Efficient C3-alkylsulfenylation of indoles under mild conditions using Lewis acid-activated 8-quinolinethiosulfonates

Article abstract of DOI:10.1016/j.tetlet.2020.152748

The activation of 8-quinolinethiosulfonates by zinc chloride promotes the usually difficult to achieve C3-alkylsulfenylation of indoles at room temperature under aerobic conditions. This strategy is compatible with substrates containing various functional

Full text of DOI:10.1016/j.tetlet.2020.152748

Tetrahedron Letters 65 (2021) 152748
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Tetrahedron Letters
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Efficient C3-alkylsulfenylation of indoles under mild conditions using
Lewis acid-activated 8-quinolinethiosulfonates
Erwan Galardon
UMR 8601, LCBPT, CNRS-Université de Paris, 45 rue des Sts Pères, 75006 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The activation of 8-quinolinethiosulfonates by zinc chloride promotes the usually difficult to achieve C3-
alkylsulfenylation of indoles at room temperature under aerobic conditions. This strategy is compatible
with substrates containing various functional groups.
Received 13 November 2020
Revised 3 December 2020
Accepted 7 December 2020
Available online 4 January 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Sulfenylation
Thiosulfonate
Indole
Lewis acid
CAS bond
Introduction
[9]. However, despite this large pool of sulfenylation reagents,
the difficult activation of the chalcogen centre essentially limits
The importance of sulfur-containing compounds in various
fields, ranging from materials science [1] to medicinal chemistry
[2], has resulted in the development of various synthetic strategies
to form carbon–sulfur (CAS) bonds. Thus, numerous approaches
based on the nucleophilicity of thiols have been reported over
the years, which mostly utilize air-sensitive noble metal catalysts
[3]. The use of electrophilic sulfur reagents is another powerful,
more eco-friendly approach, in particular for the sulfenylation of
CAH bonds to give CAS bonds [4]. In this context, the sulfenylation
of indoles (Equation 1) has become a benchmark reaction to
develop and test new sulfenyl transfer reagents, because indoles
are good nucleophiles and their occurrence in various natural
products or biologically active compounds makes them attractive
synthetic targets [5].
these reagents to the formation of CAS(aryl) bonds. On the other
hand, the transfer of alkylsulfenyl groups is more difficult and
often requires harsh activating conditions (Table 1).
For instance, most protocols require heating or microwave acti-
vation [6a,9–10], and to the best of our knowledge only a single
report of the alkylsulfenylation of indole at room temperature
has been published [11]. Herein, we propose a new approach based
on novel quinoline-containing thiosulfonates (QSO2SR, Scheme 1)
to efficiently transfer alkylsulfenyl groups to indoles under mild
reaction conditions. Coordination of a Lewis acid to the quinoline
nitrogen enhances the electrophilicity of the sulfur atom compared
to thiosulfonates.
Initially, the reaction between equimolar amounts of QSO2SEt,
indole and various divalent cations acting as Lewis acids was mon-
itored by 1H NMR spectroscopy at room temperature (Equation 2)
in dichloromethane. While most of these reactions proved unsuc-
cessful (Table 2), including the control experiment without a Lewis
acid, significant changes were observed in the 1H NMR spectrum
with ZnCl2ꢀ6H2O
+
+
For instance, metal-catalyzed or metal-free protocols have been
reported, in which disulfides, sulfinic acids and their salts, sulfonyl
chlorides, sulfonylhydrazine, or N-thiophthalimides are used as the
source of electrophilic sulfur [4a,6]. Thiosulfonates (RSO2SR0) are
another class of recently reviewed [7] reagents, which were also
studied for CAS bond formation [8] and for indole sulfenylation
2
2
2
2
Two features are indicative of the transformation of the starting
materials into the expected 3-(ethylthio)indole as illustrated in
E-mail address: erwan.galardon@parisdescartes.fr
https://doi.org/10.1016/j.tetlet.2020.152748
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

E. Galardon
Tetrahedron Letters 65 (2021) 152748
Table 1
Representative protocols for the C3-alkylsulfenylation of indoles.
