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Current Catalysis, 2013, 2, 000-000
1
Ultrasound Assisted One-Pot Synthesis of Some 1, 5-Benzodiazepine
Derivatives
Rupesh V. Chikhale1,* and Pramod B. Khedekar2
1
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur (MS) 440033, India
2
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Mahatma Jyotiba Fuley
Shaikshanik Parisar, Amravati Road, Nagpur– 440033, India
Abstract: A successful cyclocondensation reaction using silica gel as a green catalyst and ultrasound as green reaction
medium was carried out. Ten derivatives (I a-j) were synthesized of which eight 2, 2, 4-trisubstituted-2, 3-dihydro-1H-1,
5-benzodiazepine derivatives (I a-h) were prepared from variety of ketones. 2, 4-disubstituted-2, 3-dihydro-1H-1, 5benzodiazepine (I-ia) and (I-ib) were obtained by using ethyl acetoacetate, I-ib as a minor product resulted from the enolic form of ethyl acetoacetate while indicating that the keto form of 1, 3-β-dicarbonyls led to major product formation. Intermolecular imine-enamine type of cyclization was catalyzed by silica-gel acting as a Lewis acid.
Keywords: 1, 5-Benzodiazepine, Cyclocondensation, One-pot reaction, Silica gel catalyst, Ultrasound, Green catalyst.
1. INTRODUCTION
Benzodiazepines are bicyclic heterocyclic compounds
possessing various types of biological activities over N, Npositioned skeletal types [1]. Over the last two decades, benzodiazepines have widely been used therapeutically for their
ability to reduce anxiety, to act as tranquilizers and for their
anticonvulsant effects in epilepsy. Benzodiazepine such as
diazepam (a) was first launched in 1960s and since then is
widely being used as a drugs in therapy for treatment of
anxiety. Quazepam (b) was introduced in 1970s as potential
anticonvulsant drug with less overdose potential than other
benzodiazepines [2].
F
H3C
CI
F
O
N
N
CI
F
S
N
N
F
(a) Diazepam
(b) Quazepam
The traditional synthesis of 1, 5-benzodiazepine, reported
almost a century ago is associated with condensation of ophenylendiamine with aryl/alkyl ketones or α, β- unsaturated
carbonyl compound in presence of a catalyst. This synthesis
took not only longer reaction time but also afforded poor
yield.[3] Several attempts have been made to modify the reaction involving some solid surface and many other metal catalysts which are abundant in literature [4]. However, their
*Address correspondence to this author at the Department of Pharmaceutical
Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur (MS)
440033, India; Tel: +91 8983387871; Fax: ????????????;
E-mail: [email protected]
2211-5447/13 $58.00+.00
application poses some limitations like expensive chemicals,
corrosive nature of the acid catalyst. In addition to these
flaws, long refluxing period required by the traditional
method entailed high energy consumption leading to side
reaction and thereby tedious work-up procedure for product
isolation. Green reaction techniques like applying sonication
for synthesis of 1, 5-BDZ derivatives employing cheap and
inexpensive silica-gel as catalyst were undertaken in this
work (Scheme I), since the use of silica-gel as catalyst in
various types of cyclocondensation reactions is well documented [3].
The cyclocondensation reaction of o-phenylenediamine
with various ketones and α, β-dicarbonyl compounds in
presence of catalytic amount of silica gel gave the 1, 5benzodiazepine derivatives [1, 5-BDZ] in excellent yield
under sonication technique. This may be considered as first
application of one pot facile 1,5-benzodiazepine synthesis
under eco-friendly condition using a cheap, easily available
catalyst i.e. silica gel; which has not yet been reported earlier
as to our knowledge. Literature is abundant of similar types
of reactions for synthesis of 1,5-BDZ derivatives using many
reagents, which have been employed as catalyst for these
reactions viz: CdCl2 [5], [(L)proline]2Zn [6], molecular iodine [7], BF3-etherate[8], NaBH4 [9], Tungstophosphoric
acid[10], Yb(OTf)3 [11], Low Valent Titania [12],
Al2O3/P2O5[13], AcOH under microwave irradiation[14],
CeCl3-NaI-SiO2 [15], Polymer (PSS) supported Sulfoxide
/Ruthenate[16], ionic liquid medium [17], Polymer (PVP)
supported ferric chloride [18] and NBS [19]. However, majority of these reactions suffers from one or other drawbacks
such as expensive reagent, low to moderate yield, longer
reaction time leading to side reactions, tedious workup procedure for product isolation and environmental pollution.
