Theophylline as the catalyst for the diastereoselective synthesis of: Trans -1,2-dihydrobenzo [a] furo[2,3- c] phenazines in water

Article abstract of DOI:10.1039/c6ra18750a

An efficient, convenient and environmentally benign procedure for the synthesis of novel 1,2-dihydrobenzo[a]furo[2,3-c]phenazine derivatives with high diastereoselectivity has been developed by a domino four-component condensation reaction between 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamines, aromatic aldehyde and pyridinium ylide in the presence of a catalytic amount of theophylline as an expedient, eco-friendly and reusable solid base catalyst in water. This one-pot process produces biologically and pharmacologically significant heterocycles with the formation of five new bonds (two C-C, two CN and one C-O) and two new rings in a single operation and this effective green process provides considerable advantages such as: operational simplicity, short reaction time, high yields, reusability of catalyst, absence of any tedious workup or purification and avoiding hazardous reagents/solvents.

Full text of DOI:10.1039/c6ra18750a

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Theophylline as the catalyst for the
diastereoselective synthesis of trans-1,2-
Cite this: RSC Adv., 2016, 6, 84326
dihydrobenzo[a]furo[2,3-c]phenazines in water†
a
b
Afshin Yazdani-Elah-Abadi, Razieh Mohebat and Malek-Taher Maghsoodlouc
*
An efficient, convenient and environmentally benign procedure for the synthesis of novel 1,2-dihydrobenzo
[a]furo[2,3-c]phenazine derivatives with high diastereoselectivity has been developed by a domino four-
component condensation reaction between 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamines,
aromatic aldehyde and pyridinium ylide in the presence of a catalytic amount of theophylline as an
expedient, eco-friendly and reusable solid base catalyst in water. This one-pot process produces
biologically and pharmacologically significant heterocycles with the formation of five new bonds (two
C–C, two C]N and one C–O) and two new rings in a single operation and this effective green process
provides considerable advantages such as: operational simplicity, short reaction time, high yields,
reusability of catalyst, absence of any tedious workup or purification and avoiding hazardous reagents/
solvents.
Received 23rd July 2016
Accepted 29th August 2016
DOI: 10.1039/c6ra18750a
www.rsc.org/advances
strategy in the synthesis of complex heterocyclic molecules due
to their advantages such as higher productivity, simple proce-
Introduction
dures, facile execution, lower costs, minimum waste production,
structural diversity, shorter reaction times, environmentally
friendliness, atom economy, high selectivity and allowing
savings of both solvents and reagents.20–23
Synthesis of polyfunctionalized heterocyclic compounds from
readily available starting materials in a cost and time effective
manner has received signicant attention in organic synthesis
due to their extensive applications in pharmaceuticals, agro-
chemicals and in materials sciences.1–3 Benzofurans and its
derivatives are an important category of oxygen-containing
heterocycles owing to their wide existence in natural products,
pharmaceuticals and biologically active compounds.4–6 Benzo-
furans are integral to a large number of drug substances with
activities including antifungal, antibacterial, antidepressant,
and antitubercular properties.7,8 Some benzofurans serve as
versatile synthetic intermediates that can synthesize various
useful compounds.9–11 Also, phenazine based compounds are
nitrogen-containing heterocycles that are the main core of many
natural and synthetic organic materials.12–14 Phenazines are
showing a variety of biological functions, including fungicidal,15
trypanocidal,16 antimalarial,17 antiplatelet18 and antitumour19
activities.
Furthermore, replacement of hazardous solvents with envi-
ronmentally benign solvents24–26 is one of the major focus areas
of green chemistry. Organic solvents used in most of the
synthetic organic chemistry evaporate into the atmosphere with
destructive effects on the environment and ozone layer.27 Thus,
aqueous phase organic synthesis has attracted the attention of
chemists as it overcomes the harmful effects associated with the
organic solvents and is environmentally benign. Moreover,
using water as the medium, surfactants can be used to build
micelles and provide better chemical yields and shorter reaction
times due to its strong hydrogen bonding ability, hydrophobic
effects and high polarity.28–30
Xanthine is a common structural component in medicinal
chemistry and new chemical entities (NCEs) development.31
Xanthine-based lead molecules have been exploited in
numerous therapeutic areas, for instance, Alzheimer's disease,32
asthma,33 diabetes,34 Parkinson's disease35 and cancer.36 In
addition, xanthine derivatives are one of the most abundant
chemical classes of adenosine receptor antagonists.37 Theoph-
ylline is a methylxanthine drug used in therapy for respiratory
diseases such as chronic obstructive pulmonary disease (COPD)
and asthma under a variety of brand names. Theophylline has
the chemical name 1,3-dimethyl-7H-purine-2,6-dione, and is
represented by the following structural formula (Fig. 1):
In this area, multi-component domino reactions (MDRs), in
which more than two components are combined in a single
synthetic operation, have been extensively used as a powerful
aYoung Researchers and Elite Club, Yazd Branch, Islamic Azad University, Yazd, Iran
bDepartment of Chemistry, Yazd Branch, Islamic Azad University, Yazd, Iran. E-mail:
mohebat@iauyazd.ac.ir
cDepartment of Chemistry, Faculty of Science, University of Sistan and Baluchestan, P.
O. Box: 98135-674, Zahedan, Iran
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra18750a
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Table 1 Optimization of reaction conditions of compound 6a
Fig. 1 The structure of theophylline.
Entry Cat (mol%)
Reaction conditions Time (h) Yielda (%)
1
2
3
4
5
6
7
8
No catalyst
Et3N (20)
CH3CN, reux
CH3CN, reux
CH3CN, reux
CH3CN, reux
CH3CN, reux
CH3CN, reux
CH3CN, reux
CH3CN, reux
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
NR
76
68
40
85
83
Trace
62
81
64
67
84
90
90
73
89
81
Trace
Piperidine (20)
DBU (20)
DABCO (20)
Imidazole (20)
Histidine (20)
Caffeine (20)
9
Theophylline (20) CH3CN, reux
Theophylline (20) CHCl3, reux
10
11
12
13
14
15
16
17
18
Theophylline (20) DMF, 100 ꢀ
C
Theophylline (20) EtOH, reux
Theophylline (20) H2O, reux
Theophylline (30) H2O, reux
Theophylline (10) H2O, reux
Scheme 1 One-pot, four-component synthesis of novel 1,2-dihy-
drobenzo[a]furo[2,3-c]phenazine derivatives in the presence of
theophylline.
Theophylline (20) H2O, 70 ꢀ
Theophylline (20) H2O, 50 ꢀ
Theophylline (20) H2O, rt
C
C
a
Isolated yields.
