An efficient, environmentally benign, and solvent-free protocol for the synthesis of 4-substituted 1,5-benzodiazepines catalyzed by reusable sulfated polyborate

Article abstract of DOI:10.1016/j.tetlet.2017.10.030

An efficient and environmentally benign method has been developed for the one-pot solvent-free synthesis of 4-substituted-1,5-benzodiazepines via three-component reaction of o-phenylenediamine, dimedone with a variety of aldehydes catalyzed by sulfated po

Full text of DOI:10.1016/j.tetlet.2017.10.030

Accepted Manuscript
An efficient, environmentally benign, and solvent-free protocol for the synthesis
of 4-substituted 1,5- benzodiazepines catalyzed by reusable sulfated polyborate
Krishna S. Indalkar, Manisha S. Patil, Ganesh U. Chaturbhuj
PII:
S0040-4039(17)31310-2
https://doi.org/10.1016/j.tetlet.2017.10.030
TETL 49392
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 August 2017
11 October 2017
12 October 2017
Please cite this article as: Indalkar, K.S., Patil, M.S., Chaturbhuj, G.U., An efficient, environmentally benign, and
solvent-free protocol for the synthesis of 4-substituted 1,5- benzodiazepines catalyzed by reusable sulfated
polyborate, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.030
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Graphical Abstract
An efficient, environmentally benign and
solvent-free protocol for the synthesis of
4-substituted 1,5- benzodiazepines catalyzed
by reusable sulfated polyborate.
Krishna S. Indalkar, Manisha S. Patil, and Ganesh U. Chaturbhuj*

1
Tetrahedron Letters
jour nal homepage: w ww.elsevier. com
An efficient, environmentally benign, and solvent-free protocol for the synthesis of
4-substituted 1,5- benzodiazepines catalyzed by reusable sulfated polyborate.
Krishna S. Indalkar, Manisha S. Patil, and Ganesh U. Chaturbhuj*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai- 400019 India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and environmentally benign method has been developed for the one-pot
solvent-free synthesis of 4-substituted-1,5-benzodiazepines via three-component
reaction of o-phenylenediamine, dimedone with a variety of aldehydes catalyzed by
sulfated polyborate under solvent-free condition. The major advantages of the present
method are good to excellent yields, shorter reaction time, simple experimental
procedure, easy workup procedure, solvent-free reaction conditions, recyclability of
the catalyst and ability to tolerate a variety of functional groups which gives
economical as well as ecological rewards.
Available online
Keywords:
Sulfated polyborate
Benzodiazepines
Dimedone
2016 Elsevier Ltd. All rights reserved.
Aldehyde
o-Phenylenediamine
Recently, the development of a simple, highly elegant, and
eco-friendly synthetic method for widely used organic
compounds from readily available catalyst or reagents is one of
1
the major challenges for chemists . Multicomponent reactions
have emerged as a powerful tool in generating products in
medicinal chemistry as well as organic synthesis because they
trigger the conversion of three or more starting components in
one pot to a highly functionalized product showing maximum
molecular diversity, complexity, and selectivity. Therefore, these
reactions are eco-friendly, highly atom economical, and
synthetically efficient in terms of reduced time, steps, energy,
and the consumption of chemicals as well as solvents 2-6. N-
heterocyclic compounds represent one of the most valuable
building blocks for biologically active molecules, drugs and
intermediates.7
Benzodiazepines are the important heterocyclic compounds,
acquired considerable attention in medicinal chemistry due to
their widespread biological and pharmacological activities.8,9
(Fig. 1). Its remarkable central nervous system (CNS) depressant
activity10 made them one of the most widely prescribed classes of
psychotropics.11,12 Some important examples are diazepam and
chlordiazepoxide that act as anti-anxiety drugs8 and clozapine
from the piperidinyl dibenzodiazepine in schizophrenia drugs, as
well as apafant act as the platelet-activating factor inhibitor and
pirenzepine act as the muscarinic receptor-M1 antagonist.13 They
are also used as dyes for acrylic fibres14 in photography.
Modifications in these heterocycles have been made and the
anxiolytic effect of benzodiazepines (clobazam) has been
described. Benzodiazepine compounds are extensively sold as
psychoactive drugs worldwide due to their anxiolytic and
anticonvulsant activity. In addition, 1,5-benzodiazepines are used
Fig.1. Pharmacological active compounds
as synthons for the preparation of other fused ring systems such
as oxadiazolo-, triazolo-, oxazino- or furanobenzodiazepines.15-17
The 1,5-dibenzodiazepines have been reported to exhibit
inhibitory activities towards HIV-1 protease18,19 and hepatitis C
virus (HCV) NS5B20 as well as finding several applications in
medicinal chemistry,21 where they have been used as hypnotic,22
anti-inflammatory,23
anticoagulant,24
antibacterial,25
antiepileptic,26,27 antidepressant,28 and analgesic agents.29
Due to the versatile applicability highlights the importance
of accessing efficient synthetic routes to well-designed 4-
substituted-1,5-benzodiazepines. A number of methods have
been developed for the synthesis of 4-substituted-1,5-
benzodiazepines. It has been carried out by three-component
condensation of o-phenylenediamine, dimedone and
∗
Corresponding author. Tel.: +91-223-361-2212; fax: +91-222-414-
5614; e-mail: gu.chaturbhuj@gmail.com

