Bi(NO3)3·5H2O: An efficient and green catalyst for synthesis of 1,5-benzodiazepines and β-amino carbonyl compounds

Article abstract of DOI:10.14233/ajchem.2013.14353

Bismuth nitrate pentahydrate is found to be an efficient catalyst for the synthesis of 1,5-benzodiazepines and β-amino carbonyl compounds using condensation of o-phenylenediamine with ketones and one pot three component Mannich reaction, respectively under solvent free conditions at room temperature. This method offers a simple, solvent free, room temperature, environment friendly synthesis of 1,5-benzodiazepines and β-amino carbonyl compounds. The products are isolated by column chromatography and recrystallization, respectively and were characterized by their melting point, IR and ¹H NMR spectroscopy.

Full text of DOI:10.14233/ajchem.2013.14353

Asian Journal of Chemistry; Vol. 25, No. 12 (2013), 6545-6549
http://dx.doi.org/10.14233/ajchem.2013.14353
Bi(NO3)3·5H2O: An Efficient and Green Catalyst for Synthesis of
1,5-Benzodiazepines and β-Amino Carbonyl Compounds
*
JASPREET KAUR RAJPUT and GAGANDEEP KAUR
Department of Chemistry, Dr. B.R. Ambedkar National Institute of Technology, Jalandhar-144 011, India
*Corresponding author: E-mail: rajputj@nitj.ac.in; gagandeepnit@gmail.com
(Received: 20 July 2012;
Accepted: 20 May 2013)
AJC-13518
Bismuth nitrate pentahydrate is found to be an efficient catalyst for the synthesis of 1,5-benzodiazepines and β-amino carbonyl compounds
using condensation of o-phenylenediamine with ketones and one pot three component Mannich reaction, respectively under solvent free
conditions at room temperature. This method offers a simple, solvent free, room temperature, environment friendly synthesis of 1,5-
benzodiazepines and β-amino carbonyl compounds. The products are isolated by column chromatography and recrystallization, respectively
and were characterized by their melting point, IR and 1H NMR spectroscopy.
Key Words: 1,5-Benzodiazepines, β-Amino carbonyl compounds, Bi(NO3)3·5H2O, Solvent free conditions.
FeCl328, zeolite29, Sc(OTf)330, ceric ammonium nitrate31, ionic
INTRODUCTION
liquid32, kaolin33, NbCl534, keggin hetropolyacids35. Whereas
the synthesis of β-amino carbonyl compounds involves the
three-component one pot reaction using aromatic aldehydes,
The development of solvent free organic synthesis has
become important research area, aiming to make the synthesis
simpler, to prevent hazardous solvent waste, to save energy
aromatic ketones and aromatic amines. Several methods have
and toxicity in chemical processes. Many organic solvents are
been reported in the literature and few catalysts, including conc.
HCl36, NbCl537,Al(CH3SO3)3·4H2O38, dodecylbenzenesulfonic
ecologically harmful and their use should be minimized as far
as possible or should be avoided altogether1,2.
Benzodiazepines are very important biologically active
compounds as these are used as anticonvulsant, antianxiety,
acid39, SnCl240, ionic liquid41, InCl3 and polymer-support
42
sulphonic acid43, GuHCl44, Me2SBr245 etc., have been developed.
However, most of these methods suffer from disadvantages
antiinflammatory, analgesic, hypnotic, antidepressive and
such as strong acids or expensive catalysts, longer reaction
time, elevated reaction temperature, toxic reagents, low yield.
sedative agents3. Inspite of their biological importance,
benzodiazepines have application in industries such as dyes
Hence there is an increasing interest in developing environ-
mentally benign reactions and atom-economic catalytic
for acrylic fibres in photography4. Additionally, 1,5-benzodi-
azepines are useful synthons for the preparation of other fused
processes for the synthesis of 1,5-benzodiazepines and β-
amino carbonyl compounds.
ring compounds such as triazolo-5-7, oxadiazolo-8-10, oxazino11
and furano-benzodiazepines12. Mannich reaction is important in
Recently, bismuth(III) salts are used as Lewis acid
carbon-carbon bond forming reaction in organic synthesis13-15
,
catalysts46-49 in organic synthesis because of low cost, easy
handling and friendly ecological behaviour. In continuation
to our work on green synthesis50 we report a rapid synthesis of
1,5-benzodiazepines and β-amino carbonyl compounds in
presence of Bi(NO3)3·5H2O because it is non-toxic, cheaper,
easy available and stable in air.
as it provides β-amino carbonyl compounds which are impor-
tant synthetic intermediates for various nitrogen containing
natural products and pharmaceutical16,17. The increasing popu-
larity of Mannich reaction has been fuelled by the ubiquitous
nature of nitrogen-containing compounds in drugs and natural
products18.
EXPERIMENTAL
1,5-Benzodiazepines are prepared by condensation reac-
tion of o-phenylenediamine with α,β-unsaturated carbonyl
compounds19, β-haloketones20, β-diketones21, chalcones22 or
ketones using variety of catalysts such as BF3·OEt223, NaBH424,
Al2O3-P2O5 under microwave25, HOAc microwave26, InBr327,
Melting points were recorded on gallen kamp apparatus
and are uncorrected. 1H NMR (400 MHz) spectra were deter-
mined with a BruckerAdvance 400 spectrometer (CDCl3) using
tetramethylsilane (TMS) as internal standard. Infrared spectra

