Oxidative Coupling of Benzylamines with Indoles in Aqueous Medium to Realize Bis-(Indolyl)Methanes Using a Water-Soluble Cobalt Catalyst and Air as the Oxidant

Article abstract of DOI:10.1002/asia.201901313

Oxidative coupling of benzylamines with indoles to bis-(indolyl)methanes (BIMs) was achieved using an inexpensive water-soluble cobalt complex, Co(bpb). The catalyst was found to be quite effective when air was used as the oxidant and water as solvent under mild reaction conditions. Aromatic amines were successfully converted to the corresponding BIMs with yields up to 85 %. We have successfully carried out a 1 gram scale reaction, and few pharmaceutically relevant compounds were also synthesised by this method in good yields. Control experiments have also been carried out to understand the possible reaction mechanism.

Full text of DOI:10.1002/asia.201901313

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Oxidative coupling in aqueous medium of benzylamines with
indoles to realize bis-(indolyl)methanes using a water soluble
cobalt catalyst and air as the oxidant
Authors: Parul Saini, Pratishtha Kumari, Susanta Hazra, and Anil
Jacob Elias
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To be cited as: Chem. Asian J. 10.1002/asia.201901313
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Oxidative coupling in aqueous medium of benzylamines with
indoles to realize bis-(indolyl)methanes using a water soluble
cobalt catalyst and air as the oxidant
Parul Saini,$ Pratishtha Kumari,$ Susanta Hazra and Anil J. Elias*
*Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi-110016, India. Email: eliasanil@gmail.com.
$ These authors have contributed equally.
Abstract: Oxidative coupling of benzylamines with indoles to bis-
(indolyl)methanes (BIMs) was achieved using an inexpensive water
soluble cobalt complex, Co(bpb). The catalyst was found to be quite
effective when air was used as the oxidant and water as solvent
under mild reaction conditions. Aromatic amines were successfully
converted to the corresponding BIMs with yields up to 85ꢀ%. We
have successfully carried out a 1 gram scale reaction and few
pharmaceutically relevant compounds were also synthesised by this
method in good yields. Control experiments have also been carried
out to understand the possible reaction mechanism.
heterocycles. Synthesis of BIM’s using aldehydes and indoles
have also been reported with promoters such as SnCl2.2H2O,
PCBS, Fe3O4@SiO2-SO3H,P2O5/SiO2, SbCl3, Alum etc.7
However, these methods suffer from drawbacks such as the use
of toxic reagents, requirement of high temperature and volatile
organic solvents. Some reports demonstrate the use of green
solvents such as ionic liquids or solvent free reactions and room
temperature conditions to synthesize BIM’s.7a-d All such reports
involved either aldehydes or ketones as substrates to give BIM’s
by reaction with indoles. Unlike aldehydes and ketones, there
are very few reports on catalytic methods for oxidative synthesis
of BIM’s using alcohols and amines as substrates.7k,8In particular,
Gopalaiah and co-workers have reported iron catalyzed
oxidative coupling of benzylamines and indoles, but the reaction
has been carried out in chlorobenzene at 110 oC with higher
catalyst loading.8a
Indoles and their derivatives are important compounds which are
present in a variety of natural products.1 Bis-(indolyl)methane
(BIM) derivatives have been considered as active compounds in
pharmaceuticals due to their proved biological activity.2 These
compounds show many interesting properties including
anticancer, antimicrobial, analgesic, cardiovascular and
selective COX-2 inhibitory activities.3 Selected drug molecules
having bis-indolyl methane moieties are shown (Scheme 1).
These compounds are also present in cruciferous plants and
promote oestrogen metabolism and induce apoptosis in human
cancer cells.4 In addition, these compounds also find
applications as highly selective colorimetric and fluorescent
molecular chemosensors for Cu2+cations.5
Scheme 2: Existing methods for oxidative coupling of benzyl amines and
benzyl alcohols with indoles to obtain BIM‘s.