Hence establishment of a solvent free alternate synthesis of
1, 5-BDZ derivatives using a cheap catalyst like silica-gel
(which could be filtered off from most of the solvents) was
of great importance. Silica gel or silicon dioxide is obtained
from sodium silicate; it presents high surface area and pos©2013 Bentham Science Publishers
2 Current Catalysis, 2013, Vol. 2, No. 2
Chikhale and Khedekar
O
NH2
+
NH2
O
R'
R
R'
H
N
Silica Gel
))))
R
N
I a-j
R'
R
R
Scheme I. Ultrasound assisted synthesis of 1, 5 Benzodiazepines (I a-j).
sesses the property to absorb moisture owing to its high surface area. It finds wide application as an absorbent of moisture, as stationary phase in chromatography and in various
desiccator apparatus. It is inert to many chemicals and can be
washed very easily [20].
The generality of this multicomponent cyclocondensation
reaction using a variety of ketones (acyclic, acylic or aromatic) or β-dicarbonyl compounds has been established and
the 1, 5-BDZ compound thus obtained has many potential
for further preparing a variety of other 1, 5-BDZ derivatives
as well as their fused ring systems such as astriazolo, oxazino, or furanobenzodiazepines [21].
In order to generalize the facile one pot three component
reaction to synthesize 1, 5-BDZ derivatives as shown in the
Scheme I; we subjected a variety of ketones e.g. acyclic,
cyclic and aromatic as well as 1,3-β-carbonyl compounds for
preparing 2,3-dihydro-1H or 3H-1, 5-benzodiazepine (1, 5BDZ) derivatives. The 1,5-benzodiazepine derivatives were
prepared by carrying out the reaction in presence of a mixture of two ketones with a view to study their reactivity and
subsequently analyzing the major product thus obtained by
comparison of their spectral data and melting points with
their respective authentic sample.
2. EXPERIMENTAL
All the chemicals used for experimental and analytical
purpose were purchased from Sigma-Aldrich and solvents
used were of AR grade obtained from SRL fine chemicals.
Melting point (mp) reported here (0C) were taken in Veego
melting point apparatus (Vmp-mp) and were uncorrected.
Thin layer chromatography (TLC) was carried out using silica gel (G-60). The solvent system used for compounds was
ethyl acetate: pet. ether (2:8). The spots were located using
either by the iodine vapor chamber or under the UV lamp.
High performance liquid chromatography (HPLC) was carried out using C18 column (250×4.6mm, 5µ), mobile phase
consisting of methanol: acetonitrile: water (30:20:50) at a
flow rate 1ml/min, with detection by UV detector at 242 nm
to determine Retention Time (RT). The λmax of the respective
synthesized compounds was found by using methanol as the
solvent on the 1700 Shimadzu UV-visible spectrophotometer
and their molar absorbity was calculated. IR spectra of the
synthesized compounds were obtained by preparing KBr
pellet, using Shimadzu 8400 FTIR spectrophotometer. 1 H
NMR studies were carried out on the Shimadzu FT-NMR
spectrophotometer (300 MHz).
