Efficient synthesis of 3-selanyl- and 3-sulfanylindoles employing trichloroisocyanuric acid and dichalcogenides

Article abstract of DOI:10.1016/j.tet.2012.09.022

3-Arylselanyl- and 3-arylsulfanylindoles were prepared in EtOAc, by the reaction of indole with the diaryl dichalcogenide-trichloroisocyanuric acid (TCCA) reagent system. The products were efficiently and conveniently obtained, at room temperature and in

Full text of DOI:10.1016/j.tet.2012.09.022

Tetrahedron 68 (2012) 10464e10469
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of 3-selanyl- and 3-sulfanylindoles employing
trichloroisocyanuric acid and dichalcogenides
,
b
a
a
a
Claudio C. Silveira a , Samuel R. Mendes , Lucas Wolf , Guilherme M. Martins , Lisandro von Muhlen
*
€
a Departamento de Química, Universidade Federal de Santa Maria, UFSM, 97105-900 Santa Maria, RS, Brazil
b GAPAM, Departamento de Química, Universidade do Estado de Santa Catarina, 89219-719 Joinville, SC, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2012
Received in revised form 27 August 2012
Accepted 4 September 2012
Available online 20 September 2012
3-Arylselanyl- and 3-arylsulfanylindoles were prepared in EtOAc, by the reaction of indole with the diaryl
dichalcogenideetrichloroisocyanuric acid (TCCA) reagent system. The products were efficiently and
conveniently obtained, at room temperature and in short reaction times.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Arylchalcogenides
TCCA
Antitumor activity
1. Introduction
In view of our interest in the development of new methods for
the synthesis of organochalcogenium compounds,14 and consider-
Substituted indoles constitute a permanent focus of scientific
interest because the indole ring is an important structural unit
found in numerous biologically active natural products and phar-
maceutical agents1 and several indole derivatives are known to
have therapeutic value.2
ing our recent results on the synthesis of sulfenyl indoles,15 we
decided to explore the synthesis of 3-chalcogenylindoles (5aen) by
the electrophilic substitution reaction of indoles (3aed) with the
diaryl dichalcogenideeTCCA reagent system (Scheme 1).
MeO
OMe
t-Bu
Some 3-arylthioindoles were shown to act on specific targets,
which in recent years have attracted the attention of researchers.3
For example, compound 1, is a powerful inhibitor of tubulin poly-
merization,4 which inhibits the growth of certain breast cancer
cells.5 On the other hand, compound 2 (MK-886) is an inhibitor of
5-lipoxygenase, which may increase the antitumor activity of cel-
ecoxib in human colorectal cancer.6
i-Pr
S
Me
Me
COOH
MeO
Br
N
S
OMe
N
H
Cl
O
Analogously, organoselenium compounds are bioactive7 and
potentially useful as valuable synthetic intermediates.8 However,
there is a lack of general methods for the preparation of 3-
chalcogenylindoles, suitable for the use of indoles as starting
material8b,9 (Fig. 1).
1
2
Fig. 1. Some bioactive 3-arylthioindoles.
Trichloroisocyanuric acid (TCCA) is a stable and inexpensive
solid, frequently found in commercial products for swimming-pool
disinfection,10 which has been widely used in organic synthesis.
Recent examples of its application include oxidation11 and halo-
genation12 reactions as well as key steps during total synthesis
sequences.13
XAr
R3
TCCA, ArX-XAr
R3
X= S, Se
R1
R1
N
N
R2
R2
3
5
Scheme 1.
* Corresponding author. E-mail address: silveira@quimica.ufsm.br (C.C. Silveira).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.022

C.C. Silveira et al. / Tetrahedron 68 (2012) 10464e10469
10465
2. Results and discussion
its congeners (entries 7e9). The beneficial effect of MgO can be
observed even for the N-methylindole 3c. In the absence of MgO
the yield of compound 5g was reduced to 55%.
In view of the characteristics of the new method, which uses the
odorlessdiselenidesand TCCAas a highlyconvenient reagent system
for the generation of electrophilic arylselenide species, the method
was extended tothe corresponding sulfurderivatives, employingthe
same procedure. Luckily, the transformation exhibited similar be-
havior, since the 3-sulfenylindoles 5jel were obtained in 72e85%
isolated yield (entries 10e12), in very fast reactions.