As part of our continuing interest in the development of
new synthetic methods in heterocyclic compounds38,39 and
benzo[a]phenazin-5-ol-based multi-component reactions,40–43
in this paper we would like to report new sequence of a one-
pot, four-component condensation reaction between 2-
hydroxynaphthalene-1,4-dione 1, benzene-1,2-diamines 2,
aromatic aldehydes 4 and 1-(2-(4-bromophenyl)-2-oxoethyl)
pyridinium bromide44 5 in the presence of theophylline as
an efficient, non-toxic and inexpensive solid base catalyst for
the synthesis of novel 1,2-dihydrobenzo[a]furo[2,3-c]phena-
10 minutes an orange solid of benzo[a]phenazine 3a was formed
without using any catalyst. Next, 4-chlorobenzaldehyde and 1-(2-(4-
bromophenyl)-2-oxoethyl)pyridinium bromide were added and the
mixture was heated in acetonitrile under reux. The desired
product 6a was not obtained when the reaction was carried out in
acetonitrile for 4 h under reux and catalyst-free conditions (Table
1, entry 1). However, 6a was obtained in 72% yield when the
reaction was conducted in the presence of triethylamine (20 mol%)
in acetonitrile (Table 1, entry 2). Several bases were evaluated in the
reaction as catalyst, including Et3N, piperidine, DBU, DABCO,
imidazole, histidine, caffeine and theophylline; these were all
added in substoichiometric amount (20 mol%) and the reactions
were carried out in acetonitrile under reux conditions. Although
the catalytic efficiency of DABCO was the highest (Table 1, entry 5)
but we chose the theophylline as an effective and attractive catalyst
due to features such as efficiency, non-toxicity, recoverability, and
most importantly it used as drug. Different solvents were then
appraised to determine the impact of the solvent on the reaction
yields. Water due to its strong hydrogen bonding ability, hydro-
phobic effects and high polarity gave the best product yield (Table
1, entry 13). We then evaluated the amount of catalyst required for
this transformation. An increase in the amount of theophylline
more than 20 mol% showed no remarkable improvement in the
yield, whereas the yield was reduced by decreasing the amount of
theophylline to 10 mol% (Table 1, entries 13–15). Finally, the
reaction was performed at different temperatures to determine the
optimum reaction temperature. The reaction was conducted with
ꢀ
zine derivatives 6 in aqueous medium at 70 C (Scheme 1).
Results and discussion
The vast biological and pharmacological importance of phen-
azine and furan derivatives inspired us to develop a novel
protocol for their efficient synthesis. In this area, theophylline is
economically cost-effective and commercially available reagent,
and its structure convinced us that this reagent could be used as
an efficient, green and basic catalyst in the synthesis of novel
1,2-dihydrobenzo[a]furo[2,3-c]phenazine derivatives.
In order to investigate the optimizing reaction conditions for
the synthesis of highly diastereoselective 1,2-dihydrobenzo[a]furo
[2,3-c]phenazines, we carried out the four-component domino
reaction between 2-hydroxynaphthalene-1,4-dione 1 (1 mmol),
benzene-1,2-diamine 2a (1 mmol), 4-chlorobenzaldehyde 4 (1
mmol) and 1-(2-(4-bromophenyl)-2-oxoethyl)pyridinium bromide 5
(1 mmol) in acetonitrile as a model. We initially, to minimize the
formation of byproducts, the 2-hydroxynaphthalene-1,4-dione and
benzene-1,2-diamine were reuxed in acetonitrile until in less than
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20 mol% theophylline in water at rt, 50, 70 and 100 C, and the analysis. In IR spectrum, stretching frequency at 1691 cmꢁ1
ꢀ
desired product 6a was formed in yields of trace, 81%, 89% and conrmed the presence of C]O functional group of compound
1
90% (Table 1, entries 13 and 16–18), respectively.
6a. In the H NMR spectra, the two protons at 2,3-position of
Aer extensive screening, we found that the optimized best dihydrobenzofuran ring display two doublets at d 5.46 and
yields and time proles were obtained with 20 mol% of 6.10 ppm with the vicinal coupling constant J ¼ 4.2 Hz. It has
theophylline in H2O at 70 ꢀC, which furnished the correspond- been documented that in cis-2,3-dihydrobenzofuran the vicinal
ing (4-bromophenyl)(1-(4-chlorophenyl)-1,2-dihydrobenzo[a]furo coupling constant of the two methine protons J ¼ 7–10 Hz,
[2,3-c]phenazin-2-yl)methanone 6a in 89% yield within 3 h while in trans-2,3-dihydrobenzofuran vicinal coupling constant
(Table 1, entry 16).
J ¼ 4–7 Hz (Fig. 2).45 So we concluded that thermodynamically
Using these optimized conditions, we turned our attention to stable trans isomer of 2,3-dihydrobenzofuran derivatives with
investigate the scope and general applicability of this method- high diastereoselectivity was formed. The 13C NMR spectrum of
ology by carrying out the synthesis of 1,2-dihydrobenzo[a]furo 6a showed twenty-six distinct resonances in agreement with the
[2,3-c]phenazines using different benzene-1,2-diamines and proposed structure (see Experimental section). The mass
various aromatic aldehydes (Table 2).
spectra of this compound displayed molecular ion peak at the
All the reactions were complete in 3–4 h and resulted in the appropriate m/z value at 565. Similarly, compounds 6b–p were
formation of the target structures (Scheme 1, Table 2, entries 1– characterized (Table 2).
16) in high yields using the theophylline as environment-
Recovery of the catalysts is important in green organic
friendly catalyst and this domino reaction was efficiently synthesis. Thus, we also for recyclability of the catalyst, investi-
promoted using benzene-1,2-diamine with reduced reaction gated the recycling of the theophylline in aqueous medium at 70
times and increased yields rather than other aromatic 1,2- ꢀC using a selected model reaction of 2-hydroxynaphthalene-1,4-
diamines and benzaldehydes with electron-withdrawing groups dione, benzene-1,2-diamine, 4-chlorobenzaldehyde and 1-(2-(4-
reacted rapidly and gave higher yields, while substitutions of bromophenyl)-2-oxoethyl)pyridinium bromide in the presence
electron-rich groups on the benzene ring required longer reac- of theophylline as homogeneous catalyst (Table 2, entry 1). Aer
tion times and got lower yields.
completion of the reaction, then reaction mixture was cooled to
The isolated products 6 were fully characterized on the basis room temperature. Then, 5 mL of water was added to the
of IR, 1H, 13C NMR and MS spectroscopy and elemental mixture. The theophylline was dissolved in water and ltered for
separation of the crude product. The separated product was
washed twice with water (2 ꢂ 5 mL). The resulting product
subsequently recrystallized from hot ethanol to give the pure
solid. In order to recover the catalyst, since theophylline is
soluble in water, the ltrate was extracted with diethyl ether. The
aqueous layer (including theophylline) was separated, and its
solvent was evaporated under reduced pressure and theophyl-
line was recovered and reused.
Table 2 Domino one-pot four-component synthesis of 1,2-dihy-
drobenzo[a]furo[2,3-c]phenazine derivatives by using theophylline (20
mol%) as catalyst in water at 70 ꢀ
C
As shown in Fig. 3, the recovered catalyst works with the
same performance up to 2nd run, while in the 3rd, 4th and 5th
runs product yield gets reduced slightly that may be due to little
weight loss of catalyst during each recovery process.
