Acid-promoted selective synthesis of trifluoromethylselenolated benzofurans with Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate

Article abstract of DOI:10.1016/j.tetlet.2020.152809

A Br?nsted acid-promoted trifluoromethylselenolation of benzofurans was disclosed by using Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate as a stable and easily prepared electrophilic trifluoromethylselenolating reagent. A wide range of SeCF₃-substituted benzofuran derivatives were obtained in moderate to good yields with excellent regioselectivity. The tandem cyclization/trifluoromethylselenolation procedure of 1-methoxy-2-(arylethynyl)benzenes were also realized by engaging FeCl₃ as the catalyst.

Full text of DOI:10.1016/j.tetlet.2020.152809

Tetrahedron Letters 66 (2021) 152809
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Acid-promoted selective synthesis of trifluoromethylselenolated
benzofurans with Se-(trifluoromethyl)
4-methylbenzenesulfonoselenoate
⇑
⇑
Juyan Liu, Miaomiao Tian, Ankun Li, Liangshuo Ji, Di Qiu , Xia Zhao
College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin 300387, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Brönsted acid-promoted trifluoromethylselenolation of benzofurans was disclosed by using Se-(triflu-
oromethyl) 4-methylbenzenesulfonoselenoate as a stable and easily prepared electrophilic trifluo-
romethylselenolating reagent. A wide range of SeCF3-substituted benzofuran derivatives were obtained
in moderate to good yields with excellent regioselectivity. The tandem cyclization/trifluoromethylseleno-
lation procedure of 1-methoxy-2-(arylethynyl)benzenes were also realized by engaging FeCl3 as the
catalyst.
Received 4 November 2020
Revised 16 December 2020
Accepted 28 December 2020
Available online 13 January 2021
Keywords:
Trifluoromethylselenolation
Acid-promoted
Ó 2021 Elsevier Ltd. All rights reserved.
Heterocycles
Se-(trifluoromethyl) 4-
methylbenzenesulfonoselenoate
Introduction
Aiming to achieve the synthesis of fluoroalkylselenolated ben-
zofurans, Billard and co-workers disclosed a metal-free process of
The benzofuran scaffold constitutes prevalent in biologically
active natural products or pharmaceutically active molecules [1].
Benzofuran derivatives, especially for 2-arylbenzofurans, exhibit
a broad range of biological activities, such as anti-HIV, anticancer,
antifungal, immunosuppressive, and anti-cardiovascular aging
activity [2]. The pharmaceutical and biochemical significance of
benzofuran scaffold has made it great demanding to develop new
routes for assembling this privileged structure [3]. Great progress
has been made to develop efficient synthetic methods for accessing
poly-substituted benzofurans
On the other hand, owing to the enhancement of lipophilicity,
good cell membrane permeability and better resistance during
metabolism process, the trifluoromethyl chalcogenation protocol
has attracted great attentions [4]. Compared with the well-devel-
oped trifluoromethoxylation (OCF3) [5] and trifluoromethylthiola-
tion (SCF3) [6] process, the introduction of trifluoromethylselanyl
group (SeCF3) into organic molecules has still less development.
Due to the specific electronic effect and superior lipophilicity
1-methoxy-2-(2-phenylethynyl)benzene using in situ formed CF3-
SeCl as the selenium source (Scheme 1, a) [8a]. However, the insta-
bility of CF3SeCl limited its application in organic synthesis. In
addition, a series of nucleophilic trifluoromethylthiolating reagents
has also been developed [9]. In 2017, Se-(trifluoromethyl)
4-methylbenzenesulfonoselenoate (TsSeCF3), which was synthe-
sized and characterized by Tlili and Billard for the first time, has
been engaged as a stable and efficient trifluoromethylselenolating
reagent to successfully realize the trifluoromethylselenolation of
various substrates [10]. In 2019, we have achieved the FeCl3-cat-
alyzed trifluoromethylselenolation of a wide range of N-containing
heterocycles with TsSeCF3 (Scheme 1, b) [11]. Considering about
the importance of functionalized benzofuran motif, we have
designed an acid-promoted direct trifluoromethylselenolation of
benzofurans, as well as a one-pot electrophilic ring-closure trifluo-
romethylselenolation of 1-methoxy-2-(arylethynyl)benzenes by
using bench-stable TsSeCF3 under mild conditions (Scheme 1, c).
