Carbohydrate-based tolylsulfonyl hydrazines: Effective catalysts for Michael addition of indoles to electron-deficient olefins in water

Article abstract of DOI:10.1055/s-2008-1072735

Carbohydrate-based tolylsulfonyl hydrazines were used for the first time to catalyze the Michael reaction of indoles to electron-deficient olefins in aqueous media to afford 3-substituted indole derivatives in good to excellent yields at room temperature.

Full text of DOI:10.1055/s-2008-1072735

LETTER
1193
Carbohydrate-Based Tolylsulfonyl Hydrazines: Effective Catalysts for
Michael Addition of Indoles to Electron-Deficient Olefins in Water
C
arbohydrate-
e
Based Toly
n
lsulfonyl
H
y
g
drazines Wu,a,b Yiqian Wan,b Jiwen Cai*a,b
a
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510080, P. R. of China
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. of China
Fax +86(20)87334718; E-mail: puscjw@mail.sysu.edu.cn
b
Received 20 December 2007
ly.8 These acid-catalyzed reactions of indoles required
precise control of acidity to avoid side reactions such as
dimerization or polymerization. Moreover, the metal salt
employed as Lewis acid catalyst is often expensive and
toxic to the environment. As part of our effort to develop
green catalytic systems,9 we report herein the catalytic re-
sults of carbohydrate-based tolylsulfonyl hydrazines
(Figure 1) for the conjugate addition of indoles to elec-
tron-deficient olefins in aqueous media.
Abstract: Carbohydrate-based tolylsulfonyl hydrazines were used
for the first time to catalyze the Michael reaction of indoles to elec-
tron-deficient olefins in aqueous media to afford 3-substituted in-
dole derivatives in good to excellent yields at room temperature.
Key words: carbohydrate-based tolylsulfonyl hydrazines, catalyst,
Michael addition of indole, water
The question of how to carry out catalytic organic reac-
tions in aqueous media is of current interest, because wa-
ter is cheap, safe and environmentally benign.1 However,
using water as the sole medium for organic reactions is not
always practical because of the poor solubility of organic
molecules in water, as well as the fact that water could in-
hibit the catalyst’s activity.1 Consequently, catalysts suit-
able for the activation of organic reactions in water
require special design.
OH
O
O
S
O
H
HO
HO
1
N N
H
Tol
OH
OH
HO
HO
O
O
S
O
H
2
3
N N
H
Tol
Tol
OH
Amine-based organocatalysis is an effective platform for
carrying out organic transformations, and many powerful
amine-based catalysts have been developed in recent
years.2 Although a few aminocatalysts could be used in
water,3 most of the reactions were typically performed in
organic solvents. On the other hand, organic reactions in
nature could readily occur in water. Enzymes exploit hy-
drogen bonding interaction together with other nonbond-
ed dipole-dipole, electrostatic, and steric interactions, to
orient the substrate and stabilize the transition state, and
therefore promote the reaction effectively.4 This observa-
tion indicated that hydrogen bonding plays a key role in
organocatalysis in water and made us wonder whether
carbohydrate-based compounds could be used as catalysts
to activate organic reaction in water.
O
O
S
O
H
HO
HO
N N
H
OH
Figure 1 Carbohydrate-based tolylsulfonyl hydrazines10
We chose the addition of indole to b-nitrostyrene in aque-
ous media as the model reaction, and the catalytic effi-
ciency of the three glycosyl derivatives 1–3 in aqueous
media was evaluated. As summarized in Table 1, good
yields were achieved for all the three catalysts, with the
glucose derivative (compound 1) being the most efficient
(Table 1, entries 1–3). Furthermore, the effect of the cata-
lyst loading was investigated. It was found that 10 mol%
of catalyst gave the best result. Increasing the catalyst
loading to 20 mol% did not improve the yield of the de-
sired product (Table 1, entry 8). Interestingly, the reaction
occurred sluggishly in organic solvents such as CHCl3 and
THF (Table 1, entries 5 and 6). Finally, it was found that
the target Michael adduct was obtained only in a trace
amount in the absence of catalyst even with prolonged re-
action time (Table 1, entry 7).
Indole derivatives are known to possess various biological
properties, and 3-substituted indole compounds are im-
portant building blocks for the synthesis of different ther-
apeutic agents and natural products.5 Most of the reported
synthetic protocols to attain 3-alkylated indoles involved
conjugate addition to electron-deficient olefin in the pres-
ence of proton6 or other Lewis acids.7 Kobayashi and Fir-
ouzabadi reported two procedures to prepare 3-alkylated
indoles using scandium dodecyl sulfate and aluminum
dodecyl sulfate as catalysts in aqueous media, respective-
Based upon the results obtained above, the scope of the
substrates was investigated and the results are summa-
rized in Table 2. In general, good-to-excellent yields of
Michael adducts were obtained. The reaction uniquely oc-
curred at the 3-position of the indole ring, indicating that
the addition reaction was regioselective. The catalyst was
effective for indole and substituted indoles, affording 3-
substituted target compounds in 81–96% yields. The cat-
SYNLETT 2008, No. 8, pp 1193–1198
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072735; Art ID: W21907ST
© Georg Thieme Verlag Stuttgart · New York

