The use of anhydrous CeCl3 as a catalyst for the synthesis of 3-sulfenyl indoles

Article abstract of DOI:10.1016/j.tetlet.2010.02.038

Anhydrous CeCl₃ was successfully used as a catalyst for the synthesis of several 3-sulfenyl indoles in good to excellent yields through the reaction of indole with N-(alkylthio) and N-(arylthio)phthalimides in DMF.

Full text of DOI:10.1016/j.tetlet.2010.02.038

Tetrahedron Letters 51 (2010) 2014–2016
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The use of anhydrous CeCl3 as a catalyst for the synthesis of 3-sulfenyl indoles
*
Claudio C. Silveira , Samuel R. Mendes, Lucas Wolf, Guilherme M. Martins
Departamento de Química, Universidade Federal de Santa Maria, UFSM, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Anhydrous CeCl3 was successfully used as a catalyst for the synthesis of several 3-sulfenyl indoles in good
to excellent yields through the reaction of indole with N-(alkylthio) and N-(arylthio)phthalimides in DMF.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 November 2009
Revised 3 February 2010
Accepted 5 February 2010
Available online 11 February 2010
Keywords:
Indole
3-Sulfenyl indoles
Cerium(III) chloride
1. Introduction
O
N SR
SR
Indole and its derivatives are widely present in bioactive
metabolites of numerous compounds isolated from natural
sources.1 Sulfenyl indoles are an important class of compounds
due to their activity towards the treatment of several diseases,
such as bacterial infection, HIV, obesity, heart diseases, and aller-
gies.2 They are also very useful as COX-2 inhibitors in medicinal
chemistry3 and potent inhibitors of tubulin polymerization.4
Several approaches for the preparation of 3-sulfenyl indoles
were described in the recent years. Most of methods are based
on electrophilic aromatic sulfenylation reaction.5 Nucleophilic sub-
stitution on the indole system6 and electrophilic sulfur cyclization7
are also known. However, major drawbacks are still present such
as accessibility, substrate compatibility, and stability of these re-
agents. Hence, a mild general approach for the 3-arylthiolation of
indoles is still necessary.
Cerium chloride has emerged as a very useful Lewis acid
imparting high regio- and chemoselectivity in various chemical
transformations over the past few years, as a cheap, nontoxic,
and water-tolerant catalyst. It has been used in several different
forms, such as heptahydrate, anhydrous, and in combination with
NaI.8 In view of our interest in the development of new, cleaner
methods for classical reactions promoted by cerium(III) species
and in the organosulfur chemistry,9 we decide to study the electro-
philic substitution reaction of indoles 1 with N-(alkylthio) and N-
(arylthio)phthalimides 2 to obtain 3-sulfenyl indoles 3 (Scheme
1, Tables 1 and 2).
X1
X2
X1
X2
2 a-d
O
10 mol% CeCl3,
DMF, 70 °C, Ar
N
H
N
H
1 a-c
X1= H, Br
X2= H, MeO
3 a- j
R= Ph, 4-MeOC6H4,
4-ClC6H4, C12H25
Scheme 1.
Table 1
Optimization of conversion of 1a–3aa
Entry
Solvent
CeCl3 (equiv)
Temp (°C)
Time (h)
Yield (%)
43
1
2
3
4
5
6
7
8
9
MeCN
CH2Cl2
DMA
DMF
NMP
DMF
DMF
DMF
DMF
DMF
0.1
0.1
0.1
0.1
0.1
0.05
0.2
0.1
0.1
0.1c
Reflux
Reflux
70
70
70
70
70
rt
90
4
4
3
3
3
3
3
10
3
3
b
–
68
88
73
79
88
21
88
61
10
70
a
Reaction conditions: indole (1a, 1.0 mmol); N-(phenylthio)phthalimide (2a,
1.1 mmol).
b
No reaction.
c
Reaction performed with CeCl3Á7H2O.
2. Results and discussion
Initially, we chose indole (1a) and the commercially available
N-(phenylthio)phthalimide (2a) as starting materials to establish
* Corresponding author. Tel./fax: +55 55 220 8754.
E-mail address: silveira@quimica.ufsm.br (C.C. Silveira).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.038

