Synthesis of bis(indolyl)methanes catalyzed by acidic ionic liquid immobilized on silica (ILIS)

Article abstract of DOI:10.1055/s-2007-977453

A new organocatalytic procedure for the synthesis of bis(indolyl)methanes with acidic ionic liquid immobilized on silica gel (ILIS-SO₂Cl) has been developed. The reaction condition is applicable to a variety of aryl and aliphatic aldehydes and indoles. The mild nature of the reaction conditions showed that the acetoxy or TBDMS group in the aldehyde was maintained intact. The catalyst was reused four times in 93% average yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977453

1320
LETTER
Synthesis of Bis(indolyl)methanes Catalyzed by Acidic Ionic Liquid
Immobilized on Silica (ILIS)
S
ynthesis of Bis(in
i
dolyl)m
s
ethanes
C
a
atalyzed b
h
y Acidic ILI
i
S
ro Hagiwara,*a Masayoshi Sekifuji,a Takashi Hoshi,b Kun Qiao,c Chiaki Yokoyamac
a
b
c
Graduate School of Science and Technology, Niigata University, 8050, Ikarashi 2-nocho, Niigata 950-2181, Japan
Faculty of Engineering, Niigata University, 8050, Ikarashi 2-nocho, Niigata 950-2181, Japan
Institute of Multidisciplinary Research of Advanced Materials, Tohoku University, 2-1-1, Katahira, Aoba-ku, Sendai 980-8577, Japan
Fax +81(25)2627368; E-mail: hagiwara@gs.niigata-u.ac.jp
Received 19 February 2007
R1–CHO 1
R1
Abstract: A new organocatalytic procedure for the synthesis of
bis(indolyl)methanes with acidic ionic liquid immobilized on silica
gel (ILIS-SO2Cl) has been developed. The reaction condition is
applicable to a variety of aryl and aliphatic aldehydes and indoles.
The mild nature of the reaction conditions showed that the acetoxy
or TBDMS group in the aldehyde was maintained intact. The cata-
lyst was reused four times in 93% average yield.
+
R3
R3
R3
ILIS-SO2Cl
MeCN
r.t.
N
R2
N
R2
N
R2
2
3
+
OMe
Key words: catalysis, condensation, indoles, ionic liquids, support-
ed catalysis
O
O
N
N
S
Si
SiO2
SO2X
–
CF3SO3
4 ILIS–SO2Cl: X = Cl
5 ILIS–SO3H : X = OH
Room temperature ionic liquids have played important
roles not only as environmentally benign and recyclable
reaction media, but also as support for organomolecular
catalysts for purposes of recycling, owing to their immis-
cibility with other organic solvents as well as with water.1
We recently anchored a sulfonic acid residue on an ionic
liquid to afford 6 and demonstrated its capability as a
supported and recyclable organomolecular catalyst for
Beckmann rearrangement, Friedel–Crafts alkylation and
nitration.2
Scheme 1 Synthesis of bis(indolyl)methanes 3 catalyzed by ILIS-
SO2Cl (4)
In this paper, we report an efficient, mild and recyclable
procedure for nucleophilic condensation of indoles 2 with
aldehydes 1 leading to bis(indolyl)methanes 3 catalyzed
by the acidic ILIS 4 (Scheme 1).
Optimized reaction conditions were investigated employ-
ing a reaction of benzaldehyde (1, R1 = Ph) and indole (2,
R2 = R3 = H), and the results are shown in Table 1. Among
the solvents investigated, acetonitrile gave the best result
(Table 1, entry 1) in the reaction catalyzed by ILIS-SO2Cl
An additional method for the immobilization of liquid cat-
alysts for easy recycling and better handling is to graft the
organomolecular moiety of the catalyst on solid surface.3
To this end, the acidic ionic liquid catalysts 7 and 8 were (4), which afforded higher yield than Brønsted acid, ILIS-
grafted onto a silica surface. The resulting catalysts SO3H (5), silica or HCl (Table 1, entries 5–7). Other acid-
(ILIS = ionic liquid immobilized on silica) 4 and 5 ex- ic catalysts, p-toluenesulfonyl chloride, acidic ILs 7 and 8
hibited better reactivity for esterification and nitration.4
or acidic silica 9 and 10 (Figure 1) resulted in lower yields
(Table 1, entries 8–12). It is noteworthy that the reaction
proceeded smoothly at ambient temperature.
Bis(indolyl)methanes 3 are found widely distributed in
the bioactive metabolites of terrestrial and marine organ-
isms.5 Some compounds have potent pharmaceutical
activities such as tranquilizers6 or anticarcinogen.7 Due to
their intriguing physiological activities, many synthetic
procedures have been reported so far,8 in which develop-
ment of the environmentally benign aspect is of current
interest from the standpoint of process chemistry by em-
ploying Lewis acid in ionic liquid9 or task-specific acidic
ionic liquid.10
+
OMe
O
O
N
N
SO2X
Si
SiO2
SO2X
R
–
CF3SO3
6
7
8
9
X = Cl
R = Me, X = OH or Cl
R = allyl, X = Cl
R = allyl, X = OH
10 X = OH
Figure 1
Based on the optimized reaction conditions (Table 1, en-
try 1), the present protocol was applied to a variety of
aldehydes 1. As shown in Table 2 (entries 1–6), aryl alde-
hydes 1 with both electron-withdrawing and electron-
donating characteristics provided bis(indolyl)methane 3
in good to high yields. The mild nature of the reaction
conditions was exemplified in the reaction of aryl
SYNLETT 2007, No. 8, pp 1320–1322
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977453; Art ID: U01207ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
0
5.
2
0
0
7

