Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by Cu(II)-imine complex

Article abstract of DOI:10.1016/j.cclet.2011.04.013

A series of new ligands L₁-L₇ were readily prepared in one step. Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by a novel Cu(II)-L complex has been developed. The remarkable advantages of this reaction are mild rea

Full text of DOI:10.1016/j.cclet.2011.04.013

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1155–1158
www.elsevier.com/locate/cclet
Friedel–Crafts alkylation of indoles with nitroalkenes
catalyzed by Cu(II)–imine complex
Ning Ning Wan a,b, Yong Lei Yang a,b, Wen Ping Wang a,b,
b,
Zheng Feng Xie a, , Ji De Wang
*
*
a College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, China
b Key Laboratory of Oil & Gas Fine Chemicals of Ministry of Education, Xinjiang University, Urumqi 830046, China
Received 11 January 2011
Available online 18 July 2011
Abstract
A series of new ligands L1–L7 were readily prepared in one step. Friedel–Crafts alkylation of indoles with nitroalkenes catalyzed
by a novel Cu(II)–L complex has been developed. The remarkable advantages of this reaction are mild reaction conditions, simple
workup procedure, high yields of products and the use of ethanol as a green solvent.
# 2011 Ji De Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Friedel–Crafts alkylation; Indole; Nitroalkene; Copper; Imine
The indole nucleus is frequently found in natural products [1], pharmaceuticals, functional materials, and
agrochemicals [2–4]. Substituted indoles are capable of binding to many receptors with high affinity [5]. Among the
receptors, nitroalkenes are very attractive, since the nitromoiety is a strong electron-withdrawing group that can be
readily transformed into a range of different functionalities [6], which lead to important building blocks and products [7].
Therefore, using nitroalkenes as substrates to achieve Friedel–Crafts alkylation of indoles has been paid considerable
attention since the nitro functional group is a strongly electron-withdrawing group that can be readily transformed into an
amino functional group [8]. Owing to the importance of this transformation, several efficient Lewis acids derived from
ligands and metal salts have been successfully applied in Friedel–Crafts reaction of heterocycles with electron-deficient
olefins in some pioneering reports [9]. On the other hand, a wide variety of metal salts such as Yb(OTf)3, InBr3, InCl3,
SmI3, CeCl3Á7H2O–NaI–SiO2, and iodine were used for this purpose [10]. More specially, in recent years, small organic
molecules such as thiourea were also found to catalyze the above-mentioned [11].
However, the Friedel–Crafts alkylation of indole needs to undergo continuous development, its application with
nitroalkene for Friedel–Crafts reaction has been rarely explored [12]. Moreover, in these pioneer reports, relatively high
catalyst loading, long reaction time, tedious workup procedures, severity of reaction condition and difficulties in product
isolation [13]. The research for achieving a general and environmental accessible method for conjugative addition of
indoles to nitroalkenes remains in great demand [14]. Hence, a series of new ligands L1–L7 were readily synthesized in
one step and were used for this purpose. In this contest, we reveal a new, mild and easy procedure for the Friedel–Crafts
alkylation of indole with nitroalkene in environmentally benign medium, catalyzed by Cu(II)–imine complex.
* Corresponding authors.
E-mail address: xiezhf@sohu.com (Z.F. Xie).
1001-8417/$ – see front matter # 2011 Ji De Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.04.013

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N.N. Wan et al. / Chinese Chemical Letters 22 (2011) 1155–1158
R3
R4
N
N
N
N
N
N
R2
N
N
N
NO2
N
N
N
L+M
N
NO2
+
R2
SH
SH
N
N
solvent, rt
R1
R1
1
2
3
L1: R3=CH3; L2: R3=CF3; L3: R3=Ph; L4: R3=CH2CH3
L5: R4=CH3; L6: R4=CF3; L7: R4=Ph
Scheme 1. Ligands used in the Friedel–Crafts alkylation of indole with nitroalkene.
1. Results and discussion
1.1. Selection of catalyst
These ligands L1–L7 (Scheme 1) derived from amine (1.0 mmol) were synthesized from the reaction with aromatic
and heteroaromatic aldehydes (2.1 mmol) [15] in ethanol in the presence of glacial acetic acid at reflux for 5 h in 83–
94% yields. Eventually the imines may be crystallized from ethanol. Our research began with the optimization of the
model reaction between indole (1a) and nitroalkene (2a). With different ligands were subsequently investigated as
only catalyst in the reaction (Table 1, entries 1À7), L3 was found to be the best ligand to provide the highest yield (up to
43%). In addition, a variety of salt–ligand complex generated in situ form metal salts and ligand L3 were also evaluated
as shown in the illustrate reaction, and results were summarized in Table 1, entries 8À14. While in the presence of
Cu(II)–L3 complex, indole reacted with nitroalkene smoothly, giving the product 3-(2-nitro-1-phenyethyl)-1H-indole
(3aa) in good yields, 87% (Table 1, entry 10).
1.2. Solvent and catalyst loading effect
With the best catalyst being identified, we next examined the solvent such as ethanol, toluene, THF, CH2Cl2 and so
on. Ethanol is the best solvent to provide F–C alkylation product in high yield (up to 87%). On the other hand, the
Table 1
Friedel–Crafts alkylation of indole 1a with nitroalkene 2a catalyzed by catalyst.a
Entry
Ligand
Time (h)
Yield (%)b
Entry
M-Ligand
Time (h)
Yield (%)b
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
8
8
8
8
8
8
8
17%
Trace
43%
Trace
Trace
–
8
9
Mn(Ac)2Á4H2O–L3
Zn(Ac)2Á2H2O–L3
Cu(ClO4)2 6H2O–L3
Zn(ClO4)2Á6H2O–L3
Mg(ClO4)2Á6H2O–L3
CuSO4Á5H2O–L3
8
8
8
8
8
8
8
47
–
10
11
12
13
14
87
Trace
Trace
73
13%
Co(NO3)2Á6H2O–L3
41
a
All reactions were carried out in C2H5OH using catalyst (5 mol%) at room temperature. Indole (1 mmol), b-nitroalkene (1 mmol).
Isolated yield by column chromatography.
b
a
b
0
10
20
30
2Theta
40
50
60
Fig. 1. XRD patterns of (a) L3 (b) Cu(II)–imine complex.