2.1. General Procedure for Synthesis of 2, 2, 4trisubstituited 2, 3-dihydro-1H-1, 5-benzodiazepine Derivatives [1, 5-BDZ-Ia-h]
The respective aryl or alkyl substituted ketones (22
mmole) o-phenylendiamine (1.08 g, 10 mmole) and silica gel
(0.15g) were taken in a 50 ml iodine flask, mixed well by gentle shaking. The contents of the flask were then irradiated in a
sonicator for 30 min at room temperature. After completion of
the reaction as monitored by TLC [EtOAc: Pet. ether (9: 1)],
chloroform (15 ml) was added in the reaction mixture and
filtered to remove silica gel, which was washed with chloroform (3-5 ml x 2). The combined organic layer was washed
twice with water (2-5 ml) and dried over anhydrous Na2SO4.
The dried organic layer was concentrated under vacuo to get a
thick dark liquid; which on trituration with hexane gave the
crude product in around 90-95% yield. A portion of the crude
product on two or three recrystallization from alcohol gave the
pure product; whose mp remained underpressed in admixture
with an authentic sample. The each of the products (a-h) as
listed below was prepared by this procedure and was characterized by comparison of their mp and spectral [UV, IR,
1
HNMR] data with an authentic sample.
The authentic sample was prepared by carrying out identical reaction as above by refluxing the reaction mixture for
4-6 hr. in methanol as reported in literature and the pure
product was isolated by following usual procedure in about
80-86% yield.
2.1.1. Synthesis of 2, 2, 4-trimethyl-2, 3-dihydro-1H-1, 5benzodiazepine (Ia)
Acetone – (2ml), o-phenylenediamine (1.08 g), silica gel
(0.15g), Reaction time- 25 minutes. Practical yield-2.8 g.
(92%), mp- 136-138 0C, λmax (εmax)2- 260 (7436), Rf - 0.63,
RT-2.89. IR (KBr)- 3384, 3316 (NH stretch), 3039 (aromatic-CH stretch), 2918 (aliphatic-CH stretch), 1623 (isolated-C=C stretch) , 1591(isolated-C=C stretch), 1600-1465
(aromatic-C=C stretch), 759, 700 (aromatic -CH bend) cm-1.
1
H NMR- δ7.3 (s, 2H, aromatic), 7.1 (s, 2H, aromatic), 3.45
(s br, 1H, -NH, D2O exchange), 2.2 (s, 2H, -CH2), 1.5 (s, 3H,
-CH3), 0.9 (s, 3H, -CH3)
2.1.2. Synthesis of 2, 4-diethyl-2-methyl-2, 3-dihydro-1H-1,
5-benzodiazepine (Ib)
Ethyl methyl ketone- (2.5ml), o-phenylenediamine
(1.08g), silica gel (0.15g), Reaction time- 25 minutes, Practical yield-3.1 g. (87%), mp- 137-139 0C. λmax (εmax)2- 263
(9440), Rf - 0.52, RT-2.87, IR (KBr)- 3384, 3315 (NH
stretch), 3043 (aromatic-CH stretch), 2900 (aliphatic-CH
stretch), 1633 (isolated-C=C stretch) , 1585(isolated-C=C
stretch), 1600-1455 (aromatic-C=C stretch), 759, 720 (aromatic -CH bend) cm-1. 1H NMR- δ7.3 (s, 2H, aromatic), 7.2
(s, 2H, aromatic), 3.43 (s br, 1H, -NH, D2O exchange), 2.4
(s, 2H, -CH2), 1.4 (s, 3H, -CH3), 0.8 (s, 3H, -CH3)
2.1.3. Synthesis of 2-methyl-2, 4-diphenyl-2, 3-dihydro-1H1, 5-benzodiazepine (Ic)
