Application of FeCl3/diorganyl diselenides to cyclization of o -alkynyl anilines: Synthesis of 3-organoselenyl-(N -methyl)indoles

Article abstract of DOI:10.1055/s-0033-1338427

In this manuscript we described the FeCl₃/diorganyl diselenides promoted intramolecular cyclization of o-alkynyl anilines, as an alternative for the construction of functionalized 3-organoselenyl indoles. The cyclization reactions proceeded smoothly at room temperature in the presence of air giving the 3-organoselenyl indoles in good yields. Additionally, the 3-organoselenyl indoles proved to be quite useful as synthetic intermediates for the construction of more functionalized indole units through a selenium-lithium exchange reaction followed by trapping the lithium intermediate with different electrophiles. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338427

LETTER
▌1125
lAettper plication of FeCl3/Diorganyl Diselenides to Cyclization of o-Alkynyl Anili-
nes: Synthesis of 3-Organoselenyl-(N-methyl)indoles
3-Organoselenyl-(N-methyl)indoles
Adriane Sperança,a Benhur Godoi,b Paulo Henrique Menezes,c Gilson Zeni*a
a
Laboratório de Síntese, Reatividade, Avaliação Farmacológica e Toxicológica de Organocalcogênios, CCNE, UFSM, Santa Maria, Rio
Grande do Sul, CEP 97105-900, Brazil
Fax +55(55)32208978; E-mail: gzeni@ufsm.br
b
Universidade Federal da Fronteira Sul, Cerro Largo, Rio Grande do Sul 97900-000, Brazil
c
Universidade Federal de Pernambuco, Departamento Química Fundamental, Recife, Pernambuco 50670-901, Brazil
Received: 11.02.2013; Accepted after revision: 26.03.2013
ing cross-coupling reactions,9 carbon–heteroatom bond
Abstract: In this manuscript we described the FeCl3/diorganyl di-
formation10 and intramolecular cyclization processes.11
selenides promoted intramolecular cyclization of o-alkynyl ani-
We have described the use of FeCl3/diorganyl dichalco-
genides as a promising reaction system for the preparation
lines, as an alternative for the construction of functionalized 3-
organoselenyl indoles. The cyclization reactions proceeded
smoothly at room temperature in the presence of air giving the 3-or- of different heterocyclic units under mild reaction condi-
tions.12 In the organochalcogen chemistry there is a grow-
ganoselenyl indoles in good yields. Additionally, the 3-organo-
selenyl indoles proved to be quite useful as synthetic intermediates
for the construction of more functionalized indole units through a
bonds, such as chalcogen-containing heterocycles, espe-
selenium–lithium exchange reaction followed by trapping the lithi-
um intermediate with different electrophiles.
ing interest in the formation of new C(sp2)–chalcogen
cially due to their biological properties13 as well as versa-
tility as intermediates in organic synthesis.14 For instance,
Key words: indole, iron salt, cyclization, selenium
organoselenium groups constitute a very interesting reac-
tive site since the carbon–chalcogen bond can be readily
replaced by carbon–hydrogen,15 carbon–halogen16 and
carbon–carbon bonds.17 Regarding the potential toxicity
of organochalcogen compounds, in particular diorganyl
diselenides, they are considered toxic in high doses, but
are known to provide pharmacological effects when em-
ployed in low doses.18 Based on the pharmacological and
synthetic importance of organochalcogen compounds, the
implication of indoles in the field of chemistry and medic-
inal chemistry and the growing application of iron salts in
the cyclization process, we have described herein an alter-
native approach for the preparation of functionalized 3-or-
ganochalcogen indoles 2 through the FeCl3/diorganyl
diselenide mediated intramolecular cyclization reaction of
o-alkynyl anilines 1 (Scheme 1).
