l-Proline catalyzed domino cyclization for the green synthesis of novel 1,4-dihydrobenzo[a]pyrido[2,3-c]phenazines

Article abstract of DOI:10.1007/s00706-017-2008-7

Abstract: l-Proline has been used as an efficient, reusable, and bifunctional organocatalyst for the one-pot, two-step, five-component synthesis of novel 1,4-dihydrobenzo[a]pyrido[2,3-c]phenazines by the condensation reaction of 2-hydroxynaphthalene-1,4-dione, aromatic 1,2-diamines, aldehydes, ammonium acetate, and ethyl acetoacetate under conventional heating in solvent-free conditions. In this domino transformation, six bonds and two new rings are efficiently formed. High yields, short reaction time (20–30?min), operational simplicity, easy work-up procedure, avoidance of hazardous or toxic catalysts and organic solvents are the main advantages of this green methodology.

Full text of DOI:10.1007/s00706-017-2008-7

Monatsh Chem
DOI 10.1007/s00706-017-2008-7
ORIGINAL PAPER
L-Proline catalyzed domino cyclization for the green synthesis
of novel 1,4-dihydrobenzo[a]pyrido[2,3-c]phenazines
Afshin Yazdani-Elah-Abadi1 Sajjad Abbasi Pour2 Mehrnoush Kangani2 Razieh Mohebat3
•
•
•
Received: 2 April 2017 / Accepted: 21 May 2017
Ó Springer-Verlag Wien 2017
Abstract L-Proline has been used as an efficient, reusable, and
bifunctional organocatalyst for the one-pot, two-step, five-
component synthesis of novel 1,4-dihydrobenzo[a]pyrido[2,3-
c]phenazines by the condensation reaction of 2-hydroxy-
naphthalene-1,4-dione, aromatic 1,2-diamines, aldehydes,
ammonium acetate, and ethyl acetoacetate under conventional
heating in solvent-free conditions. In this domino transforma-
tion, six bonds and two new rings are efficiently formed. High
yields, short reaction time (20–30 min), operational simplicity,
easy work-up procedure, avoidance of hazardous or toxic cat-
alysts and organic solvents are the main advantages of this
green methodology.
Keywords Multi-component domino reactions Á
1,4-Dihydrobenzo[a]pyrido[2,3-c]phenazines Á L-Proline Á
Solvent-free Á Environmentally friendly
Introduction
Organocatalysis has emerged as a powerful methodology in
organic synthesis for the synthesis of simple and complex
bioactive heterocycles [1–6] due to their improved stabil-
ity, lack of sensitivity to moisture and oxygen, ready
availability, low cost, lesser toxicity, and metal-free reac-
tion conditions. Among organocatalysts, L-proline is a
readily obtainable naturally occurring amino acid and is
easy to obtain in high enantiomeric purity it has been
reported as an eco-friendly catalyst for the synthesis of
several heterocycles [7–12].
Graphical abstract
In the past few years, the development of environmen-
tally friendly, efficient, and economical methods have
received significant attention for the synthesis of biologi-
cally interesting compounds [13, 14]. Considerable
advances have been made on chemical processes to attain
the hazard-free, waste-free, and energy-effective syntheses
as a final goal. In this area, multi-component domino
reactions (MDRs) in which more than two components are
combined in a single synthetic operation, have considerable
ecological interest as a powerful strategy in the synthesis of
chemically and biologically important organic frameworks.
These processes avoid the isolation and purification of
intermediates, higher productivity, minimize solvent waste,
and enhance the greenness of the transformations [15–18].
Heterocycles having phenazine [19, 20] and 1,4-dihy-
dropyridine moieties are important targets in the synthetic
organic and medicinal chemistry. While phenazines and
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-2008-7) contains supplementary
material, which is available to authorized users.
& Afshin Yazdani-Elah-Abadi
afi_yazdani@yahoo.com
1
Department of Biology, Science and Art University, Yazd,
Iran
2
Department of Chemistry, Faculty of Science, University of
Sistan and Baluchestan, Zahedan, Iran
3
Department of Chemistry, Yazd Branch, Islamic Azad
University, Yazd, Iran
123