LETTER
Synthesis of Bis(indolyl)methanes Catalyzed by Acidic ILIS
1321
The present protocol was also applicable to various sub-
stituted indoles 2 (Table 3), in which even the electron-
poor bromoindole 2 provided the product 3 (entry 1).
Table 1 Investigation of Optimum Reaction Conditions of Benz-
aldehyde (1, R1 = Ph) and Indole (2, R2 = R3 = H)a
Entry Catalyst
Solvent
MeCN
Time (h) Yield (%)b
Table 3 Reaction of Benzaldehyde (1, R1 = Ph) with Various
Indoles 211
1
ILIS-SO2Cl (4)
5.5
6.5
5.0
4.0
5.5
5.5
2.0
5.5
97
88
88
80
45
0
2c
3
Entry
Substituted indole 2
R2 = H, R3 = Br
Time (h)
3.5
Yield (%)a
EtOH
H2O
1
2
3
81
93
88
4
R2 = H, R3 = OMe
R2 = Me, R3 = H
17.5
5
ILIS-SO3H (5)
silica
MeCN
EtOH
MeCN
5.5
6
a Isolated pure product yield based on indole derivative 2.
7d
8
HCl
0
TsCl
44
60
45
87
75
45
In order to increase stability and to diminish loss of the
catalyst in recycle use, the catalyst was immobilized on
cylindrical silica pellets (3 × 2.5 mm OD, loading of sul-
fonylchloride moiety: 0.30 mmol/g), which was superior
to a powdery catalyst and could be recycled four times in
93% average yield simply after trituration of the product
with Et2O followed by evacuation of the catalyst in vacuo
(Table 4). Handling of the viscous acidic ionic liquid
catalyst2 in recycle use was improved by immobilization
on silica pellets, though slight decrease of catalytic activ-
ity was observed as shown in cycle 4.
9
acidic IL 7
acidic IL 8
acidic silica 9
acidic silica 10
ILIS-SO2Cl (4)
10
11
12
13e
6.0
a Reaction was carried out as described in ref. 11 in the presence of
catalyst (0.1 equiv).
b Isolated pure product yield based on indole 2.
c ILIS-SO2Cl 4 (0.05 equiv) was used.
d p-Chlorobenzaldehyde was used.
Table 4 Recycling of ILIS-SO2Cl (4) in the Reaction of p-Chloro-
benzaldehyde (1, R1 = p-ClC6H4) with Indole (2, R2 = R3 = H)11
e Powdered molecular sieves were added.
Cycle
Time (h)
2.5
Yield (%)a
86 (82)b
97 (95)b
92 (98)b
96 (78)b
aldehydes 1 having base- or acid-sensitive substituents
(Table 2, entries 4 and 6), which might be deprotected by
other previously known reaction conditions. Not only aryl
aldehydes 1 but also aliphatic aldehydes 1 provided the
desired bis(indolyl)methanes 3 (Table 2, entries 7–9).
1
2
3
4
5.0
12.0
24.0
a Isolated pure product yield based on indole 2.
Table 2 Reaction of a Variety of Aldehydes 1 with Indole (2, R2 =
b In parentheses: yield after 2.5 h.
R3 = H)11
Entry Aldehyde 1
Time
(h)
Yield
(%)a
Although the reaction pathway is yet to be clarified, the
sulfonylchloride moiety of ILIS-SO2Cl (4) might work as
