A solvent- and metal-free synthesis of 3-chacogenyl-indoles employing DMSO/I2 as an eco-friendly catalytic oxidation system

Article abstract of DOI:10.1021/jo5000779

Herein, we describe a solvent- and metal-free method for the synthesis of 3-chalcogenyl-indoles from indoles and diorganyl dichalcogenides using an equivalent amount of DMSO as an oxidant, under catalysis by molecular iodine. This mild and eco-friendly ap

Full text of DOI:10.1021/jo5000779

Note
pubs.acs.org/joc
A Solvent- and Metal-Free Synthesis of 3‑Chacogenyl-indoles
Employing DMSO/I2 as an Eco-friendly Catalytic Oxidation System
Juliano B. Azeredo,† Marcelo Godoi,† Guilherme M. Martins,‡ Claudio C. Silveira,*,‡
and Antonio L. Braga*,†
†Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianop
́
olis, Santa Catarina, Brazil
‡Departamento de Química, Universidade Federal de Santa Maria, UFSM, 97105-900 Santa Maria, Rio Grande do Sul, Brazil
S
* Supporting Information
ABSTRACT: Herein, we describe a solvent- and metal-free
method for the synthesis of 3-chalcogenyl-indoles from indoles
and diorganyl dichalcogenides using an equivalent amount of
DMSO as an oxidant, under catalysis by molecular iodine. This
mild and eco-friendly approach allowed the preparation of a
wide range of 3-selenyl- and 3-sulfenyl-indoles in good to
excellent yields.
Wey and co-workers21 reported a simple protocol for the
he indole core is a ubiquitous heterocycle found in many
synthesis of 3-sulfenyl-indoles in dimethyl carbonate (DMC),
employing an equivalent amount of DMSO as stoichiometric
Tbioactive natural products, pharmaceuticals, and agro-
chemicals,1 and as a consequence has been continuously
oxidant and catalytic quantity of molecular iodine (I2).
Very recently, a similar system of I2 and DMSO was also
used for the preparation of 3-sulfenyl-indoles by using aryl
sodium sulfinates as an organosulfur source, in the presence of
diethyl fosfite as an additive and anisole as solvent.22 In spite of
their good features, long reaction times and use of solvent or
additives are required and the synthesis of 3-selenyl-indoles by
these methods was not explored.
On the other hand, the use of microwave (MW) irradiation
in organic transformations, including C−Se and C−S bond
formation,23 can provide higher yields in shorter reaction
times.24 In addition, with the development of sustainable
technologies, solvent-free conditions have emerged as a benign
alternative for organic synthesis.25 Besides avoiding problems
related to flammability and toxicity, these methodologies
decrease significantly the amount of waste generated.
In this regard, the combination of a solvent-free reaction
medium with microwave irradiation heating has been used
successfully for the synthesis of organochalcogen compounds.26
However, to date, there are no reports of studies in which this
attractive strategy was applied to the synthesis of 3-chalcogenyl-
indoles.
capturing the interest of chemists worldwide. Recent studies
have shown that 3-sulfenylindoles act on specific targets,
attracting the attention of a number of researchers2 due their
several potential activities such as inhibitor of tubulin
polymerization at submicromolar concentration and cell growth
at low nanomolar concentrations,3 antitumor4 and antiviral
activities.5
Analogously, organoselenium compounds are bioactive6 and
have been highlighted because of their ability to mimic natural
compounds with biological proprieties, such as antioxidant
activity,7 and potential usefulness as valuable synthetic
intermediates.8 Thus, 3-chalcogenyl-indoles have emerged as
a powerful class by virtue of their potent pharmacological
activity in the treatment of several diseases.
The methodologies reported for the preparation of 3-
chalcogenyl-indoles commonly involve the direct reaction of
the indole core with diorganoyl dichalcogenides catalyzed by
metals such as iron(III),9 copper,10 VO(acac)2,11 and MgBr.12
In addition, the chalcogenylation of indoles has been
developed employing quinone-mono-O,S-acetals,13 N-chalco-
genoimides,14 sulfonylhydrazides,15 thiols,9 and arylsulfonyl
chlorides16 as chalcogenylation agents.
