Microwave-assisted Domino Cyclization for the Synthesis of Novel Spiro-benzo[a]phenazine Annulated Heterocycles Catalyzed by a Basic Ionic Liquid

Article abstract of DOI:10.1002/jccs.201700034

An efficient and green strategy for the improved synthesis of a biologically and pharmaceutically interesting multi-functionalized diverse novel spiro-benzo[a]phenazine annulated heterocycles was developed with the assistance of microwave irradiation. A sequential one-pot, two-step domino reaction starting from 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamines, a cyclic carbonyl compound, and 1,3-indandione in the presence of a basic ionic liquid (1-butyl-3-methylimidazolium hydroxide) as an expedient, ecofriendly and reusable catalyst afforded the corresponding novel spiro[benzo[a]indeno[2′,1′:5,6]pyrano[2,3-c]phenazine] derivatives with high yield under solvent-free conditions. This domino Knoevenagel–Michael annulation reaction provided five new bonds (two C–C, two C?N, and one C–O) and two new rings through multiple operations in a single flask.

Full text of DOI:10.1002/jccs.201700034

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Microwave-assisted Domino Cyclization for the Synthesis of Novel Spiro-benzo[a]
phenazine Annulated Heterocycles Catalyzed by a Basic Ionic Liquid
a
b
c
*
Afshin Yazdani-Elah-Abadi, Razieh Mohebat and Mehrnoush Kangani
aDepartment of Biology, Science and Art University, Yazd, Iran
bYoung Researchers and Elite Club, Yazd Branch, Islamic Azad University, Yazd, Iran
cDepartment of Chemistry, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran
(Received: January 27, 2017; Accepted: March 19, 2017; DOI: 10.1002/jccs.201700034)
An efficient and green strategy for the improved synthesis of a biologically and pharmaceutically
interesting multi-functionalized diverse novel spiro-benzo[a]phenazine annulated heterocycles was
developed with the assistance of microwave irradiation. A sequential one-pot, two-step domino
reaction starting from 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamines, a cyclic carbonyl
compound, and 1,3-indandione in the presence of
a
basic ionic liquid (1-butyl-3-
methylimidazolium hydroxide) as an expedient, ecofriendly and reusable catalyst afforded the cor-
responding novel spiro[benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazine] derivatives with high yield
under solvent-free conditions. This domino Knoevenagel–Michael annulation reaction provided
five new bonds (two C–C, two C N, and one C–O) and two new rings through multiple opera-
tions in a single flask.
Keywords: Multicomponent domino reactions; Microwave-assisted reaction; Solvent-free reaction;
Ionic liquid; Spiro[benzo[a]pyrano[2,3-c]phenazine]; Green chemistry.
INTRODUCTION
this regard, microwave-assisted organic synthesis
(MAOS) has developed into a cherished branch of syn-
thetic organic chemistry and the synthesis of complex
heterocyclic molecules. The advantages of microwave
conditions relative to conventional thermal heating are
lesser reaction time, high yields of the products, and
better selectivity.12
So, the design of novel MDRs using microwave
irradiation for the synthesis of simple and complex bio-
active heterocycles has become a significant topic in the
drug discovery process and analysis of drugs.13,14 The
effective structure of polyheterocyclic skeletons bearing
several diverse functionalities is a challenging theme in
modern organic synthesis.15,16 Among these polyhetero-
cyclic skeletons, the various structurally different phe-
nazines have received further interest because of their
biological characteristics such as trypanocidal,17
fungicidal,18 antimalarial,19 and antiplatelet20 activities.
By virtue of their DNA-accommodating ability, they
represent antitumor activity in leukemia and solid
tumors. For instance, some benzophenazines are dual
inhibitors of topoisomerase I and II, two key enzymes
In recent years, interest in green chemistry1–3 has
developed, and a major challenge to organic chemists is
to identify facile, efficient, and nonpolluting synthetic
procedures that reduce the use of organic solvents and
toxic reagents. In this area, replacement of hazardous
solvents with environmentally benign solvents in
organic reactions has received considerable attention
due to their green credentials4,5; also, ionic liquids (ILs)
have become increasingly popular over the last few
years in the field of green organic synthesis6 owing to
their several advantages such as their catalytic role,
ability to dissolve a wide range of materials, mild reac-
tion conditions, noninflammability, high isolation and
purification yields, reusability, and high thermal
stability.7,8
In order to achieve cost savings and pollution pre-
vention, multicomponent domino reactions (MDRs)
have considerable ecological interest as a powerful
strategy in the synthesis of complex heterocyclic mole-
cules, drug design, and drug discovery, arising from the
minimization of time, wastage, energy, and cost.9–11 In
*Corresponding author. Email: afi_yazdani@yahoo.com
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Article
Yazdani-Elah-Abadi et al.