Initially, indole (3a) and diphenyl diselenide (4a, 1.2 equiv) were
chosen as starting materials to establish the optimum reaction
conditions, and the effects of the solvent, amount of TCCA, and
reaction temperature on the efficiency of the transformation were
evaluated (Table 1). MeOH, DCE, EtOAc, and H2O were tested as
potential solvents (entries 1e4), finding that a reasonable yield of
5a (45%) was obtained in EtOAc, after stirring the reagents with
3.0 equiv TCCA at room temperature for 15 min (entry 4).
The transformation also accepted 2-substituted indoles as sub-
strates. The sulfenylation of 2-methylindole, under the established
conditions, furnished almost instantaneously the 3-sulfur derivative
5n in 90% isolated yield, at room temperature. The corresponding
reaction with diphenyl diselenide followed a more complex path-
way, since a mixture of 3-selanyl-2-methylindole (minor) and 3-
chloro-2-methylindole (major) was obtained at room temperature.
However, at ꢁ78 ꢀC clean formation of the 3-selanyl derivative 5m
was observed (71% isolated yield) after 40 min.
Noteworthy, this widened the scope of the TCCA-based alter-
native because indole nitrogen protection is not required for
accessing the product and there is no significant difference in
product yields when comparing those resulting from protected and
unprotect indoles (Table 2).
GCeMS monitoring of the reaction revealed the quick formation
of PhSeCl and PhSCl, which were consumed during the reaction.
Therefore, it can be assumed that this is the actual active electro-
philic species in the reaction.
The transformation seems to be general, since reacting indoles
and TCCA (0.4 mmol; 1.2 equiv) in EtOAc, gave the corresponding
3-chloroindoles in unoptimized 47% yield. This compound is un-
stable and usually generated and used in situ.17 Under the same
conditions, 5-bromoindole furnished the corresponding 3-
chloroindole in 92% isolated yield. This procedure can be an al-
ternative for the preparation of 3-chloroindoles, which usually
employs corrosive and less convenient sources of chlorine, such as
Cl2 and SO2Cl2.17,18
The use of excess diaryl disulfides was also tested, resulting in
the known formation of 2,3-disubstituted disulfenyl indoles such as
5o (Scheme 2). Employing diphenyl sulfide (1.0 equiv) and TCCA
(0.8 equiv) in EtOAc, in the presence of MgO (1.0 equiv), 56% of 5o
was obtained after 5 h. TLC and GCeMS monitoring of the trans-
formation confirmed the formation of 3-(phenylthio)-1H-indole
(5j) as an intermediate. Therefore, 5j was employed as substrate
under similar conditions, affording an improved 90% yield of 5o
after 4.5 h. Unfortunately, however, under the same conditions,
a similar reaction with the corresponding selenium derivative was
unsuccessful.
Table 1
Optimization of the synthesis of 5a from indole (3a)a
SePh
TCCA, PhSe-SePh
Conditions
N
H
N
H
3a
5a
Entry no.
Solvent
TCCA
MgO
Temp
(ꢀC)
Time
(min)
Yieldb
(%)
(equiv)
(equiv)
1
2
3
4
5
6
7
8
MeOH
DCE
H2O
3.0
3.0
3.0
3.0
1.2
6.0
1.2
1.2
1.2
1.2
1.2
d
rt
rt
rt
rt
rt
rt
0
60
rt
rt
rt
15
15
15
15
15
15
15
15
4
10
18
d
d
d
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
d
45
56
32
21
49
63
81
80
d
d
d
d
9
10
11
0.5
1.0
2.0
5
4
a
The reaction was performed with indole (3a, 1.0 mmol) and diphenyl diselenide
(4a, 0.6 mmol); 1 mol of TCCA is capable of forming 3 mol of ArXCl.
b
Isolated yield.
In view of the convenience of use of this low toxicity solvent,
EtOAc was employed as solvent when the effect of the amount of
TCCA in the reaction was evaluated. Under these conditions, it was
observed that 1.2 equiv TCCA afforded 56% yield of 5a (entry 5),
while use of larger amounts of this reagent did not improve the
yields. Interestingly, however, it was observed that excess of TCCA
led to the formation of 3-chloro-1H-indole, being this side reaction
responsible for the decrease in the yields of the expected chalcogen
derivative product (entry 6).