a mild Lewis acid12 to activate aldehyde 1 and other elec-
trophilic intermediates, since Brønsted acid ILIS-SO3H
(5), IL 8 and acidic silica 10 gave unsatisfactory results
(Table 1, entries 5–7, 10 and 12). It was considered that
the catalysis by HCl generated by hydrolysis of ILIS-
SO2Cl (4) takes place during the reaction, but this hypoth-
esis was ruled out based on the negative result in Table 1
(entry 7). Lower catalytic activities of sulfonyl chlorides
such as p-toluenesulfonyl chloride, ionic liquid 7, and sil-
ica 9 (Table 1, entries 8, 9 and 11) suggest the importance
of the ionic liquid tether on silica for the higher catalytic
activity of ILIS-SO2Cl (4). Addition of molecular sieves
powder disturbed the reaction (Table 1, entry 13). An ion-
ic liquid, 1-n-hexyl-3-methylimidazolium tetrafluorobo-
rate ([hmim]BF4), is known to have no catalytic activity.10
1
2
3
4
5
6
7
8
9
benzaldehyde
5.5
4.5
2.0
4.0
9.0
97
97
90
64
97
95
98
67
65
p-nitrobenzaldehyde
p-chlorobenzaldehyde
p-acetoxybenzaldehyde
p-methoxybenzaldehyde
p-(tert-butyldimethylsilyloxy)benzaldehyde 3.0
hydrocinnamaldehyde
n-decanal
4.0
19.5
1.5
n-heptanal
a Isolated pure product yield based on indole (2).
Synlett 2007, No. 8, 1320–1322 © Thieme Stuttgart · New York

1322
H. Hagiwara et al.
LETTER
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In summary, we have developed a new protocol for the
synthesis of bis(indolyl)methanes 3 from aldehydes 1 and
indoles 2 catalyzed by Lewis acidic ionic liquid immobi-
lized on silica, ILIS-SO2Cl (4), which exhibited an effi-
cient, mild, practical and recyclable nature.
Acknowledgment
(6) Povszasz, J.; Katakin, G. P.; Foleat, S.; Malkovics, B. Acta
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This work was partially supported by Grant-in-Aid for Scientific
Research on Priority Areas (17073007 for H.H. and T.H.) from The
Ministry of Education, Culture, Sports, Science and Technology
(MEXT).
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(11) Typical Experimental Procedure: A suspension of the
benzaldehyde (1) (30 mL, 0.3 mmol), indole(2) (60 mg, 0.5
mmol) and ILIS-SO2Cl(4) (143 mg, loading of sulfonyl
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stirred gently at ambient temperature under nitrogen
atmosphere for 5.5 h. The product was triturated with Et2O
and the combined organic layer was evaporated to dryness.
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n-hexane, 3:1) afforded bis(indolyl)methane(3) (79 mg, 97%
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