Acidic ionic liquid - Catalyzed highly efficient reaction of indoles to α,β-unsaturated ketones

Article abstract of DOI:10.1080/00397910701866304

A novel method for the Michael reaction of indoles to α,β- unsaturated ketones catalyzed by acidic ionic liquid is reported. We obtained the corresponding products in excellent yields in the presence of [hmim]HSO4. Development of this method has resulted

Full text of DOI:10.1080/00397910701866304

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Acidic Ionic Liquid–Catalyzed Highly Efficient
Reaction of Indoles to α,β‐Unsaturated
Ketones
Da‐gong Gu a , Shun‐jun Ji a , Hong‐xia Wang a & Qiu‐yan Xu a
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry and Chemical Engineering, Suzhou University, Suzhou, China
Version of record first published: 17 Apr 2008.
To cite this article: Da‐gong Gu , Shun‐jun Ji , Hong‐xia Wang & Qiu‐yan Xu (2008): Acidic Ionic
Liquid–Catalyzed Highly Efficient Reaction of Indoles to α,β‐Unsaturated Ketones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:8, 1212-1223
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Synthetic Communicationsw, 38: 1212–1223, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701866304
Acidic Ionic Liquid–Catalyzed Highly
Efficient Reaction of Indoles
to a,b-Unsaturated Ketones
Da-gong Gu, Shun-jun Ji, Hong-xia Wang, and Qiu-yan Xu
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry and Chemical Engineering, Suzhou University, Suzhou, China
Abstract: A novel method for the Michael reaction of indoles to a,b-unsaturated
ketones catalyzed by acidic ionic liquid is reported. We obtained the corresponding
products in excellent yields in the presence of [hmim]HSO4. Development of this
method has resulted in a new protocol for the synthesis of b-indolylketones.
Keywords: Acidic ionic liquid, indole, Michael reaction, a,b-unsaturated ketone
In recent years, room-temperature ionic liquids (RTILs) have generated con-
siderable excitement as potential green-chemistry designer solvents. In view
of their special properties (good solvating capability, wide liquid range,
negligible vapor pressure, ease of recycling), ionic liquids have found wide
application in catalytic and noncatalytic reactions.[1] Lately, the synthesis of
task-specific ionic liquids (TSILs), which have a functional group in their
frameworks, have been widely reported.[2] In these papers, the use of ionic
Received June 25, 2007
Address correspondence to Shun-jun Ji, Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou Univer-
sity, Hengyi Road, Suzhou Industrial Park, Suzhou City 215123, China. E-mail:
chemjsj@suda.edu.cn
1212

Indoles to a,b-Unsaturated Ketones
1213
liquids as reaction media and catalyst can offer a solution to solvent emission
and catalyst recyclability problems. These new ionic liquids are likely to make
synthetic processes less expensive and potentially more efficient and environ-
mentally friendly.
Because b-indolylketones are important building blocks for the
synthesis of many natural products such as hapalindole D 1,[3] the
Michael reactions of indoles to a,b-unsaturated ketones [Eq. (1)] have
attracted tremendous attention for the simplification or improvement of
the existing methods.[4] During the past few years, several different
Lewis acid catalysts available for the Michael reaction, such as InBr3,[5a]
Yb(OTf)3,[6a] Zr(OTf)4,[6a] CAN,[7] I2,[8] Bi(OTf)3,[9a] CeCl3,[10b] and so
on.[11] However, many of these procedures involve strong acidic conditions,
expensive reagents, longer reaction time, lower yields of products, complex
handling, and difficulty of reuse. Therefore, a green and efficient catalyst is
still desirable.
Scheme 1. Structure of acidic ionic liquids.
In continuation of our interest in TSIL-mediated reactions of indoles,[12d,13]
we subsequently investigated a novel reaction of indoles and a,b-unsaturated
ketones catalyzed by acidic ionic liquids. Herein, three acidic ionic liquids,
[acmim]Cl[12a,12b] (ac ¼ acetoxy, m ¼ methyl, im ¼ imidazolium), [hmim]
[12c–f]
HSO4
(h ¼ n-hexyl, m ¼ methyl, im ¼ imidazolium), and [hmim]
Tfa[14] (h ¼ n-hexyl, m ¼ methyl, im ¼ imidazolium), are employed to
catalyze the reaction of indoles and a,b-unsaturated ketones. Acidic ionic
liquid [hmim]HSO4 is an effective and reusable catalyst for this reaction.
In our initial research, 1,3-diphenylpropenone as a typical representative
of a,b-unsaturated ketones was selected to react with indole using different
acidic ionic liquids to optimize the reaction.
As shown in Table 1, the reaction did not occur in the absence of a
catalytic amount of acidic ionic liquids (Table 1, entry 1), and it is more
important to notice that [hmim]PF6 cannot promote this addition (Table 1,
entry 2). Interestingly, the use of [acmim]Cl and [n-Bu4 N]HSO4 could not
promote the reaction (Scheme 1). Because of the acidity of these ionic
liquids, the reaction proceed smoothly in the presence of 20 mol%
[hmim]HSO4 and 20 mol% [hmim]Tfa. Then we screened the effect of a
variety of solvents on the Michael reaction. Alcohol, especially ethanol,
was the best solvent in terms of yield, reaction time, low toxicity (compared
with CH3CN), and economic viability. In addition, we reduced the amount

