Iron(III) chloride: A versatile catalyst for the practical synthesis of 3-sulfenylindoles

Article abstract of DOI:10.1055/s-0028-1088035

The direct sulfenylation of indoles with aromatic thiols has been accomplished in the presence of 20 mol% of FeCl₃ in refluxing acetonitrile to produce 3-arylthioindoles in relatively good to excellent yields and with high selectivity. This met

Full text of DOI:10.1055/s-0028-1088035

1520
PAPER
Iron(III) Chloride: A Versatile Catalyst for the Practical Synthesis of
3-Sulfenylindoles
F
eCl3-Cath
a
lyzed Synth
i
e
sis of
l
3-Sulfe
l
nylind
uoles S. Yadav,* Basi V. Subba Reddy, Yerabolu Jayasudhan Reddy, Karanam Praneeth
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 15 December 2008; revised 29 December 2008
etc.9 Moreover, iron salts are inexpensive, easy to handle,
and are environmentally friendly.
Abstract: The direct sulfenylation of indoles with aromatic thiols
has been accomplished in the presence of 20 mol% of FeCl3 in re-
fluxing acetonitrile to produce 3-arylthioindoles in relatively good
to excellent yields and with high selectivity. This method works
even with 2-unsubstituted indoles.
In this article, we report a direct FeCl3-catalyzed selective
sulfenylation of indoles at the 3-position with aromatic
thiols. We first attempted the coupling of indole (1) with
thiophenol (2) using 20 mol% anhydrous FeCl3 in aceto-
nitrile. The reaction was sluggish at room temperature but
went to completion in six hours at reflux temperature giv-
ing product 3a in 89% yield (Scheme 1).
Key words: thiolation, indoles, thiols, 3-arylthioindoles
The selective introduction of C–S bond into organic mol-
ecules, in particular in heterocycles, has played significant
role in medicinal chemistry.1 Specifically, 3-thiolated in-
doles are popular for their activity towards the treatment
of HIV, obesity, cancer, heart diseases, and allergies.2
Generally, 3-arylthioindoles are prepared via electrophilic
substitution of indoles with thiols. A catalytic method has
been reported for substitution of indole at the 3-position
with disulfide using AlCl3 as a catalyst, but harsh reaction
conditions are required and the reported yields of 3-sulfe-
nylindoles are relatively low.3a Also heterogeneous vana-
dium-catalyzed synthesis of 3-sulfenylindoles from
indoles and thiols has been reported, but yields are quite
low.3b However, these methods are limited to 2-substitut-
ed indoles only. The direct 3-arylthiolation of indoles has
been reported using various sulfenylating agents such as
disulfides, sulfenyl halides, quinone mono-O,S-acetals,
N-thioarylphthalimides, and by intramolecular capture of
sulfides in Pummerer Reaction.4–6 Various reagents such
as N-chlorosuccinamide, phenyliodine(III) bistrifluoro-
acetate, and transition metal catalysts have been utilized
for the activation of thiols under mild conditions.7,8 How-
ever, most of these methods require additional steps to
prepare activated thiols. Therefore, the development of a
simple, convenient, and general methodology for the
sulfenylation of indoles utilizing stable and eco-friendly
catalysts are desirable to introduce C–S functionality that
would extend the scope of this reaction for the discovery
of new selective COX-2 inhibitors.8
S
SH
FeCl3
+
N
H
MeCN
reflux
N
H
1
2
3a: 89%
Scheme 1
This result provided incentive for further study of reac-
tions with various indoles and thiols. Interestingly, substi-
tuted indoles such as 5-bromo-, 5-methoxy-, 7-ethyl-, and
2-methylindole, reacted rapidly with a range of thiols to
afford the corresponding 3-arylthioindole derivatives
(Table 1, entries b–e). Furthermore, this method worked
equally well with sterically hindered thionaphthol and
mercaptobenzothiazole (Table 1, entries n and o). In addi-
tion, N-benzylindole also participated well at room tem-
perature (Table 1, entries f and i). In all cases, the products
were 3-sulfenylindoles as confirmed by 1H NMR spectra.
