An efficient three-component tandem reaction leading to pentacyclic isoindole-fused benzo[b,e][1,4]diazepines in water

Article abstract of DOI:10.1246/cl.2011.834

An efficient methodology for the synthesis of highly functionalized pentacyclic isoindole-fused benzo[b,e][1,4]- diazepine derivatives from readily available common reactants in water has been developed. The tandem reaction resulted in efficient assembly

Full text of DOI:10.1246/cl.2011.834

doi:10.1246/cl.2011.834
834
Published on the web July 16, 2011
An Efficient Three-component Tandem Reaction Leading
to Pentacyclic Isoindole-fused Benzo[b,e][1,4]diazepines in Water
Shu-Liang Wang, Chuang Cheng, Fei-Yue Wu, Jing Li, Bo Jiang,* and Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Xuzhou Normal University, Xuzhou 211116, P. R. China
(Received May 2, 2011; CL-110370; E-mail: jiangchem@xznu.edu.cn, laotu@xznu.edu.cn)
R1
An efficient methodology for the synthesis of highly
functionalized pentacyclic isoindole-fused benzo[b,e][1,4]-
R1
diazepine derivatives from readily available common reactants
in water has been developed. The tandem reaction resulted in
efficient assembly of two new rings and four · bonds including
three C-N bonds in a one-pot operation.
R1
O
0.1 equiv
HOAc
Water
O
O
R1
COOH
O
H2N
H2N
R2
R2
N
R2
R2
+
+
MW
N
H
CHO
1
2
3
4
The search for efficient approaches to chemical and
potentially biological products, containing C-N bonds and
bridgehead nitrogen moieties, from common starting materials
has become an important issue in modern organic synthesis.1
In this regard, multicomponent domino reactions, particularly
those performed in aqueous media, have become increasingly
useful tools for the synthesis of natural products and their
building blocks1f,2 due to their atom economy and green
chemistry characteristics. Those processes can avoid time-
consuming protection-deprotection, and tedious workup as well
as purifications in multistep reactions. In addition, these
reactions often proceed with excellent chemo- and regioselecti-
vies.3
Scheme 1.
Table 1. Optimization of reaction conditions for 4a
Entry
HOAc/equiv
T/°C
Time/min
Yield/%
1
2
3
4
5
6
7
0
100
100
100
100
120
150
160
15
15
15
15
15
15
15
21
40
40
41
68
85
84
0.1
0.2
0.3
0.1
0.1
0.1
On the other hand, heterocycles containing bridgehead
nitrogen moieties constitute an important class of natural and
unnatural products and many of them exhibit useful biological
activities.4 For example, 1,4-diazepine containing heterocycles
has been proven to control cell proliferative disorders, partic-
ularly oncological disorders,5 and to be useful in the prevention
or treatment of several other diseases.6 In addition, benzo-
diazepine derivatives show remarkable depressant activity in the
central nervous system7 and HCV NS5B polymerase inhibitors.8
Orlov and co-workers reported the synthesis of benzodiazepines
via three-component reaction of 5,5-dimethylcyclohexane-1,3-
dione with benzene-1,2-diamine and aromatic aldehydes.9 These
products were also obtained by reacting 4-(2-aminophenyl-
amino)furan-2(5H)-one with aldehydes in organic media.10
However, to the best of our knowledge, the synthesis of
pentacyclic isoindole-fused benzo[b,e][1,4]diazepines contain-
ing bridgehead nitrogen moieties using o-formylbenzoic acid in
water has not been reported so far.
During our continuous efforts on the development of
multicomponent domino reactions for the construction of useful
heterocyclic compounds,11 herein, we would like to report a
green three-component tandem approach to pentacyclic iso-
indole-fused benzo[b,e][1,4]diazepine derivatives (Scheme 1).
This reaction was achieved by reacting 2-formylbenzoic acids,
1,2-diamines, and 1,3-dicarbonyl compounds as starting materi-
als in water under microwave irradiation without the use of any
strong acids or metal catalysts.
ation.12 We thus started performing the reaction of 2-formyl-
benzoic acid (1a) with benzene-1,2-diamine (2a), and furan-
2,4(3H,5H)-dione (3a) in the presence of 0.1 equiv of various
acids, such as HOAc, p-toluenesulfonic acid (TsOH), and
trifluoroacetic acid (TFA) as a Brønsted acid catalyst at 100 °C.
Although the isoindole-fused benzo[b,e][1,4]diazepines 4a
can be generated in the presence of all of these acids, only
HOAc resulted in a good yield of 40%. In fact, a poor yield
(21%) product 4a was observed in the absence of HOAc. We
next carefully examined the use of different amounts of HOAc
and reaction temperatures. As revealed in Table 1, no significant
improvement in chemical yields was observed even when more
than 0.1 equiv of HOAc was used (Table 1, Entries 3 and 4).
Interestingly, performing the reaction in the presence of a
catalytic amount of HOAc (10 mol %) under microwave irra-
diation resulted in a higher yield of 85%. The reaction
was furnished within 15 min at 150 °C in a sealed vessel
(Entry 6).
With this result in hand, the scope of the methodology was
investigated under the above optimized conditions. As shown in
Table 2, the reaction of 2-formylbenzoic acids, 1,2-diamines,
and furan-2,4(3H,5H)-dione in water provided a series of new
pentacyclic isoindole-fused benzo[b,e][1,4]diazepine 4a-4h in
81-88% yields within a short period (15-24 min). It is worth
noting that there has not been a literature precedent for the
synthesis of highly functionalized pentacyclic isoindole-fused
benzo[b,e][1,4]diazepine yet.
Water is usually among the first choices for MW-assisted
reactions due to its efficient absorbance of microwave irradi-
Chem. Lett. 2011, 40, 834-836
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