The reaction was also performed at different temperatures,
observing that at 60 ꢀC the yields were similar to those obtained at
room temperature, while carrying out the transformation at 0 ꢀC
resulted in a significant decrease in product yield, even after long
reaction times (entry 7).
In general, it was detected that the products were formed in
a few minutes after mixing the reagents, and then no further
modification was observed, even after a long reaction time or by
adding an excess of TCCA or diaryl dichalcogenide.
Insearch ofimproved conditions, MgO (1.0 equiv) was tested as an
additive, taking into account that metal-oxides have been described
as convenient and practical bases that form strong metalenitrogen
bonds and thereby increase the nucleophilicity of the annular carbon
centers of the heteroarene.16 Under these new conditions, 81% of 5a
was obtained (entry 10); however, its yields could not be improved by
the use of larger amounts of MgO (entry 11).
Once the optimum reaction conditions were established, the
protocol was extended to other indoles (3aed) and diaryl dical-
chogenides (4aed). These afforded 3-chalcogenylindoles in good
yields after stirring at room temperature for 3e40 min (Table 2).
Interestingly, 5-bromo-1H-indole (3b) furnished slightly di-
minished yields of the corresponding indole derivatives (entries
4e6), while N-methyl-1H-indole (3c) comparatively outperformed
The mechanism of the C-3 substitution and the bis sulfenylation
at C-2 and C-3 was studied in detail and seems to be following the
mechanism shown in Scheme 2.19 The C-3 position of the indole
nucleus is very nucleophilic, allowing a nucleophilic substitution to
take place in the presence of the chalcogenyl halide, to form the
corresponding 3-arylchalcogenyl indole (Scheme 2).
In the case of sulfur derivatives, and in the presence of excess
arylsulfenyl chloride, this is followed by a second sulfenylation at
the 3-position, which leads to a 3,3-substituted indolinium in-
termediate. Subsequent migration of an arenesulfenyl moiety to the
C-2 position, yields the 2,3-bis(phenylthio)-1H-indole product.
Removal of the HCl formed during the reaction seems to be the key
role of MgO, the presence of which leads to greatly improved yields.
3. Conclusion
In conclusion, we have developed a convenient method for
the preparation of 3-selenyl- and 3-sulfenylindoles from the

10466
C.C. Silveira et al. / Tetrahedron 68 (2012) 10464e10469
Table 2
Synthesis of 3-chalcogenylindoles 5
R1
R1
XAr
R3
4a-c
MgO, TCCA, (ArX)2
EtOAc, rt
R3
N
N
R2
R2
5a-n
3a-d
R1 = H, Br
X
= Se, S
R2 = H, CH3
Ar = C6H5, p-CH3C6H4, p-ClC6H4
R3
= H, CH3
Entry no.
1
Indole (3)
X, Ar
Product (5)
Time (min)
5
Yielda (%)
81
Se
Se, C6H5
4a
N
H
3a
N
H
5a
Se
CH3
2
3
3a
Se, p-C6H4CH3
4b
3
7
81
74
5b
N
H
Se
Cl
3a
Se, p-C6H4Cl
4c
5c
N
H
Br
Br
Se
4
5
6
7
4a
4b
4c
4a
5
10
9
80
77
69
84
N
H
N
5d
3b
H
Br
Se
CH3
3b
3b
N
5e
H
Br
Se
Cl
5f
N
H
Se
7
N
5g
N
CH3
3c
CH3
Se
CH3
8
3c
4b
4c
12
82
5h
N
CH3
Se
Cl
9
3c
3a
17
5
79
75
5i
N
CH3
S
10
S, C6H5
4d
5j
N
H
Br
S
11
3b
4d
5
72
5k
N
H

C.C. Silveira et al. / Tetrahedron 68 (2012) 10464e10469
10467
Table 2 (continued )
Entry no.