Donor
Experimental conditions
Alkyl
(1.0 eq.)
groups
Phthal-
SR
Indole (0.9 eq.), 0.5% MgBr2, DMAc, 90 °C [6a]
Me, Et, c-
Hex, i-Pr
Et, Bz
Me, Bn, n-
Bu
MBTa-SR
RSO2Cl
Indole (0.9 eq.), 10% CuI, DMSO, rt [11]
Indole (2.0 eq.), 10% I2, 80 °C, 1,4-dioxane[12]
Indole (0.5 eq.), TBAI (1.5 eq.), 60 °C, DMF [10b]
Et, i-Pr
RSO2H
Indole (0.8 eq.), TBAI (1.0 eq.), TsOH (0.3 eq.), 110 W, Me, n-Oct
70 °C[13]
RSO2Na
Indole (0.8 eq.), 8% I2, H2O2 (2.0 eq.),
diethylphosphite (2.6 eq.), PEG400, 100 W, 70 °C
[10c]
Me
Indole (0.5 eq.) 5% I2, DMSO (1.5 eq.),
diethylphosphite (1.0 eq.), 100 °C, anisole, argon
[10d]
Indole (1.0 eq.), 5% I2, DMSO (3.0 eq.), 100 W, 80 °C Et, Bn
[9]
Me, Et, Pr
Fig. 1. 1H NMR spectrum (recorded at 500 MHz in CDCl3) for the crude reaction
mixture between QSO2SEt and indole in the presence of ZnCl2ꢀ6H2O in dichlor-
omethane after 1 and 3 h.
RS-SR
RSO2SR
Indole (1.2 eq.), 120 °C, H2O under argon[8a]
Me
a
MBT: mercaptobenzotriazole.
Table 3
Isolated yields for the reaction of various indoles (0.95 equiv.) with QSO2SEt and
ZnCl2ꢀ6H2O (1.0 equiv. each, ~0.2 M in dichloromethane for 18 h or in ethyl acetate for
42 h at rt).
H
Entry
Indole
Product
Solvent
Yield (%)
CO2Me
R = Cys
1
2
3
4
5
6
7
8
Indole
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
88
84
89
85
81
0
78
83
76
91
79
R = Et
NHBoc
CO2Et
5-Methylindole
2-Methylindole
1-Methylindole
5-Methoxyindole
3-Methylindole
5-Fluoroindole
5-Chloroindole
6-Bromoindole
2-Methyl-5-bromoindole
5-Hydroxyindole
R = Allyl
R = BuEt
N
R
3
CN
2
R = Prop
S
S
R = PrCN
R = Ph
O
O
Ph
R = Bn
Ph
9
10
11
9
10
11
Scheme 1. Sulfenylating reagents (QSO2SR) used in this study.
Table 2
deficient indoles (Table 3, entries 7–9) to their 3-sulfenylated
derivatives [14]. Unsurprisingly, the reaction is faster with 5-
methoxyindole than with 5-bromoindole, as shown in Figs. S1
and S2. For instance, after 3 h only a 50% conversion is obtained
with the latter whereas the reaction is almost complete with the
former. The presence of substituents at the 1- or 2-position of
the indole ring does not interfere with the C3-sulfenylation
(Entries 3, 4, 10), and QSO2SEt was fully recovered after the reac-
tion with 3-methylindole (Entry 6), as expected from the absence
of 2-sulfenylated by-products discussed above. Interestingly, the
reaction also proceeds smoothly at room temperature in ethyl
acetate, although at a slower rate than in dichloromethane. Thus,
the full conversion of indole to 3-(ethylthio)indole requires 42 h
in ethyl acetate, while the reaction was complete after 3 h in
dichloromethane. However, this allowed for the use of substrates
which are insoluble in dichloromethane, such as 5-hydroxyindole
(Entry 11). The reaction is not catalytic, indicating that the Lewis
acid remains coordinated to the quinoline moiety after the sulfenyl
transfer. A tentative mechanism is proposed in the ESI.
Conversions\ of QSO2SEt (determined by 1H NMR
spectroscopy) when reacted with stoichiometric
amounts of both indole and various Lewis acids (0.2 M
in dichloromethane, room temperature, 18 h).