In order to determine the catalytic behavior of theophylline,
the suggested mechanism for the formation of the products is
shown in Scheme 2 according to the literature.45a,b On the basis
of this mechanism, at rst, 2-hydroxynaphthalene-1,4-dione 1
tautomerizes to intermediate 7. The primary condensation of 4-
hydroxy-1,2-naphthoquinone 7 with benzene-1,2-diamine 2
Entry Diamine Ar
Product Time (h) Yielda (%)
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
4-ClC6H4
6a
6b
6c
6d
3
3
3
3
4
4
4
4
4
4
3
3
4
3
3
3
89
87
89
90
85
80
81
83
78
79
87
87
80
85
88
85
2
2-ClC6H4
3
4
2,4-Cl2C6H3
4-NO2C6H4
5
2-OH-5-NO2C6H4 6e
6
2-Thienyl
6f
7
4-MeC6H4
6g
6h
6i
8
9
4-OMeC6H4
3,4-(OMe)2C6H3
10
11
12
13
14
15
16
2-OH-3-OMeC6H4 6j
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-ClC6H4
4-NO2C6H4
2-ClC6H4
6k
6l
6m
6n
6o
6p
a
Fig. 2 Stereogenic centers on the structure of 1,2-dihydrobenzo[a]
furo[2,3-c]phenazines.
Isolated yields.
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analyser at the analytical laboratory of Islamic Azad University
Yazd branch. Mass spectra were recorded on an Agilent Tech-
nology (HP) spectrometer operating at an ionization potential of
70 eV. The 1H nuclear magnetic resonance (NMR) and 13C NMR
spectra were recorded in CDCl3 on a Bruker DRX-300 spec-
trometer operating at 300 MHz for 1H analysis and 75 MHz for
13C analysis. Thin-layer chromatography (TLC) was performed
on silica-gel Polygram SILG/UV 254 plates. All reagents and
solvent were purchased from Merck and Aldrich and used
without further purication.
General procedure for the synthesis of novel 1,2-dihydrobenzo
[a]furo[2,3-c]phenazine derivatives (6a–p)
Fig. 3 The reusability of the catalyst (100 mg) in the synthesis of (4-
bromophenyl)(1-(4-chlorophenyl)-1,2-dihydrobenzo[a]furo[2,3-c]
phenazin-2-yl)methanone in water at 70 ꢀC (3 h).
Initially, a mixture of 2-hydroxynaphthalene-1,4-dione 1 (1
mmol), benzene-1,2-diamine 2 (1 mmol), theophylline (20
mol%) and water (10 mL) was placed in a 50 mL round-bottomed
ask mounted over a magnetic stirrer. The contents were stirred
magnetically in an oil-bath maintained at 70 ꢀC until in less than
10 minutes benzo[a]phenazin-5-ol 3 was formed. Then, aryl
aldehyde 4 (1 mmol) and 1-(2-(4-bromophenyl)-2-oxoethyl)
pyridinium bromide 5 (1 mmol) were added to the above reac-
tion mixture which was heated further at same temperature for
an appropriate time as shown in Table 2. Upon completion of
the reaction, monitored by TLC, the reaction mixture was
allowed to cool to room temperature. Then, 5 mL of water was
added to the mixture and ltered for separation of the crude
product. The separated product was washed twice with water (2
ꢂ 5 mL). The solid crude product subsequently recrystallized
from hot ethanol to give the pure product 6.
The spectral and analytical data of all the compounds are
given as follows.
(4-Bromophenyl)(1-(4-chlorophenyl)-1,2-dihydrobenzo[a]furo-
[2,3-c]phenazin-2-yl)methanone (6a). Yellow powder; yield 0.502
g (89%), mp 279–281 ꢀC; IR (KBr): nmax ¼ 3045, 2900, 1691, 1627,
1591, 1535, 1499, 1415, 1386, 1332, 1224, 1131, 1045, 978, 800,
759 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 5.46 (d, 1H, J ¼ 4.2 Hz,
CH), 6.10 (d, 1H, J ¼ 4.2 Hz, CH), 7.22 (d, 2H, J ¼ 8.4 Hz, Ar-H),
7.32 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.59–7.67 (m, 4H, Ar-H), 7.78–7.83
(m, 4H, Ar-H), 7.89–7.92 (m, 1H, Ar-H), 8.15–8.20 (m, 2H, Ar-H),
9.32–9.35 (m, 1H, Ar-H) ppm; 13C NMR (75 MHz, CDCl3): d 50.1
and 91.9 (2CH), 115.4, 122.6, 123.9, 126.1, 128.6, 128.8, 128.9,
129.0, 129.2, 129.5, 129.7, 129.9, 130.0, 130.6, 132.3, 132.5,
133.2, 140.2, 140.4, 141.3, 141.5, 142.5 and 157.9 (Colenic and
Scheme 2 Plausible mechanism for the synthesis of 1,2-dihydrobenzo
[a]furo[2,3-c]phenazine derivatives.
obtain benzo[a]phenazin-5-ol 3. On this mechanism, theophyl-
line is an efficient catalyst to form the 6-benzylidenebenzo[a]
phenazin-5(6H)-one 8, which easily prepares in situ from
Knoevenagel condensation of benzo[a]phenazin-5-ol 3 with
carbonyl group of aldehyde 4. On the other hand, the pyr-
idinium ylide 9, which forms from the reaction of 1-(2-(4-
bromophenyl)-2-oxoethyl)pyridinium
5
with theophylline
C
arom), 192.7 (C]O) ppm; MS (m/z, %): 565 (M+, 1), 448 (1), 381
undergoes Michael addition to intermediate 8 to afford the
enolate intermediate 10. Eventually, the enolate 10 eliminates
pyridine (intramolecular SN2) and cyclizes instantly to produce
novel 1,2-dihydrobenzo[a]furo[2,3-c]phenazine derivatives 6.
(100), 246 (91), 185 (15), 43 (76); anal. calcd for C31H18BrClN2O2:
C, 65.80; H, 3.21; N, 4.95%. Found: C, 66.03; H, 3.46; N, 4.87%.
