Three component mannich reaction and 1,5-benzodiazepine synthesis catalyzed by a tetranitrile-silver complex

Article abstract of DOI:10.2174/157017809787003188

This manuscript describes the first example of silver ion complex of a dendritic tetranitrile ligand catalyzed one-pot three component Mannich reaction and 1,5-benzodiazepine synthesis. The catalyst can be separated from the products by a change in the solvent. The catalyst is reusable.

Full text of DOI:10.2174/157017809787003188

Letters in Organic Chemistry, 2009, 6, 17-21
17
Three Component Mannich Reaction and 1,5-Benzodiazepine Synthesis
Catalyzed by a Tetranitrile-Silver Complex
Gopalakrishnapanicker Rajesh Krishnan, Radhakrishnan Sreerekha and Krishnapillai Sreekumar*
Department of Applied Chemistry, Cochin University of Science and Technology, Cochin-682022, Kerala, India
Received June 13, 2008: Revised August 22, 2008: Accepted August 22, 2008
Abstract: This manuscript describes the first example of silver ion complex of a dendritic tetranitrile ligand catalyzed
one-pot three component Mannich reaction and 1,5-benzodiazepine synthesis. The catalyst can be separated from the
products by a change in the solvent. The catalyst is reusable.
Keywords: Homogeneous catalysis, tetranitrile, silver complex, Mannich reaction, 2-aminoketones, 1,5 benzodiazepine.
INTRODUCTION
long reaction time, high temperature, use of expensive cata-
lysts, low yields and occurrence of side products. Search for
novel catalytic methods which eliminate these problems is
going on. An interesting example to mention is the use of
AgNO3 under solvent free conditions [11].
The search for novel catalysts, which show atom effi-
ciency and environmental friendliness, is continuing in aca-
demic and industrial laboratories due to the rising concern
over environmental issues and the need for more efficient
catalysts. Homogeneous catalysis using organometallic com-
plexes is advancing into the modern fine chemical and bulk
chemical industry [1]. In this paper we describe a novel ho-
mogeneous catalyst derived from silver complex of a tetrani-
trile ligand. Polydentate ligands have found extensive appli-
cation in molecular and crystal engineering [2]. Among the
polydentate ligands, polynitrile ligands have received par-
ticular attention due to their special property to co-ordinate
with silver ions. This property was exploited in the synthesis
of silver complexes having excellent properties and beautiful
topologies [3]. But catalysis using these polynitrile-silver
complexes is a less explored area.
The present paper reports the primary results of three
component Mannich reaction and 1,5-benzodiazepine syn-
thesis catalyzed by silver complex of a tetranitrile ligand. To
the best of our knowledge this is the first report of one pot
three component Mannich reaction catalyzed by a tetranitrile
silver complex. The present catalyst eliminates the require-
ment of pre-formed imines and enolates for obtaining good
results. This provides a more simplified process to obtain
Mannich product in high yield. Even though some inorganic
silver derivatives are used for 1,5-benzodiazepine synthesis
under solventless conditions, this is the first example of ben-
zodiazepine synthesis catalyzed by silver complexes under
homogeneous conditions. Thus the Ag complex is able to
catalyze two mechanistically distinct reactions of synthetic
importance under mild conditions. The pinpointing of such
“privileged” catalyst classes showing general superiority for
many reaction types is undoubtedly one of the most intrigu-
ing aspects and may have a considerable impact on the de-
velopment of new catalytic systems [12].Moreover the pre-
sent catalyst can be easily removed and recycled.
The synthetic utility of Mannich reaction is evident from
its application in the synthesis of many natural products and
biologically important compounds [4]. Recently the focus
has been shifted to catalyst assisted three component Man-
nich reaction because of the simplicity and atom economy of
the reaction [5, 6]. Snapper and Hoveyda [7] have exploited
catalytic properties of some silver complexes in Mannich
reactions of enol ethers and silylketene acetals with various
imines, while Asao [8] used AgOTf as the catalyst in Man-
nich and nitro Mannich reactions of pre-formed alkynylaryl
aldimines.
RESULTS AND DISCUSSION
The tetranitrile ligand used to prepare the catalyst was
propylenediaminetetrapropionitrile (1). The ligand was de-
rived from 1,3-diaminopropane and acrylonitrile according
