A facile route to polysubstituted indoles via three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin

Article abstract of DOI:10.1021/ol102775s

A copper-catalyzed three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin is reported. This reaction generates functionalized indoles in good yields and proceeds smoothly under mild conditions. Some hits as an HCT-116 inhibitor are

Full text of DOI:10.1021/ol102775s

ORGANIC
LETTERS
2011
Vol. 13, No. 5
848–851
A Facile Route to Polysubstituted Indoles
via Three-Component Reaction
of 2-Ethynylaniline, Sulfonyl Azide,
and Nitroolefin
Zhiyuan Chen,† Danqing Zheng,† and Jie Wu*,†,‡
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China
jie_wu@fudan.edu.cn
Received November 21, 2010
ABSTRACT
A copper-catalyzed three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin is reported. This reaction generates
functionalized indoles in good yields and proceeds smoothly under mild conditions. Some hits as an HCT-116 inhibitor are found from the
preliminary biological screening.
The indole core is recognized as a “privileged motif”
because of its presence in many biologically active natural
products and pharmaceuticals.1 Much effort has been paid
toward the synthesis and functionalization of indoles, and
methods for the preparation of indole derivatives have been
well developed.2-5 Classical routes for indole formation
include Fischer synthesis3 (from arylhydrazone), Batcho-
Leimgruber synthesis (from o-nitrotoluenes and dimethyl-
formamide acetals), Gassman synthesis (from N-halo-
anilines), Madelung cyclization of N-acyl-o-toluidines,
and the reductive cyclization of o-nitrobenzyl ketones.4
Recently, transition-metal-catalyzed transformations and
multicomponent reactions have also been widely applied
in indole synthesis.5 While these methods have contributed
greatly to this area, the development of efficient catalytic
methods for the preparation of functionalized indoles using
a diversity-oriented synthesis strategy remains an active
research field.
† Fudan University.
‡ Chinese Academy of Sciences.
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r
10.1021/ol102775s
Published on Web 02/07/2011
2011 American Chemical Society

Scheme 1. Proposed Synthetic Route for 3-(2-Aminoethyl)-1H-
indol-2-amine Formation
Figure 1. Structure of 3-(2-aminoethyl)-1H-indol-2-amine.
Among the family of indoles, compounds containing
3-(2-aminoethyl)-1H-indol-2-amine (Figure 1) have at-
tracted much attention recently. For example, Celogentin
C is a bicyclic octapeptide isolated from the seeds of
(6) (a) Kobayashi, J.; Suzuki, H.; Shimbo, K.; Takeya, K.; Morita,
H. J. Org. Chem. 2001, 66, 6626. (b) Morita, H.; Shimbo, K.; Shigemori,
H.; Kobayashi, J. Bioorg. Med. Chem. Lett. 2000, 10, 469. For synthesis
of Celogentin C, see:Ma, B.; Banerjee, B.; Litvinov, D. N.; He, L.;
Castle, S. L. J. Am. Chem. Soc. 2010, 132, 1159 and references cited
therein.
(7) For recent selected examples, see: (a) Chen, Z.; Wu, J. Org. Lett.
2010, 12, 4856. (b) Qiu, G.; Ding, Q.; Ren, H.; Peng, Y.; Wu, J. Org. Lett.
2010, 12, 3975. (c) Chen, Z.; Yu, X.; Wu, J. Chem. Commun. 2010, 46,
6356. (d) Ye, S.; Yang, X.; Wu, J. Chem. Commun. 2010, 46, 5238. (e) Ye,
S.; Yang, X.; Wu, J. Chem. Commun. 2010, 46, 2950. (f) Ye, S.; Gao, K.;
Wu, J. Adv. Synth. Catal. 2010, 352, 1746. (g) Yu, X.; Ye, S.; Wu, J. Adv.
Synth. Catal. 2010, 352, 2050. (h) Yu, X.; Wu, J. J. Comb. Chem. 2010,
12, 238. (i) Yu, X.; Chen, Z.; Yang, X.; Wu, J. J. Comb. Chem. 2010, 12,
374. (j) Ye, S.; Ren, H.; Wu, J. J. Comb. Chem. 2010, 12, 670. (k) Yu, X.;
Ding, Q.; Wu, J. J. Comb. Chem. 2010, 12, 743. (l) Ren, H.; Ye, S.; Liu,
F.; Wu, J. Tetrahedron 2010, 66, 8242.
