Copper-cascade catalysis: Synthesis of 3-functionalized indoles

Article abstract of DOI:10.1039/c0cc04922k

A three-component reaction of indoles, sulfonyl azides and terminal alkynes afforded 3-functionalized indoles in a single step via copper-cascade catalysis.

Full text of DOI:10.1039/c0cc04922k

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 3275–3277
www.rsc.org/chemcomm
COMMUNICATION
Copper-cascade catalysis: synthesis of 3-functionalized indolesw
Jing Wang, Jinjin Wang, Yuanxun Zhu, Ping Lu* and Yanguang Wang*
Received 12th November 2010, Accepted 5th January 2011
DOI: 10.1039/c0cc04922k
A three-component reaction of indoles, sulfonyl azides and
terminal alkynes afforded 3-functionalized indoles in a single
step via copper-cascade catalysis.
Table 1 CuBr-catalyzed multicomponent reaction of indoles 1,
sulfonyl azides 2 and alkynes 3 under O2 atmospherea
Indole and its derivatives are one important class of organic
compounds because the indole skeletons widely exist in bio-
active synthetic and natural products and are of a privileged
structure in drug discovery.1 Consequently, lots of efforts have
been made to construct or modify the indole ring. Among
indole derivatives, both 2,30-biindolyl2 and cyclopenta[b]-
indole skeletons3 are attractive. The published methods for the
synthesis of 2,30-biindolyls include enzymatic strategy,4
palladium catalyzed cross coupling5 and palladium catalyzed
oxidative coupling,6 while the synthetic ways leading to cyclo-
penta[b]indoles are typically the annulation of indoles,7 such as
the rhodium-catalyzed [3+2] annulation of indoles.8
Product/
yieldb (%)
Entry 1 (R1/R2/R3)
2 (R4)
3 (R5)
1
2
1a (H/Me/H)
1a
2a (4-MeC6H4) 3a (Ph)
2a
2a
4a/75
3b (3-ClC6H4) 4b/62
3c (4-MeOC6H4) 4c/36
3
4
1a
1a
2b (Ph)
3a
4d/79
4e/58
4f/80
4g/43
5
6
1a
1a
2c (4-MeOC6H4) 3a
2d (4-BrC6H4) 3a
2e (2-MeC6H4) 3a
2d
2a
2a
2a
2d
7
8
1a
1a
When organic synthesis focused on the classic ‘‘stop and go’’
sequence of individual reactions, biological synthesis
presented a new and efficient concept: cascade catalysis9 or
concurrent tandem catalysis10 which integrated a series of
individual catalyzed reactions in a continuous process with
minimum workup, or change in conditions. Recently, the
copper-catalyzed azide–alkyne cycloaddition (CuAAC) was
developed and used to construct various compounds with
economic and ecological values.11–16 Meanwhile, the copper-
3d (4-MeC6H4) 4h/63
3e (2-BrC6H4) 4i/61
3f (3-BrC6H4) 4j/58
3g (4-BrC6H4) 4k/55
9
1b (H/Me/Cl)
10
11
12
13
14
15
16
17
18
19
1b
1b
1b
3a
3g
3a
3f
3a
3a
3a
3d
4l/54
4m/59
4n/60
4o/58
4p/60
4q/65
4r/19
4w/0
1c (H/Me/OMe) 2b
1a
1c
1d (Me/Me/H)
1e (H/n-Bu/H)
1f (H/Ph/H)
1g
2f (Me)
2f
2a
2d
2a
2b
catalyzed
C
sp3–H activation17 and oxidation consuming
oxygen as an oxidant18 also attracted considerable
attention. Stimulated by our previous investigations on
CuAAC12b,13a–c,14a,15 and the literature works on the copper-
catalyzed Csp3–H activation and oxidation, we investigated the
reaction of 2-methylindole (1a), 4-methylbenzenesulfonyl
azide (2a) and 3a using CuBr as the catalyst. Fortunately, a
multi-component adduct, 2-methyl-3-(10-imino-20-oxo-20-
phenyl)ethyl indole (4a, Table 1), was obtained when the
reaction was exposed to an oxygen atmosphere. This single
step reaction eventually involved a CuAAC three-component
reaction and a sequential copper-catalyzed Csp3–H activation
and oxidation.
(H/CH2CO2Me/H)
1h (H/H/H)
1i (Me/H/H)
1j (TBS/Me/H)
1k (Boc/Me/H)
20
21
22
23
2a
2a
2a
2a
3a
3a
3a
3a
4s/0
4t/0
4u/0
4v/0
a
Substituted indole (0.5 mmol), sulfonyl azide (1 mmol), alkyne
(1 mmol), pyridine (1 mmol) and CuBr (0.05 mmol) in DCM (1.6 mL).
b
Isolated yields refer to substituted indole.