Indole (3)
X, Ar
Product (5)
Time (min)
Yielda (%)
S
12
13
3c
4d
5
85
N
CH3
5l
Se
4a
4d
40
4
71b
CH3
N
H
CH3
N
3d
H
5m
S
14
3d
90
CH3
5n
N
H
a
Yields of pure products isolated by column chromatography (hexanes/EtOAc) and identified by GCeMS, 1H and 13C NMR.
Reaction performed at ꢁ78 ꢀC.
b
chromatography (TLC) carried out on Whatman-AL SIL G/UV plates.
Column chromatography was carried out using Merck silica gel 60
(230e400 mesh).
ArS Cl
X
ArX Cl
XAr
H
Ar
ArXCl
Cl-
..
..
N+
H
i
N
H
3a
N
H
X= S, Se
-HCl
4.2. General synthesis procedure
ii
TCCA (0.4 mmol, 1.2 equiv) was added to a solution of the diaryl
dichalcogenide (0.6 mmol) in EtOAc (5 mL), and the solution was
stirred at room temperature until colorless. Then, a mixture of indole
(1.0 mmol) and MgO (1.0 mmol) in EtOAc was added and the reaction
mixture was stirred at room temperature for the specified time. Then,
a saturated solution of NH4Cl (20 mL) and EtOAc (3e10 mL) were
added and the organic phase was separated and successively washed
with water (20 mL) and brine (20 mL). The extract was dried over
anhydrous MgSO4, concentrated under reduced pressure, and the
residue was purified by flash chromatography on silica gel (hexanes/
EtOAc 95:5) to afford the pure products (5aeo).
X= S
SAr
ArSCl
Ar
S
S
Ar
Ar
SAr
+
S
Ar
-HCl
S
H
N
H
N
H
N+
H
5o
iv
Scheme 2.
iii
corresponding indoles and diaryl dichalcogenides by means of
a TCCA mediated reaction in the presence of MgO. No additional
Lewis acid is necessary. The method is simple, fast, general, and
highly convenient, providing an easy access to a wide range of
potentially valuable 3-chalcogenylindoles in a few minutes at
room temperature.
4.2.1. 3-(Phenylselanyl)-1H-indole
134e137 ꢀC (lit.9c 135.4e137.0 ꢀC); 1H NMR (400 MHz, CDCl3):
¼8.34 (br s, 1H), 7.63 (d, J¼7.9, 1H), 7.43e7.38 (m, 2H), 7.25e7.20
(m, 4H), 7.15e7.08 (m, 3H); 13C NMR (100 MHz, CDCl3):
(5a). White
solid;
mp
d
d¼136.37,
133.77, 131.18, 129.94, 128.92, 128.66, 125.58, 122.91, 120.83, 120.34,
111.34, 98.16; MS (EI): m/z 273 (Mþ, 19), 193 (100), 116 (6), 77 (9).
4. Experimental section
4.1. General
4.2.2. 3-(p-Tolylselanyl)-1H-indole
(5b). White
solid;
mp
104e106 ꢀC; 1H NMR (200 MHz, CDCl3):
d¼8.17 (s,1H), 7.62 (d, J¼7.6,
1H), 7.32e7.12 (m, 7H), 6.90 (d, J¼7.6, 1H), 2.19 (s, 3H); 13C NMR
Solvents were purified and dried according to usual techniques
before use.20 All reagents were used as obtained from commercial
sources. The 1H (400 and 200 MHz) and 13C (100 and 50 MHz) NMR
spectra were recorded on Bruker DPX 400 and DPX 200 in-
(50 MHz, CDCl3):
d
¼136.48, 135.55, 133.35, 130.82, 130.45, 129.74,
129.37, 122.83, 120.76, 120.40, 111.29, 98.99, 20.80; MS (EI): m/z 287
(Mþ, 16), 207 (100), 192 (3), 178 (4), 165 (4), 116 (6), 89 (17), 77 (5).