2
Scheme 2. Synthesis of 3,3-dimethyl-11-phenyl-2,3,4,5,10,11-hexahydro-1H-
dibenzo[b,e][1,4]diazepin-1-one
Table 1
Scheme 1. Schematic representation of sulfated polyborate catalyzed
synthesis of 4-substituted-1,5-benzodiazepines.
Effect of catalyst loading and temperature for the synthesis of 3,3-dimethyl-
11-phenyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one a
Entry
Catalyst
(wt %)
Temperature
(°C)
Yieldb
Time
(min)
(%)
aldehyde variants under various conditions such as oxalic acid in
water,30 acetic acid in ethanol under reflux,8 acetic acid in
toluene, 31 HCl in ethanol,32 and H2SO4 in ethanol.33 In addition,
they have been synthesized by the condensation of 2-formyl
benzoic acid, o-phenylenediamine and tetronic acid in water
under microwave irradiation as a hetero-Cope rearrangement,34
cycloaddition reaction of 2,2-dihydroxy-1-phenylethanone, o-
phenylenediamine, and dimedone derivatives. 35
Recently, some strategies have been introduced for the
synthesis of 4-substituted benzodiazepines in the presence of a
wide variety of catalysts such as Cu/GA/Fe3O4@SiO2 NCPs,36 N-
methyl-2-pyrrolidonium hydrogen sulfate as an ionic liquid,37
zinc sulfide nanoparticles via grinding method,38 graphene oxide
nanosheets,39 ZnS nanoparticles,13 ZrO2-Al2O3,40 chitosan-
supported superparamagnetic iron oxide nanocomposite,41 DES
(choline chloride:urea),42 and promoted by microwaves.43
1
2
-
2.5
5
100
100
100
100
100
100
r.t.
180
90
30
15
10
10
60
60
60
10
NRc
72
3
80
4
7.5
10
15
10
10
10
10
89
95
5
6
95
NRc
30
7
8
60
80
9
74
10
120
95
a Reaction conditions: o-phenylenediamine (1 mmol), dimedone (1mmol), benzaldehyde
(1 mmol) b Isolated yield. cNo reaction
Table 2
Each of these methods has their own advantages but may
suffer from one or more shortcomings such as long reaction time,
multi-step sequences or need anhydrous conditions, poor yields,
laborious workup, use of organic solvents, difficult recovery and
reusability of the catalysts, and the use of hazardous as well as
excess of catalysts or reagent. Hence, the development of clean,
efficient, environmentally benign, and high yielding rapid
reaction procedure using cost-effective and recyclable catalyst is
very much desirable.
In the perpetuation of the development of eco-friendly,
convenient, and practical catalytic methods for the current
interest in organic synthesis and commercial process; recently we
have synthesized, characterized sulfated polyborate and proved
its efficiency for various useful organic transformations. 44-56 Its
easy preparation, mild acidity, eco-friendliness, and reusability
have encouraged us to investigate its potential to catalyze many
other useful organic transformations. Therefore, inspired by our
previous finding, herein we report a rapid, efficient, and green
method for synthesis of 4-substituted-1,5-benzodiazepines via
one-pot, solvent-free condensation of a variety of aldehydes with
o-phenylenediamine and dimedone in the presence of a sulfated
polyborate as a recyclable catalyst under solvent-free conditions
(Scheme 1). This reaction provided facile access to the target
molecules in high yields over short reaction times using sulfated
The effect of the solvents on the synthesis of 3,3-dimethyl-11-phenyl-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one a
Entry
Solvent
Temperature
(°C)
Time
(min)
Yieldb
(%)
1
2
3
4
5
6
7
8
Solvent-free
Water
100
10
60
60
60
60
60
60
60
95
Reflux
Reflux
Reflux
Reflux
Reflux
100
traces
25
MeCN
THF
32
EtOH
70
Toluene
DMF
43
55
DMSO
100
58
a Reaction conditions: o-phenylenediamine (1 mmol), dimedone (1mmol), benzaldehyde
(1 mmol), sulfated polyborate 10 wt % b Isolated yield.
character. Boron being an electron deficient element and
electron-withdrawing effect of adjacent sulfate enhances its
Lewis acidity; hence sulfated polyborate has both Lewis as well
as Bronsted acid characters (Scheme 1).
For initial screening, the study was designed for the
synthesis of 4-substituted-1,5-benzodiazepines to investigate the
suitability of sulfated polyborate as a catalyst at different reaction
conditions. In the initial experiment, an equimolar mixture of o-
phenylenediamine, dimedone, and benzaldehyde a representative
substrate was used (Scheme 2). The results are summarized in
polyborate as
a
catalyst. Furthermore, this method is
environmentally benign and robust and involves easy product
separation and workup procedures.
Table 1
Table 3
A literature search revealed that boric acid catalyzes many
useful organic transformations above 100 °C.57,58 Boric acid
dehydrates above 100 °C and turns to its polymeric forms, which
could be the active species catalyzing the reaction.59 Dehydrative
polymerization of boric acid liberates water molecules which
may hamper the progress of the reaction.
This persuades us to develop a polymeric boric acid catalyst
with mild Bronsted acidity. To accomplish this boric acid was
dehydrated at 200 °C to convert it into its polymeric Lewis acid
form and then sulfonated to introduce the mild Bronsted acid
Results of the conditional experiments to ascertain role of sulfated
polyborate.
Entry
Catalyst
Condition
Time
(min)
10
Yieldb
(%)
1.
Sulfated
polyborate
Polyboric acid
Boric acid
HCl
Neat/100 °C
95
2.
3.
4.
5.
Neat/100 °C
Neat/100 °C
EtOH/reflux
EtOH/reflux
300
300
300
300
NRc
NRc
NRc
NRc
H2SO4
a Reaction conditions: o-phenylenediamine (1 mmol), dimedone (1mmol), benzaldehyde
(1 mmol) b Isolated yield. cNo reaction