Other processes for the preparation of 3-chalcogenyl-indoles
involves the electrophilic cyclization of o-alkynylanilines17 or 2-
(gem-dibromo(chloro)vinyl)anilines employing organochalco-
gen electrophilic species as cyclization agents18 and the use of
ionic liquids as a recyclable solvent.19 Nevertheless, most of
these methods have drawbacks such as the use of toxic
solvents/metals or long reaction times. In addition, we have
described an alternative approach for the synthesis of 3-
chalcogenyl indoles by using trichloroisocyanuric acid (TCCA)
and dichalcogenides.20
Thus, herein we detail the synthesis of 3-chalcogenyl-indoles
in the absence of solvents, under microwave irradiation in a
very short reaction time and employing molecular iodine as a
catalyst (Scheme 1).
Optimization of the reaction conditions was initiated using
indole (1) and diphenyl diselenide as standard substrates, 5 mol
% of catalyst, and 3 equiv of the stoichiometric oxidant (Table
1). Initially, the influence of the reaction time on the
Received: January 17, 2014
Published: April 8, 2014
© 2014 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 1. Molecular Iodine Catalyzed 3-Chalcogenylation
of Indoles under Solvent-Free Conditions
Table 2. Optimization of Reaction Conditions
entry
I2 (mol %)
oxidant (equiv)
yield (%)
1
2
3
4
5
6
7
1
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (1)
−
22
64
84
86
−
40
15
80
55
2.5
5
Table 1. Optimization of Microwave Parameters
10
−
5
5
a
8
−
5
DMSO (3)
9
H2O2 (3)
a
entry
power (W)
T (°C)
t (min)
yield (%)
a
Reaction performed using 5 mol % of HI.
1
2
3
4
5
6
7
8
9
100
100
100
100
100
100
150
50
80
80
80
80
100
60
80
80
80
1
59
70
84
85
84
50
86
79
3
With the best catalyst loading in hand, the effect of the
5
amount of the oxidant on the transformation was evaluated. It
was observed that decreasing the amount of added DMSO
decreased the yields of 3a to 40% (entry 6), while in its absence
the yield dropped to 15% (entry 7). When HI was used instead
of I2 the reaction also worked well, indicating that most likely
the HI is one of the intermediates of this reaction (entry 8).
The employment of H2O2 instead of DMSO resulted in a less
efficient transformation (entry 9). Thus, the optimal reaction
conditions are shown in entry 3.
7
5
5
5
5
b
−
b
12 h
75
a
Isolated yields. Conventional heating.
performance of the transformation was investigated. Carrying
out the reaction for 1 min provided the desired product in only
59% yield (entry 1). However, when the time was increased to
3 min, a significant improvement in the yield was observed
(entry 2).
Notably, when the reaction was carried out for 5 min at 80
°C and 100 W, product 3a was accessed in 84% yield (entry 3).
However, no significant change in the yield was observed on
applying a 7 min reaction time (entry 4).
Next, the influence of temperature was investigated.
Increasing the temperature from 80 to 100 °C produced no
appreciable variation in the yield (entry 5). Nonetheless, a
considerable decrease was detected when the reaction was
performed at a lower temperature (entry 6). The reaction was
also performed employing different levels of irradiation power.
Carrying out the reaction at 150 W did not affect the yield
(entry 7). However, when the power was decreased to 50 W a
significant decreased in the yield was observed (entry 8).
In order to evaluate the influence of the heating method-
ology the reaction was also performed under conventional
heating (entry 9). Under this condition, the desired product 3a
was obtained in 75% yield after 12 h, highlighting the
importance of the use of microwaves.
The influence of the catalyst and the stoichiometric oxidant
on the reaction system was next explored (Table 2). Carrying
out the reaction with 1 mol % of iodine afforded only 22% of 3-
selenyl-indole 3a (entry 1). Increasing the catalyst amount to
2.5 mol % caused an increase to 64% yield (entry 2), which
further improved to 84% when 5 mol % of iodine was used
(entry 3).
With the best result in hand, a library of 3-selenyl-indoles was
synthesized in order to evaluate the scope of the protocol
(Table 3). The effect of different groups bound to selenium was
evaluated at first, reacting 1a with several diorganoyl
diselenides.
The electronic characteristics of the substituent attached to
the para position of the aromatic ring (electron donor or
acceptor) did not affect performance of the transformation, and
the corresponding 3-selenyl-indoles were obtained in very high
yield. Notably, when a diselenide with a CF3 group at the meta
position was employed, the respective product was obtained in
86% yield. Furthermore, steric effects did not significantly affect
the reaction, and on using an ortho-methoxyphenyl diselenide
the corresponding product was delivered in good yield.
However, aliphatic diselenides, which are less reactive than
their aromatic analogues,27 were not efficient substrates for this
transformation.