1194
P. Wu et al.
LETTER
alytic efficiency toward substituted indoles was similar
for catalysts 1–3 (Table 2, entry 10). Indole carrying Br
group resulted in a lower yield, and needed a longer reac-
tion time (Table 2, entry 16).
Table 1 Catalytic Efficiency of Carbohydrate-Based Tolylsulfonyl
Hydrazines on the Michael Reaction in Various Media
H
N
NO2
For the activated olefin, a different substituent such as
methoxy at the phenyl ring in b-nitrostyrene was tolerated
(Table 2, entry 5). When 2-(2-nitrovinyl)furan was em-
ployed, the target product was obtained under the same re-
action conditions (Table 2, entry 9). In the case of an
acyclic a,b-unsaturated carbonyl compound, the Michael
adduct was obtained, with slightly lower yield (Table 2,
entry 15). For cyclic a,b-unsaturated carbonyl substrates,
the target products were obtained in 91% and 89% yields
(Table 2, entries 17 and 18). In addition, even though the
carbohydrate-based amine could effectively catalyze the
reaction of 1-methylindole with electron-deficient olefins
(Table 2, entries 10–14), N-Boc-indole was not reactive
under the same reaction conditions. The electron-with-
drawing Boc group might deactivate the indole ring and
result in failure of the reaction.
H
NO2
N
catalysts
+
solvent, r.t.
Entry
Catalyst (mol%) Solvent
Time (h)
14
Yield (%)b
1
2
3
4
5
6
7
8
1 (10)
2 (10)
3 (10)
1 (10)
1 (10)
1 (10)
–
H2O
92
H2O
16
85
H2O
16
82
toluene
CHCl3
THF
H2O
24
20
24
23
24
32
48
trace
93
1 (20)
H2O
14
a All reactions were performed at r.t.11
b Yield of isolated product.
Table 2 Michael Addition of Indoles to Electron-Deficient Olefins Catalyzed by Carbohydrate-Based Tolylsulfonyl Hydrazinea
R1
R2
Y
R1
R2
catalyst (10 mol%)
H2O, r.t.
Y
EWG
+
N
X
EWG
N
X
Entry
Indole
X
Olefin
Product
Time
(h)
Yield
(%)b
Y
H
NO2
1
H
H
14
15
93
90
NO2
NO2
NO2
N
H
Cl
NO2
2
H
Cl
N
H
Br
NO2
3
H
H
18
85
Br
N
H
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LETTER
Carbohydrate-Based Tolylsulfonyl Hydrazines
1195
Table 2 Michael Addition of Indoles to Electron-Deficient Olefins Catalyzed by Carbohydrate-Based Tolylsulfonyl Hydrazinea (continued)
R1
R2
Y
R1
R2
catalyst (10 mol%)
H2O, r.t.
Y
EWG
+
N
X
EWG
N
X
Entry
Indole
X
Olefin
Product
Time
(h)
Yield
(%)b
Y
H
NO2
4
H
H
H
H
12
14
19
20
90
86
87
85
NO2
NO2
NO2
NO2
N
H
MeO
NO2
5
6
7
H
H
H
MeO
N
H
O2N
NO2
O2N
N
H
NO2
NO2
O2N
N
H
NO2
NO2
8
9
H
H
H
H
22
15
82
96
NO2
NO2
N
H
O
O
NO2
NO2
N
H
NO2
94
10
Me
H
14
83c
81d
NO2
N
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1196
P. Wu et al.
LETTER
Table 2 Michael Addition of Indoles to Electron-Deficient Olefins Catalyzed by Carbohydrate-Based Tolylsulfonyl Hydrazinea (continued)
R1
R2
Y
R1
R2
catalyst (10 mol%)
H2O, r.t.
Y
EWG
+
N
X
EWG
N
X
Entry
Indole
X
Olefin
Product
Time
(h)
Yield
(%)b
Y
H
Cl
NO2
11
Me
Me
Me
19
15
22
90
93
86
NO2
NO2
NO2
Cl
N
N
N
Br
NO2
12
H
Br
O2N
NO2
13
H
O2N
O
14
15
Me
H
H
15
24
95
82
NO2
O
O
NO2
N
Ph
O
Ph
H
Ph
Ph
N
H
NO2
16
17
H
H
Br
24
12
81
91
Br
NO2
N
H
O
O
H
N
H
Synlett 2008, No. 8, 1193–1198 © Thieme Stuttgart · New York