A. Yazdani-Elah-Abadi et al.
Results and discussion
The vast biological and pharmacological importance of
phenazine and 1,4-dihydropyridine derivatives inspired us
to develop a novel protocol for their efficient synthesis. So,
we were willing to find a practical and general method for
their synthesis in high yields and purities and also, owing to
the development of efficient and environmentally friendly
synthetic procedures is always desirable, we decided to
peruse whether those phenazines could be prepared by
condensation of 2-hydroxynaphthalene-1,4-dione, ben-
zene-1,2-diamines, aldehydes, ammonium acetate, and
ethyl acetoacetate in the absence of any organic solvent.
In order to investigate the optimizing reaction conditions
for the synthesis of 1,4-dihydrobenzo[a]pyrido[2,3-
c]phenazines, we carried out the five-component domino
reaction between 2-hydroxynaphthalene-1,4-dione (1,
1 mmol), benzene-1,2-diamine (2a, 1 mmol) 4-chlorobenz-
aldehyde (1 mmol), ammonium acetate (5, 2 mmol), and
ethyl acetoacetate (6, 1.5 mmol) in solvent-free condition
as a model. We initially, to minimize the formation of
byproducts, the 2-hydroxynaphthalene-1,4-dione and ben-
zene-1,2-diamine were mixed at 80 °C until in less than
5 min an orange solid of benzo[a]phenazine 3a was formed
without using any catalyst. Next, 4-chlorobenzaldehyde,
ammonium acetate, and ethyl acetoacetate were added and
the mixture was stirred under thermal conditions at 80 °C.
The desired product 7a was not obtained when the reaction
was carried out in solvent-free condition for 30 min under
solvent and catalyst-free conditions (Table 1, entry 1).
However, 7a was obtained in 57% yield when the reaction
was conducted in the presence of FeCl3 (20 mol%) in
solvent-free condition at 80 °C (Table 1, entry 2). Several
catalysts were evaluated in the reaction, including InCl3,
Yb(OTf)3, nano-Fe3O4, PTSA, DABCO, oxalic acid, L-
histidine and L-proline; the reactions were carried out under
Fig. 1 The structure of designed compound
1,4-dihydropyridine have attracted great attention in drug
discovery, the preparation of compounds incorporating
both of these motifs (Fig. 1) has not been reported.
1,4-Dihydropyridine (DHP) systems are an important
class of aza-polycyclic compounds showing a variety of
medical, biological, and pharmacological activities
[21–24], including antiatherosclerotic, bronchodilator,
vasodilator, hepatoprotective, antidiabetic, geroprotective,
anticonvulsant, anti-HIV, and antitumor agent [25–30].
Also, 1,4-DHPs are widely used as calcium channel
blockers in the treatment of cardiovascular diseases, such
as hypertension [31].
Considering the considerable potential of novel DHP
and phenazine derivatives as a source of valuable drug
candidates and with our continued interest in multi-com-
ponent reactions and our ongoing program for the synthesis
of heterocyclic systems based on green chemistry protocols
[32–35], herein, we report a green and efficient method for
the synthesis of novel 1,4-dihydrobenzo[a]pyrido[2,3-
c]phenazines through a single-pot, domino, five-component
condensation reaction between 2-hydroxy-1,4-naphtho-
quinone (1), aromatic 1,2-diamines 2, aldehydes 4,
ammonium acetate (5) and ethyl acetoacetate (6) catalyzed
by L-proline as a bifunctional organocatalyst under con-
ventional heating in solvent-free conditions (Scheme 1).
Scheme 1
123