1
The products were characterized by H NMR, IR, and
mass spectroscopy and also by comparison with authentic
samples.1,6,7 The advantages of this procedure include
milder conditions than when using corrosive chlorine or
sulfuryl chloride, as well as high conversions, and easy
workup. This method is effective even with unprotected
indoles. There was no considerable difference in yields
when comparing protected and unprotected indoles. Un-
like reported methods, no bis-sulfenylation was observed
in this reaction. This method also avoids the formation of
one equivalent of thiol waste that occurs when using a di-
sulfide as the electrophilic sulfur source. No chlorination
of indole was observed under the reaction conditions. In
most cases, the products were obtained in good to excel-
lent yields with high degree of regioselectively. As sol-
vent, acetonitrile appeared to give the best results. The
effects of various Lewis acids such as InCl3, InBr3, BiCl3,
YbCl3, YCl3, and CeCl3·7H2O were studied for this con-
Iron is one of the most abundant transition metals and its
salts, in particular anhydrous FeCl3, is used as a powerful
Lewis acid catalyst in organic synthesis. It is quite effi-
cient in generating carbon–carbon and carbon–heteroat-
om bonds by additions, substitutions, and rearrangements,
SYNTHESIS 2009, No. 9, pp 1520–1524
x
x
.
x
x
.2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088035; Art ID: Z27808SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
FeCl3-Catalyzed Synthesis of 3-Sulfenylindoles
1521
version. Of these catalysts, anhydrous FeCl3 was found to spect to various indoles and thiols and the results are pre-
be effective in terms of conversion. In the absence of cat- sented in the Table 1.
alyst, the reaction failed to give the desired product. The
scope and generality of this process is illustrated with re-
Table 1 Synthesis of 3-Sulfenylindoles Using Anhydrous FeCl3
Entry
Indole 1
Thiol 2
Product 3a
Time (h)
6.0
Yield (%)b
S
a
89
SH
N
H
N
H
Br
S
b
c
6.0
6.0
85
92
Br
SH
SH
N
H
N
H
MeO
S
MeO
N
H
N
H
Br
S
d
e
f
6.0
6.0
6.0
89
90
86
Br
SH
N
H
N
Et
H
Et
S
SH
SH
N
H
N
H
S
N
N
Ph
Ph
Cl
S
g
6.0
6.0
89
92
N
H
N
H
Cl
MeO
S
h
MeO
N
H
N
H
Cl
S
i
6.0
85
N
N
Ph
Ph
Synthesis 2009, No. 9, 1520–1524 © Thieme Stuttgart · New York

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J. S. Yadav et al.
PAPER
Table 1 Synthesis of 3-Sulfenylindoles Using Anhydrous FeCl3 (continued)
Entry
Indole 1
Thiol 2
Product 3a
Time (h)
6.0
Yield (%)b
S
j
89
SH
N
H
N
Et
H
Et
S
k
l
6.0
6.0
6.0
7.0
91
90
87
84
N
H
N
H
Cl
S
N
H
N
H
S
m
n
N
H
o
p
q
7.0
6.0
7.0
82
80
82
a All products were characterized by 1H NMR, IR, and mass spectroscopy.
b Yield refers to pure products after chromatography.
In summary, anhydrous FeCl3 has proved to be a useful readily available FeCl3 makes this method simple, conve-
and highly efficient catalyst for the sulfenylation of in- nient, cost-effective, and practical.
doles at the 3-position under mild conditions. In addition
to its simplicity and efficiency, this method produces 3-
Melting points were recorded on Büchi R-535 apparatus and are un-
sufenylindoles in excellent yields in reasonable reaction
times. This method provides an easy access to a wide
range of potentially valuable 3-sulfenylindoles. The use of
corrected. IR spectra were recorded on a Perkin-Elmer FT-IR 240-c
spectrophotometer using KBr optics. 1H NMR spectra were record-
ed on Varian Unity 300 spectrometer in CDCl3 using TMS as inter-
Synthesis 2009, No. 9, 1520–1524 © Thieme Stuttgart · New York

PAPER
FeCl3-Catalyzed Synthesis of 3-Sulfenylindoles
1523
nal standard. Mass spectra were recorded on a Finnigan MAT 1020
mass spectrometer operating at 70 eV.
1H NMR (200 MHz, CDCl3): d = 6.80–7.69 (m, 15 H), 5.15–5.52
(m, 2 H).
LC-MS: m/z = 315 (M+).
3-Sulfenylindoles; 3-(Phenylthio)-1H-indole (3a); Typical Pro-
cedure
3-(4-Chlorophenylthio)-1H-indole (3g)
A mixture of indole (1; 117 mg, 1 mmol), thiophenol (2; 110 mg, 1
mmol) and anhyd FeCl3 (32 mg, 20 mol%) in MeCN (5 mL) was
stirred at 80 °C for the appropriate time (Table 1). After complete
conversion as indicated by TLC, the reaction mixture was quenched
with H2O (15 mL) and extracted with CH2Cl2 (2 × 15 mL). The
combined extracts were dried (Na2SO4) and concentrated in vacuo.