With the optimized reaction conditions (see ESIw), we
examined the substrate diversity (Table 1). Electronic effects
on aromatic rings of 1, 2 and 3 were not significant (Table 1,
entries 1–13) except for the entries of 3 and 7. Substitution of
phenylacetylene by methoxy at the para position influenced
the formation of acetylenic copper and decreased the yield of
4c apparently. Aliphatic sulfonyl azide (2f) also worked for
this transformation (Table 1, entries 14 and 15). Methyl
substitution at the 1 position of indole didn’t influence the
yield (Table 1, entry 16), the structure of 4p was confirmed by
X-ray diffraction.19 However, the substituent at the 2-position
Department of Chemistry, Zhejiang University, Hangzhou 310027,
P. R. China. E-mail: orgwyg@zju.edu.cn, pinglu@zju.edu.cn;
Fax: +86 571-87951512; Tel: +86 571-87951512
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, characterization data, and copies of 1H
and 13C NMR spectra for all products. CCDC 784633 (4p) and
784634 (8). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc04922k
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3275–3277 3275

View Article Online
Scheme 1 Cascade catalysis mechanism for the formation of 4a.
of the indole ring was very important. When, 2-n-butyl-1H-
indole (1e) or 2-phenyl-1H-indole (1f) was used as the sub-
strate, 4q and 4r were obtained, respectively (Table 1, entries
17 and 18). When the 2 position of indole was occupied by
CH2COOMe, we didn’t detect the desired product (4s) due
to the electron-withdrawing nature of the ester (Table 1,
entry 19). Lacking of a substituent at the 2 position of indole,
in cases of indole (1h) and 1-methyl-1H-indole (1i), reactions
failed to afford the anticipated products (Table 1, entries 20
and 21). Reactions were also unsuccessful when 1-(tert-butyl-
dimethylsilyl)-2-methyl-1H-indole (1j) or tert-butyl 2-methyl-
1H-indole-1-carboxylate (1k) was used as a substrate (Table 1,
entries 22 and 23), respectively. A preliminary conclusion
could thus be made that the electron density of the 2 position
of indole played a key role in the construction of the products.
Based on the survey of the substrate diversity and the
previous reports,17a a possible mechanism is outlined in
Scheme 1. The click reaction between 2a and 3a in the presence
of Cu(I) and base leads to the formation of triazole A. Via
Dimorth rearrangement and subsequent nitrogen release, a
ketenimine intermediate B is generated. Nucleophilic attack of
the electron-rich carbon of 1a to the central carbon of
ketenimine B finishes the first catalytic cycle (Cycle I in
Scheme 1) and affords adduct 5a. Under the basic conditions,
5a is converted to an enaminate anion, which nucleophilically
attacks the in situ generated [Cu(II)–OH] species.17a The
resulting amidocopper(II) (C) is oxidized to peroxycopper(III)
(D).18b Intramolecular electron transfer of D forms E.
Subsequent isomerization of E to F followed by an elimination
of [Cu(II)–OH] species18b finishes the oxidation cycle (Cycle II
in Scheme 1) and affords 4a finally.
Table 2 CuBr-catalyzed multicomponent reaction of substituted
indoles, sulfonyl azides and alkynes under argon atmospherea
Product/
yieldb (%)
Entry 1 (R1/R2/R3)
2 (R4)
3 (R5)
1
2
3
4
5
6
1a (H/Me/H)
2a (4-MeC6H4) 3a (Ph)
5a/75
5b/71
5c/76
5d/38
5e/68
5f/60
1a
1a
1a
1a
2d (4-BrC6H4)
2b (Ph)
3a
3a
2c (4-MeOC6H4) 3a
2f (Me)
3a
3a
1c (H/Me/OMe) 2d
7
8
9
10
11
12
1c
1b (H/Me/Cl)
1b
1a
1a
2a
2b
2f
2a
2a
3g (4-BrC6H4) 5g/58
3a 5h/57
3b (3-ClC6H4) 5i/51
3f (3-BrC6H4) 5j/58
3g
3a
5k/50
5l/48
1d (Me/Me/H) 2a
a
Substituted indole (0.5 mmol), sulfonyl azide (1 mmol), alkyne
(1 mmol), pyridine (1 mmol) and CuBr (0.05 mmol) in DCM (1.8 mL).
b
Isolated yields refer to substituted indole.
was clearly established by 1H NMR. A downfield singlet at
6.32 ppm could be assigned to the alkenic proton, while the
sulfamide proton was recorded at 9.68 ppm, the signal of
which could be partially exchanged by D2O. In comparison,
In order to evidence the proposed mechanism, we ran the
reaction under the argon atmosphere for 3 hours. As we
expected, 2-methyl-3-(10-imino-20-phenyl)ethyl indoles 5 were
isolated in 38–76% yields with a variety of substrates (Table 2,
entries 1–12). The resulting 5a could be converted to 4a under
the oxygen atmosphere using either a Cu(I) or Cu(II) catalyst.