Lewis acid
Conversion (%)
NiCl2
CoCl2
CuCl2
MgCl2
10
15
35
0
ZnCl2ꢀ6H2O
>90
\
Conversions are rounded to the nearest 5% and
determined by 1H NMR spectroscopy.
Fig. 1: i) the disappearance of the signal at 6.34 ppm, correspond-
ing to the proton at the 3-indole position (green), and ii) the
appearance of a new quadruplet at 2.65 ppm, corresponding to
the new 3-S-CH2-CH3 moiety (orange), replacing the corresponding
protons in the starting QSO2SEt (3.29 ppm, blue). Protons from the
quinoline moiety also disappear due to the formation of an insol-
uble adduct with the Lewis acid. The thiosulfonate QSO2SEt was
consumed within 3 h, and no trace of the possible 2-sulfenylated
by-product was detected by 1H NMR spectroscopy, pointing
towards a non-radical pathway. The lack of reaction with other
Lewis acid may be at least partially attributed to the poor solubility
of most inorganic salts in the chlorinated solvent.
2
2.6
2
2
2
Finally, we investigated the sulfenylation of 5-methylindole
with the various thiosulfonates depicted in Scheme 1, which are
easily obtained from the reaction between the 8-quinolinethiosul-
fonate pyridinium salt and primary alkyl bromides [7]. However,
we were unable to obtain thiosulfonates from secondary alkyl
halides, despite the previous preparation of phenylthiosulfonates
The screening of various indoles and QSO2SEt with zinc chloride
(Equation 3) in dichloromethane at room temperature efficiently
converts both electron-rich (Table 3, entries 2–5) and electron-
2

E. Galardon
Tetrahedron Letters 65 (2021) 152748
Table 4
References
Isolated yields for the reaction of 5-methylindole with 1.05 equiv. of various
thiosulfonates and 1.05 equiv. ZnCl2ꢀ6H2O (reagents ~ 0.2 M in dichloromethane for
18 h at rt).
[1] a) H. Mutlu, E.B. Ceper, X. Li, J. Yang, W. Dong, M.M. Ozmen, P. Theato,
Macromol. Rapid Comm. 40 (2019) e1800650;
b) M.J.H. Worthington, R.L. Kucera, J.M. Chalker, Green Chem. 19 (2017) 2748–
2761.
Entry
Thiosulfonate
Product
Yield (%)
[2] M.H. Feng, B.Q. Tang, S.H. Liang, X.F. Jiang, Curr. Top. Med. Chem. 16 (2016)
1200–1216.
1
2
3
4
5
6
7
QSO2SBn
QSO2SAllyl
QSO2SCys
QSO2SPropyne
QSO2SBuEt
QSO2SPrCN
QSO2SPh
12
13
14
15
16
17
18
81
91
48
83
85
89
79
[3] a) P. Bichler, J.A. Love, Top. Organomet. Chem. 31 (2010) 39–64;
b) P. Chauhan, S. Mahajan, D. Enders, Chem. Rev. 114 (2014) 8807–8864;
c) T. Kondo, T.A. Mitsudo Ta, Chem. Rev. 100 (2000) 3205–3220;
d) X.D. Li, Y.T. Gao, Y.J. Sun, X.Y. Jin, D. Wang, L. Liu, L. Cheng, Org. Lett. 21
(2019) 6643–6647;
e) K. Tanimoto, R. Ohkado, H. Iida, J. Org. Chem. 54 (2019) 14980;
f) Q.-H. Teng, Y. Yao, W.-X. Wei, H.-T. Tang, J.-R. Li, Y.-M. Pan, Green Chem. 21
(2019) 6241.
using this synthetic strategy [7,15]. As reported in Table 4, 5-
methylindoles (Equation 4) were obtained in good to high yields,
even with the more functionalized substrate QSO2SCys. The reac-
tion is not limited to alkylthiosulfonates, and although this
methodology may not be the most appropriate to introduce -S
(aryl) groups, 3-(phenylthio)-5-methylindole 18 was formed from
indole and QSO2SPh.
[4] a) D.Q. Dong, S.H. Hao, D.S. Yang, L.X. Li, Z.L. Wang, Eur. J. Org. Chem. (2017)
6576–6592;
b) C. Shen, P.F. Zhang, Q. Sun, S.Q. Bai, T.S.A. Hor, X.G. Liu, Chem. Soc. Rev. 44
(2015) 291–314.