The resulting crude product was purified by column chromatogra-
phy on silica gel (Merck, 100–200 mesh, EtOAc–hexane, 1:9) to af-
ford pure 3a; yield: 200 mg (89%); liquid.
Pale brownish solid; mp 126–130 °C.
IR (KBr): 3403, 2923, 1640, 1505, 1473, 1452, 1090, 1008, 811,
745 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.33 (br s, 1 H), 7.32–7.58 (m, 4
H), 6.89–7.20 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 100.6, 111.5, 119.5, 121.1, 123.4,
127.5, 128.7, 130.6.
LC-MS: m/z (%) = 260 (M + H, 45), 161 (100), 177 (30), 169 (20),
149 (15), 117 (10), 101 (5).
IR (neat): 3405, 3051, 2923, 2853, 1738, 1754, 1574, 1455, 1335,
1234, 1087, 741 cm–1.
HRMS: m/z calcd for C14H10ClNS: 259.0144; found: 259.0141.
1H NMR (300 MHz, CDCl3): d = 8.30 (br s, 1 H), 6.85–7.72 (m, 10
H).
3-(4-Chlorophenylthio)-5-methoxy-1H-indole (3h)
Pale brownish solid; mp 97–105 °C.
LC-MS: m/z = 248 (M + Na).
IR (KBr): 3406, 2922, 2852, 1632, 1581, 1475, 1285, 1206, 1090,
1030, 813 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.36 (br s, 1 H), 7.41 (s, 1 H),
7.20–7.33 (m, 2 H), 7.02–7.18 (m, 1 H), 6.77–7.03 (m, 4 H), 3.78
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 47.2, 99.3, 101.5, 106.5, 109.5,
125.7, 125.9, 126.0, 126.8, 128.0, 128.1, 128.2, 155.2.
5-Bromo-3-(phenylthio)-1H-indole (3b)
Brown solid; mp 109–111 °C.
IR (KBr): 3413, 2923, 2853, 1713, 1454, 739 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.43 (br s, 1 H), 7.71 (s, 1 H), 7.44
(d, J = 8.1 Hz, 1 H), 7.21–7.34 (m, 2 H), 7.11–7.18 (m, 2 H), 6.99–
7.06 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 137.2, 136.5, 132.8, 129.0, 128.3,
128.6, 126.5, 123.9, 120.7, 117.2, 106.3, 101.4.
LC-MS: m/z (%) = 289 (M+, 30), 279 (20), 257 (10), 197 (20), 169
(15), 147 (100), 117 (10).
LC-MS: m/z = 305 (M + H).
HRMS: m/z calcd for C15H12ClNOS: 289.0249; found: 289.0250.
5-Methoxy-3-(phenylthio)-1H-indole (3c)
Liquid.
1-Benzyl-3-(4-chlorophenylthio)-1H-indole (3i)
Liquid.
IR (neat): 2923, 2853, 1690, 106, 1458, 739, 696 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.14–5.36 (m, 2 H), 6.57–7.64 (m,
14 H).
IR (neat): 3410, 3057, 2924, 2853, 1720, 1623, 1581, 1480, 1285,
1207, 1167, 1028, 741 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.28 (br s, 1 H), 7.43 (d, J = 2.2
Hz, 1 H), 7.27–7.33 (m, 1 H), 7.12–7.22 (m, 2 H), 6.96–7.11 (m, 4
H), 6.90 (dd, J = 2.2, 8.0 Hz, 1 H), 3.80 (s, 3 H).
LC-MS: m/z = 350 (M + H).
LC-MS: m/z (%) = 256 (87, M + H,), 245 (55), 229 (75), 220 (77),
181 (100), 172 (172).
7-Ethyl-3-(phenylthio)-1H-indole (3j)
Liquid.
IR (neat): 3414, 2959, 2926, 2856, 1758, 1586, 1469, 1380, 1214,
1112, 755 cm–1.
3-[(4-Bromophenyl)sulfanyl]-7-ethyl-1H-indole (3d)
Brown solid; mp 125–127 °C.
1H NMR (300 MHz, CDCl3): d = 8.27 (br s, 1 H), 7.41 (m, 2 H),
6.94–7.20 (m, 7 H), 2.89 (q, J = 7.5 Hz, 2 H), 1.41 (t, J = 7.5 Hz, 3
IR (KBr): 3412, 2961, 2923, 2852, 1716, 1470, 1006, 809, 749
cm–1.
H).
1H NMR (300 MHz, CDCl3): d = 8.31 (br s, 1 H), 6.86–7.48 (m, 8
H), 2.89 (q, J = 7.5 Hz, 2 H), 1.41 (t, J = 7.5 Hz, 3 H).
