Copper-catalyzed synthesis of 2-sulfenylindoles from indoline-2-thiones and aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2016.12.028

A novel and efficient method for synthesis of 2-sulfenylindole via copper-catalyzed coupling reaction of indoline-2-thiones with aryl iodides has been developed. A series of N-substituted and N-free 2-sulfenylindole were obtained in high yields. Furthermo

Full text of DOI:10.1016/j.tetlet.2016.12.028

Accepted Manuscript
Copper-catalyzed synthesis of 2-sulfenylindoles from indoline-2-thiones and
aryl iodides
Shiping Zhou, Genhua Xiao, Yun Liang
PII:
S0040-4039(16)31654-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.028
TETL 48440
Reference:
Tetrahedron Letters
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6 December 2016
9 December 2016
Please cite this article as: Zhou, S., Xiao, G., Liang, Y., Copper-catalyzed synthesis of 2-sulfenylindoles from
indoline-2-thiones and aryl iodides, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.028
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Tetrahedron Letters
Copper-catalyzed synthesis of 2-sulfenylindoles from indoline-2-thiones and aryl iodides
Shiping Zhou, Genhua Xiao, Yun Liang*
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of the Assembly and Application of
Organic Functional Molecules, Hunan Normal University, Changsha, Hunan 410081, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and efficient method for synthesis of 2-sulfenylindole via copper-catalyzed coupling reaction
of indoline-2-thiones with aryl iodides has been developed. A series of N-substituted and N-free 2-
sulfenylindole were obtained in high yields. Furthermore, the method was employed to synthesis of
benzothieno[2,3-b]indoles from indoline-2-thiones with 1,2-diiodobenzene in the presence of CuI and
Pd(OAc)2 as catalysts.
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Indoline-2-thiones
Copper
2-Sulfenylindoles
Benzothieno[2,3-b]indoles
Sulfenylindoles1, categorized as significant derivatives of
indoles, are broadly found in bioorganic and medicinal chemistry
with application in drug discovery and development for the
treatment of various diseases (Figure 1), such as HIV,2
cancer,3 vascular,4 respiratory disorders,5 heart disease,6 and
allergies.7 Consequently, many efficient methods were
developed for the synthesis of sulfenylindoles.8 Among them,
the direct sulfenylation of indoles is an efficient and common
strategy.9 Due to the nucleophilic of indoles, the thioethers can be
easily introduce in the 3-position of indoles and a variety of
sulenylating reagents such as sulfenyl halide,10 disulfides,11
thiols,12 arylsulfonyl chorides,13 arylsulfonyl hydrazides,14
sulfonium salts,15 sulfinic acids16 were smoothly coupled with
indoles to 3-sulfenylindoles. However, the synthesis of 2-
sulfenylindole was limited applying this protocol. The classic
method to 2-sulfenylindole was used acid-catalyzed
rearrangement of 3-sulfenylindole17 and the sulfenylation of 2-
lithioindoles.18 Recently, Cossy and coworkers have found TFA-
promoted direct C-H sulfenylation at C2 position of non-
protected indoles for the synthesis of 2-sulfenylindoles.19
Nevertheless, these methods suffer from use of strong acids and
strong bases, incompatible with various functional groups. Thus,
it is highly desirable to provide efficient and facile strategy for
the preparation of 2-sulenylindoles.
Figure 1 Representative examples of biologically active sulfenylindoles
Scheme 1 Method for preparation of 2-sulenylindoles
Initially, the coupling reaction of N-methylindoline-2-thione
with iodobenzene was selected for optimization of reaction
conditions, and the results are summarized in Table 1. Our
investigation started by an attempted thiolation of N-
o
methylindoline-2-thione with iodobenzene in DMF at 120 C in
the presence of CuI as the catalyst, and the desired product 3a
was isolated in 80% yield (entry 1). This result encouraged us to
develop an efficient catalytic system to synthesize 2-
sulfenylindoles from indoline-2-thiones and aryl iodides. A
variety of copper catalysts, such as CuCl, CuBr, Cu(OAc)2,
CuCl2, were screened and the results indicated that the catalyst of
CuI is the best for this coupling reaction yet (entries 2-5).
Without the copper catalyst, the desired product could not be
isolated (entry 6). Subsequently, the effects of ligands were
checked, and 2,2'-bipyridine was found to be an efficient ligand
(entries 7-10). The effects of base (including K3PO4, KOAc, KF,
Indole-2-thiones are an efficient synthon to construct 2-
sulfenylindoles.20 However, they are commonly used to
synthesize the 2-alkyl thiolester indoles. Herein, we would like to
disclose
a useful application of indole-2-thones for the
production of 2-sufenylindoles (Scheme 1).
