Triflic acid-catalyzed Michael reactions of indole and pyrrole compounds with α,β-unsaturated ketones in water

Article abstract of DOI:10.1080/00397910601031504

The Michael reactions of indole and pyrrole compounds to α,β-unsaturated ketones catalyzed by triflic acid (HOTf, 0.1-1 mol%) were performed in water to give alkylated indoles (3a-m) and dialkylsubstituted pyrroles (6a-b) in good to excellent yields. Copy

Full text of DOI:10.1080/00397910601031504

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Triflic Acid–Catalyzed Michael Reactions
of Indole and Pyrrole Compounds with
α,β‐Unsaturated Ketones in Water
Hai‐Bo Zhang a , Li Liu a , Yu‐Liang Liu a , Yong‐Jun Chen a , Jun Wang a &
Dong Wang a
a Center for Molecular Science, Institute of Chemistry, Chinese Academy of
Sciences, Beijing, China
Published online: 25 Jul 2007.
To cite this article: HaiBo Zhang , Li Liu , YuLiang Liu , YongJun Chen , Jun Wang & Dong Wang (2007) Triflic
Acid–Catalyzed Michael Reactions of Indole and Pyrrole Compounds with α,β‐Unsaturated Ketones in Water,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
37:2, 173-181, DOI: 10.1080/00397910601031504
To link to this article: http://dx.doi.org/10.1080/00397910601031504
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Synthetic Communicationsw, 37: 173–181, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601031504
Triflic Acid–Catalyzed Michael Reactions
of Indole and Pyrrole Compounds with
a,b-Unsaturated Ketones in Water
Hai-Bo Zhang, Li Liu, Yu-Liang Liu, Yong-Jun Chen,
Jun Wang, and Dong Wang
Center for Molecular Science, Institute of Chemistry, Chinese Academy
of Sciences, Beijing, China
Abstract: The Michael reactions of indole and pyrrole compounds to a,b-unsaturated
ketones catalyzed by triflic acid (HOTf, 0.1–1 mol%) were performed in water to give
alkylated indoles (3a–m) and dialkylsubstituted pyrroles (6a–b) in good to excellent
yields.
Keywords: catalytic and aqueous Michael reaction, indole, pyrrole, triflic acid,
a,b-unsaturated ketone
INTRODUCTION
Indole and pyrrole moieties are important structural units in compounds
with many pharmacologically and biologically interesting activities.[1]
A
lot of synthetic methods for these compounds have been developed.
Among them, the conjugate addition reaction of indoles and pyrroles to
a,b-unsaturated carbonyl compounds is very efficient and convenient.
Numerous research works on these reactions have been reported, which
include the uses of protic acids in acetic acid medium,[2] acidic clay,[3]
Lewis acid,[4] inorganic salts,[5] and iodine[6] in organic solvent as
promoters or catalysts in the conjugate addition reaction of indole and
Received December 18, 2005
Address correspondence to Dong Wang, Center for Molecular Science, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100080, China. E-mail:
dwang210@iccas.ac.cn
173