Next, the influence of the indole moiety was evaluated,
employing heterocycles with different functionalities attached at
the 5-position of the ring, including methyl, methoxy, bromo,
and ester group. The results indicate that both electron-
withdrawing and electron-donating groups are suitable
substrates, affording the corresponding products 3h−k in
72−85% yield.
Substituents at the 1-position of the indole also modulated
the performance of the process. For example, the 1-methyl and
1-phenyl derivatives afforded the expected 3-selenyl-indoles
3l,m in 89 and 78% yield, respectively. However, the reaction
failed when electron-withdrawing groups such as the N-Boc
(3n) and N-Ts (3r) were used (Table 3).
Furthermore, no significant additional changes were
observed upon increasing the catalyst load to 10 mol %
(entry 4). The requirement of iodine as a catalyst was
demonstrated when the reaction was carried out in its absence.
In this case, no product was observed (entry 5).
Indoles substituted at 2 position such as 2-methyl and 2-
phenyl indoles afforded the corresponding products (3o,p) in
88 and 67% yield, respectively. We have also observed that all
indoles used as starting materials, including 2-phenylindole with
high melting point, were melted in our reaction conditions.
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Note
Table 3. Synthesis of 3-Selanylindoles
Table 4. Synthesis of 3-Sulfenyl Indoles
Scheme 2. Proposed Reaction Mechanism
The reaction of 2 equiv of HI with DMSO would then
regenerate iodine, through the intermediacy of the protonated
sulfur species, including iododimethylsulfonium iodide (iodine-
dimethyl sulfide adduct),29 simultaneously releasing water and
dimethyl sulfide.
In summary, a rapid, economic, and highly efficient
methodology for the preparation of 3-selenyl- and 3-sulfenyl-
indoles, a class of compounds of interest for therapeutic
applications, has been developed. The new approach afforded
the desired products in good to excellent yields in only 5 min,
under solvent- and metal-free conditions. Thus, the chemistry
described herein represents a feasible eco-friendly synthetic
alternative for accessing 3-chalcogenyl indoles.
Furthermore, the reaction also tolerated a 1,2-disubstituted
indole, furnishing the respective product 3q in very high yield.
The scope of the reaction regarding the preparation of 3-
sulfenyl-indoles was explored next. Using diphenyl disulfide as
the substrate, the sulfenyl indole 4a was obtained in 92% yield.
Likewise, the use of di-para-methyl disulfide afforded 4b in 86%
yield. Notably, the presence of chloro- at the para position of
the disulfide was beneficial for the reaction, furnishing 97% of
the desired product. Moreover, the reaction also worked well
with dialkyl disulfides, affording the corresponding products in
reasonable yields.
Subsequently, some substituted indoles were reacted with
diphenyl disulfide in order to obtain different 3-sulfenyl-indoles.
At the same way, high yields were obtained with both 1- and 2-
substituted indoles (Table 4, compounds 4f and 4g).
EXPERIMENTAL SECTION
■
1H and 13C NMR spectra were recorded in CDCl3 at 400 and 200
MHz or at 100 and 50 MHz, respectively. Chemical shifts (δ) are
reported (ppm) relative to the TMS (1H NMR) and the solvent (13C
NMR). APPI-Q-TOFMS measurements were performed with a mass
spectrometer equipped with an automatic syringe pump for sample
injection. Infrared spectra were recorded on a commercial Fourier
transformer spectrometer. The indoles were obtained from commer-
cial sources and used without further purification. All reactions were
performed in 10 mL sealed glasses tubes in a commercially available
microwave monomode CEM reactor with IR monitoring and a
noninvasive pressure transducer. The yields are based on isolated
compounds after purification.
In addition, substituents attached at the 5-position did not
significantly affect the reaction, furnishing the desired products
in good to excellent yields. For example, reaction of 5-
bromoindole with di-p-chlorophenyl and di-p-methoxyphenyl
disulfides afforded 4j and 4k in 98 and 86% yields, respectively.
On the basis of literature reports,28,21 a plausible reaction
pathway for the synthesis of the sulfenyl/selenyl derivatives is
described in Scheme 2. Probably, an electrophilic species of the
form RYI (Y = S, Se) is generated when the diorganyl
dichalcogenide RYYR is submitted to reaction with I2. In turn,
the reactive RYI intermediate would react with the indole at the
3-position, affording the desired 3-chalcogenyl-indole, with
concomitant formation of HI.