to a standard procedure (Scheme 1) [13].
1,5-benzodiazepines are biologically important mole-
cules and are extensively used clinically as analgesic, hyp-
notic, sedative and antidepressive agents [9]. 1,5-benzo-
diazepines are generally synthesized by acid catalyzed con-
densation of o-phenylenediamines with ketones. A large
number of catalytic processes are reported for the synthesis
of benzodiazepines which include the use of various metal
salts, CAN, heteropolyacids, ionic liquids etc. [10]. However
many of these processes are associated with problems like
The complex (2) was prepared by stirring the ligand and
AgNO3 (1:2 ratio) in methanol. The formation of the com-
plex was indicated by the development of a reddish brown
color. On evaporation of the solvent, a brownish mass was
formed which in turn changed to black on exposure to light
and air. Even if the complex underwent blackening upon
exposure to light and air, there was no reduction in the cata-
lytic activity. UV-Vis-NIR spectra of the complex, ligand
and silver nitrate in methanol were compared. The spectrum
of the complex showed an additional band in the NIR region
*Address correspondence to this author at the Department of Applied
Chemistry, Cochin University of Science and Technology, Cochin-682022,
Kerala, India; Tel: +91-484-2862430 (Office, direct), +91-484-2575804
(indirect); Fax: +91-484-2577595; E-mail: ksk@cusat.ac.in
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Krishnan et al.
NC
NC
H2O
NH2
NH2
CN
4
N
N
NC
CN
1
Scheme 1. Synthesis of the ligand.
O
O
N
O
O
NC
CN
NC
NC
N
O
Ag
Ag
O
AgNO3
CH3OH
N
N
N
N
NC
CN
NC
CN
2
Scheme 2. Synthesis of the catalyst.
at 491 cm-1, which was assigned to be due to the formation
of Ag-N bond. FTIR spectral analysis revealed that the
stretching band due to the nitrile group underwent a shift
from their original values after complex formation and occu-
pied a higher value [14]. The efficiency of ligands carrying
nitrile groups towards complex formation with silver was
previously shown by many researchers [3]. The synthetic
scheme and tentative structure of the complex is shown in
Scheme 2. The structure of the complex was predicted ac-
cording to previous reports [3a, c].
in methanol, the reaction was performed in methanol and
after the reaction, the solvent was evaporated and the product
mixture was extracted by ethanol leaving the catalyst behind.
The general scheme of the reaction is shown in Scheme 3.
Table1.
Effect of the Concentration of the Catalyst on Reac-
tion
Enrty
Mol % of Catalyst
% Yield a
Mannich
Benzodiazepine
Reaction b
Synthesis c
A similar complex was previously reported with another
tetranitrile ligand [3a]. But the solubility of that was limited
and was soluble in DMSO only. The present complex is
soluble in methanol also but is insoluble in most other or-
ganic solvents including ethanol. This offers the possibility
of using the catalyst more fruitfully and easy separation of
the catalyst from the product mixture.
1
0
1
2
5
20
50
65
93
0
2
30
62
94
3
4
aIsolated yield.
bReaction conditions: 5mmol benzaldehyde, 5 mmol cyclohexanone, 5.1 mmol aniline,
5 mol% catalyst, 5 mL methanol.
Initially, the three component Mannich reaction between
benzaldehyde, aniline and cyclohexanone and the synthesis
of 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine from
acetone and o-phenylene diamine were performed in the
presence of various amounts of the catalyst as model reac-
tions. The results are presented in Table 1.
cReaction conditions: 1 mmol o-phenylene diamine, 2.5 mmol acetone, 5 mol%
catalyst, 5 mL methanol.
The feasibility of the catalyzed process was shown by us-
ing various substrates. The reaction procedure and charac-
terization data of selected products are given in the experi-
mental section. The results are presented in Table 2. Gener-
ally, all substrates gave good yields. Comparatively low
yield was observed with substrates carrying electron with-
drawing groups (Table 2, entry 5). When acetophenone was
used instead of cyclohexanone the yield of the product was
The yield of the Mannich product (3) was poor with low
catalyst loading and there was a gradual increase in the yield
of product with increase in the catalyst loading. Maximum
yield was obtained when the catalyst loading was 5 mol%
with respect to the aldehyde. Since the catalyst was soluble
R2
CHO
NH2
O
NH
O
5 mol% of catalyst
CH3OH, 30 oC
R4
R4
R1
R2
R3
R3
R1
3
Scheme 3. Three component Mannich reaction catalyzed by the silver complex.