3
Table 4
Sulfated polyborate catalyzed synthesis of 4-substituted 1,5-benzodiazepines
a, 60
11.
12.
2-HO-C6H4
4-HO-C6H4
15
12
88
90
H
N
R1
O
Sulfated Polyborate
R
O
R
NH2
NH2
R1
+
+
Solvent free, 100 o
C
O
H
N
H
O
R= H, CH3, Cl, NO2
4a-u
3
2
1
Entry
Aldehyde
(R1)
Product
Time
Yield
(%)
(Min)
1
C6H5
10
95
13.
C6H5CH2
2-Thienyl
12
91
2.
3.
2-Cl-C6H4
3-Cl-C6H4
12
10
90
93
14.
15.
15
15
88
86
5-Methyl
furan-2-yl
2-Pyridyl
16.
15
15
85
86
4.
5.
4-Cl-C6H4
4-Br-C6H4
10
10
95
93
17.
18.
c-C6H11
n-C3H7
15
83
6.
7.
2- O2N-C6H4
3-O2N-C6H4
10
10
95
96
19.
C6H5
10
10
93
95
C6H5
C6H5
20.
21.
10
94
8.
4-O2N-C6H4
10
98
a Reaction conditions: o-phenylenediamine (1 mmol), dimedone (1mmol), aldehyde (1
mmol), sulfated polyborate 10 wt % b Isolated yield.
9.
4-CH3-C6H4
12
12
92
90
The amount of catalyst and temperature mainly affect
the efficiency of the reaction. To understand the effect of the
catalyst loading on time and yields of the product (Table 1,
entries 1-6), a control experiment was performed in the absence
of a catalyst at 100 °C but the reaction does not proceed. (Table
1, entry 1). Further experiments were conducted to optimize the
amount of sulfated polyborate catalyst and an increase in the
catalyst loading increased the product yield with a significant
reduction in the reaction time was observed (Table 1, entries 2-
10.
4-CH3O-C6H4