6546 Rajput et al.
Asian J. Chem.
(cm-1) were measured with Perkin Elmer spectrometer. All
reactions were carried out using reagent-grade solvents and
the reagents were purchased from local suppliers.
R
O
O
2
NH
C HO
NH
2
C H
3
Bi
NO
5. HO
2
3
General procedure for synthesis of 1,5-benzodiazepines:
To a mixture of o-phenylenediamine (1 mmol) and ketone (2.2
mmol), catalyst Bi (NO3)3·5H2O (0.05 mmol or 5 mol %) was
added and the mixture was stirred at room temperature. The
progress of the reaction was monitored by TLC. After the
completion of reaction catalyst was removed by filtration and
then reaction mixture was diluted with ethyl acetate and washed
with water. The organic layer was dried over anhydrous sodium
sulphate and concentrated under reduced pressure to give crude
product. Then crude product was purified by silica gel columm
chromatography using hexane:ethyl acetate as an eluent to
afford the desired compound in pure form.
3
+
+
1
r.t.
R
R
R
2
4
1
2
3
Scheme-II: Synthesis of β-amino carbonyl compounds using
Bi(NO3)3·5H2O as a catalyst at room temperature under solvent
free conditions
TABLE-1
EFFECT OF THE AMOUNT OF THE CATALYST
ON THE YIELD OF 1,5-BENZODIAZEPINES
AND β-AMINO CARBONYL COMPOUNDS
Yield (%)
Amount of
catalyst (mmol
or mol %)
General procedure for synthesis of β-amino carbonyl
compounds: To the mixture of acetophenone (1 mmol),
aldehyde (1 mmol) and aniline (1 mmol) catalyst Bi(NO3)3·5H2O
(0.1 mmol or 10 mol %) was added and the mixture was stirred
at room temperature until the completion of reaction as indi-
cated by TLC. The catalyst was removed by filtration. Then
the resulting mixture was washed with water. The crude
product was purified by recrystallization from ethanol to give
corresponding pure compound.
Entry
1, 5-
Benzodiazepines
β-Amino carbonyl
compounds
1
2
3
4
5
2
5
65
92
85
83
81
65
75
80
85
79
7
10
12
85
90
80
70
60
50
40
30
20
10
0
80
79
75
2,2,4-Trimethyl -2,3-dihydro-1H-1,5-benzodiazepines
(3a): m.p. 135-137 ºC, IR (KBr, νmax, cm-1): 3293.3, 1632.3,
1H NMR (400 MHz, CDCl3) δ, ppm (J, Hz): 1.34 (6H, s); 2.25
(2H, s); 2.36 (3H, s); 2.95 (1H, NH, br, s); 6.71-7.14 (4H, m).
1, 3-Diphenyl-3-(phenylamino) propan-1-one (4a): m.p.
142-143 ºC, IR (KBr, νmax, cm-1) : 3384.8, 2917.8, 1671,
1291.5. 1H NMR (400 MHz, CDCl3) δ: ppm (J, Hz): 357-3.58
(d, 2H), 5.01- 5.042 (m, 1H), 6.64-6.66 (d, 2H), 6.74 (t, 1H),
7.10-7.60 (m, 10H), 7.91-7.92 (d, 2H).
65
2
5
7
10
12
Mol % of catalyst
RESULTS AND DISCUSSION
Fig. 1. Effect of amount of catalyst on the yield of 1,5-benzodiazepines
In this paper we report a facile, efficient and practical
method for the synthesis of 1,5-benzodiazepines by conden-
sation of o-phenylenediamine with ketones and β-amino
carbonyl compounds by one pot three component reaction of
aromatic aldehydes, aromatic ketones and aromatic amines
using Bi(NO3)3·5H2O as catalyst (Schemes I and II).
Further the optimized amount of catalyst was screened by
taking o-phenylenediamine and acetone as model reactants.
Using less amount of catalyst i.e., 2 and 4 mol % resulted in
the decrease of yield and by increasing the amount of catalyst
up to 12 mol % did not improve the yield. However in the
absence of catalyst the reaction did not proceed. It was found
that reaction occurs in short time producing high yields of
products. Further it was screened that 5 mol % of catalyst is
sufficient for carrying out the synthesis of 1,5-benzodiazepines.
An increase in the amount of catalyst did not improve the yield.
To show the feasibility of reaction method the reaction
was explored by carrying out the reaction using various subs-
trates (Table-2) with optimized amount of catalyst at room
temperature under solvent free conditions. Both the acyclic
and cyclic ketones gave excellent yields of products. It was
observed that both primary and secondary ketones such as
methyl ethyl ketones and methyl iso-butyl ketones were reacted
and less hindered primary ketone is involved in cyclisation to
give the product. The products are formed successfully under
ambient condition within 10-30 min.
H
N
NH2
O
Bi(NO3)3.5H2O
r.t.
NH2
N
3
1
2
Scheme-I:Synthesis of 1,5-benzodiazepines using Bi(NO3)3·5H2O as a
catalyst at room temperature under solvent free conditions
Initially, the optimized reaction conditions were screened
by conducting the reaction with different catalyst amount at
room temperature for the preparation of 1,5-benzodiazepines
(Table-1, Fig. 1). At first stage, reaction was investigated with
o-phenylenediamine, acetone and Bi(NO3)3·5H2O (5 mol %)
under solvent free conditions at room temperature. The reaction
occurred in 15 min and product was obtained in 85 % yield.
The efficiency of the present method and catalytic activity
of catalyst was compared with the reported procedures and

