Conjugate addition of indoles to aα,β-Unsaturated Ketones Using a Broonsted acid ionic liquid as an efficient catalyst

Article abstract of DOI:10.3390/molecules14093222

The Broonsted acid ionic liquid [PyN(CH₂)4SO ₃H][p-CH₃PhSO₃] has been reported as an efficient catalyst for the Michael addition reaction of indoles to aα,β-unsaturated ketones. Satisfactory results were obtaine

Full text of DOI:10.3390/molecules14093222

Molecules 2009, 14, 3222-3228; doi:10.3390/molecules14093222
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molecules
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Article
Conjugate Addition of Indoles to α,β-Unsaturated Ketones
Using a Brønsted Acid Ionic Liquid as an Efficient Catalyst
Chuan-Ji Yu and Chen-Jiang Liu *
School of Chemistry and Chemical Engineering, Xinjiang University, Key Laboratory of Oil and Gas
Fine Chemicals, Ministry of Education, 830046 Urumqi, China; E-mail: cjxyycj@126.com (C.-J.Y.)
* Author to whom correspondence should be addressed; E-mail: pxylcj@126.com;
Tel.: +86-9918581211; Fax: +86-9918582809.
Received: 6 July 2009; in revised form: 20 August 2009 / Accepted: 24 August 2009 /
Published: 27 August 2009
Abstract: The Brønsted acid ionic liquid [PyN(CH2)4SO3H][p-CH3PhSO3] has been
reported as an efficient catalyst for the Michael addition reaction of indoles to α,β-
unsaturated ketones. Satisfactory results were obtained, with excellent yields and a simple
experimental procedure. The catalyst could be recycled and reused up to three times
without any noticeable decrease in the catalytic activity.
Keywords: Brønsted acid ionic liquid; β-indolylketones; Michael addition
Introduction
β-indolylketones have received much attention as important building blocks for the synthesis of
various natural products and biologically active compounds [1]. Consequently, numerous methods
have been developed for their synthesis using various catalysts such as Bi(OTf)3 [2], HfCl4 and ScCl3
-
[3], NO+BF4 [4], CAN [5], InBr3 [6], PTSA [7], Bi(NO3)3 [8], GaCl3 [9], PVSA [10], Cu(OTf)2 [11],
I2 [12], GaI3 [13], PDA [14], FAP [15], Zr(OtBu)4 [16] and so on. However, most of the catalysts
cannot be recovered and reused because they decompose under the quenching conditions. Furthermore,
many of these reported protocols suffer from drawbacks such as strong acidic conditions, long reaction
times and low yields of products. Recently, Gu et al. [17] reported silica-supported sodium sulfonate
with ionic liquid as catalyst for Michael reactions of indoles. Although the yield was excellent, the
reaction temperature is low and the catalyst can be recovered twice, the reaction time is too long.

