Synthesis of bis(indolyl)methanes using ammonium niobium oxalate (ANO) as an efficient and recyclable catalyst

Article abstract of DOI:10.1039/c5gc00932d

A green and efficient procedure was developed for the synthesis of bis(indolyl)methanes using ammonium niobium oxalate (ANO) NH₄[NbO(C₂O₄)₂(H₂O)_x]·nH₂O as the catalyst and water

Full text of DOI:10.1039/c5gc00932d

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Synthesis of bis(indolyl)methanes using
ammonium niobium oxalate (ANO) as an
Cite this: DOI: 10.1039/c5gc00932d
efficient and recyclable catalyst†
a
b
b
a
Samuel R. Mendes,* Samuel Thurow, Filipe Penteado, Maitê S. da Silva,
a
b
b
Rogério A. Gariani, Gelson Perin and Eder J. Lenardão*
A green and efficient procedure was developed for the synthesis of bis(indolyl)methanes using
ammonium niobium oxalate (ANO) NH [NbO(C O ) (H O) ]·nH O as the catalyst and water or glycerol as
Received 2nd May 2015,
Accepted 20th June 2015
4
2
4 2
2
x
2
the solvent. Products were obtained in good to excellent yields under conventional heating (water, 50 °C)
or under sonication (glycerol, 110 °C). In the reaction in water, the catalyst was easily reused for further
reactions without loss of activity.
DOI: 10.1039/c5gc00932d
www.rsc.org/greenchem
6
free conditions, non classical energy sources such as micro-
Introduction
7
8
9
waves, ultrasound and infrared, eco-friendly reagents and
1
0
Indoles and their derivatives are important compounds which catalysts are among the alternatives to improve the greenness
1
are present in a variety of natural products. In addition, bis- of the synthesis of BIMs.
(
indolyl)methanes (BIMs) and their analogues present various
In this sense, ultrasonic irradiation is a useful technique to
1
1
important biological and pharmacological activities, such as increase the energy efficiency in organic synthesis. Short
antifungal, anti-inflammatory, antibacterial, antibiotic and reaction times, and the formation of pure products in high
2
analgesic properties. Recently, BIMs were shown to exhibit yields under mild reaction conditions are among features that
3
anticancer activity, inhibiting the growth of cancer cells,
put this technique as a green tool for organic synthesis. One of
3
a,b
3c
3d,e
3f
including prostate,
colon, pancreatic
and lung. One the twelve Principles of Green Chemistry, principle #6, ‘design
of the metabolites of indole-3-carbinol, the dimeric 3,3′-bis- for energy efficiency’, is strongly covered by sonochemistry.
1
2
(
indolyl)methane (also called DIM), has an important role in
On the other hand, the use of niobium compounds as cata-
lysts has emerged in recent years as an alternative to both
3
g,h
preventing breast cancer.
1
3
Due to the important pharmacological properties of BIMs, Lewis and Bronsted acid catalysts. The use of niobium pent-
there are in the literature many methods to prepare this class oxide and niobic acid (hydrated Nb ) as catalysts in organic
Ammonium niobium oxalate
]·nH O, in turn, is used as a
2 5
O
1
3a–e
of compound. Generally, the acid promoted electrophilic sub- synthesis is well described.
stitution of indoles with carbonyl compounds is the method of (ANO), NH [NbO(C (H O)
4
2
O
4
)
2
2
x
2
4
choice. Although highly atom-efficient, the use of toxic niobium precursor in the preparation of functionalized
reagents, high temperature and volatile organic solvents are materials including ceramic, optical lenses, high purity
4
14
among the drawbacks of most of these protocols. Thus, the niobium oxides, tin films and catalysts. Besides, in contrast
search for methodologies which decrease the environmental to the more famous derivative NbCl , ANO is cheap, easy to
impact of the preparation of BIMs is of great interest to the handle and is not sensitive to air or moisture.
5
1
4,15
The rela-
pharmaceutical industry. The use of green solvents or solvent- tively low toxicity of niobium, allied to its solubility in
5
16
1
4
water, make ANO a very attractive compound to be explored
in organic synthesis.