Vol. 25, No. 12 (2013)
Bi(NO3)3·5H2O: A Catalyst for Synthesis of 1,5-Benzodiazepines and β-Amino Carbonyl Compounds 6547
TABLE-2
Bi(NO3)3·5H2OCATALYZED SYNTHESIS OF 1,5-BENZODIAZEPINES USING
o-PHENYLENEDIAMINE AND VARIOUS KETONES AT ROOM TEMPERATURE
S.
m.p. (ºC)
observed
m.p. (ºC)
reported
Diamine
No.
Ketone
Product
Time (min)
Yield (%)
H
NH
2
N
O
15
92
134-136
135-137
137-139
137-139
a
NH
N
2
H
N2H
N2H
N
O
b
15
25
80
79
N
N2H
N2H
H
O
N
c
117-119
118-120
N
H
N
N2H
N2H
O
O
14
83
87
135-138
134-136
137-139
138-139
d
N
H
N
N2H
N2H
5
e
N
H
N
N2H
N2H
O
25
90
110-111
107-109
f
N
85
catalysts. Condensation of o-phenylenediamine with acetone
afforded 96 % yield after 3 h at 50 ºC in hexane in the presence
of NbCl5 (5 mol %)34. Kaolin33 catalysed condensation of
o-phenylenediamine with acetone gave 90 % yield in
dichloroethane after 3 h. While in case of Sc(OTf)3 (5 mol
%)30, reaction proceeded in 3 h at room temperature afforded
96 % yield. The reaction in presence of InBr327 provided the
96 % yield in 0.5 h. Compared to above methods and catalysts
Bi(NO3)3·5H2O catalyzed condensation of o-phenylenediamine
with acetone gave 92 % yield in 15 min at room temperature
under solvent free conditions.
90
80
70
60
50
40
30
20
10
0
80
79
75
65
20
5
7
Mol % of catalyst
10
12
After the successful application of Bi(NO3)3·5H2O as
catalyst in the synthesis of 1,5-benzodiazepines, we tried to
explore its activity in synthesis of β-amino carbonyl compounds
using various aromatic aldehydes, aromatic ketones and
aromatic amines at room temperature under solvent free
conditions.
Fig. 2. Effect of amount of catalyst on the yield of β-amino carbonyl
compounds
increase in the yield of product with increase in amount of
catalyst. Maximum yield was obtained when the 10 mol % of
catalyst was used. Further increase of catalyst did not improve
the yield.
In this reaction, optimization of amount of catalyst was
also screened (Table-1, Fig. 2). The yield of the product was
poor with low amount of catalyst and there was gradual

