An efficient synthesis of 2-bromo(chloro)-3-selenyl(sulfenyl)indoles via tandem reactions of 2-(gem-dibromo(chloro)vinyl)anilines with diselenides(disulfides)

Article abstract of DOI:10.1039/c2cc34800d

A novel and efficient synthesis of 2-bromo(chloro)-3-selenyl(sulfenyl) indoles through tandem reactions of 2-(gem-dibromo(chloro)vinyl)-N- methylsulfonylanilines with diselenides and disulfides in the presence of t-BuOLi and I₂ (10 mol%) in DMS

Full text of DOI:10.1039/c2cc34800d

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An efficient synthesis of 2-bromo(chloro)-3-selenyl(sulfenyl)indoles via
tandem reactions of 2-(gem-dibromo(chloro)vinyl)anilines with
diselenides(disulfides)w
Jie Liu,ab Pinhua Li,b Wei Chenb and Lei Wang*abc
Received 5th July 2012, Accepted 23rd August 2012
DOI: 10.1039/c2cc34800d
A novel and efficient synthesis of 2-bromo(chloro)-3-selenyl(sulfenyl)-
indoles through tandem reactions of 2-(gem-dibromo(chloro)vinyl)-
N-methylsulfonylanilines with diselenides and disulfides in the
presence of t-BuOLi and I2 (10 mol%) in DMSO was developed.
The reactions generated the desired products in good yields with high
regio-selectivity under transition-metal-free conditions in one-pot.
tandem reactions,12 have been developed. Most importantly,
2-bromoindoles from 2-(gem-dibromovinyl)anilines for the first
time via Pd-catalyzed intramolecular reactions by Lautens et al.13
As a part of our interest in the organic transformations of
gem-dihaloolefins under metal-free conditions,14 herein we wish to
report
a novel and efficient tandem reaction of 2-(gem-
dibromo(chloro)vinyl)-N-methylsulfonylanilines with diselenides
and disulfides. In the presence of t-BuOLi and I2, the one-pot
reactions generated the corresponding 2-bromo(chloro)-3-
selenyl(sulfenyl)indoles in good yields in DMSO with high regio-
selectivity under transition-metal free conditions (Scheme 1).
At the beginning of our investigation, a model reaction of
2-(gem-dibromovinyl)-N-methylsulfonylaniline (1a) with diphenyl-
diselenide (2a) in 2 : 1 molar ratio was employed to optimize the
reaction conditions and the results are summarized in Table 1.
Initially, a series of bases were tested, t-BuOLi was found to be the
best one in the presence of I2 in DMSO (Table 1, entry 1). Na2CO3,
K2CO3 and Cs2CO3 exhibited the comparable reactivity to t-BuOLi
(Table 1, entries 2À4). Other bases, TBAF, Et3N, NaOAc, K3PO4,
t-BuONa, and t-BuOK, were less effective (Table 1, entries 5À10).
Next, the effect of solvents was examined. DMSO was the best
reaction media when the model reaction was carried out in the
presence of t-BuOLi and I2 (10 mol%). Significantly lower
yields (17À41%) of 3a were obtained when DMF, NMP,
C2H5OH and CH3CN were used as solvents instead of DMSO
(Table 1, entries 11À14). Unfortunately, no product was
detected when DCE, DME, dioxane and THF were used as
solvents (Table 1, entries 15À19). When the model reaction was
performed in the absence of I2, poor yield of 3a was obtained
(Table 1, entry 20). When other ‘I’ sources such as HI, TBAI
and ICl were used, HI gave a comparable yield of 3a with I2,
TBAI and ICl were inferior (Table 1, entries 21À23).
Organochalcogen compounds are of considerable interest in
organic synthesis and the pharmaceutical industry due to their
synthetic versatility and wide applications.1 To synthesize
them, dichalcogenides are often used as substrates since they
are stable and easy to handle in air,2 and the general method is
based on the reaction of dichalcogenides with appropriate
electrophiles, such as organic halides, acyl chlorides, etc.3
Indole derivatives are widely used as dyes, natural products,
materials, and pharmaceutical ingredients, as well as starting
materials for the synthesis of a large number of alkaloids.4 Among
the numerous indole nuclei, 3-selenylindoles and 3-sulfenylindoles
have attracted considerable interest due to their curative effect
in diseases, such as HIV, obesity, cancer, and heart disease.5
Generally, the preparation of such compounds is achieved by the
direct selenylations and sulfenylations at the 3-position of indoles.