(
pR = 1.29) [7], incorporation the SeCF3 group into the benzofuran
Results and discussion
derivatives will significantly enhance their biological and medical
properties.
At the outset, we started the investigation by using FeCl3 as the
catalyst to promote the trifluoromethylselenolation of 2-phenyl-
benzofuran 1a with Se-(trifluoromethyl) 4-methylbenzenesul-
fonoselenoate 2a in DCE at 70 °C. To our delight, the selective
⇑
Corresponding authors.
E-mail addresses: qiudi@pku.edu.cn (D. Qiu), hxxyzhx@mail.tjnu.edu.cn
(X. Zhao).
https://doi.org/10.1016/j.tetlet.2020.152809
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

J. Liu, M. Tian, A. Li et al.
Tetrahedron Letters 66 (2021) 152809
2a. However, diminished yields were obtained (entry 15, 16).
Therefore, the optimized reaction conditions for the trifluo-
romethylselenolation of benzofuran 1a were as follows: 1a
(0.25 mmol), 2a (0.375 mmol), TfOH (1 mol/L in toluene)
(0.025 mmol, 25 lL), toluene (0.6 mL), stirred 6 h at 70 °C.
After obtaining the optimal reaction conditions, we then exam-
ined the generality of this trifluoromethylselenolation reaction
with a wide range of benzofurans as the substrates (Scheme 2).
In most cases, the reaction proceeded smoothly, and the desired
3-trifluoromethylselenolated benzofurans were obtained in mod-
erate to good yields (31–83%). For example, the substrates contain-
ing electron-donating or electron-withdrawing groups attaching
on 4-position of benzofuran scaffold are compatible during this
transformation (1b-1f). However, when there are substituents
attached to the 5-position (1g, 1h) of benzofuran, the yields are
diminished. Then we investigated the effect of the reaction with
substituents attached to the aromatic ring of 2-arylbenzofuran
derivatives. The results indicate that when an electron-withdraw-
ing substituent is attached to the para-position of the aryl group,
such as halogen (1k-1m), ester group (1o), the desired products
can be obtained in moderate yields. However, when a strong elec-
tron-withdrawing group, such as cyano (1p) and nitro group (1q)
or an electron-donating group (1j) is attached to the para-position
of the aryl group, a relative low yields were observed. When the
meta- (1r-1u) and ortho-position (1v-1x) of the aryl group are sub-
stituted, the corresponding 3-trifluoromethylselenolated benzofu-
rans can be obtained in good yields. In addition, the 2-alkyl
substituted benzofurans are also suitable in this protocol, affording
the corresponding products with moderate yields (3y, 3z). More-
over, when the 3-position is blocked, this reaction can also occur,
2- trifluoromethylselenolated product 3aa can be obtained with
53% yield (Scheme 2).
Scheme 1. Electrophilic trifluoromethylselenolation.
