Water-soluble (salicyladimine)2Cu complex as an efficient and renewable catalyst for Michael addition of indoles to nitroolefins in water

Article abstract of DOI:10.1080/00397911.2016.1258478

An efficient and environmentally friendly protocol has been demonstrated for water-soluble (salicyladimine)₂Cu complex-catalyzed Michael addition of indoles to nitroolefins in water at 30 °C. A variety of substituted indoles and β-nitrostyrenes could be worked well to provide the title products in 81–97% yields. Moreover, the catalyst can be reused directly at least for four times without significantly decreasing activity.

Full text of DOI:10.1080/00397911.2016.1258478

Water-soluble (salicyladimine)2Cu complex as an efficient and renewable catalyst
for Michael addition of indoles to nitroolefins in water
Haojie Jiang1, Jie Zhang1, Jianwei Xie1, Ping Liu1, Mei Xue1
1School of Chemistry and Chemical Engineering/The Key Laboratory for Green
Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi,
Xinjiang, China
Corresponding author. Jianwei Xie, Email: cesxjw@foxmail.com
Abstract
An efficient and environmentally friendly protocol has been demonstrated for
water-soluble (salicyladimine)2Cu complex-catalyzed Michael addition of indoles to
nitroolefins in water at 30 °C. A variety of substituted indoles and -nitrostyrenes could
be worked well to provide the title products in 81-97% yields. Moreover, the catalyst can
be reused directly at least for four times without significantly decreasing activity.
Graphical Abstract:
1

KEYWORDS: (salicyladimine)2Cu complex; Michael addition; water; indole;
nitroolefin
INTRODUCTION
Indole and its derivatives are present in many natural products, biologically active
structures and medicinally relevant compounds.[1] Among them, 3-substituted indoles are
versatile building blocks for the synthesis of targeted and pharmaceutical indole
compounds,[2] such as the amino acid tryptamine, anti-tumor agents[3] and 5-HT6
serotonin agonist[4] or antagonist[5] (Figure 1). Consequently, their preparation has
attracted considerable attention. The Michael addition between indoles and
electron-deficient alkenes is currently the most widely used approach for the synthesis of
3-substituted indoles. Undoubtedly, nitroalkenes are the strongest Michael acceptors,
since the activating effect of the nitro group and of the easy transformation into a number
of diverse functionalities (Scheme 1). In the past few years, significant progresses have
been achieved for 3-alkylated indoles synthesis via Michael addition of indoles to
β-nitrostyrene by using Lewis or Brønsted acids as the catalyst.[6] At the same time,
catalyst-free[7] or solvent-free[8] methods are also demonstrated. However, most of the
presented methods suffer from one or more of the following drawbacks, such as high
catalyst loading, long reaction time, un-recyclable catalyst, using organic solvents and
difficult work-up procedures. Therefore, there is still a need to develop a generally
efficient catalytic system for this class of reaction.
2

Salen-type Schiff base ligands are recognized as some of the most efficient ligands for
coordination to various metal ions, and their metal complexes exhibit a number of
important applications to various organic transformations.[9] Recently, we have
synthesized four typical water-soluble (salicyladimine)2Cu complexes (Figure 2), and
found that they could efficiently catalyzed N-arylation of imidazoles in water[10] and
oxidation of benzylic alcohols to corresponding aldehydes in water[11]. In an endeavor to
extend the reaction scope of these copper catalysts, we herein report (salicyladimine)2Cu
complexes as remarkable catalyst for Michael addition of indoles to -nitrostyrenes in
water.
RESULTS AND DISCUSSION
Initially, the conjugate addition of indole to -nitrostyrene in water was chosen as the
model reaction, and the catalytic efficiency of the four (salicyladimine)2Cu complexes
1-4 was evaluated. The results are summarized in Table 1. To our delight, excellent yields
of the target product were observed within 10 h for all the four catalysts with 2 mol%
loading, and complex 1 was found to be the best one (entries 1-4). Decreasing the catalyst
loading from 2 mol% to 1 mol% resulted lower yield from 97% to 90%. However, only a
trace product was obtained in the absence of catalyst or using Cu(OAc)2 as the sole
catalyst, even with prolonging the reaction time to 24 h. As mentioned above, the optimal
reaction conditions were 2 mol% of (salicyladimine)2Cu complex 1 as the catalyst in
water at 30 °C for 10 h.
3

To establish the generality of this protocol, a variety of indoles and -nitrostyrenes
bearing different substituents were investigated under the optimized reaction conditions,
and the results are listed in Table 2. We were pleased to find that the -nitrostyrenes
containing both electron-releasing and electron-withdrawing groups were converted
smoothly into the corresponding Michael addition products with 85-97% yields (7a-7k).
Interestingly, the ortho-substituted -nitrostyrenes did not seem to hamper the reaction
and afforded 85% yield. When 2-(2-nitrovinyl)thiophene and 2-(2-nitrovinyl)furan were
used as the Michael acceptors, the target product were obtained with 88% and 83% yields,
respectively, under the same reactions (7l and 7m). Reactions of indoles bearing 1-Me,
2-Me, 5-OMe, and 5-Br with several -nitrostyrenes gave the Friedel-Crafts adducts in
81-92% yields (7n-7w). Unfortunately, the 5-nitroindole reacted with -nitrostyrene
afforded only trace of product under the standard condition, which may be due to the
strong electron-withdrawing effect of nitro group (7x). Notably, the reaction, which was
carried out on a large-scale with 5 mmol -nitrostyrene, proceeded without any difficulty
to gives a yield of 93%, corresponding to 1.24 g of product 7a.
Because the catalysts are water-soluble and the reaction was performed in aqueous, we
carried out consecutive reactions between indole and -nitrostyrenes to evaluate the
reusability of complex 1 as the catalyst. After complete disappearance of -nitrostyrene,
the reaction mixture was extracted with ethyl acetate. And Then indole and -nitrostyrene
4

