A green and efficient four-component sequential protocol for the synthesis of novel 16-(aryl)benzo[a]indeno[2′,1′:5,6]pyrano[2,3-c]phenazin-15(16H)-one derivatives using oxalic acid as a reusable and cost-effective organic catalyst

Article abstract of DOI:10.1007/s11164-016-2522-y

A sequential one-pot four-component reaction for the efficient synthesis of novel 16-(aryl)benzo[a]indeno[2′,1′:5,6]pyrano[2,3-c]phenazin-15(16H)-one derivatives has been developed. The synthesis was achieved by reacting 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamine, aromatic aldehydes, and 1,3-indandione in the presence of oxalic acid as a reusable and homogenous organocatalyst in EtOH/H₂O (1:1) under reflux. The present approach of this methodology offers several advantages such as high yields, clean reaction profiles, operational simplicity, simple work-up procedures, and green aspects by avoiding toxic catalysts and solvents.

Full text of DOI:10.1007/s11164-016-2522-y

Res Chem Intermed
DOI 10.1007/s11164-016-2522-y
A green and efficient four-component sequential
protocol for the synthesis of novel
16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-
c]phenazin-15(16H)-one derivatives using oxalic acid
as a reusable and cost-effective organic catalyst
Razieh Mohebat1 Afshin Yazdani Elah Abadi2
•
•
Malek-Taher Maghsoodlou2 Mohsen Mohammadi1
Reza Heydari2
•
•
Received: 7 January 2016 / Accepted: 15 March 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A sequential one-pot four-component reaction for the efficient synthesis of
novel 16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one deriva-
tives has been developed. The synthesis was achieved by reacting 2-hydroxynaph-
thalene-1,4-dione, benzene-1,2-diamine, aromatic aldehydes, and 1,3-indandione in the
presenceofoxalicacidasareusableandhomogenousorganocatalystinEtOH/H2O(1:1)
under reflux. The present approach of this methodology offers several advantages such
as high yields, clean reaction profiles, operational simplicity, simple work-up proce-
dures, and green aspects by avoiding toxic catalysts and solvents.
Keywords Multi-component reactions (MCRs) Á Green chemistry Á
1,3-Indandione Á Oxalic acid
Introduction
In recent years, interest in green chemistry [1–3] has developed, and a major
challenge to organic chemists is that of reducing the use of organic solvents and
toxic reagents for facile, efficient, and nonpolluting synthetic procedures. In order to
have economic savings and pollution prevention, multi-component reactions
Electronic supplementary material Theonlineversionofthisarticle(doi:10.1007/s11164-016-2522-y)
contains supplementary material, which is available to authorized users.
&
Razieh Mohebat
raziehmohebat@yahoo.com; mohebat@iauyazd.ac.ir
1
2
Department of Chemistry, Islamic Azad University, Yazd Branch, P.O. Box 89195-155, Yazd,
Iran
Department of Chemistry, Faculty of Science, University of Sistan and Baluchistan, Zahedan,
Iran
123

R. Mohebat et al.
(MCRs) [4–7] have considerable ecological interest as a powerful strategy in the
synthesis of complex heterocyclic molecules, drug design, and drug discovery,
arising from minimization of time, waste, energy, and cost.
Phenazine-based compounds are nitrogen-containing heterocycles that are the
main core of many natural and synthetic organic materials [8–10]. Phenazines
exhibit important biological activities and wide applications in pharmaceutical use
such as trypanocidal [11], fungicidal [12, 13], antimalarial [14, 15], antiplatelet [16],
and antitumour [17] activities.
Furthermore, pyran annulated heterocyle derivatives are an important class of
oxygen-containing heterocycles and are usually structural subunits in a variety of
important natural compounds, including carbohydrates, alkaloids, polyether antibi-
otics, pheromones, and iridoids [18]. Pyarans are widely employed as cosmetics,
pigments [19] and potential biodegradable agrochemicals [20] and have various
biological properties such as being anti-leishmanial [21], anti-HIV [22], antioxidant
[23], anti-tumor [24] and central nervous system (CNS) activities and effects [25];
they are also used for treatment of Alzheimer’s disease [26] and schizophrenia [27].
Oxalic acid is the only possible compound in which two carboxylic groups are
joined directly, and; hence, is supposed to be one of the strongest organic acids. It is
abundantly present in many plants so it can be used in green chemistry. The use of
organic catalysts as a catalyst is increasing because of their significant advantages,
such as the possibility of performing reactions in the presence of acid-sensitive
substrates, performing reactions in milder reaction conditions, and selectivity [28].
In the past years, oxalic acid was efficiently used as a catalyst in a variety of
chemical reactions like the imino Diels–Alder reaction [29], Beckmann rearrange-
ment [30], protection of carbonyl to thioacetal changes,and deprotection of
thioacetal to carbonyls as well [31].
Considering the importance of phenazine, pyran, and quinoxaline derivatives and in
continuation of our ongoing program for the synthesis of complex organic compounds
based on green chemistry protocols [32–36], herein, we have presented a novel and
efficient method for synthesis of 16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-
Scheme 1 Synthesis of 16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one derivatives
in the presence of oxalic acid as a homogenous catalyst
123

