Synthesis of 3-indole derivatives by copper sulfonato Salen catalyzed three-component reactions in water

Article abstract of DOI:10.1039/c0cc05695b

An efficient three-component reaction of indole, aldehyde, and malononitrile in water catalyzed by a copper(ii) sulfonato Salen complex afforded 3-indole derivatives in good to excellent yields up to 97%. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc05695b

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COMMUNICATION
Synthesis of 3-indole derivatives by copper sulfonato Salen catalyzed
three-component reactions in waterw
Yanyang Qu,a Fang Ke,a Li Zhou,a Zhengkai Li,a Haifeng Xiang,a Di Wuab and
Xiangge Zhou*ab
Received 21st December 2010, Accepted 28th January 2011
DOI: 10.1039/c0cc05695b
Table 1 Screening of catalysts and reaction conditions for the
catalytic three-component reaction
An efficient three-component reaction of indole, aldehyde, and
malononitrile in water catalyzed by a copper(II) sulfonato Salen
complex afforded 3-indole derivatives in good to excellent yields
up to 97%.
Multi-component reactions (MCRs), by virtue of their
convergence, ease of execution and generally high yields of
products, have attracted considerable attention1,2 and
emerged as a powerful tool in the synthesis of biologically
important compounds for reducing operative steps and
enhancing synthesis efficiency.3
Entry
Metal (mol%)
L (mol%)
Base/acid
Yield (%)b
1
2
3
4
5
6
7
8
Mn(OAc)2 (5)
Ni(OAc)2 (5)
Co(OAc)2 (5)
Cu(OAc)2 (5)
CuI (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
—
—
—
—
—
—
—
—
K2CO3
K3PO4
KOAc
KHCO3
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
63
49
60
80
74
23
12
43
34
70
24
90
75
61
78
58
83
74
79
63
88
87
82
Indole frameworks have been widely known as prominent
agents in compounds of high biological, agrochemical and
pharmacological relevance.4,5 Several MCR methods have
been reported for the synthesis of substituted indoles.6 However,
the development of simple, efficient and environmentally benign
synthetic approaches remains a challenging task, especially for
3-substituted indole derivatives, which represent important
building blocks in many synthetic plans.
Cu(OAc)2 (5)
—
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L2 (5)
L3 (5)
L4 (5)
L5 (5)
L6 (5)
L7 (5)
L8 (5)
L1 (5)
L1 (2)
L1 (1)
L1 (0.5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (2)
Cu(OAc)2 (1)
Cu(OAc)2 (0.5)
9
10
11
12
13
14
15
16
17
18
19
20c
21
22
23
Normally, MCRs are carried out in organic solvents. Owing
to its low cost, non-flammability and environmental friendliness,
water is now witnessing a sort of renaissance, which has
become of growing interest both in industry and academia.7
In continuation of our efforts in aqueous catalysis,8 we wish
to report here three-component reactions involving indoles,
aldehydes, and malononitrile to afford 2-((1H-indol-3-yl)(aryl)-
methyl)malononitriles in water.9
a
Unless otherwise specified, all reactions were carried out using
benzaldehyde (0.1 mmol), malononitrile (0.11 mmol), indole (0.11 mmol)
Our initial efforts were focused on searching for an efficient
catalytic system based on indole, benzaldehyde, and malononitrile
as model substrates. As shown in Table 1, among the different
transition metals tested in the catalysis with the same ligand L1
(Scheme 1), Cu(OAc)2 exhibited higher catalytic ability than
others, including Mn(II), Ni(II) and Co(II) (Table 1, entries
1–5). Control experiments indicated the necessity of metal and
ligand, only 12% and 23% yields were obtained in the absence
b
and 1.0 equiv. of acid/base in water (3 mL) at 60 1C for 6 h. Isolated
yield. The reaction temperature was 40 1C.
c
of them (Table 1, entries 6 and 7). Different bases/acids were
screened, and the weak acid KH2PO4 was indicated to be