struments, using CDCl3 as solvent. Chemical shifts (
d
) are expressed
4.2.3. 3-(4-Chlorophenylselanyl)-1H-indole (5c). White solid; mp
in parts per million downfield from internal tetramethylsilane or
CHCl3, and J values are given in hertz. Infrared spectra were
recorded on a Shimadzu IRPrestige-21 spectrometer. Melting point
(mp) determinations were performed by using an MQAPF-301 in-
strument and are informed uncorrected. The mass spectra were
obtained in a Shimadzu GCMS-QP2010 Plus gas chromatograph
coupled to a mass detector. The molecular ion and its fragments are
described as the relations between their atomic mass and corre-
sponding charge (m/z), together with their percent relative abun-
dance (%). The reactions were monitored by thin layer
116e120 ꢀC; 1H NMR (200 MHz, CDCl3):
d
¼8.38 (br s, 1H), 7.58 (d,
J¼7.7 Hz, 1H), 7.43e7.38 (m, 2H), 7.29e7.03 (m, 6H); 13C NMR
(50 MHz, CDCl3):
d
¼136.58, 132.09, 131.80, 130.27, 129.87, 129.03,
123.15, 121.07, 120.30, 111.41, 98.42; MS (EI): m/z 309 [Mþ2] (7), 307
(Mþ, 15), 227 (100), 191 (6), 116 (8), 77 (6).
4.2.4. 5-Bromo-3-(phenylselanyl)-1H-indole (5d). White solid; mp
107e110 ꢀC (lit.9c 108.1e109.4 ꢀC); 1H NMR (400 MHz, CDCl3):
d
¼8.39 (br s, 1H), 7.75 (s, 1H), 7.39 (d, J¼2.2, 1H), 7.33e7.09 (m, 8H);
13C NMR (100 MHz, CDCl3):
d
¼134.99,133.29,132.37,131.82,129.04,

10468
C.C. Silveira et al. / Tetrahedron 68 (2012) 10464e10469
128.69, 125.90, 125.82, 122.88, 114.32, 112.85, 97.83; MS (EI): m/z
(br s, 1H), 7.53 (d, J¼7.4 Hz, 1H), 7.31 (d, J¼7.3 Hz, 1H), 7.22e7.00 (m,
7H), 2.47 (s, 3H); 13C NMR (50 MHz, CDCl3):
¼141.1, 139.2, 135.3,
130.2, 128.6, 125.3, 124.4, 122.1, 120.6, 118.9, 110.6, 99.1, 12.1.
351 (Mþ, 44), 271 (100), 196 (5), 115 (13), 77 (14).
d
4.2.5. 5-Bromo-3-(p-tolylselanyl)-1H-indole (5e). White solid; mp
119e123 ꢀC; 1H NMR (200 MHz, CDCl3):
d
¼8.41 (br s, 1H), 7.76 (s,
1H), 7.41 (d, J¼2.3,1H), 7.30e7.12 (m, 4H), 6.95 (d, J¼8.0, 2H) 2.36 (s,
3H); 13C NMR (50 MHz, CDCl3):
4.2.15. 2,3-Bis(phenylthio)-1H-indole
(5o). White solid, mp
97e99 ꢀC (lit.21 97e99 ꢀC); 1H NMR (200 MHz, CDCl3):
d
¼8.26 (br s,
d
¼135.78, 134.99, 132.11, 131.84,
1H), 7.57 (d, J¼7.9, 1H), 7.28e7.17 (m, 7H), 7.11e7.08 (m, 5H),
129.85, 129.28, 129.16, 125.84, 122.94, 114.26, 112.80, 98.40, 20.89;
HRMS calcd for C15H12BrNSe 364.9318, found 364.9321.
7.06e7.0 (m, 1H); 13C NMR (50 MHz, CDCl3):
d¼138.0, 136.9, 134.3,
133.6, 130.0, 129.8, 129.3, 128.6, 127.2, 126.7, 125.1, 123.8, 121.2,
119.9, 111.0, 109.4; MS (EI): m/z 333 (Mþ, 54), 224 (100), 152 (4), 121
(9), 77 (12).
4.2.6. 5-Bromo-3-(4-chlorophenylselanyl)-1H-indole
solid; mp 118e121 ꢀC; 1H NMR (400 MHz, CDCl3):
(5f). White
d
¼8.48 (br s, 1H),
Acknowledgements
7.72 (d, J¼1.7, 1H), 7.42 (d, J¼2.5, 1H), 7.33e7.25 (m, 2H), 7.12e7.06
(m, 4H); 13C NMR (100 MHz, CDCl3):
d¼135.00, 132.40, 131.80,
This project was funded by FAPERGS, CAPES, MCT/CNPq.