A green and efficient four-component sequential protocol…
c]phenazin-15(16H)-one derivatives 6a–j. This reaction was achieved via a sequen-
tial, one-pot, four-component condensation reaction between 2-hydroxynaphthalene-
1,4-dione 1, benzene-1,2-diamine 2, aromatic aldehydes 4 and 1,3-indandione 5 using
oxalic acid as a green, inexpensive, and easily available catalyst (Scheme 1).
Experimental
General
All melting points were determined on an Electrothermal 9100 apparatus and are
uncorrected. IR spectra were recorded on a Shimadzu IR-470 spectrometer.
Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid
analyzer at the Iranian Central Research of Petroleum Company. Mass spectra were
recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization
1
potential of 70 eV. The H nuclear magnetic resonance (NMR) and 13C NMR
spectra were recorded on a Bruker DRX-400 Avance instrument with deuterated
dimethyl sulfoxide (DMSO-d6) as solvent. Thin-layer chromatography (TLC) was
performed on silica-gel Polygram SILG/UV 254 plates. All reagents and solvents
were purchased from Merck and Aldrich and used without further purification.
General experimental procedure for the synthesis
of 16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one
derivatives (6a–j)
Initially, 2-hydroxynaphthalene-1,4-dione 1 (1 mmol) and benzene-1,2-diamine 2
(1 mmol) were mixed at 75 °C (solvent free) until in less than 5 min an orange solid
of benzo[a]phenazine 3 was formed. Then, aryl aldehyde 4 (1 mmol), 1,3-
indandione 5 (1 mmol), and oxalic acid (20 mol%) were added, and this mixture
was heated to reflux under stirring in EtOH/H2O [1/1 (v/v), 30 mL] for the specific
time (2–2.5 h). Upon completion of the reaction, monitored by TLC, then, the
reaction mixture was cooled to room temperature, and H2O (5 mL) was added to
this mixture. The precipitate formed was collected by filtration, then, the separated
product was washed twice with water (2 9 5 mL). The resulting product
subsequently recrystallized from hot ethanol to give the pure solid. After isolation
of the product, the filtrate was extracted with CHCl3 (2 9 20 mL). The aqueous
layer (including oxalic acid) was separated, and its solvent was evaporated, and
oxalic acid was recovered and reused. The spectral and analytical data are presented
below.
16-(4-Nitrophenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one
(6a)
Yellow solid; yield 92 %, 0.466 g; mp 250–252 °C; IR (KBr) (mmax, cm-1): 2930,
1697, 1628, 1592, 1516, 1456, 1404, 1342, 1238, 1126, 973, 760; 1H NMR
(400 MHz, DMSO-d6): dH 6.03 (s, 1H, CH), 7.56–7.61 (m, 1H, Ar–H), 7.80–7.84
123