Selenylating and sulfenylating agents, such as thiols, disulfides,
diselenides, selenyl and sulfenyl halides, and quinone mono-O,S-
acetals, have been reported.6 However, these methods are limited
not only by the requirements of indole derivatives as starting
materials, but also by the necessity of a transition-metal as catalyst.
gem-Dihaloolefins have received great attention because of
their higher reactivity and ready accessibility from aldehydes.7
Especially, the synthesis of various indole derivatives from
2-(gem-dibromovinyl)anilines via the transition-metal-catalyzed
cross-coupling reactions, such as C–N/C–C,8 C–N/C–N,9 C–N/
C–H,10 C–N–carbonylation,11 and C–N–carbonylation–C–C
Next, other N-substituted derivatives of 2-(gem-dibromovinyl)-
aniline, such as N-benzyl, N-tert-butoxycarbonyl, N-acetyl, and
N-trifluoroacetyl ones, were used instead of 1a under t-BuOLi–
I2–DMSO conditions, but, no desired 3a was detected.
a College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou, Jiangsu 215123, P R China
b Department of Chemistry, Huaibei Normal University, Huaibei,
Anhui 235000, P R China. E-mail: leiwang@chnu.edu.cn;
Fax: +86 561 309 0518; Tel: +86 561 380 2069
c State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P R China
w Electronic supplementary information (ESI) available. See DOI: 10.
1039/c2cc34800d
Scheme 1
c
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Table 1 Optimization of the reaction conditions for the model
reaction of 1a with 2aa
Entry
Base
‘I’ source
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
t-BuOLi
Na2CO3
K2CO3
Cs2CO3
TBAF
Et3N
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
––
HI
TBAI
ICl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
85
75
71
69
34
27
25
21
15
12
41
34
28
17
0
0
0
0
0
23
79
38
26
NaOAc
K3PO4
9
t-BuONa
t-BuOK
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NMP
C2H5OH
CH3CN
Toluene
DCE
DME
Dioxane
THF
DMSO
DMSO
DMSO
DMSO
a
Reaction conditions: 1a (0.50 mmol), 2a (0.25 mmol), base
(1.0 mmol), ‘I’ source (0.050 mmol), solvent (2.0 mL), sealed tube,
b
110 1C, air, 12 h. Isolated yields.
Scheme 2 The reactions of 2-(gem-dibromo(chloro)vinyl)-N-methyl-
sulfonylanilines with diphenyldiselenide(disulfide)a.
2-(gem-Dibromovinyl)-N-(p-tolylsulfonyl)aniline was inferior to
1a, and generated 3a in 72% yield. When 2-(gem-dibromovinyl)-
aniline was used instead of 1a, the reaction did not occur. The
results indicated that this tandem reaction depends on the nitrogen
substituents of substrates. When the amine is activated by a strong
electron-withdrawing group such as sulfonyl, the tandem reaction
can occur efficiently in one-pot. Here, the sulfonyl linker serves as
a dual-activating group to undergo indole cyclization.
substrates 1, without a substituted group or bearing the electron-
donating groups on the aromatic rings, also conducted the reactions
smoothly and afforded the corresponding products in good yields
(Scheme 2, 4aÀj). 2-(gem-Dichlorovinyl)-N-methylsulfonylaniline
(1j) also reacted with 2b to generate 4j in 80% yield. It is worth
mentioning that gem-dibromoolefins with the electron-withdrawing
substitution on the aromatic ring could react with 2b, but, the
product yield was low (Scheme 2, 4k). However, the present method
was not suitable for alkyl disulfides.
Under the optimized conditions, the reaction scope of 2-(gem-
dibromovinyl)-N-methylsulfonylanilines (1) with 1,2-diphenyldisel-
enide (2a) was examined. Substrates 1 with the electron-donating
groups on the benzene rings reacted with 2a smoothly and
generated the corresponding products in good yields (Scheme 2,
3b, 3c, 3i). Halogen substituents on the aromatic rings of 1dÀh
were also tolerated, affording good yields of polyhalogenated
indole derivatives 3dÀh, which provides an attractive route for
their further transformation into natural and unnatural product
skeletons via transition-metal-catalyzed reactions. It is obvious
that there is no ortho-position effect of 1 in the tandem reactions
(3h and 3i). Notably, 2-(gem-dichlorovinyl)-N-methylsulfonyl-
aniline (1j) could also proceed with the tandem reaction to
generate the corresponding product 3j in good yield under the
present reaction conditions. However, 2-(gem-dibromovinyl)-
N-methylsulfonylaniline 1k with an electron-withdrawing
substitution on the aromatic ring did not proceed the reaction
with 2a (Scheme 2, 3k).
