Letter pubs.acs.org/OrgLett
Synthesis of 3‑(Arylsulfonyl)benzothiophenes and Benzoselenophenes via TBHP-Initiated Radical Cyclization of 2‑Alkynylthioanisoles or -selenoanisoles with Sulfinic Acids Jian Xu, Xiaoxia Yu, Jianxiang Yan, and Qiuling Song* Institute of Next Generation Matter Transformation, College of Chemical Engineering and College of Material Sciences Engineering, Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, P. R. China S Supporting Information *
ABSTRACT: tert-Butyl hydroperoxide-initiated radical cyclization of 2-alkynylthioanisoles or -selenoanisoles with sulfinic acids has been developed. This reaction is applicable to a wide substrate scope via one C(sp3)−S(Se) bond cleavage and two C(sp2)−S(Se) bond formation, leading to the synthesis of 3(arylsulfonyl)benzothiophenes or -benzoselenophenes under mild conditions.
B
electrophilic reagents.5d,f Recently, the Blum and Ingleson groups independently reported ClBcat- or BCl3-induced borylative cyclization of 2-alkynylthioanisoles for the synthesis of C3-borylated benzothiophenes.5a,b Synthesis of sulfone-containing compounds via radical cascade reactions has attracted significant attention because of their simple operation and easily accessible substrates.6 These transformations allow access to a wide range of sulfonecontaining heterocycles including 3-sulfonylindoles, 3-sulfonated 4-quinolones and 3-arylsulfonylquinolines. Despite these advances, continuous efforts are still required, especially for the synthesis of 3-sulfonylbenzothiophene due to their importance in biology and the pharmaceutical chemistry (Figure 1).7
enzothiophene and its derivatives are an important class of heterocyclic compounds that have been extensively exploited in medical chemistry, natural products, and materials science.1 Among them, 3-substituted benzothiophenes are especially important since many pharmaceuticals as well as drug candidates contain this scaffold.2 A variety of concise and robust synthetic protocols have been developed to access 3substituted benzothiophenes;3 among them, 2-alkynylthioanisoles are usually chosen as the substrates. To date, two pathways have been proven efficient and valuable to access 3substituted benzothiophenes from 2-alkynylthioanisoles: (i) [1,3] shift of the migrating groups including silyl, alkoxyalkyl, and benzyl on the sulfur atom (Scheme 1a)4 and (ii) electrophilic cyclization of the o-(1-alkynyl)thioanisoles (Scheme 1b).5 Larock and co-workers reported the synthesis of 3-halo-substituted benzothiophenes with I2 and Br2 as Scheme 1. Strategies for the Synthesis of 3-Substituted Benzothiophene from 2-Alkynylthioanisoles
Figure 1. Representative examples of biologically active 3sulfonylbenzothiophene derivatives.
Meanwhile, radical cascade reactions have also emerged as efficient approaches for the construction of benzothiophenes. For example, the Li group reported the synthesis of benzothiophene scaffolds through Mn-catalyzed intermolecular cyclization of alkynes and thiophenols.8 Zanardi’s, McDonald’s, Schiesser’s and König’s groups disclosed the synthesis of Received: September 27, 2017 Published: November 21, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b02971 Org. Lett. 2017, 19, 6292−6295
Letter
Organic Letters Scheme 2. Scope of Sulfinic Acidsa
benzothiophenes via annulation reaction between o-methylthioarenediazonium salts and alkynes.9 Very recently, Zhang and co-workers improved this method by using anilines instead of diazonium salts.10 As part of our ongoing interests in the synthesis of heterocycles via radical cascade reactions,11 herein we described a new approach to the construction of benzothiophenes via radical cyclization of 2-alkynylthioanisoles with sulfinic acids (Scheme 1c). Initially, we utilized p-tolylsulfinic acid (1a) and methyl-(2alkynylphenyl)sulfanes (2a) as the model substrates to optimize the reaction conditions. When TBHP (100 mol %) was chosen as the initiator with DMF as the solvent, 3a was obtained in 55% yield at 80 °C under argon (Table 1, entry 1). Encouraged Table 1. Optimization of Reaction Conditionsa
entry
initiator (mol %)
temp (°C)
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
TBHP (100) DTBP (100) BPO (100) TBHP (100) TBPB (100) DCP (100) TBHP (100) TBHP (100) TBHP (100) TBHP (100) TBHP (100) TBHP (100) TBHP (100) TBHP (80)
80 80 80 80 80 80 80 80 80 80 80 100 70 100
DMF DMF DMF DMF DMF DMF DCE dioxane toluene CH3CN DMSO CH3CN CH3CN CH3CN
55 34 40 48 33 39 49 58 60 78 65 81 75 82
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), TBHP (80 mol %), in CH3CN (2 mL) stirring under argon in 100 °C for 1 h.