Table 1
Optimization of the trifluoromethylselenolation of 2-phenylbenzofuran.a
Entry Loading of 2 (equiv.) Solvent
T (°C) Cat. (mol %)
Yield
(%)b
1
2
3
4
5
6
1.2
1.2
1.2
1.2
1.2
1.2
DCE
MeCN
Toluene
Toluene
Toluene
Toluene
70
70
70
70
70
70
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeBr3 (10)
AlCl3 (10)
TsOHÁH2O
(10)
37
trace
60
53
0
47
Furthermore, we have optimized the electrophilic ring-closure
trifluoromethylselenolation reaction of 1-methoxy-2-(phenylethy-
nyl)benzene 4a with 2a. Unfortunately, when using TfOH as the
acid, only trace product of 3a was observed (Table 2, entry 1). After
evaluating different acid promoters, this reaction afforded 3a with
37% yield catalyzing by 10 mol % FeCl3 (entry 2). The variation of
7
8
9
10
11
12c
13d
14
15e
16f
1.2
1.2
1.0
1.5
2.0
1.5
1.5
1.5
1.5
1.5
Toluene
Toluene
Toluene
70
70
70
TfOH (10)
TfOH (15)
TfOH (10)
TfOH (10)
TfOH (10)
TfOH (10)
TfOH (10)
TfOH (10)
TfOH (10)
TfOH (10)
63
49
56
72
51
56
46
51
56
53
Toluene 70
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
70
70
70
60
70
70
a
Reaction conditions: 2-phenylbenzofuran 1a (0.25 mmol, 1.0 equiv), 2a (0.25–
0.5 mmol, 1–2 equiv), solvent (0.6 mL), 6 h.
b
Isolated yields.
Toluene (0.3 mL).
Toluene (1.0 mL).
c
d
e
Using Se-(trifluoromethyl) 4-fluorobenzenesulfonoselenoate 2b instead of 2a.
Using Se-(trifluoromethyl) 4-methoxybenzenesulfonoselenoate 2c instead of
f
2a. DCE = 1,2-dichloroethane.
trifluoromethylselenolated product 3a was obtained with 37%
yield (Table 1, entry 1). In order to improve the yield, we screened
other solvents, including acetonitrile, toluene, among which
toluene gave the highest yield (entry 2, 3). After testing various
acids, the results indicated that the yield of 3a was highest when
using trifluoromethanesulfonic acid as the catalyst (entry 4–7).
Then the loadings of 2a and TfOH were tested (entry 8–11), and
found that increasing the loading of TfOH to 1.5 equiv diminished
the yield, while increasing the loading of 2a to 1.5 equiv increased
the yield to 72% (entry 10). However, further increasing the loading
of 2a to 2 equiv did not afford superior result (entry 11). Variation
of the concentration or temperature could not give better yields
(entry 12–14). We also tested other trifluoromethylselenolating
reagents, such as Se-(trifluoromethyl) 4-fluorobenzenesulfonose-
lenoate 2b or 4-methoxybenzenesulfonoselenoate 2c to replace
Scheme 2. Scope of substrates. aReaction conditions: 1a-z, 1aa (0.25 mmol), 2a
(0.375 mmol), TfOH (1 mol/L in toluene) (0.025 mmol, 25
lL), toluene (0.6 mL),
70 °C, 6–10 h. Isolated yields.
2

J. Liu, M. Tian, A. Li et al.
Tetrahedron Letters 66 (2021) 152809
Table 2
Optimization of the trifluoromethylselenolation of 1-methoxy-2-(phenylethynyl)benzene.a
Entry
Loading of 2a (equiv.)
Solvent
T (°C)
Cat. (mol %)
Yield (%)b
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
2.0
Toluene
Toluene
Toluene
Toluene
Toluene
C6H5Cl
DCE
110
110
110
110
110
110
110
110
80
TfOH (10)
FeCl3 (10)
FeCl3 (20)
FeCl3 (30)
FeCl3 (50)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
trace
37
50
47
trace
37
21
47
41
25
MeCN
9
Toluene
Toluene
Toluene
Toluene
10c
11
12
110
110
110
80
70
a
b
c
Reaction conditions: 1-methoxy-2-(phenylethynyl)benzene 4a (0.25 mmol, 1.0 equiv), 2a (0.3–0.5 mmol, 1.2–2 equiv), solvent (0.6 mL), 5 h.
Isolated yields.