1214
D.-g. Gu et al.
Table 1. Synthesis of 3-(3-indolyl)-1,3-diphenylpropan-2-one in different solvents
using acidic ionic liquids
Entry
Cat. (mol%)
None
20% [hmim]PF6
Solvent
Time (h)
Yield (%)a
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
7
4
0
0
3
20% [acmim]Cl
20% [hmim]Tfa
11
12
4
0
4
73
0
5
20% [n-Bu4 N]HSO4
20% [hmim]HSO4
20% [hmim]HSO4
20% [hmim]HSO4
20% [hmim]HSO4
20% [hmim]HSO4
20% [hmim]HSO4
20% [hmim]HSO4
10% [hmim]HSO4
5% [hmim]HSO4
6
6
4
7
MeOH
CH3CN
CH2Cl2
THF
3
94
98
9
8
6
9
7
10
11
12
13
14
8
88
49
97
99
99
EtOAc
EtOH
EtOH
EtOH
6
2
3
5
aIsolated yields.
of [hmim]HSO4 to 5 mol%. The reaction went to completion within 5 h at
80 8C with a yield of 99%.
Using the best conditions mentioned previously, we continued to investi-
gate the reactions of indole to a variety of a,b-unsaturated ketones at 80 8C.
The results are listed in Table 2, which indicated that all the aromatic
a,b-unsaturated ketones underwent smooth reaction with indole to give
the corresponding products with high yields. Unexpectedly, the yield of
4-methylpent-3-en-2-one (Table 2, entry 12) is only 48%. This catalyst
system is more efficient for the aromatic a,b-unsaturated ketones.
Next, we studied the Michael reaction of various substituted indoles to
1,3-diphenyl-propenone under identical conditions (Table 1, entry 13). The
results were summarized in Table 3.
The Michael addition on the indole occurred exclusively at the 3-position.
In accordance with this finding, the Michael reaction of 3-methylindole
(Table 3, entry 3) did not take place after the mixture was magnetically
stirred at an external temperature of 80 8C for 4 h. The reaction of other sub-
stituted indoles and 1,3-diphenyl-propenone proceeded smoothly in EtOH in
the presence of 10 mol% [hmim]HSO4 to provide the desired products in
high yields.

Indoles to a,b-Unsaturated Ketones
1215
Table 2. Reaction of indole catalyzed by 10 mol% [hmim]HSO4 with various
a,b-unsaturated ketones in EtOH
Entry
1
a,b-Unsaturated ketones
Producta
Time (h)
3
Yield (%)b
99
2a
2
3
2b
2c
4
88
98
3.1
4
5
6
2d
2e
2f
3.5
3
90
81
94
4.1
7
8
9
2g
2h
2i
3
99
91
96
4.5
5.5
10
2j
5.5
96
(continued)

1216
D.-g. Gu et al.
Table 2. Continued
Entry
11
a,b-Unsaturated ketones
Producta
Time (h)
5
Yield (%)b
95
2k
12
2l
6
48
1
aAll products were characterized by H NMR, IR, and HRMS spectroscopy and
elemental analysis.
bIsolated yields.
Table 3. Reaction of 1,3-diphenyl-propenone catalyzed by 10 mol% [hmim]HSO4
with various substituted indoles in EtOH
Entry
1
Indole
Producta
Time (h)
3
Yield (%)b
99
3a
2
3
3b
3c
2.5
4
93
—
4
5
6
3d
3e
3f
1
4
3.25
4
92
63
46
aAll products were characterized by H NMR, IR, and HRMS spectroscopy and
elemental analysis.
bIsolated yields.