131.55, 131.54, 129.99, 129.07, 126.04, 122.70, 114.44, 114.44, 112.94;
MS (EI): m/z 386 [(Mþ1)þ, 33], 385 (Mþ, 35), 307 (100), 271 (5), 196
(4), 192 (5), 116 (4), 75 (15).
References and notes
1. (a) Sundberg, R. J. The Chemistry of Indoles; Academic: New York, NY, 1996; (b)
Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Oxford,
2000; (c) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278; (d) Agarwal, S.;
Caemmerer, S.; Filali, S.; Froehner, W.; Knoell, J.; Krahl, M. P.; Reddy, K. R.;
Knolker, H. J. Curr. Org. Chem. 2005, 9, 1601; (e) O’Connor, S. E.; Maresh, J. J. Nat.
Prod. Rep. 2006, 23, 532; (f) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed.
2009, 48, 9608.
2. (a) Aygun, A. ,; Pindur, U. Curr. Med. Chem. 2003, 10, 1113; (b) Gupta, L.; Talwar,
A.; Chauhan, M. S. Curr. Med. Chem. 2007, 14, 1789; (c) La Regina, G.; Edler, M. C.;
Brancale, A.; Kandil, S.; Coluccia, A.; Piscitelli, F.; Hamel, E.; De Martino, G.;
Matesanz, R.; Díaz, J. F.; Scovassi, A. I.; Prosperi, E.; Lavecchia, A.; Novellino, E.;
Artico, M.; Silvestri, R. J. Med. Chem. 2007, 50, 2865; (d) Funk, C. D. Nat. Rev. Drug
Discov. 2005, 4, 664; (e) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem.
Rev. 2010, 110, 4489.
4.2.7. 1-Methyl-3-(phenylselanyl)-1H-indole (5g). White solid; mp
65e68 ꢀC (lit.9b 67 ꢀC); 1H NMR (200 MHz, CDCl3):
d
¼7.62 (d, J¼7.8,
1H), 7.35e7.06 (m, 9H), 3.80e3.73 (s, 3H); 13C NMR (50 MHz,
€
CDCl3):
d
¼137.62, 135.46, 134.20, 130.83, 129.34, 128.86, 125.55,
122.44, 120.52, 120.41, 109.45, 96.44, 32.95; MS (EI): m/z 287 (Mþ,
20), 207 (100), 130 (13), 77 (7).
4.2.8. 1-Methyl-3-(p-tolylselanyl)-1H-indole (5h). White solid; mp
123e125 ꢀC; 1H NMR (200 MHz, CDCl3):
d
¼7.62 (d, J¼7.9, 1H),
7.36e6.87 (m, 8H), 3.80 (s, 3H), 2.23 (s, 3H); 13C NMR (50 MHz,
CDCl3):
d
¼137.59, 135.41, 135.23, 130.84, 130.23, 129.68, 129.31,
3. (a) La Regina, G.; Gatti, V.; Famiglini, V.; Piscitelli, F.; Silvestri, R. ACS Comb. Sci.
122.37, 120.56, 120.33, 109.40, 96.98, 32.84, 20.81; HRMS calcd for
C16H15NSe 301.0370, found 301.0364.
2012, 14, 258; (b) Zhou, N.; Zeller, W.; Krohn, M.; Anderson, H.; Zhang, J.; Onua,
ꢀ
E.; Kiselyov, A. S.; Ramirez, J.; Halldorsdottir, G.; Andresson, P.; Gurney, M. E.;
Singh, J. Bioorg. Med. Chem. Lett. 2009, 19, 123.
4. De Martino, G.; La Regina, G.; Collucia, A.; Edler, M. C.; Barbera, M. C.; Brancale,
A.; Wilcox, E.; Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2004, 47, 6120.
5. De Martino, G.; Edler, M. C.; La Regina, R.; Coluccia, A.; Barbera, M. C.; Barrow,
D.; Nicholson, R. I.; Chiosis, G.; Brancale, A.; Hamel, E.; Artico, M.; Silvestri, R. J.
Med. Chem. 2006, 49, 947.