Toluene (0.3 mL).
equivalent of catalyst showed that 20 mol % of FeCl3 gave the best
yields (entry 3–5). Then we tested different solvents including
chlorobenzene, DCE, MeCN (entry 6–8). Neither of these solvents
gave superior results than toluene. We also found that decreasing
the reaction temperature or increasing the concentration dimin-
ished the yields (entry 9, 10). Finally, after tuning the loading of
2a (entry 11, 12), we have got the optimized reaction condition
as follows: 4a (0.25 mmol), 2a (1.5 equiv), FeCl3 (20 mol %), toluene
(0.6 mL), stirred 5 h at 110 °C.
Continuously, the substrate scope of this FeCl3-catalyzed elec-
trophilic ring-closure trifluoromethylselenolation reaction was
examined (Scheme 3). Overall, these 1-methoxy-2-(arylethynyl)
benzene substrates containing various substituents either on the
benzene ring or on the triple bond can proceed smoothly, affording
3-trifluoromethylselenolated benzofurans with moderate yields.
Compared with the previous protocol, when the aryl moiety
attaching to triple bond has an electron-donating group, the reac-
tion can also obtain the product with 52% yield (3j). The alkyl sub-
stituents attaching to the triple bond are also compatible, affording
corresponding products (3y, 3z) in slightly higher yields than pre-
vious protocol.
Scheme 4. Possible reaction mechanism.
Based on our previous investigation and literature precedents
[8], an electrophilic pathway was proposed to account for the
Brönsted acid-promoted trifluoromethylselenolation of benzofu-
rans. As shown in Scheme 4, TsSeCF3 2a is activated by TfOH, which
facilitates the nucleophilic attack by benzofuran to afford interme-
diate A along with the extrusion of 4-methylbenzenesulfinic acid.
Finally, deprotonative aromatization of A affords desired product
3. As for the electrophilic cyclotrifluoromethylselenylation, FeCl3-
catalyzed decomposition of TsSeCF3 2a initially occurs to generate
SeCF3 cation B. Then, triple bond moiety of alkyne 4 attacks B to
form intermediate C, followed by sequential intramolecular
cyclization to generate intermediate D. Upon the attack of 4-
methylbenzenesulfinate or chloride anion, the methyl group of D
leaves to obtain product 3.
Conclusion
In conclusion, we utilized TsSeCF3 as the electrophilic trifluo-
romethylselenolating reagent to realize the TfOH-catalyzed selec-
tive trifluoromethylselenolation reaction of benzofurans, as well
as the FeCl3-catalyzed intramolecular electrophilic ring-closure tri-
fluoromethylselenolation of 1-methoxy-2-(arylethynyl)benzene
derivatives. These methods feature a mild reaction conditions,
stable and easily prepared trifluoromethylselenolating reagent
which makes it an alternative and practical strategy for the
Scheme 3. Scope of substrates. aReaction conditions:
(0.375 mmol), FeCl3 (0.05 mmol), toluene (0.6 mL), 110 °C, 5–10 h. Isolated yields.
4 (0.25 mmol), 2a
3

J. Liu, M. Tian, A. Li et al.
Tetrahedron Letters 66 (2021) 152809
(2006) 10694;
trifluoromethylselenolation of the electron-rich heterocyclic com-
pounds. Considering about the importance of benzofuran scaffold,
this synthetic route demonstrate potential applications in pharma-
ceutical and biochemical research.
(f) N. Isono, M. Lautens, Org. Lett. 11 (2009) 1329–1331;
(g) M.C. Henry, A. Sutherland, Org. Lett. 22 (2020) 2766–2770.