N-Heterocyclic derivatives have a prominent position in
synthetic organic chemistry, due to their important phar-
macological properties including antiviral and antifungal
activities.1 In this context, the indole unit is one of the
most prevalent heterocyclic nucleus found in natural
products and therapeutic agents.2 Indole derivatives are
known to be active in the treatment of different diseases
such as HIV,3 obesity,4 cancer5 and heart-related disor-
ders.6 For this reason, the synthetic chemists are constant-
ly interested in the development of alternative methods for
the construction of functionalized indole skeletons. In this
sense, much progress has been made over the past ten
years on the synthesis of substituted indoles. Among
them, the Larock indole synthesis constitutes the most at-
tractive and practical method for this purpose.7 Moreover,
indole heterocyclic nuclei have been constructed through
electrophilic cyclization reactions of o-alkynyl anilines by
employing different halogen-based electrophilic sources
as well as organochalcogen electrophilic species as the
cyclization agents.8 The main advantage of these methods
lies in the potential synthetic application of the resulting
halogen or organochalcogen functionalities, enabling the
further preparation of more complex structures. In the last
years, the necessity of developing synthetic methodolo-
gies involving environmentally friendly processes has in-
fluenced chemists to study alternative reagents for
classical reactions. In this way, iron salts have been used
as promoter agents in many synthetic approaches includ-
..
R2
SeR3
R2
R1
R1
FeCl3, R3SeSeR3
CH2Cl2, air, 25 °C
N
NMe2
Me
1
2
R1 = H, Me, Cl; R2, R3 = alkyl, aryl
Scheme 1
In order to determine the ideal reaction conditions for the
iron(III)/diorganyl diselenide mediated intramolecular
cyclization of o-alkynyl anilines 1, we performed a series
of experiments by varying different reaction parameters
using the o-alkynyl aniline 1a and diphenyl diselenide as
standard substrates (Table 1). Using the previously opti-
mized cyclization conditions that we applied for the syn-
thesis of chromenone derivatives,19 the desired cyclized
product 2a was obtained in 51% yield (Table 1, entry 1).
SYNLETT 2013, 24, 1125–1132
Advanced online publication: 23.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338427; Art ID: ST-2013-S0135-L
© Georg Thieme Verlag Stuttgart · New York

1126
A. Sperança et al.
LETTER
During the optimization studies we screened different
combinations of FeCl3 and diphenyl diselenide amounts
(Table 1, entries 1–6). When we employed 1.5 equivalents
of FeCl3 and increased the diphenyl diselenide amount
from 0.5 equivalent to 1.0 equivalent, an improvement in
the reaction yields was observed giving the indole 2a in
61% and 64% yields, respectively (Table 1, entries 2 and
3). The cyclization reaction proved to be influenced by the
FeCl3 amount since the efficiency of the cyclization sys-
tem was improved when the FeCl3 amount was increased
from 1.5 equivalents to 2.0 equivalents leading to the ex-
pected 3-phenylselenylindole 2a in 86% and 81% yields,
respectively (Table 1, entries 4 and 5). However, the use
of 3.0 equivalents of FeCl3 led to a decrease in the yield
for the cyclization (Table 1, entry 7). It is important to
point out that this cyclization protocol presents an impor-
tant economic advantage once it was tolerant to the pres-
ence of air in the reaction system and was run at room
temperature (Table 1, entries 8 and 9). By studying the in-
fluence of the solvent nature, we found that the cyclization
reaction was most effective with dichloromethane as sol-
vent. The use of other solvents, such as DCE, dioxane,
MeCN, DMF, MeNO2 and THF gave only poor yields of
the 3-phenylselenylindole 2a (Table 1, entries 10–15). In
most of these cases, the presence of a heteroatom in the
solvent structure, which could potentially act as a Lewis
base, can be the main factor for these undesirable reaction
behaviors by causing a partial or complete inactivation of
the iron(III) Lewis acid species. The iron(III) chloride
also proved to play an important role in this cyclization
system since the hydrous iron species FeCl3·6H2O and
FeCl2·4H2O proved to be ineffective in promoting the cy-
clization of the o-alkynyl aniline 1a (Table 1, entries 16
and 17). In the same way, other iron sources, such as
Fe(acac)3 and Fe0 were demonstrated to be not effective in
this cyclization reaction (Table 1, entries 18 and 19). It
suggests that chlorine atoms must play a key role in the
cyclization reaction as we have demonstrated in a previ-
ous work.12 At various intervals during the optimization
reactions, samples of the reaction mixture were analyzed
by TLC which showed that a reaction time of 24 hours
was necessary for the complete consumption of the start-
ing material. In accordance with the above experiments,
we found that the optimum set of reaction parameters to
promote the intramolecular cyclization of the o-alkynyl
aniline 1a consists of the use of FeCl3 (2.0 equiv), diphe-
nyl diselenide (0.75 equiv), dichloromethane as solvent at
room temperature for 24 hours carrying out the reaction
into a flask open to the air atmosphere. Through these re-
action conditions the desired 3-phenylselenylaniline 2a
was obtained in 81% yield (Table 1, entry 5).
