PTSA-catalyzed four-component domino reactions for the one-pot synthesis of functionalized 11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-diones in PEG

Article abstract of DOI:10.1007/s11164-015-2413-7

An efficient p-toluenesulfonic acid catalyzed synthesis of 11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-dione derivatives has been described by one-pot, four-component condensation of 2-hydroxynaphthalene-1,4-dione, o-phenylenediamine, aromatic aldehydes using polyethylene glycol as solvent. This domino protocol produces biologically considerable heterocycles with the formation of C–C, C=C, C–N, C=N, C–O bonds in a single operation and this efficient green process provides significant advantages such as: operational simplicity, easy work-up procedure, high yields, avoidance of hazardous or toxic catalysts and organic solvents, and is devoid of inessential derivatization and generation of hazardous substances.

Full text of DOI:10.1007/s11164-015-2413-7

Res Chem Intermed
DOI 10.1007/s11164-015-2413-7
PTSA-catalyzed four-component domino reactions
for the one-pot synthesis of functionalized 11H-
benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-
11,16(17H)-diones in PEG
Razieh Mohebat1 Afshin Yazdani Elah Abadi2
•
•
Malek-Taher Maghsoodlou2 Mohsen Mohammadi1
•
Received: 6 October 2015 / Accepted: 28 December 2015
Ó Springer Science+Business Media Dordrecht 2016
Abstract An efficient p-toluenesulfonic acid catalyzed synthesis of 11H-ben-
zo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-dione derivatives has been
described by one-pot, four-component condensation of 2-hydroxynaphthalene-1,4-
dione, o-phenylenediamine, aromatic aldehydes using polyethylene glycol as sol-
vent. This domino protocol produces biologically considerable heterocycles with the
formation of C–C, C=C, C–N, C=N, C–O bonds in a single operation and this
efficient green process provides significant advantages such as: operational sim-
plicity, easy work-up procedure, high yields, avoidance of hazardous or toxic cat-
alysts and organic solvents, and is devoid of inessential derivatization and
generation of hazardous substances.
Keywords Multi-component reactions (MCRs) Á One-pot synthesis Á 2-
Hydroxynaphthalene-1 Á 4-Dione Á o-Phenylenediamine Á p-Toluenesulfonic acid Á
Polyethylene glycol
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2413-7)
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.
Introduction
Synthesis of simple and complex bioactive heterocycles such as natural products
and analogues, drugs, diagnostics, agrochemicals and any kind of material is a
significant subject in modern chemistry [1–3]. Diversity-oriented synthesis (DOS)
has played a critical role in the development of the design and synthesis of new
diverse polycyclic heterocycles with potential medicinal and biological activity in
the field of organic, combinatorial, and medicinal chemistry [4, 5]. DOS provides
the synthetic means 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 [6]. Multicom-
ponent reactions (MCRs) and multicomponent domino or tandem reactions are
useful tools in combinatorial and DOS chemistry due to their advantages such as
higher productivity, simple procedures, 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 [7–12].
Nitrogen-containing heterocyclic molecules in five- and six-membered rings
constitute the largest portion of chemical entities, which are part of many natural
products playing important roles in medicinal chemistry due to their pharmaceutical
and biological activities [13, 14]. In this area, phenazine derivatives that are present
in natural and synthetic products have attracted considerable interest due to their
useful biological properties such as antimalarial [15], fungicidal [16], trypanocidal
[17], antiplatelet [18], antitumor and antiparasitic [19] activities.
In addition, heterocyclic compounds containing chromene moieties are an
important class of natural and synthetic compounds that have received significant
attention from organic chemists because of their biological and pharmaceutical
activities [20]. They are present widely in plants such as edible vegetables and fruits
[21], showing a variety of biological functions, including antifungal [22],
antimicrobial [23], antileishmanial [24, 25], anti-oxidant [26], antitumor [27],
hypotensive [28] and antiproliferation agents [29].
Organic solvents used in most of the synthetic organic chemistry evaporate into
the atmosphere with destructive effects on the environment and the ozone layer
[30]. Water [31, 32], ionic liquids [33], phase-transfer catalysts [34], polyethylene
glycol (PEG) [35–37], etc. can be used instead of hazardous, toxic, flammable,
volatile, difficult to recycle and expensive organic solvents.