----------------
* Corresponding author.
t
and BuOK) and solvent (including DMSO, CH3CN and toluene)
E-mail address: yliang@hunnu.edu.cn (Y. Liang);
were examined. K2CO3 was found to give the best result and

2
Tetrahedron Letters
DMF was found to be the best solvent for the reaction (entries
benylthioindoles. The electronic properties of substituents in the
benzene ring exerted an obvious influence on the reaction. The
electron-withdrawing groups substituted N-methyl indole-2-
thiones showed higher activity than the electron-donating groups
substituted N-methyl indole-2-thiones. Besides N-methyl indole-
2-thione, N-free and other N-substituted groups (phenyl, benzyl
and cyclopropylmethyl) were also involved. To our delight, non-
protected 2-sulfenylindole 3g given the perfect yield. However,
the N-benzyl substituted 2-sulfenylindole 3i only gain 30% yield.
These results indicated that the steric effect of substituents is a
main impact factor.
11-17). Finally, the amount of catalyst and the reaction
temperature were evaluated. Relatively low yields were found
when the reaction carried out in 100 or 140 C, and the yield of
3a was the highest when using 10 mmol % loading of CuI and 20
mmol % of 2,2'-bipyridine (entries 18-20). Thus, the optimized
reaction conditions were as follows: 1a (0.3 mmol), 2a (0.36
mmol), CuI (10 mmol %), 2,2'-bipyridine (20 mmol %), K2CO3
(0.9 mmol), in DMF (2 mL) at 120 oC.
o
Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope for the reaction of indole-2-thiones 1
with iodobenzene 2a a,b
.
Entry
Copper
Ligand
Base
Solvent Yield
(%)b
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
81
CuI
CuCl
26
CuBr
70
Cu(OAc)2
CuCl2
71
trace
60
-
CuCl
TEMDA
CuCl
CuCl
2,2'-bipyridine K2CO3
89
1,10-
K2CO3
83
phenanthroline
10
11
12
13
14
15
16
17
18c
19d
20e
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
L-proline
K2CO3
DMF
DMF
DMF
DMF
DMF
75
83
79
77
77
75
86
0
2,2'-bipyridine K3PO4
2,2'-bipyridine KOAc
2,2'-bipyridine KF
a
Reaction conditions: 1 (0.3 mmol), 2a (0.36 mmol), CuCl (10
mmol %), 2,2'-bipyridine (20 mmol %), K2CO3 (3.0 equiv), DMF (2
mL), 120 oC, N2, 6 h.
b Isolated yield.
2,2'-bipyridine tBuOK
We next examined the scope of various substituted
iodobenzenes in order to accessing
a
variety of 2-
2,2'-bipyridine K2CO3 DMSO
2,2'-bipyridine K2CO3 CH3CN
2,2'-bipyridine K2CO3 Toluene
arylsulfenylindoles（Table 3）. All of the substrates provided a
good to excellent yields, showing good functional group
tolerance. o-, m- or p-Methyl-iodobenzene all could efficiently
react with indole-2-thione and afford 85-98% yields of the
corresponding product respectively. Likewise, the o-, m- or p-
Flour-iodobenzene all gave the corresponding product in perfect
yields under standard reaction conditions. These results indicated
the steric effects and electron effects of substituents shown a very
limited influence on this reaction due to the inherent reactive
activity of iodobenzene. Furthermore, the iodobenzene, bearing
the electron-donating groups such as OMe and the electron-
withdrawing groups such as Cl, NO2 could give good to perfect
yields. Importantly, -extend 4-iodo-1,1'-biphenyl and 1-
iodonaphthalene could performed with indole-2-thione and
produce the desired product in 81% and 65% yield. In addition,
the heterocyclic aryl substituted 2-(pyridin-2-ylthio)-1H-indole
was afforded in 52% yield. Unfortunately, the bromobenzene
could not efficiently react with indole-2-thione, and the 2-
(phenylthio)-1H-indole was not observed under standard
conditions.