were added to the aqueous layer for the next run. As evident from Table 3, the catalyst
could be reused at least four times without significantly loss of catalytic activity.
CONCLUSIONS
In summary, we have developed an efficient, and renewable (salicyladimine)2Cu catalyst
for Michael addition between a wide range of substituted indoles and -nitrostyrenes in
water. The protocol offers low catalyst loading, broad substrates scope, convenient
operation, environmental friendliness, and the efficient process for large scale
preparation.
EXPERIMENTAL
Materials And Methods
Unless otherwise stated, all reagents were purchased from commercial suppliers and used
without further purification. Column chromatography was performed with silica gel
(200-300 mesh) purchased from Qingdao Haiyang Chemical Co. Ltd. Thin-layer
chromatography was carried out with Merck silica gel GF254 plates and visualized by
exposure to UV light (254 nm). All 3-alkylated indoles are characterized by 1H NMR and
13C NMR, which were compared with the previously reported data. 1H NMR spectra and
13C NMR spectra were recorded at room temperature on a Bruker Avance III HD 400
instrument at 400 MHz and 100 MHz, respectively.
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General Procedure For The Synthesis Of 3-(2-Nitro-1-Phenylethyl)-1H-Indole 7a
To a 25 mL Schlenk tube was charged with complex 1 (0.01 mmol, 6.6 mg),
-nitrostyrene (0.5 mmol, 74.5 mg), indole (0.6 mmol, 70.2 mg) and water (1 mL). The
mixture was stirred at 30 C and monitored by TLC. After complete disappearance of
nitroolefins, the reaction mixture was extracted with ethyl acetate (3×10 mL), washed
with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatograph on silica gel to provide 7a as a solid
(129 mg, 97%).
3-(2-Nitro-1-phenylethyl)-1H-indole 7a[6f]: 1H NMR (400 MHz, CDCl3): δ 8.14 (br s,
1H), 7.41 (d, J = 8.0 Hz, 2H), 7.29-7.22 (m, 6H), 7.20-7.13 (m, 2H), 7.06-7.00 (m, 1H),
6.93-6.92 (m, 1H), 5.15 (t, J = 8.0 Hz, 1H), 5.02 (dd, J = 12.4, 7.6 Hz, 1H), 4.85 (dd, J1 =
12.4, 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 139.3, 136.5, 129.0, 127.8, 127.6,
126.1, 122.7, 121.8, 119.9, 118.9, 114.2, 111.5, 79.6, 41.6.
General Procedure For The Recycling Of The Catalyst
The Michael addition of indole to -nitrostyrene was carried out as described in the
general procedure. After complete disappearance of -nitrostyrene, the reaction mixture
was extracted with ethyl acetate. Then indole and -nitrostyrene were added to the
aqueous layer for the second run. This process was then repeated.
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SUPPORTING INFORMATION
Full experimental section, analytical data for compounds 7a-7w, and the copies of 1H and
13C NMR spectra can be found via the “Supplementary Content” section of this article’s
webpage.
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from the Training Program for
Distinguished Youth Scholars of Shihezi University (no. 2014ZRKXJQ05).
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8

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Table 1. (Salicyladimine)2Cu complexes catalyzed the Michael addition of indole to
-nitrostyrenea
Entry
Catalyst/mol%
Time/h
10
Yield/%
97
2
3
4
5
6
7
8
1/2
2/2
10
95
3/2
10
89
4/2
10
95
1/1
10
90
-
24
trace
trace
Cu(OAc)2
24
a Reaction conditions: indole (0.6 mmol), -nitrostyrene (0.5 mmol), H2O (1 mL), 30 °C.
bIsolated yield.
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Table 2. (Salicyladimine)2Cu complexes catalyzed the Michael addition of indole to
-nitrostyrenea
7a, 97% (93%,
7b, 95%
7c, 90%
7d, 87%
1.24g)b
7e, 88%
7i, 90%
7m, 83%
7f, 85%
7j, 92%
7n, 86%
7g, 88%
7k, 90%
7o, 92%
7h, 91%
7l, 88%
7p, 87%
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7q, 83%
7u, 83%
7r, 83%
7v, 89%
7s, 90%
7t, 81%
7x, trace
7w, 90%
a Reaction conditions: indole (0.6 mmol), -nitrostyrene (0.5 mmol), complexes 1 (2
mol%), H2O (1 mL), 30 °C; isolated yield. bIsolated yield of the large-scale reaction.
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Table 3. Recycling of complex 1 for the Michael addition of indole to -nitrostyrene a
Run
0
1
2
3
Yield/%b
97
93
92
87
a Reaction conditions: indole (0.6 mmol), -nitrostyrene (0.5 mmol), complexes 1 (2
mol%), H2O (1 mL), 30 °C; isolated yield. b Isolated yield.
13

Figure 1. Examples of biologically active indole compounds.
14

Scheme 1. Michael addition between indole and -nitroalkenes for the synthesis of
bioactive indole derivatives.
15

Figure 2. Structures of (salicyladimine)2Cu complexes 1-4.
16