Copper nitrate trihydrate catalyzed efficient synthesis of bis(indolyl)methanes in acetonitrile at room temperature

Article abstract of DOI:10.1002/jhet.5570440440

(Chemical Equation Presented) A catalytic amount of easily available and inexpensive Cu(NO₃)₃.3H₂O (10 mol%) enables electrophilic substitution reaction of indole with structurally divergent aldehydes in acetonitrile to af

Full text of DOI:10.1002/jhet.5570440440

Jul-Aug 2007
983
Copper Nitrate Trihydrate Catalyzed Efficient Synthesis of
Bis(indolyl)methanes in Acetonitrile at Room Temperature
Aayesha Nasreen, Ravi Varala and Srinivas R. Adapa*
Indian Institute of Chemical Technology, Hyderabad-7, India,
Fax: (+91)-40-27160921; E-mail: rvarala_iict@yahoo.co.in
Received October 26, 2006
R
H
Cu(NO ) .3H O (10 mol%)
3
2
2
+
RCHO
N
CH CN, RT
N
3
N
H
H
H
R=aryl, alkyl
1
2
3
(16 examples)
A catalytic amount of easily available and inexpensive Cu(NO ) .3H O (10 mol%) enables electrophilic
3
3
2
substitution reaction of indole with structurally divergent aldehydes in acetonitrile to afford the
corresponding bis(indolyl)methanes in moderate to excellent yields (65-98%) at ambient temperature. The
reaction is highly chemoselective and applicable only to aldehydes and not to ketones.
J. Heterocyclic Chem., 44, 983 (2007).
INTRODUCTION
available Lewis acid catalysts that secure low toxicity,
efficient catalytic activity and air tolerance are still
desirable.
Indole fragment is featured in a wide variety of
pharmacologically and biologically active compounds [1].
For example, bisindolylalkanes and their derivatives are
found in bioactive metabolites of terrestrial and marine
origin (e.g. Vibrindole A) [2]. Interestingly, bis(indolyl)-
methane is known to promote estrogen metabolism in
both women and men and is expected to have an
application in the prevention of breast cancer [3].
Therefore, there is a great deal of interest in the synthesis
of this class of compounds [4]. Among the many methods,
the synthesis of this class of compounds in the presence of
Lewis acids, Bronsted acids or montmorillonite clay K-10
to promote the reaction of indoles with other aromatic or
aliphatic aldehydes and ketones have been widely studied
RESULTS AND DISCUSSION
In our continued interest in the development of a highly
expedient methodology for the synthesis of fine chemicals
and heterocyclic compounds of biological importance
[
13], we report here the first example of the synthesis of
bis(indolyl)methanes from the condensation of various
aldehydes and indole in acetonitrile at room temperature
in the presence of Cu(NO ) .3H O as an efficient catalyst
3
2
2
(
Scheme 1).
R
H
Cu(NO
3
)
2
2
.3H O (10 mol%)
[
5-11]. More recently, bis(indoly)methanes were found to
be formed in the presence of other catalysts such as metal
+
RCHO
R=aryl, alkyl
N
CH CN, RT
3
N
N
H
H
H
triflates, InCl , I , NBS, PPh ꢀHClO , AlPW O , silica
3
2
3
4
12 40
1
(
2a-2p)
(3a-3p)
sulfuric acid, ZrCl , ionic liquids, FeCl .6H O, La(PFO) ,
4
3
2
3
HClO -SiO and so on [12]. However many of these
4
2
Scheme 1
Lewis acids are deactivated or some times decomposed by
nitrogen containing reactants. Although, these catalysts
are very useful and efficient, there are still some
drawbacks in most of these catalytic systems including
the requirement of stoichiometric amounts of catalysts,
use of expensive catalysts/media e.g. lanthanide triflates
and ionic liquids, longer reaction times, low yields of the
products, drastic conditions for the catalyst preparation
and also require tedious work-up procedures [12].
Keeping in view of the tremendous pharmalogical
importance of bis(indolyl)methanes, cheaper and readily
Initially, we have studied the efficacy of several metal
nitrates chosen (10 mol% as standard) for the model
reaction using indole 1 (2 mmol) and benzaldehyde 2a
1 mmol) in acetonitrile (3 mL), being stirred at ambient
temperature for 1 h, to afford the corresponding bis-
indolyl)methane and the results are shown in Table 1.
(
(
While comparing the effect of catalysts, we found that,
Cu(NO ) .3H O (entry 7, Table 1) was more effective
3
2
2
than other nitrates tested, in terms of isolated yields
(96%). As shown in Table 1, while other nitrates such as