Indoles to a,b-Unsaturated Ketones
1217
Table 4. Recyclability of 20 mol% [hmim]HSO4 in EtOH
Mass of the IL and flask
before reaction (g)
Entry
Time (h)
Yield (%)a
0
1
2
3
2
2
6
9
97
98
69
56
41.2783
41.2823
41.2859
41.2802
aIsolated yields.
With the success of these reactions, we continued our task by studying the
reusability of ionic liquid [hmim]HSO4 in EtOH (Table 4). The catalytic
activity of acidic ionic liquids gradually decreased in the second and third
cycles (entries 2 and 3). The reason was probably that the a few acidic ionic
liquids were lost in the extraction procedure.
In brief, we provide a novel method for the reaction of indole with
a,b-unsaturated ketones. Instead of Lewis acids, [hmim]HSO4/EtOH make
this procedure quite simple, more convenient, and environmentally benign.
This preliminary work demonstrates the potential application of ionic
liquids with acidic counterions as good acid catalysts in the synthesis of
3-(3-indolyl)-1,3-diphenylpropan-2-one and their derivatives of biological
importance. Further studies of other ionic liquids with acidic counterions
for promoting other acid-catalyzed reactions are under way.
EXPERIMENTAL
Melting points were recorded on an Electrothermal digital melting-point
1
apparatus and are uncorrected. H NMR (400 MHz) spectra were recorded
on a Varian Mercury spectrometer in CDCl3. IR spectra were obtained on a
Nicolet FT-IR500 spectrophotometer using KBr pellets. Elemental analysis
was performed by a Carlo-Erba EA1110 CNNO-S analyzer. High-resolution
mass spectra (HRMS) were obtained using a GCT-TOF instrument. Ultraso-
nication was performed in a KQ-250E ultrasonic cleaner with a frequency
of 40 KHz and a normal power of 250 W. The reaction flask was located in
the water bath of the ultrasonic cleaner, and the temperature of the water
bath was controlled by heating.
Typical Experimental Procedure
A mixture of indoles (0.0702 g, 0.60 mmol), 1,3-diphenylpropenone (0.104 g,
0.50 mmol), and [hmim]HSO4 (0.0132 g, 0.05 mmol) in EtOH (4.0 mL) was
stirred at 80 8C. After completion of the reaction as indicated by thin-layer

1218
D.-g. Gu et al.
chromatography (TLC), the mixture was concentrated in vacuo to remove the
solvent. The resulting solution was extracted with ether (5 ꢀ 10.0 mL). The
ether layer was dried (Na2SO4), concentrated under vacuum, and purified by
column chromatography to afford the pure product. For synthetic procedures
of acidic ionic liquids, please see Ref. [12].
Data
3-(3-Indolyl)-1,3-diphenylpropan-2-one (2a)
Solid; mp 125–127 8C; IR (KBr): n ¼ 3413 (NH), 1679 (CO) cm21; 1H NMR
(400 MHz, CDCl3): d ¼ 3.67–3.83 (m, 2H, CH2), 5.04 (t, J ¼ 7.2 Hz, 1H,
CH), 6.97–7.53 (m, 13H), 7.91–7.96 (m, 3H). HRMS: m/z calcd. for
C23H19NO: 325.1467; found: 325.1431. Anal. calcd. for C23H19NO: C,
84.89; H, 5.89; N, 4.30. Found: C, 84.74; H, 5.84; N, 4.35.
3-(4-Chlorophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (2b)
Please see Ref. 8(a).
3-(2-Chlorophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (2c)
Please see Ref. 12(e).
3-(1H-Indol-3-yl)-1-phenyl-3-(thiophen-3-yl)propan-1-one (2d)
Solid; mp 129–130 8C; IR (KBr): n ¼ 3395 (NH), 1681 (CO) cm21; 1H NMR
(400 MHz, CDCl3): d ¼ 3.77 (d, J ¼ 6.4 Hz, 2H, CH2), 5.16 (s, 1H, CH),
7.01–7.54 (m, 11H), 7.92–7.96 (m, 3H). HRMS: m/z calcd. for
C21H17NOS: 331.1031; found: 331.1037. Anal. calcd. for C21H17NOS: C,
76.10; H, 5.17; N, 4.23. Found: C, 76.16; H, 5.21; N, 4.25.
3-(1H-Indol-3-yl)-1-phenyl-3-(thiophen-2-yl)propan-1-one (2e)
Please see Ref. 8(a).
3-(Benzo[d][1,3]dioxol-6-yl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (2f)
Solid; mp 115–116 8C; IR (KBr): n ¼ 3370 (NH), 1675 (CO) cm21; 1H NMR
(400 MHz, CDCl3): d553.64–3.80 (m, 2H, CH2), 4.99 (t, J ¼ 7.0 Hz, 1H,
CH), 5.81–5.91 (m, 2H, OCH2O), 6.69–7.56 (m, 11H), 7.93–7.97 (m, 3H).
HRMS: m/z calcd. for C24H19NO3: 369.1365; found: 369.1362. Anal.
calcd. for C24H19NO3: C, 78.03; H, 5.18; N, 3.79. Found: C, 78.10; H, 5.20;
N, 3.84.