Table 1 Influence of Reaction Parameters in the Iron(III)/Diphenyl
Diselenide Mediated Cyclization Reaction of the o-Alkynyl Aniline
1a
Ph
SePh
iron salt, PhSeSePh
Ph
solvent, temperature
N
NMe2
Me
2a
1a
Entry
Iron salt
(equiv)
Solvent
(PhSe)2
(equiv)
Yield
(%)a
1
2
FeCl3 (1.5)
FeCl3 (1.5)
FeCl3 (1.5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
0.5
51
61
64
86
81
70
60
78b
49c
42
traces
15
–
0.75
1.0
3
4
FeCl3 (2)
1.0
FeCl3 (2)
5
0.75
0.6
6
FeCl3 (2)
FeCl3 (3)
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3·6H2O (2)
FeCl2·4H2O (2)
Fe(acac)3 (2)
Fe0 (2)
7
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
–
8
9
10
11
12
13
14
15
16
17
18
19
20
21
dioxane
MeCN
DMF
MeNO2
THF
28
10
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
FeCl3 (2)
–
–
0.75
–
a The reaction was performed using 1a (0.25 mmol) and solvent
(5 mL) in the presence of air, at 25 °C for 24 h.
b The reaction was carried out under an argon atmosphere.
c The reaction was performed at reflux temperature.
mechanistic aspects. For example, when the o-alkynyl an-
iline 1a was submitted to the optimized condition (Table
1, entry 5) in the absence of diphenyl diselenide, neither
3-phenylselenylaniline 2a nor the cyclized product 3a was
obtained (Scheme 2). These results suggest that the FeCl3-
mediated cyclization of 1a followed by an in situ replace-
ment of the C–Fe bond by an electrophilic organoseleni-
um species could be discarded (Scheme 2, equation 1).