Recently, Yue and co-workers have also reported oxidative
coupling of benzyl amines and indoles catalyzed by
TEMPO/CuI.8b However, synthesis of BIM from benzyl amine
involves organic solvents, higher catalyst loading and also use
TEMPO free radical as co-catalyst. Therefore, search for new
methodologies which are efficient, economically viable and
which decreases the environmental impact for the preparation of
BIMs are of great interest and current relevance to the
pharmaceutical industry using readily available amines. The use
of green solvents such as water or solvent free conditions, air as
oxidant, earth abundant metals as catalysts and lower catalyst
loading are some of the modifications which can possibly
improve the greenness in the synthesis of BIM‘s. Although, the
complexes of early transition metals with the bispicolinamide
ligand [N,N-bis(2-pyridinecarboxamide)-1,2-benzene] (bpb) were
first reported by Vagg and co-workers in 1979, the use of such
complexes as catalysts has been very little explored.9a, b Very
recently, we have shown that the aerobic oxidation of primary
amines to imines can be made possible by using the water
soluble cobalt complex of N,N’-bis(2’-pyridinecarboxamide)-1,2-
benzene [Co(bpb)] under near ambient conditions and using
water as the only solvent.9c Therefore, we envisaged whether
reactions can be carried out between benzylamines and indoles
Scheme 1: Some selected example of bis-indolylmethane (BIM) based drugs.
Due to their immense and diverse biological and pharmaceutical
activities, synthesis of bis-(indolyl)methane derivatives has
become very significant in recent times. Generally, the synthesis
of bis-(indolyl)methanes is carried out by electrophilic
substitution reaction of indoles with aromatic or aliphatic
aldehydes and ketones catalyzed by protic acids or Lewis
acids.6 However, Lewis acids are required in excess because
these are destroyed by the presence of even small amounts of
moisture or they get trapped as adducts by nitrogen based
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to give the corresponding 3-substituted indoles which may
undergo oxidative coupling with another indole molecule to
produce 3,3'-benzylidenebis(1H-indole) molecule as the product.
From our studies we have found that it is indeed feasible and
herein we present an attractive and sustainable method for the
synthesis of bis(indolyl)methane derivatives using the water
soluble cobalt catalyst N,N’-bis(2’-pyridinecarboxamide)-1,2-
benzene [Co(bpb)] with air as the oxidant under mild conditions
and using pure water as the solvent. This method provides a
greener synthetic procedure for a variety of functionalized
bis(indolyl)methanes by a simple and one-pot reaction.
After varying the reaction parameters and after detailed studies
(Tables S1–S5), it was found that 3 mol% of catalyst, water as
solvent and atmospheric air as oxidant with reaction time of 12-
15 h at 70 °C are the conditions suited to get the best yields of
the product (Scheme 2). After the optimization of the reaction
conditions, we examined the substrate scope of the reaction with
different benzylamines and indoles. This reaction was extended
to compounds having electron-donating as well as electron-
withdrawing substituents on the aryl ring of benzylamines and
indoles (Figure 1 and Figure 2).
We began our work by investigating the reaction of benzylamine
and 1H-indole in the presence of 2 mol% of Co(bpb) in water at
70 °C by bubbling air. We observed the formation of 3,3'-
benzylidenebis(1H-indole) in 72% yield. Further, we used
different cobalt catalysts (see supporting info. Table S1) under
similar reaction conditions and obtained the desired product but
in lower yields as compared to when Co(bpb) was used. Hence,
we optimized the reaction conditions using the Co(bpb) catalyst.
When a reaction was carried out under N2 atmosphere, the
desired product was not obtained. This suggested that
atmospheric O2 plays
a
crucial role for this oxidative
transformation. The reaction was also carried out with external
oxidants, H2O2 and aq. TBHP but only 45% and 37% yields of
the BIM‘s were obtained (see supporting info. Table S5).
Although, aq. H2O2 and TBHP are considered as stronger
oxidants than air, we obtained lesser yields when these were
used as oxidants in our study. Analysis of reaction mixture with
TBHP indicated formation of benzonitrile as a side product. The
reduction in yields may also be due to the reactivity of indole
with such strong oxidants. Recently, Ganesan and co-workers
have reported oxidative dearomatization of indoles to C2/C3-
quaternary indolinones in the presence of TBHP.12 We also
observed that the yields of the desired products decreased
slightly when we increased the temperature. We have observed
that indole partially decomposes at high temperatures in the
presence of the cobalt catalyst.9c
Figure 2: Substrate scope for oxidative coupling of different benzyl amines
with different indoles in water. Isolated yields in parenthesis.
To demonstrate the applicability of our methodology, we have
also carried out a gram scale reaction of benzylamine 1 under
identical reaction conditions (Scheme 3). The reaction
proceeded smoothly and resulted in the formation of the desired
BIM 3e in 73% isolated yield (Scheme 3).
Scheme 3: Gram scale synthesis of BIM 3e. Reaction conditions: amine (1.0g,
9.34 mmol), Indole (2.2g, 18.69 mmol), catalyst (3 mol%), 2 mL of H2O at 70
oC for 15h.