Three Component Mannich Reaction and 1,5-Benzodiazepine
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
19
little lower and the reaction required longer time to get com-
pleted (Table 2, entry 6 & 7).
The catalyst was recycled after the completion of each set
of reactions. The catalyst showed no practical loss of effi-
ciency for three cycles under the given conditions for both
the reactions and the results of the recycling experiment is
summarized in Table 4.
Table 2. Three Component Mannich Reaction Catalyzed by
the Silver Complex
% Yield a,b
Table 4. Effect of Recycling on Catalysis
Entry
R1
R2
Ketone
Time h
1
2
3
4
5
6
7
H
4-OCH3
4-Cl
2-OH
H
H
H
C6H10O
C6H10O
4
4
93
91
90
94
85
90
87
Enrty
% Yield a
No. of recycling
steps
Mannich
Benzodiazepine
Reaction b
Synthesis c
H
C6H10O
6
H
C6H10O
6
1
1
2
3
4
93
93
92
89
94
93
93
87
NO2
H
C6H10O
8
2
H
C6H5COCH3
10
3
4-Cl
H
C6H5COCH3
10
aReaction conditions: 5mmol aldehyde, 5 mmol ketone, 5.1 mmol aniline, 5 mol%
4
catalyst, 5 mL methanol.
aIsolated yield.
bIsolated yield.
bReaction conditions: 5mmol benzaldehyde, 5 mmol cyclohexanone, 5.1 mmol aniline,
5 mL methanol.
The tetranitrile-Ag complex was used as a homogeneous
catalyst in the preparation of benzodiazepine derivatives (4)
from o-phenylene diamine and various ketones. Generally
benzodiazepine synthesis is carried out using solid catalysts
under solventless conditions. The present paper deals with
the synthesis of benzodiazepine in methanol which elimi-
nates problems associated with solventless synthesis. The
catalyst was highly efficient and the reaction was completed
within a very short period of time. But the reaction was slow
compared to the procedure using AgNO3 alone under solvent
free conditions reported by Kumar et al. [11]. As observed
from Table 1 only five mol percent of catalyst was required
for efficient conversion. After the completion of the reaction,
the catalyst was removed without any difficulty. For this, the
reaction medium i.e. methanol was removed under vacuum
and the product was extracted using ethyl acetate. The pure
product was isolated by column chromatography on silica.
The catalyst remained in the reaction vessel was used for
another cycle of reaction. The general scheme of the reaction
is shown in Scheme 4 and the results are summarized in Ta-
ble 3.
cReaction conditions: 1 mmol o-phenylene diamine, 2.5 mmol acetone, 5 mol% cata-
lyst 5 mL methanol.
CONCLUSION
In summary, a tetranitrile silver complex was prepared
and used as homogeneous catalyst for one pot three compo-
nent Mannich reaction and benzodiazepine synthesis from o-
phenylene diamine and ketones. The reactions proceeded
efficiently with good yields. The catalyst can be separated
from the product by changing the solvents. The catalyst is
reusable.
EXPERIMENTAL
Preparation of Propylenediaminetetrapropionitrile (1)
1,3 diaminopropane (5 mL, 59 mmol) was dissolved in
water (30 mL) in a round bottom flask. Acrylonitrile (19.7
mL, 297 mmol) was added to it with constant stirring at
room temperature. The exothermic reaction caused the tem-
o
perature to rise to 40 C. After this exothermic effect, the
R5
reaction mixture was transferred to an oil bath kept at 80 oC
and stirred at that temperature for 1 h to complete the reac-
tion. The excess of acrylonitrile was removed as a water
azeotrope by vacuum distillation in the rotavapour (16 mbar,
bottom temperature 40 oC). The oily material formed was
dissolved in 20 mL methanol. The product was obtained in
pure form by evaporating the solvent under vacuum. Yield
16.05 g, 95%. FTIR (KBr, ꢀmax (cm-1)): 2954, 2924, 2832,
2247, 1465, 1420, 1365, 1136, 759.
H
N
R6
R6
O
NH2
NH2
5 mol% of catalyst
CH3OH, 30 oC
R5
R6
N
R5
4
Scheme 4. Benzodiazepine synthesis catalyzed by the silver com-
plex.
Table 3. Benzodiazepine Synthesis Catalyzed by the Silver
Complex
Preparation of Propylenediaminetetranitrile-Silver Com-
plex (2)
Enrty
Ketone
Time h
% Yield a,b
The nitrile ligand (0.035 g, 0.125 mmol) was dissolved in
5 mL methanol in a two necked round bottom flask. N2 gas
was bubbled through the solution for half an hour. AgNO3
(0.042 g, 0.250 mmol) was added and stirred for 1 h. Initially
the reaction mixture was colorless. A light orange color
started developing after 10 minutes and it intensified to
maximum within one hour. On evaporating the solvent a
light brown solid was formed which turned black on expo-
1
2
3
4
CH3COCH3
C6H5COCH3
C6H5COC6H5
C6H10O
1
1
94
91
90
90
2.5
2
aReaction conditions: 1 mmol o-phenylene diamine, 2.5 mmol ketone, 5 mol% catalyst,
5 mL methanol.
bIsolated yield.

20
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Krishnan et al.
sure to air and light for some time. Anal. Calc. for
C15H22Ag2N8O4 C, 30.32; H, 3.73; N, 18.86; O, 10.77.
Found: C, 30.30; H, 3.69; N, 18.94; O, 10.74 FTIR (KBr,
ꢀmax (cm-1)): 2954, 2924, 2832, 2257, 1465, 1420, 1365,
1100, 835, 759, 723, 491.
2-Methyl-2, 4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine
(Table 3 Entry 2)
FTIR (KBr, ꢀmax (cm-1)): 3330, 1635; 1H NMR (CDCl3,
300MHz): ꢁ 1.80 (s, 3H), 2.95 (d, 1H, J=13.1 Hz), 3.16 (d,
1H, J=13.1 Hz), 3.44 (s, 1H), 6.53-7.02 (m, 3H), 7.16-7.34
(m, 7H), 7.55-7.65 (m, 4H).
General Procedure for Three-Component One Pot Man-
nich Reaction
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(10:1) as eluent. After the completion of the reaction the
solvent was removed by evaporation and the reaction mix-
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1H), 6.62-7.31 (m, 4H).

Three Component Mannich Reaction and 1,5-Benzodiazepine
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