LC-MS: m/z = 254 (M + H).
LC-MS: m/z = 333 (M + H).
2-Methyl-3-(p-tolylthio)-1H-indole (3k)
Liquid.
2-Methyl-3-(phenylthio)-1H-indole (3e)
IR (KBr): 3395, 2924, 2854, 1735, 1626, 1456, 1220, 1082, 1019,
803, 764 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.20 (br s, 1 H), 7.44–7.55 (m, 1
H), 7.20–7.29 (m, 1 H), 6.99–7.17 (m, 2 H), 6.83–6.96 (m, 4 H),
2.50 (s, 3 H), 2.24 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 12.1, 20.7, 100.0, 110.5, 119.0,
120.6, 122.1, 125.8, 129.4, 130.3, 135.4, 135.6, 140.8.
Semi-solid.
IR (neat): 3399, 3053, 2922, 2853, 1581, 1541, 1477, 1455, 1403,
1290, 1224, 1078, 1022, 783 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12 (br s, 1 H), 7.50 (d, J = 8.1
Hz 1 H), 7.20–7.33 (m, 1 H), 6.89–7.19 (m, 7 H), 2.51 (s, 3 H).
LC-MS: m/z = 240 (M + H).
LC-MS: m/z (%) = 254 (M + H, 100), 175 (40), 140 (20).
HRMS: m/z calcd for C16H16NS: 254.1003; found: 254.1011.
1-Benzyl-3-(phenylthio)-1H-indole (3f)
Liquid.
IR (neat): 3029, 2923, 2853, 1690, 1606, 1578, 1458, 1303, 1224,
1179, 748 cm–1.
3-(4-Chlorophenylthio)-2-methyl-1H-indole (3l)
Liquid.
Synthesis 2009, No. 9, 1520–1524 © Thieme Stuttgart · New York

1524
J. S. Yadav et al.
PAPER
IR (KBr): 3393, 2920, 2851, 1576, 1542, 1473, 1455, 1088, 1009,
814, 745 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.20 (br s, 1 H), 7.44–7.55 (m, 1
H), 7.02–7.32 (m, 5 H), 6.86–6.99 (m, 2 H), 2.50 (s, 3 H).
Acknowledgment
Y.J.R. and K.P. thank CSIR, New Delhi for the award of a fel-
lowship.
13C NMR (75 MHz, CDCl3): d = 12.1, 99.1, 110.7, 118.8, 120.8,
122.3, 126.7, 128.7, 130.0, 130.3, 135.4, 137.9, 141.1.
References
LC-MS: m/z (%) = 274 (M + H, 100), 260 (50), 206 (35), 132 (20),
120 (10).
(1) (a) Avis, I.; Martinez, A.; Tauler, J.; Zudaire, E.; Mayburd,
A.; 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. (c) Funk, C. D. Nat. Rev. Drug
Discov. 2005, 4, 664. (d) Khandekar, S. S.; Gentry, D. R.;
Van Aller, G. S.; Doyle, M. L.; Chambers, P. A.;
Konstantinidis, A. K.; Brandt, M.; Daines, R. A.; Lonsdale,
J. T. J. Biol. Chem. 2001, 276, 30024.
HRMS: m/z calcd for C15H13ClNS: 274.0457; found: 274.0459.
3-(p-Tolylthio)-1H-indole (3m)
White solid; mp 123–125 °C.
IR (KBr): 3401, 2920, 2851, 1717, 1461, 722 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.30 (br s, 1 H), 6.87–7.69 (m, 9
H), 2.25 (s, 3 H).
(2) (a) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.;
Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.;
Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’Brien,
J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.;
Anderson, P. S. J. Med. Chem. 1993, 36, 1291.
13C NMR (75 MHz, CDCl3): d = 138.9, 138.4, 136.3, 130.7, 129.0,
128.6, 126.4, 125.7, 122.9, 120.8, 119.5, 111.6, 102.6, 21.3.
LC-MS: m/z = 240 (M + H).
3-(2-Naphthylsulfanyl)-1H-indole (3n)
Solid; mp 175–177 °C.
IR (KBr): 3410, 2923, 1780, 1732, 1478, 741 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.35 (br s, 1 H), 7.05–7.96 (m,
12 H).
13C NMR (75 MHz, CDCl3): d = 130.3, 128.3, 127.67, 127.0, 127.5,
126.7, 126.2, 125.7, 125.0, 124.8, 123.6, 123.2, 121.1, 120.0, 111.5,
96.2.