2,2'-bipyridine K2CO3
2,2'-bipyridine K2CO3
2,2'-bipyridine K2CO3
DMF
DMF
DMF
83
77
80
a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), Copper (10
mmol %), Ligand (20 mmol %), Base (3.0 equiv), Solvent (2 mL),
120 oC, N2, 6 h.
b Isolated yield.
c Copper (20 mmol %), Ligand (40 mmol %).
d 100 oC.
e 140 oC.
With optimized the reaction conditions in hand, the coupling
reaction of various indole-2-thiones with iodobenzene were
investigated, and the results are summarized in Table 2. The N-
methyl indole-2-thiones containing electron-donating substituents
(Me and OMe) and electon-withdrawing substituents (F, Cl and
Br) in the benzene ring were examined, and they all could
tolerate the reaction conditions and give the corresponding 2-

Table 3 Substrate scope for the reaction of indole-2-thiones 1g
Based on the present expermental results and the previous
reported mechanism,22 a proposed catalytic cycle for the
formation of 2-sulfenylindoles from indoline-2-thiones and aryl
halides is given in Scheme 2. First, the indole 2-thione is
deprotonated by potassium carbonate to form a stabilized anion
A. Then the anion A reacted with iodobenzene via copper-
catalyzed coupling reaction and afford the desired product 2-
sulfenylindole.
with aryl iodides 2 a,b
.
Scheme 2 Plausible mechanism
In summary, we have demonstrated a novel copper-
catalyzed coupling reaction of indoline-2-thiones with aryl
halides. This method provides an effective approach to
synthesize N-substituted or N-free 2-sulfenylindoles, which are
ubiquitous structural units in a number of biologically active
componds. Furthermore, this strategy could extend to synthesize
the -extend polycyclic heterocyclic benzothiophene fused
indoles. Further studies on the applications of this method are
underway.
a
Reaction conditions: 1g (0.3 mmol), 2 (0.36 mmol), CuCl (10
mmol %), 2,2'-bipyridine (20 mmol %), K2CO3 (3.0 equiv), DMF (2
mL), 120 oC, N2, 6 h.
Acknowledgments
b Isolated yield.
This work was supported by the Natural Science Foundation
of China (21572051), the Ministry of Education of China
(213027A), and the Scientific Research Fund of Hunan Provincial
Education Department (15A109).
To further demonstrate the synthetic utility of this
sulfenylation reaction, we applied this methodology to synthesis
of a -extend polycyclic benzothiophene fused indoles.21 When
the 1,2-diiodobenzene was chosen as the substrate in this
coupling reaction, the corresponding sulfenylated products
(benzothieno[2,3-b]indoles) should be produced. To our delight,
the benzothieno[2,3-b]indoles could be obtained in moderate
yield by copper- and palladium-catalyzed tandem coupling
reaction (Table 4).
References and notes
1. (a) Zhang, M. Z.; Chen, Q.; Yang, G. F. Eur. J. Med. Chem.
2015, 89, 421; (b) Silveira, C. C.; Mendes, S. R.; Soares, J. R.;
Victoria, F. N.; Martinez, D. M.; Savegnago, L. Tetrahedron
Lett. 2013, 54, 4926; (c) La Regina, G.; Coluccia, A.; Brancale,
A.; Piscitelli, F.; Gatti, V.; Maga, G.; Samuele, A.;
Pannecouque, C.; Schols, D.; Balzarini, J.; Novellino, E.;
Silvestri, R. J. Med. Chem. 2011, 54, 1587; (d) Holenz, J.;
Pauwels, P. J.; Díaz, J. L.; Mercè, R.; Codony, X.; Buschmann,
H. Drug Discov. Today 2006, 11, 283; (e) De Martino, G.; La
Regina, G.; Coluccia, A.; Edler, M. C.; Barbera, M. C.;
Brancale, A.; Wilcox, E.; Hamel, E.; Artico, M.; Silvestri, R. J.
Med. Chem. 2004, 47, 6120; (f) Hiroi, K.; Izawa, I.; Takizawa,
T.; Kawai, K. Tetrahedron 2004, 60, 2155; (g) Pedras, M. S. C.;
Zaharia, I. L. Phytochemistry, 2000, 55, 213; (h) Marino, J. P.;
Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992, 114, 5566.
2. (a) Ragno, R.; Coluccia, A.; La Regina, G.; De Martino, G.;
Piscitelli, F.; Lavecchia, A.; Novellino, E.; Bergamini, A.;
Ciaprini, C.; Sinistro, A.; Maga, G.; Crespan, E.; Artico, M.;
Silvestri, R. J. Med. Chem. 2006, 49, 3172; (b) Silvestri, R.;
Artico, M.; Bruno, B.; Massa, S.; Novellino, E.; Greco, G.;
Marongiu, M. E.; Pani, A.; De Montis, A.; La Colla, P. Antivir.
