Ir(IV) species and CH3Cl is formed eventually upon encountering Cl.

image file: c8qo00147b-s6.tif
Scheme 6 A possible reaction mechanism.

In conclusion, we have successfully developed an effective and facile approach for the preparation of 3-sulfonyl benzothiophenes and benzoselenophenes in good yields via visible light photocatalyzed cascade annulation reactions by employing easily available sulfonyl chlorides as radical precursors. This protocol features simple operation, mild conditions, good functional group tolerance and no involvement of transition metals or additives.

Conflicts of interest

The authors declare no competing financial interest.


Financial support from the National Natural Science Foundation (21772046), the Program of Innovative Research Team of Huaqiao University (Z14X0047), the Recruitment Program of Global Experts (1000 Talents Plan), and the Natural Science Foundation of Fujian Province (2016J01064) is gratefully acknowledged. We also thank the Instrumental Analysis Center of Huaqiao University for analysis support. J. Y. thanks the Subsidized Project for Cultivating Postgraduates’ Innovative Ability in Scientific Research of Huaqiao University.


  1. (a) M. Pieroni, E. Azzali, N. Basilico, S. Parapini, M. Zolkiewski, C. Beato, G. Annunziato, A. Bruno, F. Vacondio and G. Costantino, J. Med. Chem., 2017, 60, 1959 CrossRef CAS PubMed; (b) C. Mitsui, T. Okamoto, M. Yamagishi, J. Tsurumi, K. Yoshimoto, K. Nakahara, J. Soeda, Y. Hirose, H. Sato, A. Yamano, T. Ueura and J. Takeya, Adv. Mater., 2014, 26, 4546 CrossRef CAS PubMed; (c) I. Osaka, S. Shinamura, T. Abe and K. Takimiya, J. Mater. Chem. C, 2013, 1, 1297 RSC; (d) L. Berrade, B. Aisa, M. J. Ramirez, S. Galiano, S. Guccione, L. R. Moltzau, F. O. Levy, F. Nicoletti, G. Battaglia, G. Molinaro, I. Aldana, A. Monge and S. Perez-Silanes, J. Med. Chem., 2011, 54, 3086 CrossRef CAS PubMed.
  2. (a) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174 CrossRef CAS PubMed; (b) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147 CrossRef CAS PubMed; (c) B. Godoi, R. F. Schumacher and G. Zeni, Chem. Rev., 2011, 111, 2937 CrossRef CAS PubMed.
  3. (a) R. Leardini, G. F. Pedulli, A. Tundo and G. Zanardi, J. Chem. Soc., Chem. Commun., 1985, 1390 RSC; (b) F. E. McDonald, S. A. Burova and L. G. Huffman Jr., Synthesis, 2000, 970 CrossRef CAS; (c) M. K. Staples, R. L. Grange, J. A. Angus, J. Ziogas, N. P. H. Tan, K. T. Taylor and C. H. Schiesser, Org. Biomol. Chem., 2011, 9, 473 RSC; (d) D. P. Hari, T. Hering and B. Köning, Org. Lett., 2012, 14, 5334 CrossRef CAS PubMed; (e) K. Liu, F. Jia, H. Xi, Y. Li, X. Zheng, Q. Guo, B. Shen and Z. Li, Org. Lett., 2013, 15, 2026 CrossRef CAS PubMed.
  4. (a) J. Sheng, S. Y. Li and J. Wu, Chem. Commun., 2014, 50, 578 RSC; (b) R. C. Larock and D. Yue, Tetrahedron Lett., 2001, 42, 6011 CrossRef CAS; (c) A. J. Warner, A. Churn, J. S. McGough and M. J. Ingleson, Angew. Chem., Int. Ed., 2017, 56, 354 CrossRef CAS PubMed; (d) D. J. Faizi, A. J. Davis, F. B. Meany and S. A. Blum, Angew. Chem., Int. Ed., 2016, 55, 14286 CrossRef CAS PubMed; (e) T. Yamauchi, F. Shibahara and T. Murai, Tetrahedron Lett., 2016, 57, 2945 CrossRef CAS; (f) D. Yue and R. C. Larock, J. Org. Chem., 2002, 67, 1905 CrossRef CAS PubMed.
  5. (a) I. Nakamura, T. Sato, M. Terada and Y. Yamamoto, Org. Lett., 2008, 10, 2649 CrossRef CAS PubMed; (b) I. Nakamura, T. Sato, M. Terada and Y. Yamamoto, Org. Lett., 2007, 9, 4081 CrossRef CAS PubMed; (c) I. Nakamura, T. Sato and Y. Yamamoto, Angew. Chem., Int. Ed., 2006, 45, 4473 CrossRef CAS PubMed.
  6. (a) Z. Qin, I. Kastrati, R. E. P. Chandrasen, H. Liu, P. Yao, P. A. Petukhov, J. L. Bolton and G. R. J. Thatcher, J. Med. Chem., 2007, 50, 2682 CrossRef CAS PubMed; (b) B. L. Flynn, E. M. Hamel and K. J. Jung, J. Med. Chem., 2002, 45, 2670 CrossRef CAS PubMed; (c) C. N. Hsiao and T. Kolasa, Tetrahedron Lett., 1992, 33, 2629 CrossRef CAS.
  7. J. Xu, X. Yu, J. Yan and Q. Song, Org. Lett., 2017, 19, 6292–6295 CrossRef CAS PubMed.
  8. W. Kong, H. An and Q. Song, Chem. Commun., 2017, 53, 8968–8971 RSC.
  9. W. Kong, C. J. Yu, H. An and Q. Song, Org. Lett., 2018, 20, 349–352 CrossRef CAS PubMed.
  10. (a) K. Takimiya, Y. Kunugi, Y. Konda, H. Ebata, Y. Toyoshima and T. Otsubo, J. Am. Chem. Soc., 2006, 128, 3044 CrossRef CAS PubMed; (b) T. Yamamoto and K. Takimiya, J. Am. Chem. Soc., 2007, 129, 2224 CrossRef CAS PubMed; (c) H. Ebata, E. Miyazaki, T. Yamamoto and K. Takimiya, Org. Lett., 2007, 9, 4499 CrossRef CAS PubMed; (d) P. Arsenyan, E. Paegle, S. Belyakov, I. Shestakova, E. Jaschenko, I. Domracheva and J. Popelis, Eur. J. Med. Chem., 2011, 46, 3434 CrossRef CAS PubMed.
  11. M. Chen, Z. T. Huang and Q. Y. Zheng, Org. Biomol. Chem., 2014, 12, 9337 CAS.
  12. S. Cai, D. Chen, Y. Xu, W. Weng, L. Li, R. Zhang and M. Huang, Org. Biomol. Chem., 2016, 14, 4205 CAS.


Electronic supplementary information (ESI) available. See DOI: 10.1039/c8qo00147b

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