Molecules 2009, 14
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Therefore, to avoid these limitations, the introduction of a more efficient method affording higher
yields is needed.
In recent years, ionic liquids (ILs) have attracted increasing interest in the context of Green
Chemistry owing to their advantageous properties such as negligible vapor pressure, high chemical
stability, etc. ILs have gone far beyond the role of solvent, showing their significant importance as new
catalysts in controlling the reactions in which they participate [18,19]. Recently, the synthesis of
‘‘task-specific’’ ILs with special functions according to the requirement of a particular reaction has
become an attractive field [20,21]. To the best of our knowledge, there have been no reports on the use
of Brønsted acid ionic liquids as catalysts for Michael additions of indoles. Herein we wish to report
for the first time a novel, environment-friendly and efficient methodology for the synthesis of β-
indolylketones by the reaction of indoles and α,β-unsaturated ketones using the SO3H-functionalized
Brønsted acid ionic liquid [PyN(CH2)4SO3H][p-CH3PhSO3] as catalyst (Scheme 1).
Scheme 1. The synthesis of β-indolylketones catalyzed by [PyN(CH2)4 SO3H][p-CH3PhSO3].
O
R3
R1
O
R4
[PyN(CH2)4SO3H][p-CH3PhSO3]
N
CH3CN, 80 °C
R
R3
R4
R1
R2
R2
N
R
1
2
3
SO3H
p-CH3PhSO3
[PyN(CH ) SO H][p-CH PhSO ]
=
N
2 4
3
3
3
Results and Discussion
To evaluate the effect of the catalyst [PyN(CH2)4SO3H][p-CH3PhSO3] under different reaction
conditions, the reaction of indole and chalcone was selected as a model reaction. The results are
presented in Table 1. Initially the effect of solvent on the reaction was studied (Table 1, entries 1–4)
and acetonitrile was found to be the best one. Next, we optimized the amount of [PyN(CH2)4SO3H][p-
CH3PhSO3] required (Table 1, entries 4-8) and the optimum amount was found to be 10 mol%. In the
absence of [PyN(CH2)4SO3H][p-CH3PhSO3], the reaction did not yield the desired product (Table 1,
entry 5). The influence of the reaction time on the yield was also investigated (Table 1, entries 4, 9–
14). It was clear that the highest yield was produced when the reaction time was 6 h, although the yield
did not improve to any greater extent when the reaction time was increased from 4 h to 6 h. For the
purpose of saving energy, we therefore chose 4 h as the reaction time. Hence, the best condition
employs 0.1:1:1 mole ratio of [PyN(CH2)4SO3H][p-CH3PhSO3], indole and chalcone at 80 °C for 4 h
using acetonitrile as solvent.

Molecules 2009, 14
3224
When optimizing the reaction conditions, the recycling of the catalyst in the reaction of indole and
chalcone was investigated. After the separation of products, ethyl acetate was added to the filtrate,
which split into two layers. The upper ethyl acetate layer contained unreacted raw material. The lower
aqueous layer included the ionic liquid. The lower layer was concentrated on a rotary evaporator at
80 °C for 1 h under vacuum to remove excess solvent. [PyN(CH2)4SO3H][p-CH3PhSO3] could be
recovered easily and directly reused in subsequent runs. As shown in Table 1, the desired product was
obtained in 97, 93, 90% yields after 1–3 runs, respectively (entry 12b). This indicated that the ionic
liquid [PyN(CH2)4SO3H][p-CH3PhSO3] was an efficient and recyclable catalyst for the conjugated
addtion of indoles to α, β-unsaturated ketones.
Table 1. Effect of the catalyst [PyN(CH2)4SO3H][p-CH3PhSO3] under different conditions
for the reaction of indole and chalcone.
Entry Solvent
Catalyst (mol %)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
EtOH
Ethyl acetate
THF
10
10
10
10
none
1
6
6
6
6
6
6
6
6
1
2
3
4
5
7
93
88
77
98
0
74
92
95
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
5
15
10
10
10
10
10
10
9
79
94
95
10
11
12b
13
14
97, 93, 90
97
95
Reaction conditions: indole (2 mmol), chalcone (2 mmol) and catalyst in solvent (10 mL), 80 °C;
a Isolated yield; b Catalyst was recycled three times.
To explore the generality and scope of this method, a wide variety of substituted indoles and α,β-
unsaturated ketones were reacted with 10 mol% of [PyN(CH2)4SO3H][p-CH3PhSO3] catalyst under the
optimized experimental conditions to afford the corresponding β-indolylketones in excellent yields.
(Table 2). The results obtained indicated that the electron donating or withdrawing groups at the indole
ring did not seem to affect the reaction significantly in terms of yields, nor do aromatic rings of α,β-
unsaturated ketones.
A plausible mechanism for the conjugate addition of indoles to chalcones is proposed in Scheme 2.
[PyN(CH2)4SO3H][p-CH3PhSO3] coordinates with oxygen atom of α,β-unsaturated ketones (2) to give
intermediate 4. The electron rich β-position of the indole ring then attacks the electron deficient
conjugated carbon-carbon double bond of 4 to afford 5, followed by a hydrogen transfer to yield 6.
Finally 6 rearranged to give target compound 3 and [PyN(CH2)4SO3H][p-CH3PhSO3] catalyzes the
next cycle.