(4-Bromophenyl)(1-(2-chlorophenyl)-1,2-dihydrobenzo[a]furo-
[2,3-c]phenazin-2-yl)methanone (6b). Orange powder; yield 0.492
g (87%), mp 243–245 ꢀC; IR (KBr): nmax ¼ 3035, 2895, 1692, 1626,
1594, 1534, 1498, 1414, 1386, 1332, 1223, 1129, 1045, 978, 800,
759 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 6.11 (s, 2H, 2CH), 6.99–
7.14 (m, 3H, Ar-H), 7.39 (d, 1H, J ¼ 7.8 Hz, Ar-H), 7.60 (d, 2H, J ¼
Experimental
General
All melting points were determined on an Electrothermal 9100 8.7 Hz, Ar-H), 7.64–7.67 (m, 2H, Ar-H), 7.73–7.82 (m, 2H, Ar-H),
apparatus and are uncorrected. IR spectra were recorded on 7.88 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.93–7.96 (m, 1H, Ar-H), 8.08–8.11
a shimadzu IR-470 spectrometer. Elemental analyses for C, H, (m, 1H, Ar-H), 8.17–8.21 (m, 1H, Ar-H), 9.33–9.36 (m, 1H, Ar-H)
and N were performed using a Costech ECS 4010 CHNS-O ppm; 13C NMR (75 MHz, CDCl3): d 46.6 and 90.9 (2CH), 115.3,
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122.5, 124.0, 125.7, 126.1, 127.3, 128.5, 128.6, 128.8, 129.1, g (80%), mp 160 ꢀC; IR (KBr): nmax ¼ 3050, 2895, 1687, 1629,
129.3, 129.6, 129.7, 129.8, 129.9, 130.8, 131.4, 131.9, 132.2, 1579, 1524, 1489, 1412, 1386, 1330, 1219, 1133, 1063, 973, 834,
132.5, 132.9, 133.5, 139.3, 140.3, 141.2, 141.7, 142.7 and 158.1 750 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 5.79 (d, 1H, J ¼ 3.9 Hz,
(Colenic and Carom), 191.9 (C]O) ppm; MS (m/z, %): 565 (M+, 1), CH), 6.21 (d, 1H, J ¼ 3.9 Hz, CH), 7.87–8.89 (m, 1H, Ar-H), 7.05
529 (1), 381 (100), 246 (9), 183 (11), 76 (4); anal. calcd for C31
-
(d, 1H, J ¼ 3.3 Hz, Ar-H), 7.11 (d, 1H, J ¼ 4.8 Hz, Ar-H), 7.60–7.68
H18BrClN2O2: C, 65.80; H, 3.21; N, 4.95%. Found: C, 65.93; H, (m, 5H, Ar-H), 7.76–8.79 (m, 2H, Ar-H), 7.89 (d, 1H, J ¼ 8.4 Hz,
3.51; N, 5.10%. Ar-H), 7.95–7.98 (m, 1H, Ar-H), 8.14–8.19 (m, 2H, Ar-H), 9.30–
(4-Bromophenyl)(1-(2,4-dichlorophenyl)-1,2-dihydrobenzo 9.34 (m, 1H, Ar-H) ppm; 13C NMR (75 MHz, CDCl3): d 45.6 and
[a]furo[2,3-c]phenazin-2-yl)methanone (6c). Yellow powder; 91.8 (2CH), 115.0, 122.7, 123.9, 124.7, 125.4, 126.0, 127.1, 128.5,
yield 0.534 g (89%), mp 256–257 ꢀC; IR (KBr): nmax ¼ 3110, 2905, 128.8, 128.9, 129.5, 129.6, 129.7, 129.8, 129.9, 130.7, 132.0,
1683, 1626, 1591, 1534, 1500, 1412, 1380, 1351, 1221, 1134, 132.3, 132.5, 132.6, 140.2, 141.3, 141.6, 142.5, 145.0, and 157.8
1065, 978, 800, 761 cmꢁ1; 1H NMR (300 MHz, DMSO-d6): d 5.92 (Colenic and Carom), 192.5 (C]O) ppm; MS (m/z, %): 537 (M+, 1),
(d, 1H, J ¼ 3.9 Hz, CH), 6.74 (d, 1H, J ¼ 3.9 Hz, CH), 7.16 (d, 1H, J 426 (2), 353 (100), 246 (18), 183 (14), 76 (5); anal. calcd for C29
-
¼ 8.4 Hz, Ar-H), 7.25 (dd, 1H, J1 ¼ 8.7 Hz, J2 ¼ 2.1 Hz, Ar-H), 7.73 H17BrN2O2S: C, 64.81; H, 3.19; N, 5.21; S, 5.97%. Found: C,
(d, 1H, J ¼ 2.1 Hz, Ar-H), 7.84–7.89 (m, 4H, Ar-H), 7.94–8.02 (m, 65.06; H, 3.26; N, 5.30; S, 5.82%.
3H, Ar-H), 8.05 (d, 2H, J ¼ 8.7 Hz, Ar-H), 8.13–8.16 (m, 1H, Ar-H),
(4-Bromophenyl)(1-(p-tolyl)-1,2-dihydrobenzo[a]furo[2,3-c]
8.28–8.32 (m, 1H, Ar-H), 9.31–9.34 (m, 1H, Ar-H) ppm; 13C NMR phenazin-2-yl)methanone (6g). Green powder; yield 0.441 g
(75 MHz, DMSO-d6): d 49.3 and 90.4 (2CH), 114.9, 122.9, 123.7, (81%), mp 260–263 ꢀC; IR (KBr): nmax ¼ 3045, 2900, 1684, 1633,
126.1, 128.3, 128.8, 129.0, 129.3, 129.8, 131.1, 131.2, 131.7, 1594, 1533, 1500, 1416, 1382, 1331, 1222, 1130, 1063, 978, 828,
132.1, 132.6, 133.0, 133.2, 134.0, 138.2, 140.0, 140.9, 141.5, 142.3 749 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 2.27 (s, 3H, CH3), 5.37
and 158.5 (Colenic and Carom), 193.2 (C]O) ppm; MS (m/z, %): (d, 1H, J ¼ 3.9 Hz, CH), 6.15 (d, 1H, J ¼ 4.2 Hz, CH), 7.06 (d, 2H, J
600 (M+, 1), 523 (1), 415 (100), 352 (16), 182 (20), 57 (14); anal. ¼ 7.8 Hz, Ar-H), 7.29 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.58–7.66 (m, 4H,
calcd for C31H17BrCl2N2O2: C, 62.03; H, 2.85; N, 4.67%. Found: Ar-H), 7.77–7.82 (m, 4H, Ar-H), 7.89–7.94 (m, 1H, Ar-H), 8.15–
C, 62.27; H, 2.64; N, 4.76%.
8.22 (m, 2H, Ar-H), 9.32–9.35 (m, 1H, Ar-H) ppm; 13C NMR (75
(4-Bromophenyl)(1-(4-nitrophenyl)-1,2-dihydrobenzo[a]furo MHz, CDCl3): d 21.1 (CH3), 50.6 and 92.2 (2CH), 116.0, 122.6,
[2,3-c]phenazin-2-yl)methanone (6d). Yellow powder; yield 124.1, 126.0, 127.7, 128.4, 128.7, 128.8, 129.3, 129.6, 129.7,
0.516 g (90%), mp 283–285 ꢀC; IR (KBr): nmax ¼ 3025, 2905, 1689, 129.8, 129.9, 130.6, 132.2, 132.5, 132.6, 137.1, 138.9, 140.2,
1624, 1593, 1532, 1507, 1447, 1393, 1336, 1223, 1132, 1046, 941, 141.3, 141.8, 142.5 and 157.9 (Colenic and Carom), 192.9 (C]O)
803, 754 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 5.72 (d, 1H, J ¼ 4.8 ppm; MS (m/z, %): 545 (M+, 1), 466 (2), 361 (100), 270 (5), 183 (9),
Hz, CH), 6.10 (d, 1H, J ¼ 4.8 Hz, CH), 7.56–7.70 (m, 7H, Ar-H), 57 (3); anal. calcd for C32H21BrN2O2: C, 70.47; H, 3.88; N, 5.14%.
7.78–7.83 (m, 2H, Ar-H), 7.86–7.89 (m, 3H, Ar-H), 8.11–8.14 Found: C, 70.71; H, 3.69; N, 5.22%.