Without the Cu(I) or Cu(II) catalyst, however, this transforma-
tion didn’t occur.
It is noteworthy that enamine product 6 was isolated when
2-bromoacetylene (3e) was employed for the reaction under
the argon atmosphere (Scheme 2). The enamine structure of 6
Scheme 2 Construction of 2,30-biindoles 7.
c
3276 Chem. Commun., 2011, 47, 3275–3277
This journal is The Royal Society of Chemistry 2011

View Article Online
6 (a) Y. Li, W. H. Wang, S. D. Yang, B. J. Li, C. Feng and Z. J. Shi,
Chem. Commun., 2010, 46, 4553; (b) Z. J. Liang, J. L. Zhao and
Y. H. Zhang, J. Org. Chem., 2010, 75, 170.
7 (a) B. Bajtos, M. Yu, H. D. Zhao and B. L. Pagenkopf, J. Am.
Chem. Soc., 2007, 129, 9631; (b) G. Z. Zhang, X. G. Huang,
G. T. Li and L. M. Zhang, J. Am. Chem. Soc., 2008, 130, 1814;
(c) B. M. Trost and J. Quancard, J. Am. Chem. Soc., 2006, 128,
6314; (d) R. Kuwano, K. Sato, T. Kurokawa, D. Karube and
Y. Ito, J. Am. Chem. Soc., 2000, 122, 7614.
Scheme 3 Construction of cyclopenta[b]indole derivative 8.
8 Y. J. Lian and H. M. L. Davies, J. Am. Chem. Soc., 2010, 132, 440.
9 (a) A. Bruggink, R. Schoevaart and T. Kieboom, Organic Process
Research & Development, 2003, 7, 622; (b) Y. Huang, A. M. Walji,
C. H. Larsen and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 15051.
both 3-bromoacetylene (3f) and 4-bromoacetylene (3g)
afforded the normal imine adducts 5g, 5j and 5k (Table 2,
entries 7, 10 and 11). For compounds 5g, 5j and 5k, an upfield
singlet about 4.80 ppm was assigned to the two protons of
the methylene group adjacent to imine without question.
Formation of enamine of 6 might be driven by the weak intra-
molecular hydrogen bonding of N–Hꢀ ꢀ ꢀBr,20 which engen-
dered a cyclic-like structure. We examined the Ullmann
coupling reaction of 6 and successfully obtained 2,30-biindoles
7, intramolecular C–N coupling products (Scheme 2).
10 J.-C. Wasilke, S. J. Obrey, R. T. Baker and G. C. Bazan, Chem.
Rev., 2005, 105, 1001.
11 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and
K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596;
(b) C. W. Tornoe, C. Christensen and M. Meldal, J. Org. Chem.,
2002, 67, 3057; (c) P. Lu and Y. G. Wang, Synlett, 2010, 165;
(d) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39,
1302; (e) E. J. Yoo and S. Chang, Curr. Org. Chem., 2009, 13,
1766.
The cyclopenta[b]indole skeleton is a key structure of many
bioactive compounds, such as prostaglandin-(D) receptor
antagonists.21 When n-butyl lithium was used as the base to
abstract the proton from the 2-methyl part of 4a, an intra-
molecular nucleophilic addition occurred and the cyclopenta-
[b]indole derivative 8 was effectively constructed (Scheme 3)
and its structure was confirmed by X-ray analysis.22
12 Four-component reactions via the CuAAC mechanism:
(a) E. J. Yoo, S. H. Park, S. H. Lee and S. Chang, Org. Lett.,
2009, 11, 1155; (b) W. Z. Song, W. Lu, J. Wang, P. Lu and
Y. G. Wang, J. Org. Chem., 2010, 75, 3481; (c) R. Husmann,
Y. S. Na, C. Bolm and S. Chang, Chem. Commun., 2010, 46, 5494.
13 (a) H. W. Jin, X. L. Xu, J. R. Gao, J. H. Zhong and Y. G.
Wang, Adv. Synth. Catal., 2010, 352, 347; (b) S. L. Cui, J. Wang
and Y. G. Wang, Org. Lett., 2008, 10, 1267; (c) S. L. Cui, J. Wang
and Y. G. Wang, Org. Lett., 2007, 9, 5023; (d) I. Bae, H. Han and
S. Chang, J. Am. Chem. Soc., 2005, 127, 2038; (e) E. J. Yoo, I. Bae,
S. H. Cho, H. Han and S. Chang, Org. Lett., 2006, 8, 1347;
(f) J. Kim and S. Chang, Chem. Commun., 2008, 3052.