Similarly, when the o-alkynyl aniline 1a was submitted to
the optimized condition (Table 1, entry 5) in the absence
of the iron(III) salt, no traces of the indole 2a were detect-
A plausible mechanism for this FeCl3/diorganyl disele-
nide mediated intramolecular cyclization process is still
unclear and an extensive study is needed in order to better
understand this recent and versatile synthetic tool. Our
group has continuously worked to increase the knowledge
about this reaction system. With this aim, we carried out
some experiments that could help to understand some
Synlett 2013, 24, 1125–1132
© Georg Thieme Verlag Stuttgart · New York

LETTER
3-Organoselenyl-(N-methyl)indoles
1127
SePh
PhSe+
(1)
(2)
Ph
Ph
Fe
N
Me
2a
3a
FeCl3 (2.0 equiv)
CH2Cl2, 25 °C, air
Ph
H
N
NMe2
Me
1a
H+
(3)
Ph
N
Me
SeCl
FeCl3, CH2Cl2
25 °C, air atmosphere
Se
Se
Scheme 2
ed and the starting aniline 1a was recovered quantitatively Alkynyl anilines containing electron-rich groups in the ar-
(Table 1, entry 21). By analyzing the above experiments omatic ring afforded the expected indoles 2h–j in reason-
it became clear that the cyclization depends on the con- able yields (Table 2, entries 8–10). However, the presence
comitant presence of FeCl3 with diphenyl diselenide. Fi- of an electron-withdrawing and a bulky naphthalene
nally, the classical electrophilic cyclization pathway, groups next to the triple bond led to a slight decrease in the
involving an electrophilic species of diorganyl diselenide cyclization yield furnishing 3-phenylselenylindoles 2k
(PhSeCl) as the active cyclization agent, seems to be un- and 2m in 52% and 50% yields, respectively (Table 2, en-
feasible. This conclusion is supported by the fact that no tries 11 and 14). When anilines 1f and 1g bearing butyl
PhSeCl20 was detected, by GC–MS analysis of the reac- and hexyl groups directly bonded to the triple bond were
tion under the optimized conditions, in the absence of the submitted to the cyclization conditions, the corresponding
starting 1a (Scheme 2, equation 3). However, the in situ 3-phenylselenylindoles 2l and 2m were obtained in good
formation of PhSeCl cannot be totally discarded.
yields (Table 2, entries 12 and 13). In order to better un-
derstand the electronic influence of the aromatic substitu-
ents on the cyclization efficiency, we submitted the o-
alkynyl aniline derivatives 1i and 1j, which contain an
electron-donating and an electron-withdrawing group in
the aniline ring, respectively, to the cyclization conditions
(Table 2, entries 15–20). Through these experiments, we
realized that the presence of neutral and electron-donating
aryl groups in both substrates does not harmfully affect
the cyclization behavior and the indoles 2o and 2p were
synthesized in good yields (Table 2, entries 15 and 16).
On the other hand, a decrease in the cyclization efficiency
was observed when the substrate 1i reacted in the pres-
ence of a diorganyl diselenide bearing an electron-with-
drawing chlorine atom in the aromatic ring, affording the
expected product 2q in 50% yield (Table 2, entry 17). The
presence of an electron-withdrawing chlorine atom in the
aniline ring of the substrate 1j caused a significant de-
crease in the reaction yield, giving the product 2r in 61%
yield (Table 2, compare entries 1 and 18). Similarly, when
the o-alkynyl aniline 1j was submitted to the cyclization
conditions by using the bis(4-chlorophenyl)diselenide the
desired indole derivative 2t was obtained in only 37%
yield (Table 2, entry 20). This result was expected, since
both substrates contain an electron-withdrawing chlorine
atom in their aromatic rings. According to the last experi-
ments, we concluded that the cyclization reaction of the
o-alkynyl anilines 1 is strongly influenced by electronic
effects from the substituents in the aniline ring and the di-
organyl diselenide aromatic rings, in particular electron-
withdrawing groups led to a significant decrease in the
cyclization efficiency.
In order to extend the scope of this methodology, allowing
an easy access to 3-organoselenyl anilines,21 we prepared
various o-alkynyl anilines22 and diorganyl diselenides
bearing different substituents and studied their cyclization
behavior under optimized conditions described in Table 1.
In general, this synthetic method proved to be versatile,
being tolerant to a number of functionalities. Initially, we
examined the influence of electronic and steric effects of
different groups bonded to the selenium atom from substi-
tuted diorganyl diselenides (Table 2, entries 1–7). The cy-
clization process was shown to be tolerant to neutral,
electron-withdrawing and electron-donating aromatic
rings directly bonded to the chalcogen atom leading to the
expected indoles 2a–e in moderate to good yields. How-
ever, the presence of electron-withdrawing groups (F and
CF3) on the aromatic rings led to lower yields for the cy-
clized products (Table 2, entries 3 and 4). When the dibu-
tyl diselenide was employed as the organochalcogen
source the corresponding 3-butylselenylindole 2f was iso-
lated in 52% yield (Table 2, entry 6). These results are sig-
nificant since the alkyl group directly bonded to the
selenium atom could undergo β-selenoxide elimination
giving the indole without the organoselenium group in-
corporated in the structure. The cyclization reaction
proved to be extremely influenced by steric effects from
diorganyl diselenides. For example, the cyclization reac-
tion using the sterically hindered bis(naphthalen-1-yl) dis-
elenide gave the corresponding indole derivative 2g in
36% yield (Table 2, entry 7). Next, we studied the influ-
ence of different aryl and alkyl groups directly bonded to
the carbon–carbon triple bond (Table 2, entries 8–14). o-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1125–1132