Acetophenone- (2.7ml), o-phenylenediamine (1.08g), silica gel (0.15g), Reaction time-25 minutes, Practical yield-3.6
Ultrasound Assisted One-Pot Synthesis
g. (92%), mp- 137-139 0C. λmax (εmax)2- 265 (10255), Rf 0.72, RT-2.83, IR (KBr)- 3362, 33603362, 3360, 3029 (aromatic-CH
stretch),
2971(aliphatic-CH
stretch),
1650(isolated-C=C
stretch),
1600-1464(aromatic-C=C
stretch), 786, 754(aromatic -CH bend)cm-1. 1H NMR- δ7.3(
m, 5H, aromatic ), 7.1(m, 5H, aromatic), 6.8(m, 4H, aromatic), 3.85(s br, 1H, -NH, D2O exchange), 3.2(d, 2H, -CH2 )
2.9(d, 2H, -CH2), 0.9(s, 3H, -CH3)
2.1.4. Synthesis of 2,4-bis(4-chlorophenyl)-2-methyl-2,3dihydro-1H-1,5-benzodiazepine (Id)
4-chloroacetophenone- (3.2ml), o-phenylenediamine
(1.08g), silica gel (0.15g), Reaction time-30 minutes, Practical yield-3.8 g. (83%), mp- 160-163 0C. λmax (εmax)2- 260
(8540), Rf - 0.52, RT-2.83. IR (KBr)- 3342, 3216(NH
stretch), 3039(aromatic-CH stretch), 2921(aliphatic-CH
stretch), 1640 (isolated-C=C stretch), 1500-1464(aromaticC=C stretch), 831, 748 (aromatic -CH bend) cm-1. 1H NMRδ7.5 (m, 5H, aromatic), 7.3 (m, 5H, aromatic), 6.8 (m, 4H,
aromatic), 3.8 (s br, 1H, -NH, D2O exchange), 3.1 (d, 2H, CH2) 2.5 (d, 2H, -CH2), 0.9 (s, 3H, -CH3)
2.1.5. Synthesis 2,4-bis(4-methylphenyl)-2-methyl-2,3dihydro-1H-1,5-benzodiazepine (Ie)
4-methylacetophenone–(3.1ml);
o-phenylenediamine
(1.08g), silica gel (0.15g), Reaction time-30 minutes, Practical yield-3.85 g. (90%), mp- 141-145 0C, λmax (εmax)2- 262
(7038), Rf - 0.58, RT-1.42. IR(KBr)- 3242, 3115 (NH
stretch), 3040 (aromatic-CH stretch), 2975 (aliphatic-CH
stretch), 1650 (isolated-C=C stretch), 1600-1462 (aromaticC=C stretch), 786, 754 (aromatic -CH bend) cm-1. 1H NMRδ7.3 (m, 5H, aromatic), 7.1 (m, 5H, aromatic), 6.8 (m, 4H,
aromatic), 3.85 (s br, 1H, -NH, D2O exchange), 3.2 (d, 2H, CH2) 2.9 (d, 2H, -CH2), 0.9 (s, 3H, -CH3)
2.1.6. Synthesis 2,4-bis(4-hydroylphenyl)-2-methyl-2,3dihydro-1H-1,5-benzodiazepine (If)
4-hydroylaminoacetophenone–(2.8ml), o-phenylenediamine (1.08g), silica gel (0.15g). Reaction time- 30 minutes,
Practical yield- 3.75 g (89%), mp- 145-148 0C, λmax (εmax)2252 (9540), Rf - 0.58, RT- 1.42. IR (KBr)- 3242, 3116 (NH
stretch), 3039 (aromatic-CH stretch), 2971 (aliphatic-CH
stretch), 1650 (isolated-C=C stretch), 1600-1464 (aromaticC=C stretch), 786, 754 (aromatic -CH bend) cm-1. 1H NMRδ7.3 (m, 5H, aromatic), 7.1 (m, 5H, aromatic), 6.8 (m, 4H,
aromatic), 3.85 (s br, 1H, -NH, D2O exchange), 3.2 (d, 2H, CH2) 2.9 (d, 2H, -CH2), 0.9 (s, 3H, -CH3)
2.1.7. Synthesis of 10-Spirocyclopentane-1,2,3,9,10,10ahexahydro benzo[b] cyclopenta[e] [1,4]diazepine (Ig)
Cyclopentanone –(2.0ml), o-phenylenediamine (1.08g),
silica gel (0.15g). Reaction time- 25 minutes, Practical yield2.7 g (85%), mp- 121-124 0C. λmax (εmax)2- 261 (9235), Rf 0.42, RT- 2.83. IR (KBr)- 3356, 3267(NH stretch),