that perform the topology of DNA at various points in
the cell cycle.21,22 Also, pyran ring systems are an
important category of oxygen-containing heterocycles
and exist in a broad variety of important natural com-
pounds, including carbohydrates, alkaloids, polyether
antibiotics, pheromones, and iridoids.23 Pyaran-based
compounds are widely applied as cosmetics, pigments,24
and potential biodegradable agrochemicals,25 and show
a variety of biological functions including anti-leishma-
nial26 anti-HIV,27 antioxidant,28 antitumor,29 and cen-
tral nervous system (CNS) activities and effects30 they
are also used for the treatment of Alzheimer’s disease31
and schizophrenia.32
Moreover, spiro-heterocyclic compounds contain-
ing one sp3 carbon atom common to two rings are
found in a number of natural and synthetic mole-
cules33,34 and have many inimitable virtues.35,36 For
example, this type of framework has been found as a
core structure of many bioactive natural alkaloids such
as spirotryprotatins, gelsemine, mitraphylline, horsfi-
line, chitosenine, and others37 (Figure 1). Molecules
with spirocyclic structures are uniquely interesting
because the conformational restriction associated with
the structural rigidity affects significantly their biologi-
cal and pharmaceutical activity.38,39
indeno[20,10:5,6]pyrano[2,3-c]phenazine]
derivatives
6 through a domino, one-pot, four-component conden-
sation reaction between 2-hydroxynaphthalene-1,4-
dione 1, benzene-1,2-diamines 2, cyclic ketones 4, and
1,3-indandione 5 in a basic IL [BMIM]OH (1-butyl-3-
methylimidazolium hydroxide), which acts as reaction
medium as well as a basic catalyst, under microwave
irradiation (Scheme 1).
RESULTS AND DISCUSSION
At first, we evaluated the four-component domino
reaction of benzo[a]phenazin-5-ol 3a, which was derived
from the reaction of 2-hydroxy-1,4-naphthoquinone 1 with
benzene-1,2-diamine 2a, isatin 4a, and 1,3-indandione 5.
The reaction mixture, which consisted of a 1:1:1 mixture
of 3a, 4a, and 5a for the synthesis of compound 6a, was
selected as a model reaction in the presence of different
catalytic systems such as 1-butyl-3-methylimidazolium
hydroxide [BMIM]OH, N-methylimidazolium formate
[Hmim][HCOO], pyrrolidinium formate [Pyrr][HCOO],
piperidinium formate [Pip][HCOO], and 1,8-diazabicyclo
[5.4.0]-undec-7-en-8-ium acetate [DBU][CH3COO]
(various basic ILs) under conventional heating and
microwave irradiation, and the results are summarized
in Table 1.
Considering the considerable potential of spirocyc-
lic compounds, especially when fused to phenazine and
pyran derivatives as a source of valuable drug candi-
dates, and with our continued interest on multicompo-
nent reactions and our ongoing program for the
synthesis of heterocyclic systems based on green chemis-
try protocols,40–44 here we report a green and efficient
procedure for the synthesis of novel spiro[benzo[a]
The best result was obtained when the reaction was
carried out in the presence of [BMIM]OH as catalyst
under microwave irradiation in solvent-free condition at
300 W (max. 100ꢀC), which afforded the corresponding
15H-spiro[benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phena-
zine-16,30-indoline]-20,15-dione 6a in 8 min with 91%
yield (Table 1, entry 8).
To generate a small library of functionalized spiro
[benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazine] deri-
vatives, we tested a variety of substrates (various
benzene-1,2-diamines and different cyclic ketones) to
explore the synthetic scope and universality of this
accelerated one-pot Knoevenagel condensation/Michael
addition/cyclization cascade reaction under the optimal
conditions. The results are shown in Table 2.
In the first step of this four-component domino or
tandem reaction, different aromatic 1,2-diamines con-
taining benzene-1,2-diamine 2a, 4,5-dimethylbenzene-
1,2-diamine 2b, 4-methylbenzene-1,2-diamine 2c, and
4-nitrobenzene-1,2-diamine 2d were condensed with
2-hydroxynaphthalene-1,4-dione 1 to form the corre-
sponding benzo[a]phenazine. Using benzene-1,2-
Fig. 1. Some biologically active alkaloids containing
a heterocyclic spirooxindole.
2
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comparison with ninhydrin and acenaphthoquinone
(Table 2, entries 1–3).