[4] (a) A. Tlili, F. Toulgoat, T. Billard, Angew. Chem. Int. Ed. 48 (2016) 11726–
11735;
(b) T. Besset, P. Jubault, X. Pannecoucke, T. Poisson, Org. Chem. Front. 3 (2016)
1004–1010;
Declaration of Competing Interest
(c) X.X. Shao, C.F. Xu, L. Lu, Q.L. Shen, Acc. Chem. Res. 48 (2015) 1227–1236;
(d) X.H. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 115 (2015) 731–764;
(e) H. Chachignon, D. Cahard, Chin. J. Chem. 34 (2016) 445–454;
(f) H. Zheng, Y. Huang, Z. Weng, Tetrahedron Lett. 57 (2016) 1397–1409;
(g) P.P. Zhang, L. Lu, Q.L. Shen, Acta. Chim. Sinica 75 (2017) 744–769;
(h) C. Ghiazza, Q. Glenadel, A. Tlili, T. Billard, Eur. J. Org. Chem. (2017) 3812–
3814.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[5] (a) C. Huang, T. Liang, S. Harada, E. Lee, T. Ritter, J. Am. Chem. Soc. 133 (2011)
13308–13310;
Acknowledgements
(b) K.N. Hojczyk, P. Feng, C. Zhan, M.Y. Ngai, Angew. Chem. Int. Ed. 53 (2014)
14559–21456;
(c) S. Guo, F. Cong, R. Guo, L. Wang, P. Tang, Nat. Chem. 9 (2017) 546–551;
(d) X. Jiang, Z. Deng, P. Tang, Angew. Chem. Int. Ed. 57 (2018) 292–295.
[6] (a) G. Teverovskiy, D.S. Surry, S.L. Buchwald Angew, Chem. Int. Ed. 50 (2011)
7312–7314;
The authors sincerely thank the financial support from Natural
Science Foundation of Tianjin City (Grants 18JCQNJC76600) and
National Natural Science Foundation of China (Grants 21572158).
(b) X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 52 (2013)
3457–3460;
Appendix A. Supplementary data
(c) T. Bootwicha, X.-Q. Liu, Q. Pluta, I. Atodiresei, M. Rueping, Angew. Chem.
Int. Ed. 52 (2013) 12856–12859;
(d) Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki, M. Shiro, N. Shibata, J. Am.
Chem. Soc. 135 (2013) 8782–8785;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152809.
(e) C. Xu, B. Ma, Q. Shen, Angew. Chem. Int. Ed. 53 (2014) 9316–9320;
(f) S. Alazet, L. Zimmer, T. Billard, Chem. Eur. J. 20 (2014) 8589–8593;
(g) J. Liu, X. Xu, Z. Chen, F.-L. Qing, Angew. Chem. Int. Ed. 54 (2015) 897–900.
[7] (a) C. Hansch, A. Leo, R.W. Taft, Chem. Rev. 91 (1991) 165–195;
(b) Q. Glenadel, E. Ismalaj, T. Billard, Eur. J. Org. Chem. 2017 (2017) 530–533;
(c) T. Billard, F. Toulgoat, When Fluorine Meets Selenium in Emerging
Fluorinated Motifs, Chapter 23, Ed: D. Cahard, J.-A. Ma, Wiley-VCH,
Wheineim, 2020, 691–721..
References
[1] (a) D.A. Horton, G.T. Bourne, M.L. Smythe, Chem. Rev. 103 (2003) 893–930;
(b) D.M.X. Donnelly, M. Meegnan, In Comprehensive Heterocyclic Chemistry,
Vol. 4, Ed.: Katrizky, A. R., Pergamon Press, New York, 1984, p. 657–712.;
(c) S.O. Simonetti, E.L. Larghi, A.B.J. Bracca, T.S. Kaufman, Nat. Prod. Rep. 30
(2013) 941–969;
(d) Y. Miao, Y. Hu, J. Yang, T. Liu, J. Sun, X. Wang, RSC Adv. 9 (2019) 27510–
27540.
[2] (a) E. Navarro, S.J. Alonso, J. Trujillo, E. Jorge, C. Perez, J. Nat. Prod. 64 (2001)
134–135;
[8] (a) Q. Glenadel, E. Ismalaj, T. Billard, Org. Lett. 20 (2018) 56–59;
(b) , For other examples using CF3SeCl, see:Q. Glenadel, E. Ismalaj, T. Billard J.