1128
A. Sperança et al.
LETTER
Table 2 Synthesis of 3-Organoselenyl Indoles 2a–t
R2
SeR3
R2
R1
FeCl3 (2 equiv),
R1
diselenide (0.75 equiv)
CH2Cl2 (5 mL), air, 25 °C
N
NMe2
Me
1
2
Entry
o-Alkynyl aniline
R3SeSeR3
Product (yield%)a
Ph
SePh
Ph
1
Se)2
N
NMe2
Me
2a (81%)
1a
Cl
Se
Ph
Cl
Se)2
2
3
4
1a
1a
1a
N
Me
2b (60%)
F
Se
Ph
F
Se)2
N
Me
2c (53%)
Se
Ph
F3C
CF3
Se)2
N
Me
2d (45%)
Me
Se
Ph
Me
Se)2
5
6
1a
1a
N
Me
2e (67%)
SeBu
Ph
(n-BuSe)2
N
Me
2f (52%)
Se)2
Se
Ph
7
1a
N
Me
2g (36%)
Synlett 2013, 24, 1125–1132
© Georg Thieme Verlag Stuttgart · New York

LETTER
3-Organoselenyl-(N-methyl)indoles
1129
Table 2 Synthesis of 3-Organoselenyl Indoles 2a–t (continued)
R2
SeR3
R1
R1
FeCl3 (2 equiv),
diselenide (0.75 equiv)
R2
CH2Cl2 (5 mL), air, 25 °C
N
NMe2
Me
1
2
Entry
o-Alkynyl aniline
R3SeSeR3
Product (yield%)a
SePh
8
Me
Se)2
Se)2
Se)2
N
Me
Me
NMe2
2h (57%)
1b
1c
SePh
Me
Me
9
10
11
N
Me
Me
NMe2
2i (55%)
SePh
Me
N
Me
NMe2
2j (72%)
1d
Cl
SePh
Cl
Se)2
N
Me
NMe2
NMe2
NMe2
2k (52%)
1e
1f
Bu
SePh
Bu
Se)2
12
13
N
Me
2l (70%)
Hex
SePh
Hex
Se)2
N
Me
2m (69%)
1g
SePh
N
Se)2
14
Me
NMe2
2n (50%)
1h
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1125–1132

1130
A. Sperança et al.
LETTER
Table 2 Synthesis of 3-Organoselenyl Indoles 2a–t (continued)
R2
SeR3
R1
R1
FeCl3 (2 equiv),
diselenide (0.75 equiv)
R2
CH2Cl2 (5 mL), air, 25 °C
o-Alkynyl aniline
Me
N
NMe2
Me
1
2
Entry
R3SeSeR3
Product (yield%)a
Ph
SePh
Me
Ph
Ph
Ph
15
Se)2
N
NMe2
Me
2o (75%)
1i
Me
Se
Me
Me
Se)2
16
1i
1i
N
Me
2p (72%)
Cl
Se
Me
Cl
Se)2
17
18
19
N
Me
2q (51%)
Ph
SePh
Cl
Cl
Ph
Ph
Ph
Se)2
N
NMe2
Me
2r (61%)
1j
Me
Se
Cl
Me
Se)2
1j
1j
N
Me
2s (75%)
Cl
Se
Cl
Cl
Se)2
20
N
Me
2t (37%)
a The reaction was performed in the presence of 1 (0.25 mmol), diorganyl diselenide (0.75 equiv), FeCl3 (2.0 equiv), using CH2Cl2 (5 mL) as
solvent, in the presence of air (open tube), at 25 °C for 24 h.