Celosia argentea,6a which inhibits the polymerization of
tubulin.6b As part of our program for combinatorial
construction of privileged scaffolds used in different
biological assays,7 we are interested in the generation
of 3-(2-aminoethyl)-1H-indol-2-amine derivatives. Re-
cently, a Cu-catalyzed multicomponet reaction of sulfo-
nyl azide, a terminal alkyne, and a nucleophile has been
well developed.8-11 The reaction involves a Cu-catalyzed
azide-alkyne cycloaddition which generates a keteni-
mine intermediate. In this field, most of the effort is
contributed by Chang and Wang.8-10 As described, the
developed procedures are characterized by high selectiv-
ity, mild reaction conditions, a wide substrate scope, and
excellent functional group tolerance. Prompted by the
advancement mentioned above, we conceive that 3-
(2-aminoethyl)-1H-indol-2-amine derivatives could be
synthesized as well from a reaction of sulfonyl azide, a
terminal alkyne, and a nucleophile. The proposed syn-
thetic route is described in Scheme 1. We envisioned that
the target compound A could be traced back to indole 3,
which might be generated from the three-component
reaction of 2-ethynylaniline 1, sulfonyl azide, and nitro-
olefin 2. Herein, we wish to disclose our recent efforts for
this transformation.
(8) For a recent review, see: (a) Lu, P.; Wang, Y.-G. Synlett 2010, 165.
(b) Yoo, E. J.; Chang, S. Curr. Org. Chem. 2009, 13, 1766.
(9) Iminocoumarin: (a) Shen, Y.; Cui, S.; Wang, J.; Chen, X.; Lu, P.;
Wang, Y.-G. Adv. Synth. Catal. 2010, 352, 1139. (b) Cui, S. L.; Lin,
X. F.; Wang, Y.-G. Org. Lett. 2006, 8, 4517. N-Sulfonylazetidin-2-
imine:(c) Xu, X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9,
1585. (d) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45,
3157. Indoline or pyrroline:(e) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10,
1163. (f) Cui, S. L.; Wang, J.; Wang, Y.-G. Org. Lett. 2007, 9, 5023. (g)
Yao, W.; Pan, L.; Zhang, Y.; Wang, G.; Wang, X.; Ma., C. Angew.
Chem., Int. Ed. 2010, 49, 9210. 2H-1,2,4-Benzothiadiazine 1,1-dioxide:
(h) Kim, J.; Lee, Y.; Lee, J.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73,
9454. 2-Imino-1,2-dihydroquinoline and 2-iminothiochromene:(i) Cui,
S. L.; Wang, J.; Wang, Y.-G. Tetrahetron 2008, 64, 487. Pyrazoline:(j)
Cui, S.-L.; Wang, J.; Wang, Y.-G. Org. Lett. 2008, 10, 13. Benzimida-
zole:(k) She, J.; Jiang, Z.; Wang, Y.-G. Synlett 2009, 2023. N-Sulfonyl-
triazoles:(l) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (m) Wang, F.; Fu, H.; Jiang,
Y.; Zhao, Y. Adv. Synth. Catal. 2008, 350, 1830. (n) Maisonneuve, S.;
Xie, J. Synlett 2009, 2977. 4,5-Dihydrofuran:(o) Shang, Y.; Ju, K.; He,
X.; Hu, J.; Yu, S.; Zhang, M.; Liao, K.; Wang, L.; Zhang, P. J. Org.
Chem. 2010, 75, 5743. Oxazole:(p) Shang, Y.; He, X.; Hu, J.; Wu, J.;
Zhang, M.; Yu, S.; Zhang, Q. Adv. Synth. Catal. 2009, 351, 2709. (q)
Initial studies were performed for the reaction of N-
acetyl-2-ethynylaniline 1a, p-toluenesulfonic azide, and
(E)-(2-nitrovinyl)benzene 2a in the presence of copper salt
as a catalyst. At the beginning, CuI was used as the
catalyst and triethylamine (TEA) was employed as the
base. To our delight, the desired product 3a was obtained
in 73% yield after 6 h when the reaction occurred in
anhydrous CH3CN under a N2 atmosphere (Table 1,
entry 1). The structure of 3a was confirmed by X-ray
ꢀ
Cano, I.; Alvarez, E.; Nicasio, M. C.; Perez, P. J. J. Am. Chem. Soc. 2011,
133, 191. Cyclic amidinesa:(r) Chang, S.; Lee, M.; Jung, D. Y.; Yoo,
E. J.; Cho, S. H.; Han, S. K. J. Am. Chem. Soc. 2006, 128, 12366.
(10) (a) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett.