R. Mohebat et al.
(m, 2H, Ar–H), 7.85–7.92 (m, 5H, Ar–H), 8.13 (d, 2H, J = 8.8 Hz, Ar–H),
8.19–8.23 (m, 1H, Ar–H), 8.24–8.32 (m, 3H, Ar–H), 8.79 (d, 1H, J = 7.6 Hz, Ar–
H), 9.21–9.25 (m, 1H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6): dC 36.1,
110.3, 113.9, 119.0, 120.9, 121.0, 121.8, 122.5, 123.4, 124.7, 125.2, 128.0, 128.9,
129.2, 129.3, 129.7, 130.6, 130.8, 131.3, 131.9, 139.4, 139.7, 139.9, 142.4, 145.4,
147.1, 148.1, 150.8, 151.1, 190.4 ppm; MS (m/z, %): 507 (M?, 4); Anal. Calcd for
C32H17N3O4: C, 75.73; H, 3.38; N, 8.28 %. Found: C, 75.86; H, 3.45; N, 8.13 %.
16-(4-Chlorophenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one
(6b)
Yellow solid; yield 89 %, 0.441 g; mp 261–263 °C; IR (KBr) (mmax, cm-1): 2900,
1716, 1660, 1587, 1537, 1448, 1327, 1262, 1123, 935, 757; H NMR (400 MHz,
1
DMSO-d6): dH 5.95 (s, 1H, CH), 7.40–7.45 (m, 1H, Ar–H), 7.83–7.86 (m, 2H, Ar–
H), 7.88–7.91 (m, 5H, Ar–H), 8.14 (d, 2H, J = 7.6 Hz, Ar–H), 8.25–8.27 (m, 2H,
Ar–H), 8.28–8.32 (m, 2H, Ar–H), 8.74 (d, 1H, J = 7.6 Hz, Ar–H), 9.23–9.26 (m,
1H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6): dC 34.5, 106.6, 114.0, 122.5,
122.8, 123.4, 124.1, 124.5, 124.8, 124.9, 126.3, 127.0, 127.4, 127.6, 127.9, 129.2,
129.4, 129.9, 130.1, 130.5, 131.8, 132.4, 140.1, 146.0, 147.1, 148.9, 150.3, 152.3,
188.6 ppm; MS (m/z, %): 496 (M?, 6); Anal. Calcd for C32H17ClN2O2: C, 77.34; H,
3.45; N, 5.64 %. Found: C, 77.48; H, 3.58; N, 5.80 %.
16-(3-Nitrophenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one
(6c)
Yellow solid; yield 90 %, 0.456 g; mp 234–235 °C; IR (KBr) (mmax, cm-1): 2905,
1720, 1678, 1589, 1525, 1448, 1399, 1338, 1241, 1179, 960, 754; 1H NMR
(400 MHz, DMSO-d6): dH 6.03 (s, 1H, CH), 7.57–7.62 (m, 2H, Ar–H), 7.79–8.03
(m, 6H, Ar–H), 8.19–8.26 (m, 3H, Ar–H), 8.35 (d, 1H, J = 7.6 Hz, Ar–H), 8.40 (dd,
1H, J1 = 8.0 Hz, J2 = 2.0 Hz, Ar–H), 8.59 (s, 1H, Ar–H), 8.64 (d, 1H, J = 8.0 Hz,
Ar–H), 9.12 (d, 1H, J = 7.6 Hz, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6): dC
35.5, 113.9, 121.5, 122.0, 122.3, 123.0, 123.2, 123.3, 123.7, 124.8, 126.6, 126.9,
128.7, 129.0, 129.1, 129.7, 129.8, 130.1, 130.4, 130.7, 130.8, 135.4, 136.1, 136.2,
136.6, 139.6, 142.1, 144.9, 147.8, 150.1, 152.2, 188.8 ppm; MS (m/z, %): 507 (M?,
7); Anal. Calcd for C32H17N3O4: C, 75.73; H, 3.38; N, 8.28 %. Found: C, 75.85; H,
3.46; N, 8.41 %.
16-(2-Chlorophenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one
(6d)
Brown solid; yield 88 %, 0.436 g; mp 296–298 °C; IR (KBr) (mmax, cm-1): 2900,
1703, 1618, 1591, 1526, 1447, 1390, 1338, 1218, 1130, 999, 754; 1H NMR
(400 MHz, DMSO-d6): dH 6.05 (s, 1H, CH), 7.05–7.07 (m, 1H, Ar–H), 7.56–7.60
(m, 1H, Ar–H), 7.82–7.93 (m, 8H, Ar–H), 8.07–8.09 (m, 1H, Ar–H), 8.14 (d, 1H,
J = 8.4 Hz, Ar–H), 8.23–8.33 (m, 3H, Ar–H), 9.24–9.27 (m, 1H, Ar–H) ppm; 13C
NMR (100 MHz, DMSO-d6): dC 32.2, 109.3, 113.8, 118.7, 122.1, 122.3, 122.9,
123