174
H.-B. Zhang et al.
pyrrole to a,b-unsaturated ketones. Recently, aqueous organic reactions
have received considerable attention in view of their synthetic efficiency
and environmental friendliness.[7] The Michael addition reaction is one of
the most important carbon–carbon bond formation reactions, which is
also considered an efficient and atom-economical reaction in terms of
green chemistry. The development of the aqueous Michael reaction
should be very interesting to organic chemists. However, in some cases,
the use of water as solvent or cosolvent, including addition of surfactant,
is not favorable to the aqueous catalytic Michael addition reaction.[4d,6a]
For improvement, Kobayashi[8] reported that in the presence of a new
kind of catalyst, scandium tris(dodecyl sulfate), the conjugate addition
reaction of indoles with a,b-unsaturated carbonyl compounds can be
smoothly carried out in water. The aluminium analogue of the
Kobayashi-tytpe catalyst, aluminium dodecyl sulfate trihydrate, was also
employed in the same aqueous reaction.[9] More recently, p-totylsulfonic
acid (PTSA)–catalyzed Michael reaction of indoles in anhydrous ethanol
under ultrasonic irradiation was reported.[10] It should be interesting to
investigate the ability of protic acid for catalyzing the aqueous Michael
addition reaction. Herein, we report triflic acid (CF3SO3H, HOTf)–
catalyzed Michael addition reaction of indole and pyrrole compounds to
a,b-unsaturated ketones in water.
RESULTS AND DISCUSSION
To start the investigation, the reactions of indole (1a) with vinylmethylke-
tone (2a) were carried out in water at room temperature in the presence of
several Brønsted acids to give the addition product 3a (R, R1, R2, R3 ¼ H;
R4 ¼ CH3) (Scheme 1). The Brønsted acids included triflic acid (HOTf), tri-
fluoroacetic acid (TFA), p-toluensulfonic acid (PTSA), and dilute hydro-
chloric acid. The reaction depended on the acidity (pKa value) of the
catalyst (Table 1). TFA and PTSA have moderate catalytic abilities with
yields of 55–68% in the reaction of indole (1a) with vinylmethylketone
(2a) (entries 10–13), whereas in dilute hydrochloric acid (10 mol% HCl
Scheme 1.

Michael Reactions of Indole and Pyrrole Compounds
175
Table 1. Acid-catalyzed Michael reaction of 1a with 2aa in water
Acid catalyst
(mol%)
Yieldb
(%)
Entry
pKa
214
Time (h)
1
2
HOTf (10)
3.5
3.5
8
72
89
96
85c
98
86d
72e
89
89
62
55
68
65
—
—
HOTf (5)
HOTf (2)
HOTf (2)
HOTf (1)
HOTf (1)
HOTf (1)
HOTf (0.5)
HOTf (0.1)
TFA (10)
TFA (1)
3
4
8
5
6
6
3
7
1.5
14
24
4
8
9
10
11
12
13
14
15
20.25
2.55
24
24
24
24
24
PTSA (10)
PTSA (1)
HCl (10)
—
28.0
a1a/2a ¼ 1:3, 258C.
bIsolated yield.
c1a/2a ¼ 1:2.
d408C.
e608C.
in 2 mL of water), no product was detected by thin-layer chromatography
(TLC) after stirring the reaction mixture for 24 h (entry 14). Without the
use of any catalyst, the reaction in water did not proceed at all (entry
15). Fortunately, the strong acid HOTf exhibits good catalytic ability. By
using only 1 mol% of HOTf as catalyst, the reaction of 1a with 2a in
water proceeded smoothly to give the Michael adduct 3a in 98% yield
(entry 5). More HOTf (e.g., 5 or 10 mol%, entry 1 and 2) is not helpful
to increase yield of the product, probably because of the formation of a
by-product. Although the amount of HOTf used decreased down to
0.5 mol%, even to 0.1 mol%, the reaction still provided high yields of 3a
(89%), in spite of relatively longer reaction times (entries 8 and 9).
Comparing the results listed in entries 3 and 4, the best choice of ratio
of 1a/2a is 1:3. By increasing the reaction temperature, indole disappeared
faster, but the yields decreased (Table 1, entries 5–7).
After workup, the water phase containing HOTf can be reused in the
reaction of 1a with 2a as an aqueous solution of the catalyst (catalyst
loading: 1 mol%, in 2 mL of water). In cycles 3 and 4, the yields of 3a
decreased slightly, probably because of the slight loss of catalyst HOTf
during the workup operation. However, if the reaction time was prolonged