3039(aromatic-CH stretch), 2947(aliphatic-CH stretch),
2931(aliphatic-CH stretch), 1602(isolated-C=C stretch) ,
1600-1464(aromatic-C=C stretch) cm-1. 1H NMR- δ6.8 (m,
4H, aromatic), 3.85 (s br, 1H, -NH, D2O exchange), 1.6-1.8
(s, 2H, -CH2), 2.2 (s, 2H, -CH2), 1.6-1.8 (m, 8H, -CH2), 1.21.3 (m, 12H, -CH2), 1.34-1.3 (s, 2H, -CH2)
Current Catalysis, 2013, Vol. 2, No. 2
3
2.1.8. Synthesis of 10-Spirocyclohexane-2,3,4,10,11,11ahexahydro 1H-dibenzo [b,e] [1,4]diazepine (Ih)
Cyclohexanone – (2.1ml), o-phenylenediamine (1.08g),
silica gel (0.15g). Reaction time- 25 minutes, Practical yield2.71 g (86%). mp- 136-139 0C. λmax (εmax)2- 258 (9540), Rf 0.58, RT- 1.42, IR (KBr)- 3356, 3267(NH stretch),
3039(aromatic-CH stretch), 2947(aliphatic-CH stretch),
2931(aliphatic-CH stretch), 1602(isolated-C=C stretch) ,
1600-1464(aromatic-C=C stretch) cm-1. 1H NMR- δ6.8(m,
4H, aromatic), 3.85(s br, 1H, -NH, D2O exchange), 1.6-1.8(s,
2H, -CH2), 2.2(s, 2H, -CH2), 1.6-1.8(m, 8H, -CH2), 1.21.3(m, 12H, -CH2), 1.34-1.3(s, 2H, -CH2)
2.2. General Procedure for synthesis of 2, 4-disubstituted1H or-3H-1, 5-benzodiazpine derivatives[1,5-BDZ-I i-j]
R
R
O
NH2
+
NH2
N
N
O
))))
R
R'
&
Silica gel , r.t.
i) R=CH3, R'=OEt
j) R & R'=CH3
i-a
N
H
O
R
N
H
R'
i-b
N
N
j
R'
The respective α, β-unsaturated carbonyl compound
(12mmole), o-phenylendiamine (1.08g, 10mmole) and silica
gel (0.18g) were taken in the flask and mixed well. The contents of the flask were then irradiated in a sonicator for
35minuted at room temperature. After completion of the
reaction as monitored by TLC [EtOAc:pet.ether (9: 1)], chloroform (10ml) was added in the reaction mixture and was
filtered to remove silica gel, which was washed with chloroform (3-5ml x 2). The combined organic layer was washed
twice with water (2-5ml) and dried over anhydrous Na2SO4.
The dried organic layer was concentrated under vacuo to get
a thick dark liquid; which was triturated with hexane and
kept overnight in freezer to get the crude product (88-90%).
A portion of compound was recrystallized twice from
methanol to get the pure product, whose mp remained undepressed in admixture with an authentic sample (prepared
by reported method). The product thus prepared by this procedure was characterized by comparison of its mp and spectral [UV, IR, 1HNMR] data with an authentic sample.
On fractional crystallization, the major fraction obtained
was found to be i-a which was compared with an authentic
sample and was found to be same in all respects (spectral
data and mp). When the the pooled mother liquid was kept
overnight in freezer, some shining crystals melting at 120125oC were obtained, which on two more recrystallizations
from methanol melted at 112-15oC which was shown as ester
C=O peak at 1725 cm-1 (I.R) and δ 3.8 (1HNMR peak) and
was assigned i-b compound.