14 (a) Y. Shen, S. L. Cui, J. Wang, X. P. Chen, P. Lu and Y. G. Wang,
Adv. Synth. Catal., 2010, 352, 1139; (b) S. H. Cho, E. J. Yoo, I. Bae
and S. Chang, J. Am. Chem. Soc., 2005, 127, 16046.
15 S. L. Cui, J. Wang and Y. G. Wang, Tetrahedron, 2008, 64, 487.
16 (a) S. H. Cho and S. Chang, Angew. Chem., Int. Ed., 2008, 47,
2836; (b) Y. J. Shang, K. Ju, X. W. He, J. S. Hu, S. Y. Yu,
M. Zhang, K. S. Liao, L. F. Wang and P. Zhang, J. Org. Chem.,
2010, 75, 5743.
17 (a) H. R. Lucas, L. Li, A. A. N. Sarjeant, M. A. Vance,
E. I. Solomon and K. D. Karlin, J. Am. Chem. Soc., 2009, 131,
3230; (b) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2006, 128, 56;
(c) Y. Zhang and C.-J. Li, J. Am. Chem. Soc., 2006, 128, 4242.
18 (a) C. Zhang and N. Jiao, J. Am. Chem. Soc., 2010, 132, 28;
(b) S. Chiba, L. Zhang and J. Y. Lee, J. Am. Chem. Soc., 2010, 132,
7266; (c) O. Basle0 and C.-J. Li, Green Chem., 2007, 9, 1047;
(d) Y. Shen, M. Li, S. Wang, T. Zhan, Z. Tan and C.-C. Guo,
Chem. Commun., 2009, 953.
In conclusion, we have developed a copper-cascade cata-
lyzed reaction of indoles, sulfonyl azides and terminal alkynes,
which furnished functionalized indoles efficiently. In the
presence of oxygen, the reaction afforded the corresponding
oxidative products via a copper-catalyzed three-component
reaction and a sequential copper-catalyzed C–H bond activa-
tion and oxidation. A substituent at the 2-position of indole
rings, with a certain electron-donating property, was found to
be essential for this cascade catalysis to proceed. Moreover,
the resulting adducts could be elegantly used for constructing
the 2,30-biindolyl and cyclopenta[b]indole skeletons. Further
studies to clearly understand the reaction mechanism and the
synthetic applications are ongoing in our laboratory.
We are grateful for the financial support from the National
Natural Foundation of China (No. 21032005, 20872128 and
J0830413) and the Fundamental Research Funds for the
Central Universities (2010QNA3011).
19 CCDC 784633 contains the supplementary crystallographic data
for compound 4p.
20 For an example about the hydrogen bonding interaction between
bromine atom and a functional group, see: S. N. Murthy,
B. Madhav, A. V. Kumar, K. R. Rao and Y. V. D. Nageswar,
Helv. Chim. Acta, 2009, 92, 2118.
21 (a) M. C. Hillier, J. F. Marcoux, D. L. Zhao, E. J. Grabowski,
A. E. McKeown and R. D. Tillyer, J. Org. Chem., 2005, 70, 8385;
(b) A. Shafiee, V. Upadhyay, E. G. Corley, M. Biba, D. L. Zhao,
J. F. Marcoux, K. R. Campos, M. Journet, A. O. King, R. D.
Larsen, E. J. J. Grabowski, R. P. Volante and R. D. Tillyer,
Tetrahedron: Asymmetry, 2005, 16, 3094; (c) K. R. Campos,
M. Journet, S. Lee, E. J. J. Grabowski and R. D. Tillyer, J. Org.
Chem., 2005, 70, 268.
Notes and references
1 For a recent review: (a) G. R. Humphrey and J. T. Kuethe, Chem.
Rev., 2006, 106, 2875; (b) S. Cacchi and G. Fabrizi, Chem. Rev.,
2005, 105, 2873.
2 L. Capelli, P. Manini, A. Pezzella, A. Napolitano and M. d’Ischia,
J. Org. Chem., 2009, 74, 7191.
3 (a) P. M. Dewick, Medicinal Natural Products: A Biosynthetic
Approach, Wiley, New York, 2nd edn, 2002; (b) R. R. Gataullin,
Russ. J. Org. Chem., 2008, 45, 321.
4 L. Panzella, A. Pezzella, A. Napolitano and M. d’Ischia, Org.
Lett., 2007, 9, 1411.
22 CCDC 784634 contains the supplementary crystallographic data
for compound 8.
5 H. A. Duong, S. Chua, P. B. Huleatt and C. L. L. Chai, J. Org.
Chem., 2008, 73, 9177.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3275–3277 3277