General Procedure for Solvent-Free Iodine-Catalyzed 3-
Chalcogenylation of Indoles. A mixture of indole (0.5 mmol),
dichalcogenide (0.25 mmol), iodine (5 mol %), and DMSO (3 equiv)
were added in a glass tube, which was sealed and placed in a CEM
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The Journal of Organic Chemistry
Note
Discover microwave apparatus. A maximum irradiation power of 100
W and a temperature of 80 °C were applied for 5 min. When the
reaction was finished, it was dissolved in EtOAc (20 mL) and washed
with 15 mL of an aqueous solution of 10% Na2S2O4, and the crude
product was purified by column chromatography over silica gel using a
mixture of hexane/EtOAc as the eluent.
3-(Phenylselenyl)-1H-indole (3a). 0.1142g, Yield: 84%; white solid;
mp 134−137 °C (lit.20 135.4−137.0 °C); 1H NMR (400 MHz,
CDCl3) δ = 8.34 (br s, 1H), 7.63 (d, J = 7.9, 1H), 7.43−7.38 (m, 2H),
7.25−7.20 (m, 4H), 7.15−7.08 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ = 136.4, 133.8, 131.2, 129.9, 128.9, 128.6, 125.6, 122.9,
120.8, 120.4, 111.3, 98.1.
7.55 (d, J = 2.34 Hz, 1H), 7.46 (d, J = 8.60 Hz, 1H), 7.26−7.22 (m,
3H), 7.16−7.10 (m, 2H), 3.90 (s, 3H); 13C NMR (CDCl3, 100 MHz,
CDCl3) δ = 167.8, 139.00, 133.4, 132.6, 129.7, 129.0, 128.8, 125.8,
124.4, 123.2, 123.1, 111.2, 100.0, 51.9; HRMS (APPI+) m/z calculated
for C16H14NO2Se [M + H]+ 332.0185, found 332.0186.
1-Methyl-3-(phenylselenyl)-1H-indole (3l). 0.1272g, Yield: 89%;
white solid; mp 65−68 °C (lit.20 67 °C); 1H NMR (200 MHz,
CDCl3) δ = 7.69 (d, J= 7.03, 1H), 7.42−7.13 (m, 8H), 3.85 (s, 3H);
13C NMR (50 MHz, CDCl3) δ =137.6, 135.8, 134.3; 130.5, 129.0,
128.7, 125.6, 122.5; 120.5, 109.7, 96.0, 33.1.
1-Phenyl-3-(phenylselenyl)-1H-indole (3m). 0.1355g, Yield: 78%;
1
yellow oil; H NMR (200 MHz, CDCl3) δ = 7.69−7.65 (m, 1H),
3-(p-Tolylselenyl)-1H-indole (3b). 0.144g, Yield: 80%; white solid;
7.59−7.49 (m, 6H), 7.42−7.26 (m, 4H), 7.23−7.08 (m, 4H); 13C
NMR (50 MHz, CDCl3) δ = 138.8, 136.5, 134.3, 133.4, 131.1, 129.6,
128.9, 128.8, 126.9, 125.6, 124.23, 123.1, 121.2, 120.7, 110.7, 99.17;
HRMS (APPI+) m/z calculated for C20H15NSe [M]+ 349.0365, found
349.0372.
mp 104−106 °C (lit.20 104−106); H NMR (200 MHz, CDCl3) δ =
1
8.34 (br s, 1H), 7.71−6.98 (m, 9H), 2.28 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ = 136.5, 135.4, 131.0, 129.9, 129.8; 129.7, 129.0, 122.8,
120.7, 120.2, 111.3, 98.4, 20.8.
3-(4-Chlorophenylselenyl)-1H-indole (3c). 0.1300g, Yield: 85%;
2-Methyl-3-(phenylselenyl)-1H-indole (3o). 0.1258g, Yield: 88%;
white solid; mp 97−98 °C (lit.20 98 °C); 1H NMR (200 MHz,
CDCl3) δ = 8.22 (br s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.33−7.06 (m,
8H), 2.51 (s, 3H); 13C NMR (50 MHz, CDCl3) δ = 140.8, 135.7,
133.9, 131.1, 128.9, 128.2, 125.3, 122.0, 120.5, 119.7, 110.4, 96.74;
13.1.
white solid; mp 117.0−120.0 °C (lit.20 116−120); H NMR (200
1
MHz, CDCl3) δ = 8.38 (br s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7,43−7.38
(m, 2H), 7.29−7.03 (m, 6H); 13C NMR (50 MHz, CDCl3) δ = 136.4,
133.4, 132.0, 131.6, 131., 130.0, 129.0, 123.1, 121.0, 120.2, 111.4, 97.9.
