Sulfamic acid as a cost-effective and recyclable solid acid catalyst for Friedel-Crafts alkylation of indole with α,β-unsaturated carbonyl compound and benzyl alcohol

Article abstract of DOI:10.1016/j.cclet.2011.06.006

Sulfamic acid was proved to be a cost-effective and recyclable catalyst for Friedel-Crafts type reaction of indole with α,β-unsaturated carbonyl compound and benzyl alcohol. Various indoles, α,β-unsaturated carbonyl compounds and a benzyl alcohol were suc

Full text of DOI:10.1016/j.cclet.2011.06.006

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1391–1394
www.elsevier.com/locate/cclet
Sulfamic acid as a cost-effective and recyclable solid acid catalyst
for Friedel–Crafts alkylation of indole with a,b-unsaturated
carbonyl compound and benzyl alcohol
Jing Yang a, Juan Zhang a, Tian Tian Chen b, De Mei Sun a, Ji Li c, Xue Fen Wu a,
*
a Henan University of Traditional Chinese Medicine, Zhengzhou 450008, China
b Henan Chemical Industry Research Institute Co., Ltd., Zhengzhou 450052, China
c Institute of Chemistry, Henan Academy of Science, Zhengzhou 450002, China
Received 25 April 2011
Available online 29 July 2011
Abstract
Sulfamic acid was proved to be a cost-effective and recyclable catalyst for Friedel–Crafts type reaction of indole with a,b-
unsaturated carbonyl compound and benzyl alcohol. Various indoles, a,b-unsaturated carbonyl compounds and a benzyl
alcohol were successfully used in this type of reaction, and the corresponding products were obtained in good to excellent
yields.
# 2011 Xue Fen Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Sulfamic acid; Michael reaction of indole; Acid catalysis; Alkylation of indole with benzyl alcohol
Recently, the development of new and efficient transformations of heterocyclic compounds into several derivatives
has attracted much attention in organic synthesis [1]. The Michael reaction of indoles with a,b-unsaturated carbonyl
compounds provides easy access to 3-substituted indoles, which are important building blocks for the synthesis of
biologically important compounds and natural products. Several Lewis acids were found to catalyze the conjugate
addition of heterocyclic compounds to electron deficient olefins, such as Bi [2], In [3], Yb [4], Sc [5], Cu [6] and Au
salts [7]. In view of the fact that 3-substituted indoles are generally used in pharmaceutical synthesis, therefore
potential contaminations of metal species to the products have to be considered when the reactions were applied in a
practical synthesis. For this purpose, many organocatalysts were used as alternative catalysts, such as triflic acid [8], I2
[9], cyanuric chloride [10], ionic liquid [11], and tetrabutylammonium hydrogen sulfate (TBAHS) [12]. However,
recovery of these homogeneous catalysts is generally not easy. In order to overcome this problem, some solid acids,
such as clay [13] and sulfonated amorphous carbon [14], were also examined. Although promising results were
obtained in these cases, in order to further improve the synthetic efficiency and facilitate the recovery of the catalyst, an
eco-friendly and a cost-effective catalyst system that enables selective formation of the desired product and easy
recovery of the catalyst is still appealingly needed.
* Corresponding author.
E-mail address: xfwwxf@163.com (X.F. Wu).
1001-8417/$ – see front matter # 2011 Xue Fen Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.06.006