To further investigate the application of the obtained products
through transition-metal-catalyzed organic transformation, 4a
reacted with 4-methoxyphenylboronic acid under the classic
Suzuki reaction conditions, and the cross-coupling product 5a
was obtained in 92% yield (Scheme 3). This transformation is
an introduction of an aryl group to the 2-position of 4a via
carbon–carbon formation to afford a complicated indole scaffold.
When the reaction of 1a in the absence of 2a or 2b was
performed under t-BuOLi–DMSO conditions without I2,
an intermediate 2-bromoindole (6a) was isolated in 41%
yield (Scheme 4, eqn (1)). To further investigate the reaction
mechanism, the isotope experiments were conducted. When
the reaction of deuterium-labeled 1a-D was performed in
DMSO–t-BuOLi, 6a was obtained in 40% yield and 100%
D-enriched element was lost in the product (Scheme 4, eqn (2)).
These results suggested that the intramolecular tandem cyclization
of 1a was through a key intermediate phenylethynyl bromide,15
On the other hand, the tandem reaction of 1 with diphenyl-
disulfide (2b) was also examined. The results indicated that
c
Chem. Commun.
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This work was financially supported by the National Science
Foundation of China (No. 21172092 and 20972057).
Notes and references
1 (a) A. Krief and L. Hevesi, Organoselenium Chemistry, Springer
Verlag, Berlin, 1988, vol. 1; (b) S. Patai and Z. Rappoport, The
Chemistry of Organic Selenium and Tellurium Compounds, vol. 1
and 2, 1986; (c) R. J. Cremlyn, An Introduction to Organo-Sulfur
Chemistry, Wiley & Sons, New York, NY, 1996.
Scheme 3 Suzuki reaction of 4a with 4-MeOC6H4B(OH)2.
2 (a) I. P. Beletskaya and V. P. Ananikov, Chem. Rev., 2011,
111, 1596; (b) M. Wang, K. Ren and L. Wang, Adv. Synth. Catal.,
2009, 351, 1586.
3 (a) V. P. Reddy, A. V. Kumar, K. Swapna and K. R. Rao, Org.
Lett., 2009, 11, 951; (b) K. Ajiki, M. Hirano and K. Tanaka, Org.
Lett., 2005, 7, 4193; (c) B. C. Ranu, T. Mandal and S. Samanta,
Org. Lett., 2003, 5, 1439; (d) D. Singh, E. E. Alberto, O. E.
D. Rodrigues and A. L. Braga, Green Chem., 2009, 11, 1521;
(e) T. Nishino, M. Okada, T. Kuroki, T. Watanabe, Y. Nishiyama
and N. Sonoda, J. Org. Chem., 2002, 67, 8696.
4 (a) G. Bartoli, G. Bencivenni and R. Dalpozzo, Chem. Soc. Rev.,
2010, 39, 4449; (b) S. Cacchi and G. Fabrizi, Chem. Rev., 2005,
105, 2873; (c) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006,
106, 2875.
5 (a) J.-R. Weng, C.-H. Tsai, S. K. Kulp and C.-S. Chen, Cancer
Lett., 2008, 262, 153; (b) G. La Regina, M. C. Edler, A. Brancale,
S. Kandil, A. Coluccia, F. Piscitelli, E. Hamel, G. De Martino,
R. Matesanz, J. F. Dıaz, A. I. Scovassi, E. Prosperi, A. Lavecchia,
´
E. Novellino, M. Artico and R. Silvestri, J. Med. Chem., 2007,
50, 2865; (c) C. D. Funk, Nat. Rev. Drug Discovery, 2005, 4, 664.
6 (a) I. Ninomiya, C. Hashimoto, T. Kiguchi, T. Naito, D. H. R.
Barton, X. Lusinchi and P. Milliet, J. Chem. Soc., Perkin Trans. 1,
1990, 707; (b) P. Hamel and P. Preville, J. Org. Chem., 1996,
´
61, 1573; (c) M. Matsugi, K. Murata, K. Gotanda, H. Nambu,
G. Anilkumar, K. Matsumoto and Y. Kita, J. Org. Chem., 2001,
66, 2434; (d) K. M. Schlosser, A. P. Krasutsky, H. W. Hamilton,
J. E. Reed and K. Sexton, Org. Lett., 2004, 6, 819; (e) Y. Maeda,
M. Koyabu, T. Nishimura and S. Uemura, J. Org. Chem., 2004,
69, 7688; (f) X.-L. Fang, R.-Y. Tang, P. Zhong and J.-H. Li,
Synthesis, 2009, 4183; (g) Y. Chen, C.-H. Cho, F. Shi and
R. C. Larock, J. Org. Chem., 2009, 74, 6802; (h) Y. Chen,
C.-H. Cho and R. C. Larock, Org. Lett., 2009, 11, 173;
(i) Y.-J. Guo, R.-Y. Tang, J.-H. Li, P. Zhong and X.-G. Zhang,
Adv. Synth. Catal., 2009, 351, 2615; (j) H.-A. Du, R.-Y. Tang,
C.-L. Deng, Y. Liu, J.-H. Li and X.-G. Zhang, Adv. Synth. Catal.,
2011, 353, 2739.