In the last few years we have developed greener methodo-
logies to prepare bioactive molecules and fine chemicals com-
bining two or more of the Green Chemistry Principles,
a
Grupo de Análise, Preparação e Aplicação de Materiais – GAPAM – Departamento
de Química – Universidade do Estado de Santa Catarina – UDESC, 89219-710
Joinville, SC, Brazil. E-mail: samuel.mendes@.udesc.br; Tel: +55 (47)4009-7840
b
17
Laboratório de Síntese Orgânica Limpa - LASOL - Universidade Federal de Pelotas -
including the use of green solvents, cheap and available
UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil. E-mail: lenardao@ufpel.edu.br;
18
19
catalysts and energy-efficient protocols. In this line, we
describe herein the first use of NH [NbO(C O ) (H O) ]·nH O
Tel: +55 (53) 3275-7533
†
4
2
4 2
2
x
2
Electronic supplementary information (ESI) available: Detailed experimental
as a catalyst to promote the electrophilic substitution of indoles
with carbonyl compounds to prepare bis(indolyl)methanes
procedures as well as spectral data of all synthesized compounds are presented.
See DOI: 10.1039/c5gc00932d
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obtained (Table 1, entry 6). Thus, the best reaction conditions
to prepare BIMs under conventional heating was the use of
indole 1 (1.0 mmol), aldehyde 2 (0.6 mmol), H
1.0 mL) and ammonium niobium oxalate complex (ANO) as
the catalyst (5.0 mol%) at 50 °C under air atmosphere for 2 h
2
O as solvent
(
Scheme 1 General scheme of the reaction.
(
Table 1, entry 8).
Aiming to verify the effect of ultrasound in accelerating the
under green reaction conditions (Scheme 1). A detailed study reaction, an ultrasonic probe sonicator with a processor power
on the use of water and glycerol as a solvent, as well as on of 130 W and frequency of 20 kHz operating at 60% of ultra-
thermal and ultrasonic irradiation as energy sources, was also sonic amplitude was used. The first experiment was performed
performed.
using our best conditions determined above under convention-
al heating using ANO (water as the solvent at 50 °C). The
temperature of the reaction was monitored (with an I.R. thermo-
meter) and it was observed that after 3 min of sonication,
the reaction temperature was 47 °C, remaining at around 50 °C
over a total time of 30 min under sonication. Unfortunately,
after 3 min, 4% of indole 1a was converted to product 3a and
after 30 min of sonication in water, the conversion was only
Results and discussion
Our initial studies were focused on the development of an
optimum set of reaction conditions to the synthesis of BIMs
using ANO in aqueous media (Scheme 1).
23% (Table 2, entries 1 and 2). Then, an investigation was per-
Initially, indole 1a (1.0 mmol) and benzaldehyde 2a
formed to find a better solvent for the reaction. Fortunately, it
was revealed that glycerol, a biobased solvent, afforded 3a in
(0.6 mmol) were chosen as starting materials (Table 1). Firstly,
the reaction was performed in H O (1.0 mL) using 1 mol% of
2
9
9% yield after only 3 min (Table 2, entry 3). At the final time
of sonication in glycerol, the temperature of the reaction
mixture was 110 °C. Toluene, DMSO, DMF and CH Cl were
ineffective in promoting the reaction under sonication for
min, with conversion rates of 1.0, 0.05, 1.0 and 2.0%
ANO as the catalyst under constant stirring at room tempera-
ture for 1 h and open atmosphere. Under these conditions, the
desired product 3a was obtained in 11% yield (Table 1, entry
2
2
1
). Looking for a higher yield, the amount of catalyst was
3
increased and, gratifyingly, when 5 and 10 mol% of ANO were
used, 3a was obtained in 65% yield (Table 1, entries 2 and 3).