[5] a) N.K. Kaushik, N. Kaushik, P. Attri, N. Kumar, C.H. Kim, A.K. Verma, E.H. Choi,
Molecules 18 (2013) 6620–6662;
b) K.N. Pham, A. Lewis-Ballester, S.R. Yeh, J. Am. Chem. Soc. 141 (2019) 18771;
c) T.V. Sravanthi, S.L. Manju, Eur. J. Pharm. Sci. 91 (2016) 1–10.
[6] a) M. Tudge, M. Tamiya, C. Savarin, G.R. Humphrey, Org. Lett. 8 (2006) 565–
568;
b) D. Equbal, R. Singh, A.G. Saima, A.K. Lavekar, Sinha,, J. Org. Chem. 84 (2019)
2660–2675;
2
c) A. Hosseinian, S. Arshadi, S. Sarhandi, A. Monfared, E. Vessally, J. Sulfur
Chem. 40 (2019) 289–311.
[7] P. Mampuys, C.R. McElroy, J.H. Clark, R.V.A. Orru, B.U.W. Maes, Adv. Synth.
Catal. 362 (2020) 3–64.
2.6
2
2
2
[8] a) C. Ravi, A. Joshi, S. Adimurthy, Eur. J. Org. Chem. 2017 (2017) 3646–3651;
b) T.T. Song, H.Y. Li, F. Wei, C.H. Tung, Z.H. Xu, Tetrahedron Lett. 60 (2019)
916–919;
c) R.J. Reddy, A.H. Kumari, J.J. Kumar, J.B. Nanubolu, Adv. Synth. Catal. 361
(2019) 1587–1591.
[9] J.B. Azeredo, M. Godoi, G.M. Martins, C.C. Silveira, A.L. Braga, J. Org. Chem. 79
(2014) 4125–4130.
In conclusion, a new methodology is reported to efficiently
introduce alkylsulfenyl moieties at the C3-position of indoles
under mild conditions. The extension of this methodology to other
activated CAH bonds is currently under study.
[10] a) P.P. Kumar, Y.D. Reddy, C.V.R. Reddy, B.R. Devi, P.K. Dubey, J. Sulfur Chem.
35 (2014) 356–361;
Declaration of Competing Interest
b) Y.Z. He, J. Jiang, W.H. Bao, W. Deng, J.N. Xiang, Tetrahedron Lett. 58 (2017)
4583–4586;
c) R. Rahaman, P. Barman, Eur. J. Org. Chem. (2017) 6327–6334;
d) F.H. Xiao, H. Xie, S.W. Liu, G.J. Deng, Adv. Synth. Catal. 356 (2014) 364–368;
e) X.Q. Yang, Y.S. Bao, Z.H. Dai, Q.F. Zhou, F.L. Yang, Green Chem. 20 (2018)
3727–3731.
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.
[11] W.L. Ge, Y.Y. Wei, Synthesis 44 (2012) 934–940.
[12] G. Kumaraswamy, R. Raju, V. Narayanarao, RSC Adv. 5 (2015) 22718–22723.
[13] R. Rahaman, N. Devi, J.R. Bhagawati, P. Barman, RSC Adv. 6 (2016) 18929–
18935.
Acknowledgments
[14] Representative experimental procedure: indole (70 mg, 0.60 mmol) and
thiosulfonate QSO2SEt (159 mg, 0.63 mmol) were vigorously stirred in
dichloromethane (3 mL) and hydrated zinc chloride (159 mg, 0.63 mmol)
was added. After stirring for 18 h at rt, the reaction mixture was diluted and
filtered through a short plug of silica gel. After removal of the solvent, 3-
(ethylthio)indole (93 mg, purity > 90% by NMR spectroscopy) was isolated
after filtration through a short plug of silica gel as a brownish powder (88%
yield).
EG thanks I. Martin for her help, and Pr. H. Dhimane (UMR
8601) for useful discussions.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152748.
[15] D.P. Gamblin, P. Garnier, S.J. Ward, N.J. Oldham, A.J. Fairbanks, B.G. Davis, Org.
Biomol. Chem. 1 (2003) 3642–3644.
3