In order to evaluate the synthetic applicability of 3-or- the obtained indoles 2a and 2o with n-butyllithium which
ganoselenyl indole derivatives, we tested their versatility gave the corresponding indolyllithium intermediate A that
as precursors for the preparation of more elaborate indole was trapped by different electrophiles affording the target
derivatives. In fact, the resulting organoselenyl group may molecules 3a–d in reasonable yields (Scheme 3).
potentially undergo chalcogen–lithium exchange reac-
In summary, in this manuscript we have described an al-
tions, which constitute a useful synthetic tool for the con-
ternative synthetic protocol for the preparation of 3-or-
struction of highly functionalized organic molecules;23
ganoselenyl indole derivatives via FeCl3/diorganyl
diselenides promoted intramolecular cyclization of o-al-
kynyl anilines. Through this cyclization method the prep-
once generated the organolithium species can be trapped
by different electrophilic reagents. In this way, we reacted
Synlett 2013, 24, 1125–1132
© Georg Thieme Verlag Stuttgart · New York

LETTER
3-Organoselenyl-(N-methyl)indoles
1131
(d) Kidwai, M.; Venktaramanan, R.; Mohan, R.; Sapra, P.
Curr. Med. Chem. 2002, 9, 1209.
(2) Bandgar, B. P.; Sarangdhar, R. J.; Viswakarma, S.; Ahamed,
F. A. J. Med. Chem. 2011, 54, 1191.
E
SePh
Ph
R1
1. n-BuLi (2.5 equiv),
THF, 0 °C, 15 min
R1
Ph
N
N
2. electrophile, THF,
0 °C to 25 °C, 1 h
Me
Me
(3) (a) Ragno, R.; Coluccia, A.; La Regina, G.; De Martino, G.;
Piscitelli, F.; Lavecchia, A.; Novellino, E.; Bergamini, A.;
Ciaprini, C.; Sinistro, A.; Maga, G.; Crespan, E.; Artico, M.;
Silvestri, R. J. Med. Chem. 2006, 49, 3172. (b) Silvestri, R.;
Artico, M.; Bruno, B.; Massa, S.; Novellino, E.; Greco, G.;
Marongiu, M. E.; Pani, A.; De Montis, A.; La Colla, P.
Antiviral Chem. Chemother. 1998, 9, 139.
(4) (a) Choia, Y.; Kima, Y.; Parka, S.; Leeb, K. W.; Parka, T. J.
Nutr. Biochem. 2012, 23, 1732. (b) Sashidhara, K. V.;
Kumar, M.; Sonkar, R.; Singh, B. S.; Khanna, A. K.; Bhatia,
G. J. Med. Chem. 2012, 55, 2769.
(5) 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.
(6) Funk, C. D. Nat. Rev. Drug Discov. 2005, 4, 664.
(7) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113,
6689.
2a,o
3a–d
Li
R1
Ph
N
Me
A
R1 = H, Me; electrophile = H2O, Br2, I2; E = H, Br, I
Br
Me
Ph
Ph
N
Me
N
Me
3c (50%)
I
3a (62%)
Me
Me
Ph
Ph
N
N
Me
3b (60%)
Me
3d (45%)
Scheme 3
(8) (a) Du, H.-A.; Tang, R.-Y.; Deng, C.-L.; Liu, Y.; Li, J.-H.;
Zhang, X.-G. Adv. Synth. Catal. 2011, 353, 2739. (b) Chen,
Y.; Cho, C.-H.; Shi, F.; Larock, R. C. J. Org. Chem. 2009,
74, 6802. (c) Chen, Y.; Cho, C.-H.; Shi, F.; Larock, R. C.