4
5). The catalyst loading beyond 10 wt % was not advantageous
(Table 1, entries 5 and 6). Hence, 10 wt % catalyst loading was
chosen for further study. (Table 1, entry 5).
Temperature played a vital role in the synthesis of 4-
substituted-1,5-benzodiazepines (Table 1, entries 7-10). The
temperature effect was assessed at ambient, 60, 80, 100 and 120
°C in presence of sulfated polyborate. The reaction did not
proceed at room temperature (Table 1, entry 7) while proceeded
at 60 and 80 °C but took longer reaction time with a poor yield
(Table 1, entries 8 and 9). The reaction proceeds at 100 °C with
increased product yield in shorter reaction time (Table 1, entry
5). The reaction temperature beyond 100 °C was not
advantageous (Table 1, entry 9). Therefore, 100 °C was chosen
as optimum temperature.
The effect of various solvents on time and yield of the
reaction was ascertained (Table 2, entries 1-8). None of the
solvents should the advantage of time and yield over solvent-free
condition. Hence, the solvent-free condition was regarded as best
for the cost and environmental benefits. In all the experiments,
the products were isolated by aqueous quenching followed by
filtration and recrystallized from methanol. To understand the
role of the sulfated polyborate for the synthesis of 4-substituted
1,5-benzodiazepines, conditional experiments were carried out
separately with boric acid, polyboric acid, as well as with
ethanolic H2SO4, and HCl. The results substantiate the catalytic
role of sulfated polyborate over other acids (Table 3).
Scheme 3. Proposed reaction mechanism for the sulfated polyborate
catalyzed formation of 4-substituted-1,5-benzodiazepine.
The enamine intermediate then reacts with the aromatic aldehyde
(3) to give the corresponding diimine B, which would undergo an
intramolecular dehydrative cyclization to give 4-substituted-1,5-
benzodiazepines (4a) via intermediate (C) after intramolecular
1,3-proton transfer.
Table 5.
Recyclability of the catalysta
Yieldb (%)
To study the synthetic utility and scope, optimized reaction
condition60 was applied to various aldehydes and substituted o-
phenylenediamine. All the substituted aromatic, heterocyclic,
alicyclic and aliphatic aldehydes, as well as substituted o-
phenylenediamine with dimedone, reacted well to afford good to
excellent yields of the corresponding 4-substituted-1,5-
benzodiazepines in shorter reaction time (Table 4, entries 1–21).
To judge the substituent effect on reaction time and yields,
aromatic aldehydes bearing various electron-donating or
electron-withdrawing functional groups at the ortho, meta and
para positions were tested. The nature of substitutions on
aromatic aldehydes has no significant effect on the reaction time
and yields (Table 4, entries 1–12) except ortho-hydroxy
benzaldehyde (Table 4, entry 11). This protocol was also
extended to heterocyclic, alicyclic and aliphatic aldehydes,
resulted in corresponding 4-substituted-1,5-benzodiazepines in
good yields but took slightly longer time compared to others
(Table 4, entries 13–18). Further, the optimized reaction protocol
was also extendable to substituted o-phenylenediamine (Table 4,
entries 19–21), resulted in good yields of the corresponding 4,7-
disubstituted-1,5-benzodiazepines.
Entry
Number of Cycle
Time (min)
1
2
3
4
5
Fresh
10
10
10
10
10
95
94
92
91
91
1
2
3
4
a Reaction conditions: o-phenylenediamine (1 mmol), dimedone (1mmol), benzaldehyde
(1 mmol), sulfated polyborate 10 wt % solvent-free, 100 °C.
b Isolated yield.
Conclusion
In summary, we have developed a rapid, simple,
efficient, and environmentally benign one-pot, a three-component
protocol for the synthesis of 4-substituted-1,5-benzodiazepines in
the presence of reusable sulfated polyborate as a mild, efficient,
eco-friendly, and inexpensive catalyst. Excellent yields, simple
experimental procedure, easy workup procedure, shorter reaction
time, solvent-free condition, non-hazardous and environment-
friendly reaction condition are the key features of this procedure.
Moreover, this protocol has the ability to tolerate a wide variety
of substituents.
Recyclability of the catalyst is an important attribute for the
industrial suitability. Therefore, reusability of the catalyst in the
model reaction of o-phenylenediamine, dimedone, and
benzaldehyde under optimized reaction condition was evaluated.
In this study, after completion of each reaction cycle, the reaction
mixture was quenched with water, and the product was filtered
off. The catalyst dissolves in water which was recovered
quantitatively by evaporation in a rotary evaporator. The
recovered catalyst was recycled for four times with no significant
loss in a catalytic activity (Table 5).
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/00.0000/
Acknowledgements
Authors are thankful to University Grants Commission, India
and Department of Science and Technology, India for their
financial support.
Based on the results of the current study, we propose a
mechanism for the formation of 4-substituted-1,5-benzodiazepine
from o-phenylenediamine, dimedone, and benzaldehyde in the
presence of sulfated polyborate (Scheme 3).
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6
Highlights:
•
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Rapid,
efficient,
solvent-free
and
environmentally benign synthesis of 1,5-
benzodiazepines.
Key advantages are high yields, short
reaction time and simple work-up
procedure.
Protocol tolerates a variety of aromatic,
aliphatic, benzylic, and heterocyclic
aldehydes.
Recyclable catalyst with no significant loss
in activity.