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J. Yang et al. / Chinese Chemical Letters 22 (2011) 1391–1394
Sulfamic acid (H2NSO3H) is a common inorganic acid with mild acidity that is nonvolatile, noncorrosive, and
utilized as a stable, low cost, highly efficient green catalyst in organic synthesis [15]. Sulfamic acid has also been used
in Michael addition of indoles to electron-deficient nitroolefins [16]. However, there are no reports of using sulfamic
acid as a catalyst for Friedel–Crafts alkylation of indole with a,b-unsaturated carbonyl compound. Herein, we report a
sulfamic acid-catalyzed Friedel–Crafts alkylation of indoles with two kinds of electrophiles including a,b-unsaturated
carbonyl compound and benzyl alcohol. Particularly, Friedel–Crafts alkylation reaction of indole with benzyl alcohol
catalyzed by sulfamic acid has not been reported yet.
Initially, sulfamic acid was used as a catalyst in a Michael reaction of indole 1a with cyclopent-2-enone 2a [17]. As
shown in Table 1, 15 mmol% of sulfamic acid is sufficient enough for catalyzing the model reaction toward
completion (entries 1 and 2). Among all the solvents examined, acetonitrile was found to be the best, and after 8 h of
reaction in this solvent, a maximum yield of 3a, 89%, was obtained (entries 3–7). With a shortened reaction time, 4 h,
the yield of 3a decreased to 68% (entry 8). At lower temperature, 50 8C, the yield obtained is rather poor. It should be
noted that a solid could be observed after cooling the reaction system from 80 8C to room temperature (15 8C). After
filtration and washing, the solid could be recovered. Following measurement of melting point revealed that the
obtained solid is sulfamic acid. We thus examined the performance of the recovered sulfamic acid in the model
reaction. In order to facilitate recycling of sulfamic acid, in this case, the reaction was performed in a large scale
(10 mmol). As we expected, the yield of 3a remains unchanged, and therefore, the catalyst here is, indeed, recyclable.
With this experiment, the applicability of this method for practical synthesis was also well elucidated.
The substrate scope with respect to both indole and a,b-unsaturated carbonyl compound was then examined. As
shown in Table 2, when 2a was used as electrophile, various indoles could be used in the sulfamic acid system, and the
corresponding adducts were obtained in generally high yields. Particularly, functional groups, such as methoxy and
nitrile, which are generally unstable under strongly acidic condition, were also proved to be applicable in this reaction.
The scope of the reaction with respect to a,b-unsaturated compound was next investigated and also found to be
excellent. As Table 3 illustrates, many a,b-unsaturated ketones could be employed without significantly affecting the
yield of the Michael adduct. Particularly, a,b-unsaturated ketones containing sulfur- or oxygen-heterocycle
functionalities were also applied in the reaction uneventfully (entries 4 and 5). However, a limitation was found when
using a,b-unsaturated ester as substrate (Table 3, entry 8).
Encouraged by the promising results obtained in Michael reaction of indole, we then tried to extend the catalytic
system to the other Friedel–Crafts type reaction. Recently, alkylation reactions of indoles with benzyl alcohols have
been extensively investigated [18]. Although various acid catalysts were proved to be effective for this type of reaction
[19], alkylation reaction of indole with benzyl alcohol catalyzed by sulfamic acid has not been reported yet. We thus
Table 1
Sulfamic acid-catalyzed Michael reaction of indole with cyclopent-2-enone.a
O
sulfamic acid
O
+
solvent
N
H
N
H
1a
2a
3a
Entry
Catalyst amount (mol%)
Solvent
Time (h)
Temperature (8C)
Yield (%)
1
2
10
15
15
15
15
15
15
15
15
15
CH3CN
CH3CN
1,4-Dioxane
DCE
8
8
8
8
8
8
8
4
8
8
80
80
80
80
80
80
80
80
50
80
74
89
63
48
12
17
35
68
41
89
3
4
5
Toluene
DMF
6
7
DMSO
CH3CN
CH3CN
CH3CN
8
9
10b
a
Solvent: 1.0 mL, 1a: 1.0 mmol, 2a: 1.0 mmol.
The reaction scale: 10 mmol, and sulfamic acid was used in the second run.
b