C. C. Silveira et al. / Tetrahedron Letters 51 (2010) 2014–2016
2015
Table 2
Synthesis of 3-sulfenyl indoles 3
Entry
Indoles 1
R
Product 3
Time (h)
3.0
Yielda (%)
S
S
N
H
1
Ph
88
93
1a
N
H
3a
3b
Cl
2
1a
4-ClC6H4
4.0
N
H
S
S
OMe
3
4
5
1a
4-MeOC6H4
C12H25
Ph
2.0
3.5
3.0
90
80
95
N
H
3c
C12H25
1a
N
H
3d
Br
S
Br
Br
Br
N
H
1b
N
3e
H
S
Cl
6
7
1b
4-ClC6H4
4-MeOC6H4
Ph
4.0
3.5
2.0
1.5
4.0
95b
90b
87
N
3f
H
S
OMe
1b
N
3g
H
S
N
H
MeO
8
1c
N
MeO
MeO
MeO
3h
H
S
S
Cl
9
1c
1c
4-ClC6H4
4-MeOC6H4
88
N
H
3i
3j
OMe
10
81
N
H
a
Yields of pure products isolated by column chromatography (hexanes/AcOEt) and identified by mp, GC–MS, 1H and 13C NMR.
Reaction performed in DMA as the solvent.
b
the best conditions for the reaction. We examined the solvent,
amount of CeCl3, and the reaction temperature (Table 1). At first,
we found that by using 0.1 equiv of CeCl3, in MeCN, the 3-sulfenyl
indole (3a) was obtained in 43% yield after stirring under reflux for
4 h (Table 1, entry 1). We also used other solvents, such as dichlo-
romethane, DMF, DMA, and NMP (Table 1, entries 2–5). The best
yield was obtained when DMF was used as a solvent (88% isolated
yield; Table 1, entry 4). In a search for even higher yield, we re-
placed anhydrous CeCl3 by CeCl3Á7H2O; however, it was observed
a reduction in the yield to 61% (Table 1, entry 10). The effect of
the amount of the catalyst was also evaluated. When 0.05 equiv
of dry CeCl3 was used, 3a was obtained in 79% yield (Table 1, entry
O
N SPh
S
2a
O
10 mol% CeCl3,
DMF, 70 °C, Ar
N
R2
N
R2
3k R2 = Me (60%), 3l R2 = Ts (no reaction)
Scheme 2.
6). The use of larger amounts of CeCl3 had no effect on the yield of
reaction and the time to completion of reaction was the same (Ta-

