Microwave-assisted aqueous reactions: An efficient route to benzodiazepines

Article abstract of DOI:10.1002/jhet.1988

Microwave-assisted three-component reaction has been established for the synthesis of benzodiazepines. This reaction promoted by HOAc was conducted by using readily available and inexpensive starting materials in water under microwave irradiation. The pre

Full text of DOI:10.1002/jhet.1988

Month 2014
Microwave-Assisted Aqueous Reactions: An Efficient
Route to Benzodiazepines
b
a
a
a
*
*
Xiao-Tong Zhu, Jia-Yan Liu, Bo Jiang, and Shu-Jiang Tu
aSchool of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, Jiangsu 221116, People’s
Republic of China
bSchool of Basic Education Sciences, Xuzhou Medical College, Jiangsu 221000, People’s Republic of China
*
E-mail: jiangchem@jsnu.edu.cn (or) laotu@jsnu.edu.cn
Received October 12, 2012
DOI 10.1002/jhet.1988
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Microwave-assisted three-component reaction has been established for the synthesis of benzodiazepines.
This reaction promoted by HOAc was conducted by using readily available and inexpensive starting materials
in water under microwave irradiation. The present green synthesis shows fascinating characteristics such as
the use of water as the reaction solution, concise one-pot conditions, short reaction periods, easy purification,
and reduced waste production without the use of any strong acids or metal promoters.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
complicated purifications and saving both solvents and
reagents [10]. Therefore, MCRs combined with aqueous
media can dramatically reduce the generation of chemical
waste and the cost of the starting materials, shorten
reaction periods, and giving higher overall chemical yields
[12].
In connection with our development of MCRs [12–15],
here we would like to report another efficient approach to
benzodiazepine that are of chemical and potentially
biological importance (Scheme 1). This reaction was
conducted by reacting simple 5,5-dimethylcyclohexane-
1,3-dione, benzene-1,2-diamines, and aldehydes in water
under microwave irradiation without strong acid or any
metal catalyst.
Heterocycles containing benzodiazepine rings belong to
important building blocks because of their remarkable
depressant activity in central nervous system [1] and their
being one of the most widely prescribed class of psychotro-
pics [1h–i]. In addition, some of these compounds also
possess bioactivities on analgesic, antidepressive, and
hypnotic activities [2], and act as neuromedin B receptor
antagonists [3a] as well as HCV NS5B polymerase inhibitors
[3b]. The remarkable applications of these compounds
prompted us to synthesize them. A survey of the literature
shows that the majority of the strategies involve either
multistep sequences [3–5] or anhydrous conditions [3a],
lengthy reaction times [3,4], and laborious workup [3b,4],
and is environmentally unfriendly and uneconomical
[3,4]. The continuing search for new efficient approaches
to benzodiazepine remains a challenge in terms of mild
reaction conditions, operational simplicity, economic viabil-
ity, and eco-friendliness [6].
At the same time, to be a safe, readily available, and
environmentally friendly solvent, water has also been
recognized as an effective reaction medium with unique
properties and possibilities for many organic reactions
[7]. There has been growing recognition that water is an
attractive medium with unique properties and possibilities
for many organic reactions [8]. Multicomponent reactions
(MCRs), especially those performed in aqueous medium,
have enjoyed a very high prestige in the present synthesis
of chemically and biologically important compounds on
account of their environmentally friendly atom economy
and green characteristics [9–11]. These reactions provide
a wide range of possibilities for the efficient construction
of a variety of invaluable products in a single operation
instead of a tedious multistep synthesis, thus avoiding
RESULTS AND DISCUSSION
We began this study by subjecting 5,5-dimethy-
lcyclohexane-1,3-dione and benzene-1,2-diamine to react
with aromatic aldehydes in HOAc or other solvents includ-
ing EtOH, glycol, DMF, and water in the presence of
1.0 equiv of HOAc under microwave irradiation for
condition optimization. As shown in Table 1, the use of
glacial acetic acid (HOAc) as a solvent gave product 4a in
89% chemical yield at 100ꢀC under microwave irradiation.