A green and efficient four-component sequential protocol…
123.4, 124.7, 124.8, 126.9, 127.7, 128.2, 128.4, 128.7, 129.0, 129.1, 129.2, 129.5,
129.6, 130.0, 130.2, 130.4, 130.7, 130.9, 136.4, 139.3, 141.7, 148.5, 150.3, 152.2,
190.8 ppm; MS (m/z, %): 496 (M?, 3); Anal. Calcd for C32H17ClN2O2: C, 77.34; H,
3.45; N, 5.64 %. Found: C, 77.25; H, 3.58; N, 5.77 %.
16-(4-Chloro-3-nitrophenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-
15(16H)-one (6e)
Yellow solid; yield 91 %, 0.492 g; mp 243–245 °C; IR (KBr) (mmax, cm-1): 2910,
1719, 1674, 1589, 1530, 1476, 1401, 1344, 1201, 1135, 951, 754; 1H NMR
(400 MHz, DMSO-d6): dH 5.96 (s, 1H, CH), 7.57–7.59 (m, 1H, Ar–H), 7.67 (d, 1H,
J = 8.4 Hz, Ar–H), 7.84–7.87 (m, 2H, Ar–H), 7.91 (d, 3H, J = 8.0 Hz, Ar–H), 7.97
(t, 2H, J = 8.0 Hz, Ar–H), 8.14 (d, 1H, J = 7.2 Hz, Ar–H), 8.22–8.26 (m, 2H, Ar–
H), 8.33 (d, 1H, J = 7.6 Hz, Ar–H), 8.36 (s, 1H, Ar–H), 9.16 (d, 1H, J = 7.2 Hz,
Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6): dC 34.8, 113.2, 122.1, 122.3, 122.9,
123.6, 124.8, 125.4, 127.4, 128.7, 129.0, 129.7, 130.3, 130.4, 130.7, 130.8, 131.3,
132.0, 133.5, 134.0, 136.3, 136.5, 138.1, 139.3, 139.9, 140.7, 141.5, 143.8, 147.3,
150.2, 152.1, 191.5 ppm; MS (m/z, %): 541 (M?, 9); Anal. Calcd for C32H16ClN3-
O4: C, 70.92; H, 2.98; N, 7.75 %. Found: C, 71.09; H, 3.14; N, 7.90 %.
16-(3-Methoxyphenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-
one (6f)
Brown solid; yield 86 %, 0.423 g; mp 290–292 °C; IR (KBr) (mmax, cm-1): 2985,
1709, 1670, 1589, 1526, 1446, 1396, 1337, 1219, 1135, 996, 755; 1H NMR
(400 MHz, DMSO-d6): dH 3.69 (s, 3H, OCH3), 5.91 (s, 1H, CH), 7.17 (t, 1H,
J = 8.0 Hz, Ar–H), 7.25 (d, 1H, J = 8.0 Hz, Ar–H), 7.29 (s, 1H, Ar–H), 7.52–7.54
(m, 1H, Ar–H), 7.84–7.93 (m, 7H, Ar–H), 8.15 (d, 1H, J = 8.4 Hz, Ar–H),
8.27–8.34 (m, 3H, Ar–H), 9.25–9.27 (m, 1H, Ar–H) ppm; 13C NMR (100 MHz,
DMSO-d6): dC 35.8, 54.8, 110.8, 117.7, 122.2, 122.7, 123.3, 124.7, 124.8, 125.3,
125.4, 126.7, 128.8, 129.3, 130.0, 130.2, 130.4, 130.9, 131.0, 133.7, 135.8, 139.3,
139.4, 139.6, 140.3, 144.7, 146.6, 148.0, 150.3, 152.4, 190.3 ppm; MS (m/z, %):
492 (M?, 6); Anal. Calcd for C33H20N2O3: C, 80.47; H, 4.09; N, 5.69 %. Found: C,
80.58; H, 4.26; N, 5.82 %.
3-(15-Oxo-15,16-dihydrobenzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-16-
yl)benzonitrile (6g)
Brown solid; yield 90 %, 0.438 g; mp 230–232 °C; IR (KBr) (mmax, cm-1): 2895,
2200, 1709, 1679, 1590, 1529, 1454, 1410, 1335, 1252, 1124, 959, 767; H NMR
1
(400 MHz, DMSO-d6): dH 5.96 (s, 1H, CH), 7.50 (t, 1H, J = 8.0 Hz, Ar–H),
7.55–7.57 (m, 1H, Ar–H), 7.65 (d, 1H, J = 7.6 Hz, Ar–H), 7.67 (t, 1H, J = 8.0 Hz,
Ar–H), 7.83–7.90 (m, 3H, Ar–H), 7.91–8.04 (m, 3H, Ar–H), 8.10 (s, 1H, Ar–H),
8.25 (t, 2H, J = 8.0 Hz, Ar–H), 8.31 (d, 1H, J = 7.6 Hz, Ar–H), 8.65 (d, 1H,
J = 8.0 Hz, Ar–H), 9.15–9.17 (m, 1H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-
d6): dC 35.3, 111.2, 114.2, 118.9, 122.0, 122.2, 123.2, 123.3, 123.6, 124.8, 128.7,
123