candidates as well, and the corresponding products 3l and 3m were obtained in 55% and 42% yields, respectively, by the reaction with 2a. Unfortunately, when aliphatic sulfinic acids were used as substrates under the optimal reaction conditions, no desired product was detected. We next investigated the scope of 2-alkynylthioanisoles (Scheme 3). Alkynes with electron-donating substituents on the aromatic rings could be engaged in this reaction, providing the desired benzothiophenes in good yields (3n−r). Halogens at different positions of phenyl rings were also compatible (3s− w). It is of note that electron-withdrawing substituents such as NO2 or CN on the right benzene ring affect the transformation significantly, and the corresponding products were only obtained in acceptable yields (3x and 3y, 32% and 55%). In terms of aliphatic alkynes, such as 1aa and 1ab, no corresponding desired products were obtained probably due to the unstable alkenyl radical intermediate. Additionally, our approach is also applicable for constructing the thiophene ring in view of 3ac. Most importantly, substituted 2-alkynylselenoanisoles were also suitable substrates to deliver a series of 3-(arylsulfonyl)benzoselenophene derivatives in moderate yields (5a−f, 52− 65%) (Scheme 4). The reaction could be easily scaled up to 4.0 mmol with the model substrates, affording 3a in a slightly reducing yield (75% yield). Furthermore, the Ts moiety could be easily removed under reductive conditions to obtain 2-phenyl benzothiophene (6) in 78% yield, and 3a also could be transformed to 7 with mCPBA as an oxidant (Scheme 5). To gain some mechanistic insights, a series of control experiments were performed. First, the reaction was conducted in the absence of p-tolylsulfinic acid; not surprisingly, no desired product 6 was observed (2a was recovered in 85%
a Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), initiator (0.15 mmol) in solvent (2 mL) stirring under argon for 1 h. bYields of isolated ones.
by this result, a variety of initiators, including DTBP, BPO, TBPB, and DCP (Table 1, entries 2−6), were examined carefully; however, no better results were observed. Subsequently, different solvents were investigated, and CH3CN was found to be the most efficient one (78%) among THF, dioxane, and DCE (Table 1, entries 7−11). Further temperature and initiator loading optimization showed that 80 °C and 80 mol % of TBHP were the best choice. With the optimized reaction conditions in hand, a wide range of sulfinic acids 1b−m were then examined with 2a, and the results are summarized in Scheme 2. Sulfinic acids with electron-donating substituents such as t-Bu and OMe on the para position of the phenyl ring proceeded smoothly, and the corresponding products 3c and 3d were obtained in 70% and 75% yields. Halide substituents such as F, Cl, and Br on different positions of the phenyl rings proceeded smoothly, affording the desired products in moderate to good yields (3e− i, 68−76%). Moreover, substrates bearing strong electronwithdrawing groups such as NO2 and CN were also compatible under the standard conditions, rendering the target molecules 3j and 3k in 40% and 65% yields, respectively. Of note, naphthyl- and thienyl-based sulfinic acids 1l and 1m were good 6293
DOI: 10.1021/acs.orglett.7b02971 Org. Lett. 2017, 19, 6292−6295
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Organic Letters Scheme 3. Scope of Alkynesa
Scheme 6. Control Experiments
reaction was completely inhibited (Scheme 6b). These results implied that a single electron transfer pathway (SET) might be involved in this transformation. When the methyl in the sulfur atom was changed to ethyl and benzyl, 3a also could be obtained in 81% and 85% yields, respectively. However, the yield of 3a was reduced to 45% when phenyl was used as a substituent, which might be due to the unstable of phenyl radical. Additionally, benzene and toluene could be detected by GC−MS in our reaction mixtures, which might be generated from phenyl and benzyl radicals. On the basis of control experiments as well as previous reports, a plausible mechanism for this radical mediated cyclization reaction is proposed in Scheme 7. Initially, the
a
Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), TBHP (80 mol %), in CH3CN (2 mL) stirring under argon in 100 °C for 1 h.
Scheme 4. Scope for the Formation of 3(Arylsulfonyl)benzoselenophene Derivativesa
Scheme 7. Proposed Mechanism
combination of TBHP and sulfinic acid 1a leads to the formation of sulfonyl radical A, which selectively attacks the C− C triple bond of 2a to afford the vinyl radical B. This in situ generated vinyl radical subsequently reacts with SMe moiety via 5-exo-trig cyclization mode to lead to the final product 3a along with the release of methyl radical. The methyl radical further react via H-abstraction from the reaction mixture. In conclusion, we have successfully developed a TBHPinitiated tandem radical addition−cyclization reaction between 2-alkynylthioanisoles and sulfinic acids, rendering 3(arylsulfonyl)benzothiophenes in good yields with two C(sp2)−S bonds formation and one C(sp3)−S bond cleavage in one pot. This method features easily accessible substrates, simple operation, and short reaction time.
a
Reaction conditions: 1 (0.4 mmol), 4 (0.2 mmol), TBHP (80 mol %), in CH3CN (2 mL) stirring under argon in 100 °C for 1 h.
Scheme 5. Gram Scale-up and the Transformation of Product 3a
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02971. Experimental procedure, characterization data, and 1H, 13 C, and 19F NMR spectra (PDF)
yield) (Scheme 6a). When radical scavengers TEMPO or BHT were added to the model reaction, the tandem cyclization 6294
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Letter
Organic Letters Accession Codes
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CCDC 1571247 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*Fax: 86-592-6162990. E-mail:
[email protected]. ORCID
Qiuling Song: 0000-0002-9836-8860 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Global Experts (1000 Talents Plan), National Natural Science Foundation of China (21602065), Fujian Hundred Talents Plan and Program of Innovative Research Team of Huaqiao University (Z14X0047), and the China Postdoctoral Science Foundation (163633) are gratefully acknowledged. We also thank the Instrumental Analysis Center of Huaqiao University for analysis support.
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