6. Cianchi, F.; Cortesini, C.; Magnelli, L.; Fanti, E.; Papucci, L.; Schiavone, N.;
Messerini, L.; Vannacci, A.; Capaccioli, S.; Perna, F.; Lulli, M.; Fabbroni, V.;
Perigli, G.; Bechi, P.; Masini, E. Mol. Cancer Ther. 2006, 5, 2716.
4.2.9. 3-(4-Chlorophenylselanyl)-1-methyl-1H-indole
solid; mp 110e114 ꢀC; 1H NMR (200 MHz, CDCl3):
(5i). White
d
¼7.58 (d, J¼7.7,
1H), 7.38e7.03 (m, 8H), 3.82 (s, 3H); 13C NMR (50 MHz, CDCl3):
d
¼137.48, 135.58, 132.46, 131.45, 130.41, 129.85, 128.92, 122.55,
120.54, 120.26, 109.60, 91.73, 33.04; MS (EI): m/z 323 (Mþ, 9), 321
(3), 241 (100), 191 (2), 130 (15), 77 (6).
7. (a) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004, 104, 6255; (b)
Alberto, E. E.; Nascimento, V.; Braga, A. L. J. Braz. Chem. Soc. 2010, 21, 2032; (c)
Nogueira, C. W.; Rocha, J. B. T. J. Braz. Chem. Soc. 2010, 21, 2055.
4.2.10. 3-(Phenylthio)-1H-indole (5j). White solid; mp 150e151 ꢀC
(lit.9c 150.1e151.0 ꢀC); 1H NMR (200 MHz, CDCl3):
d
¼8.38 (br s, 1H),
7.61 (d, J¼8.3 Hz, 1H), 7.48e7.41 (m, 2H), 7.30e7.19 (m, 2H),
7.15e7.05 (m, 5H); 13C NMR (50 MHz, CDCl3):
8. (a) Back, T. G. Organoselenium ChemistrydA Practical Approach; Oxford Uni-
versity Press: Oxford, UK, 1999; (b) Chen, Y.; Cho, C. H.; Larock, R. C. Org. Lett.
2009, 11, 173; (c) Guo, Y. J.; Tang, R. Y.; Li, J. H.; Zhong, P.; Zhang, X. G. Adv. Synth.
Catal. 2009, 351, 2615; (d) Sanz, R.; Guilarte, V.; Castroviejo, M. P. Synlett 2008,
3006; (e) Barraja, P.; Diana, P.; Carbone, A.; Cirrincione, G. Tetrahedron 2008, 64,
11625; (f) Yadav, J. S.; Reddy, B. S.; Reddy, Y. J.; Praneeth, K. Synthesis 2009, 1520.
9. (a) Barton, D. H. R.; Lusinchi, X.; Milliet, P. Tetrahedron 1985, 41, 4727; (b) Zhao,
X.; Yu, Z.; Xu, T.; Wu, P.; Yu, H. Org. Lett. 2007, 9, 5263; (c) Fang, X. L.; Tang, R. Y.;
Zhong, P.; Li, J. H. Synthesis 2009, 4183; (d) Li, Z.; Hong, L.; Liu, R.; Shen, J.; Zhou,
X. Tetrahedron Lett. 2011, 52, 1343; (e) Schlosser, K. M.; Krasutsky, A. P.;
Hamilton, H. W.; Reed, J. E.; Sexton, K. Org. Lett. 2004, 6, 819; (f) Ge, W.; Wei, Y.
Green Chem. 2012, 14, 2066.
10. (a) Hiegel, G. A.; Nalbandy, M. Synth. Commun. 1992, 22, 1589; (b) Walters,
T. R.; Zajac, W. W., Jr.; Woods, J. M. J. Org. Chem. 1991, 56, 316; (c)
Wengert, M.; Sanseverino, A. M.; de Mattos, M. C. S. J. Braz. Chem. Soc.
2002, 13, 700.
11. (a) Zhong, P.; Guo, M. P.; Huang, N. P. Synth. Commun. 2002, 32, 175; (b)
Tilstam, U.; Weinmann, H. Org. Process Res. Dev. 2002, 6, 384; (c) Ho, D. K.