N.N. Wan et al. / Chinese Chemical Letters 22 (2011) 1155–1158
1157
a
b
0
500 1000 1500 2000 2500 3000 3500 4000 4500
Wavenumber [cm ]
Fig. 2. FT-IR spectra of (a) L3 (b) Cu(II)–imine complex.
R
NO2
Ph
N
S
[Cu(L3)2]2+
NO2
O
N
H
N
R
N
N
N
N
NH
N
2+
Ph
Ph
Cu
2+
N
N
Cu(L3)2
N
O
S
R
N
Cu(L3)2
O
N
N
R
O
N
N
N
Ph
NH+
N
H
2+
O
O
Cu(L3)2
H
R
N
Cu(L3)2
Scheme 2. Proposed catalytic cycle for the alkylation of indole with nitroalkene.
catalyst loading has not played a significant role in activity. For example, when the amount of catalyst was increased to
10 mol%, only 81% yield was achieved in ethanol.
1.3. Catalyst characterization
In particular, the Cu(II)–L3 complex interaction of the catalytic system was studied by XRD and FT-IR analysis.
XRD spectra (Fig. 1) of the L3 before and after cooper loading also showed a change. In addition, IR spectrum (Fig. 2)
Table 2
Friedel–Crafts alkylation reaction of indoles with nitroalkenes using Cu(II)–L3 complex.a
Entry
R1
R2
T (h)
Prod.
Yield (%)b
1
2
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
CH3 (1b)
CH3 (1b)
CH3 (1b)
Ph (2a)
8
8
8
8
8
8
8
8
8
8
8
8
8
3aa
3ab
3ac
3ad
3ae
3af
87
97
96
95
85
83
89
87
96
94
77
81
78
4-Cl-C6H5 (2b)
4-Br-C6H5 (2c)
2,4-Cl2-C6H4 (2d)
4-N(CH3)2-C6H5 (2e)
2-Furyl (2f)
3
4
5
6
7
4-Me-C6H5 (2g)
4-OMe-C6H5 (2h)
4-NO2-C6H5 (2i)
2-NO2-C6H5 (2i)
4-OMe-C6H5 (2h)
Ph (2a)
3ag
3ah
3ai
8
9
10
11
12
13
3aj
3bh
3ba
3bb
4-N(CH3)2-C6H5 (2b)
a
All reactions were carried out using Cu(II)–L3 complex (5 mol%) as catalyst in EtOH at room temperature, indoles or indole derivatives
(1 mmol), various substituted nitroalkenes (1 mmol). All the products were characterized by 1H NMR, 13C NMR, IR and elemental analysis.
b
Isolated yield by column chromatography.

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N.N. Wan et al. / Chinese Chemical Letters 22 (2011) 1155–1158
of the complex showed a strong absorption bands at 1087 cmÀ1 and 439 cmÀ1, which were attributed to the formation
of C N and M–N, respectively. These variations could be confirmed the coordination of cooper ion with the
azomethine nitrogen of the imine ligand [16]. A possible mechanism of the Cu(II)–L3 complex-catalyzed Friedel–
Crafts reaction between indoles and nitroalkenes is proposed in Scheme 2 [17].
1.4. Effect of substituent
Under the optimal reaction conditions, a variety of nitroalkenes and indoles were investigated, and the results were
summarized in Table 2. Most nitroalkenes reacted well with indoles to produce alkylated indoles in high yields. The
reactions of nitroalkenes containing electron-donating groups in the phenyl group had a slightly lower reaction rate
than the reaction of nitroalkenes containing electron-withdrawing groups. The substituent effect on the indole ring was
also studied. When a 1-Me was introduced into the indole ring, the yield was decreased.
2. Conclusion
In conclusion, a series of new ligands L1–L7 were readily synthesized in one step, and an efficient protocol for the
synthesis of wide range of indole derivatives (3aa–3bb) in presence of Cu(II)–imine as catalyst in ethanol has been
developed. Mild reaction condition, simple workup procedure, easy isolation and environmentally acceptable medium
are the best features in this process. Further work is in progress to extrapolate the catalytic activity of imine ligand to
other organic transformation.
Acknowledgments
We appreciate the financial support from the National Natural Science Foundation of China (Nos. 20962018,
20862015, 20762009 and 20562011).
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