(m, 3H, Ar-H), 9.34–9.37 (m, 1H, Ar-H) ppm; 13C NMR (75 MHz,
(4-Bromophenyl)(1-(4-methoxyphenyl)-1,2-dihydrobenzo[a]
CDCl3): d 50.5 and 90.6 (2CH), 115.3, 122.3, 124.0, 125.5, 127.3, furo[2,3-c]phenazin-2-yl)methanone (6h). Brown powder; yield
128.0, 128.5, 128.7, 129.1, 129.5, 129.7, 130.0, 130.1, 130.2, 0.566 g (83%), mp 180–181 ꢀC; IR (KBr): nmax ¼ 3025, 2895, 1688,
130.3, 131.6, 132.5, 132.9, 133.5, 139.3, 140.3, 141.4, 141.5, 1628, 1583, 1531, 1507, 1410, 1390, 1330, 1223, 1133, 1061, 948,
142.5, and 157.5 (Colenic and Carom), 192.6 (C]O) ppm; MS (m/ 820, 750 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 3.68 (s, 3H, OCH3),
z, %): 576 (M+, 1), 530 (1), 384 (2), 344 (48), 271 (68), 57 (100); 5.35 (d, 1H, J ¼ 3.9 Hz, CH), 6.12 (d, 1H, J ¼ 4.2 Hz, CH), 6.77 (d,
anal. calcd for C31H18BrN3O4: C, 64.60; H, 3.15; N, 7.29%. 2H, J ¼ 8.4 Hz, Ar-H), 7.30 (d, 2H, J ¼ 8.7 Hz, Ar-H), 7.53–7.62
Found: C, 64.48; H, 3.37; N, 7.53%.
(m, 4H, Ar-H), 7.67–7.80 (m, 5H, Ar-H), 8.12–8.19 (m, 2H, Ar-H),
(4-Bromophenyl)(1-(2-hydroxy-5-nitrophenyl)-1,2-dihydrobenzo 9.29–9.32 (m, 1H, Ar-H) ppm; 13C NMR (75 MHz, CDCl3): d 50.3
[a]furo[2,3-c]phenazin-2-yl)methanone (6e). Green powder; yield (CH), 55.2 (OCH3), 92.2 (CH), 114.2, 116.0, 122.6, 124.0, 126.0,
0.503 g (85%), mp 156–157 ꢀC; IR (KBr): nmax ¼ 3050, 2910, 1688, 128.4, 128.7, 128.8, 128.9, 129.3, 129.6, 129.7, 129.9, 130.6,
1632, 1591, 1527, 1500, 1415, 1386, 1336, 1224, 1152, 1063, 948, 132.2, 132.4, 132.5, 134.0, 140.1, 141.3, 141.8, 142.5 and 158.8
811, 754 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 5.74 (d, 1H, J ¼ 4.8 (Colenic and Carom), 193.0 (C]O) ppm; MS (m/z, %): 561 (M+, 1),
Hz, CH), 6.13 (d, 1H, J ¼ 4.5 Hz, CH), 7.43 (t, 1H, J ¼ 7.8 Hz, Ar- 425 (1), 377 (100), 246 (20), 183 (12), 76 (4); anal. calcd for
H), 7.60–7.67 (m, 3H, Ar-H), 7.75–7.84 (m, 3H, Ar-H), 7.86–7.90
C32H21BrN2O3: C, 68.46; H, 3.77; N, 4.99%. Found: C, 68.57; H,
(m, 3H, Ar-H), 8.03–8.06 (m, 1H, Ar-H), 8.12–8.19 (m, 2H, Ar-H), 3.96; N, 5.18%.
8.30 (t, 1H, J ¼ 2.1 Hz, Ar-H), 9.32–9.35 (m, 1H, Ar-H), 10.80 (s,
(4-Bromophenyl)(1-(3,4-dimethoxyphenyl)-1,2-dihydrobenzo
1H, OH) ppm; 13C NMR (75 MHz, CDCl3): d 49.7 and 91.6 (2CH), [a]furo[2,3-c]phenazin-2-yl)methanone (6i). Brown powder;
114.8, 122.5, 122.7, 123.1, 126.1, 128.7, 129.1, 129.7, 129.8, yield 0.460 g (78%), mp 162–164 ꢀC; IR (KBr): nmax ¼ 3040, 2910,
130.0, 130.7, 130.9, 131.2, 131.5, 131.6, 132.3, 132.6, 134.2, 1688, 1629, 1594, 1551, 1512, 1415, 1386, 1331, 1223, 1137,
137.2, 138.5, 140.2, 141.4, 141.9, 143.9 and 157.8 (Colenic and 1048, 948, 800, 752 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 3.76 (s,
C
arom), 192.4 (C]O) ppm; MS (m/z, %): 592 (M+, 1), 575 (2), 415 3H, OCH3), 3.78 (s, 3H, OCH3), 5.37 (d, 1H, J ¼ 4.2 Hz, CH), 6.18
(100), 345 (22), 182 (49), 57 (92); anal. calcd for C31H18BrN3O5: C, (d, 1H, J ¼ 4.2 Hz, CH), 6.73 (d, 1H, J ¼ 8.4 Hz, Ar-H), 6.91 (dd,
62.85; H, 3.06; N, 7.09%. Found: C, 62.63; H, 3.15; N, 7.26%.
1H, J1 ¼ 8.1 Hz, J2 ¼ 1.8 Hz, Ar-H), 6.99 (d, 1H, J ¼ 1.8 Hz, Ar-H),
(4-Bromophenyl)(1-(thiophen-2-yl)-1,2-dihydrobenzo[a]furo 7.58–7.67 (m, 4H, Ar-H), 7.77–8.84 (m, 4H, Ar-H), 7.89–7.93 (m,
[2,3-c]phenazin-2-yl)methanone (6f). Brown powder; yield 0.431 1H, Ar-H), 8.16–8.21 (m, 2H, Ar-H), 9.32–9.35 (m, 1H, Ar-H)
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ppm; 13C NMR (75 MHz, CDCl3): d 50.6 (CH), 55.8 and 56.0
(2OCH3), 92.1 (CH), 111.4, 111.5, 115.8, 119.7, 122.6, 124.0,
126.0, 128.4, 128.7, 129.4, 129.7, 129.8, 129.9, 130.6, 131.7,
131.9, 132.2, 132.4, 132.5, 134.4, 140.1, 141.3, 141.8, 142.5,
148.3, 149.0 and 157.8 (Colenic and Carom), 193.0 (C]O) ppm;
MS (m/z, %): 591 (M+, 1), 454 (1), 407 (100), 345 (13), 182 (23), 57
(11); anal. calcd for C33H23BrN2O4: C, 67.01; H, 3.92; N, 4.74%.
Found: C, 67.19; H, 3.85; N, 4.90%.