176
H.-B. Zhang et al.
Table 2. Reuse of aqueous solution of HOTf
Recycle
Time (h)
Yielda (%)
1
2
3
4
5
6
6
6
98
95
83b
82b
91
6
6
12
12
95
aIsolated yield.
bAfter workup, a little starting material was recovered.
to 12 h, after recycling five times, the yield of 3a still remained at 91–95%
(Table 2).
Based on these experimental results, various indole compounds (1a–f)
were employed in the Michael addition reactions with a,b-unsaturated
carbonyl compounds (2a–d) (1/2 ¼ 1:3) in water at room temperature in
the presence of 1 mol% catalyst, HOTf (Table 3). For the aqueous reactions
of 1-methylindole (1b), 2-methylindole (1c), or 1,2-dimethylindole (1d)
with 2a, HOTf exhibited good catalytic ability (entries 2–4). Of these
indole compounds, 1c has the best reactivity in the reaction with various
a,b-unsaturated carbonyl compounds (entries 8 vs. 9, 10 vs. 11, 12 vs. 13).
Having an electron-donating group on the 5-position of indole, 5-methoxyin-
dole (1e) also exhibits very good reactivity (entry 5). The reaction time was
prolonged to 2–3 days, notably for 5-bromoindole (1f) and methyl indole-
5-carboxylate (1g) bearing an electron-withdrawing group in the phenyl
ring of indole, which decreases the aromatic nucleophilicity of indole
(entries 6 and 7). 4-Phenyl-3-buten-2-one 2b also showed low reactivity
(entries 8 and 9). In the case of 2-cyclohexen-1-one 2c, a mixture of 1,1,3-
tris(indol-30-yl)cyclohexane (4) and 3-(indol-30-yl)cyclohexan-1-one (3j)
was obtained in the aqueous reaction with 1a (69 and 21% yield, respectively,
entry 9), even though the ratio of substrate 1a to 2c is 1:3. (On formation of
triindolyl product 4 during the Zr(OTf)4-catalyzed Michael reaction of
indole, see Ref.[4c]). As supposed by Shi,[4c] the formation of triindolylcyclo-
hexane would be through a 1,4-addition, a 1,2-addition, and a dehydration
process. The results mentioned previously indicated that the 1,2-addition is
a faster reaction step in the course of the aqueous reaction than the 1,4-
addition. In contrast, in the reaction of 2-methylindole 1c, the 1,4-conjugate
addition reaction is predominant, to give 2-methyl-3-(indol-30-yl)cyclo-
hexan-1-one 3k exclusively (entry 11). For other cyclic substrates, 2-cyclo-
pente-1-one 2d, no triindolylcyclopentane product was detected in the
reaction mixture, whereas reactivity in the 1,4-addition reaction was higher
and only a single Michael adduct, indolylcyclopentanone 3l, was obtained

Table 3. HOTf-catalyzed Michael addition of indoles with enones in watera
Entry
1
Indole
Enone
Time
6 h
Product
Yieldb (%)
98
2a
2a
2a
2a
2a
2a
2a
3a
3b
1c
3d
3e
3f
1a
1b
2
3
4
5
6
7
12 h
7 h
7 h
6 h
2 d
3 d
93
95
85
94
90
60
1c
1d
1e
1f
1g
3g
(continued)

Table 3. Continued
Entry
Indole
Enone
Time
2 d
Product
Yieldb (%)
53
8
1a
2b
3h
9
10
11
12
13
1c
1a
1c
1a
1c
2b
2c
2c
2d
2d
2 d
3i
81
2.5 d
40 h
30 h
8 h
3j
21 þ 69
70
3k
3l
60
3m
81
aCatalyst (HOTf) loading: 1 mmol%, room temperature, indole/enone ¼ 1:3.
bIsolated yield.

Michael Reactions of Indole and Pyrrole Compounds
179
Scheme 2.
in 60% yield (entry 12). Probably both the steric effect of indole and the ring
size of the cyclic a,b-unsaturated ketone play an important role in the ratio of
1,4-addition to 1,2-addition.
Pyrrole 5a and 1-methylpyrrole 5b were also used in the HOTf-catalyzed
Michael addition reactions with a,b-unsaturated ketones (2a) (5/2a ¼ 1:3) in
Table 4. HOTf-catalyzed Michael addition of pyrroles with enones in watera
Yieldb
(%)
Entry
1
Indole
5a
Enone
Time
3 h
Product
2a
6a
6a
6b
84
2
3
5ac
5b
2ac
2a
4 h
5 h
72d
76
4
6
5a
5b
2c
2c
8 h
8 h
6c
60
69
6d
aCatalyst (HOTf) loading: 1 mmol%, room temperature, pyrrole/enone ¼ 1:3.
bIsolated yield.
cta/2a ¼ 1:1.
dBased on 2a.