By increasing the reaction temperature to 50 and 100 °C (oil
bath), product 3a was obtained in 85 and 82% yield, respecti-
vely (Table 1, entries 4 and 5). Finally, we observed that when
the reaction time was increased to 2 h, 3a was obtained in 97%
yield (Table 1, entry 8). Because ANO is usually used as a
niobium oxide precursor, we also tested the use of Nb O as
respectively (Table 2, entries 4–7). Bioethanol was a reasonable
solvent for this reaction, affording the desired product 3a in
49% yield after 3 min (Table 2, entry 8). We decided to also
explore the use of anhydrous and hydrated Nb in glycerol;
2 5
O
2
5
Table 2 Optimization studies using indole 1a and aldehyde 2a, under
the catalyst for the reaction; however, no satisfactory result was
a
ultrasound irradiation
Table 1 Optimization studies using indole 1a and aldehyde 2a in water
a
and under conventional heating
Solvent
(1.0 mL)
Conversion
to 3a (%)
b
b
Entry
Catalyst (mol%)
1
2
3
4
5
6
7
8
ANO (5.0)
ANO (5.0)
ANO (5.0)
ANO (5.0)
ANO (5.0)
ANO (5.0)
ANO (5.0)
ANO (5.0)
Water
Water
Glycerol
Toluene
DMSO
DMF
4
23
99
1
NR
1
2
49
27
32
92
95
97
c
d
Catalyst
(mol%)
Temperature
(°C)
Yield of
3a (%)
b
Entry
1
2
3
4
5
6
7
8
25
25
25
50
100
50
11
65
65
85
82
12
2
CH Cl
2
EtOH
9
Nb
Nb
2
O
O
5
(5.0)
·H O (5.0)
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
10
11
12
13
2
5
2
ANO (3.0)
ANO (10.0)
ANO (15.0)
c
25
50
85
97
c
a
a
Reactions performed with indole 1a (1.0 mmol), benzaldehyde 2a
Reactions performed with indole 1a (1.0 mmol), benzaldehyde 2a
(
0.6 mmol), H
2
O as the solvent (1.0 mL) and the niobium species at (0.6 mmol) and the solvent (1 mL) under ultrasonic irradiation (20
b
b
the indicated temperature for 1 h. Yields of pure 3a were isolated kHz, 60% sonic amplitude) for 3 min. Determined by GC, based on
c
c
by column chromatography (hexanes/AcOEt). Reaction time was the amount of indole 1a. The reaction was sonicated for 30 min (final
increased to 2 h.
d
temperature = 50 °C). The final temperature was 110 °C.
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a
Table 3 Scope and generality of the niobium-catalyzed synthesis of bis(indolyl)methanes 3a–k using indoles 1a–c and carbonyl compounds 2a–i
b
c
Indole
Carbonyl compound
Product
Conventional
Time (h)
2.0
Ultrasound
d
d
Entry
1
1
2
3
Yield (%)
Time (min)
3
Yield (%)
97
99
2
3
1a
1a
1.0
3.0
92
89
5
8
92
82
4
1a
2.0
99
15
90
5
6
1a
1a
1.0
3.0
89
83
5
2
92
88
7
1a
1.0
96
1
88
8
9
1a
1a
3.0
3.0
60
68
20
15
35
20
1
1
0
1
2b
2b
8.0
3.0
99
65
5
2
90
93
a
b
Amounts used: indole 1 (1.0 mmol) and carbonyl compound 2 (0.6 mmol).
2
H O (1 mL) as the solvent at 50 °C (oil bath) and stirring under air
d
c
atmosphere. Glycerin (1 mL) as the solvent under ultrasonic irradiation (20 kHz) and air atmosphere. Yields of pure products isolated by
column chromatography (hexanes/AcOEt) and identified by GC-MS and H and C-NMR.
1
13
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however, lower yields of 3a were obtained in both cases
(Table 2, entries 9 and 10). Higher amounts of ANO did not
improve the reaction performance (Table 2, entries 11 and 12),
while the use of a lower amount led to a decrease in the
product yield (Table 2, entry 10).
In order to explore the scope and limitations of the
niobium-based catalysis, the protocol was extended to other
examples, under the optimized conditions in water (conven-
tional heating) and in glycerol (under sonication).
Firstly, various aromatic aldehydes (2a–g) were reacted with
indole 1a under conventional heating in water, affording BIMs
3
1
a–g in good to excellent yields after 1–3 h (Table 3, entries
–7). No remarkable differences in reactivity were observed
when electron-withdrawing or electron-donor groups were
present in the aromatic ring. An exception was the electron-
rich 1,3-dioxole benzaldehyde 2f, which gave the respective
BIM 3f in lower yield (82%) compared to other benzaldehydes
Fig. 1 Reuse of ANO/water in the synthesis of 3a.