(4-Bromophenyl)(11-methyl-1-(p-tolyl)-1,2-dihydrobenzo[a]
furo[2,3-c]phenazin-2-yl)methanone (6m). Brown powder;
yield 0.449 g (80%), mp 205–207 ꢀC; IR (KBr): nmax ¼ 2995, 2910,
1692, 1631, 1595, 1532, 1502, 1479, 1396, 1331, 1223, 1147,
1049, 950, 820, 758 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 2.33 (s,
3H, CH3), 2.57 (s, 3H, CH3), 5.48 (d, 1H, J ¼ 4.2 Hz, CH), 6.23 (d,
1H, J ¼ 3.9 Hz, CH), 7.16 (d, 2H, J ¼ 7.2 Hz, Ar-H), 7.38 (d, 2H, J
¼ 7.8 Hz, Ar-H), 7.53–7.58 (m, 2H, Ar-H), 7.68 (d, 2H, J ¼ 8.4 Hz,
Ar-H), 7.82–8.82 (m, 5H, Ar-H), 8.27–8.30 (m, 1H, Ar-H), 9.37–
9.41 (m, 1H, Ar-H) ppm; 13C NMR (75 MHz, CDCl3): d 21.1 and
21.9 (2CH3), 50.6 and 92.1 (2CH), 116.0, 122.5, 123.8, 125.8,
125.9, 127.4, 127.7, 128.1, 128.3, 128.5, 128.6, 129.1, 129.3,
129.6, 129.7, 130.6, 131.0, 132.2, 132.3, 132.5, 137.0, 138.8,
139.0, 140.3, 141.1, 142.6, 157.4 and 157.7 (Colenic and Carom),
193.0 (C]O) ppm; MS (m/z, %): 559 (M+, 1), 440 (2), 375 (100),
260 (20), 183 (10), 57 (3); anal. calcd for C33H23BrN2O2: C, 70.85;
H, 4.14; N, 5.01%. Found: C, 70.77; H, 3.37; N, 5.25%.
(4-Bromophenyl)(1-(2-hydroxy-3-methoxyphenyl)-1,2-dihy-
drobenzo[a]furo[2,3-c]phenazin-2-yl)methanone (6j). Orange
ꢀ
powder; yield 0.458 g (79%), mp 251–252 C; IR (KBr): nmax
¼
3025, 2900, 1674, 1620, 1581, 1524, 1468, 1416, 1392, 1337,
1220, 1133, 1063, 979, 809, 753 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 3.82 (s, 3H, OCH3), 5.67 (d, 1H, J ¼ 3.0 Hz, CH), 6.55 (d,
1H, J ¼ 3.0 Hz, CH), 6.74–6.77 (m, 1H, Ar-H), 6.85 (t, 1H, J ¼ 7.8
Hz, Ar-H), 7.07 (d, 1H, J ¼ 6.9 Hz, Ar-H), 7.55 (d, 2H, J ¼ 8.4 Hz,
Ar-H), 7.66–7.82 (m, 6H, Ar-H), 8.15–8.21 (m, 3H, Ar-H), 9.25–
9.28 (m, 1H, Ar-H), 10.12 (s, 1H, OH) ppm; 13C NMR (75 MHz,
CDCl3): d 44.0 (CH), 56.0 (OCH3), 90.3 (CH), 111.0, 116.1, 118.1,
121.5, 122.7, 124.1, 126.0, 127.5, 128.7, 129.0, 129.4, 129.8,
129.9, 130.2, 130.3, 130.7, 131.8, 132.1, 132.4, 140.3, 140.6,
141.9, 143.8, 150.5 and 158.5 (Colenic and Carom), 192.4 (C]O)
ppm; MS (m/z, %): 577 (M+, 1), 407 (1), 358 (96), 285 (100), 142
(6), 89 (4); anal. calcd for C32H21BrN2O4: C, 66.56; H, 3.67; N,
4.85%. Found: C, 66.78; H, 3.90; N, 4.89%.
(4-Bromophenyl)(1-(4-chlorophenyl)-10-nitro-1,2-dihydro-
benzo[a]furo[2,3-c]phenazin-2-yl)methanone
powder; yield 0.518 g (85%), mp 275–277 C; IR (KBr): nmax
(6n).
Yellow
ꢀ
¼
3055, 2900, 1684, 1625, 1590, 1551, 1514, 1415, 1388, 1332,
1220, 1125, 1046, 1005, 818, 761 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 5.43 (d, 1H, J ¼ 4.5 Hz, CH), 6.16 (d, 1H, J ¼ 4.5 Hz,
CH), 7.23–7.35 (m, 4H, Ar-H), 7.63 (d, 2H, J ¼ 8.7 Hz, Ar-H),
7.80–7.88 (m, 4H, Ar-H), 8.00 (d, 1H, J ¼ 9.3 Hz, Ar-H), 8.19–
8.22 (m, 1H, Ar-H), 8.40 (dd, 1H, J1 ¼ 8.7 Hz, J2 ¼ 2.4 Hz, Ar-H),
(4-Bromophenyl)(1-(4-chlorophenyl)-11-methyl-1,2-dihydro-
9.11 (d, 1H, J ¼ 2.4 Hz, Ar-H), 9.31–9.35 (m, 1H, Ar-H) ppm; 13
C
benzo[a]furo[2,3-c]phenazin-2-yl)methanone
powder; yield 0.504 g (87%), mp 307–309 C; IR (KBr): nmax
(6k).
Yellow
ꢀ
¼
NMR (75 MHz, CDCl3): d 49.8 and 92.2 (2CH), 115.6, 122.9,
123.1, 126.4, 126.5, 128.6, 128.8, 128.9, 129.0, 129.1, 129.2,
129.8, 130.2, 130.6, 131.0, 132.4, 132.5, 139.8, 140.4, 141.3,
141.5, 142.5 and 157.9 (Colenic and Carom), 192.2 (C]O) ppm;
MS (m/z, %): 610 (M+, 1), 551 (1), 426 (53), 291 (100), 182 (23), 43
(44); anal. calcd for C31H17BrClN3O4: C, 60.95; H, 2.81; N, 6.88%.
Found: C, 70.19; H, 2.88; N, 6.98%.
3025, 2910, 1690, 1624, 1593, 1530, 1501, 1405, 1352, 1315,
1225, 1132, 1047, 1003, 817, 761 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 2.54 (s, 3H, CH3), 5.45 (d, 1H, J ¼ 4.2 Hz, CH), 6.08 (d,
1H, J ¼ 4.2 Hz, CH), 7.22 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.32 (d, 2H, J
¼ 8.4 Hz, Ar-H), 7.49 (dd, 1H, J1 ¼ 8.7 Hz, J2 ¼ 1.8 Hz, Ar-H), 7.61
(d, 2H, J ¼ 8.4 Hz, Ar-H), 7.76–7.83 (m, 5H, Ar-H), 7.95 (s, 1H, Ar-
H), 8.14–8.17 (m, 1H, Ar-H), 9.29–9.33 (m, 1H, Ar-H) ppm; 13C
NMR (75 MHz, CDCl3): d 21.9 (CH3), 50.1 and 91.9 (2CH), 115.4,
122.6, 126.0, 128.2, 128.3, 128.4, 128.7, 129.0, 129.2, 129.4,
129.8, 130.6, 131.1, 132.3, 132.5, 132.6, 133.2, 135.0, 137.1,
137.2, 139.2, 140.5, 141.0, 157.4 and 157.7 (Colenic and Carom),
192.8 (C]O) ppm; MS (m/z, %): 579 (M+, 1), 439 (1), 395 (27),
260 (100), 130 (12), 57 (14); anal. calcd for C32H20BrClN2O2: C,
66.28; H, 3.48; N, 4.83%. Found: C, 66.45; H, 3.51; N, 4.98%.