H.; Chan, L.; Hooper, A.; Brennan, P. E. Tetrahedron Lett. 2011, 52, 820; (d)
Crane, Z. D.; Nichols, P. J.; Sammakia, T.; Stengel, P. J. J. Org. Chem. 2011, 76,
277; (e) Lee, J. C.; Kim, J.; Lee, S. B.; Chang, S.-U.; Jeong, Y. J. Synth. Commun.
2011, 41, 1947.
12. (a) Mendonc¸ a, G. F.; Sindra, H. C.; Almeida, L. S.; Esteves, P. M.; Mattos, M. C. S.
Tetrahedron Lett. 2009, 50, 473; (b) Whitehead, D. C.; Staples, R. J.; Borhan, B.
Tetrahedron Lett. 2009, 50, 656; (c) Silva, B. V.; Esteves, P. M.; Pinto, A. C. J. Braz.
Chem. Soc. 2011, 22, 257.
13. (a) Araki, K.; Saito, K.; Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed. 2004, 43,
81; (b) Yamatsugu, K.; Kanai, M.; Shibasaki, M. Tetrahedron 2009, 65, 6017; (c)
Ikeda, R.; Iwaki, T.; Iida, T.; Okabayashi, T.; Nishi, E.; Korosawa, M.; Sakai, N.;
Konakahara, T. Eur. J. Med. Chem. 2011, 46, 636.
14. Silveira, C. C.; Rinaldi, F.; Guadagnin, R. C.; Braga, A. L. Synthesis 2009, 469; (b)
Silveira, C. C.; Santos, P. C. S.; Braga, A. L.; Mendes, S. R. J. Organomet. Chem.
2008, 693, 3787; (c) Silveira, C. C.; Mendes, S. R.; Rosa, D.; Zeni, G. R. Synthesis
2009, 4015; (d) Petragnani, N.; Mendes, S. R.; Silveira, C. C. Tetrahedron Lett.
d
¼134.2, 131.7, 126.3,
124.9, 124.5, 121.9, 120.9, 119.3, 117.3, 116.2, 108.8, 100.7; MS (EI):
m/z 225 (Mþ, 100), 193 (21), 148 (12), 121 (11), 77 (19).
4.2.11. 5-Bromo-3-(phenylthio)-1H-indole (5k). White solid; mp
120e122 ꢀC (lit.9c 120.9e123.1 ꢀC); 1H NMR (200 MHz, CDCl3):
d¼8.42
(br s, 1H), 7.74 (t, J¼1.8, 1H), 7.47 (d, J¼2.5, 1H), 7.33e7.03 (m, 7H); MS
(EI): m/z305 [Mþ2](16), 303 (23), 302 (100), 223 (99) 120(20), 77 (12).
4.2.12. 1-Methyl-3-(phenylthio)-1H-indole (5l). White solid; mp
85e87 ꢀC (lit.18 84.9e87.2 ꢀC); 1H NMR (200 MHz, CDCl3):
d¼7.59
(s, 1H), 7.35e7.20 (m, 3H), 7.17e7.03 (m, 6H), 3.74 (s, 3H), 13C NMR
(50 MHz, CDCl3):
d
¼134.6, 132.6, 130.3, 125.5, 124.4, 121.7, 120.7,
118.8, 116.9, 116.2, 107.0, 98.4, 36.4; MS (EI): m/z 239 (Mþ, 100), 223
(19), 162 (11), 119 (11), 77 (17).
4.2.13. 2-Methyl-3-(phenylselanyl)-1H-indole (5m). White solid;
mp 97e98 ꢀC (lit.9a 98 ꢀC); 1H NMR (200 MHz, CDCl3):
d
¼8.22 (br s,
1H), 7.54 (d, J¼7.6 Hz, 1H), 7.33e7.06 (m, 8H), 2.51 (s, 3H); 13C NMR
(50 MHz, CDCl3):
122.0, 120.5, 119.7, 110.4, 13.1.
d
¼140.8, 135.7, 133.9, 131.1, 128.9, 128.2, 125.3,
4.2.14. 2-Methyl-3-(phenylthio)-1H-indole (5n). White solid; mp
109e111 ꢀC (lit.9c 110.9e111.2 ꢀC); 1H NMR (200 MHz, CDCl3):
d¼8.20

C.C. Silveira et al. / Tetrahedron 68 (2012) 10464e10469
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