2006, 8, 1347. (b) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007, 46,
1897. (c) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47, 2836. (d)
Yoo, E. J.; Park, S. H.; Lee, S. H.; Chang, S. Org. Lett. 2009, 11, 1155. (e)
Yoo, E. J.; Ahlquist, M.; Bae, I.; Sharpless, K. B.; Fokin, V. V.; Chang,
S. J. Org. Chem. 2008, 73, 5520. (f) Bae, I.; Han, H.; Chang, S. J. Am.
Chem. Soc. 2005, 127, 2038. (g) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S.
J. Am. Chem. Soc. 2005, 127, 16046. (h) Husmann, R.; Na, Y. S.; Bolm,
C.; Chang, S. Chem. Commun. 2010, 46, 5494. (i) Kim, J. Y.; Kim, S. H.;
Chang, S. Tetrahedron Lett. 2008, 49, 1745. (j) Lu, W.; Song, W. Z.;
Hong, D.; Lu, P.; Wang, Y.-G. Adv. Synth. Catal. 2009, 351, 1768. (k)
Jin, H.; Xu, X.; Gao, J.; Zhong, J.; Wang, Y.-G. Adv. Synth. Catal. 2010,
352, 347. (l) Cui, S. L.; Wang, J.; Wang, Y.-G. Org. Lett. 2008, 10, 1267.
(m) Song, W.; Lu, W.; Wang, J.; Lu, P.; Wang, Y.-G. J. Org. Chem. 2010,
75, 3481.
(11) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057. (b) Xu, M.; Kuang, C.; Wang, Z.; Yang, Q. Synlett 2010,
2664. (c) Liu, N.; Tang, B.-Y.; Chen, Y.; He, L. Eur. J. Org. Chem. 2009,
2059. (d) Mandal, S.; Gauniyal, H. M.; Pramanik, K.; Mukhopadhyay,
B. J. Org. Chem. 2007, 72, 9753. (e) Xu, X.; Cheng, D.; Li, J.; Guo, H.;
Yan, J. Org. Lett. 2007, 9, 1585. (f) Whiting, M.; Fokin, V. V. Angew.
Chem., Int. Ed. 2006, 45, 3157.
Org. Lett., Vol. 13, No. 5, 2011
849

Table 1. Initial Studies for the Three-Component Reaction of
2-Ethynylaniline, Sulfonyl Azide, and Nitroolefin
Table 2. Generation of Polysubstituted Indoles via Three-
Component Reaction of 2-Ethynylaniline, Sulfonyl Azide, and
Nitroolefin
time
(h)
yield
entry
R1, R2
R3
yield (%)a
entry
Lewis acid
base
TEA
solvent
(%)a
1
H, Ac (1a)
4-MeOC6H4 (2a)
C6H5 (2b)
91 (3a)
83 (3b)
95 (3c)
60 (3d)
88 (3e)
86 (3f)
40 (3g)
70 (3h)
60 (3i)
61 (3j)
92 (3k)
91 (3l)
92 (3m)
55 (3n)
71 (3o)
50 (3p)
65 (3q)
52 (3r)
60 (3s)
messy
1
CuI
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
6
6
73
81
32
25
24
52
21
trace
61
32
54
91
45
54
48
24
83
60
2
H, Ac (1a)
2
CuBr
CuCl
TEA
TEA
TEA
TEA
TEA
DIPEA
Py
3
H, Ac (1a)
1-naphthalene (2c)
4-FC6H4 (2d)
3
24
24
24
24
12
24
8
4
H, Ac (1a)
4
Cu(OTf)2
IPr/CuI
IPr/CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBrb
CuBrc
5
H, Ac (1a)
4-BrC6H4 (2e)
2-BrC6H4 (2f)
n-pentyl (2g)
5
6
H, Ac (1a)
6
7
H, Ac (1a)
7
8
H, Ac (1a)
furan-2-yl (2h)
thiophen-2-yl (2i)
4-MeOC6H4 (2a)
4-MeOC6H4 (2a)
4-BrC6H4 (2e)
furan-2-yl (2h)
4-MeOC6H4 (2a)
4-BrC6H4 (2e)
furan-2-yl (2h)
C6H5 (2b)
8
9
H, Ac (1a)
9
n-Bu3N
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
10
11
12
13
14
15
16
17
18
19
20
21
22
4-Me, Ac (1b)
4-nBu, Ac (1c)
4-nBu, Ac (1c)
4-nBu, Ac (1c)
4-F, Ac (1d)
4-F, Ac (1d)
4-F, Ac (1d)
4-CF3, Ac (1e)
4-CF3, Ac (1e)
4-CF3, Ac (1e)
H, H (1f)
10
11
12
13
14
15
16
17
18
8
DMSO
4
1,4-dioxane
Toluene
CHCl3
6
6
10
12
6
DCE
DMF
1,4-dioxane
1,4-dioxane
8
2-BrC6H4 (2f)
thiophen-2-yl (2i)
4-MeOC6H4 (2a)
1-naphthalene (2c)
4-BrC6H4 (2e)