6548 Rajput et al.
Asian J. Chem.
TABLE-3
Bi(NO3)3·5H2O CATALYZED SYNTHESIS OF β-AMINO CARBONYL COMPOUNDS USING AROMATIC KETONE,
SUBSTITUTED AROMATIC ALDEHYDES AND SUBSTITUTED AROMATIC AMINES AT ROOM TEMPERATURE
Entry
1
R1
R2
H
Product
4a
4b
4c
Time (min)
30
Yield (%)
85
m.p. (ºC) (observed)
142-144
180-182
168-170
119-121
158-160
–
Ref. m.p. (ºC) (reported)
H
H
143-144
2
4-NO2
4-Cl
60
61
184-186
3
H
45
78
170-171
4
H
4-OCH3
4-F
90
74
124-125
4d
4e
5
H
20
64
162-163
6
H
2-CH3
3-CH3
2-OCH3
2-Cl
360
30
Trace
76
–
4f
7
H
129–130
–
131-132
4g
4h
4i
8
H
300
120
180
105
25
Trace
43
–
9
H
112-114
101-103
142-145
155-156
145-146
–
–
10
11
12
13
15
16
17
18
19
H
2-NO2
H
48
–
4j
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-Cl
4-Cl
72
147–149
4k
4l
4-Cl
62
158-160
4-OCH3
2-Cl
10
62
–
4m
4o
4p
4q
4r
360
420
450
60
Trace
Trace
Trace
64
–
2-NO2
2-CH3
H
–
–
–
–
110-111
115-116
114-115
118-119
4-Cl
90
69
4s
A series of β-amino carbonyl compounds were prepared
from various aromatic aldehydes, aromatic ketones and
aromatic amines (Table-3). The scope of the reaction was
examined by reacting various substituted aldehydes and substi-
tuted amines. All the reactions proceeded well in the presence
of Bi(NO3)3·5H2O (10 mol %) at room temperature to give
corresponding products in moderate to good yields. It was
observed that the substituted aldehydes with electon-withdrawing
(-Cl) and electron-donating (-OCH3) groups gave good results.
Further it was seen that the substituted amines with both
electon-withdrawing and electron-donating groups at the meta
and para positions gave the product in good yields, but the
ortho substituted amines gave very low or trace amount of
yield.
ACKNOWLEDGEMENTS
The authors are thankful to SAIF (Panjab University,
Chandigarh for NMR and IR. One of the authors (G.K.) is thank-
ful to MHRD and NIT Jalandhar for giving the fellowship.
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Bi(NO3)3·5H2O: A Catalyst for Synthesis of 1,5-Benzodiazepines and β-Amino Carbonyl Compounds 6549
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