LETTER
Carbohydrate-Based Tolylsulfonyl Hydrazines
1197
Table 2 Michael Addition of Indoles to Electron-Deficient Olefins Catalyzed by Carbohydrate-Based Tolylsulfonyl Hydrazinea (continued)
R1
R2
Y
R1
R2
catalyst (10 mol%)
H2O, r.t.
Y
EWG
+
N
X
EWG
N
X
Entry
Indole
X
Olefin
Product
Time
(h)
Yield
(%)b
Y
H
O
O
18
Me
12
24
89
N
Ph
NO2
19
H
H
27e
NO2
N
H
a All reactions were performed at r.t.
b Yield of isolated product.
c Catalyzed by catalyst 2.
d Catalyzed by catalyst 3.
e Catalyzed by PhNHNHSO2PhMe + SDS.
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It was noteworthy that the reaction did not proceed when
it was catalyzed by PhNHNHSO2Tol, in which the carbo-
hydrate group of the effective catalysts 1–3 was substitut-
ed by a phenyl group. However, when assisted by sodium
dodecyl sulfonate (SDS), the target product could be ob-
tained in 27% yield (Table 2, entry 19). This observation
indicated that the tolylsulfonyl hydrazine group was the
effective catalytic functional group in the catalyst mole-
cule, and the carbohydrate part functioned as a surfactant
to promote better interaction between the organic sub-
strates and the catalyst in aqueous media.
In conclusion, we have reported the first carbohydrate-
based tolylsulfonyl hydrazines for Michael addition of in-
doles to electron-deficient olefins in water. It is a green
process for the synthesis of 3-substituted indole deriva-
tives. The reaction conditions are mild and could produce
product in high yield and with good substrate scope.
Acknowledgment
We are thankful for the financial support from the 985 project, Sun
Yat-Sen University.
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Synlett 2008, No. 8, 1193–1198 © Thieme Stuttgart · New York

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LETTER
(9) (a) Deng, D.-S.; Liu, P.; Cai, J. Eur. J. Org. Chem. 2007,
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stirred at r.t. and the reaction was monitored by TLC until the
starting material was consumed. The mixture was quenched
with a sat. aq NaCl solution and then extracted with EtOAc
(3 × 20 mL). The organic layers were combined and washed
with brine, and dried over anhyd MgSO4. The solvent was
removed in vacuo to yield the crude product. Purification by
silica gel chromatography using 100–200 mesh ZCX II
eluted with hexane–EtOAc (5:1) afforded the Michael
product.
(10) Ojala, W. H.; Ojala, C. H.; Gleason, W. B. J. Chem.
Crystallogr. 1999, 29, 19.
(11) Typical Experimental Procedure: A mixture of the olefin
(1 mmol) and catalyst 1 (0.1 mmol) in H2O (1 mL) was
treated with indole (2 mmol). The resulting suspension was
Synlett 2008, No. 8, 1193–1198 © Thieme Stuttgart · New York