Multicomponent synthesis of poly-substituted benzo[a]pyrano-[2, 3-c]phenazine derivatives under microwave heating

Article abstract of DOI:10.1021/co1000376

A new one-pot two-step tandem synthesis of highly functionalized benzo[a]pyrano[2, 3-c]phenazine derivatives via microwave-assisted multicomponent reactions of 2-hydroxynaphthalene-1, 4-dione, diamines, aldehydes, and malononitrile is reported. The procedures are facile, avoiding time-consuming and costly syntheses, tedious workup, and purifications of precursors, as well as protection/deprotection of functional groups. The method is expected to find application in the combinatorial synthesis of biologically active compounds, since phenazine and chromene motifs have a broad spectrum of biological activities.

Full text of DOI:10.1021/co1000376

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Multicomponent Synthesis of Poly-Substituted Benzo[a]pyrano-
[2,3-c]phenazine Derivatives under Microwave Heating
Shu-Liang Wang, Fei-Yue Wu, Chuang Cheng, Ge Zhang, Yin-Ping Liu, Bo Jiang,* Feng Shi, and
Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou, 221116, P. R. China
S Supporting Information
b
ABSTRACT: A new one-pot two-step tandem synthesis of highly
functionalized benzo[a]pyrano[2,3-c]phenazine derivatives via mi-
crowave-assisted multicomponent reactions of 2-hydroxynaphtha-
lene-1,4-dione, diamines, aldehydes, and malononitrile is reported.
The procedures are facile, avoiding time-consuming and costly
syntheses, tedious workup, and purifications of precursors, as well
as protection/deprotection of functional groups. The method is
expected to find application in the combinatorial synthesis of biologi-
cally active compounds, since phenazine and chromene motifs have a
broad spectrum of biological activities.
KEYWORDS: 2-hydroxynaphthalene-1,4-dione, tandem synthesis,
benzo[a]pyrano[2,3-c]phenazine, microwave heating, multicompo-
nent reactions
’ INTRODUCTION
synthesis of benzo[a]pyrano[2,3-c]phenazine derivatives, requir-
ing harsh conditions, long reaction times, and providing a narrow
substrate scope.16 We therefore sought to develop a facile and
versatile method for the combinatorial synthesis of benzo[a]-
pyrano[2,3-c]phenazine library for biological screening.
Diversity-oriented synthesis (DOS) is a useful tool at the
interface of the fields of organic synthesis and chemical biology.1
At the heart of DOS are the synthetic means needed for the
generation of collections of functionally and regiochemically
diverse small molecules, particularly those possessing skeletons
resembling those found in natural products or drug-like molecules.2
An efficient method for generating these collections of molecules
is by turns multicomponent reactions (MCRs) with subsequent
transformations that further increase molecular complexity and
diversity, requiring a minimum of time, labor, cost, and waste
production.3 Therefore, the design of novel MCRs for the synthesis
of diverse groups of compounds, especially the ones that are
biologically active, have commanded great attention.4
Phenazines (I) are present in natural and synthetic products
showing a variety of biological functions, including antimalarial,5
trypanocidal,6 fungicidal,7 and antiplatelet8 activities. By virtue of
their DNA intercalating ability, they exhibit antitumor activity in
leukemia and solid tumors. For example, some benzophenazines
(II) are dual inhibitors of topoisomerase I and II, two key enzymes
that affect the topology of DNA at different points in the cell cycle.9
In addition, chromenes (III) as an important class of compounds,
widely present in plants, including edible vegetables and fruits10
also exhibit remarkable effects as pharmaceuticals,11 including
antifungal12 and antimicrobial activity.13 While phenazines14 and
chromenes15 have attracted great attention, compounds incorpo-
rating both phenazine and chromene motifs (IIII) have seldom been
described. In 2005, Perez-Sacau and co-workers reported a two-step
As part of our continuing interest in the development of
new synthetic methods in heterocyclic compounds17 and
Received: October 15, 2010
Revised:
December 1, 2010
Published: January 10, 2011
r
2011 American Chemical Society
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|