Indoles to a,b-Unsaturated Ketones
1219
3-(Benzo[d][1,3]dioxol-6-yl)-3-(1H-indol-3-yl)-1-(4-
methoxyphenyl)propan-1-one (2g)
1
Solid; mp 72–74 8C; IR (KBr): n ¼ 3405 (NH), 1666 (CO) cm21; H NMR
(400 MHz, CDCl3): d ¼ 3.58–3.89 (m, 2H, CH2), 4.11 (s, 3H, OCH3), 4.98
(t, J ¼ 7.2 Hz, 1H, CH), 5.81–6.03 (m, 2H, OCH2O), 6.64–7.75 (m, 10H),
7.91–8.04 (m, 3H). HRMS: m/z calcd. for C25H21NO4: 399.1471; found:
399.1461. Anal. calcd. for C25H21NO4: C, 75.17; H, 5.30; N, 3.51. Found:
C, 75.16; H, 5.24; N, 3.53.
3-(Benzo[d][1,3]dioxol-6-yl)-1-(4-chlorophenyl)-3-(1H-indol-3-
yl)propan-1-one (2h)
1
Solid; mp 68–70 8C; IR (KBr): n ¼ 3411 (NH), 1660 (CO) cm21; H NMR
(400 MHz, CDCl3): d ¼ 3.67–3.83 (m, 2H, CH2), 4.95 (t, J ¼ 7.4 Hz, 1H,
CH), 5.86–6.68 (m, 2H, OCH2O), 6.70–7.45 (m, 11H), 7.85–7.98 (m, 3H).
HRMS: m/z calcd. for C24H18ClNO3: 403.0957; found: 403.0958. Anal.
calcd. for C24H18ClNO3: C, 71.38; H, 4.49; N, 3.47. Found: C, 71.34; H,
5.52; N, 3.47.
1-(4-Chlorophenyl)-3-(1H-indol-3-yl)-3-p-tolylpropan-1-one (2i)
1
Solid; mp 84–85 8C; IR (KBr): n ¼ 3420 (NH), 1674 (CO) cm21; H NMR
(400 MHz, CDCl3): d552.32 (s, 3H, CH3), 3.63–3.79 (m, 2H, CH2), 4.99
(t, J ¼ 7.2 Hz, 1H, CH), 6.97–7.44 (m, 11H), 7.84–7.97 (m, 3H). HRMS:
m/z calcd. for C24H20ClNO: 373.1233; found: 373.1227. Anal. calcd. for
C24H20ClNO: C, 77.10; H, 5.39; N, 3.75. Found: C, 77.06; H, 5.44; N, 3.72.
1,3-Bis(4-chlorophenyl)-3-(1H-indol-3-yl)propan-1-one (2j)
Solid; mp 136–138 8C; IR (KBr): n ¼ 3395 (NH), 1669 (CO) cm21; 1H NMR
(400 MHz, CDCl3): d ¼ 3.67–3.76 (m, 2H, CH2), 5.02 (m, 1H, CH), 6.98–
7.42 (m, 11H), 7.85–8.00 (m, 3H). HRMS: m/z calcd. for C23H17Cl2NO:
393.0687; found: 393.0680. Anal. calcd. for C23H17Cl2NO: C, 70.06; H,
4.35; N, 3.55. Found: C, 70.14; H, 4.34; N, 3.47.
1-(4-Chlorophenyl)-3-(1H-indol-3-yl)-3-(thiophen-2-yl)propan-1-one (2k)
Solid; mp 116–117 8C; IR (KBr): n ¼ 3417 (NH), 1671 (CO) cm21; 1H NMR
(400 MHz, CDCl3): d ¼ 3.78–3.80 (m, 2H, CH2), 5.34 (t, J ¼ 6.2 Hz, 1H,
CH), 6.85–7.55 (m, 10H), 7.85–8.00 (m, 3H). HRMS: m/z calcd. for
C21H16ClNOS: 365.0641; found: 365.0640. Anal. calcd. for C21H16ClNOS:
C, 68.94; H, 4.41; N, 3.83. Found: C, 69.01; H, 4.47; N, 3.90.