2.2.1. Synthesis of 4-methyl-1, 3-dihydro-1H-1,
benzodiazepine-2one and 2-ethoxy-4-methyl-1H-1,
benzodiazepine (Ii-a and Ii-b)
55-
Ethyl acetoacetate (1.5ml), o-phenylenediamine (1.08g),
silica gel (0.18g). Reaction time- 35 minutes. Practical yield2.1 g. (78%), i-a) mp- 140-145 and i-b) mp- 110-115 0C. λmax
(εmax)2- 260 (7436), Rf - 0.63, RT- a) 3.70, b) 2.87. IR (KBr)3033(aromatic-CH stretch), 2972(aliphatic-CH stretch),
4 Current Catalysis, 2013, Vol. 2, No. 2
Chikhale and Khedekar
3328(NH stretch), 1643(isolated-C=C stretch), 15501465(aromatic-C=C
stretch),
1388-1289(ester-C-0-C
stretch), 759, 700(aromatic -CH bend) cm-1. 1H NMR- δ 9.8(
s, 1H, NH), 7.1(m, 4H, aromatic), 4.2(d, 2H, 0CH2-), 2.8(s,
2H, -CH2), 1.9(s, 3H, -CH3), 1.2(m, 5H, -OCH2 CH3).
2.2.2. Synthesis of 2, 4-dimethyl 3H-1, 5-benzodiazepine
(Ij)
Acetyl acetone (1.3ml), o-phenylenediamine (1.08g), silica gel (0.15g). Reaction time- 30 minutes, Practical yield1.9 g (75%). mp- 183-185 0C. λmax (εmax)2- 263 (9440), Rf 0.52, RT-2.89. IR (KBr)- 3096(aromatic-CH stretch),
2971(aliphatic-CH stretch), 1631 (isolated-C=C stretch),
2939(aliphatic-CH
stretch),
1600-1464(aromatic-C=C
stretch), 786, 754(aromatic -CH bend)cm-1. 1H NMRδ7.35(s, 2H, aromatic), 7.25(s, 2H, aromatic), 2.85(s, 2H, CH2), 1.8(s, 3H, -CH3).
2.3. Synthesis of 1, 5-benzodiazepine (1, 5-BDZ) using
mixture of ketones and 1, 3-β- dicarbonyl compounds.
In order to evaluate the reactivity of the variety of ketones and 1, 3-dicarbonyl compound employed herein for
synthesis of 1, 5-BDZ derivatives; identical experiments as
described earlier were undertaken using a mixture of two
ketones or one ketone along with one 1, 3-dicarbonyl compound (2 equivalent each), and the major product obtained
(70-78% yield) was characterized by comparison of its mp
and spectral (IR, 1HNMR) data.
Four such experiments (I-IV) have been described below
by reaction scheme showing the major product isolated in
I). Synthesis of BDZ compound from Acetophenone and Acetone.
O
NH2
CH3
))) sillica gel
+
75%
NH2
N
N
H
CH3
II). Synthesis of BDZ compound from Acetone and Cyclohexane.
O
CH3
H3C
O
NH2
)))), silica gel
72%
+
NH2
CH3
N
N
H
CH3
CH3
III). Synthesis of BDZ compound from Acetophenone and
Cyclohexanone.
O
CH3
NH2
))) silico gel
+
NH2
O
N
73%
N
H
CH3
IV). Synthesis of BDZ compound from Acetone and Ethylacetoacetate.
O
NH2
+
NH2
CH3
CH3
CH3
N
CH3
)))), silico gel
O
O
75%
OC2H6
N
H
CH3
CH3
these reactions. The mixed mp of each of these products remained undepressed in admixture with their respective
authentic samples. No cross-over product could be isolated.
3. RESULTS AND DISCUSSION
Eight 2, 2, 4-trisubstituted-2, 3-dihydro-1H-1, 5benzodiazepine derivatives (Ia-h) were prepared by employing a variety of ketones, whereas 2, 4-disubstituted-2, 3dihydro-1H-1, 5-benzodiazepine (I-ia) and (I-ib) were obtained by the said cyclocondensation reaction using ethylacetoacetate. Hence it appeared that I-ib obtained as minor
product resulted from the enolic form of ethylacetoactate;
indicating that the keto form of 1, 3-β-dicarbonyl compound
is responsible for the major product formation.