Other organic solvents, such as DMF, EtOH, and glycol
Scheme 1. Three-component synthesis of benzodiazepines.
Copyright © 2014 HeteroCorporation

X.-T. Zhu, J.-Y. Liu, B. Jiang, and S.-J. Tu
Vol 000
Table 1
Optimizations of reaction conditions under microwave.
Entry
Promoter
Solvent
Temperature (ꢀC)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
—
HOAc
EtOH
Glycol
DMF
Water
—
100
100
100
100
100
100
80
12
12
12
8
10
10
15
10
89
79
81
75
87
83
72
86
HOAc (1.0 equiv)
HOAc (1.0 equiv)
HOAc (1.0 equiv)
HOAc (1.0 equiv)
HOAc (1.0 equiv)
HOAc (1.0 equiv)
HOAc (1.0 equiv)
Water
Water
120
gave yields of 75–81% at the same temperature promoted
by 1.0 equiv of HOAc (entries 2–4), whereas water can
achieve a slightly higher yield (87%) when the reaction
promoted by 1.0 equiv of HOAc was performed at
100 ꢀC for 10 min under microwave irradiation (entry 5).
The same reaction promoted by 1.0 equiv of HOAc was
carried out at 100 ꢀC under solvent-free conditions, pro-
viding slightly lower yield of 4a (83%) (entry 6). Water
as a good absorber for microwave energy is selected as a
reaction solvent in view of its relatively environmentally
friendly characteristics [16].
To further optimize the reaction temperature, the identical
reaction was carried out at different temperatures ranging
from 80 ꢀC to 120 ꢀC. We found that the yield of product
4a was improved and the reaction time was shortened as
the reaction temperature was increased to 100 ꢀC from
80 ꢀC (entry 7). The similar outcome was obtained as the
temperature was further increased to 120ꢀC (entry 8).
We then investigated the substrate scope of this synthe-
sis by subjecting a series of aromatic aldehydes 3b–m to
the reactions with 1 and 2a under the optimal condition.
As shown in Table 2, various readily available aromatic
Table 2
The synthesis of compounds 4 under microwave irradiation.a
Entry
4
Ar
R
Time (min)
Yieldb (%)
mp (ꢀC)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4-ClC6H4 (3a)
3,4-Cl2C6H3 (3b)
4-BrC6H4 (3c)
4-FC6H4 (3d)
4-NO2C6H4 (3e)
C6H5 (3f)
4-CH3C6H4 (3g)
4-CH3OC6H4 (3h)
3,4-(CH3O)2C6H3 (3i)
2,3-(CH3O)2C6H3 (3j)
3,4,5-(CH3O)3C6H2 (3k)
4-N(CH3)2C6H4 (3l)
2-Thienyl (3m)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
H (2b)
10
15
16
18
12
20
20
22
22
23
24
24
18
14
18
20
22
87
89
92
87
92
84
87
85
84
79
74
76
79
85
87
84
79
236–237 (239–240) [5]
138–141
245–246 (241–242) [5]
236–237 (237–239) [5]
271–272 (274–275) [5]
254–256 (251–252) [5]
232–233
194–196 (203–205) [5]
128–129
236–239
129–131
221–222 (228–230) [5]
240–241
2-CNC6H4 (3n)
223–225
146–148
223–225
130–132
4-CH3C6H4 (3g)
2,3-(CH3O)2C6H3 (3j)
3,4,5-(CH3O)3C6H2 (3k)
H (2b)
H (2b)
H (2b)
aConditions: the synthesis of products 4, HOAc (1.0 equiv), water (1.0 mL), 100ꢀC, microwave heating.
bIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Microwave-Assisted Aqueous Reactions: An Efficient Route to Benzodiazepines
aldehydes bearing either electron-withdrawing or electron-
donating functional groups, such as nitro, chloro, bromo,
or methyl, were all found to be suitable for the reaction
(Table 2, entries 1–13). And after careful analysis, we also
observed the delicate electronic effects: aromatic aldehydes
with electron-withdrawing groups reacted with a rapid
speed, whereas electron-rich groups decreased the reactivity,
requiring longer reaction times. Moreover, the reaction of
thiophene-2-carbaldehyde with 1 and 2a was finished within
18min to give thienyl-substituted benzodiazepines 4m in
79% yield under this standard condition.
In summary, a green and high-efficient approach to
benzodiazepine derivatives has been developed by
performing the reaction in one-pot fashion in water under
microwave irradiation without any metal catalyst. The
reactions showed broad substrates of using readily avail-
able and inexpensive starting materials of cyclohexane-
1,3-dione, benzene-1,2-diamines, and aromatic aldehydes.
Particularly, this green synthesis shows several attractive
characteristics such as the use of water as the reaction
media, simple conditions, short reaction periods, easy
work-up, and straightforwardness of the procedure.
In a further investigation, the scope of the methodology
was studied; cyclohexane-1,3-dione was employed
instead of 5,5-dimethylcyclohexane-1,3-dione to react
with benzene-1,2-diamines and aromatic aldehydes. The
reactions occurred rapidly to give the desired products
4n–4q in 79–87% yields (Scheme 2).
EXPERIMENTAL
Microwave irradiation was carried out with Initiator from
Biotage Company, Sweden. Melting points were determined
in open capillaries and were uncorrected. IR spectra were
taken on an FTIR Tensor 27 spectrometer (Bruker Company,
In general, the benzodiazepine of types 4 with molecular
versatility and multisubstitutions indicated the efficiency of
the three-component one-pot reaction. Furthermore, the
functional groups on the framework and the flexible place-
ment of the latent functionalities in these products make them
extremely versatile intermediates in further synthetic transfor-
mations. The reaction occurred at a very fast speed with all
cases finished within 10–24 min. The structures of products
4 have been unambiguously determined by NMR analysis.
On the basis of all the aforementioned results, a plausible
mechanism for the reaction was described in Scheme 3. The
reaction underwent initial nucleophilic addition and subse-
quent dehydration to generate intermediate A. Then, the
intermediate A was condensed with aromatic aldehydes to
give the intermediate B, which is then converted into the
final product 4 through intramolecular [6 + 1]cyclization.
This type of reaction mechanism is well presented [5,6].
Ettlingen, Germany) in KBr pellets and reported in cmÀ1
.
1H NMR spectra were measured on a Bruker DPX 400 MHz
spectrometer (Bruker Company, Ettlingen, Germany) in
DMSO-d6. The exact mass measurements were obtained by
high-resolution mass instrument (Bruker Company, Ettlingen,
Germany) (GCT TOF instrument).
General procedure for the synthesis of compounds 4. In a
10-mL reaction vial, a benzene-1,2-diamines 1 (1 mmol), a
5,5-dimethylcyclohexane-1,3-dione or cyclohexane-1,3-dione
2 (1 mmol), HOAc (1 mmol), and water (1 mL) were mixed
and stirred within 20 min at room temperature. And then, an
aromatic aldehyde 3 (1 mmol) was added into the mixture
and capped. The system was subjected to microwave
irradiation at 100ꢀC, for a given time. Upon completion,
monitored by TLC, the reaction mixture was cooled to room
temperature and filtered to give the crude product, which
was further washed by 50% EtOH to give pure product 4.
The analytical data of new products are as follows.
11-(3,4-Dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-
dibenzo[b,e][1,4]diazepin-1-one (4b). IR (KBr, n, cmÀ1): 3321,
1
Scheme 2. Three-component synthesis of benzodiazepines.