1220
D.-g. Gu et al.
4-(1H-Indol-3-yl)-4-methylpentan-2-one (2l)
Please see Ref. 8(a).
3-(2-Methyl-1H-indol-3-yl)-1,3-diphenyl-propan-1-one (3b)
Solid; mp 115–116 8C. IR (KBr): n ¼ 3409 (NH), 1673 (CO), 1596, 1488,
1
1457 (ArH) cm21. H NMR (400 MHz, CDCl3): d ¼ 2.43 (s, 3H, CH3),
3.91–3.95 (m, 2H, CH2), 5.09 (s, 1H, CH), 6.69–7.50 (m, 12H), 7.73–7.89
(m, 3H). HRMS: m/z calcd. for C24H21NO: 339.1623; found: 339.1621.
Anal. calcd. for C24H21NO: C, 84.92; H, 6.24; N, 4.13. Found: C, 85.01; H,
6.31; N, 4.05.
3-(5-Methyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3d)
Solid; mp 167–168 8C. IR (KBr): n ¼ 3434 (NH), 1675 (CO), 1593, 1480,
1447 (ArH) cm21
.
1H NMR (400 MHz, CDCl3): d ¼ 2.36 (s, 3H CH3),
3.73–3.78 (m, 2H, CH2), 5.02 (s, 1H, CH), 6.94–7.53 (m, 12H), 7.86–7.94
(m, 3H). HRMS: m/z calcd. for C24H21NO: 339.1623; found: 339.1613.
Anal. calcd. for C24H21NO: C, 84.92; H, 6.24; N, 4.13. Found: C, 84.90; H,
6.31; N, 4.21.
3-(7-Methyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3e)
Solid; mp 104–105 8C. IR (KBr): n ¼ 3276 (NH), 1656 (CO), 1596, 1491,
1
1447 (ArH) cm21. H NMR (400 MHz, CDCl3): d ¼ 2.44 (s, 3H, CH3),
3.73–3.80 (m, 2H, CH2), 5.05 (t, J ¼ 6.8 Hz, 1H, CH), 6.94–7.54
(m, 12H), 7.88–7.93 (m, 3H). HRMS: m/z calcd. for C24H21NO: 339.1623;
found: 339.1621. Anal. calcd. for C24H21NO: C, 84.92; H, 6.24; N, 4.13.
Found: C, 84.96; H, 6.19; N, 3.94.
3-(1-Methyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3f)
Solid; mp 127–129 8C. IR (KBr): n ¼ 3401 (NH), 1673 (CO), 1581, 1481,
1
1450 (ArH) cm21. H NMR (400 MHz, CDCl3): d ¼ 3.70–3.84 (m, 2H,
CH2), 5.07 (s, 1H, CH), 6.83–7.53 (m, 15H), 7.92–7.96 (m, 3H). HRMS:
m/z calcd. for C24H21NO: 339.1623; found: 339.1613. Anal. calcd. for
C24H21NO: C, 84.92; H, 6.24; N, 4.13. Found: C, 84.79; H, 6.26; N, 4.21.
Recycling the Acidic Ionic Liquid
A mixture of indoles (0.0702 g, 0.60 mmol), 1,3-diphenylpropenone (0.104 g,
0.50 mmol), and [hmim]HSO4 (0.0264 g, 0.10 mmol) in EtOH (4.0 mL) was
stirred at 80 8C. After completion of the reaction as indicated by TLC, the

Indoles to a,b-Unsaturated Ketones
1221
mixture was concentrated in vacuo to remove the solvent. The resulting
solution was extracted with ether (5 ꢀ 10.0 mL). The ether layer was dried
(Na2SO4), concentrated under vacuum, and purified by column chromato-
graphy to afford the pure product. The insoluble [hmim]HSO4 could be
directly recycled in subsequent runs.
ACKNOWLEDGMENTS
This work was partially supported by the Key Laboratory of Organic Synthesis
of Jiangsu Province at Suzhou University (No. JSK008), the National Science
Foundation of Jiangsu Province (No. BK2004038), the National Science
Foundation of China (Nos. 20172039 and 20472062), and Jiangsu Provincial
Key Laboratory of Fine Petrochemical Technology (KF0402).
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