(4-Bromophenyl)(11-methyl-1-(4-nitrophenyl)-1,2-dihydrobenzo
[a]furo[2,3-c]phenazin-2-yl)methanone (6l). Yellow powder; yield
0.511 g (87%), mp 296–297 ꢀC; IR (KBr): nmax ¼ 3045, 2900, 1690,
1629, 1594, 1563, 1508, 1480, 1391, 1330, 1226, 1144, 1062, 943,
820, 761 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 2.51 (s, 3H, CH3),
5.72 (d, 1H, J ¼ 4.5 Hz, CH), 6.07 (d, 1H, J ¼ 4.5 Hz, CH), 7.49–
7.64 (m, 6H, Ar-H), 7.76–7.88 (m, 5H, Ar-H), 8.09–8.13 (m, 3H,
Ar-H), 9.32–9.35 (m, 1H, Ar-H) ppm; 13C NMR (75 MHz, CDCl3):
d 21.7 (CH3), 51.2 and 90.4 (2CH), 110.9, 115.9, 118.1, 121.5,
122.8, 124.1, 126.1, 127.4, 128.8, 129.0, 129.4, 129.7, 129.9,
130.2, 130.4, 130.6, 131.8, 132.0, 132.4, 140.2, 140.6, 141.8,
143.9, 150.6 and 158.4 (Colenic and Carom), 192.3 (C]O) ppm;
MS (m/z, %): 590 (M+, 1), 406 (100), 360 (20), 284 (7), 184 (16), 57
(20); anal. calcd for C32H20BrN3O4: C, 65.10; H, 3.41; N, 7.12%.
Found: C, 65.33; H, 3.52; N, 7.01%.
(4-Bromophenyl)(10-nitro-1-(4-nitrophenyl)-1,2-dihydrobenzo
[a]furo[2,3-c]phenazin-2-yl)methanone (6o). Yellow powder;
yield 0.544 g (88%), mp 312–314 ꢀC; IR (KBr): nmax ¼ 3070, 2910,
1688, 1629, 1589, 1552, 1510, 1412, 1386, 1337, 1225, 1141,
1046, 979, 822, 762 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 5.69 (d,
1H, J ¼ 4.5 Hz, CH), 6.16 (d, 1H, J ¼ 4.5 Hz, CH), 7.53–7.59 (m,
2H, Ar-H), 7.65 (d, 2H, J ¼ 8.7 Hz, Ar-H), 7.88–7.89 (m, 4H, Ar-H),
8.13–8.20 (m, 3H, Ar-H), 8.33 (d, 1H, J ¼ 9.3 Hz, Ar-H), 8.42 (dd,
1H, J1 ¼ 9.3 Hz, J2 ¼ 2.4 Hz, Ar-H), 8.80 (d, 1H, J ¼ 2.4 Hz, Ar-H),
9.34–9.37 (m, 1H, Ar-H) ppm; 13C NMR (75 MHz, CDCl3): d 51.1
and 90.5 (2CH), 113.8, 115.8, 122.2, 123.4, 125.3, 125.5, 127.1,
128.1, 129.2, 130.3, 130.4, 130.9, 131.0, 132.2, 133.0, 133.5,
137.3, 139.9, 140.2, 141.1, 141.7, 143.0 and 157.3 (Colenic and
C
arom), 191.7 (C]O) ppm; MS (m/z, %): 621 (M+, 1), 577 (2), 437
(17), 375 (65), 184 (33), 43 (100); anal. calcd for C31H17BrN4O6: C,
59.92; H, 2.76; N, 9.02%. Found: C, 60.11; H, 2.59; N, 8.90%.
(4-Bromophenyl)(1-(2-chlorophenyl)-10-nitro-1,2-dihydrobenzo
[a]furo[2,3-c]phenazin-2-yl)methanone (6p). Yellow powder; yield
0.521 g (85%), mp 300 ꢀC; IR (KBr): nmax ¼ 3030, 2900, 1686,
1627, 1583, 1526, 1493, 1409, 1386, 1333, 1223, 1145, 1048,
1004, 808, 757 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 6.07 (d, 1H, J
¼ 4.2 Hz, CH), 6.18 (d, 1H, J ¼ 4.2 Hz, CH), 7.06–7.14 (m, 3H, Ar-
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H), 7.34 (d, 1H, J ¼ 7.8 Hz, Ar-H), 7.62 (d, 2H, J ¼ 8.4 Hz, Ar-H),
7.83–7.88 (m, 4H, Ar-H), 8.14–8.17 (m, 1H, Ar-H), 8.32 (d, 1H, J ¼
9 F. R. Petronijevic and P. Wipf, J. Am. Chem. Soc., 2011, 133,
7704–7707.
9.3 Hz, Ar-H), 8.40 (dd, 1H, J1 ¼ 9.3 Hz, J2 ¼ 2.4 Hz, Ar-H), 8.83 10 J. Boonsompat and A. Padwa, J. Org. Chem., 2011, 76, 2753–2761.
(d, 1H, J ¼ 2.4 Hz, Ar-H), 9.34–9.37 (m, 1H, Ar-H) ppm; 13C NMR 11 S. Kiren, X. Hong, C. A. Leverett and A. Padwa, Org. Lett.,
(75 MHz, CDCl3): d 50.3 and 91.3 (2CH), 113.9, 122.9, 125.2,
2009, 11, 1233–1235.
125.3, 127.1, 127.2, 128.1, 128.2, 128.9, 129.0, 129.1, 129.6, 12 N. V. De Witte, A. O. Stoppani and M. Dubin, Arch. Biochem.
129.7, 129.9, 131.6, 132.2, 132.8, 132.9, 140.1, 140.5, 141.4, Biophys., 2004, 432, 129–135.
141.5, 142.8 and 156.9 (Colenic and Carom), 192.5 (C]O) ppm; 13 A. L. B. S. Barreiros, J. M. David and J. P. David, Quim. Nova,
MS (m/z, %): 610 (M+, 1), 572 (1), 426 (100), 316 (20), 182 (20), 76
2006, 29, 113–123.
(6); anal. calcd for C31H17BrClN3O4: C, 60.95; H, 2.81; N, 6.88%. 14 S. B. Ferreira, K. Salomao, F. C. da Silva, A. V. Pinto,
˜
Found: C, 61.12; H, 2.94; N, 6.71%.
C. R. Kaiser, A. C. Pinto, V. F. Ferreira and S. L. de Castro,
Eur. J. Med. Chem., 2011, 46, 3071–3077.
15 J. Ligon, S. Dwight, P. Hammer, N. Torkewitz, D. Hofmann,
H. Kempf and K. Pee, Pest Manage. Sci., 2000, 56, 688–695.
16 C. Neves-Pinto, V. Malta, M. Pinto, R. Santos, S. Castro and
A. Pinto, J. Med. Chem., 2002, 45, 740–743.
17 M. Makgatho, R. Anderson, J. O'Sullivan, T. Egan, J. Freese,
N. Cornelius and C. Van Rensburg, Drug Dev. Res., 2000,
50, 195–202.
18 M. Muller and T. Sorrell, Prostaglandins, 1995, 50, 301–311.
19 H. J. Lee, J. S. Kim, S. Y. Park, M. E. Suh, H. J. Kim, E. K. Seo
and C. O. Lee, Bioorg. Med. Chem., 2004, 12, 1623–1628.