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RESEARCH ARTICLE
naphthoquinone-based multicomponent reactions,18 in this pa-
per we would like to report new sequence of a four-component
reaction for the synthesis of poly substituted benzo[a]pyrano-
[2,3-c]phenazines. This reaction was achieved by reacting simple
2-hydroxynaphthalene-1,4-dione, diamines (Figure 1), aldehydes
(Figure 2), and malononitrile under microwave irradiation (MWI
in the absence of strong acids, metal catalysts or promoters
(Scheme 1).
The one-pot four-component reactions were examined under
different reaction temperatures, with results summarized in Table 1.
The yield of product 5{1,1,1,4} was found to increase and the
reaction time decrease as the temperature was raised from 90 to
120 °C (Table 1, entries 1-4). No significant improvement in
yield was obtained past that point, so 120 °C was chosen as the
reaction temperature for all further studies.
Scheme 2. Synthesis of Benzo[a]pyrano[2,3-c]phenazine
Derivatives 5{1,1,1,4}
’ RESULTS AND DISCUSSION
We began this study by subjecting 2-hydroxynaphthalene-1,
4-dione, benzene-1,2-diamine, and 4-chlorobenzaldehyde to
reactions with malononitrile in HOAc under microwave irradiation
(Scheme 2). Unfortunately, complex mixtures were observed. To
minimize the formation of byproducts, the 2-hydroxynaphtha-
lene-1,4-dione and benzene-1,2-diamine were first stirred at
room temperature for 5 min, and orange solid was observed.
Next, 4-chlorobenzaldehyde and malononitrile were added and
the mixture was heated under microwave irradiation for 15 min at
90 °C. The desired product was obtained as a yellow solid in 67%
yield. This two-step procedure allows the one-pot four-compo-
nent reaction to be controlled, avoiding the separation of
intermediates, as well as time-consuming and costly purifica-
tion processes.
Table 1. Temperature Optimization for the Synthesis of
5{1,1,1,4} under Microwave Irradiation
entry
temp/°C
time/min
yield (%)
1
2
3
4
5
6
90
100
110
120
130
140
15
15
13
10
8
67
71
79
89
84
81
Figure 1. Aromatic diamine components 2{1-3}.
7
Figure 2. Aromatic aldehyde components 3{1-15}.
Scheme 1. One-Pot Two-Step Tandem Synthesis of Benzo[a]pyrano[2,3-c]phenazine Derivatives
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Using these optimized conditions, the reaction scope was
evaluated by using different diamines and aldehydes (Figure 2).
Commercially available aromatic aldehydes bearing either elec-
tron-withdrawing or electron-donating functional groups, such
as chloro (3{1}, 3{2}), fluoro (3{4}), bromo (3{3}), nitro
(3{5}, 3{6}, 3{11}), methyl (3{8}), methoxy (3{9}, 3{10},
3{12}, 3{13}), or dimethylamino (3{14}) were all found to be
suitable for the reaction with 2-hydroxynaphthalene-1,4-dione 1
benzene-1,2-diamine (2{1}) and malononitrile 4 to obtain
benzo[a]pyrano[2,3-c]phenazines in very good yields of 85-92%
under microwave heating (Table 2, entries 1-13). Even sub-
strate (3{15}), which contains a 2-thienyl group, was effectively
incorporated to give the 1-thienylsubstituted benzo[a]pyrano-
[2,3-c]phenazine 5{1,1,15,4} with 87% yield (Table 2, entry 14).
We also utilized 4,5-dichlorobenzene-1,2-diamine (2{2}) and
4,5-dimethylbenzene-1,2-diamine (2{3}) instead of benzene-
1,2-diamine (2{1}) to afford the corresponding benzo[a]pyrano-
[2,3-c]phenazines within 10-14 min in very good yields
(81-86%) and excellent regioselectivities (Table 2, entries
15-26). Given the large number of commercially available
aldehydes, and the easy access to diamine, the present method
should be applicable to the synthesis of libraries with high func-
tional group diversity. We expect this method to find application
in the field of combinatorial chemistry, diversity-oriented synthe-
sis and drug discovery.
Table 2. Synthesis of Poly-Substituted Benzo[a]pyrano[2,3-c]-
phenazine Derivatives 5
entry
product
time/min
yield/%
Similar to our previous four-component reaction process,17
the present reaction also showed the following attractive char-
acteristics: (1) fast reaction rates which enable the reaction to be
completed within 7-14min, (2) convenient workup requiringonly
simple filtration since the products precipitate upon dilution of