The structures of these new compounds were
1
deduced from their elemental and spectral (IR, H, 13C
NMR, and elemental analysis) studies. The mass spec-
tra of these compounds displayed molecular ion peaks
at the appropriate m/z values.
1
For example, the H nuclear magnetic resonance
(NMR) spectrum of 6a exhibited four doublets, one tri-
plet, and five multiplets in the range δ 6.91–9.24 ppm,
characteristic for the 16 aromatic protons; the NH pro-
ton resonates at δ 10.84 ppm. The 13C NMR spectrum
of 6a showed 29 distinct resonances, in agreement with
the proposed structure (see Experimental section). The
characteristic signal due to the spiro-carbon was present
at δ 51.3, and the carbon of the C O groups resonated
at δ 177.3 and 189.2. The structural assignments made
on the basis of the NMR spectra of compound 6a were
supported by its IR spectrum. The NH and carbonyl
groups exhibited strong absorption bands at 3310,
Scheme 1. One-pot, four-component synthesis of
novel spiro[benzo[a]indeno[20,10:5,6]pyr-
ano[2,3-c]phenazine] derivatives, cata-
lyzed by [BMIM]OH.
diamine and 4,5-dimethylbenzene-1,2-diamine, higher
yields of the spiro products resulted in shorter reaction
times in comparison with other benzene-1,2-diamines
(Table 2, entries 1, 4, 7, and 9).
In the next step of this one-pot domino protocol,
various cyclic ketones containing isatin 4a, ninhydrin
4b, and acenaphthoquinone 4c were used. The use of
isatin led to a higher yield and shorter reaction time in
1695, and 1663 cm−1
.
We also studied the recycling of the IL using a
selected model reaction of 2-hydroxynaphthalene-1,
Table 1. Optimization of reaction conditions of compound 6a in different basic ILs (2 mL) as catalyst
Conventional heating1
Microwave irradiation2
Entry
Ionic liquid
T (ꢀC)
Time (min)
Yield3 (%)
Power4 (W)
Time (min)
Yield3 (%)
1
2
3
6
5
8
9
[BMIM]OH
70
70
70
70
70
100
40
100
30
30
30
30
30
20
60
30
82
58
79
73
50
83
64
84
180
180
180
180
180
300
100
300
10
10
10
10
10
8
87
65
83
80
52
91
73
85
[Hmim][HCOO]
[Pyrr][HCOO]
[Pip][HCOO]
[DBU][CH3COO]
[BMIM]OH
[BMIM]OH
[BMIM]OH
20
5
10
1
The reaction was carried out under thermal (Δ) and solvent-free conditions.
2
3
4
The reaction was carried out under microwave irradiation (MW) and solvent-free conditions.
Isolated yields.
The reaction was tested at different microwave powers (100–300 W) in the range 40–100ꢀC.
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Article
Yazdani-Elah-Abadi et al.
Table 2. Solvent-free synthesis of spiro[benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazine] derivatives 6 in the presence of [BMIM]
OH (2 mL) as catalyst under microwave irradiation (300 W, max. 100ꢀC)
Entry
Diamine
Cyclic ketone
Product
Time (min)
Yield (%)1
1
2
3
4
5
6
7
8
9
2a
2a
2a
2b
2b
2b
2c
2c
2d
2d
4a
4b
4c
4a
4b
4c
4a
4b
4a
4c
6a
6b
6c
6d
6e
6f
6g
6h
6i
8
8
8
10
10
10
12
12
12
12
91
85
87
87
80
84
85
76
81
78
10
1
6j
Isolated yields.
4dione 1, benzene-1,2-diamine 2a, isatin 4a, and 1,3-
indandione 5 in the presence of [BMIM]OH (2 mL)
under microwave irradiation (Table 2, entry 1). After
completion of the reaction, 5 mL of water was added,
and the precipitate was filtered off for the separation of
crude products. After washing the solid products with
water completely (2 × 5 mL), since the IL is soluble in
water, the [BMIM]OH was recovered by evaporation of
the water and washed with diethyl ether and reused for
the subsequent catalytic runs. As shown in Figure 2, the
reaction media could be successfully recycled for up to
six runs with limited loss of activity (the yield decreased
from 91% to 85% after 6 runs, Figure 1).
5 attacks the Knoevenagel adduct I in a Michael-type
addition to produce the intermediate II, which then makes
the inner molecular ring to be formed after a tautomeric
proton shift to generate 6 (Scheme 2).
EXPERIMENTAL
General
All melting points were determined on an Electro-
thermal 9100 apparatus and are uncorrected. IR spectra
were recorded on a Shimadzu IR-470 spectrometer.
The probable mechanism for the domino cyclocon-
densation of spiro[benzo[a]indeno[20,10:5,6]pyrano[2,3-c]
phenazine] derivatives 6 using [BMIM]OH, which acts as
an efficient basic catalyst in all steps, is given in Scheme
3 according to the literature.4 On the basis of this sug-
gested mechanism, the primary condensation of 2-hydro-
xynaphthalene-1,4-dione 1 with benzene-1,2-diamine 2 in
the presence of [BMIM]OH gives benzo[a]phenazin-5-ol 3.
Then, the Knoevenagel condensation between the benzo
[a]phenazin-5-ol 3 and cyclic ketone 4 produces adduct I,
which acts as a Michael acceptor. The 1,3-indandione
Fig. 2. Investigation of the recycling of [BMIM]OH.
4
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Scheme 2. Proposed mechanism for the formation of spiro[benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazine] derivatives
in the presence of [BMIM]OH.
Elemental analyses for C, H, and N were performed
using a Costech ECS 4010 CHNS-O analyzer at the
analytical laboratory of Islamic Azad University (Yazd
branch). Mass spectra were recorded on an Agilent
Technology (HP) spectrometer operating at an ioniza-
as monitored by TLC, the reaction mixture was allowed
to cool to room temperature. Then, 5 mL of water was
added to the mixture, which was filtered for separation
of the crude product. The separated product was
washed twice with water (2 × 5 mL). The resulting
product was subsequently recrystallized from hot etha-
nol to afford the pure product 6 in good to excellent
yield. The analytical and spectroscopic data for the
unknown compounds are as follows:
1
tion potential of 70 eV. The H NMR and 13C NMR
spectra were recorded in deuterated dimethylsulfoxide
(DMSO-d6) on a Bruker DRX-300 spectrometer oper-
1
ating at 300 MHz for H analysis and 75 MHz for 13C
15H-Spiro[benzo[a]indeno[20,10:5,6]pyrano[2,3-c]
analysis. All reactions were carried out using a labora-
tory microwave oven (MicroSYNTH, Milestone Com-
pany, Italy). 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. The
weak basic ILs [BMIM]OH,45 [Hmim][HCOO],46 [Pyrr]
[HCOO],47 [Pip][HCOO]48 and DBU[CH3COO]49 were
synthesized according to the reported procedure.
phenazine-16,30-indoline]-20,15-dione (6a). Yellow solid;
yield 0.458 g (91%), mp 273–275ꢀC; IR (KBr, cm−1):
νmax 3310, 3142, 2974, 1695 (C O), 1663 (C O), 1587,
1532, 1451, 1331, 1275, 1119, 921, 758; 1H NMR
(300 MHz, DMSO-d6): δH 6.91 (d, J = 7.8 Hz, 1H, Ar-
H), 7.21 (t, J = 7.5 Hz, 1H, Ar-H), 7.41–7.45 (m, 1H,
Ar-H), 7.78–7.83 (m, 2H, Ar-H), 7.92–7.95 (m, 4H, Ar-
H), 8.11 (d, J = 7.8 Hz, 1H, Ar-H), 8.23–8.26 (m, 2H,
Ar-H), 8.33-–8.36 (m, 2H, Ar-H), 8.58 (d, J = 7.8 Hz,
1H, Ar-H), 9.24 (d, J = 8.1 Hz, 1H, Ar-H), 10.84 (s,
1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6): δC
51.3 (Cspiro), 111.5, 114.7, 122.5, 122.7, 123.7, 124.4,
124.9, 125.1, 126.4, 127.0, 127.8, 129.2, 129.5, 129.8,
129.9, 130.1, 130.2, 130.5, 131.7, 132.4, 140.4, 146.2,
147.7, 148.5, 150.4 and 157.5 (Colefinic and Carom), 177.3
and 189.2 (2C O) ppm; MS (m/z, %): 503 (M+, 7);
Anal. Calcd for C33H17N3O3: C, 78.72; H, 3.40; N,
8.35%. Found: C, 78.97; H, 3.61; N, 8.48%.
General procedure for the synthesis of spiro[benzo[a]
indeno[20,10:5,6]pyrano[2,3-c]phenazine] derivatives (6a–j)
A
mixture of 2-hydroxynaphthalene-1,4-dione
1 (1 mmol) and benzene-1,2-diamine 2 (1 mmol) in the
basic IL [BMIM]OH (2 mL) was irradiated in a micro-
wave oven at 300 W for less than 2 min until benzo[a]
phenazin-5-ol 3 was formed. The microwave was pro-
grammed to give a maximum internal temperature of
100ꢀC. Then, cyclic ketone 4 (1 mmol) and 1,3-
indandione 5 (1 mmol) were added to the above reac-
tion mixture, which was irradiated further at same tem-
perature (300 W, max. 100ꢀC) for an appropriate time
as shown in Table 2. Upon completion of the reaction,
15H-Spiro[benzo[a]indeno[20,10:5,6]pyrano[2,3-c]
phenazine-16,20-indene]-10,30,15-trione (6b). Yellow solid;
yield 0.439 g (85%), mp 294–295ꢀC; IR (KBr, cm−1):
νmax 3324, 3165, 2971, 1711 (C O), 1697 (C O), 1663
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(C O), 1592, 1521, 1453, 1412, 1345, 1237, 1133,
970, 761; H NMR (300 MHz, DMSO-d6): δH 7.34 (d,
121.9, 122.5, 123.7, 123.9, 124.5, 126.1, 126.7, 127.1,
128.5, 129.1, 129.2, 129.8, 129.9, 130.0, 130.2, 130.6,
131.5, 132.4, 141.6, 146.4, 146.9, 148.4, 150.8 and 158.2
(Colefinic and Carom), 179.1 and 190.6 (2C O) ppm; MS
(m/z, %): 531 (M+, 4); Anal. Calcd for C35H21N3O3: C,
79.08; H, 3.98; N, 7.91%. Found: C, 79.42; H,
4.19; N, 7.75%.
1
J = 7.8 Hz, 1H, Ar-H), 7.52–7.56 (m, 1H, Ar-H),
7.79–7.84 (m, 3H, Ar-H), 7.87–7.94 (m, 5H, Ar-H),
8.17 (d, J = 8.1 Hz, 1H, Ar-H), 8.20–8.23 (m, 1H, Ar-
H), 8.25–8.30 (m, 2H, Ar-H), 8.61 (d, J = 7.8 Hz, 1H,
Ar-H), 9.31 (d, J = 7.5 Hz, 1H, Ar-H) ppm; 13C NMR
(75 MHz, DMSO-d6): δC 65.1 (Cspiro), 111.7, 116.2,
122.5, 122.6, 123.8, 124.2, 124.9, 125.1, 126.3, 127.5,
128.1, 129.2, 129.6, 129.8, 129.9, 130.2, 130.4, 130.5,
131.7, 132.6, 140.3, 146.5, 147.2, 148.1, 150.4 and 157.6
(Colefinic and Carom), 190.7 and 205.4 (2C O) ppm; MS
(m/z, %): 516 (M+, 3); Anal. Calcd for C34H16N2O4: C,
79.06; H, 3.12; N, 5.42%. Found: C, 79.34; H,
3.31; N, 5.80%.
2,3-Dimethyl-15H-spiro[benzo[a]indeno[20,10:5,6]
pyrano[2,3-c]phenazine-16,20-indene]-10,30,15-trione (6e).
Yellow solid; yield 0.435 g (80%), mp >300ꢀC; IR
(KBr, cm−1): νmax 3350, 3178, 2954, 1708 (C O), 1694
(C O), 1667 (C O), 1590, 1532, 1461, 1408, 1362,
1
1253, 1118, 968, 757; H NMR (300 MHz, DMSO-d6):
δH 2.44 (s, 6H, 2CH3), 7.11 (t, J = 7.8 Hz, 1H, Ar-H),
7.32–7.36 (m, 4H, Ar-H), 7.51–7.55 (m, 3H, Ar-H),
7.81–7.90 (m, 3H, Ar-H), 8.12 (d, J = 7.8 Hz, 1H, Ar-
H), 8.47 (d, J = 8.1 Hz, 1H, Ar-H), 9.18 (d,
J = 8.1 Hz, 1H, Ar-H) ppm; 13C NMR (75 MHz,
DMSO-d6): δC 19.8 and 20.4 (2CH3), 64.6 (Cspiro),
112.5, 115.4, 121.2, 122.3, 122.7, 124.5, 124.8, 125.3,
126.4, 126.5, 128.3, 129.3, 129.5, 129.8, 129.9, 130.1,
130.6, 130.8, 131.9, 132.5, 140.2, 146.2, 146.8, 148.7,
150.2 and 158.3 (Colefinic and Carom), 191.1 and 207.2
(2C O) ppm; MS (m/z, %): 544 (M+, 2); Anal. Calcd
for C36H20N2O4: C, 79.40; H, 3.70; N, 5.14%.
Found: C, 79.67; H, 3.94; N, 5.46%.
2H,150H-Spiro[acenaphthylene-1,160-benzo[a]
indeno[20,10:5,6]pyrano[2,3-c]phenazine]-2,150-dione (6c).
Yellow solid; yield 0.468 g (87%), mp 251–253ꢀC; IR
(KBr, cm−1): νmax 3335, 3128, 2962, 1709 (C O), 1687
(C O), 1575, 1531, 1450, 1328, 1265, 1132, 918, 758;
1H NMR (300 MHz, DMSO-d6): δH 7.06–7.08 (m, 1H,
Ar-H), 7.54–7.58 (m, 1H, Ar-H), 7.81–7.93 (m, 7H, Ar-
H), 8.01–8.05 (m, 3H, Ar-H), 8.12 (d, J = 8.1 Hz, 1H,
Ar-H), 8.36 (d, J = 7.8 Hz, 1H, ArH), 8.43–8.49 (m,
3H, Ar-H), 9.27 (d, J = 7.8 Hz, 1H, Ar-H) ppm; 13C
NMR (75 MHz, DMSO-d6): δC 57.2 (Cspiro), 112.4,
117.3, 120.3, 121.1, 122.4, 123.2, 123.5, 124.7, 125.2,
126.1, 126.5, 127.4, 128.6, 129.2, 129.4, 129.8, 129.9,
130.4, 130.6, 131.5, 131.8, 132.0, 140.6, 140.9, 141.7,
146.5, 148.4, 150.6, 156.4 and 158.4 (Colefinic and
20,30-Dimethyl-2H,150H-spiro[acenaphthylene-1,160-
benzo[a]indeno[20,10:5,6]pyrano[2,3-c]phenazine]-2,150-
dione (6f ). Yellow solid; yield 0.475 g (84%), mp
259–261ꢀC; IR (KBr, cm−1): νmax 3335, 3128, 2962,
1711 (C O), 1685 (C O), 1571, 1528, 1462, 1332,
C
arom), 189.7 and 203.5 (2C O) ppm; MS (m/z, %):
1
538 (M+, 2); Anal. Calcd for C37H18N2O3: C, 82.52; H,
3.37; N, 5.20%. Found: C, 82.76; H, 3.64; N, 5.37%.
2,3-Dimethyl-15H-spiro[benzo[a]indeno[20,10:5,6]
1248, 1161, 923, 760; H NMR (300 MHz, DMSO-d6):
δH 2.53 (s, 3H, CH3), 2.56 (s, 3H, CH3), 7.12 (d,
J = 8.1 Hz, 1H, Ar-H), 7.48–7.51 (m, 2H, Ar-H),
7.85–7.94 (m, 5H, Ar-H), 8.12–8.17 (m, 3H, Ar-H),
8.24–8.28 (m, 1H, Ar-H), 8.39 (d, J = 7.8 Hz, 1H,
ArH), 8.62–8.66 (m, 2H, Ar-H), 9.24 (m, 1H, Ar-H)
ppm; 13C NMR (75 MHz, DMSO-d6): δC 20.6 and 20.8
(2CH3), 58.5 (Cspiro), 114.2, 118.1, 121.4, 122.3, 122.7,
123.1, 124.5, 124.7, 125.1, 126.7, 127.2, 127.4, 128.5,
129.0, 129.3, 129.8, 130.1, 130.4, 130.5, 131.6, 131.8,
132.0, 140.8, 141.2, 141.7, 147.4, 148.7, 150.3, 157.5
and 158.6 (Colefinic and Carom), 190.3 and 204.1 (2C O)
ppm; MS (m/z, %): 566 (M+, 12); Anal. Calcd for
C39H22N2O3: C, 82.67; H, 3.91; N, 4.94%. Found: C,
82.85; H, 4.07; N, 5.14%.
pyrano[2,3-c]phenazine-16,30-indoline]-20,15-dione (6d).
Yellow solid; yield 0.462 g (87%), mp 286–287ꢀC; IR
(KBr, cm−1): νmax 3364, 3170, 2966, 1703 (C O), 1658
(C O), 1584, 1533, 1457, 1328, 1269, 1131, 916, 760;
1H NMR (300 MHz, DMSO-d6): δH 2.41 (s, 3H, CH3),
2.44 (s, 3H, CH3), 7.36 (d, J = 8.1 Hz, 1H, Ar-H),
7.56–7.62 (m, 5H, Ar-H), 7.95–8.04 (m, 3H, Ar-H),
8.07–8.12 (m, 2H, Ar-H), 8.35 (dd, J1 = 8.1 Hz,
J2 = 2.1 Hz, 1H, Ar-H), 8.51 (d, J = 8.1 Hz, 1H, Ar-
H), 9.18 (dd, J1 = 7.8 Hz, J2 = 2.1 Hz, 1H, Ar-H),
10.69 (s, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-
d6): δC 20.4 and 20.7 (2CH3), 50.7 (Cspiro), 110.4, 116.2,
6
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JOURNAL OF THE CHINESE
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Spiro-benzo[a]phenazine Annulated Heterocycles
2-Methyl-15H-spiro[benzo[a]indeno[20,10:5,6]pyrano
[2,3-c]phenazine-16,30-indoline]-20,15-dione (6g). Yellow
solid; yield 0.439 g (85%), mp 291–293ꢀC; IR (KBr,
cm−1): νmax 3325, 3166, 2965, 1708 (C O), 1665
(C O), 1591, 1530, 1462, 1345, 1263, 1124, 917, 760;
1H NMR (300 MHz, DMSO-d6): δH 2.40 (s, 3H, CH3),
6.87 (d, J = 7.8 Hz, 1H, ArH), 6.98 (dd, J1 = 7.8 Hz,
J2 = 2.1 Hz, 1H, ArH), 7.07 (s, 1H, ArH), 7.15 (d,
J = 8.1 Hz, 1H, ArH), 7.52 (d, J = 8.1 Hz, 1H, ArH),
7.86–7.91 (m, 5H, ArH), 8.03–8.05 (m, 2H, ArH),
8.22–8.26 (m, 1H, ArH), 8.54 (d, J = 7.8 Hz, 1H,
ArH), 9.23–9.26 (m, 1H, ArH), 10.91 (s, 1H, NH) ppm;
13C NMR (75 MHz, DMSO-d6): δC 21.8 (CH3), 52.1
(Cspiro), 112.7, 114.5, 121.2, 122.6, 123.5, 124.7, 124.9,
125.3, 125.6, 127.3, 127.9, 128.8, 129.0, 129.2, 129.7,
129.9, 130.1, 130.6, 130.8, 131.2, 132.8, 140.5, 141.3,
146.2, 148.8, 149.7 and 155.6 (Colefinic and Carom), 178.2
and 189.5 (2C O) ppm; MS (m/z, %): 517 (M+, 3);
Anal. Calcd for C34H19N3O3: C, 78.91; H, 3.70; N,
8.12%. Found: C, 79.22; H, 3.96; N, 8.29%.
7.63–7.68 (m, 3H, Ar-H), 7.94–7.97 (m, 4H, Ar-H),
8.08 (d, J = 8.1 Hz, 1H, Ar-H), 8.21–8.25 (m, 1H,
Ar-H), 8.37–8.40 (m, 1H, Ar-H), 8.62 (d, J = 7.8 Hz,
1H, Ar-H), 9.31–9.35 (m, 1H, Ar-H), 10.86 (s, 1H,
NH) ppm; 13C NMR (75 MHz, DMSO-d6): δC 51.0
(Cspiro), 114.2, 117.3, 121.4, 122.7, 123.6, 124.8, 125.2,
125.6, 126.7, 127.1, 128.5, 129.2, 129.6, 129.8, 129.9,
130.3, 130.6, 130.9, 131.3, 131.9, 141.7, 147.5, 147.8,
148.2, 152.6, 156.3 and 158.0 (Colefinic and Carom), 175.6
and 189.7 (2C O) ppm; MS (m/z, %): 548 (M+, 3);
Anal. Calcd for C33H16N4O5: C, 72.26; H, 2.94; N,
10.21%. Found: C, 72.63; H, 3.08; N, 10.42%.
30-Nitro-2H,150H-spiro[acenaphthylene-1,160-benzo
[a]indeno[20,10:5,6]pyrano[2,3-c]phenazine]-2,150-dione
(6j). Brown solid; yield 0.455 g (78%), mp >300ꢀC; IR
(KBr, cm−1): νmax 3335, 3152, 2964, 1712 (C O), 1691
(C O), 1575, 1530, 1442, 1331, 1283, 1149, 924, 756;
1H NMR (300 MHz, DMSO-d6): δH 7.24–7.30 (m, 2H,
Ar-H), 7.68–7.72 (m, 3H, Ar-H), 7.84–7.91 (m, 5H, Ar-
H), 8.11–8.14 (m, 2H, Ar-H), 8.25–8.29 (m, 1H, Ar-H),
8.41 (d, J = 7.8 Hz, 1H, ArH), 8.52 (d, J = 7.8 Hz,
1H, ArH), 8.59–8.61 (m, 1H, Ar-H), 9.27–9.30 (m, 1H,
Ar-H) ppm; 13C NMR (75 MHz, DMSO-d6): δC 57.8
(Cspiro), 111.2, 115.4, 121.5, 121.8, 122.2, 123.5, 123.6,
125.2, 125.4, 125.6, 126.2, 127.3, 128.5, 129.0, 129.4,
129.6, 129.9, 130.5, 130.9, 131.2, 132.1, 132.6, 140.2,
140.8, 141.4, 141.8, 146.4, 148.6, 150.3, 157.2 and 158.6
(Colefinic and Carom), 191.2 and 204.8 (2C O) ppm; MS
(m/z, %): 583 (M+, 4); Anal. Calcd for C37H17N3O5: C,
76.15; H, 2.94; N, 7.20%. Found: C, 76.43; H,
3.11; N, 7.45%.
2-Methyl-15H-spiro[benzo[a]indeno[20,10:5,6]pyrano
[2,3-c]phenazine-16,20-indene]-10,30,15-trione (6h). Yel-
low solid; yield 0.403 g (76%), mp 256–258ꢀC; IR
(KBr, cm−1): νmax 3325, 3165, 2983, 1705 (C O),
1694 (C O), 1667 (C O), 1590, 1525, 1462, 1422,
1338, 1252, 1150, 942, 758; 1H NMR (300 MHz,
DMSO-d6): δH 2.43 (s, 3H, CH3), 6.94 (d, J = 7.5 Hz,
1H, Ar-H), 7.27 (d, J = 7.5 Hz, 1H, Ar-H), 7.50–7.53
(m, 2H, Ar-H), 7.81–7.92 (m, 6H, Ar-H), 8.06 (d,
J = 7.8 Hz, 1H, Ar-H), 8.24–8.28 (m, 1H, Ar-H),
8.32–8.35 (m, 1H, Ar-H), 8.59 (d, J = 7.8 Hz, 1H, Ar-
H), 9.28–9.31 (m, 1H, ArH) ppm; 13C NMR
(75 MHz, DMSO-d6): δC 22.1 (CH3), 64.8 (Cspiro),
111.3, 115.4, 122.7, 122.9, 123.5, 124.0, 124.6, 126.2,
126.7, 127.8, 128.1, 129.3, 129.5, 129.8, 129.9, 130.3,
130.6, 130.9, 131.6, 132.6, 140.5, 145.9, 147.6, 148.2,
150.8 and 156.8 (Colefinic and Carom), 191.3 and 205.8
(2C O) ppm; MS (m/z, %): 530 (M+, 1); Anal. Calcd
for C35H18N2O4: C, 79.24; H, 3.42; N, 5.28%.
Found: C, 79.55; H, 3.21; N, 5.52%.
CONCLUSIONS
In this work, we have demonstrated a one-pot,
four-component domino cyclization for the diastereose-
lective synthesis of spiro[benzo[a]indeno[20,10:5,6]pyrano
[2,3-c]phenazine] derivatives in excellent yields and
purities with very short reaction times, from readily
available starting materials by using a basic IL [BMIM]
OH as an environmentally benign catalyst, under
microwave irradiation conditions. This green and effi-
cient procedure has a number of advantages such as
atom economy, operational simplicity, easy work-up,
use of an inexpensive, nontoxic, and reusable catalyst
without any byproduct under solvent-free conditions,
and its may find a wide range of applications in
diversity-oriented synthesis and drug discovery, which
3-Nitro-15H-spiro[benzo[a]indeno[20,10:5,6]pyrano
[2,3-c]phenazine-16,30-indoline]-20,15-dione (6i). Brown
solid; yield 0.444 g (81%), mp >300ꢀC; IR (KBr, cm−1):
νmax 3325, 3154, 2987, 1694 (C O), 1660 (C O), 1591,
1530, 1448, 1335, 1264, 1148, 919, 758; 1H NMR
(300 MHz, DMSO-d6): δH 6.94 (d, J = 8.1 Hz, 1H, Ar-
H), 7.12–7.16 (m, 1H, Ar-H), 7.37–7.40 (m, 1H, Ar-H),
J. Chin. Chem. Soc. 2017
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Article
Yazdani-Elah-Abadi et al.
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ACKNOWLEDGMENTS
We gratefully acknowledge the financial support
from the Research Council of the University of Science
and Arts of Yazd, Iran, and Young Researchers and Elite
Club, Yazd Branch, Islamic Azad University, Yazd.
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