R. Mohebat et al.
128.9, 129.1, 129.5, 129.7, 129.8, 130.2, 130.4, 130.7, 130.8, 131.7, 133.4, 135.4,
136.1, 136.2, 136.5, 137.5, 141.7, 142.2, 144.2, 150.2, 152.3, 191.0 ppm; MS (m/z,
%): 487 (M?, 10); Anal. Calcd for C33H17N3O2: C, 81.30; H, 3.51; N, 8.62 %.
Found: C, 81.46; H, 3.45; N, 8.77 %.
16-(3,4-Dimethoxyphenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-
15(16H)-one (6h)
Yellow solid; yield 85 %, 0.444 g; mp 246–247 °C; IR (KBr) (mmax, cm-1): 2935,
1701, 1664, 1563, 1496, 1444, 1415, 1336, 1264, 1135, 994, 754; 1H NMR
(400 MHz, DMSO-d6): dH 3.89, 3.90 (s, 6H, 2OCH3), 5.88 (s, 1H, CH), 7.14 (d, 1H,
J = 8.4 Hz, Ar–H), 7.77 (s, 1H, Ar–H), 7.82–7.86 (m, 1H, Ar–H), 7.89–7.92 (m,
5H, Ar–H), 7.95–7.96 (m, 1H, Ar–H), 8.00 (dd, 1H, J1 = 8.4 Hz, J2 = 2.0 Hz, Ar–
H), 8.14 (d, 1H, J = 7.6 Hz, Ar–H), 8.27 (d, 1H, J = 8.0 Hz, Ar–H), 8.30–8.32 (m,
1H, Ar–H), 8.66 (d, 1H, J = 2.0 Hz, Ar–H), 9.24–9.26 (m, 1H, Ar–H) ppm; 13C
NMR (100 MHz, DMSO-d6): dC 34.8, 55.4, 55.8, 111.4, 111.6, 112.4, 115.7, 122.7,
122.8, 124.7, 126.0, 126.1, 128.0, 128.4, 128.7, 129.2, 129.6, 130.0, 130.2, 130.7,
130.9, 131.0, 135.5, 135.6, 139.2, 141.7, 146.3, 148.2, 149.1, 150.8, 189.8 ppm; MS
(m/z, %): 522 (M?, 5); Anal. Calcd for C34H22N2O4: C, 78.15; H, 4.24; N, 5.36 %.
Found: C, 78.28; H, 4.43; N, 5.19 %.
16-(2-Hydroxy-3-methoxyphenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-
15(16H)-one (6i)
Yellow solid; yield 87 %, 0.442 g; mp 248–250 °C; IR (KBr) (mmax, cm-1): 2935,
1708, 1669, 1591, 1505, 1446, 1394, 1338, 1254, 1120, 960, 754; 1H NMR
(400 MHz, DMSO-d6): dH 3.93 (s, 3H, OCH3), 6.02 (s, 1H, CH), 6.96 (d, 1H,
J = 8.4 Hz, Ar–H), 7.76 (s, 1H, OH), 7.83–7.88 (m, 2H, Ar–H), 7.90–7.95 (m, 7H,
Ar–H), 8.16 (d, 1H, J = 7.2 Hz, Ar–H), 8.28 (d, 1H, J = 8.4 Hz, Ar–H), 8.31–8.33
(m, 1H, Ar–H), 8.71 (d, 1H, J = 1.6 Hz, Ar–H), 9.25–9.27 (m, 1H, Ar–H) ppm; 13
C
NMR (100 MHz, DMSO-d6): dC 34.9, 55.5, 111.4, 111.6, 112.4, 115.6, 116.8,
122.6, 122.7, 122.8, 124.7, 125.1, 128.0, 128.5, 128.7, 129.2, 130.0, 130.2, 130.9,
131.6, 135.3, 135.5, 139.1, 141.6, 146.8, 147.7, 147.9, 153.2, 189.9 ppm; MS (m/z,
%): 508 (M?, 4); Anal. Calcd for C33H20N2O4: C, 77.94; H, 3.96; N, 5.51 %.
Found: C, 78.12; H, 3.81; N, 5.68 %.
16-(2-Hydroxy-5-nitrophenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-
15(16H)-one (6j)
Yellow solid; yield 88 %, 0.460 g; mp 227–229 °C; IR (KBr) (mmax, cm-1): 2890,
1716, 1678, 1586, 1525, 1453, 1402, 1338, 1248, 1198, 960, 730; 1H NMR
(400 MHz, DMSO-d6): dH 6.03 (s, 1H, CH), 7.57–7.60 (m, 1H, Ar–H), 7.83 (t, 1H,
J = 8.0 Hz, Ar–H), 7.86–7.95 (m, 3H, Ar–H), 7.97–8.05 (m, 4H, Ar–H), 8.20 (d,
1H, J = 7.6 Hz, Ar–H), 8.24–8.29 (m, 1H, Ar–H), 8.35 (d, 1H, J = 8.0 Hz, Ar–H),
8.41 (dd, 1H, J1 = 8.0 Hz, J2 = 1.6 Hz, Ar–H), 8.66 (d, 1H, J = 8.0 Hz, Ar–H),
9.14–9.18 (m, 1H, Ar–H), 9.55 (s, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6):
123

A green and efficient four-component sequential protocol…
dC 34.9, 108.4, 108.5, 109.3, 112.4, 121.5, 122.9, 123.2, 123.4, 126.6, 126.9, 128.7,
129.0, 129.7, 130.1, 130.5, 130.9, 133.9, 135.4, 136.1, 136.2, 136.6, 139.7, 142.1,
146.3, 151.0, 152.8, 153.9, 191.3 ppm; MS (m/z, %): 523 (M?, 7); Anal. Calcd for
C32H17N3O5: C, 73.42; H, 3.27; N, 8.03 %. Found: C, 73.60; H, 3.43; N, 8.11 %.
Results and discussion
In this article, we began this study by subjecting 2-hydroxynaphthalene-1,4-dione,
benzene-1,2-diamine and 4-nitrobenzaldehyde to reactions with 1,3-indandione in
the presence of oxalic acid as catalyst in EtOH under reflux. Unfortunately, complex
mixtures were observed. To minimize the formation of byproducts, the 2-hydrox-
ynaphthalene-1,4-dione and benzene-1,2-diamine were mixed at 75 °C until in less
than 5 min an orange solid of benzo[a]phenazine was formed without using any
catalyst under solvent-free conditions. Next, 4-nitrobenzaldehyde, 1,3-indandione,
and oxalic acid as catalyst were added and the mixture was heated to reflux under
stirring in EtOH for 3 h. The desired product was obtained as a yellow solid in 82 %
yield. This two-step procedure allows the one-pot four-component reaction to be
controlled, avoiding the separation of intermediates, as well as time-consuming and
costly purification processes.
Then, to find optimized reaction conditions, our initial efforts focused on the
search for a catalyst for the one-pot, four-component condensation reaction between
2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamine, aromatic aldehydes, and
1,3-indandione. For this purpose, the condensation reaction between 2-hydroxy-
naphthalene-1,4-dione, benzene-1,2-diamine, 4-nitrobenzaldehyde and 1,3-indan-
dione for the synthesis of compound 6a was selected as a model reaction in the
presence of different catalytic systems. So, 2-hydroxynaphthalene-1,4-dione
(1 mmol) and benzene-1,2-diamine (1 mmol) were mixed at 75 °C until in less
than 5 min an orange solid of benzo[a]phenazine was formed without using any
catalyst under solvent-free conditions. Then, 4-nitrobenzaldehyde (1 mmol), 1,3-
indandione (1 mmol), and catalyst were added, and this mixture was heated to reflux
under stirring in EtOH, and the results are summarized in Table 1.
To select the best solvent for the reaction, the synthesis of compound 6a was
examined in different solvents (Table 1). As Table 1 indicates, the examined
solvents were not efficient separately. Higher yields and shorter reaction times were
obtained when the reaction was carried out in EtOH/H2O (1:1), due to its strong
hydrogen bonding ability, hydrophobic effects, and high polarity. Thus, EtOH/H2O
(1:1) was used as reaction media for all reactions.
After extensive screening, we found that the optimized best yields and time
profiles were obtained with 20 mol% of oxalic acid in EtOH/H2O (1:1) under reflux
conditions, which furnished the corresponding 16-(4-nitrophenyl)benzo[a]in-
deno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one 6a in 92 % yield within 2 h
(Table 1, entry 12). Increasing the amount of oxalic acid to more than 30 mol%,
showed no substantial improvement in the yield, whereas the yield decreased by
decreasing the amount of the catalyst to 10 mol%. Moreover, it was observed that
the reaction did not proceed efficiently in the absence of oxalic acid after a long
123