the reaction mixtures with acetone, and (3) readily available start-
ing materials of 2-hydroxynaphthalene-1,4-dione, diamines, alde-
hydes, and malononitrile. Moreover, regioselectivity is completely
1
5{1,1,1,4}
5{1,1,3,4}
5{1,1,4,4}
5{1,1,5,4}
5{1,1,6,4}
5{1,1,7,4}
5{1,1,8,4}
5{1,1,9,4}
5{1,1,10,4}
5{1,1,11,4}
5{1,1,12,4}
5{1,1,13,4}
5{1,1,14,4}
5{1,1,15,4}
5{1,2,2,4}
5{1,2,4,4}
5{1,2,5,4}
5{1,2,6,4}
5{1,2,11,4}
5{1,2,13,4}
5{1,3,2,4}
5{1,3,3,4}
5{1,3,5,4}
5{1,3,6,4}
5{1,3,7,4}
5{1,3,13,4}
10
8
89
87
90
92
91
90
88
86
86
87
86
85
88
87
81
84
84
83
86
86
81
85
82
82
83
86
2
3
9
4
9
5
8
6
10
10
11
9
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
10
7
9
10
10
11
11
10
10
12
12
13
12
12
12
13
14
Figure 3. X-ray crystallographic structure of compound 5{1,1,5,4}.
Scheme 3. Possible Mechanism for the Formations of Benzo[a]pyrano[2,3-c]phenazine Derivatives 5
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RESEARCH ARTICLE
controlled by changing the charging sequence in this one-pot
reaction.
Structural assignments of these new compounds have been
characterized by IR, 1H NMR, and 13C NMR spectroscopy and
HRMS (ESI) (see the Supporting Information). Additionally,
the structures of 5{1,1,5,4} was confirmed by single-crystal X-ray
diffraction analysis (Figure 3).
125.6, 124.9, 122.2, 120.0, 113.3, 57.6. IR (KBr, ν, cm-1): 3452,
3309, 3174, 2189, 1660, 1624, 1593, 1488, 1473, 1402, 1385,
1350, 1329, 1291, 1268, 1163, 1105, 1088, 1053, 1015, 848, 759,
749. HRMS (ESI): m/z calcd C26H16ClN4O, 435.1008; found
435.1019.
’ ASSOCIATED CONTENT
A reaction mechanism consistent with the above results is shown
in Scheme 3. The formation of 5 is expected to proceed via initial
condensation of 2-hydroxynaphthalene-1,4-dione 1 and diamine
2 to afford benzo[a]phenazin-5-ol 6, which undergoes in situ
Michael addition with 2-benzylidenemalononitrile 7, formed
from condensation of aldehydes with malononitrile, to yield
intermediate 8, which is then cyclized to afford the products 5.
S
Supporting Information. Representative experimental
b
procedures and characterizations and crystallographic data for
5{1,1,5,4}.This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel.: 0086-516-83500065. Fax: 0086-516-83500065. E-mail:
laotu@xznu.edu.cn (B.J.) or jxznu07@126.com (S.-J.T).
’ CONCLUSION
We have demonstrated a simple and efficient route for the
one-pot, four-component synthesis of benzo[a]pyrano[2,3-c]-
phenazines and in good to excellent yields. Particularly valuable
features of this method included operational simplicity, increased
safety for small-scale high-speed synthesis, and broad substrate
scope. Furthermore, this series of benzo[a]pyrano[2,3-c]phenazine
derivatives may provide new class of biologically active com-
pounds for biomedical screening, which is in progress in our
laboratory.
Author Contributions
B. Jiang and S.-J. Tu conceived and designed the experiments,
S. L. Wang and F.-Y Wu performed the experiments, and co-
wrote the manuscript. B. Jiang, revised the manuscript. C. Cheng
and G. Zhang co-wrote the Supporting Information. Y.-P. Liu
and F. Shi checked the references.
Funding Sources
We are grateful for financial support from the National Science
Foundation of China (Nos. 21072163 and 21002083), Sci. Foun-
dation in Interdisciplinary Major Res. Project of XZNU (No.
09XKXK01), Qing Lan Project (08QLT001) of Jiangsu Educa-
tion Committee and Graduate Foundation of XZNU (No.
2010YLB031).
’ EXPERIMENTAL SECTION
General. Microwave irradiation was carried out with Biotage
microwave synthesizer from Personal Chemistry, Sweden. Melt-
ing points were determined in open capillaries and were un-
corrected. IR spectra were taken on a FT-IR-Tensor 27 spec-
trometer in KBr pellets and reported in cm-1. 1H NMR spectra
were measured on a Bruker DPX 400 MHz spectrometer in
DMSO-d6 (100 MHz, 13C NMR) with chemical shift (δ) given
in ppm relative to TMS as internal standard. ESI-MS was deter-
mined by using the LCQ Advantage HPLC/MS instrument
(Thermo Finnigan). HRMS (ESI) was determined by using
microTOF-Q HRMS/MS instrument (BRUKER). X-ray crys-
tallographic analysis was performed with a Siemens SMART
CCD and a Siemens P4 diffractometer.
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