beneficial to the reaction, while normal bases showed negative
effects on the results (Table 1, entries 8–12). Then, a series of
water-soluble Salen ligands L1–L8 (Scheme 1) were tested.10 L1
was found to be superior to the others, with a 90% yield
(Table 1, entries 12–19). Further experiments suggested that it
was not good for the reaction if the reaction temperature was
lower than 60 1C. Finally, when the catalyst loading
was dropped from 5% to 2%, 1% and 0.5%, the yields
decreased from 90% to 88%, 87% and 82%, respectively
a Institute of Homogeneous Catalysis, College of Chemistry,
Sichuan University, Chengdu610064, China.
E-mail: zhouxiangge@scu.edu.cn; Fax: +86-28-85412026;
Tel: +86-28-85412026
b State Key Laboratory of Coordination Chemistry, Nanjing
University, Nanjing 210093, China
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c0cc05695b
c
3912 Chem. Commun., 2011, 47, 3912–3914
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Table 2 (continued )
Entry
Aldehyde
Product
Yield (%)b
8
82
9
87
10
11
12
13
93
91
89
Scheme 1 Different water soluble Salen ligands used in this work.
Table 2 Catalytic three-component reaction using different aldehydes
Entry
1
Aldehyde
Product
Yield (%)b
84
78
90
14
2
3
97
93
a
Unless otherwise noted, all reactions were performed with aldehyde
(0.1 mmol), malononitrile (0.11 mmol), 1H-benzopyrrole (0.11 mmol),
Cu–L1 (1 mol%), KH2PO4 (1.0 equiv.), water (3 mL) at 60 1C for
b
6 h. Isolated yield.
(Table 1, entries 12, 21–23). Thus, the optimal catalytic
conditions consist of 1 mol% Cu(OAc)2 and L1, with KH2PO4
as an additive, at 60 1C.
Then, a variety of aldehydes were tested under the optimized
reaction conditions, to explore the scope of this methodology.
As shown in Table 2, aromatic aldehydes bearing electron-
withdrawing substituents seemed to be beneficial to the cata-
lysis, and the steric hindrance seemed to have few effects on the
results (Table 2, entries 2–4). Aliphatic aldehydes, such as
pivalaldehyde also formed the desired products in 78% yield.
To extend the scope of the methodology, two other kinds of
indoles were tested. As shown in Table 3, 2-methyl indole
reacted well with various aldehydes and malononitrile to give
the corresponding products in excellent yields ranging from
82–96% (Table 3, entries 1–6). Meanwhile, N-methyl indole
gave slightly lower yields, around 77–83% (Table 3, entries 7–9).
In conclusion, we have developed an efficient three-compo-
nent reaction of indoles, aldehydes, and malononitrile in a
simple one-pot procedure. In this catalytic system, water is
4
5
95
68
6
7
76
73
c
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Table
substrates
3
Catalytic three-component reaction for other indole
tolerance with diverse functional groups makes the present
methodology attractive.
This project was supported by the Natural Science Foundation
of China (Nos. 20901052, 21072132), Sichuan Provincial
Foundation (08ZQ026-041) and the Ministry of Education
(NCET-10-0581). We also thank Analytical & Testing Centre
of Sichuan University for NMR measurements.
Entry Aldehyde
Indole
Product
Yield (%)b
Notes and references
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a
Unless otherwise noted, all reactions were performed with aldehyde
(0.1 mmol), malononitrile (0.11 mmol), indole (0.11 mmol), Cu–L1
(1 mol%), KH2PO4 (1.0 equiv.), 3 mL water at 60 1C for 6 h.
b
Isolated yield.
used in place of commonly-used volatile organic solvents
without adding any surfactant. The catalyses can be easily
performed in air with low catalyst loading. Furthermore, the
10 Some other usually used ligands were also tried (see: D. S. Surry
and S. L. Buchwald, Chem. Sci., 2010, 1, 13–31), and the related
results could be found in the ESIw.
c
3914 Chem. Commun., 2011, 47, 3912–3914
This journal is The Royal Society of Chemistry 2011