20
a Isolated yield based on N-acetyl-2-ethynylaniline 1a. b In the pre-
H, Boc (1g)
H, Boc (1g)
85 (3t)
81 (3u)
sence of 8 mol % of CuBr. c In the presence of 5 mol % of CuBr.
a Isolated yield based on N-acetyl-2-ethynylaniline 1.
diffraction analysis as well. However, it seems that there is
still a chance of spreading the double bond character over
the ring and “tosylamido” moiety by analyzing the related
bond lengths (see Supporting Information). Other copper
catalysts were screened subsequently (Table 1, entries
2-6). The results showed that CuBr was the best one
for the transformation (81% yield), compared with CuCl
(32%), Cu(OTf)2 (25%), IPr/CuI (24%), and IPr/CuCl
(52%). Further screening of bases including diisopropy-
lethylamine (DIPEA), pyridine (Py), and n-Bu3N re-
vealed that no obvious improvement was achieved
(Table 1, entries 7-9). The reaction was tested in various
solvents as well, which showed that the best result (91%
yield) was generated in 1,4-dioxane (Table 1, entry 12).
Inferior yields were isolated when the catalyst loading was
reduced (Table 1, entries 17-18).
Having defined an efficient catalytic system [CuBr (10
mol %), Et3N, 1,4-dioxane, room temperature], the scope
of this three-component reaction of 2-ethynylaniline 1,
sulfonyl azide, and nitroolefin 2 was explored. The results
are summarized in Table 2. To assess the impact of the
structural and functional motifs on the reaction, we tested
a range of 2-ethynylanilines and nitroolefins. For all
cases, N-acetyl-2-ethynylaniline 1 reacted with sulfonyl
azide and nitroolefin 2 leading to the corresponding
polysubstituted indoles 3 in good to excellent yields.
For instance, reaction of N-(2-ethynylphenyl)acetamide
1a, sulfonyl azide, and nitrostyrene 2b gave rise to the
desired product 3b in 83% yield (Table 2, entry 2). When
(E)-1-(2-nitrovinyl)naphthalene 2c was employed in the
above reaction, the desired product 3c was isolated in
95% yield (Table 2, entry 3). A lower yield was obtained
when (E)-1-fluoro-4-(2-nitrovinyl)benzene 2d was used
as a replacement (60% yield, Table 2, entry 4). Good
results were generated when (E)-1-bromo-4-(2-nitrovinyl)
benzene 2e was utilized as a partner in the reaction
(Table 2, entries 5 and 6). However, an inferior yield
was displayed when aliphatic-substituted nitroolefin 2g
was employed in the reaction (40% yield, Table 2, entry
7). This result is reasonable due to the less reactive alkyl
nitroolefin.12a,b Additionally, other factors, such as poly-
merization of alkyl nitroolefin, may also affect the
efficiency of the transformation.12c An electrophile con-
taining a heterocycle, such as furanyl or thiophenyl, was
also tolerated, leading to the desired products in good
(12) (a) Dong, X.-Q.; Teng, H.-L.; Tong, M.-C.; Huang, H.; Tao,
H.-Y.; Wang, C.-J. Chem. Commun. 2010, 46, 6840. (b) Cao, C.-L.; Ye,
M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901. (c) Noland, W. E.;
Christensen, G. M.; Sauer, G. L.; Dutton, G. G. S. J. Am. Chem. Soc.