Molecules 2009, 14
Table 2. [PyN(CH2)4SO3H][p-CH3PhSO3]-catalyzed synthesis of β-indolylketones.
3225
Mp (°C)b
Reported (Lit.)
Entry R R1 R2
R3
R4
Yieldsa (%)
Found
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
4-Cl-Ph
4-Cl-Ph
4-CH3-Ph Ph
4-CH3-Ph 4-Cl-Ph
4-CH3-Ph 4-CH3O-Ph
4-Cl-Ph
4-CH3-Ph 4-CH3O-Ph
Ph
97
96
98
90
90
98
94
96
95
98
98
92
126-129 127-128[17]
153-156 151-152[9]
174-177
118-121
202-205
132-134 130-131[9]
146-149
183-186
169-172
172-175
4-Cl-Ph
4-CH3O-Ph
Ph
4-CH3O-Ph
Me H
Me H
H
H
4-CH3O-Ph
3j
3k
3m
5-Br
5-CH3O Ph
Ph
4-Cl-Ph
Ph
189-191 188-189[13]
150-153
Reaction conditions: indole or substituted indoles (2 mmol), α, β-unsaturated ketones (2 mmol),
a
b
[PyN(CH2)4SO3H][p-CH3PhSO3] (0.02 mmol), acetonitrile (10 mL), 80 °C, 4 h; Isolated yield;
Melting points were uncorrected.
Scheme 2. The proposed mechanism of synthesizing β-indolyketones catalyzed by
[PyN(CH2)4SO3H][p-CH3PhSO3].
O
R3
SO3H
p-CH3PhSO3
N
R4
R3
R4
O
2
N
H
3
SO3
p-CH3PhSO3
N
OH
R4
R3
R4
R3
H
R4
4
R3
OH
OH
N
NH
N
H
H
SO3
p-CH3PhSO3
6
N
1
5

Molecules 2009, 14
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Conclusions
In conclusion, we have described for the first use of the Brønsted acid ionic liquid
[PyN(CH2)4SO3H][p-CH3PhSO3] as an efficient catalyst for the synthesis of β-indolylketones. The
procedure reported here has the advantages of mild reaction conditions, high yields of products,
operational simplicity and catalyst recyclability.
Experimental
General
1
All compounds were characterized by IR, H-NMR spectra and elemental analysis. The IR spectra
were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, U.S.A). The
1H-NMR spectra were obtained on a Varian Inova-400 spectrometer using DMSO-d6 as solvent and
TMS as an internal standard; chemical shifts are given in ppm. Elemental analyses (C, H, N) were
performed on a Perkin-Elmer Analyzer 2400. Melting points were determined using a Büchi B-540
instrument. All melting points are uncorrected. The Brønsted acid ionic liquid [PyN(CH2)4SO3H][p-
CH3PhSO3] was synthesized according to previous literature [22].
General procedure for the synthesis of β-indolylketones
A mixture of indole or substituted indole (2 mmol), α,β-unsaturated ketone (2 mmol) and
[PyN(CH2)4SO3H][p-CH3PhSO3] (0.2 mmol) was refluxed at 80 °C in acetonitrile (10 mL) for 4 h with
stirring. The completion of the reaction was monitored by TLC. After cooling, the reaction mixture
was poured onto crushed ice (30 g). The resulting precipitate was filtered under suction, and then
recrystallized from ethanol to afford the pure product. The results are summarized in Tables 2. All
products (except 3e, 3g, 3i, 3j, 3m) are known compounds, which were characterized by mp, IR,
1H-NMR spectra, elemental analyses.
3-(4-Chlorophenyl)-3-(1H-indol-3-yl)-1-(4-methoxylphenyl)propan-1-one (3e): light yellow powder.
1
Mp 202-205 °C; H-NMR δ: 3.74 (dd, 1H, J =7.6, 8.0 Hz, CH), 3.83 (s, 3H, OCH3), 3.86 (dd, 1H,
J = 7.6, 8.0 Hz, CH), 4.85 (t, 1H, J = 7.6 Hz, CH), 6.88-8.00 (m, 13H, ArH), 10.83 (s, 1H, NH); IR
(νmax; cm–1): 3383, 2971, 1657, 1599, 1489, 1256, 1180, 742; Anal. calcd. (%) for C24H20NO2Cl: C
73.94, H 5.17, N 3.59. Found: C 73.79, H 5.13, N 3.67.
1-(4-Chlorophenyl)-3-(1H-indol-3-yl)-3-(4-methylphenyl)propan-1-one (3g): light yellow powder. Mp
146-149 °C; 1H-NMR δ: 2.19 (m, 3H, CH3), 3.77 (dd, 1H, J = 7.6, 7.6 Hz, CH), 3.88 (dd, 1H, J =7.6,
7.6 Hz, CH), 4.80 (t, 1H, J = 7.6 Hz, CH), 6.85-8.03 (m, 13H, ArH), 10.83 (s, 1H, NH); IR (νmax.
;
cm–1): 3418, 2914, 1674, 1587, 1455, 1244, 1179, 741; Anal. Calcd. (%) for C24H20NOCl: C 77.10, H
5.39, N 3.75. Found C 77.27, H 5.34, N 3.68.
3-(4-Chlorophenyl)-1-(4-methoxylphenyl)-3-(2-methyl-1H-indol-3-yl)propan-1-one(3i): brown powder.
1
Mp 169-172 °C; H-NMR δ: 2.38 (s, 3H, CH3); 3.81 (s, 3H, OCH3); 3.87 (dd, 1H, J = 7.6, 7.6 Hz,