(
Table 3, entry 6). Under our best conditions, the hetero-
aromatic furaldehyde 2g was converted to 3g in 96% yield after
h (entry 7). It is noteworthy that the reaction worked also
1
with aliphatic valeraldehyde 2h, giving the alkyl substituted
BIM 3h in 60% yield after 3 h (Table 3, entry 8). It was also
possible to apply our niobium-catalyzed procedure to the reac-
tion of indole with acetophenone 2i; in this case, tetrasubsti-
tuted BIM 3i was obtained in 68% yield after 3 h (Table 3,
entry 9).
Next, the behavior of different indoles (1b–c) on the Nb-
catalyzed electrophilic substitution was evaluated (Table 3,
entries 10–11). Thus, 5-bromo-1H-indole 1b produced, after Scheme 2 Chemoselectivity of the reaction.
reaction with 4-methylbenzaldehyde 2b, the bromo-containing
BIM 3j in 99% yield. A longer reaction time was necessary in
this case, probably due to the deactivation of the indole by the
bromo atom (Table 3, entry 10). N-Methyl substituted indole 1c
was equally converted to the respective BIM 3k in 65% yield
after 3 h (Table 3, entry 11).
We also studied the reuse of the catalyst and solvent in the
glycerol-mediated reaction of 1a with 2a. We observed,
however, that the catalyst was inactive after the first reaction
and more ANO was required for the next reaction. The same
solvent (glycerol) was used in four reactions, giving 3a in 99,
Following this, the reaction between indoles and carbonyl
compounds was performed using our previously optimized
protocol with glycerol and ultrasound. In most cases, the BIMs
were obtained with similar yields to those obtained by the
in water reactions under conventional heating. The reaction
times, on the other hand, were reduced from hours to a few
minutes (Table 3). Valeraldehyde (2h) and acetophenone (2i)
afforded the respective BIMs in 35 and 20% yields respectively,
which are inferior to those obtained using water and conven-
tional heating (Table 3, entries 8 and 9). In contrast, a better
yield of 3k, derived from N-methyl indole 1c and 4-methyl-
benzaldehyde 2b, was obtained using glycerol/ultrasound com-
pared to the in-water protocol (93% vs. 65%, Table 3, entry 11).
Furthermore, a study regarding the reuse of the ANO was
also performed. It was observed that the aqueous solution of
the catalyst could be successfully reused up to 5 times without
any pre-treatment, with good results. Thus, after the completion
of the reaction, the crude product 3a was simply extracted with
92, 89 and 70% yields. Besides the need to add a new ANO for
each reaction, a large amount of AcOEt was necessary for an
efficient extraction of 3a (6 × 3 mL); these features make the
recycling of glycerol in this case somewhat unattractive.
The chemoselectivity of the reaction in water was also
investigated. Thus, a mixture of benzaldehyde 2a (0.6 mmol),
acetophenone 2i (0.6 mmol) and indole 1a (1.0 mmol) was
subjected to the reaction under conventional heating con-
ditions for 8 h. The only product obtained was 3a, derived
from benzaldehyde 2a, in 97% yield, while acetophenone
remained unreacted and could be recovered (Scheme 2). This
result shows the high chemoselectivity of our method.
Conclusions
ethyl acetate (3 × 5 mL) and the aqueous catalyst was reused Ammonium niobium oxalate (ANO), NH
4
[NbO(C
2 4 2 2 x
O ) (H O) ]·
directly in a new reaction. The product 3a was obtained in nH
2
O, proved to be an effective, selective and reusable cata-
yields between 97 and 95% after successive cycles (Fig. 1).
lyst for the green synthesis of bis(indolyl)methanes under
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conventional heating in water or under ultrasonic irradiation
in glycerol. Besides being a simple procedure, the niobium
catalyst was easily reused in the reaction in water. The use of
glycerol allows the use of sonication to accelerate the reaction
from hours to only a few minutes. The low toxicity of niobium
allied to an atom-economic reaction, and the use of green sol-
vents and sonication are features which make this new,
Nb-based protocol, a green alternative to access bis(indolil)
methanes selectively.
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