(b) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.;
Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.;
La Colla, P. J. Med. Chem. 2003, 46, 2482 . (c) Hamel, P.
J. Org. Chem. 2002, 67, 2854.
(3) (a) Ranken, P. F.; McKinnie, B. G. J. Org. Chem. 1989, 54,
2985. (b) Maeda, Y.; Koyabu, M.; Nishimura, T.; Uemura,
S. J. Org. Chem. 2004, 69, 7688.
(4) (a) Atkinson, J. G.; Hamel, P.; Girard, Y. Synthesis 1988,
480. (b) Scoffone, E.; Fontana, A.; Rocchi, R. Biochemistry
1968, 7, 971. (c) Anzai, K. J. Heterocycl. Chem. 1979, 16,
567.
LC-MS: m/z = 276 (M + H).
(5) (a) Raban, M.; Chern, L. J. Org. Chem. 1980, 45, 1688.
(b) Ranken, P. F.; McKinnie, B. G. J. Org. Chem. 1989, 54,
2985. (c) Browder, C. C.; Mitchell, M. O.; Smith, R. L.;
El-Sulayman, G. Tetrahedron Lett. 1993, 34, 6245.
(6) (a) Matsugi, M.; Murata, K.; Gotanda, K.; Nambu, H.;
Anilkumar, G.; Matsumoto, K.; Kita, Y. J. Org. Chem. 2001,
66, 2434. (b) Tudge, M.; Tamiya, M.; Savarin, C.;
Humphrey, G. R. Org. Lett. 2006, 8, 565. (c) Horiguchi, Y.;
Sonobe, A.; Saitoh, K.; Toda, J.; Sano, T. Chem. Pharm.
Bull. .
2-(2-Methyl-1H-indol-3-ylthio)benzo[d]thiazole (3o)
White solid; mp 165–168 °C.
IR (KBr): 3638, 3212, 2922, 1663, 1544, 1454, 1426, 1229, 981,
747 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.44 (br s, 1 H), 7.85 (d, J =
8.3 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H),
7.32–7.40 (m, 2 H), 7.14–7.37 (m, 3 H), 2.65 (s, 3 H).
LC-MS: m/z = 297 (M + H).
(7) Schlosser, K. M.; Krasutsky, A. P.; Hamilton, H. W.; Reed,
J. E.; Sexton, K. Org. Lett. 2004, 6, 819.
(8) (a) Maeda, Y.; Koyabu, M.; Nishimura, T.; Uemura, S.
J. Org. Chem. 2004, 69, 7688. (b) Campbell, J. A.; Broka,
C. A.; Gong, L.; Walker, K. A. M.; Wang, J.-H. Tetrahedron
Lett. 2004, 45, 4073.
3-(Benzylsulfanyl)-2-methyl-1H-indole (3p)
Liquid.
IR (neat): 3405, 2922, 2853, 1632, 1452, 745 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.86 (br s, 1 H), 7.56–7.84 (m, 1
H), 7.06–7.24 (m, 6 H), 6.86–6.94 (m, 2 H), 3.70 (s, 3 H).
(9) (a) Bolm, C.; Legros, J.; Paiti, J. L.; Zani, L. Chem. Rev.
2004, 104, 6217. (b) Ruping, M.; Nactshim, B. J.; Scheidt,
T. Org. Lett. 2006, 8, 3717. (c) Komeyma, K.; Morimoto,
T.; Takaki, K. Angew. Chem. Int. Ed. 2006, 45, 2938.
(d) Kischel, J.; Jovel, I.; Mertins, K.; Zapf, A.; Beller, M.
Org. Lett. 2006, 8, 19. (e) Diaz, D. D.; Miranda, P. O.;
Padron, J. I.; Martin, V. S. Curr. Org. Chem. 2006, 10, 457.
(f) Iovel, I.; Kristin, M.; Kischel, J.; Zapf, A.; Mathias, B.
Angew. Chem. Int. Ed. 2005, 44, 3913.
LC-MS: m/z = 254 (M + H).
3-(4-Chlorophenylthio)-2-phenyl-1H-indole (3q)
Liquid.
IR (neat): 3420, 2928, 1719, 1457, 1221, 756 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.48 (br s, 1 H), 7.70 (d, J = 7.9
Hz, 2 H), 7.55 (d, J = 7.9 Hz, 1 H), 7.31–7.48 (m, 5 H), 7.04–7.20
(m, 3 H), 6.98 (d, J = 8.0 Hz, 2 H).
LC-MS: m/z = 336 (M + H).
Synthesis 2009, No. 9, 1520–1524 © Thieme Stuttgart · New York