Therefore, considering our work on multi-component reactions [38–41], and in
continuation of our ongoing program for the synthesis of heterocyclic compounds
based on green chemistry protocols [42–45], we report here on the preparation of
functionalized
11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-
dione derivatives 5 through a domino, one-pot, four-component condensation
reaction between 2-hydroxynaphthalene-1,4-dione 1, o-phenylenediamine 2, aro-
matic aldehydes 4 in the presence of PTSA as a mild, efficient, non-toxic and
inexpensive Lewis acid catalyst using PEG-400 as eco-friendly solvent system at
80 °C (Scheme 1).
123

PTSA-catalyzed four-component domino reactions for the…
Scheme 1 Synthesis of 11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-dione derivatives
in the presence of PTSA as solid acid catalyst
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 Bruker DRX-400 Advance instrument with dimethyl
sulfoxide (DMSO) 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 11H-benzo[a]
benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-dione derivatives (5a–k)
At the first step, 2-hydroxynaphthalene-1,4-dione 1 (1 mmol), o-phenylenediamine
2 (1 mmol) and PTSA (20 mol% or 0.2 mmol) and 5 mL of PEG-400 were mixed
in a 50-mL round-bottomed flask and the contents were stirred magnetically in an
oil-bath maintained at 80 °C until in\30 min an orange solid of benzo[a]phenazine
3 was formed. Then, aryl aldehyde 4 (1 mmol) and 2-hydroxynaphthalene-1,4-dione
1 (1 mmol) were added to the above reaction mixture which was heated further for
the times reported in Table 2. Upon completion of the reaction, monitored by TLC,
the reaction mixture was cooled to room temperature and was quenched with H2O
(5 mL). The precipitate formed was collected by filtration at pump, then the
separated product was washed with water. The resulting product subsequently
recrystallized from hot ethanol to give the pure solid 5. The spectral and analytical
data are presented below.
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R. Mohebat et al.
17-(4-Nitrophenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-
dione (5a)
Yellow solid; yield 93 %, 0.497 g; mp 273–275 °C; IR (KBr) (mmax, cm-1): 2920,
1693, 1662, 1635, 1585, 1512, 1340, 1289, 1168, 1054, 758; H NMR (400 MHz,
1
DMSO-d6): dH 5.93 (s, 1H, CH), 7.75–7.79 (m, 1H, Ar–H), 7.78 (d, 2H, J = 8.8 Hz,
Ar–H), 7.85–7.94 (m, 5H, Ar–H), 7.97 (d, 2H, J = 9.2 Hz, Ar–H), 8.04 (d, 1H,
J = 7.6 Hz, Ar–H), 8.17 (t, 2H, J = 8.8 Hz, Ar–H), 8.40 (d, 1H, J = 7.6 Hz, Ar–
H), 8.62 (d, 1H, J = 8.0 Hz, Ar–H), 9.12 (d, 1H, J = 8.0 Hz, Ar–H); 13C NMR
(100 MHz, DMSO-d6): dC 32.1, 111.5, 113.8, 114.2, 118.0, 121.5, 122.6, 122.8,
122.9, 124.7, 128.0, 128.5, 128.7, 129.2, 130.0, 130.2, 130.6, 132.6, 133.7, 134.5,
136.1, 137.2, 134.5, 136.1, 137.2, 138.7, 140.3, 144.1, 144.9, 145.6, 147.6, 154.5,
177.1, 178.6; MS (m/z, %): 535 (M?, 6); Anal. Calcd for C33H17N3O5: C, 74.01; H,
3.20; N, 7.85 %. Found: C, 74.15; H, 3.36; N, 7.92 %.
17-(4-Chlorophenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-
dione (5b)
Orange solid; yield 91 %, 0.476 g; mp 324–326 °C; IR (KBr) (mmax, cm-1): 3035,
1688, 1651, 1632, 1590, 1483, 1352, 1286, 1164, 1049, 757; H NMR (400 MHz,
1
DMSO-d6): dH 5.98 (s, 1H, CH), 7.19 (d, 2H, J = 8.4 Hz, Ar–H), 7.56 (d, 2H,
J = 8.4 Hz, Ar–H), 7.77 (td, 1H, J1 = 1.2 Hz, J2 = 7.6 Hz, Ar–H), 7.93–7.98 (m,
3H, Ar–H), 8.00 (dd, 1H, J1 = 1.2 Hz, J2 = 7.2 Hz, Ar–H), 8.04 (t, 2H,
J = 6.7 Hz, Ar–H), 8.25–8.27 (m, 2H, Ar–H), 8.46 (d, 1H, J = 7.6 Hz, Ar–H),
8.70 (d, 1H, J = 7.6 Hz, Ar–H), 9.22 (d, 1H, J = 7.6 Hz, Ar–H); 13C NMR
(100 MHz, DMSO-d6): dC 33.3, 113.5, 116.6, 117.5, 120.7, 121.7, 122.4, 124.7,
127.8, 128.6, 128.8, 129.1, 129.3, 130.6, 130.8, 130.9, 131.0, 131.6, 135.2, 138.5,
140.3, 140.8, 141.6, 142.3, 144.9, 149.9, 154.4, 156.2, 176.8, 178.1; MS (m/z, %):
524 (M?, 11); Anal. Calcd for C33H17ClN2O3: C, 75.50; H, 3.26; N, 5.34 %. Found:
C, 75.64; H, 3.19; N, 5.46 %.
17-(3-Nitrophenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-
dione (5c)
Orange solid; yield 90 %, 0.481 g; mp 368–370 °C; IR (KBr) (mmax, cm-1): 3020,
1686, 1660, 1636, 1590, 1524, 1339, 1286, 1166, 1049, 759; H NMR (400 MHz,
1
DMSO-d6): dH 6.16 (s, 1H, CH), 7.46 (t, 1H, J = 7.6 Hz, Ar–H), 7.57 (t, 1H,
J = 8.0 Hz, Ar–H), 7.79–8.12 (m, 9H, Ar–H), 8.27–8.30 (m, 1H, Ar–H), 8.45 (s,
1H, Ar–H), 8.54–8.56 (m, 1H, Ar–H), 8.81 (d, 1H, J = 8.0 Hz, Ar–H), 9.26 (t, 1H,
J = 8.0 Hz, Ar–H); 13C NMR (100 MHz, DMSO-d6): dC 31.5, 113.0, 114.8, 119.4,
120.2, 120.6, 121.0, 123.0, 125.5, 125.7, 125.8, 128.1, 128.9, 129.0, 129.8, 130.7,
134.4, 138.3, 139.6, 140.1, 140.5, 144.9, 146.4, 153.5, 154.9, 175.4, 178.1; MS (m/
z, %): 535 (M?, 3); Anal. Calcd for C33H17N3O5: C, 74.01; H, 3.20; N, 7.85 %.
Found: C, 74.12; H, 3.33; N, 7.73 %.
123

PTSA-catalyzed four-component domino reactions for the…
17-(2-Nitrophenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-
dione (5d)
Brown solid; yield 90 %, 0.481 g; mp 293–295 °C; IR (KBr) (mmax, cm-1): 3035,
1688, 1655, 1630, 1590, 1526, 1341, 1286, 1171, 1048, 761; H NMR (400 MHz,
1
DMSO-d6): dH 6.14 (s, 1H, CH), 7.39–7.44 (m, 1H, Ar–H), 7.53 (t, 1H, J = 7.6 Hz,
Ar–H), 7.61–7.66 (m, 1H, Ar–H), 7.73 (t, 1H, J = 8.0 Hz, Ar–H), 7.85–8.11 (m,
8H, Ar–H), 8.24 (d, 1H, J = 8.0 Hz, Ar–H), 8.49 (t, 1H, J = 7.2 Hz, Ar–H), 8.71
(d, 1H, J = 8.4 Hz, Ar–H), 9.18 (t, 1H, J = 7.6 Hz, Ar–H); 13C NMR (100 MHz,
DMSO-d6): dC 32.6, 114.1, 115.0, 116.1, 119.0, 120.0, 121.0, 122.8, 126.2, 126.3,
126.4, 127.3, 129.2, 130.2, 130.5, 130.7, 131.1, 131.4, 132.3, 133.7, 135.2, 139.6,
140.5, 143.7, 145.5, 146.9, 155.1, 156.5, 177.4, 178.3; MS (m/z, %): 535 (M?, 7);
Anal. Calcd for C33H17N3O5: C, 74.01; H, 3.20; N, 7.85 %. Found: C, 74.11; H,
3.38; N, 8.02 %.
17-(2-Chlorophenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-
dione (5e)
Orange solid; yield 89 %, 0.466 g; mp 336–338 °C; IR (KBr) (mmax, cm-1): 3035,
1687, 1657, 1635, 1585, 1493, 1349, 1286, 1165, 1048, 757; H NMR (400 MHz,
1
DMSO-d6): dH 5.49 (s, 1H, CH), 7.04 (t, 1H, J = 8.0 Hz, Ar–H), 7.20 (d, 1H,
J = 8.0 Hz, Ar–H), 7.36–7.49 (m, 2H, Ar–H), 7.73–8.28 (m, 10H, Ar–H), 8.54 (d,
1H, J = 8.0 Hz, Ar–H), 9.23–8.28 (m, 1H, Ar–H); 13C NMR (100 MHz, DMSO-
d6): dC 32.0, 114.0, 114.4, 115.1, 121.6, 122.5, 123.1, 128.6, 129.0, 129.3, 129.4,
131.4, 131.8, 131.9, 132.7, 133.4, 133.9, 134.0, 134.3, 134.7, 139.0, 139.6, 140.3,
143.5, 144.1, 146.7, 148.3, 156.2, 175.9, 176.8; MS (m/z, %): 524 (M?, 10); Anal.
Calcd for C33H17ClN2O3: C, 75.50; H, 3.26; N, 5.34 %. Found: C, 75.42; H, 3.34;
N, 5.47 %.
17-(p-tolyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-dione
(5f)
Orange solid; yield 87 %, 0.438 g; mp 333–335 °C; IR (KBr) (mmax, cm-1): 2895,
1687, 1655, 1635, 1588, 1493, 1350, 1285, 1162, 1048, 752; H NMR (400 MHz,
1
DMSO-d6): dH 2.20 (s, 3H, CH3), 5.08 (s, 1H, CH), 6.98 (t, 1H, J = 7.6 Hz, Ar–H),
7.06 (d, 2H, J = 8.0 Hz, Ar–H), 7.32 (d, 2H, J = 8.0 Hz, Ar–H), 7.46–7.52 (m, 1H,
Ar–H), 7.74 (t, 1H, J = 8.0 Hz, Ar–H), 7.88–8.13 (m, 6H, Ar–H), 8.35 (t, 1H,
J = 8.0 Hz, Ar–H), 8.54–8.59 (m, 1H, Ar–H), 9.31 (t, 1H, J = 8.0 Hz, Ar–H); 13
C
NMR (100 MHz, DMSO-d6): dC 20.6, 33.8, 112.5, 114.2, 115.3, 115.7, 120.7,
121.6, 122.3, 123.4, 125.9, 128.4, 128.7, 128.8, 128.9, 129.0, 129.9, 130.3, 131.2,
131.7, 132.8, 134.7, 136.4, 138.9, 139.6, 140.3, 140.7, 144.6, 155.1, 155.5, 177.2,
178.1; MS (m/z, %): 504 (M?, 6); Anal. Calcd for C34H20N2O3: C, 80.94; H, 4.00;
N, 5.55 %. Found: C, 81.09; H, 4.14; N, 5.39 %.
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17-(2,4-Dichlorophenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16
(17H)-dione (5g)
Orange solid; yield 85 %, 0.474 g; mp 330–332 °C; IR (KBr) (mmax, cm-1): 3040,
1686, 1655, 1640, 1588, 1493, 1351, 1286, 1166, 1048, 750; H NMR (400 MHz,
1
DMSO-d6): dH 5.43 (s, 1H, CH), 7.08 (d, 1H, J = 9.2 Hz, Ar–H), 7.26 (d, 1H,
J = 8.4 Hz, Ar–H), 7.39–7.43 (m, 1H, Ar–H), 7.46 (d, 1H, J = 8.4 Hz, Ar–H),
7.72–8.23 (m, 8H, Ar–H), 8.44 (d, 1H, J = 7.2 Hz, Ar–H), 8.69 (d, 1H, J = 8.0 Hz,
Ar–H), 9.18 (d, 1H, J = 8.4 Hz, Ar–H); 13C NMR (100 MHz, DMSO-d6): dC 32.4,
110.3, 114.7, 115.7, 116.2, 118.5, 120.3, 122.5, 124.7, 124.8, 126.1, 127.1, 127.2,
128.0, 128.6, 129.4, 130.7, 131.8, 135.4, 137.4, 138.9, 140.5, 141.2, 141.7, 146.7,
147.5, 149.3, 154.6, 155.1, 174.9, 175.4; MS (m/z, %): 558 (M?, 8); Anal. Calcd for
C33H16Cl2N2O3: C, 70.85; H, 2.88; N, 5.01 %. Found: C, 70.77; H, 3.03; N, 5.14 %.
17-(4-Methoxyphenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16
(17H)-dione (5h)
Orange solid; yield 86 %, 0.447 g; mp 341–342 °C; IR (KBr) (mmax, cm-1): 3025,
1688, 1651, 1640, 1590, 1500, 1352, 1285, 1163, 1027, 752; H NMR (400 MHz,
1
DMSO-d6): dH 3.56 (s, 3H, OCH3), 5.05 (s, 1H, CH), 6.72 (d, 1H, J = 8.8 Hz, Ar–
H), 6.81 (d, 1H, J = 8.8 Hz, Ar–H), 7.34 (d, 1H, J = 8.8 Hz, Ar–H), 7.48 (d, 1H,
J = 8.8 Hz, Ar–H), 7.71–8.10 (m, 8H, Ar–H), 8.33 (t, 1H, J = 8.4 Hz, Ar–H), 8.52
(d, 1H, J = 7.6 Hz, Ar–H), 8.78 (d, 1H, J = 7.6 Hz, Ar–H), 9.29 (t, 1H,
J = 8.4 Hz, Ar–H); 13C NMR (100 MHz, DMSO-d6): dC 33.5, 55.8, 113.6,
113.8, 114.5, 117.7, 120.9, 121.8, 124.6, 125.9, 126.8, 129.1, 129.6, 130.0, 130.3,
131.2, 131.3, 131.7, 135.5, 139.5, 140.0, 141.0, 141.6, 142.9, 146.9, 153.2, 153.6,
156.9, 176.5, 178.3; MS (m/z, %): 520 (M?, 5); Anal. Calcd for C34H20N2O4: C,
78.45; H, 3.87; N, 5.38 %. Found: C, 78.60; H, 4.01; N, 5.25 %.
3-(11,16-Dioxo-16,17-dihydro-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazin-
17-yl)benzonitrile (5i)
Brown solid; yield 89 %, 0.458 g; mp 289–291 °C; IR (KBr) (mmax, cm-1): 2935,
2260, 1689, 1660, 1643, 1591, 1496, 1347, 1287, 1165, 1049, 754; 1H NMR
(400 MHz, DMSO-d6): dH 5.89 (s, 1H, CH), 7.35 (t, 1H, J = 8.0 Hz, Ar–H), 7.47
(d, 1H, J = 8.0 Hz, Ar–H), 7.75 (d, 1H, J = 8.0 Hz, Ar–H), 7.74–8.19 (m, 10H,
Ar–H), 8.37 (t, 1H, J = 8.0 Hz, Ar–H), 8.56–8.64 (m, 1H, Ar–H), 9.08 (t, 1H,
J = 8.0 Hz, Ar–H); 13C NMR (100 MHz, DMSO-d6): dC 33.5, 113.9, 115.1, 116.6,
118.4, 121.6, 122.8, 125.2, 129.0, 129.4, 129.5, 129.6, 130.4, 130.9, 131.0, 131.1,
131.2, 131.3, 131.8, 132.0, 133.1, 134.8, 140.2, 140.3, 141.8, 143.5, 146.0, 155.9,
158.9, 175.9, 177.4; MS (m/z, %): 515 (M?, 12); Anal. Calcd for C34H17N3O3: C,
79.21; H, 3.32; N, 8.15 %. Found: C, 79.18; H, 3.44; N, 8.31 %.
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17-(5-Bromo-2-hydroxyphenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-
11,16(17H)-dione (5j)
Brown solid; yield 86 %, 0.502 g; mp 359–361 °C; IR (KBr) (mmax, cm-1): 3030,
1689, 1645, 1615, 1582, 1519, 1331, 1284, 1122, 1075, 750; H NMR (400 MHz,
1
DMSO-d6): dH 5.68 (s, 1H, CH), 7.11 (d, 1H, J = 7.6 Hz, Ar–H), 7.47 (d, 1H,
J = 8.4 Hz, Ar–H), 8.00–8.14 (m, 8H, Ar–H), 8.33–8.37 (m, 3H, Ar–H), 8.86 (d,
1H, J = 8.0 Hz, Ar–H), 9.33 (d, 1H, J = 7.6 Hz, Ar–H), 10.62 (s, 1H, OH); 13C
NMR (100 MHz, DMSO-d6): dC 32.6, 115.9, 116.9, 117.2, 120.0, 121.8, 123.7,
124.2, 125.4, 127.3, 129.3, 129.4, 129.6, 130.5, 130.8, 131.2, 131.7, 132.1, 134.2,
136.0, 140.1, 140.6, 141.4, 145.4, 148.7, 152.5, 154.1, 156.5, 176.0, 177.4; MS (m/
z, %): 584 (M?, 9); Anal. Calcd for C33H17BrN2O4: C, 67.71; H, 2.93; N, 4.79 %.
Found: C, 67.83; H, 284; N, 4.68 %.
17-(2-Hydroxy-5-nitrophenyl)-11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-
11,16(17H)-dione (5k)
Brown solid; yield 88 %, 0.484 g; mp 364–366 °C; IR (KBr) (mmax, cm-1): 3035,
1685, 1658, 1640, 1587, 1524, 1340, 1270, 1165, 1049, 759; H NMR (400 MHz,
1
DMSO-d6): dH 5.24 (s, 1H, CH), 7.46 (t, 1H, J = 8.0 Hz, Ar–H), 7.57 (t, 1H,
J = 8.0 Hz, Ar–H), 7.73–7.81 (m, 1H, Ar–H), 7.87–8.13 (m, 8H, Ar–H), 8.27 (s,
1H, Ar–H), 8.52 (d, 1H, J = 8.0 Hz, Ar–H), 8.77 (d, 1H, J = 8.0 Hz, Ar–H), 9.23
(t, 1H, J = 8.0 Hz, Ar–H), 10.15 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): dC
33.2, 112.8, 116.4, 118.5, 119.6, 121.0, 121.9, 123.8, 125.7, 125.8, 125.9, 128.4,
129.3, 129.6, 130.1, 130.5, 130.8, 131.5, 131.6, 134.1, 134.4, 135.9, 138.6, 140.1,
140.6, 142.0, 147.0, 154.3, 157.9, 176.1, 177.9; MS (m/z, %): 551 (M?, 4); Anal.
Calcd for C33H17N3O6: C, 71.87; H, 3.11; N, 7.62 %. Found: C, 71.80; H, 3.28; N,
7.74 %.
Results and discussion
The strategy provided C–C, C=C, C–N, C=N, and C–O bonds in a single operation
through condensation/Knoevenagel/Michael/annulation sequences. In order to
investigate the reaction conditions for the synthesis of 11H-benzo[a]benzo[6,7]-
chromeno[2,3-c]phenazine-11,16(17H)-dione derivatives, we carried out the reac-
tion between 2-hydroxynaphthalene-1,4-dione (2 mmol), o-phenylenediamine
(1 mmol) and 4-nitrobenzaldehyde (1 mmol) as a model. Initially, we began this
domino one-pot four-component reaction in the absence of a catalyst in EtOH under
reflux and the product was obtained in very low yield after a long time.
Thus, our efforts were focused on the search for a suitable catalyst. At first, Lewis
acids such as ZnCl2 and FeCl3 (20 mol%) were chosen as a catalyst to perform this
reaction. As a result, low yields were obtained after a prolonged time (Table 1,
entries 2, 3). Attempts with HCl and H2SO4 as a catalyst were successful, which
afforded the corresponding products in 3 h with 78 and 83 % yield, respectively
(Table 1, entries 4, 5). Eventually, we discovered that PTSA showed excellent
123

R. Mohebat et al.
Table 1 Optimization of reaction conditions to domino one-pot four-component synthesis of compound
5a from 2-hydroxynaphthalene-1,4-dione (2 mmol), o-phenylenediamine (1 mmol) and 4-nitroben-
zaldehyde (1 mmol) under various conditions
Entry
Catalyst (mol%)
Reaction conditions
Time (h)
Yield (%)a
1
No catalyst
EtOH, reflux
8
6
6
3
3
3
3
3
3
3
3
8
3
2
1
6
2
2
Trace
45
2
ZnCl2 (20 mol%)
FeCl3 (20 mol%)
HCl (20 mol%)
H2SO4 (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (20 mol%)
PTSA (30 mol%)
PTSA (10 mol%)
EtOH, reflux
3
EtOH, reflux
40
4
EtOH, reflux
78
5
EtOH, reflux
83
6
EtOH, reflux
88
7
H2O, reflux
71
8
Toluene, 100 °C
THF, reflux
62
9
70
10
11
12
13
14
15
16
17
18
a
CH3CN, reflux
DMF, 100 °C
PEG-400, rt
75
64
Trace
91
PEG-400, 70 °C
PEG-400, 80 °C
PEG-400, 100 °C
PEG-400, 100 °C
PEG-400, 80 °C
PEG-400, 80 °C
93
91
94
93
87
Isolated yields
catalytic activity in terms of reaction time as well as yield of the product. We then
examined the effect of different solvents on the model reaction. As Table 1
indicates, the best results were obtained by heating the reaction mixture in PEG-400
at 80 °C (Table 1, entry 14) and also other protic solvents showed much better
performance relative to aprotic solvents. The effect of amount of catalyst on the
conversion and rate of the reaction was evaluated by varying the amount of PTSA in
PEG-400 at 80 °C (Table 1, entries 14, 17, 18). It turned out that 20 mol% of PTSA
was enough to carry out the reaction smoothly (Table 1, entry 14). An increase in
the amount of PTSA more than 20 mol% showed no remarkable improvement in the
yield, whereas the yield was reduced by decreasing the amount of PTSA to
10 mol%. So, a domino one-pot reaction of 2-hydroxynaphthalene-1,4-dione
(2 mmol), o-phenylenediamine (1 mmol) and aldehyde (1 mmol) using 20 mol%
of PTSA as catalyst in PEG-400 at 80 °C proved to be the optimum conditions. This
two-step process allows the one-pot four-component domino or tandem reaction to
be controlled, avoiding the separation of intermediates, as well as time-consuming
and costly purification processes [46].
We next realized the generality and versatility of the PTSA as a catalyst using
these optimized conditions, the reaction scope was studied by using different
aromatic aldehydes. All the reactions were complete in 2–3 h and resulted in the
formation of the target structures (Scheme 1; Table 2, entries 1–11) in high yields
123

PTSA-catalyzed four-component domino reactions for the…
Table 2 Domino one-pot four-component synthesis of 11H-benzo[a]benzo[6,7]chromeno[2,3-c]phena-
zine-11,16(17H)-dione derivatives in the presence of PTSA (20 mol%) as catalyst in PEG-400 at 80 °C
Entry
Aldehydes
Product
Time (h)
Yield (%)a
1
4-NO2C6H4
4-ClC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
2
2
2
2
2
2
3
3
3
3
3
8
8
93
91
90
90
89
87
85
86
89
86
88
–
2
3
3-NO2C6H4
2-NO2C6H4
2-ClC6H4
4
5
6
4-CH3C6H4
2,4-Cl2C6H3
4-CH3OC6H3
3-CNC6H4
7
8
9
10
11
12
13
a
5-Br-2-OHC6H3
2-OH-5-NO2C6H3
n-Heptanal
5j
5k
–
n-Octanal
–
–
Isolated yields
and no clear electronic effects of the aldehyde were observed. In the presence of
aliphatic aldehydes such as n-heptanal and n-octanal, the expected product was not
obtained in these reaction conditions even after 8 h (Table 2, entries 12, 13).
The structures of all 11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-
1
11,16(17H)-dione derivatives 5a–k are in complete agreement with IR, H NMR,
13C NMR and elemental analysis. The mass spectra of these compounds displayed
molecular ion peaks at the appropriate m/z values.
Since hazardous organic solvents are a significant challenge in synthetic
chemistry, we used polyethylene glycol (PEG-400) as a recyclable medium instead
of volatile organic solvents without the addition of an organic co-solvent. We also,
for recyclability of the solvent, investigated the recycling of PEG-400 at 80 °C
using a selected model reaction of 2-hydroxynaphthalene-1,4-dione, o-phenylene-
diamine and 4-nitrobenzaldehyde (Table 2, entry 1). After completion of the
reaction, the reaction mixture was quenched with water and filtered for separation of
the crude product. The filtrate containing polyethylene glycol was rinsed with
diethyl ether and further vacuumed to dryness at 90 °C for 2 h to remove any
trapped water, which afforded PEG-400 which was reused directly for the next run.
As shown in Fig. 1, the reaction media could be successfully recycled for up to four
runs with limited loss of activity (the yield decreased from 93 to 82 % after four
runs; Fig. 1).
The plausible mechanism of this domino reaction consistent with the above results
is depicted in Scheme 2. Initially, in this mechanism, 2-hydroxynaphthalene-1,4-
dione 1 tautomrizes to intermediate 6. The primary condensation of 6 with o-
phenylenediamine 2 obtains 6H-benzo[a]phenazin- 5-one 7, which in tautomerism
equilibrium prepares benzo[a]phenazin-5-ol 3. The catalyst PTSA appears to play a
key role as acid in the reaction to form (6-benzylidenebenzo[a]phenazin-5(6H)-
123

R. Mohebat et al.
94
92
90
88
86
84
82
80
78
76
Run 1
93
Run 2
91
Run 3
87
Run 4
82
Product (%)
Fig. 1 Recycling and reuse of PEG-400
Scheme 2 Proposed mechanism for the synthesis of 11H-benzo[a]benzo[6,7]chromeno[2,3-
c]phenazine-11,16(17H)-dione derivatives
123

PTSA-catalyzed four-component domino reactions for the…
ylidene)oxonium 8, which prepares in situ from condensation of aldehyde 4 with
benzo[a]phenazin-5-ol 3. Subsequent Michael addition of 2-hydroxynaphthalene-
1,4-dione 1 with (6-benzylidenebenzo[a]phenazin-5(6H)-ylidene)oxonium 8, fol-
lowed by cyclization and dehydration, leads to the formation of the desired product 5.
Conclusions
In this context, we demonstrated a green and straightforward procedure for the
efficient synthesis of novel 11H-benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-
11,16(17H)-dione derivatives in high yields via one-pot, four-component domino
protocol by using PTSA as a mild, effective, non-toxic and inexpensive solid acid
catalyst and PEG-400 as a recyclable medium without the addition of organic co-
solvent. The operational simplicity, easy work-up, high atom economy, high yields
and environmentally friendly are the advantages of this protocol. In all these cases,
our work has introduced green and economically cost-effective. Furthermore, our
work is expected to exhibit interesting pharmacology activities and may act as
potential drug candidates, since phenazine and chromene motifs have a vast range of
biological activities.
Acknowledgment We gratefully acknowledge financial support from the Research Council of the
Islamic Azad University of Yazd and University of Sistan and Baluchestan.
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