3-((3-(Trifluoromethyl)phenyl)selenyl)-1H-indole (3d). 0.1462g,
1
Yield: 86%; yellow solid; mp 75.8−77.0 °C; H NMR (400 MHz,
2-Phenyl-3-(phenylselenyl)-1H-indole (3p).17a 0.1166g, Yield:
CDCl3) δ = 8.33 (br s, 1H), 7.59 (d, J = 8.21, 1H), 7.53 (s, 1H), 7.39−
7.36 (m, 2H), 7.31−7.23 (m, 3H), 7.19−7.10 (m, 2H); 13C NMR
(100 MHz, CDCl3) = 136.3, 135.2, 131.7, 131.5, 131.1 (q, J = 32 Hz),
129.5, 129.1, 124.5 (q, J = 4.4 Hz), 123.8 (q, J = 272.0 Hz), 123.1,
122.3 (q, J = 4.4 Hz), 121.0, 120.0, 111.5, 97.1; HRMS (APPI+) m/z
calculated for C15H10F3NSe [M]+ 340.9926, found 340.9930.
3-((2-Methoxyphenyl)selenyl)-1H-indole (3e). 0.1071g, Yield: 71%;
black solid; mp 117.5−118.3 °C; 1H NMR (400 MHz, CDCl3) = 8.43
(br s, 1 H), 7.60 (d, J = 8.21, 1H), 7;40−7.38 (m, 2H), 7.26−7.22 (m,
1H), 7.17−7.13 (m, 1H), 7.08−7.04 (m, 1H), 6.79 (d, J = 8.21, 1H),
6−66−6.58 (m, 2H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) =
155.9, 136.5, 131.9, 130.1, 128.0, 126.2, 123.1, 122.8, 121.5, 120.7,
120.3, 111.4, 109.9, 95.7, 55.8; IR (film) 3446, 3010, 1587, 1490, 1320,
1036, 752; HRMS (APPI+) m/z calculated for C15H14NOSe [M +
H]+ 304.0236, found 304.0234.
1
67%; yellow viscous oil; H NMR (400 MHz, CDCl3) δ = 8.57 (br
s, 1H), 7.67−7.63 (m, 3H), 7.38−7.30 (m, 3H), 7.24−7.02 (m, 8H);
13C NMR (100 MHz, CDCl3) δ = 142.0, 136.0, 134.0, 131.9, 131.8,
129.00, 128.5, 128.4, 128.1, 125.3, 123.1, 121.0, 120.7, 111.02, 95.5.
1-Methyl-2-phenyl-3-(phenylselenyl)-1H-indole (3q). 0.1719g,
1
Yield: 95%; yellow viscous oil; H NMR (400 MHz, CDCl3) δ =
7.55 (d, J = 7.82 Hz, 1H), 7.31−7.15 (m, 7H), 7.08−6.89 (m, 6H),
3.53 (s, 3H).13C NMR (100 MHz, CDCl3) δ = 145.7, 137.6, 134.5,
131.1, 130.7, 130.5, 128.8, 128.6, 128.2, 128.0, 125.1, 122.6, 120.8,
120.5, 109.7, 96.2, 31.6; HRMS (APPI+) m/z calculated for
C21H17NSe [M]+ 363.0522, found 363.0520.
3-(Phenylsulfenyl)-1H-indole (4a). 0.1035g, Yield: 92%; white
solid; mp 150−151 °C (lit.20 150.1−151.0 °C); H NMR (200 MHz,
1
CDCl3) δ = 8.38 (br s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.48−7.41 (m,
2H), 7.30−7.19 (m, 2H), 7.15−7.05 (m, 5H); 13C NMR (50 MHz,
CDCl3) δ = 134.2, 131.7, 126.3, 124.9, 124.5, 121.9, 120.9, 119.3,
117.3, 116.2, 108.8, 100.7.
3-(Benzylselenyl)-1H-indole (3f). 0.0300g, Yield: 21%; yellow oil;
1H NMR (200 MHz, CDCl3) δ = 8.09 (br s, 1H), 7.58 (d, J =, 8.31
Hz, 1 H), 7.27−7.05 (m, 8H), 6.95−6.88 (m, 1H), 3.76 (s, 2H); 13C
NMR (CDCl3, 50 MHz, CDCl3) δ = 138.6, 136.1, 130.6, 130.1, 128.7,
128.1, 126.4, 122.5, 120.4, 120.1, 111.2, 98.8, 32.1; HRMS (APPI+)
m/z calculated for C15H14NSe [M + H]+ 288.0286, found 288.0288.
5-Methoxy-3-(phenylselenyl)-1H-indole (3h). 0.1282g, Yield: 85%;
3-(p-Tolylsulfenyl)-1H-indole (4b). 0.1027g, Yield: 86%; yellow
solid; mp 123.9−125.8 °C; (lit.21 125−126 °C); 1H NMR (400 MHz,
CDCl3) δ = 8.17 (br s, 1H), 7.60 (d, J = 7.82 Hz, 1H), 7.33−7.31 (m,
2H), 7.23−7.19 (m, 1H), 7.14−7.11 (m, 1H), 6.97 (dd, J1 = 21.49, J2 =
8.21, 4H), 2.21 (s, 3H).13C NMR (100 MHz, CDCl3) δ = 136.3,
135.4, 134.6, 130.5, 129.4, 128.9, 126.1, 122.8, 120.7, 119.5, 111.6,
103.0, 20.8.
3-((4-Chlorophenyl)sulfenyl)-1H-indole (4c). 0.1259g, Yield: 97%;
yellow solid; mp 134−135 °C; (lit.21 127.5−128.3 °C); 1H NMR (400
MHz, CDCl3) δ = 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) δ = 138.6, 135.0, 131.8, 130.9, 128.8, 126.1,
125.8, 125.0, 122.2, 114.9, 113.0, 102.6.
3-(Benzylsulfenyl)-1H-indole (4d). 0.0717g, Yield: 60%; yellow oil;
1H NMR (200 MHz, CDCl3) δ = 8.00 (br s, 1H), 7.63 (d, J = 8.21,
1H), 7.27−6.88 (m, 9H), 3.77 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ = 138.9, 136.1, 129.8, 129.10, 128.9, 128.1, 126.7, 122.5, 120.4,
119.2, 111.4, 104.9, 40.9; HRMS (APPI+) m/z calculated for
C15H14NS [M + H]+ 240.0841, found 240.0846.
3-(Ethylsulfenyl)-1H-indole (4e). 0.0487g, Yield: 55%; yellow oil;
1H NMR (400 MHz, CDCl3) δ = 8.19 (br s, 1H), 7.78 (d, J = 8.21 Hz,
1H), 7.30−7.17 (m, 4H), 2.79 (q, J = 7.42 Hz, 2H), 1.17 (t, J = 7.42
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 136.1, 129.5, 129.3, 122.5,
120.2, 119.2, 111.4, 105.2, 30.2, 15.1; IR (film) 3420, 2275, 1496, 790
cm −1; HRMS (APPI+) m/z calculated for C10H12NS [M + H]+
178.0685, found 178.0684.
1
yellow viscous liquid; H NMR (400 MHz, CDCl3) δ = 8.31 (br s,
1H), 7.34 (d, J = 2.34 Hz, 1H), 7.25−7.20 (m, 3H), 7.13−7.06 (m,
4H), 6.89 (dd, J1 = 2.74 Hz, J2 = 6.25 Hz, 1H), 3.76 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ = 155.0, 133.8, 131.9, 131.3, 130.7, 128.9, 128.4,
125.5, 113.3, 112.2, 101.5, 97.4, 55.7; IR (film) 3450, 300, 1598, 1580,
1505, 1310, 1043, 516 cm−1; HRMS (APPI+) m/z calculated for
C15H13NOSe [M]+ 303.0157, found 303.0159.
5-Methyl-3-(phenylselenyl)-1H-indole (3i). 0.1085g, Yield: 76%;
1
black solid; mp =132.7−133.8 °C; H NMR (400 MHz, CDCl3) δ =
8.16 (br s, 1H), 7.41−7.42 (m, 1H), 7.32 (d, J = 2.34 Hz, 1H), 7.25−
7.18 (m, 3H), 7.12−7.04 (m, 4H), 2.40 (s, 3H).13C NMR (100 MHz,
CDCl3) δ = 134.6, 134.0, 131.4, 130.3, 130.2, 128.9, 128.4, 125.5,
124.7, 119.8, 111.0, 97.2, 21.4; IR (film) 3442, 3100, 1570, 772, 521
cm−1; HRMS (APPI+) m/z calculated for C15H13NSe [M]+ 287.0208,
found 287.0216.