1955, 77, 456.
850
Org. Lett., Vol. 13, No. 5, 2011

yield (Table 2, entries 8 and 9). We next examined the
reaction of N-acetyl-2-ethynylaniline 1 with substituents
on the aromatic ring (1b-1e) (Table 2, entries 10-19). As
expected, the corresponding products were obtained in
good yields, whether the nitroolefin was attached with an
electron-donating or -withdrawing group. As for the
protecting group of amine in 2-ethynylaniline 1, it was
found that a one-pot reaction of 2-ethynylaniline 1f,
sulfonyl azide, and nitroolefin 2a was not workable under
the standard conditions (Table 2, entry 20). In the case of
N-Boc-2-ethynylaniline 1g, the reaction worked well in
furnishing the expected products in good yields (Table 2,
entries 21 and 22). However, when N-tosyl-2-ethynylani-
line was used as the substrate in the transformation, only
a copper-catalyzed azide-alkyne [3 þ 2] cycloaddition
product was observed.13 The reaction was complex when
N-alkyl-2-ethynylaniline was employed (data were not
shown in Table 2).
Table 3. Biological Screening Result as HCT-116 Inhibitor
compd
concn
result type
result
error
3b
20 μg/mL
%Activity
8.045
4.305
8.053
7.842
15.491
11.588
13.515
7.784
13.937
9.279
19.139
7.766
4.312
3.495
17.706
11.272
4.588
6.262
17.583
8.89
5.258
0.378
3.578
0.716
3.197
1.024
13.415
0.734
3.128
1.056
3.057
0.631
0.701
0.384
1.629
1.229
0.604
0.546
6.207
0.915
2.444
0.796
1.956
0.449
1.206
2.003
IC50 (μg/mL)
%Activity
3c
3e
3f
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
20 μg/mL
IC50 (μg/mL)
%Activity
IC50 (μg/mL)
%Activity
IC50 (μg/mL)
%Activity
3h
3i
IC50 (μg/mL)
%Activity
IC50 (μg/mL)
%Activity
3j
IC50 (μg/mL)
%Activity
3k
3n
3o
3q
3r
3s
IC50 (μg/mL)
%Activity
IC50 (μg/mL)
%Activity
Scheme 2. Possible Mechanism for the Three-Component Re-
action of 2-Ethynylaniline, Sulfonyl Azide, and Nitroolefin
IC50 (μg/mL)
%Activity
6.952
7.199
5.855
4.989
48.453
17.061
IC50 (μg/mL)
%Activity
IC50 (μg/mL)
%Activity
IC50 (μg/mL)
Compound 3j was discovered as being the best (IC50
3.495 μg/mL). These results are encouraging for the
further construction of the library of indole 3.
In conclusion, we have developed an efficient copper
(I)-catalyzed three-component reaction of 2-ethynylaniline
1, sulfonyl azide, and nitroolefin 2. A variety of polysub-
stituted indole derivatives were obtained in moderate to
good yields. In this transformation, a broad substrate scope
has been demonstrated. Additionally, the reaction condi-
tions are extremely mild. Some hits as an HCT-116 inhibitor
are found from the preliminary biological screening. We
believe that this method is attractive for further library
construction.
The possible mechanism for this three-component re-
action is described in Scheme 2. As reported by Chang
and Wang,8-10 the reactive ketenimine b would be gen-
erated by the ring-opening rearrangement of triazole
intermediate a, which was formed from alkyne 1 and
sulfonyl azide in the presence of CuBr and triethylamine.
Subsequently intramolecular nucleophilic addition
occurred, leading to the intermediate c. Afterwards inter-
molecular Michael addition and tautomerization affor-
ded the desired product 3.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (21032007) is grate-
fully acknowledged. We thank Prof. Jia Li (The National
Center for Drug Screening, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences) for providing the
biological assays.
The subsequent biological screening as an HCT-116
inhibitor revealed that the results were promising. The
data for active compounds are presented in Table 3.
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 3, and X-ray crystal data of compound 3a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For selected examples, see: (a) Wang, Q.; Chan, T. R.; Hilgraf,
R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003,
ꢀ
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125, 3192. (b) Krasinski, A.; Radic, Z.; Manetsch, R.; Raushel, J.;
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