9
84
A. Nasreen, R. Varala and S. R. Adapa
Vol 44
Table 2. Cu(NO
3 2 2
) .3H O-catalyzed synthesis of bis(indolyl)methanes from
Fe(NO ) .9H O (entry 3), La(NO ) .9H O (entry 5),
3
3
2
3
3
2
indole and divergent aldehydes.
Nd(NO ) .6H O (entry 6) and Al(NO ) .9H O (entry 11)
3
3
2
3
3
2
Entry
Aldehyde (2)
Product (3)
Time Yield (%)
h) [ref]
a
are also equally efficient, we chose Cu(NO ) .3H O as the
3
2
2
(
suitable catalyst for further reactions due to its ready
availability and cost effectiveness.
CHO
1
3a 1.0 96 [12d]
Table 1. Comparison of the effect of various metal nitrates for the
condensation reaction of indole 1 with benzaldehyde 2a for a period of 1 h.
HN
N
H
2a
CH
3
a
Entry
Catalyst
Yield (%)
CHO
1
2
3
4
5
6
7
8
9
Zn(NO
AgNO
Fe(NO
Rh(NO
3
)
2
.6H
2
O
55
48
92
81
90
94
96
77
52
78
90
2
3b 1.0 92 [12d]
3
H C
3
2b
2c
HN
3
)
3
.9H
.2H
.6H
.6H
2
O
N
H
3
)
3
2
O
OCH
3
La(NO
Nd(NO
3
)
3
2
O
CHO
3
)
3
2
O
3
3c 1.5 98 [12d]
Cu(NO
Ce(NH
Ni(NO
3
)
2
.3H
2
O
3
H CO
4
)
2
3 6
(NO )
N
HN
3
)
3
.6H
.5H
.9H
2
O
O
H
1
1
0
1
Bi(NO
Al(NO
3
)
3
2
NMe
2
3
)
3
2
O
CHO
4
Me
3d
6.0 88 [12i]
a
N
Isolated Yields.
Me
2d
N
HN
H
Intrigued by these observations, we have then tested the
efficacy of several copper salts available such as
Cu(OAc) .2H O, Cu(I)X (Cl, Br, I), Cu(acac) along with
2
O N
CHO
2
2
2
5
3e 5.5
82 [12d]
Cu(NO ) .3H O for the model reaction (10 mol% as
3
2
2
O
2
N
standard) and among the copper salts screened,
Cu(NO ) .3H O was found to be the best both in terms of
reaction times and yields.
2e
N
HN
H
3
2
2
X
To examine the influence of effect of various solvents
for the model reaction, we also carried out the reaction in
various organic solvents such as DCM (85%), acetone
CHO
X= F 2f
X= F
3f
2.0
6
7
90 [12j]
X= Cl
X= Cl 2g
3g 2.5
94 [12e]
X
HN
N
H
(
65%), CH CN (96%), MeOH (86%), DMSO (77%) and
3
Br
chloroform (82%) during the period and among the
screened, acetonitrile was found to be the choice of
solvent. An optimum amount of 10 mol% of
Cu(NO ) .3H O in acetonitrile is sufficient to carry
forward the reaction. Increasing or decreasing the catalyst
loading, did not improve the yields {(1 mol% (0 %), 2
mol% (10-12%), 5 mol% (45%), 7.5 mol% (61%), 10
mol% (96%), 20 mol% (89%)} for the specified time. In
the absence of the catalyst, the reaction did not yield any
product even after stirring for 2 days.
Encouraged by these results obtained for benzaldehyde,
we generalized the reaction scope for a number of other
structurally divergent aromatic as well as aliphatic
aldehydes and ketones to probe their behaviour under the
optimized reaction parameters, i.e., 10 mol%
CHO
8
3h 3.0 92 [12i]
Br
3
3
2
2h
N
H
HN
aYields refer to the isolated pure products.
In general, electron-deficient aldehydes such as nitro, N,N-
dimethyl and so forth, required longer reaction times to
produce comparable yields than those of their simple and
electron-rich counterparts (entries 2-8). p-Hydroxy benzal-
dehyde (entry 9) and cinnamaldehyde (entry 10) are also
tolerant and revealed good reactivities without undergoing
polymerization or isomerization. Heteroaromatic aldehydes
such as pyridine 2-carboxaldehyde (entry 12) and furfural-
dehyde (entry 13) survived well without the formation of
any side products under the present reaction conditions
giving the corresponding bis(indolyl)methanes in moderate
yields. Furthermore, both cyclic and acyclic aliphatic
aldehydes gave the products in good yields (entries 14-16).
Cu(NO ) .3H O in acetonitrile, and Table 2 summarizes
3
2
2
the observations. All products were well characterized by
1
H nmr and mass spectral analysis, and compared with
authentic samples. The nature of substituents on aromatic
ring showed some effects on this conversion.