R. Mohebat et al.
Table 1 One-pot four-component synthesis of compound 6a from 2-hydroxynaphthalene-1,4-dione
(1 mmol), benzene-1,2-diamine (1 mmol), 4-nitrobenzaldehyde (1 mmol), and 1,3-indandione (1 mmol)
under various conditions
Entry
Catalyst
Reaction conditions
Time (h)
Yield (%)a
1
Oxalic acid (20 mol%)
PTSA (20 mol%)
SiO2–OSO3Hc (0.5 g)
EtOH, Reflux
2
2
2
3
3
3
3
3
3
3
2
2
3
3
3
4
82
30b
2
EtOH, Reflux
3
EtOH, Reflux
80
4
FeCl3 (20 mol%)
EtOH, Reflux
52
5
AlCl3 (20 mol%)
EtOH, Reflux
60
6
ZnCl2 (20 mol%)
EtOH, Reflux
65
7
CoCl2 (20 mol%)
EtOH, Reflux
73
8
Oxalic acid (20 mol%)
Oxalic acid (20 mol%)
Oxalic acid (20 mol%)
Oxalic acid (20 mol%)
Oxalic acid (20 mol%)
Oxalic acid (30 mol%)
Oxalic acid (10 mol%)
Oxalic acid (20 mol%)
–
H2O, Reflux
65
9
CH3CN, Reflux
CHCl3, Reflux
75
10
11
12
13
14
15
16
a
60
DMF, 100 °C
62
EtOH/H2O (1:1), Reflux
EtOH/H2O (1:1), Reflux
EtOH/H2O (1:1), Reflux
EtOH/H2O (1:1), 60 °C
EtOH/H2O (1:1), Reflux
92
92
81
75
Trace
Isolated yields
b
c
Mixture of products
Silica sulfuric acid
time (4 h). As shown in Table 1, oxalic acid as an organic catalyst afforded the
better results with respect to the inorganic catalysts.
To realize the generality and versatility of the catalyst, using these optimized
conditions, the reaction scope was evaluated by using different aromatic aldehydes.
All the reactions were complete in 2–2.5 h and resulted in the formation of the
corresponding novel 16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-
15(16H)-one derivatives (Scheme 1, Table 2, entries 1–10) in high yields as
identified by spectral data. Also, the reaction was examined in the presence of
aliphatic aldehydes such as n-heptanal and n-octanal but the product expected was
not obtained in these reaction conditions even after 8 h, because the activity of
aliphatic aldehydes are less than aromatic aldehydes (Table 2, entries 11, 12).
The influence of electron-withdrawing and electron-donating substituents on the
aromatic ring of aldehydes upon the reaction yields was investigated. The results
showed that both electron-withdrawing and electron-donating substituents had no
significant effect on the reaction yields. Moreover, the presence of halogen on the
aromatic ring of aldehydes had negligible effect on the reaction results.
Structural assignments of these new compounds have been made on the basis of
IR, 1H NMR, 13C NMR, and elemental analysis. The mass spectra of these
compounds displayed molecular ion peaks at the appropriate m/z values.
123