180
H.-B. Zhang et al.
water in the presence of 1 mol% of HOTf (Scheme 2 and Table 4), giving the
products, dialkylpyrroles (6a,b), in 74–86% yields. When the ratio of 5a/2a
changed to 1:1, dialkylsubstituted pyrrole (6a) was still obtained exclusively
(entry 3). The reaction cannot stop at the mono-alkyl-substituted pyrrole step.
When 2c was used in the aqueous Michael reaction with pyrroles (5a and 5b),
dialkylpyrroles (6c,d) were also obtained in 60–69% yields (entries 4 and 5)
instead of forming the product structurally similar to triindolylcyclohexane (4,
entry 10 in Table 2).
In conclusion, triflic acid is an efficient catalyst for the Michael addition
reaction of indole and pyrrole compounds to a,b-unsaturated ketones in water
at room temperature. The catalyst loading can be in a trace amount, even in
0.1 mol% for activated substrate. The reaction conditions are very mild and
practicable. The water phase containing HOTf can be reused several times
with high yields. The HOTf-catalyzed Michael reaction in water made the
synthesis of indole and pyrrole derivatives more environmentally friendly.
EXPERIMENTAL
IR spectra were recorded on a Bruker Tensor 27 infrared spectrometer. 1H and
13C NMR spectra were measured by a Bruker AV-300 spectrometer with
tetramethylsilane as an internal standard. Mass spectra were recorded on a
GCT-MS Micromass spectrometer. The water used as the reaction media
was redistilled. Common reagents and materials were purchased from com-
mercial sources and purified before use.
General Procedure
A mixture of indole 1a (117 mg, 1 mmol), vinylmethylketone 2a (208 mg,
3 mmol), and HOTf (1.7 mL, 5.6 ꢀ 1023 M in water, 0.01 mmol) in water
(2 mL) was stirred at room temperature for 6 h until starting material 1a dis-
appeared on TLC. The reaction mixture was extracted by ethyl acetate. The
organic layer was washed by saturated aqueous NaHCO3 solution
(sometimes, the washing operation is not necessary) and dried over Na2SO4.
After evaporating the solvent, the crude product was purified by flash chrom-
atography on silica gel (eluent: petroleum ether (30–608C)/ethyl
acetate ¼ 6:1) to give a white solid 3a (184 mg, 98%).
Data
2,5-bis(10-Cyclohexanone-30-yl)pyrrole (6c): A yellow oil. nmax: 3377, 2939,
.
2863, 1707, 1587, 1448, 1424, 1317, 1225, 1182, 772 cm21 1H NMR
d ¼ 1.71–1.77 (4H, m), 2.00–2.09 (4H, m), 2.27–2.47 (6H, m), 2.59–2.60

Michael Reactions of Indole and Pyrrole Compounds
181
(2H, m), 2.99–3.01 (2H, m), 5.78 (2H, d, J ¼ 2.7 Hz), 8.17 (1H, br, s); 13C
NMR d ¼ 24.8, 31.4, 37.5, 41.3, 47.6, 103.9, 133.8, 211.0. HRMS: calcd.
for C24H16NO2 (Mþ): 259.1572, found: 259.1569.
2,5-bis(10-Cyclohexanone-30-yl)-1-methyl-pyrrole (6d): A yellow oil. nmax
:
2927, 2867, 1708, 1449, 1423, 1316, 1299, 1261, 1220, 1033, 740 cm21. H
NMR d ¼ 1.74–1.80 (4H, m), 2.08–2.12 (4H, m), 2.36–2.64 (8H, m),
3.03–3.05 (2H, m), 3.45 (3H, s), 5.87 (2H, s); 13C NMR d ¼ 24.9, 30.0,
31.5, 36.3, 41.2, 47.8, 103.4, 135.4, 210.5. HRMS: calcd. for C24H16NO2
(Mþ): 273.1729, found 273.1723.
1
ACKNOWLEDGMENTS
The research was financially supported by the National Natural Science
Foundation of China and the Chinese Academy of Sciences.
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