Org. Chem. 81 (2016) 8268–8275;
(c) C. Ghiazza, Q. Glenadel, A. Tlili, T. Billard, Eur. J. Org. Chem. 2017 (2017)
3812–3814;
(d) C. Ghiazza, T. Billard, A. Tlili, Chem. Eur. J. 23 (2017) 10013–10016;
(e) C. Ghiazza, A. Tlili, T. Billard, Eur. J. Org. Chem. 2018 (2018) 3680–3683;
(f) C. Ghiazza, M. Ndiaye, A. Hamdi, A. Tlili, T. Billard, Tetrahedron 74 (2018)
6521–6526.
(b) S. Yoo, S.-K. Kim, S.-H. Lee, N.-J. Kim, D.-W. Lee, Bioorg. Med. Chem. 8
(2000) 2311–2316;
(c) J.L. Charlton, J. Nat. Prod. 61 (1998) 1447–1451;
(d) M.S. Malamas, J. Sredy, C. Moxham, A. Katz, W. Xu, R. McDevitt, F.O.
Adebayo, D.R. Sawick, L. Seestauer, D. Sullivan, J.R. Taylor, J. Med. Chem. 43
(2000) 1293–1310;
(e) M. Gordaliza, M. Castro, J.M. del Corral, M. Lopez-Vazquez, A.S. Feliciano, G.
T. Faircloth, Bioorg. Med. Chem. Lett. 7 (1997) 2781–2786;
(f) M. Masabuchi, K. Kawasaki, H. Ebiike, Y. Ikeda, S. Tsujii, S. Sogabe, T. Fujii, K.
Sakata, Y. Shiratori, Y. Aoki, T. Ohtsuka, N. Shimma, Bioorg. Med. Chem. Lett. 11
(2001) 1833–1837;
[9] (a) For select examples, see: Q. Lefebvre, R. Pluta, M. Rueping Chem. Commun.
51 (2015) 4394–4397;
(b) P. Zhu, X. He, X. Chen, Y. You, Y. Yuan, Z. Weng, Tetrahedron 70 (2014)
672–677;
(c) N.V. Kondratenko, A.A. Kolomeytsev, V.I. Popov, L.M. Yagupolskii, Synthesis
(1985) 667–669.
[10] (a) Q. Glenadel, C. Ghiazza, T. Billard, Adv. Synth. Catal. 359 (2017) 3414–
3420;
(g) K. Kawasaki, M. Masabuchi, K. Morikami, S. Sogabe, T. Aoyama, H. Ebiike, S.
Niizuma, M. Hayase, T. Fujii, K. Sakata, H. Shindoh, Y. Shiratori, Y. Aoki, T.
Ohtsuka, N. Shimma, Bioorg. Med. Chem. Lett. 13 (2003) 87–91.
[3] (a) For selected reviews and examples, see: Y. Zhao, W. Liu, X. Sun, G. Lin Chin.
J. Org. Chem. 32 (2012) 1919–1924;
(b) C. Ghiazza, V. Debrauwer, T. Billard, A. Tlili, Chem. Eur. J. 24 (2018) 97–
100;
(c) Ghiazza, V. Debrauwer, C. Monnereau, L. Khrouz, M. Medebielle, T. Billard,
A. Tlili, Angew. Chem. Int. Ed. 57 (2018) 11781–11785;
(d) C. Ghiazza, L. Khrouz, C. Monnereau, T. Billard, A. Tlili, Chem. Commun. 54
(2018) 9909–9912.
(b) G. Zeni, R.C. Larock, Chem. Rev. 104 (2004) 2285–2309;
(c) D. Yue, T. Yao, R.C. Larock, J. Org. Chem. 70 (2005) 10292–10296;
(d) I. Nakamura, Y. Mizushima, Y. Yamamoto, J. Am. Chem. Soc. 127 (2005)
15022–15023;
[11] X. Zhao, X. Wei, M. Tian, X. Zheng, L. Ji, Q. Li, Y. Lin, K. Lu, Tetrahedron Lett. 60
(2019) 1796–1799.
(e) K.W. Anderson, T. Ikawa, R.E. Tundel, S.L. Buchwald, J. Am. Chem. Soc. 128
4