J. Yang et al. / Chinese Chemical Letters 22 (2011) 1391–1394
1393
Table 2
Substrate scope for indoles.a
O
2a (1.0 equiv)
sulfamic acid (15 mol %)
R
N
CH3CN, 80 o
C
R
H
N
H
Entry
Indole
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
2-Methylindole
1b
1c
1d
1e
1f
3b
3c
3d
3e
3f
6
10
10
8
91
86
92
97
83
95
77
5-Bromoindole
5-Methoxyindole
1-Methylindole
6-Fluoroindole
8
2-Methyl-5-mothoxyindole
5-Cyanoindole
1g
1h
3g
3h
8
8
a
Acetonitrile: 1.0 mL, indole: 1.0 mmol, 2a: 1.0 mmol.
Table 3
Substrate scope for a,b-unsaturated compound.a
O
R
2b: R1 = Me, R2 = H
2c: R1 = Et, R2 = H
R2
R1
1a or 1b (1.0 equiv)
sulfamic acid (15 mol %)
2g: R1= C6H5, R2 = Me
2h: R1= C6H5, R2 = Et
O
2d: R1 = Me, R2 = C6H5
R1
R2
CH3CN, 80 o
C
S
2e: R1 = Me, R2=
2f: R1 = Me, R2=
2
N
H
O
2i
O
3i-3o
O
Entry
a,b-Unsaturated compound
Indole
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
1a
1a
1b
1b
1b
1a
1a
1a
3i
3j
6
6
94
96
92
81
76
90
82
0
3k
3l
8
8
3m
3n
3o
–
8
2g
2h
2i
8
10
20
a
Acetonitrile: 1.0 mL, indole: 1.0 mmol, a,b-unsaturated compound: 1.0 mmol.
investigated the feasibility of using sulfamic acid as a catalyst for this reaction. As shown in Scheme 1, the reactions of
indoles with a benzyl alcohol, 1-(4-methoxyphenyl)-1-ethanol 4a, proceeded very well, and the corresponding
alkylation products were obtained in good to excellent yields. These results indicated again that sulfamic acid is an
effective catalyst for promoting Friedel–Crafts type reactions of indoles.
1
Spectroscopic data of selected product (5d): 3-[1-(4-methoxyphenyl)ethyl]-5-methoxy-1H-indole: Red oil, H
NMR (acetone-d6): 1.62 (d, 3H, J = 7.2 Hz), 3.67 (s, 3H), 3.74 (s, 3H), 4.25 (q, 1H, J = 7.2 Hz), 6.71 (dd, 1H,
OH
OMe
sulfamic acid (20 mol %)
R
+
DCE, 80 oC, 8h
R
N
H
MeO
N
H
4a
5a: R = H (83%)
5b: R = 1-Me (85%)
5c: R = 2-Me (87%)
5d: R = 5-OMe (91%)
Scheme 1. Friedel–Crafts alkylation of indoles with 4a catalyzed by sulfamic acid.

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J. Yang et al. / Chinese Chemical Letters 22 (2011) 1391–1394
Ja = 2.8 Hz, Jb = 8.8 Hz), 6.76–6.82 (m, 3H), 7.12 (d, 1H, J = 1.6 Hz), 7.21–7.29 (m, 3H), 9.82 (bs, 1H); 13C NMR
(acetone-d6): 22.0, 36.1, 54.7, 55.0, 101.5, 111.3, 111.8, 113.6, 120.4, 122.3, 127.6, 128.3, 132.5, 139.7, 153.5, 157.9;
IR (cmÀ1): 3028, 2961, 2930, 2831, 1714, 1609, 1582, 1512, 1457, 1247, 1178, 922, 836, 799; HRMS m/z (ESI) calcd.
for C18H19NNaO2 [M+Na]+ 304.1313, found 304.1306.
In conclusion, sulfamic acid was proved to be a cost-effective and recyclable catalyst for Friedel–Crafts type
reaction of indole with a,b-unsaturated ketone and benzyl alcohol. Many substrates could be used in these reactions,
and the corresponding products were obtained in good to excellent yields.
Acknowledgment
We gratefully acknowledge the financial support from the Doctoral Research Fund of Henan University of
Traditional Chinese Medicine.
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