3253, 2957, 2359, 1589; H NMR (DMSO-d6) (d, ppm): 8.40 (d,
J= 8.4 Hz, 1H, ArH), 7.32(d, J= 1.6 Hz, 1H, ArH), 7.03–7.00 (m,
1H, ArH), 6.97–6.95 (m, 1H, ArH), 6.69–6.60 (m, 2H, ArH),
6.56–6.54 (m, 1H, ArH), 6.27 (d, J= 6.0 Hz, 1H, NH), 5.67 (d,
J= 6.0 Hz, 1H, CH), 2.60 (s, 2H, CH2), 2.20 (d, J=16.0Hz,
1H, CH2), 2.12 (d, J = 16.0 Hz, 1H, CH2), 1.08 (s, 3H, CH3),
1.03(s, 3H, CH3); HRMS (ESI): m/z Calcd for
C21H20Cl2N2NaO, 409.0846 [M + Na]+; Found: 409.0862.
3,3-Dimethyl-11-p-tolyl-2,3,4,5,10,11-hexahydro-dibenzo[b,e]
Scheme 3. Mechanism hypothesis for forming 4.
[1,4]diazepin-1-one (4g). IR (KBr, n, cmÀ1): 3305, 2964, 2357,
1584, 1539; 1H NMR (DMSO-d6) (d, ppm): 8.74(s, 1H, NH),
6.99–6.97(m, 2H, ArH), 6.92–6.90(m, 2H, ArH), 6.62–6.51 (m,
3H, ArH), 6.15(d, J = 6.0 Hz, 1H, NH), 5.67 (d, J = 5.6 Hz, 1H,
CH ), 2.58 (s, 2H, CH2), 2.20 (d, J = 16.0 Hz, 1H, CH2), 2.08 (d,
J = 16.0 Hz, 1H, CH2), 2.14 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.03
(s, 3H, CH3); HRMS (ESI): m/z Calcd for C22H24N2NaO,
355.1780 [M+ Na]+; Found: 355.1792.
11-(3,4-Dimethoxy-phenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-
dibenzo[b,e][1,4]diazepin-1-one (4i).
IR (KBr, n, cmÀ1): 3529,
3284, 2359, 1538; 1H NMR (DMSO-d6) (d, ppm): 8.73(s, 1H,
NH), 6.90(d, 1H, J= 8.0 Hz, ArH), 6.84 (d, J= 2.0 Hz, 1H, ArH),
6.64–6.59 (m, 2H, ArH), 6.58–6.54 (m, 2H, ArH), 6.50–6.47 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

X.-T. Zhu, J.-Y. Liu, B. Jiang, and S.-J. Tu
Vol 000
1H, ArH), 6.13 (d, J= 6.0 Hz, 1H, NH), 5.63 (d, J= 5.6 Hz, 1H,
CH ), 3.60 (s, 6H, OCH3), 2.60 (d, J= 16.0 Hz, 1H, CH2), 2.54
(d, J= 16.0 Hz, 1H, CH2), 2.22 (d, J= 16.0 Hz, 1H, CH2), 2.08
(d, J= 16.0 Hz, 1H, CH2), 1.08 (s, 3H, CH3), 1.05 (s, 3H, CH3);
HRMS (ESI): m/z Calcd for C23H26N2NaO, 401.1835 [M + Na]+;
(m, 2H, CH2), 2.28–2.12 (m, 2H, CH2), 1.97–1.88 (m, 2H,
CH2); HRMS (ESI): m/z Calcd for C21H22N2NaO3, 373.1522
[M + Na]+; Found: 373.1531.
11-(3,4,5-Trimethoxy-phenyl)-2,3,4,5,10,11-hexahydrodibenzo
[b,e][1,4]diazepin-1-one (4q). IR (KBr, n, cmÀ1): 3543, 3263,
1
3064, 2939, 1592, 1531; H NMR (DMSO-d6) (d, ppm): 8.79 (s,
Found: 401.1852.