Molecules 2009, 14
3227
CH), 3.90 (dd, 1H, J = 7.6, 7.6 Hz, CH), 4.88 (t, 1H, J = 7.6 Hz, CH), 6.82-8.19 (m, 12H, ArH), 10.74
(s, 1H, NH); IR (νmax.; cm–1): 3312, 1664, 1596, 1464, 1258, 1169, 748; Anal. Calcd. (%) for
C25H22NO2Cl: C 74.34, H 5.49, N 3.47. Found C 74.45, H 5.43, N 3.52.
1-(4-Methoxylphenyl)-3-(2-methyl-1H-indol-3-yl)-3-(4-methylphenyl)propan-1-one (3j): light yellow
1
powder. Mp 172-175 °C; H-NMR δ: 2.2 (s, 3H, CH3); 2.36 (s, 3H, CH3); 3.80 (s, 3H, OCH3); 3.84
(dd, 1H, J =7.2, 7.6 Hz, CH ), 3.86 (dd, 1H, J = 7.2, 7.6 Hz, CH), 4.85 (t, 1H, J = 7.6 Hz, CH), 6.81-
7.94 (m, 12H, ArH), 10.68 (s, 1H, NH); IR (νmax.; cm–1): 3338, 1663, 1595, 1463, 1260, 1168, 747;
Anal. Calcd. (%) for C26H25NO2: C 81.43, H 6.57, N 3.65. Found C 81.29, H 6.51, N 3.73.
1,3-Diphenyl-3-(5-methoxyl-1H-indol-3-yl)propan-1-one (3m): white powder. Mp 150-153 °C;
1H-NMR δ 3.67 (s, 3H, OCH3), 3.80 (dd, 1H, J =7.2, 7.6 Hz, CH), 3.90( dd, 1H, J =7.2, 7.6 Hz, CH),
4.82 (t, 1H, J = 7.2 Hz, CH), 6.66-8.02 ( m, 14H, ArH), 10.68 (s, 1H, NH); IR (νmax.; cm–1): 3365,
1678, 1597, 1485, 1214, 1169, 723; Anal. Calcd. (%) for C24H21NO2: C 81.10, H 5.96, N 3.94. Found
C. 80.93, H 6.01, N 3.90.
Acknowledgements
We gratefully ackonwledge support from the National Natural Science Foundation of China (No.
20862016).
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