835
Table 2. The synthesis of isoindazole-fused benzodiazepine
needs simple filtration since the products directly precipitate
out after the reaction is finished or when its mixtures are diluted
with cold water; (3) readily available starting materials of
2-formylbenzoic acids, 1,2-diamines, and cyclic-1,3-dicarbonyl
compounds; (4) high atom-economy and bond-forming econo-
my. Moreover, the two C=O bonds were cleaved and up to two
new rings and four new · bonds including three C-N bonds
were formed. The novelty of the present tandem reaction is
shown by the fact that multiple chemical bond breaking and
forming were simultaneously achieved in an intermolecular
manner and in a one-pot operation.
In summary, a new tandem process has been established
for the construction of pentacyclic isoindole-fused benzo-
[b,e][1,4]diazepines that are of potential chemical and biomed-
ical importance. The tandem reaction was conducted in aqueous
solution with microwave irradiation using readily available and
inexpensive starting materials. The reactions proceed very fast
(within 12-24 min) in good to excellent chemical yields without
tedious workup and isolations.
413,14
OMe
OMe
OMe
O
OMe
O
O
O
O
O
O
O
N
N
N
N
O
O
O
O
Me
Me
Me
Me
N
N
N
N
H
H
H
H
4a
4b
4c
4d
15 min, 85 %
18 min, 83 %
OMe
20 min, 88 %
24 min, 86 %
MeO
OMe
OMe
O
N
O
N
O
N
O
O
N
O
O
O
O
Cl
O
N
H
O
O
Cl
N
H
N
H
N
H
Cl
Cl
4e
4f
4g
4h
20 min, 81 %
OMe
18 min, 84 %
18 min, 82 %
18 min, 83 %
OMe
OMe
OMe
O
O
O
O
O
O
O
N
O
N
N
N
Me
Me
Me
Me
N
H
N
H
N
H
N
H
4j
4i
4k
4l
We are grateful for financial support from the NSFC
(Nos. 21072163, 21002083, and B020103), Sci. Foundation
in Interdisciplinary Major Res. Project of XZNU
(No. 09XKXK01), PAPD of Jiangsu Higher Education Institu-
tions, and Doctoral Research Foundation of XZNU
(No. 10XLR20).
13 min, 82 %
15 min, 84 %
12 min, 82 %
13 min, 80 %
OMe
OMe
O
O
O
O
O
O
O
O
N
N
N
N
Me
Me
Ph
Ph
N
H
N
H
N
H
Cl
N
H
4m
4n
4o
4p
Cl
18 min, 80 %
14 min, 82 %
16 min, 85 %
20 min, 81 %
References and Notes
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COOH
NH2
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O
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O
H2N
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O
O
-H2O
N
-H2O
O
H
A
B
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N
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Scheme 2.
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3
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of furan-2,4(3H,5H)-dione (3a) with benzene-1,2-diamine (2a)
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Chem. Lett. 2011, 40, 834-836
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

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13 Experimental section: In a 10-mL reaction vial, benzene-
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(1 mmol), acetic acid (0.1 mmol), and water (2 mL) were
mixed and then stirring for 8 min. Subsequently, 2-formyl-
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time. Upon completion, monitored by TLC, the reaction
mixture was cooled to room temperature, filtered to give the
crude product, which was further washed with 50% EtOH
to give pure product. 4bH-Benzo[2,3]furo[3¤,4¤:5,6][1,4]-
diazepino[7,1-a]isoindole-5,14(7H,8H)-dione (4a) Mp:
286-289 °C; IR (KBr): 3277, 3220, 3147, 3108, 1734,
8
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¹1
1023, 766, 757, 743, 708, 696 cm
;
1H NMR (400 MHz,
DMSO-d6): ¤ 9.99 (s, 1H, NH), 8.41 (d, J = 8.0 Hz, 1H,
ArH), 7.78 (d, J = 7.6 Hz, 1H, ArH), 7.70-7.66 (m, 1H,
ArH), 7.59-7.55 (m, 1H, ArH), 7.40-7.34 (m, 2H, ArH),
7.21-7.14 (m, 2H, ArH), 5.74 (s, 1H, CH), 4.83 (d, J =
15.2 Hz, 1H, CH2), 4.78 (d, J = 15.2 Hz, 1H, CH2); HRMS
(ESI) m/z: [M ¹ H+] calcd for C18H11N2O3: 303.0764;
found: 303.0761.
14 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2011, 40, 834-836
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/