11-(2,3-Dimethoxy-phenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-
1H, NH), 6.91 (d, J = 8.0 Hz, 1H, ArH), 6.66–6.56 (m, 3H,
ArH), 6.40 (s, 2H, ArH), 6.17 (d, J = 6.0 Hz, 1H, NH), 5.65 (d,
J = 6.0 Hz, 1H, CH), 3.59 (s, 6H, OCH3), 3.52 (s, 3H, OCH3),
2.78–2.63 (m, 2H, CH2), 2.33–2.21 (m, 2H, CH2), 2.02–1.85
(m, 2H, CH2); HRMS (ESI): m/z Calcd for C22H24N2NaO4,
403.1628 [M+ Na]+; Found: 403.1644.
dibenzo[b,e][1,4]diazepin-1-one (4j).
IR (KBr, n, cmÀ1): 3296,
2953, 2358, 1601, 1537; 1H NMR (DMSO-d6) (d, ppm): 8.86 (s, 1H,
NH), 6.99–6.97 (m, 1H, ArH), 6.75–6.73 (m, 1H, ArH), 6.67–6.55
(m, 3H, ArH), 6.44–6.42 (m, 1H, ArH), 6.24–6.22 (m, 1H, ArH),
5.99 (d, J= 5.6 Hz, 1H, NH), 5.24 (d, J= 5.6 Hz, 1H, CH), 3.94
(s, 3H, OCH3), 3.74 (s, 3H, OCH3), 2.66 (d, J= 16.0 Hz, 1H, CH2),
2.58 (d, J= 16.0 Hz, 1H, CH2), 2.19 (d, J= 16.0 Hz, 1H, CH2), 2.03
(d, J= 16.4 Hz, 1H, CH2), 1.09 (s, 3H, CH3), 1.02(s, 3H, CH3);
HRMS (ESI): m/z Calcd for C23H26N2NaO, 401.1835 [M + Na]+;
Acknowledgments. We are grateful for the financial support from
the National Science Foundation of China (21072163, 21232004,
21272095, and 21102124), PAPD of Jiangsu Higher Education
Institutions, the NSF of Jiangsu Education Committee
(11KJB150016), Jiangsu Science and Technology Support
Program (No. BE2011045), the Qing Lan Project (12QLG006),
Doctoral Research Foundation of Xuzhou Normal University
(XZNU, No. 10XLR20), and Science and Technology
Foundation of Xuzhou (No. XJ09096).
Found: 401.1850.
11-(3,4,5-Trimethoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-
dibenzo[b,e][1,4]diazepin-1-one (4k). IR (KBr, n, cmÀ1): 3555,
1
3306, 2956, 2361, 1587; H NMR (DMSO-d6) (d, ppm): 8.78
(s, 1H, NH), 6.93 (d, 1H, J = 8.0 Hz, ArH), 6.66–6.57 (m, 3H,
ArH), 6.42(s, 2H, ArH), 6.14 (d, J = 5.6 Hz, 1H, NH), 5.64 (d,
J = 6.0 Hz, 1H, CH ), 3.59 (s, 6H, OCH3), 3.53 (s, 3H, OCH3),
2.64 (d, J = 16.0 Hz, 1H, CH2), 2.54 (d, J = 16.0 Hz, 1H, CH2),
2.25 (d, J = 16.4 Hz, 1H, CH2), 2.09 (d, J = 16.4 Hz, 1H, CH2),
1.09 (s, 3H, CH3), 1.06 (s, 3H, CH3); HRMS (ESI): m/z Calcd
REFERENCES AND NOTES
for C24H28N2NaO4, 431.1941 [M + Na]+; Found: 431.1958.