2016
C. C. Silveira et al. / Tetrahedron Letters 51 (2010) 2014–2016
Silvestri, R.; De Martino, G.; La Regina, G.; Ártico, M.; Massa, S.; Vargiu, L.;
Mura, M.; Loi, A. G.; Marceddu, T.; La Colla, P. J. Med. Chem. 2003, 46, 2482; (d)
Avis, I.; Martinez, A.; Tauler, J.; Zudaine, E.; Mayburd, A.; Abu-Ghazaleh, R.;
Obndrey, F.; Mulshine, J. L. Cancer Res. 2005, 65, 4181; (e) Funk, C. D. Nat. Rev.
Drug Disc. 2005, 4, 664.
ble 1, entry 7). Finally, the reaction was performed at both 90 °C
and room temperature. The reaction carried out at 90 °C led to
the formation of the desired product in very similar yield to
70 °C. By contrast, a significant decrease in the yield of 3-sulfenyl
indole was observed when the reaction was performed at room
temperature, even after long reaction time (Table 1, entry 8).
Since the best conditions were established (Table 1, entry 4), the
protocol was extended to other N-(alkylthio) and N-(aryl-
thio)phthalimides,11 reacting with indole, 5-bromoindole and 6-
methoxyindole (Table 2, Scheme 1).12 For all the studied examples,
the 3-sulfenyl indoles 3 were obtained in good to excellent yields
after stirring at 70 °C for 1.5–4.0 h (Table 2). When 5-bromo-1H-in-
dole (1b) was used, the respective brominated products were ob-
tained in slightly higher yields, compared to 1a (Table 2, entries
5–7). However, when 5-methoxy-1H-indole (1c) was used, the in-
dole derivatives were obtained in slightly lower yields, compared
to 1a and 1b (Table 2, entries 8–10). The N-(dodecylthio)phthali-
mide (2d) reacted with indole 1a under the established standard
condition to afford, after 3.5 h, 3-(dodecylthio)-1H-indole (3d) in
80% yield (Table 2, entry 4).
It is worth mentioning that the indole nitrogen need not be pro-
tected. In fact, when the reaction was performed with 1-methyl-
1H-indole and N-(phenylthio)phthalimide (2a) the corresponding
product 3k was obtained in 60% yield after 5 h, and no reaction
was observed when 1-tosyl-1H-indole was used even after several
hours of reaction (Scheme 2).
In conclusion, we have been able to show that CeCl3 is an effec-
tive catalyst for the synthesis of 3-sulfenyl indoles. The method is
simple and general for the reaction of N-(arylthio)phthalimides
with indoles.
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Brancale, A.; Wilcox, E.; Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2004, 47,
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8. (a) Sabitha, G.; Yadav, J. S. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley-VCH: Weinheim, 2006; (b) Bartoli, G.; Di Antonio, G.;
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Vidal, V.; Genêt, J. P.; Zhang, Z. J. Org. Chem. 2008, 73, 3842.
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11. The N-(thio)phthalimides 2b–d were prepared according to: Gillis, H. M.;
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12. General procedure for the synthesis of 3-sulfenyl indoles: To a mixture of DMF
(5 mL), indole (1, 1.0 mmol), and N-thioalkyl or N-thioarylphthalimides (2,
1.1 mmol), under Ar, was added dry CeCl3 (0.0246 g, 0.1 mmol) at room
temperature. The reaction mixture was followed by TLC and stirred at 70 °C for
the time indicated on Table 2 and cooled to rt. Water (20 mL) was added and
the mixture extracted with ethyl acetate (3 Â 10 mL). The organic phase was
washed with water, aqueous 2% NaOH solution, and then brine and dried over
anhydrous MgSO4. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography on silica gel (ethyl acetate–
hexanes, 5:95) to afford pure products (3a–j). Spectral data of selected
compounds: 3a mp 152–154 °C (lit.10 151–153 °C). 1H NMR (400 MHz, CDCl3):
d = 8.34 (br s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.41 (d,
J = 8.0 Hz, 1H), 7.27–7.23 (m, 1H), 7.17–7.03 (m, 6H). 13C NMR (100 MHz,
CDCl3): d = 139.17, 136.42, 130.67, 129.04, 128.66, 125.76, 124,73, 123.01,
120.87, 119.62, 111.56, 102.70. MS: m/z (%) = 225 (M+, 100), 193 (25), 165 (13),
148 (15), 112 (10), 77 (13); 3b mp 127–129 °C (lit.3a 127.5–128.3 °C). 1H NMR
(400 MHz, CDCl3): d = 8.36 (br s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 2.6 Hz,
1H), 7.41 (d, J = 8.0 Hz, 1H), 7.28–7.24 (m, 1H), 7.18–7.14 (m, 1H), 7.10 (d,
J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): d = 137.81,
136.51, 130.65, 128.73 (2C), 127.12 (2C), 123.21, 121.05, 119.51, 111.63,
102.52. MS: m/z (%) = 259 (M+, 100), 224 (55), 148 (22), 112 (39), 77 (16).
Acknowledgments
This project is funded by MCT/CNPq, CAPES and FAPERGS.
References and notes
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