Chem. Chemother. 1998, 9, 139.
Table 4 Synthesis of benzo[b]thiophene-fused indoles a,b
a
Reaction conditions: 1 (0.3 mmol), 4 (0.36 mmol), CuI (10 mmol
%), Pd(OAc)2 (10 mmol %), K2CO3 (3.0 equiv), DMF (2 mL), 120
oC, N2, 24 h.
b Isolated yield.

4
Tetrahedron Letters
3. (a) Avis, I.; Martnez, A.; Tauler, J.; Zudaire, E.; Mayburd, A.;
69, 7688; (c) Campbell, J. A.; Broka, C. A.; Gong, L.; Walker,
K. A. M.; Wang, J. H. Tetrahedron Lett. 2004, 45, 4073.
13. (a) Chen, M.; Huang, Z. T.; Zhen, Q. Y. Chem. Commun. 2012,
48, 11686; (b) Wu, Q.; Zhao, D.; Qin, X.; Lan, J.; You, J.
Chem. Commun. 2011, 47, 9188.JJ
14. (a)1 Li, X.; Xu, Y.; Wu, W.; Jiang, C.; Qi, C.; Jiang, H. Chem.
Eur. J. 2014, 20, 1; (b) Yang, F. L.; Tian, S. K. Angew. Chem.
Int. Ed. 2013, 52, 4929.
Abu-Ghazaleh, R.; Ondrey, F.; Mulshine, J. L. Cancer. Res.
2005, 65, 4181; (b) De Martino, G.; La Regina, G.; Coluccia,
A.; Edler, M. C.; Barbera, M. C.; Brancale, A.; Wilcox, E.;
Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2004, 47,
6120.
4. Zhou, N.; Zeller, W.; Krohn, M.; Anderson, H.; Zhang, J.;
Onua, E.; Kiselyov, A. S.; Ramirez, J.; Halldorsdottir, G.;
Andresson, T.; Gurney, M. E.; Singh, J. Bioorg. Med. Chem.
Lett. 2009, 19, 123.
5. Ainge, D.; Butters, M.; Merifield, E.; Ramakrishnan, R.;
Rayapati, R. N.; Sharma, P. R.; Thomson, C. 2012, Patent No. 8,
227, 622.
6. Funk, C. D. Nat. Ret. Drug Discov. 2005, 4, 664.
7. Unangst, P. C.; Connor, D. T.; Russell Stabler, S.; Weikert, R.
J.; Carethers, M. E.; Kennedy, J. A.; Thueson, D. O.; Chestnut,
J. C.; Adolphson, R. L.; Conroyt, M. C. J. Med. Chem. 1989,
32, 1360.
15. (a) Xiao, F.; Xie, H.; Liu, S.; Deng, G. J. Adv. Synth. Catal.
2014, 356, 364; (b) Rao, H.; Wang, P.; Wang, J.; Li, Z.; Sun,
X.; Cao, S. RSC Adv. 2014, 4, 49165.
16. Liu, C. R.; Ding, L. H.; Org. Biomol. Chem. 2015, 13, 2251.
17. (a) Hamel, P.; Girard, Y.; Atkinson, J. G. J. Org. Chem. 1992,
57, 2694; (b) Hamel, P.; Girard, Y.; Atkinson, J. G. J. Chem.
Soc. Chem. Commun. 1989, 1, 63.
18. (a) Katritzky, A. R.; Lue, P.; Chen, Y. X. J. Org. Chem. 1990,
55, 3688; (b) Saulnier, M. G.; Gribble, G. W. J. Org. Chem.
1982, 47, 757.
8. (a) Han, D.; Li, Z.; Fan, R. Org. Lett. 2014, 16, 6508; (b) Liu,
J.; Li, P.; Chen, W.; Wang, L. Chem. Commun. 2012, 48, 10052;
(c) Chitra, S.; Paul, N.; Muthusubramanian, S.; Manisankar, P.
RSC Adv. 2012, 2, 1432; (d) Li, Z.; Hong, L.; Liu, R.; Shen, J.;
Zhou, X. Tetrahedron Lett. 2011, 52, 1343; (e) Chen, Y.; Cho,
C. H.; Larock, R. C. Org. Lett. 2009, 11, 173; (f) Guo, Y. J.;
Tang, R. Y.; Li, J. H.; Zhong, P.; Zhang, X. G. Adv. Synth.
Catal. 2009, 351, 2615.
9. (a) Zhang, H.; Bao, X.; Song, Y.; Qu, J.; Wang, B. Tetrahedron
2015, 71, 8885; (b) Liu, Y.; Zhang, Y.; Hu, C.; Wan, J. P.; Wen,
C. RSC Adv. 2014, 4, 35528; (c) Marcantoni, E.; Cipolletti, R.;
Marsili, L.; Menichetti, S.; Properzi, R.; Viglianisi, C. Eur. J.
Org. Chem. 2013, 2013, 132; (d) Huang, D.; Chen, J.; Dan, W.;
Ding, J.; Liu, M.; Wu, H. Adv. Synth. Catal. 2012, 354, 2123;
(e) Silveira, C. C.; Mendes, S. R.; Wolf, L.; Martins, G. M.
Tetrahedron Lett. 2010, 51, 2014; (f)r Fang, X. L.; Tang, R. Y.;
Zhong, P.; Li, J. H. Synthesis 2009, 24, 4183; (g) Yadav, J. S.;
Subba Reddy, B. V.; Reddy, Y. J.; Praneeth, K. Synthesis 2009,
9, 1520; (h) Tudge, M.; Tamiya, M.; Savarin, C.; Humphrey, G.
R. Org. Lett. 2006, 8, 565.
19. Hostier, T.; Ferey, V.; Ricci, G.; Pardoa, D. G.; Cossy, J. Chem.
Commun. 2015, 51, 13898.
20. (a) Jha, M.; Shelke, G. M.; Stanley Cameron, T.; Kumar, A. J.
Org. Chem. 2015, 80, 5272; (b) Jha, M.; Enaohwo, O.; Guy, S.
Tetrahedron Lett. 2011, 52, 684.
21. (a) Liao, Y.; Peng, Y.; Qi, H.; Deng, G. J.; Gong, H.; Li, C. J.
Chem. Commun. 2015, 51, 1031; (b) Aurelio, L.; Volpe, R.;
Halim, R.; Scammells, P. J.; Flynn, B. L. Adv. Synth. Catal.
2014, 356, 1974; (c) Kienle, M.; Wagner, A. J.; Dunst, C.;
Knochel, P. Chem. Asian J. 2011, 6, 517.
22. (a) Moghaddam, F. M.; Mirjafary, Z.; Saeidian, H.; Taheri, S.;
Doulabi, M.; Kiamehr, M.; Tetrahedron 2010, 66, 134; (b)
Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc.
2009, 131, 78; (c) Feng, Y.; Zhao, X.; Wang, J.; Zheng, F.; Xu,
H. Chin. J. Chem. 2009, 27, 2423; (d) Rout, L.; Sen, T. K.;
Punniyamurthy, T. Angew. Chem. Int. Ed. 2007, 46, 5583; (e)
Zhang, S. L.; Liu, L.; Fu, Y.; Guo, Q. X. Organometallics 2007,
26, 4546; (f) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed.
2003, 42, 5400.
10. Raban, M.; Chern, L. J. J. Org. Chem. 1980, 45, 1688.
11. (a) Ge, W.; Wei, Y. Green Chem. 2012, 14, 2066; (b) Li, Z.;
Hong, J.; Zhou, X. Tetrahedron 2011, 67, 3690; (c) Browder, C.
C.; Mitchell, M. O.; Smith, R. L.; Stdayman, G. Tetrahedron
Lett. 1993, 34, 6245.
12. (a) Schlosser, K. M.; Krasutsky, A. P.; Hamilton, H. W.; Reed,
J. E.; Sexton, K. Org. Lett. 2004, 6, 819; (b) Maeda, Y.;
Koyabu, M.; Nishimura, T.; Uemura, S. J. Org. Chem. 2004,
Supplmentary Material
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procedures
and
characterization data for all new compounds and copies of NMR
spectra) associated with this article can be found, in the online
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Copper-catalyzed synthesis of 2-
sulfenylindoles from indoline-2-
thiones and aryl iodides
Shiping Zhou, Genhua Xiao, Yun Liang*

Highlights:
1). A novel and efficient method for synthesis of 2-sulfenylindoles;
2). Copper-catalyzed the formation of C-S bond;
3). Extend to synthesize benzothiophene fused indoles.