A green and efficient four-component sequential protocol…
Table 2 One-pot four-component synthesis of 16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-
15(16H)-one derivatives in the presence of oxalic acid (20 mol%) as a catalyst in EtOH/H2O (1:1) under
reflux conditions
Entry
Aldehydes
Product
Time (h)
Yield (%)a
1
4-(NO2)C6H4
4-ClC6H4
6a
6b
6c
6d
6e
6f
6g
6h
6i
2
92
89
90
88
91
86
90
85
87
88
–
2
2
3
3-(NO2)C6H4
2-ClC6H4
2
4
2
5
4-Cl-3-(NO2)C6H3
3-CH3OC6H4
3-CNC6H4
2.5
2.5
2.5
2.5
2.5
2.5
8
6
7
8
3,4-(CH3O)2C6H3
2-(OH)-3-CH3OC6H3
2-(OH)-5-(NO2)C6H3
n-C6H13
9
10
11
12
a
6j
–
n-C7H15
–
8
–
Isolated yields
Recovery of the catalysts is important in green organic synthesis. Thus, we also,
for recyclability of the catalysts, investigated the recycling of the oxalic acid in
EtOH/H2O (1:1) under reflux conditions using a selected model reaction of
2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamine, 4-nitrobenzaldehyde and
1,3-indandione in the presence of oxalic acid as homogeneous catalyst (Table 2,
entry 1).
After completion of the reaction, the reaction mixture was cooled to room
temperature and 5 mL of water was added to this mixture. The oxalic acid was
dissolved in water and filtered for separation of the crude product. The separated
product was washed twice with water (2 9 5 mL). The resulting product
subsequently recrystallized from hot ethanol to give the pure solid. After isolation
of the product, the filtrate was extracted with CHCl3 (2 9 20 mL). The aqueous
layer (including oxalic acid) was separated, and its solvent was evaporated to obtain
pure oxalic acid.
As shown in Fig. 1, the recycled catalyst was used for the next run under
identical reaction conditions. It was observed that the recovered catalyst works with
the same performance up to the 2nd run, while in the 3rd, 4th and 5th runs product
yield gets reduced slightly that may be due to little with loss of catalyst during each
recovery process.
A reaction mechanism consistent with the above results is shown in Scheme 2.
Oxalic acid plays a key role as a Brønsted–Lowry acid catalyst in this reaction. The
formation of 6 proceeds via initial condensation of 2-hydroxynaphthalene-1,4-dione
1 and benzene-1,2-diamine 2 to afford benzo[a]phenazin-5-ol 3 as reported, which
in situ generates an ortho-quinone methide (o-QM) intermediate 7 upon nucle-
ophilic addition to aldehyde. Subsequent Michael addition of the o-QM with 1,3-
indandione 5, followed by cyclization and dehydration, leads to the formation of
product 6.
123

R. Mohebat et al.
92
90
88
86
84
82
80
Run 1
92
Run 2
91
Run 3
88
Run 4
86
Run 5
85
Product (%)
Fig. 1 The reusability of the catalyst (0.018 g, 0.2 mmol) in the synthesis of 16-(4-
nitrophenyl)benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazin-15(16H)-one from 2-hydroxynaphthalene-
1,4-dione (1 mmol), benzene-1,2-diamine (1 mmol), 4-nitrobenzaldehyde (1 mmol) and 1,3-indandione
(1 mmol) in EtOH/H2O (1:1) under reflux conditions (2 h)
Scheme 2 Proposed mechanism for the synthesis of 16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-
c]phenazin-15(16H)-one derivatives
Conclusions
In summary, we have demonstrated an eco-friendly and efficient route for the one-
pot, four-component synthesis of 16-(aryl)benzo[a]indeno[20,10:5,6]pyrano[2,3-
c]phenazin-15(16H)-one derivatives via the reaction of 2-hydroxynaphthalene-1,4-
123