This has also been supported in case of I-j wherein enolic
form of acetyl acetone has not reacted and therefore has no
role in the product formation. The reported cyclocondensation reaction for the synthesis of 2, 4-disubstituted-3H-1, 5benzodiazepine prepared by the described green methodology provides a very good percentage yield. All the compounds (1, 5-BDZ) have been characterized by their mp and
spectral (UV, IR, and1HNMR) data; which appeared satisfactory on comparison with their reported data. The homogeneity and purity of these compounds were checked by TLC
solvent system [ethyl acetate: Pet. ether (1:9)] and HPLC (C18 column (250×4.6mm, 5µ), mobile phase consisting of
methanol: acetonitrile: water (30:20:50) at a flow rate
1ml/min, detection by UV detector at 242 nm) and were
found satisfactory. The authentic samples of 1, 5-BDZ series
(Ia-j) were also prepared by conventional procedure as reported in literature for determining mixed mp in admixture
with the samples prepared by the neat reaction technology
reported herein. The mixed mp of each of the said compounds (Ia-j) was found to remain undepressed in admixture
with their respective authentic sample and thus providing
unequivocal support to the assigned structure. The homogeneity and identity of these 1, 5-BDZ derivatives were also
checked through TLC solvent system [ethyl acetate: pet.
ether (1:9)] and were found satisfactory. In order to evaluate
the reactivity of the different ketones used in this project; the
cycloaddition reaction was carried out employing mixture of
two ketones e.g. acetone and acetophenone (each 2 equivalent) and the major product isolated from the reaction was
found to be 1, 5-BDZ-Ia; and neither 1, 5-BDZ-Ib nor any
cross-over product was obtained indicating that aromatic
ketone appeared to be more reactive than acyclic ketone. On
carrying out identical cycloaddition reactions with mixture
of cyclic ketones with acetophenone or acetone; the order of
reactivity on the major product isolated appeared is based to
be as follows: aromatic > acyclic > cyclic. It has also been
Ultrasound Assisted One-Pot Synthesis
Current Catalysis, 2013, Vol. 2, No. 2
noted that the reaction does not proceed in absence of silicagel, and therefore it acts as a catalyst.
[6]
[7]
4. CONCLUSION
In the present study a successful cyclocondensation reaction using silica gel as a green catalyst and ultrasound as
green reaction medium was carried out. Ten derivatives (I aj) were synthesized of which eight 2, 2, 4-trisubstituted-2, 3dihydro-1H-1, 5-benzodiazepine derivatives (I a-h) were
prepared from variety of ketones. It was observed that in
case of 2, 4-disubstituted-2, 3-dihydro-1H-1, 5benzodiazepine, two products (I-ia) and (I-ib) were obtained
by using ethyl acetoacetate, compound (I-ib) was obtained
as a minor product which has resulted from the enolic form
of ethyl acetoacetate which indicates that the keto form of 1,
3-β-dicarbonyls substrates leads to major product formation.
Intermolecular imine-enamine type of cyclization was catalyzed by silica-gel acting as a Lewis acid giving compounds
in good percentage yield.
CONTRIBUTION OF AUTHORS
Both authors have contributed equally to the work.
[8]
[9]
[10]
[11]
[12]
[13]
[14]
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of interest.
[15]
ACKNOWLEDGMENTS
RVC is thankful to Council of Scientific and industrial
Research (CSIR) New Delhi, India for providing financial
support in form of SRF: 09/128/0080/2011/EMR-I. PBK
acknowledges financial support by University Grants Commission (UGC) New Delhi, India in form of Major Research
Project 41-744/2012 (SR).
[16]
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Revised: February 02, 2013
Accepted: February 11, 2013