11-(2-Thienyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-dibenzo
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[b,e][1,4]diazepin-1-one (4m). IR (KBr, n, cmÀ1): 3308, 3240,
1
2949, 1584,1530; H NMR (DMSO-d6) (d, ppm): 8.80 (s, 1H,
NH), 7.12 (d, J = 5.2 Hz, 1H, ArH), 6.94 (d, J = 7.6 Hz, 1H,
ArH), 6.77–6.75 (m, 1H, ArH), 6.70–6.60 (m, 4H, ArH), 6.25 (d,
J = 6.0 Hz, 1H, NH), 5.91 (d, J = 5.6 Hz, 1H, CH ), 2.60 (d,
J = 16.4 Hz, 1H, CH2), 2.50 (d, J = 16.4 Hz, 1H, CH2), 2.23 (d,
J = 16.0 Hz, 1H, CH2), 2.09 (d, J = 16.0 Hz, 1H, CH2), 1.08(s,
3H, CH3), 1.05(s, 3H, CH3); HRMS (ESI): m/z Calcd for
C19H20N2NaOS, 347.1189 [M + Na]+; Found: 347.1199.
2-(1-Oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-
11-yl)-benzonitrile (4n). IR (KBr, n, cmÀ1): 3387, 3294, 3078,
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1
2954, 2220, 1583; H NMR (DMSO-d6) (d, ppm): 9.10 (s, 1H,
NH), 7.70 (d, J = 7.2 Hz, 1H, ArH), 7.32–7.29 (m, 1H, ArH),
7.24–7.20 (m, 2H, ArH), 7.07 (d, J = 7.6 Hz, 1H, ArH), 6.86 (d,
J = 8.0 Hz, 1H, ArH), 6.72–6.68(m, 1H, ArH), 6.65–6.61 (m,
1H, ArH), 6.52 (d, J = 7.6 Hz, 1H, ArH), 5.95 (d, J = 6.0 Hz, 1H,
NH), 5.85 (d, J = 6.0 Hz, 1H, CH), 2.81–2.68 (m, 2H, CH2),
2.29–2.10 (m, 2H, CH2), 1.96–1.89 (m, 2H, CH2); HRMS (ESI):
m/z Calcd for C20H17N3NaO, 338.1263 [M + Na]+; Found:
338.1274.
11-p-Tolyl-2,3,4,5,10,11-hexahydrodibenzo[b,e][1,4] diazepin-
1-one (4o).
IR (KBr, n, cmÀ1): 3304, 3067, 2945, 2361,
1
1599; H NMR (DMSO-d6) (d, ppm): 8.74(s, 1H, NH), 6.98–
6.96 (m, 2H, ArH), 6.90–6.87(m, 3H, ArH), 6.61–6.52 (m, 3H,
ArH),6.19(d, J = 6.4 Hz, 1H, NH), 5.67 (d, J = 6.0 Hz, 1H, CH),
2.75–2.62 (m, 2H, CH2), 2.29–2.19 (m, 2H, CH2), 2.13 (s, 3H,
CH3) , 1.99–1.88 (m, 2H, CH2); HRMS (ESI): m/z Calcd for
C20H20N2NaO, 327.1467 [M + Na]+; Found: 327.1484.
11-(2,3-Dimethoxy-phenyl)-2,3,4,5,10,11-hexahydrodibenzo
[b,e][1,4]diazepin-1-one (4p). IR (KBr, n, cmÀ1): 3349, 3299,
3240, 3149, 1600, 1535; 1H NMR (DMSO-d6) (d, ppm): 8.88 (s,
1H, NH), 6.97–6.95 (m, 1H, ArH), 6.75–6.72 (m, 1H, ArH),
6.66–6.54 (m, 3H, ArH), 6.43–6.41 (m, 1H, ArH), 6.24–6.22
(m, 1H, ArH), 5.97 (d, J = 5.6 Hz, 1H, NH), 5.22 ( d, J = 6 Hz,
1H, CH ), 3.93 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 2.80–2.66
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet