A Convenient and Green Synthetic Approach for Benzo[a]pyrano[2,3-c]phenazines via Supramolecular Catalysis

Article abstract of DOI:10.1007/s10562-019-03057-2

Abstract: A pragmatic and swift method for the synthesis of Benzo[a]pyrano[2,3-c]phenazine derivatives via one pot, multicomponent strategy by employing β-cyclodextrin in EtOH:H₂O (1:1) solvent at 70?°C has been documented here. Utilization of

Full text of DOI:10.1007/s10562-019-03057-2

Catalysis Letters
https://doi.org/10.1007/s10562-019-03057-2
A Convenient and Green Synthetic Approach for Benzo[a]pyrano[2,3‑c]
phenazines via Supramolecular Catalysis
Anu Mishra1 · Yogesh Kumar Pandey1 · Fatima Tufail1 · Jaya Singh2 · Jagdamba Singh1
Received: 26 September 2019 / Accepted: 25 November 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
A pragmatic and swift method for the synthesis of Benzo[a]pyrano[2,3-c]phenazine derivatives via one pot, multicompo-
nent strategy by employing β-cyclodextrin in EtOH:H2O (1:1) solvent at 70 °C has been documented here. Utilization of
supramolecular catalyst β-cyclodextrin which is highly efcient, green, biodegradable and reusable catalyst augments the
synthesis amazingly, is the key feature of the current pathway. The catalyst could be recovered for four successive cycles
without signifcant loss in catalytic activity.
Graphic Abstract
OH
O
O
HO
O
OH
HO
OH
O
O
O
R1
N
OH
HO
R1
R1
NH2
NH2
HO
O
R1
OH
β-Cyclodextrin (20%)
O
R2
O
OH
CHO
R2
OH
O
N
(1)
(3)
HO
EtOH:H2O (1:1)
70°C
(2)
CN
CN
OH
CN
NH2
OH
O
OH
OH
O
OH
O
O
OH
(4)
OHO
OH
5(a-p)
O
OH
HO
O
Keywords Green synthesis · Supramolecular catalysis · β-cyclodextrin · EtOH:H2O (1:1) · Benzo[a]pyrano[2 · 3-c]
phenazines
1 Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-019-03057-2) contains
supplementary material, which is available to authorized users.
On the ground of environmental concerns, chemists and
researchers are switching their interest towards synthetic
processes which incorporate the environmentally benign
reagents for the synthesis of highly privileged scafolds and
this has emerged as a phenomenally recommended platform
[1–3]. Taking into account the principle of green chemis-
try, avoiding hazardous reaction conditions by utilization
of renewable feedstocks and supramolecular chemistry has
acquired prodigious significance [4–6]. Chemical reac-
tions in the presence of a supramolecular catalyst which is
* Jagdamba Singh
dr.jdsau@gmail.com
Jaya Singh
nimesh.singh@in.abb.com
1
Environmentally Benign Synthesis Lab, Department
of Chemistry, University of Allahabad, Allahabad 211002,
India
2
Department of Chemistry, LRPG College, Sahibabad,
Uttar Pradesh, India
Vol.:(0123456789)
1 3

A. Mishra et al.
derived from biomass, boost the sustainability of the proce-
dure [7–9]. Within this context, cyclodextrins (CDs), cyclic
oligosaccharides of D(+)-glucopyranosyl units which are
associated by α-1,4-glycosidic linkage, have noteworthy
engrossment with an exclusive characteristic of hydrophilic
exterior and a hydrophobic central void. Cyclodextrins, gen-
erally obtained by the enzymatic degradation of starch have
characteristic cylindrical shape with a narrow and a broad
end. One primary hydroxyl group is present at the narrower
end where as secondary hydroxyl groups are present at the
second and third carbon of the broader end of cyclodextrin
[10–12]. On the basis of the number of D(+)-glucopyranosyl
units, CDs are generally classifed into 3 categories namely
α-, β and γ-CDs having 6, 7 and 8 D(+)-glucopyranosyl
units, respectively [13–16]. The diameters of hydrophobic
cavities for diferent CDs (α-, β and γ-CDs) are in the order
of 0.47–0.56, 6.0–6.5 and 7.5–8.3 nm, respectively and the
heights of all CDs are around 0.78 nm [13]. The structure of
cyclodextrins facilitates them to form inclusion complexes
with numerous substrates via weak interactions like non-
covalent bonding, H-bonding and vander waal forces of
attraction and by ensnaring the substrate into their hydro-
phobic cavities [9, 16–18]. Among the three, β-cyclodextrin
(β-CD) is the most frequently used CD. These attributes of
CDs invigorated us to carry out our reaction in presence of
β-cyclodextrin.
ecofriendly and sustainable protocols in organic synthe-
sis [19–22].
Benzo[a]pyrano[2,3-c]phenazine, a nitrogen and oxy-
gen containing heterocyclic compound, reveals tremen-
dous biological and pharmaceutical signifcance. It con-
sists of two characteristic units of important classes of
heterocyclic compounds in which one is nitrogen-contain-
ing phenazine unit and the other one is oxygen contain-
ing pyran (Fig. 1). Phenazines form the core structure of
various natural and synthetic products [23] and exhibit
diverse biological activities as antiplatelet [24], antimalar-
ial [25], fungicidal [26], antitumor [27], trypanocidal [28]
and anti-infammatory activities [29]. In addition, they are
also used as pesticides and dyestufs [30].
Similarly, Pyrans are also present as a key motif in vari-
ous natural products and pharmaceuticals as polyether
antibiotics, alkaloids and carbohydrates [31, 32]. Com-
pounds with pyran scafold shows astonishing biological
importances such as antitumor, antifungal, antioxidant,
antileishmanial, anticoagulant, anticonvulsant and anti-
microbial activities. In addition, they are extensively used
as potential biodegradable agrochemicals, pigments and
cosmetics [33–36] (Fig. 2).
Even though, various synthetic pathways for Benzo[a]
pyrano[2,3-c]phenazine and its derivatives have been
reported [30, 37–47] but some of them are endured with
some downsides. In view of the vast biological signif-
cance of Benzo[a]pyrano[2,3-c]phenazine and our ongo-
ing interest in the development of new green synthetic
methodologies for heterocyclic compounds [48–53], we
sought to develop a straightforward and facile domino
synthetic protocol for Benzo[a]pyrano[2,3-c]phenazines
by using 2-hydroxynaphthalene-1,4-dione, o-phenylenedi-
amines, aromatic aldehydes and malononitrile as reactants
in presence of β-cyclodextrin in EtOH:H2O (1:1) solvent
at 70 °C (Scheme 1).
Now-a-days, atom and step economic approaches are
utilized under the heading of multicomponent reactions
(MCRs) for the straightforward access of diverse classes
of compounds and this has emerged as a key tool for
Fig. 1 Structure of Benzo[a]pyrano[2,3-c]phenazine showing Phena-
zine and Pyran unit
Fig. 2 Some biologically active
derivatives of Phenazines and
Pyran
O
N
CF3
N
H
N
N
O
O
COOH
N
OH
N
N
N
N
N
H3C
O
Br
O
Antimalarial activity [10]
Antifungal activity [11] Antitumor activity [12]
Anticonvulsant activity [
]
35
1 3

A Convenient and Green Synthetic Approach for Benzo[a]pyrano[2,3-c]phenazines via…
O
R1
N
R1
R1
NH2
NH2
R1
OH
R2
O
β
-Cyclodextrin (20%)
N
(1)
(2)
CN
NH2
EtOH:H2O (1:1)
70°C
CHO
CN
CN
O
R2
5(a-p)
(4)
(3)
Scheme 1 Synthesis of Benzo[a]pyrano[2,3-c]phenazines
2.3 Spectral Data of Compounds
2 Experimental
2.3.1 3‑Amino‑1‑phenyl‑1H‑benzo[a]pyrano[2,3‑c]
phenazine‑2‑carbonitrile (5a)
2.1 General Information
Reagents were obtained from commercial suppliers and
used without further purification unless otherwise speci-
fied by a reference. All reactions were performed using
oven-dried glass wares. Organic solutions were concen-
trated using a Buchi rotary evaporator. TLC was per-
formed using silica gel GF254 (Merck) plates. Melting
points were determined by open glass capillary method
and are uncorrected. IR spectra in KBr were recorded on a
Yellow solid, M.P.: 297–299 °C; IR (KBr) ν (cm−1): 3440,
3315, 3171, 2183, 1652, 1626, 1595, 1544, 1491, 1477,
1400, 1381, 1353, 1322, 1263, 1165, 1121, 1048, 1021, 759,
731, 704; 1H NMR (400 MHz, DMSO-d6) δ: 9.15 (d, 1H,
J = 7.6 Hz), 8.40 (d, 1H, J = 8.0 Hz), 8.23–8.20 (m, 1H),
8.10–8.07 (m, 1H), 8.01–7.91 (m, 4H), 7.42–7.38 (m, 4H),
7.22 (t, 2H, J=7.6 Hz), 7.10–7.06 (m, 1H), 5.43 (s, 1H); 13
C
Perkin-Elmer 993 IR spectrophotometer, 1HNMR and 13
C
NMR (100 MHz, DMSO-d6) δ: 159.6, 146.5, 145.2, 141.2,
140.2, 140.1, 139.5, 130.5, 130.3, 130.1, 129.7, 129.2,
129.0, 128.4, 128.1, 127.3, 126.3, 125.2, 124.4, 122.0,
120.3, 113.6, 58.0, 37.1; MS (ESI) m/z: 400.
NMR spectra were recorded on a Bruker AVII 400 and
100 MHz spectrometer in DMSO-d6 using TMS as inter-
nal reference with chemical shift value being reported
in ppm. All coupling constants (J) have been reported in
Hertz (Hz).
2.3.2 3‑Amino‑1‑(4‑chloro‑phenyl)‑1H‑benzo[a]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5b)
Yellow solid, M.P.: 286–289 °C; IR (KBr) ν (cm−1):
3449, 3304, 3170, 2181, 1658, 1621, 1590, 1483, 1470,
1400, 1381, 1345, 1322, 1288, 1262, 1160, 1101, 1081,
2.2 General Method for the Synthesis of Benzo[a]
pyrano[2,3‑c]phenazine Derivatives (5a‑p)
1
1049, 1012, 843, 756, 747; H NMR (400 MHz, DMSO-
To a homogeneous solution of β-cyclodextrin (20 mol%)
in 15 ml of ethanol:water (1:1) at 70 °C, 1.0 mmol of
2-hydroxynaphthalene-1,4-dione (1), o-phenylenediamine
(2), aromatic aldehyde (3) and malononitrile (4) were
added and stirred until the completion of reaction (moni-
tored by TLC) then water (10 ml) was added. Product was
precipitated out which was filtered off by using Whatman
filter paper. The crude product was purified by column
chromatography by using ethyl acetate and hexane as elu-
ent. All the desired products were known and were char-
acterized by the comparison of their spectra and melting
points with those reported in the literature [37–47].
d6) δ: 9.29–9.27 (d, 1H, J = 8.76 Hz), 8.49–8.47 (d,
1H, J = 8.6 Hz), 8.33–8.31 (m, 1H), 8.21–8.18 (m, 1H),
8.05–7.94 (m, 4H), 7.47–7.45 (m, 4H), 7.31–7.28 (m, 2H),
5.55 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 159.6,
152.0, 144.1, 140.3, 139.6, 131.1, 130.6, 130.2, 130.1,
130.0, 129.3, 129.1, 128.4, 128.0,125.3, 124.4, 122.0, 120.1,
113.1, 57.3; MS (ESI) m/z: 434.
2.3.3 3‑Amino‑1‑(2‑chlorophenyl)‑1H‑benzo[c]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5c)
Yellow solid, M.P.: 300–302 °C; IR (KBr) ν (cm−1): 3331,
3237, 3144, 2981, 1653, 1581, 1472, 1383, 1271, 1153,
1 3

A. Mishra et al.
1
1038, 950, 831, 755; H NMR (400 MHz, DMSO-d6) δ:
2.3.8 3‑Amino‑1‑(2‑methoxy‑phenyl)‑1H‑benzo[a]
9.27 (d, 1H, J=8.0 Hz), 8.48 (d, 1H, J=8.0 Hz), 8.30–8.27
(m, 1H), 8.04–7.93 (m, 3H), 7.93–7.90 (m, 2H), 7.42–7.40
(m, 1H), 7.34 (s, 2H), 7.23–7.21 (m, 1H), 7.13–7.09 (m,
2H), 6.01 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 170.1,
159.1, 146.3, 142.3, 141.2, 140.3, 140.0, 139.6, 132.0,
130.6, 130.3, 130.1, 130.0, 129.2, 129.1, 129.0, 128.3,
128.0, 127.1, 125.2, 124.5, 122.1, 119.2, 112.7, 56.6, 36.5;
MS (ESI) m/z: 434.
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5 h)
Yellow solid, M.P.: 268–270 °C; IR (KBr) ν (cm−1): 3309,
3169, 3051, 2827, 2181, 1652, 1621, 1591, 1484, 1471,
1452, 1395, 1381, 1347, 1327, 1287, 1247, 1161, 1100,
1048, 1021, 829, 751; 1H NMR (400 MHz, DMSO-d6) δ:
9.25–9.23 (m, 1H), 8.47–8.45 (m, 1H), 8.28–8.24 (m, 1H),
8.05–7.88 (m, 5H), 7.20 (s, 2H), 7.11-7.04 (m, 2H), 6.94 (d,
1H, J = 7.6 Hz), 6.75–6.71 (m, 1H), 5.84 (s, 1H), 3.85 (s,
3H); MS (ESI) m/z: 430.
2.3.4 3‑Amino‑1‑(2,4‑dichlorophenyl)‑1H‑benzo[a]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5d)
Brown solid, M.P.: 305–308 °C; IR (KBr) ν (cm−1): 3471,
3310, 3162, 3063, 2181, 1653, 1620, 1584, 1463, 1400,
2.3.9 3‑Amino‑1‑(3‑methoxyphenyl)‑1H‑benzo[a]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5i)
1
1381; H NMR (400 MHz, DMSO-d6) δ: 9.17 (d, 1H,
J = 8.0 Hz), 8.40 (d, 1H, J = 8.0 Hz), 8.19–8.21 (m, 1H),
7.86–8.02 (m, 5H), 7.51 (s, 1H), 7.38 (s, 2H), 7.18 (d, 1H,
J=8.0 Hz), 7.11 (d, 1H, J=8.0 Hz), 5.82 (s, 1H); MS (ESI)
m/z: 469.
Yellow solid, M.P.: 236–241 °C; IR (KBr) ν (cm−1): 3416,
1
3336, 3211, 2189, 1661, 1591, 1487, 1381; H NMR
(400 MHz, DMSO-d6) δ: 9.20 (d, 1H, J=8.0 Hz), 8.41 (d,
1H, J=8.0 Hz), 8.23–8.26 (m, 1H), 8.13–8.16 (m, 1H), 7.97
(t, 2H, J=8.0 Hz), 7.91–7.92 (m, 2H), 7.39 (s, 2H), 7.11 (t,
1H, J=8.0 Hz), 7.00 (s, 1H), 6.90 (d, 1H, J=8.0 Hz), 6.65
(d, 1H, J = 8.0 Hz), 5.46 (s, 1H), 3.65 (s, 3H); MS (ESI)
m/z: 430.
2.3.5 3‑Amino‑1‑(4‑bromo‑phenyl)‑1H‑benzo[a]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5e)
Yellow solid, M.P.: 281–283 °C; IR (KBr) ν (cm−1): 3464,
3311, 3171, 2184, 1657, 1621, 1588, 1400, 1381, 1346,
1327, 1289, 1219, 1161, 1101, 1051, 1007, 841, 753, 676;
1H NMR (400 MHz, DMSO-d6) δ: 9.25-9.21 (m, 1H),
8.46–8.44 (m, 1H), 8.30–8.27 (m, 1H), 8.18–8.13 (m, 1H),
8.03–7.91 (m, 4H), 7.44–7.40 (m, 4H), 7.37–7.35 (m, 2H),
5.50 (s, 1H); MS (ESI) m/z: 479.
2.3.10 3‑Amino‑1‑p‑tolyl‑1H‑benzo[a]pyrano[2,3‑c]
phenazine‑2‑carbonitrile (5j)
Yellow solid, M.P.: 291–293 °C; IR (KBr) ν (cm−1): 3439,
3307, 3171, 2183, 1657, 1621, 1591, 1492, 1471, 1394,
1380, 1346, 1322, 1286, 1261, 1219, 1157, 1101, 1051,
1
2.3.6 3‑Amino‑1‑(3‑bromophenyl)‑1H‑benzo[a]
pyrano[2,3‑c] Phenazine‑2‑carbonitrile (5f)
1018, 826, 753, 741; H NMR (400 MHz, DMSO-d6) δ:
9.22 (d, 1H, J=8.0 Hz), 8.43–8.42 (m, 1H), 8.27–8.24 (m,
1H), 8.16–8.13 (m, 1H), 8.01–7.90 (m, 4H), 7.32–7.26 (m,
Brown solid, M.P.: 266–268 °C; IR (KBr) ν (cm−1): 3481,
3300, 3165, 3057, 2191, 1658, 1622, 1587, 1467, 1381;
1H NMR (400 MHz, DMSO-d6) δ: 9.20–9.24 (m, 1H),
8.41–8.46 (m, 1H), 8.26–8.30 (m, 1H), 8.12–8.15 (m, 1H),
7.93–8.00 (m, 4H), 7.60–7.62 (m, 1H), 7.45–7.48 (m, 2H),
7.39–7.43 (m, 1H), 7.27–7.31 (m, 1H), 7.17–7.21 (m, 1H),
5.49 (s, 1H); MS (ESI) m/z: 479.
4H), 7.01 (d, 2H, J=8.0 Hz), 5.45 (s, 1H), 2.13 (s, 3H); 13
C
NMR (100 MHz, DMSO-d6) δ: 168.0, 164.1, 159.5, 150.1,
146.2, 141.3, 140.0, 135.3, 130.6, 129.9, 129.3, 129.0,
128.7, 127.4, 125.5, 123.4, 122.0, 118.1, 58.1, 36.9, 20.3;
MS (ESI) m/z: 414.
2.3.11 3‑Amino‑1‑(4‑nitro‑phenyl)‑1H‑benzo[a]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5 k)
2.3.7 3‑Amino‑1‑(4‑methoxyphenyl)‑1H‑benzo[a]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5 g)
Yellow solid, M.P.: 280–282 °C; IR (KBr) ν (cm−1): 3327,
3311, 3249, 3195, 2194, 1671, 1588, 1510, 1471, 1399,
1381, 1341, 1289, 1261, 1215, 1162, 1103, 1049, 1021,
823, 768, 741; 1H NMR (400 MHz, DMSO-d6) δ: 9.26 (d,
1H, J=7.6 Hz), 8.48 (d, 1H, J=8.0 Hz), 8.30-8.28 (m, 1H),
8.15–8.13 (m, 1H), 8.10 (d, 2H, J=8.4 Hz), 8.05–7.91 (m,
4H), 7.70 (d, 2H, J=8.8 Hz), 7.54 (s, 2H), 5.66 (s, 1H); MS
(ESI) m/z: 445.
Yellow solid, M.P.: 268–270 °C; IR (KBr) ν (cm−1): 3428,
3311, 3191, 3041, 2190, 1661, 1592, 1503, 1381; 1H NMR
(400 MHz, DMSO-d6) δ: 9.25 (d, 1H, J=8.0 Hz), 8.44 (d,
1H, J = 8.0 Hz), 8.28–8.30 (m, 1H), 8.19–8.21 (m, 1H),
7.93–7.98 (m, 4H), 7.31 (d, 2H, J=8.0 Hz), 7.17–7.19 (m,
2H), 6.75 (d, 2H, J=8.0 Hz), 5.48 (s, 1H), 3.60 (s, 3H); MS
(ESI) m/z: 430.
1 3

A Convenient and Green Synthetic Approach for Benzo[a]pyrano[2,3-c]phenazines via…
2.3.12 3‑Amino‑1‑(3‑nitro‑phenyl)‑1H‑benzo[a]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5 l)
722; 1H NMR (400 MHz, DMSO-d6) δ: 9.22–9.20 (m, 1H),
8.47–8.45 (m, 1H), 8.25 (t, 1H, J=2.0 Hz), 8.03–7.91 (m,
5H), 7.87 (s, 1H), 7.56 (d, 1H, J=8.0 Hz), 7.53 (s, 2H), 5.69
(s, 1H), 2.53 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z: 473.
Yellow solid, M.P.: 276–278 °C; IR (KBr) ν (cm−1): 3421,
3333, 3194, 2187, 1661, 1625, 1591, 1521, 1492, 1471,
1397, 1384, 1341, 1288, 1261, 1161, 1102, 1049, 1022,
808, 758, 726, 692; 1H NMR (400 MHz, DMSO-d6) δ: 9.11
(d, 1H, J=7.6 Hz), 8.40 (d, 1H, J=8.0 Hz), 8.28 (s, 1H),
8.20–8.12 (m, 1H), 8.05–8.03 (m, 1H), 7.98–7.95 (m, 2H),
7.90–7.86 (m, 4H), 7.53–7.51 (m, 3H), 5.57 (s, 1H); MS
(ESI) m/z: 445.
3 Results and Discussion
In our initial quest for the optimization of the reaction con-
ditions, we chose 2-hydroxynaphthalene-1,4-dione (1),
o-phenylenediamine (2a), 4-Chlorobenzaldehyde (3b) and
malononitrile (4) as model substrates for the synthesis of
Benzo[a]pyrano[2,3-c]phenazine (5a). Initially, due to envi-
ronmental concerns we chose water in place of widely used
organic solvents as reaction medium. Throughout optimiza-
tion studies, we scrutinized the efect of diferent catalysts,
solvents and temperature on our model reaction. The results
have been recapitulated in (Table 1).
2.3.13 3‑Amino‑11,12‑dimethyl‑1‑phenyl‑1H‑benzo[a]
pyrano[2,3‑c]phenazine‑2‑carbonitrile (5 m)
Yellow solid, M.P.: 295–297 °C; IR (KBr) ν (cm−1): 3471,
3291, 3174, 3023, 2186, 1659, 1631, 1593, 1491, 1385,
1338, 1291, 1262, 1203, 1162, 1105, 1054, 1023, 997,
861, 762; 1H NMR (400 MHz, DMSO-d6) δ: 9.11 (d, 1H,
J = 8.0 Hz), 8.39 (d, 1H, J = 8.0 Hz), 7.97–7.85 (m, 3H),
7.69 (s, 1H), 7.37–7.34 (m, 4H), 7.21 (t, 2H, J = 7.6 Hz),
7.07 (t, 1H, J=7.6 Hz), 5.41 (s, 1H), 2.42 (s, 6H); MS (ESI)
m/z: 428.
In our preliminary pursuit, we took 2-hydroxynaphtha-
lene-1,4-dione (1, 1.0 mmol) and o-phenylenediamine (2a,
1.0 mmol) in the absence of catalyst at room temperature
using water as a solvent and found that product was not
formed even after 24 h of stirring (Table 1, entry 1). After
this, we attempted the same reaction at 70 °C, yet again
formation of product did not take place efectively (Table 1,
entry 2). In our next endeavour we used some phase transfer
catalysts like cetyltrimethylammonium bromide (CTAB),
tetradecyltrimethylammonium bromide (TTAB) and sodium
dodecylsulfate (SDS) and observed that the product was
formed in very small amount after 12 h of stirring (Table 1,
entries 3–5). After that we tried our reaction with cyclodex-
trins (Table 1, entries 6–8) and observed that β-cyclodextrin
in presence of water as a solvent at 70 °C gave the best result
with 82% yield of the product within 1 h (Table 1, entry 7).
Once an apposite green catalyst had been recognized for
fostering this reaction, we carried out a batch of experiments
in presence of diferent solvents at 70 °C in order to inspect
the efect of diferent solvents on the course of the reaction
(Table 1, entries 9–15) and found that EtOH:H2O (1:1) as
a solvent is the most appropriate for our proposed pathway
(Table 1, entry 10). Subsequently, we performed a set of
reactions with diferent concentrations of β-cyclodextrin
(Table 1, entries 10 and 16–18) and concluded that 20 mol%
of β-cyclodextrin is relevant for the present strategy which
aforded a 91% yield of product (Table 1, entry 10).
2.3.14 3‑Amino‑11,12‑dimethyl‑1‑(4‑nitro‑phenyl)‑1H‑ben
zo[a]pyrano[2,3‑c]phenazine‑2‑carbonitrile (5n)
Yellow solid, M.P.: 296–298 °C; IR (KBr) ν (cm−1): 3491,
3319, 3163, 2185, 1656, 1629, 1587, 1509, 1469, 1382,
1341, 1294, 1205, 1165, 1105, 1053, 1021, 853, 824,
1
756, 711; H NMR (400 MHz, DMSO-d6) δ: 9.10 (dd,
1H, J=0.8 Hz, 8.0 Hz), 8.40 (dd, 1H, J=1.2 Hz, 8.0 Hz),
8.10–8.06 (m, 2H), 8.00–7.90 (m, 2H), 7.84 (s, 1H),
7.63–7.59 (m, 3H), 7.53 (s, 2H), 5.47 (s, 1H), 2.45 (s, 3H),
2.43 (s, 3H); MS (ESI) m/z: 473.
2.3.15 3‑Amino‑11,12‑dimethyl‑1‑(4‑bromo‑phenyl)‑1H‑b
enzo[a]pyrano[2,3‑c]phenazine‑2‑carbonitrile (5o)
Yellow solid, M.P.: 293–295 °C; IR (KBr) ν (cm−1): 3471,
3361, 3173, 2181, 1657, 1616, 1591, 1480, 1403, 1383,
1341, 1292, 1261, 1204, 1161, 1103, 1055, 1008, 858,
824, 759; 1H NMR (400 MHz, DMSO-d6) δ: 9.20–9.18 (m,
1H), 8.44–8.42 (m, 1H), 8.00–7.91 (m, 3H), 7.83 (s, 1H),
7.41–7.38 (m, 4H), 7.35–7.31 (m, 2H), 5.45 (s, 1H), 2.48 (s,
3H), 2.49 (s, 3H); MS (ESI) m/z: 507.
Further, our ensuing efort involved the optimization of
temperature for the current protocol (Table 1, entries 10 and
19–21). At frst, we carried out the reaction at room tempera-
ture which gave only 25% yield of product in 12 h (Table 1,
entry 19). Further we carried out the present protocol with
50 °C, 70 °C and 80 °C and the yield of product clearly
demonstrated that 70 °C is the most suitable temperature for
our synthetic strategy (Table 1, entry 10).
2.3.16 3‑Amino‑11,12‑dimethyl‑1‑(3‑nitro‑phenyl)‑1H‑ben
zo[a]pyrano[2,3‑c]phenazine‑2‑carbonitrile (5p)
Yellow solid, M.P.: 275–277 °C; IR (KBr) ν (cm−1): 3472,
3329, 3201, 2198, 1711, 1662, 1627, 1590, 1525, 1470,
1387, 1341, 1293, 1264, 1203, 1163, 1100, 1049, 871, 763,
1 3

A. Mishra et al.
Table 1 Optimization of reaction conditions
Entry
Solvent
Catalyst
Concentration (mol Time (h)
%)
Yield (%)a
b,c
d
1
2
3
4
5
6
7
8
Water
Water
Water
Water
Water
Water
Water
Water
–
–
–
–
24
24
12
12
12
6
1
6
1
1
1
1
12
12
12
1
1
1
–
b
Trace
34
12
10
42
82
40
72
91
80
77
59
37
29
78
91
91
25
67
91
Cetyltrimethylammonium bromide
Tetradecyltrimethylammonium bromide
Sodium dodecylsulfate
α-Cyclodextrin
β-Cyclodextrin
γ-Cyclodextrin
β-Cyclodextrin
β-Cyclodextrin
β-Cyclodextrin
β-Cyclodextrin
β-Cyclodextrin
β-Cyclodextrin
β-Cyclodextrin
β-Cyclodextrin
β-Cyclodextrin
20
20
20
20
20
20
20
20
20
20
20
20
20
10
30
40
20
20
20
9
EtOH
10
11
12
13
14
15
16
17
18
19
20
21
EtOH:H2O (1:1)
EtOH:H2O (2:1)
EtOH:H2O (3:1)
MeOH
CH3CN
DMF
EtOH:H2O (1:1)
EtOH:H2O (1:1)
EtOH:H2O (1:1)
EtOH:H2O (1:1)
EtOH:H2O (1:1)
EtOH:H2O (1:1)
β-Cyclodextrin
β-Cyclodextrinc
12
1
1
β-Cyclodextrine
β-Cyclodextrinf
Bold indicates the most suitable reaction condition for our proposed pathway
All reactions were carried out stirring with 1 (1.0 mmol) 2a (1.0 mmol) 3a (1.0 mmol) and 4 (1.0 mmol) using diferent solvent and catalyst
under air at 70 °C
aIsolated yields
babsence of catalyst
cat rt
dnot detected
eat 50 °C
fat 80 °C
Consequently we managed to identify the optimized
reaction conditions for the present transformation. Our
reaction works well by using 20 mol% of β-cyclodextrin in
EtOH:H2O (1:1) solvent at 70 °C, afording 91% yield of the
product within 1 h with our model substrates.
Once the perfect reaction conditions had been identi-
fed, in order to ensure the versatility and generality of the
1 3

A Convenient and Green Synthetic Approach for Benzo[a]pyrano[2,3-c]phenazines via…
proposed synthesis, the scope of the reported synthetic
strategy was successfully evaluated (Scheme 2). We used
diferent derivatives of o-phenylenediamine (2) and aro-
matic aldehydes (3) to achieve the illustrated pathway for
the formation of target product (5a-p) in good to excellent
yields. To our gratifcation, aromatic aldehydes (3) having
both an electron withdrawing group and an electron donat-
ing group were well endured and aforded a signifcant
yield of the product in all the instances.
3.1 Practicability of the Reaction
To set up the feasibility of the current protocol, we car-
ried out the experiment on a large scale. For this we took
our model substrates in a round bottom fask in presence
of β-cyclodextrin in EtOH:H2O (1:1) solvent at 70 °C.
2-hydroxynaphthalene-1,4-dione (1, 10 mmol, 1.7415 g),
o-phenylenediamine (2a, 10 mmol, 1.081 g), 4-chloroben-
zaldehyde (3a, 10 mmol, 1.40 g) and malononitrile (4,
Scheme 2 Substrate scope for
5. All reactions were carried
out stirring with 1 (1.0 mmol),
2 (1.0 mmol), 3 (1.0 mmol) and
4 (1.0 mmol) using 20 mol%
β-Cyclodextrin as catalyst in
EtOH:H2O (1:1) solvent under
air at 70 °C.
O
O
R1
R1
R1
NH2
R1
R2
OH
CHO
R2
NH2
N
β-Cyclodextrin (20%)
(1)
(2)
CN
CN
N
CN
EtOH:H2O (1:1)
70°C
O
NH2
(3)
(4)
5(a-p)
Cl
Cl
O
N
N
Cl
CN
N
Cl
CN
N
N
CN
NH2
N
N
N
N
CN
N
O
O
NH2
O
NH2
NH2
(5a, 1h, 89%)
(5c, 1h, 85%)
(5d, 1.5h, 90%)
(5b, 50 min, 91%)
Br
OCH3
Br
N
N
N
N
OCH3
CN
CN
NH2
(5e, 1h, 90%)
CN
NH2
CN
NH2
N
N
N
O
O
O
O
NH2
(5f, 1.5h, 86%)
(5g, 1.5h, 84%)
(5h, 1.25h, 86%)
NO2
CH3
OCH3
NO2
N
N
N
N
CN
N
CN
CN
NH2
(5k, 50 min, 92%)
N
CN
NH2
(5j, 1.5h, 84%)
NO2
N
O
NH2
O
NH2
O
O
(5i, 1.5h, 86%)
CH3
(5l, 50 min, 91%)
CH3
CH3
Br
CH3
H3C
H3C
NO2
H3C
H3C
N
N
N
N
CN
NH2
(5m, 1.5h, 85%)
N
CN
N
CN
N
CN
NH2
N
O
O
NH2
O
NH2
O
(5n, 1.5h, 84%)
(5p, 1.5h, 84%)
(5o, 1.5h, 85%)
1 3

A. Mishra et al.
100
90
80
70
60
50
40
30
20
10
0
93
10 mmol) were reacted to obtain the dihydropyrano[2,3-c]
pyrazole (5b) in 91% yield in about 50 min by using com-
mon laboratory glasswares at 70 °C (Scheme 3).
92
91
90
89 89
87
85
70
65
3.2 Recyclability of β‑CD
Yield
44
Catalyst Recovery
32
The reusability of catalyst was explored by investigating
it’s activity in six cycles in which the initial use of fresh
catalyst for the synthesis of Benzo[a]pyrano[2,3-c]phena-
zine was also taken into account. In each cycle, the catalyst
was almost quantitatively recovered and even after third and
fourth use there was a negligible decrease in the quantity
and in the efectiveness of the catalyst but after fourth cycle
there was appreciable decrease in the quantity and in the
efectiveness of the catalyst (Fig. 3).
Naꢀve
Run 1
Run 2
Run 3
Run 4
Run 5
Fig. 3 Reuse and recovery of β-CD and its consequence on yield
4 Conclusion
3.3 Mechanism
In conclusion, we have reported a facile and convenient
new pathway for the one-pot, multicomponent, sustainable
green synthesis of highly functionalized and efcacious bio-
logically signifcant scafold Benzo[a]pyrano[2,3-c]phena-
zine and its derivatives in ethanol:water solvent at 70 °C
in the catalytic activity of β-cyclodextrin. To the best of
our knowledge this is the frst synthesis of the title com-
pound. The utilization of biodegradable, environmentally
benign supramolecular catalyst as a recyclable catalyst
and EtOH:H2O mixed green solvent system has engrossed
substantial attention and has emerged as a hallmark of this
transformation. The other key attributes of the disclosed pro-
tocol are operational feasibility, short reaction time, simple
workup procedure, good to excellent yields of the product
and easy recovery plus reusability of the catalyst. All these
traits ascertain the disclosed methodology as superior to the
previously reported methods.
A plausible reaction mechanism reconcilable with the above
results is depicted in Scheme 4. The desired product is
expected to form by the Knoevenagel condensation followed
by Michael addition and at last cyclization within the cavity
of β-CD where it is anticipated that seven free primary –OH
groups of β-CD execute synergistically as a profcient host
and supramolecular catalyst [54, 55]. Reactants may form
reversible non covalent supramolecular complexes within
the cavity in order to increase the localized concentration
that results in the dissolution of reactants in the aqueous
medium. Initially, the condensation of 2-hydroxynaphtha-
lene-1,4-dione (1) and diamine (2) takes place to aford the
intermediate A. Similar condensation of aldehyde (3) and
malanonitrile (4) occurs to form the intermediate B. After
that, intermediate A reacts with intermediate B via Michael
addition to yield an intermediate C. Finally, intermediate C
undergo cyclization to aford the desired product 5.
Scheme 3 Practicability of the
O
O
Present methodology
Cl
NH2
OH
NH2
(2a, 10mmol,
1.081 g)
N
(1, 10 mmol,
1.7415 g)
β
-Cyclodextrin (20%)
N
CN
CHO
EtOH:H2O (1:1)
70°C
CN
CN
O
NH2
(5b)
(91%)
(4, 10 mmol)
Cl
(3a, 10 mmol, 1.40 g)
1 3

A Convenient and Green Synthetic Approach for Benzo[a]pyrano[2,3-c]phenazines via…
Scheme 4 Plausible mechanism
for Benzo[a]pyrano[2,3-c]
phenazine derivatives (5a-p)
Acknowledgements The authors are thankful to SAIF, Punjab Univer-
sity, Chandigarh, India for providing spectral data. Authors A. Mishra,
Y. K. Pandey and F. Tufail are thankful to UGC and CSIR, New Delhi,
for the award of Senior Research Fellowship (SRF). Prof. J. Singh
thankful to UGC for UGC BSR fellowship.
2. Horvath IT (2002) Acc Chem Res 35:685
3. Madhumitha G, Roopan SM (2013) J Nanomater 2013:1
4. Maity A, Chakraborty D, Hazra A, Bharitkar YP, Kundu S,
Maulik PR, Mondal NB (2014) Tetrahedron Lett 55:3059–3063
5. Srivastava M, Singh J, Singh SB, Tiwari K, Pathak VK, Singh
J (2012) Green Chem 14:901–905
6. Chaudhari MA, Gujar JB, Kawade DS, Shinde PV, Shingare MS
(2015) Res Chem Intermed 41:10027–10035
References
7. Sun T, Wang Q, Bi Y, Chen X, Liu L, Ruan C, Zhao Z, Jiang C
(2017) J Mater Chem B5:2644–2654
8. Ao M, Gan C, Shao W, Xing Z, Yong C (2016) Eur J Pharm Sci
91:183–189
1. Anastas PT, Warner JC (1998) Green chemistry: theory and prac-
tice. Oxford University Press, New York
1 3

A. Mishra et al.
35. Aytemir MD, Calis U, Ozalp M (2004) Arch Pharm Pharm Med
Chem 337:281–288
9. Mishra NP, Mohapatra S, Pravati P, Nayak S (2018) Curr Org
Chem 22:1956–1982
36. Esmaeilpour M, Javidi J, Dehghani F, Dodeji FN (2015) RSC Adv
5:26625–26633
10. Abbasi M (2017) J Chin Chem Soc 64:896–917
11. Rekharsky MV, Inoue Y (1998) Chem Rev 98:1875–1917
12. Connors KA (1997) Chem Rev 97:1325–1358
13. Valle EMD (2004) Biochem 39:1033–1046
37. Wang SL, Wu FY, Cheng C, Zhang G, Liu YP, Jiang B, Shi F, Tu
SJ (2011) ACS Comb Sci 13:135–139
38. Shaterian HR, Moradi F, Mohammadnia M (2012) C R Chim
15:1055–1059
14. Bender ML, Komiyama M (2012) Cyclodextin chemistry.
Springer Science & Business Media, Berlin
39. Shaterian HR, Mohammadnia M (2013) J Mol Liq 177:162–166
40. Bharti R, Parvin T (2016) Mol Divers 20:867–876
41. Hasaninejad A, Firoozi S (2013) Mol Divers 17:499–513
42. Choghamarani AG, Sahraei R, Taherinia Z (2019) Res Chem
Intermed 45(5):3199–3214
15. Seidi F, Ahmad AS, Mojtaba A, Meisam S, Daniel C (2019)
Polym Chem 10:3674–3711
16. Kumar AR, Ashok K, Brahmaiah B, Sreekanth N, Baburao C
(2013) IJPRBS 2(2):291–304
17. Rutenberg R, Leitus G, Fallik E, Poverenov E (2016) Chem Com-
mun 52:2565–2568
43. Yazdani-Elah-Abadi A, Maghsoodlou MT, Mohebat R, Heydari
R (2017) Chin Chem Lett 28(2):446–452
18. Szejtli J (1998) Chem Rev 98:1743–1754
44. Gao J, Chen M, Tong X, Zhu H, Yan H, Liu D, Li W, Qi S, Xiao
D, Wang Y, Lu Y, Jiang F (2015) Comb Chem High Throughput
Screen 18(10):960–974
19. Ramón DJ, Yus M (2005) Angew Chem Int Ed 44:1602–1634
20. Voigt B, Linke M, Mahrwald R (2015) Org Lett 17:2606–2609
21. Toure BB, Hall DG (2009) Chem Rev 109:4439–4486
22. Alvim HGO, Silva JE, Neto BAD (2014) RSC Adv 4:54282–54299
23. Barreiros ALBS, David JM, David JP (2006) Quim Nova
29:113–123
45. Zarabi MF, Naeimi H (2019) Polycycl Aromat Compd. https://doi.
org/10.1080/10406638.2019.1672202
46. Choghamarani AG, Mohammadi M, Shiri L, Taherinia Z (2019)
Res Chem Intermed 45:5705–5723
24. Muller M, Sorrell T (1995) Prostaglandins 50:301–311
25. Andrade-Nieto V, Goulart M, da Silva JF, da Silva MJ, Pinto M,
Pinto A, Zalis M, Carvalho L, Krettli A (2004) Bioorg Med Chem
Lett 14:1145–1149
47. Naeimi H, Zarabi MF (2019) RSC Adv 9:7400–7410
48. Rai P, Srivastava M, Yadav S, Singh J, Singh J (2015) Catal Lett
145:2020–2028
49. Mishra A, Srivastava M, Rai P, Yadav S, Tripathi BP, Singh J,
Singh J (2016) RSC Adv 6:49164–49172
26. Ligon J, Dwight S, Hammer P, Torkewitz N, Hofmann D, Kempf
H, Pee K (2000) Pest Manage Sci 56:688–695
50. Mishra A, Rai P, Srivastava M, Tripathi BP, Yadav S, Singh J,
Singh J (2017) Catal Lett 147:2600–2611
27. Vickr N, Burgess L, Chuckowree IS, Dodd R, Folkes AJ, Hardick
DJ, Hancox TC, Miller WH, Milton J, Sohal S, Wang S, Wren
SP, Charlton PA, Dangerefeld W, Liddle C, Mistry P, Stewart AJ,
Denny WA (2002) J Med Chem 45:721–739
51. Tripathi BP, Mishra A, Rai P, Pandey YK, Srivastava M, Yadav
S, Singh J, Singh J (2017) New J Chem 41:11148–11154
52. Mishra A, Rai P, Singh J, Singh J (2018) ChemistrySelect
3:8408–8414
28. Neves-Pinto C, Malta V, Pinto M, Santos R, Castro S, Pinto A
(2002) J Med Chem 45:740–743
53. Mishra A, Rai P, Pandey YK, Singh J, Singh J (2017) Chemis-
trySelect 2:10979–10983
29. Kondratyuk TP, Park EJ, Yu R, Van BRB, Asolkar RN, Murphy
BT, Fenical W, Pezzuto JM (2012) Mar Drugs 10:451–464
30. Esmaeilpour M, Sardarian AR, Firouzabadi H (2018) Chemis-
trySelect 3:9236–9248
54. Tayade YA, Dalal DS (2017) Catal Lett 147:1411–1421
55. Ghorad A, Mahalle S, Khillare LD, Sangshetti JN, Bhosle MR
(2017) Catal Lett 147:640–648
31. Chaniyara R, Thakrar S, Kakadiya R, Marvania B, Detroja D,
Vekariya N, Upadhyay K, Manvar A, Shah A (2014) J Hetercyclic
Chem 51:466–474
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
32. Magedov IV, Manpadi M, Ogasawara MA, Dhawan AS, Rogelj S,
Van Slambrouck S, Steelant WFA, Evdokimov NM, Uglinskii PY,
Elias EM, Knee EJ, Tongwa P, Antipin MY, Kornienko A (2008)
J Med Chem 51:2561–2570
33. Narender T, Gupta S (2004) Bioorg Med Chem Lett 14:3913–3916
34. Evidente A, Cabras A, Maddau L, Serra S, Andolf A, Motta AJ
(2003) Agr Food Chem 51:6957–6960
1 3