Org. Lett. 2009, 11, 173. (d) Zhen, Li. Z.; Hong, L.; Liu, R.;
Shen, J.; Zhou, Z. Tetrahedron Lett. 2011, 52, 1343. (e) Liu,
J.; Li, P.; Chenb, W.; Wang, L. Chem. Commun. 2012, 48,
10052.
(9) (a) Fürstner, A.; Leitner, A.; Méndez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856. (b) Fürstner, A.; Leitner, A.
Angew. Chem. Int. Ed. 2002, 41, 609. (c) Seidel, G.; Laurich,
D.; Fürstner, A. J. Org. Chem. 2004, 69, 3950. (d) Fürstner,
A.; Schlecker, A.; Lehmann, C. W. Chem. Commun. 2007,
4277. (e) Bonnamour, J.; Bolm, C. Org. Lett. 2011, 13,
2012.
(10) (a) Correa, A.; Bolm, C. Angew. Chem. Int. Ed. 2007, 46,
8862. (b) Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem. Int.
Ed. 2007, 46, 934. (c) Buchwald, S. L.; Bolm, C. Angew.
Chem. Int. Ed. 2009, 48, 5586. (d) Bistri, O.; Correa, A.;
Bolm, C. Angew. Chem. Int. Ed. 2008, 47, 586. (e) Correa,
A.; Carril, M.; Bolm, C. Angew. Chem. Int. Ed. 2008, 47,
2880.
(11) (a) Zhao, M.-N.; Liang, H.; Ren, Z.-H.; Guan, Z.-H. Adv.
Synth. Catal. 2013, 355, 221. (b) Peng Liu, P.; Li, Y.; Wang,
H.; Wang, Z.; Hu, X. Tetrahedron Lett. 2012, 53, 6654.
(c) Liu, P.; Wang, Z. M.; Lin, J.; Hu, X. M. Eur. J. Org.
Chem. 2012, 1583. (d) Guan, Z.-H.; Yan, Z.-Y.; Ren, Z.-H.;
Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2010, 46, 2823.
(e) Mukherjee, A.; Pati, K.; Liu, R.-S. J. Org. Chem. 2009,
74, 6311. (f) Wang, J.; Zhang, L.; Jing, Y.; Huang, W.;
Zhou, X. Tetrahedron Lett. 2009, 50, 4978.
aration of highly functionalized indole heterocyclic units
became achievable in moderate to good yields. This syn-
thetic approach presents important economic and environ-
mental advantages including atom and energy economy.
Besides, the cyclization reactions were carried out at room
temperature, in the presence of air (open flask) and both
RSe moieties from diorganyl diselenides (RSeSeR) were
incorporated in the final product. The 3-organoselenyl in-
doles obtained during this work proved to be convenient
synthetic intermediates for the synthesis of more substi-
tuted indole nucleus; in particular the 3-phenylselenylin-
dole 2o furnished the desired 3-bromo- and 3-iodoindole
derivatives 3c and 3d, via selenium–lithium exchange re-
action followed by trapping of the indolyllithium interme-
diate by bromine and iodine. All 3-organoselenyl indole
derivatives 2 were isolated and purified by flash chroma-
tography column. In general, these compounds do not
present an irritant or nasty odor and could be stored under
refrigeration in a simple glass vial for at least one month.
Acknowledgment
The financial support by UFSM, CAPES, FAPERGS (PRONEX re-
search grant # 10/0005-1) and CNPq (INCT-catalise) is gratefully
acknowledged. We thank CNPq for fellowships.
(12) Gai, B. M.; Stein, A. L.; Roehrs, J. A.; Bilheri, F. N.;
Nogueira, C. W.; Zeni, G. Org. Biomol. Chem. 2012, 10,
798.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(13) Nogueira, C. W.; Rocha, J. B. T. J. Braz. Chem. Soc. 2010,
21, 2055.
(14) Perin, G.; Leonardão, E. J.; Jacob, R. G.; Panatieri, R. B.