We have succesfully obtained 3a which is used as
antiparkinsonian drug, 3f used as anticancer drug and 4c
BMIPTM used in Leukemia therapy with good yields using our
method (Scheme 4).
Figure 1: Substrate scope for oxidative coupling of different benzyl amines
with indole in water. Isolated yields in parenthesis.
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The mechanism involves reaction of compound A, [CoII(bpb)]
with oxygen to generate the active intermediate B,9,10 which
coordinates with benzylamines to form the intermediate D.11
Intermediate D can also be generated via intermediate C. It is
subsequently converted to a Schiff base intermediate and
H2O.11a,c Hydrolysis of this imine intermediate induced by H2O
with the elimination of a molecule of NH3 results in the formation
of benzaldehyde E,11a,c which reacts with the indole molecule to
generate the desired 3,3'-benzylidenebis(1H-indole)product I.
Schiff base intermediate can also react with one molecule of
benzylamine via path b to give intermediate imine F with the
11d
release of a molecule of NH3. It further reacts with the indole
molecule in the presence of Co(bpb) to form intermediate G
followed by loss of benzylamine to give intermediate H.
Intermediate H reacts with another molecule of indole to give the
desired 3,3'-benzylidenebis(1H-indole) I.8a The formation of the
intermediates E and F were confirmed by H-NMR and GC-MS
analysis of reaction mixture of 4-methoxybenzylamine in the
absence of indole (Schemes 5d, 6).
Scheme 4: Synthesis of pharmaceutically relevant compounds 3a, 3f and 4c.
To study the mechanism of formation of bis(indolyl)methanes,
several control experiments were carried out as shown (Scheme
5). A reaction was carried out using benzaldehyde and indole
under the optimized reaction conditions and the product was
obtained in 70% yield (Scheme 5a). This showed that our
catalytic system works well with aldehyde as well but by using
the benzylamine, 75% yield of the same product was realized
(Scheme 5b). Futher increase in the yield up to 85% was
obtained when 4-methoxybenzylamine was used as the
substrate (Table 2, 4a). We also performed the reaction with
benzylimine with two equivalents of indole and Co(bpb) at 70 °C
and obtained 73% yield of the BIM (Scheme 5c). Therefore, it
can be concluded that the imine acts as an intermediate in this
reaction. Further, BIM was synthesized in the presence of free
radical inhibitors such as butylated hydroxytoluene, N-ascorbic
acid and TEMPO (Schemes 5a and 5b). It was observed that the
yields decreased drastically and it may be inferred that the
reaction proceeds through a free radical mechanism. To check
the stability and robustness of the catalyst, we carried out a
reaction (see supporting info. page no. S51) in which we
observed that the catalyst did not decompose during the
reaction and if required, can be reused without isolating it form
the reaction mixture. The proposed mechanism of the reaction is
shown in scheme 6.
1
Scheme 6: Proposed catalytic cycle for oxidative coupling of 4-methoxy
benzylamines with indole in water.
Conclusion:
We have, for the first time developed a methodology involving
primary amine as the substrate, water as the solvent and air as
the oxidant for the synthesis of bis(indolyl)methanes. A water
soluble and stable cobalt catalyst CoII(bpb) was used for this
simple and greener one pot synthesis. To show the potential
applications of our method, we have carried out a gram scale
reaction and also have synthesized some pharmaceutically
important compounds. This transformation is economical and
environmentally friendly. Ease of preparation of the catalyst
using an inexpensive ligand and cobalt salts are additional
interesting features of our methodology.
Scheme 5: Control experiments carried out for mechanistic studies for the
oxidative coupling of benzylamines with indole in water.
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Acknowledgements
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Conflict of interest
There is no conflict of interest to declare
Keywords: aerobic oxidation •water soluble catalyst •oxidative
coupling• cobalt catalyst •bis(indolyl)methane
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Layout 1:
COMMUNICATION
Oxidative coupling of benzylamines
with
indoles
to
bis-
Parul
Saini,$
Pratishtha
(indolyl)methaneswas achieved using
an inexpensive water soluble cobalt
complex, Co(bpb). This simple and
greener one pot synthes is produced
good yields of bis-(indolyl)methanes
when air was used as the oxidant and
water as the solvent under mild
Kumari,$ SusantaHazra and Anil J.
Elias*
Page No. – Page No.
Oxidative coupling in aqueous
medium of benzylamines with indoles
to realize bis-(indolyl)methanes using
a water soluble cobalt catalyst and air
as the oxidant
reaction
conditions.
Few
pharmaceutically relevant compounds
were also synthesised by this method
in good yields.
This article is protected by copyright. All rights reserved.