A green and efficient four-component sequential protocol…
dione, benzene-1,2-diamine, aromatic aldehydes and 1,3-indandione by using a
catalytic amount of oxalic acid in EtOH/H2O (1:1) under reflux conditions. The
advantages of this synthesis are the use of an inexpensive, readily available and
reusable catalyst, a convenient one-pot operation, short reaction times, easy work-
up, excellent yields of products, and reduced waste production without the use of
toxic catalysts and hazardous organic solvents. In all these cases, they make our
work a useful protocol for a green and economically cost-effective synthesis.
Moreover, this robust sequential reaction is expected to find immense application in
organic synthesis, medicinal chemistry, and material sciences.
Acknowledgments We gratefully acknowledge financial support from the Research Council of the
Islamic Azad University of Yazd and University of Sistan and Baluchestan.
References
1. P. Anastas, N. Eghbali, Chem. Soc. Rev. 39, 301 (2010)
2. P.T. Anastas, J.C. Warner, In Green Chemistry: Theory and Practice (Oxford University Press, New
York, 1998), p. 30
3. W. Leitner, Green Chem. 11, 603 (2009)
4. J. Zhu, H. Bienayme, Multicomponent Reactions (Wiley-VCH Verlag GmbH & Co. KGaA, Wein-
heim, 2005)
5. B.B. Toure, D.G. Hall, Chem. Rev. 109, 4439 (2009)
6. J.D. Sunderhaus, S.F. Martin, Chem. Eur. J. 15, 1300 (2009)
7. B. Ganem, Acc. Chem. Res. 42, 463 (2009)
8. J.B. Laursen, J. Nielsen, Chem. Rev. 104, 1663 (2004)
9. J. Bloxham, C.P. Dell, C. Smith, Heterocycles 38, 399 (1994)
10. S.B. Ferreira, K. Saloma˜o, F.C. da Silva, A.V. Pinto, C.R. Kaiser, A.C. Pinto, V.F. Ferreira, S.L. de
Castro, Eur. J. Med. Chem. 46, 3071 (2011)
11. C. Neves-Pinto, V. Malta, M. Pinto, R. Santos, S. Castro, A. Pinto, J. Med. Chem. 45, 740 (2002)
12. D. Cartwright, W. Chilton, D. Benson, Appl. Microbiol. Biotechnol. 43, 211 (1995)
13. J. Ligon, S. Dwight, P. Hammer, N. Torkewitz, D. Hofmann, H. Kempf, K. Pee, Pest. Manag. Sci. 56,
688 (2000)
14. M. Makgatho, R. Anderson, J. O’Sullivan, T. Egan, J. Freese, N. Cornelius, C. Van Rensburg, Drug
Dev. Res. 50, 195 (2000)
15. V. Andrade-Nieto, M. Goulart, J.F. da Silva, M.J. da Silva, M. Pinto, A. Pinto, M. Zalis, L. Carvalho,
A. Krettli, Bioorg. Med. Chem. Lett. 14, 1145 (2004)
16. M. Muller, T. Sorrell, Prostaglandins 50, 301 (1995)
17. G.W. Rewcastle, W.A. Denny, B.C. Baguley, J. Med. Chem. 30, 843 (1987)
18. L.F. Tietze, G. Kettschau, Top. Curr. Chem. 189, 12 (1997)
19. G.P. Ellis, in: A. Weissberger, E.C. Taylor (Eds.) (Wiley, New York, NY, 1977), pp. 11–139
(Chapter II)
20. E.A. Hafez, M.H. Elnagdi, A.G.A. Elagemey, F.M.A.A. El-Taweel, Heterocycles 26, 903 (1987)
21. T. Narender, S. Gupta, Bioorg. Med. Chem. Lett. 14, 3913 (2004)
22. K. Asres, A. Seyoum, C. Veeresham, F. Bucar, S. Gibbons, Phytother. Res. 19, 557 (2005)
23. A.J. Johnson, R.A. Kumar, S.A. Rasheed, S.P. Chandrika, A. Chandrasekhar, S. Baby, A. Subra-
moniam, J. Ethnopharmacol. 130, 267 (2010)
24. H. Quan-Bin, Y. Nian-Yun, T. Hong-Lei, Q. Chun-Feng, S. Jing-Zheng, C.C. Donald, C. Shi-Lin,
Q.L. Kathy, X. Hong-Xi, Phytochemistry 69, 2187 (2008)
25. F. Eiden, F. Denk, Arch. Pharm. 324, 353 (1991)
123

R. Mohebat et al.
26. C. Bruhlmann, F. Ooms, P.A. Carrupt, B. Testa, M. Catto, F. Leonetti, C. Altomare, A. Carotti, J.
Med. Chem. 44, 3195 (2001)
27. S.R. Kesten, T.G. Heffner, S.J. Johnson, T.A. Pugsley, J.L. Wright, D.L. Wise, J. Med. Chem. 42,
3718 (1999)
28. A. Khalafi-Nezhad, A. Parhami, A. Zare, A.R. Zare, A. Hasaninejad, F. Panahi, Synthesis 4, 617
(2008)
29. R. Nagarajan, P.T. Perumal, Synth. Commun. 31, 1733 (2001)
30. S. Chandrasekhar, K. Gopalaiah, Tetrahedron Lett. 44, 7437 (2003)
31. H. Miyake, Y. Nakao, M. Sasaki, Chem. Lett. 36, 104 (2007)
32. A.Y.E. Abadi, M.T. Maghsoodlou, R. Heydari, R. Mohebat, Res. Chem. Intermed. (2015). doi:10.
1007/s11164-015-2083-5
33. M.T. Maghsoodlou, N. Hazeri, M. Lashkari, F. Nejad Shahrokhabadi, B. Naghshbandi, M.S. Kazemi-
doost, M. Rashidi, F. Mir, M. Kangani, S. Salahi, Res. Chem. Intermed. (2014). doi:10.1007/s11164-
014-1793-4
34. F. Noori Sadeh, M.T. Maghsoodlou, N. Hazeri, M. Kangani, Res. Chem. Intermed. (2014). doi:10.
1007/s11164-014-1710-x
35. N. Hazeri, M.T. Maghsoodlou, F. Mir, M. Kangani, H. Saravani, E. Molashahi, Chin. J. Catal. 35,
391 (2014)
36. S.S. Sajadikhah, M.T. Maghsoodlou, N. Hazeri, S.M. Habibi-khorasani, A.C. Willis, Chin. Chem.
Lett. 23, 569 (2012)
123