Scheme 4 Proposed reaction mechanism and related experiments.
which could not be isolated owing to the fast reaction of A to B.
The reaction process for the generation of 6a was through an
elimination of HBr from 1a to intermediate A in the presence of
t-BuOLi, followed by an intramolecular nucleophilic addition
of nitrogen to the carbon–carbon triple bond of A to give
intermediate B, which underwent a cleavage of the sulfonamide
linkage with the assistance of t-BuOÀ to generate 6a (Scheme 4,
eqn (3)). For the sequential 3-selenylation of 6a, the reaction of
PhSeSePh (2a) with I2 afforded an electrophilic species PhSeI
(7a), which was followed by an electrophilic addition to the
indole moiety, providing intermediate C. After deprotonation
of C, the final product 3a was generated, along with the release
of HI, which was oxidized by DMSO to generate H2O,
dimethylsulfide and regenerated I2 for the next run (Scheme 4,
eqn (4) and (5)).16 For further verification, the obtained 6a was
reacted with 2a under the present reaction conditions, giving
3a in 92% yield.
7 G. Chelucci, Chem. Rev., 2012, 112, 1344 and references cited
therein.
8 (a) Y.-Q. Fang and M. Lautens, J. Org. Chem., 2008, 73, 538;
(b) Y.-Q. Fang and M. Lautens, Org. Lett., 2005, 7, 3549;
(c) A. Fayol, Y.-Q. Fang and M. Lautens, Org. Lett., 2006,
8, 4203; (d) M. Nagamochi, Y.-Q. Fang and M. Lautens, Org.
Lett., 2007, 9, 2955; (e) Y.-Q. Fang, J. Yuen and M. Lautens,
J. Org. Chem., 2007, 72, 5152.
9 J. Yuen, Y.-Q. Fang and M. Lautens, Org. Lett., 2006, 8, 653.
10 (a) C. S. Bryan and M. Lautens, Org. Lett., 2008, 10, 4633;
(b) Z.-J. Wang, J.-G. Yang, F. Yang and W. Bao, Org. Lett.,
2010, 12, 3034; (c) X.-R. Qin, X.-F. Cong, D.-B. Zhao, J.-S. You
and J.-B. Lan, Chem. Commun., 2011, 47, 5611.
11 T. O. Vieira, L. A. Meaney, Y.-L. Shi and H. Alper, Org. Lett.,
2008, 10, 4899.
12 M. Arthuis, R. Pontikis and J.-C. Florent, Org. Lett., 2009,
11, 4608.
13 (a) S. G. Newman, V. Aureggi, C. S. Bryan and M. Lautens, Chem.
Commun., 2009, 5236; (b) S. G. Newman and M. Lautens, J. Am.
Chem. Soc., 2010, 132, 11416.
14 W. Chen, Y. Zhang, L. Zhang, M. Wang and L. Wang, Chem.
Commun., 2011, 47, 10476.
In conclusion, a novel, efficient and facile route for the synthesis
of 2-bromo-3-selenylindoles and 2-bromo-3-sulfenylindoles via a
tandem one-pot reaction of 2-(gem-dibromovinyl)-N-methyl-
sulfonylanilines with diphenyldiselenide and diphenyldisulfide
was developed. The reactions were carried out in the presence
of t-BuOLi in DMSO, combined with a catalytic amount of I2
under transition-metal-free conditions, and generated the
desired products in good yields with high regio-selectivity.
The reaction was also extended to the preparation of 2-chloro-
3-selenylindoles and 2-chloro-3-sulfenylindoles from the corres-
ponding 2-(gem-dichlorovinyl)-N-methylsulfonylanilines. Further
investigation on the application of this strategy and a detailed
reaction mechanism is currently underway.
15 (a) M. Okutani and Y. Mori, J. Org. Chem., 2009, 74, 442;
(b) H. Xu, S. Gu, W. Chen, D. Li and J. Dou, J. Org. Chem.,
2011, 76, 2448.
16 (a) P. F. Ranken and B. G. McKinnie, J. Org. Chem., 1989,
54, 2985; (b) P. Hamel, J. Org. Chem., 2002, 67, 2854.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.