20 B. Jiang, S. J. Tu, P. Kaur, W. Wever and G. Li, J. Am. Chem.
Soc., 2009, 131, 11660–11661.
21 J. M. Knapp, J. S. Zhu, D. J. Tantillo and M. J. Kurth, Angew.
Chem., Int. Ed., 2012, 51, 10588–10591.
22 M. Li, H. Cao, Y. Wang, X. L. Lv and L. R. Wen, Org. Lett.,
2012, 14, 3470–3473.
23 J. M. Khurana, A. Chaudhary, A. Lumb and B. Nand, Green
Chem., 2012, 14, 2321–2327.
24 J. McNulty and P. Das, Eur. J. Org. Chem., 2009, 24, 4031–
4035.
Conclusions
In summary, we have described
a novel domino four-
component coupling reaction leading to selective and high-
yielding 1,2-dihydrobenzo[a]furo[2,3-c]phenazine derivatives
from readily available starting materials in aqueous medium.
The strategy provided two C–C, two C]N, one C–O bonds and
two new rings in a single operation through condensation/
Knoevenagel/Michael/annulation sequences. This protocol
also offers several advantages such as convenient one-pot
operation, high atom economy, easy work-up, short reaction
time, use of theophylline as a non-toxic, inexpensive and easily
obtained catalyst and avoidance of conventional volatile organic
solvents that make it a green, economically cost-effective and
attractive process for the synthesis of these heterocycles.
Furthermore, our work is expected to exhibit interesting phar-
macology activities and may act as potential drug candidates,
since phenazine and furan motifs have a vast range of biological
activities.
25 J. McNulty, P. Das and D. McLeod, Chem.–Eur. J., 2010, 16,
6756–6760.
Acknowledgements
26 S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb
and K. B. Sharpless, Angew. Chem., Int. Ed., 2005, 21, 3157.
27 M. Smith and J. March, March's advanced organic chemistry:
reactions, mechanisms, and structure, Wiley, 2007.
28 R. Breslow, in Organic Reactions in Water, ed. M. Lindstrom,
Blackwell, Oxford, 2007, pp. 1–28.
We gratefully acknowledge nancial support from the Research
Council of the Islamic Azad University of Yazd and University of
Sistan and Baluchestan.
Notes and references
29 R. Breslow, Acc. Chem. Res., 1991, 24, 159–164.
1 J. Yu, F. Shi and L. Z. Gong, Acc. Chem. Res., 2011, 44, 1156– 30 G. Khanna, A. Chaudhary and J. M. Khurana, Tetrahedron
1171.
Lett., 2014, 55, 6652–6654.
2 M. S. Singh, G. C. Nandi and T. Chanda, RSC Adv., 2013, 3, 31 J. W. Daly, Cell. Mol. Life Sci., 2007, 64, 2153–2169.
14183–14198.
32 L. Maia and A. De Mendonga, Eur. J. Neurol., 2002, 9, 377–382.
3 Z. Xu, M. Ayaz, A. A. Cappelli and C. Hulme, ACS Comb. Sci., 33 R. J. Stine, R. H. Marcus and C. A. Parvin, Ann. Emerg. Med.,
2012, 14, 460–464. 1989, 18, 640–646.
4 M. H. A. Aziz, P. S. Sidhu, A. Liang, J. Y. Kim, P. D. Mosier, 34 P. Cui, T. L. Macdonald, M. Chen and J. L. Nadler, Bioorg.
Q. Zhou, D. H. Farrell and U. R. Desai, J. Med. Chem., 2012,
55, 6888–6897.
5 Y. Liu, M. Kubo and Y. Fukuyama, J. Nat. Prod., 2012, 75,
2152–2157.
Med. Chem. Lett., 2006, 16, 3401–3405.
35 B. Song, T. Xiao, X. Qi, L. N. Li, K. Qin, S. Nian, G. X. Hu,
Y. Yu, G. Liang and F. Ye, Bioorg. Med. Chem. Lett., 2012,
22, 1739–1742.
6 W. Yuan and S. Ma, Org. Lett., 2014, 16, 193–195.
7 S. N. Aslam, P. C. Stevenson, S. J. Phythian, N. C. Veitch and
D. R. Hall, Tetrahedron, 2006, 62, 4214–4226.
8 Y. Izumizono, S. Arevalo, Y. Koseki, M. Kuroki and S. Aoki,
Eur. J. Med. Chem., 2011, 46, 1849–1856.
36 A. C. Roy, F. A. Lunn and S. L. Bearne, Bioorg. Med. Chem.
Lett., 2010, 20, 141–144.
37 A. J. Szentmiklosi, A. Cseppento, R. Gesztelyi, J. Zsuga,
A. Kortvely, G. Harmati and P. P. Nanasi, Curr. Med. Chem.,
2011, 18, 3695–3706.
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View Article Online
Paper
RSC Advances
38 R. Mohebat, A. Yazdani Elah Abadi, A. Soltani and 44 K. Wimalasena and D. C. Haines, J. Org. Chem., 1994, 59,
M. Sagha, ARKIVOC, 2016, iv, 1–9. 6472–6475.
39 R. Mohebat, M. Anary-Abbasinejad, S. Hajmohammadi and 45 (a) Q. F. Wang, H. Hou, L. Hui and C. G. Yan, J. Org. Chem.,
A. Hassanabadi, Synth. Commun., 2013, 43, 2833–2840.
40 R. Mohebat, A. Yazdani Elah Abadi, M. T. Maghsoodlou and
M. Mohammadi, Res. Chem. Intermed., 2016, 42, 5915–5926.
41 R. Mohebat, A. Yazdani Elah Abadi, M. T. Maghsoodlou,
M. Mohammadi and R. Heydari, Res. Chem. Intermed.,
2016, 42, 7121–7132.
42 R. Mohebat, A. Yazdani Elah Abadi and M. T. Maghsoodlou,
Res. Chem. Intermed., 2016, 42, 6039–6048.
43 A. Yazdani Elah Abadi, M. T. Maghsoodlou, R. Heydari and
R. EMohebat, Res. Chem. Intermed., 2016, 42, 1227–1235.
2009, 74, 7403–7406; (b) S. Majumder, M. Sharma and
P. J. Bhuyan, Tetrahedron Lett., 2013, 54, 6868–6870; (c)
Y. R. Lee and J. Y. Suk, Tetrahedron, 2002, 58, 2359–2367;
(d) Y. R. Lee, J. Y. Suk and B. S. Kim, Tetrahedron Lett.,
1999, 40, 6603–6607; (e) R. Antonioletti, P. Bovicelli and
S. Malancona, Tetrahedron, 2002, 58, 589–596; (f)
R. Antonioletti, G. Righi, L. Olivieri and P. Bovicelli,
Tetrahedron Lett., 2000, 41, 10127–10130; (g) G. Mross,
E. Holtz and P. Langer, J. Org. Chem., 2006, 71, 8049; (h)
B. C. Ranu, L. Adak and S. Banerjee, Tetrahedron Lett.,
2008, 49, 4613–4617.
This journal is © The Royal Society of Chemistry 2016
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