Chem. Rev. 2009, 109, 1277.
(15) Sevrin, M.; Vanende, D.; Krief, A. Tetrahedron Lett. 1976,
2643.
(16) Sevrin, M.; Dumont, W.; Hevesi, L. D.; Krief, A.
Tetrahedron Lett. 1976, 2647.
References and Notes
(1) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Curr. Opin.
Drug Discov. Dev. 2010, 13, 685. (b) Gupta, S.; Rodrigues,
L. M.; Esteves, A. P.; Oliveira-Campos, A. M. F.;
Nacimento, M. S. J.; Nazareth, N.; Cidade, H.; Neves, M. P.;
Fernandes, E.; Pinto, M.; Cerqueira, N. M. F. S. A.; Brás, N.
Eur. J. Med. Chem. 2008, 43, 771. (c) Garuti, L.; Roberti,
M.; Pizzirani, D. Mini Rev. Med. Chem. 2007, 7, 481.
(17) Silveira, C. C.; Braga, A. L.; Vieira, A. S.; Zeni, G. J. Org.
Chem. 2003, 68, 662.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1125–1132

1132
A. Sperança et al.
LETTER
(18) (a) Meotti, F. C.; Borges, V. C.; Zeni, G.; Rocha, J. B. T.;
Nogueira, C. W. Toxicol. Lett. 2003, 143, 9. (b) Nogueira, C.
W.; Meotti, F. C.; Curte, E.; Pilissao, C.; Zeni, G.; Rocha, J.
B. T. Toxicology 2003, 183, 29.
(19) Godoi, B.; Sperança, A.; Bruning, C. A.; Back, D. F.;
Menezes, P. H.; Nogueira, C. W.; Zeni, G. Adv. Synth. Catal.
2011, 353, 2042.
(20) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936.
(21) General Procedure for the FeCl3/Diorganyl Diselenide
Promoted Cyclization of o-Alkynyl Anilines: In a Schlenk
tube, open to the air, containing CH2Cl2 (3 mL) were added
FeCl3 (0.081 g, 2 equiv) and the diorganyl diselenide (0.061
g, 0.75 equiv). The reaction mixture was stirred for 20 min
at r.t. After this time, o-alkynyl aniline (0.25 mmol) was
added diluted in CH2Cl2 (2 mL). The reaction mixture was
stirred at r.t. for the required time. After that, the reaction
mixture was diluted with CH2Cl2 (20 mL) and washed with
a sat. aq solution of NaHCO3 (3 × 10 mL). The organic phase
was separated, dried over MgSO4, and concentrated under
vacuum. The residue was purified by flash chromatography,
using hexane as eluent. N-Methyl-2-phenyl-3-
(phenylselenyl)-1H-indole (2a): obtained as a pale yellow
oil; yield: 0.073 g (81%). 1H NMR (200 MHz, CDCl3): δ =
7.64–7.68 (m, 1 H), 7.26–7.44 (m, 7 H), 7.04–7.22 (m, 6 H),
3.70 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 145.8, 137.7,
134.5, 131.2, 130.7, 130.6, 128.8, 128.6, 128.4, 128.0,
125.2, 122.6, 120.8, 120.6, 109.6, 96.5, 31.6. MS (relative
intensity): m/z = 363 (19), 283 (100), 267 (12), 204 (12), 165
(7), 141 (7), 77 (3), 51 (2). HRMS: m/z calcd for C21H17NSe:
363.0526; found: 363.0539.
(22) González-Gómez, A.; Domínguez, G.; Pérez-Castells, J.
Eur. J. Org. Chem. 2009, 2057.
(23) (a) Reich, H. J.; Bowe, M. D. J. Am. Chem. Soc. 1990, 112,
8994. (b) Reich, H. J.; Bevan, M. J.; Gudmundsson, B. O.;
Puckett, C. L. Angew. Chem. Int. Ed. 2002, 41, 3436.
Synlett 2013, 24, 1125–1132
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.