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X.-Q. Li, L.-Z. Wang / Chinese Chemical Letters 25 (2014) 327–332
2
H
N
OC H
R
2
5
2
R
H N
2
NH
2
H
N
1
C
O
R
CH
S
3
CH
C
S
N
2
C OC H
2 5
1
O
N
H
O
R
OHC
CH
Fig. 1. Structures of benzimidazole.
3
CH
3
1
2
3
4
Scheme 1. One-pot synthesis of 1,5-benzodiazepine derivatives 4.
Table 1 shows that only a trace amount of the product was
obtained when the reaction was conducted in the absence of
catalyst even after 14 h. Conversely, all tested acid catalysts had
catalytic effects on the three-component condensation reaction
with the yields of the target product 4a also found to be high.
Under the same experimental conditions, we found that entry 2,
catalyzed by HOAc, can be completed within the shortest time, but
the yield of product 4a was not the highest. The catalyst PMA was
found to be the prominent catalyst and provided the highest yield
for the transformation (entry 4, 89%). Therefore, PMA was the most
effective catalyst in obtaining the yield of 1,5-benzodiazepine 4a.
Moreover, HPAs are economically attractive, environmentally
benign, possess very high Brønsted acidity, involve a mobile ionic
structure and absorb polar molecules easily in the bulk forming a
‘pseudo liquid phase’. As a result, both the surface protons and the
bulk protons of HPAs participate in their catalytic activity, which
significantly enhances the reaction rate, even at relatively low
temperatures [9]. Thus, PMA was selected for subsequent
experiments.
Accordingly, we developed an efficient, general, and convenient
protocol for the one-pot synthesis of a novel series of 1,5-
benzodiazepine derivatives containing thiophene and COOCH2CH3
groups. The reaction proceeded by a three-component condensation
of substituted thiophene aldehydes, o-phenylenediamine (o-PDA)
and ethyl acetoacetate utilizing phosphomolybdic acid (PMA) in
ethanol at 0 8C (Scheme 1). The advantages of the program are mild
reaction conditions (ethanol as a green solvent, simple ice-water
bath), and in the process, the absence of
g-selected products
produced, so the yields of -selected compounds are very high (85–
a
90%). This reaction also discussed the regioselectivity between the
thiophene aldehyde and ethyl acetoacetate when employing the
unsymmetrical o-PDA, and proposed the plausible formation
mechanism.
2. Experimental
We studied the influence of the solvent, catalyst, temperature,
and reaction time of the experiment to obtain the optimum
experimental conditions. Subsequently, the three-component
reaction of o-PDA 1 (R=H) (1 mmol), ethyl acetoacetate 2 (1 mmol),
and 2-thiophene aldehyde 3a (1 mmol) was conducted as the model
reaction to optimize the reaction condition. Since, the reaction
medium is one of the most important factors influencing any
process, several solvents including acetonitrile, dichloromethane,
chloroform, methanol, ethanol, benzene and toluene were tested.
The same high yield of the target product 4a can be obtained both by
using methanol and ethanol as a solvent. However, ethanol is
deemed to be the preferred solvent for this one-pot transformation
considering the requirements of green chemistry. Other solvents,
such as acetonitrile, dichloromethane, chloroform, benzene and
toluene, produced lower yields. Therefore, ethanol was selected as
the reaction solvent in this study. Among the existing methods, the
acid-catalyzed condensation of o-PDA and carbonyl complexes is
one of the most simple and direct approaches to the synthesis of 1,5-
benzodiazepine derivatives. Thus, some solid organic acids, like p-
TsOH, protic acids [e.g. acetic acid (HOAc)]; heteropolyacids (HPAs)
[e.g. silicotungstic acid (STA, H4SiW12O40) and PMA (H3PMo12O40)];
and Lewis acids [e.g. CeCl3Á7H2O, NiCl2Á6H2O and I2], were used to
determine the appropriate catalyst. A comparative study was then
conductedinthepresenceofthesematerialsascatalyst. Thesamples
were produced under conventional conditions at 0 8C in the
presenceofeachcatalyst. Thecorrespondingresultsaresummarized
in Table 1.
The reactions at different temperatures were then examined
to determine the effects on the reaction. Results showed that the
yield of the target product 4a was lower when the temperature
was higher, such as in refluxing ethanol conditions. Under
ethanol reflux in the three-component reaction system, it was
easier to form the isomer, ethyl 2-(4-(2-thiophenyl)-4,5-
dihydro-1H-benzo[b][1,4]diazepin-2(3H)-ylidene)acetate, which
was also reported in the document [8]. Conversely, the yield of
product 4a was higher when the temperature was lower, such as
in an ice-water bath (0 8C), even when the reaction time was
prolonged. We also conducted the reaction in an ice-salt bath
(<À10 8C) and found that the reaction time was the longest, but
the product yield was similar to the reaction in ice-water bath.
Thus, we conducted the reaction in an ice-water bath and the
reason was as follows.
The efficiency of the reaction is mainly affected by the amount
of catalyst and temperature. Several side reactions occur when the
reaction is changed either by adding excessive catalyst, or by
increasing the temperature. For instance, adding excessive catalyst
(>10 mmol%) or increasing the temperature (>0 8C) promotes the
formation of the by-product benzimidazole (Fig. 1). The structure
of this by-product was isolated and characterized by IR, 1H NMR
and elemental analysis. In our study, benzimidazole and the target
product (1,5-benzodiazepine 4) were found to be competitive
products, and benzimidazole was more stable than 1,5-benzodi-
azepine containing a seven membered ring. The high reaction
temperature and stronger acidic conditions promote the formation
of the benzimidazole by-product which reduced the yields of the
target products. Thus, we synthesized 1,5-benzodiazepine 4a using
PMA as catalyst in ethanol at 0 8C by a one-pot, three-component
condensation of 2-thiophene aldehyde, o-PDA and ethyl acetoa-
cetate.
Table 1
Screening of catalysts and optimization of reaction conditions.a
Entry
Catalystb
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
p-TsOH
HOAc
8
6.5
12
7
85
79
70
89
85
86
75
–
STA
Under the optimized conditions described above, the reactions
of substituted o-PDA 1, ethyl acetoacetate 2 and a group of
thiophene aldehydes 3a–3g were examined. In most cases, the
substrates smoothly underwent the one-pot reaction to afford the
corresponding products 4a–4u in good yields (Table 2, entries
1–21). As shown in Table 2, we synthesized 21 novel kinds of
compounds. The characterization data are listed in Supporting
information.
PMA
CeCl3Á7H2O
NiCl2Á6H2O
I2
10
10
7
Catalyst free
14
a
Solvent: EtOH, temperature: 0 8C.
10 mmol%.
b
c
Isolated yield.
Li, Xiao-Qing