5-Bromo-3-(phenylselenyl)-1H-indole (3j). 0.1263g, Yield: 72%;
white solid; mp 107−110 °C (lit.20 108.1−109.4 °C); H NMR (400
1
MHz, CDCl3) δ = 8.39 (br s, 1H), 7.75 (s, 1H), 7.39 (d, J = 2.2 Hz,
1H), 7.33−7.09 (m, 7H); 13C NMR (100 MHz, CDCl3) δ = 135.0,
133.3, 132.4, 131.8, 129.0, 128.7, 125.9, 125.8, 122.9, 114.3, 112.8,
97.8.
Methyl 3-(phenylselenyl)-1H-indole-5-carboxylate (3k). 0.132g,
1
Yield: 80%; white solid; mp 164.6−165.2 °C; H NMR (400 MHz,
CDCl3) δ = 8.71 (br s, 1H), 8.40 (m, 1H), 7.98 (d, J = 8.60 Hz, 1H),
4128
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Note
1-Phenyl-3-(phenylsulfenyl)-1H-indole (4f). 0.1264g, Yield: 84%;
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, 123−126.
(3) La Regina, G.; Bai, R.; Rensen, W. M.; Di Cesare, E.; Coluccia,
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Pozzo, E.; Costa, B.; Granata, I.; Porta, A.; Maresca, B.; Soriani, A.;
Iannitto, M. L.; Santoni, A.; Li, J.; Cona, M. M.; Chen, F.; Ni, Y.;
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Chem. 2013, 56, 123−149.
(4) 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
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Braz. Chem. Soc. 2010, 21, 2032−2041. (c) Nogueira, C. W.; Rocha, J.
B. T. J. Braz. Chem. Soc. 2010, 21, 2055−2071.
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Oxford University Press: Oxford, U.K., 1999. (b) Guo, Y. J.; Tang, R.
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2921.
1
yellow oil; H NMR (200 MHz, CDCl3) δ = 7.66−7.62 (m, 1H),
7.53−7.43 (m, 6H), 7.35−7.00 (m, 8H); 13C NMR (CDCl3, 100
MHz, CDCl3) 139.0, 138.9, 136.8, 133.7, 130.3, 129.7, 128.7, 127.1,
126.2, 124.9, 124.4, 123.3, 121.3, 120.0, 110.9, 104.2; HRMS (APPI+)
m/z calculated for C20H16NS [M + H]+ 302.0998, found 302.0996.
2-Methyl-3-(phenylsulfenyl)-1H-indole (4g). 0.1087g, Yield: 91%;
white solid; mp 109−111 °C (lit.20 110.9−111.2 °C); H NMR (400
1
MHz, CDCl3) δ = 8.20 (br s, 1H), 7.53 (d, J = 7.4 Hz, 1 H), 7.31 (d, J
= 7.3 Hz, 1H), 7.22−7.00 (m, 7H), 2.47 (s, 3H); 13C NMR (100
MHz, CDCl3) δ = 141.1, 139.2, 135.3, 130.2, 128.6, 125.3, 124.4,
122.1, 120.6, 118.9, 110.6, 99.1, 12.1.
5-Methoxy-3-(phenylsulfenyl)-1H-indole (4h).21 0.1007g, Yield:
79%; yellow viscous oil; 1H NMR (400 MHz, CDCl3) δ = 8.40 (br s,
1H), d (7.41, J = 2.74 Hz, 1H), 7.30−7.28 (m, 1H), 7.18−7.14 (m,
3H), 7.10−7.03 (m, 4H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ = 155.0, 139.3, 131.3, 129.9, 128.7, 125.6, 124.7, 113.5, 112.4, 104.9,
102.0, 100.7, 54.7.
5-Bromo-3-(phenylsulfenyl)-1H-indole (4i). 0.1200g, Yield: 79%;
white solid; mp 120−122 °C (lit.20 120.9−123.1 °C); H NMR (200
1
MHz, CDCl3) δ = 8.42 (br s, 1H), 7.74 (s, 1H), 7.47−7.03 (m, 8H),
13C (CDCl3, 50 MHz) δ = 138.6, 135.0, 131.8, 130.9, 128.7, 126.1,
125.8, 125.0, 122.1, 114.4, 113.0, 102.6.
