Catalytic conjugate addition of indole to α,β-unsaturated ketones by Co(ClO4)2·6H2O/bis-Schiff base complexes

Article abstract of DOI:10.1016/j.cclet.2012.03.015

Co(ClO₄)₂·6H₂O/bis-Schiff base complexes promoted the conjugate addition of indole to α,β- unsaturated ketones under mild conditions, giving the corresponding addition products with high yields. And the complex has been ch

Full text of DOI:10.1016/j.cclet.2012.03.015

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Chinese Chemical Letters 23 (2012) 525–528
www.elsevier.com/locate/cclet
Catalytic conjugate addition of indole to a,b-unsaturated
ketones by Co(ClO4)2Á6H2O/bis-Schiff base complexes
*
Yong Hai Hui, Chun Mei Chen, Zheng Feng Xie
Key Laboratory of Oil and Gas Fine Chemicals, Ministry of Education and Xinjiang Uyghur Autonomous Region,
College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, China
Received 1 December 2011
Available online 18 April 2012
Abstract
Co(ClO4)2Á6H2O/bis-Schiff base complexes promoted the conjugate addition of indole to a,b-unsaturated ketones under mild
conditions, giving the corresponding addition products with high yields. And the complex has been characterized with XRD and IR.
# 2012 Zheng Feng Xie. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Conjugate addition; Indole; a,b-Unsaturated ketone; Schiff base
The development of synthetic methods leading to indole derivatives has received much interest because a number of
their derivatives were found in a number of natural products and biologically active molecules [1]. Among them 3-
substituted indoles are highly interesting important building blocks for the synthesis of biologically active compounds
as well as natural products [2]. Since 3-position in indoles is the preferred site for electrophilic substitution, 3-alkyl or
acyl indoles are versatile intermediates for synthesis of a wide range of indole derivatives [3]. Furthermore, 3-
substituted indoles are components of drugs and are commonly found in molecules of pharmaceutical interest in
variety of the therapeutic areas [4].
Recently, a variety of methods have been reported for the synthesis of 3-substituted indoles [5]. Acid catalyzed
electrophilic substitution of indoles requires careful control of acidity to prevent side reactions such as dimerization
and polymerization [3]. Other method for the synthesis of 3-alkylated indoles involves the conjugate addition of
indoles to a,b-unsaturated ketones in the presence of either protic [6] or Lewis acid [7]. Although several catalytic
methods have been known to promote the addition of indoles to a,b-unsaturated ketones, only limited number of
different organometallic systems have been reported. Lewis acid catalyzed electrophilic substitution of indoles
requires careful control of acidity to prevent side reactions such as dimerization and polymerization. With a good
Lewis acidity and high coordination capability, cobalt (Co) shows good analogical actions in organic synthesis and Co
complex has been a good development [8]. And in our group, Co complexes have been proven to be efficient in the
oxidation of tetrahydrofuran [9]. Based on our previous research, the Schiff bases have been applied to many
procedures [10], we envisioned that Co(II) bis-Schiff base catalysts could represent readily available candidates as
catalytic systems to actively promote the direct addition of indoles to a,b-unsaturated ketones. Therefore, a series of
* Corresponding author.
E-mail address: xiezhf72@yahoo.com.cn (Z.F. Xie).
1001-8417/$ – see front matter # 2012 Zheng Feng Xie. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.03.015