Jul-Aug 2007
Copper Nitrate Trihydrate Catalyzed Efficient Synthesis of Bis(indolyl)methanes
985
Table 2. Continued.
sponding benzaldehyde derived bis(indolyl)methane
exclusively even after stirring for 12 h. Likewise, reaction
of benzaldehyde (1 mmol) and cyclohexanone (1 mmol)
with indole (2 mmol) also yielded the corresponding
benzaldehye condensed product chemoselectively. This
selectivity might be useful to differentiate aldehydes from
ketones through the synthesis of bis(indolyl)methanes.
Time Yield (%)a
Entry
Aldehyde (2)
Product (3)
(h)
[ref]
OH
CHO
9
3i
3.0
78 [12h]
HO
N
HN
H
CH=CH
CHO
COCH3
CH
3
CH=CH-CHO
Cu(NO
3
)
2
.3H
2
O
10
3j
2.5
2.0
83 [12n]
(
10 mol%)
+
+
+
N
H
N
H
N
H
N
H
N
HN
N
H
CH
3
CN, RT, 12 h
H
1
mmol
1 mmol
2 mmol
1
2
3
1a (exclusively)
2a (0%)
CHO
11
3k
94 [12i]
CHO
O
Cu(NO
3 2 2
) .3H O
(
10 mol%)
N
HN
N
+
+
+
N
H
H
3
CH CN, RT, 12 h
1
mmol
1 mmol
2 mmol
N
H
N
H
N
H
N
H
1
4
3
1
a (exclusively)
4a (0%)
1
2
3
3l
2.5
65 [12n]
N
CHO
Scheme 2
N
HN
H
The efficiency and generality of the present
Cu(NO .3H O-catalyzed protocol can be realized at a
O
O
3
)
2
2
CHO
1
3m 2.5
72 [12d]
glance by comparing our results for the reaction of
benzaldehyde with indole chosen as model substrate with
those of some recently developed procedures (as shown in
Table 3). The reactions have been compared with respect
to the reaction times, mol-% of the catalyst used and the
yields. As it is evident from Table 3, our protocol is
comparatively better in terms of ready availability, easy
handling, cost effectiveness and remarkably low toxicity,
with most of the recently reported catalysts.
N
H
HN
CHO
1
4
3n
3.0
76 [12o]
N
H
HN
HN
HN
The reaction most probably proceeds initially activation
of aldehyde by the catalyst to undergo electrophilic
substitution reaction at C-3 of an indole, and after loss of
water to produce azafulvenium salt. The formed
azafulvenium salt then undergoes further addition with
second indole molecule to afford bis(indolyl)methane
1
5
CHO
3o 1.5
84 [12e]
86 [12o]
N
H
1
6
3p
1.0
CHO
N
H
11
derivatives as elegantly proposed by Wang et al.
aYields refer to the isolated pure products.
Conclusion
There were some limitations for the Cu(NO ) .3H O
In summary, we have developed a practical and
new procedure for the synthesis of bis(indolyl)-
methanes using Cu(NO ) .3H O as catalyst. The
3
2
2
catalyzed reaction. The reactions with aliphatic and
aromatic ketones such as cyclohexanone and aceto-
phenone were found to be unsuccessful. On the basis of
these reactivity differences of the aldehydic and keto
functionalities, few competitive experiments were
conducted to study the efficacy of Cu(NO ) .3H O
3
2
2
present protocol has several advantages: readily
available and inexpensive catalyst, mild reaction
conditions (at room temperature), moderate to
excellent yields, greater selectivity, operational and
experimental simplicity, study of wide range of
structurally divergent aldehydes. We believe that
this Cu(NO ) .3H O-catalyzed methodology will
3
2
2
catalyzed selective synthesis of corresponding bis-
indolyl)methanes (Scheme 2).
Reaction of benzaldehyde (1 mmol) and acetophenone
1 mmol) with indole (2 mmol) afforded the corre-
(
3
2
2
(
definitely be a valuable addition to the existing

9
86
A. Nasreen, R. Varala and S. R. Adapa
Vol 44
processes in the field of syntheses of bis(indolyl)-
methanes.
(20), 77 (10); Anal Calcd. for C23
N, 8.69; Found: C, 85.59; H, 5.68; N, 8.54.
H
18
N
2
(%): C, 85.68; H, 5.63;
Acknowledgments. Ravi Varala thanks the Council of
Scientific Industrial Research (CSIR, India) and Aayesha
Nasreen (WOS-A) thanks DST (GAP-0128), India and for
financial support.
EXPERIMENTAL
All reagents were obtained from commercial sources and used
without further purification. Solvents for chromatography were
distilled before use. nmr spectra were recorded on Varian FT-
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2
00 MHz (Gemini) and Bruker UX nmr FT-300 MHz (Avance)
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3
IICT Communication number: 070306
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glass). Column chromatography was performed using Acme
silica gel (100–200 mesh).
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