5-Bromo-3-((4-chlorophenyl)sulfenyl)-1H-indole (4j).14a 0.1657g,
Yield: 98%; white solid; mp 143−144; 1H NMR (200 MHz, CDCl3) δ
= 8.41 (br s, 1H), 7.63 (s, 1H), 7.43−6.88 (m, 7H), 13C NMR
(CDCl3, 50 MHz) δ = 137.2, 135.1, 131.9, 130.8, 130.6, 128.9, 127.1,
126.2, 122.0, 114.6, 113.1, 102.3.
5-Bromo-3-((4-methoxyphenyl)sulfenyl)-1H-indole (4k).14a
1
0.1436g, Yield: 86%; white solid; mp 99−100 °C; H NMR (400
MHz, CDCl3) δ = 8.40 (br s, 1H), 7.75 (s, 1H), 7.42 (d, J = 2.4 Hz,
1H), 7.34−7.24 (m, 2H), 7.13−7.08 (m, 2H), 6.76−6.72 (m, 2H),
3.73 (s, 3H). NMR (CDCl3, 100 MHz) δ = 157.8, 135.0, 131.1, 130.8,
128.9, 128.6, 125.9, 122.1, 114.5, 114.2, 113.0, 104.5, 55.3.
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Tetrahedron Lett. 2007, 48, 7034−7037. (b) Yadav, J. S.; Subba Reddy,
B. V.; Reddy, Y. J.; Praneeth, K. Synthesis 2009, 1520−1524.
(10) (a) Li, Z.; Hong, J. Q.; Zhou, X. J. Tetrahedron 2011, 67, 3690−
3697. (b) Ge, W.; Wei, Y. Synthesis 2012, 44, 934−940.
(11) Maeda, Y.; Koyabu, M.; Nishimuraand, T.; Uemura, S. J. Org.
Chem. 2004, 69, 7688−7693.
ASSOCIATED CONTENT
■
S
* Supporting Information
All synthesized compounds were characterized by 1H NMR and
13C NMR; unknown compounds were also characterized by
infrared and high resolution mass spectra. This material is
available free of charge via the Internet at http://pubs.acs.org/.
(12) Tudge, M.; Tamiya, M.; Savarin, C.; Humphrey, G. R. Org. Lett.
2006, 8, 565−568.
(13) Matsugi, M.; Murata, K.; Gotanda, K.; Nambu, H.; Anilkumar,
G.; Matsumoto, K.; Kita, Y. J. Org. Chem. 2001, 66, 2434−2441.
(14) (a) Silveira, C. C.; Mendes, S. R.; Wolf, L.; Martins, G. M.
Tetrahedron Lett. 2010, 51, 2014−2016. (b) Zhao, X.; Yu, Z.; Xu, T.;
Wu, P.; Yu, H. Y. Org. Lett. 2007, 9, 5263−5266. (c) Marcantoni, E.;
Cipolletti, R.; Marsili, L.; Menichetti, S.; Properzi, R.; Viglianisi, C. Eur.
J. Org. Chem. 2013, 132−140.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: silveiracc@smail.ufsm.br.
*Fax: 55 48 3721 6427. Tel: 55 48 37216427. E-mail: braga.
antonio@ufsc.br.
■
Notes
(15) Yang, F. L.; Tian, S. K. Angew. Chem., Int. Ed. 2013, 52, 4929−
4932.
The authors declare no competing financial interest.
(16) Wu, Q.; Zhao, D.; Qin, X.; Lan, J.; You, J. Chem. Commun. 2011,
47, 9188−9190.
ACKNOWLEDGMENTS
The authors gratefully acknowledge CAPES, CNPq, FAPERGS,
■
(17) (a) Chen, Y.; Cho, C.; Shi, F.; Larock, R. C. J. Org. Chem. 2009,
74, 6802−6811. (b) Chen, Y.; C. Cho, C.; Larock, R. C. Org. Lett.
2009, 11, 173−176. (c) Li, Z.; Hong, L.; Liu, R.; Shen, J.; Zhou, X.
INCT-Catal
́
ise, and FAPESC for financial support. CNPq is
also acknowledged for the doctorate fellowship received by
J.B.A. Authors are also thankful to CEBIME for HRMS analysis.
Tetrahedron Lett. 2011, 52, 1343−1347. (d) Speranca̧ , A.; Godoi, B.;
Menezes, P. H.; Zeni, G. Synlett 2013, 24, 1125−1132.
(18) Liu, J.; Li, P.; Chen, W.; Wang, L. Chem. Commun. 2012, 48,
10052−10054.
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