526
Y.H. Hui et al. / Chinese Chemical Letters 23 (2012) 525–528
N
N
H2 H2
H
C
2 H
C2
N
R
O
C
C
O
2
L2, L6 R=
L4, L8 R=
L1, L5 R=
L3, L7 R=
N
N
N
N
C
N
N
N
L + M
solvent, r.t.
R
H2
R
R
+
2
N
N
H
N
N
H
R
1
R
1
2
N
L1 - L4
1
N
L5 - L8
Scheme 1. Ligands used in the conjugate addition of indole to a,b-unsaturated ketones.
bis-Schiff bases (L1–L8) (Scheme 1) were facilely synthesized according to our reported [11]. In this connection we
describe the version of this process employing the bis-Schiff base Co(II) complex as the catalyst.
1. Results and discussion
Initially, chalcone 1a and indole were chosen as model reaction to optimize the reaction conditions. A series of bis-
Schiff bases were examined in the presence of Co(ClO4)2 as metal salt. When Co(II) was used as the central metal, L2
was found to be the most suitable for this reaction (Table 1, entry 2). However, L2 or Co(ClO4)2Á6H2O as catalyst
showed the worst potential in this reaction, no products were obtained (Table 1, entries 9 and 10).
To further improve the yields, other conditions were investigated. We screened various solvents for the addition
indole to a,b-unsaturated ketone 1a, and CH3CN gave the best yield at room temperature, 88% yield (Table 1, entry 2).
Increasing the catalyst loading from 10 mol% to 15 mol% did not lead to an improvement on the yield (Table 1, entry
16). However, by reducing the catalyst loading to 5 mol%, the reaction activity was not affected, either (Table 1, entry
17). Extensive screening showed that this Friedel–Crafts reaction was well performed using 10 mol% bis-Schiff base
L2–Co(II) complex in MeCN at room temperature for 10 h.
With optimized conditions established, the substrate scope of the conjugate addition was explored. As shown in
Table 2, the electron-donating as well as electron-withdrawing substituents on the aromatic ring R1 were tolerated
under these conditions with good yields of 80–89% (Table 2, entries 1–11). Then we turned our attention to this kind of
a,b-unsaturated ketones having triazole substituents, and pleasing results with good-yield were obtained (Table 2,
entries 12–20). Notably, the electron-rich substrate was CH3, 1o and 1s gave the best results, and the corresponding
products 2o and 2s were obtained in 85% and 82% yields (Table 2, entries 15 and 19). When a substituent of R1 was
CH3O, the yield of the product 2t decreased to 78%, respectively (Table 2, entry 20). In addition, the R1 having the
electron-withdrawing group halogen proceeded smoothly and gave moderate yields (Table 2, entries 13–14 and 17–
18). Notably, when C1 were CH3, no product was obtained.
To evaluate the complex, we continued spectroscopic analysis of the catalyst. Fig. 1(a) shows the wide-angle XRD
patterns, the pattern of L2 sample exhibits several reflections at about 98, 138, 148, 168, 198, 268 and 288, which were
Table 1
Optimization of the reaction conditions.a
Entry
L
Solvent
Yield (%)b
Entry
L
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
72
88
78
75
63
60
61
65
9c
10d
11
L2
–
CH3CN
CH3CN
CH2Cl2
EtOH
0
0
L2
L2
L2
L2
L2
L2
70
71
67
30
89
86
13
14
Toluene
THF
15
16e
17f
MeCN
MeCN
a
Reaction conditions (unless noted otherwise): chalcone 1a (1 mmol), indole (1 mmol), 10 mol% L and 10 mol% Co(ClO4)2 in 5 mL CH3CN at
room temperature for 10 h.
b
Isolated yield.
c
L2 as catalyst for the reaction.
d
Co(ClO4)2Á6H2O as catalyst for the reaction.
e
Use 15 mol% catalyst.
f
Use 5 mol% catalyst.

Y.H. Hui et al. / Chinese Chemical Letters 23 (2012) 525–528
527
Table 2
Conjugated addition of indole with various a,b-unsaturated ketones.a
b
Yield (%)
Entry
R1
R2
Prod.
Yieldb (%)
Entry
R1
R2
Prod.
1
2
H
C6H5
C6H5
2a
2b
89
81
11
12
H
H
3-NO2C6H4
2k
2l
85
82
Cl
N
N
N
3
Br
C6H5
2c
80
13
Cl
2m
76
N
N
N
4
5
CH3
OCH3
H
C6H5
2d
2e
2f
89
87
85
80
83
86
88
14
15
16
17
18
19
20
Br
2n
2o
2p
2q
2r
2s
77
85
80
75
74
82
78
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
C6H5
CH3
H
6
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
Br
Br
Br
Br
Br
7
Cl
2g
2h
2i
Cl
8
Br
Br
9
CH3
OCH3
CH3
OCH3
10
2j
2t
a
Reaction conditions (unless noted otherwise): 1a–1t (1 mmol), indole (1 mmol) and 10 mol% L2–Co(II) (1:1) complex in CH3CN (5 mL) at
room temperature for 10 h.
b
Isolated yield.
attributed to functional groups of bis-Schiff base. On the other hand, the pattern of L2–Co(ClO4)2Á6H2O sample
exhibits only two reflections at about 2u = 178 and 258, the typical peaks suggesting that the cobalt salt had significant
effect on the nature of ligand. An FT-IR spectrum of the ligand (L2) and the catalyst L2–Co(II) (Fig. 1(b))
demonstrated successfully coordination of ligand and metal salt, in which relatively absorption bands around
1600 cmÀ1 for v(C N) and 450 cmÀ1 for v(N–Co) were derived from the organometallic cobalt complex [12].
In the light of the above experimental results, we propose a mechanism that involves the deprotonation of indole by
L–Co(II) accompanied (Scheme 2). The chalcone coordinates to this catalyst and undergoes the alkylation reaction of
Fig. 1. (a) Wide-angle XRD patterns of L2 and L2 + Co(II). (b) FT-IR spectrum of L2 and L2 + Co(II).

528
Y.H. Hui et al. / Chinese Chemical Letters 23 (2012) 525–528
Ph
O
Ph
Ph
Ph
N
O
N
N
ClO
ClO
4
4
N
H
Co
HClO
4
HClO
N
4
Ph
Ph
N
ClO
ClO
4
Ph
Co
+
N
H
N
4
N
O
N
N
Co
O
N
Ph
ClO
4
Co
N
ClO
4
alkylation
Scheme 2. Proposed catalytic cycle.
indole. The catalytic cycle is in according with the literature [13], which closed by a proton exchange with an incoming
indole to release the product and reform the active catalyst.
In conclusion, we have described an efficient Co(ClO4)2–L2 (bis-Schiff base) catalyst, which exhibited good
catalytic activities (up to 89%) in the conjugate addition of indole to a,b-unsaturated ketones. And the L2–Co(ClO4)2
complex has been characterized with XRD and IR. This, we believe that the cobalt salts might be of great applicability
in other reactions.
Acknowledgments
We appreciate the financial support from the National Natural Science Foundation of China (Nos. 20962018,
20862015 and 20562011).
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