L-Proline catalyzed domino cyclization for the green synthesis of novel 1,4-dihydrobenzo[a]…
Table 1 Optimization of reaction conditions of compound 7a
Entry
Catalyst
Reaction conditions
Time/min
Yielda/%
1
No catalyst
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 80 °C
EtOH, reflux
30
20
20
20
20
20
20
20
20
20
90
90
20
10
10
30
90
NR
56
2
FeCl3 (20 mol%)
3
InCl3 (20 mol%)
40
4
Yb(OTf)3 (20 mol%)
Nano-Fe3O4 (0.03 g)
PTSA (20 mol%)
47
5
78
6
Trace
Trace
Trace
Trace
81
7
DABCO (20 mol%)
Oxalic acid (20 mol%)
L-Histidine (20 mol%)
L-Proline (20 mol%)
L-Proline (20 mol%)
L-Proline (20 mol%)
L-Proline (30 mol%)
L-Proline (40 mol%)
L-Proline (30 mol%)
L-Proline (30 mol%)
L-Proline (30 mol%)
8
9
10
11
12
13
14
15
16
17
76
H2O, reflux
52
Solvent-free, 80 °C
Solvent-free, 80 °C
Solvent-free, 100 °C
Solvent-free, 50 °C
Solvent-free, rt
87
74
80
76
Trace
Reaction conditions: 2-hydroxynaphthalene-1,4-dione (1 mmol), benzene-1,2-diamine (1 mmol), 4-chlorobenzaldehyde (1 mmol), ammonium
acetate (2 mmol), and ethyl acetoacetate (1.5 mmol) in the presence of various catalytic systems at different temperatures
a
Isolated yields
solvent-free condition at 80 °C. L-Proline showed excellent
catalytic activity in terms of reaction time as well as yield
of the product (Table 1, entry 10). Then, ethanol and water
were appraised to determine the impact of the solvent on
the reaction model yields (Table 1, entries 11, 12). As
Table 1 indicates, the best results were obtained by heating
the reaction mixture in solvent-free condition at 80 °C
(Table 1, entry 10). We then evaluated the amount of
catalyst required for this transformation. An increase in the
amount of L-proline to 30 mol% showed remarkable
improvement in the yield (Table 1, entry 13). Finally, the
reaction was performed at different temperatures to deter-
mine the optimum reaction temperature. The reaction was
conducted with 30 mol% L-proline in solvent-free condi-
tion at rt, 50, 80, and 100 °C, and the desired product 7a
was formed in yields of trace, 76, 87, and 80% (Table 1,
entries 13 and 15–17), respectively.
of L-proline under solvent-free condition at 80 °C, which
furnished the corresponding ethyl 1-(4-chlorophenyl)-3-
methyl-1,4-dihydrobenzo[a]pyrido[2,3-c]phenazine-2-car-
boxylate (7a) in 87% yield within 20 min (Table 1, entry
13).
Using these optimized conditions, we turned our atten-
tion to investigate the scope and general applicability of
this methodology by carrying out the synthesis of 1,4-di-
hydrobenzo[a]pyrido[2,3-c]phenazines using different
benzene-1,2-diamines and various aromatic aldehydes
(Table 2).
All the reactions were complete in 20–30 min and
resulted in the formation of the target structures in high
yields using L-proline as environment-friendly catalyst and
this domino reaction was efficiently promoted using ben-
zene-1,2-diamine with reduced reaction times and
increased yields rather than other benzene-1,2-diamines
and no clear electronic effects of the aldehyde were
observed.
After extensive screening, we found that the optimized
best yields and time profiles were obtained with 30 mol%
123

A. Yazdani-Elah-Abadi et al.
Table 2 Domino one-pot five-component synthesis of 1,4-dihydrobenzo[a]pyrido[2,3-c]phenazine derivatives
Entry
R1
R2
Product
Time/
min
Yielda/
%
1
H
4-Cl
7a
7b
7c
7d
7e
7f
20
20
30
20
20
30
30
30
30
30
30
87
85
80
82
83
85
80
80
76
78
81
2
H
4-NO2
4-CN
2-Cl
3
H
4
H
5
H
3-NO2
4-Me
4-OMe
4-Cl
6
H
7
H
7g
7h
7i
8
Cl
Cl
Me
Me
9
4-Me
4-Cl
10
11
7j
4-NO2
7k
Reaction conditions: 2-hydroxynaphthalene-1,4-dione (1 mmol), benzene-1,2-diamine (1 mmol), aromatic aldehyde (1 mmol), ammonium
acetate (2 mmol), ethyl acetoacetate (1.5 mmol), and L-proline (30 mol%) under solvent-free condition at 80 °C
a
Isolated yields
Additionally, recyclability of the catalyst was investi-
gated under reaction conditions using a model reaction of
2-hydroxynaphthalene-1,4-dione,
benzene-1,2-diamine,
4-chlorobenzaldehyde, ammonium acetate, and ethyl ace-
toacetate. After completion of the reaction, the reaction
mixture was cooled to room temperature. Then, 10 cm3 of
water was added to the mixture and the crude solid product
was filtered and washed with H2O (2 9 5 cm3). The L-
proline was removed from the reaction media by washing
with H2O. Since the catalyst is soluble in water, the catalyst
was recovered by evaporation of the water and washed
with diethyl ether and reused for the subsequent catalytic
runs. The catalytic system worked well up to five catalytic
runs (Fig. 2).
The probable mechanism for the domino cycloconden-
sation of 1,4-dihydrobenzo[a]pyrido[2,3-c]phenazines 7
using L-proline is outlined in Scheme 2 according to the
literature [36]. On the basis of this mechanism, the primary
condensation of 2-hydroxynaphthalene-1,4-dione (1) with
benzene-1,2-diamine 2 in the presence of L-proline gives
benzo[a]phenazin-5-ol 3. On this mechanism, L-proline is
an efficient catalyst to form the olefin 8, which readily
prepares in situ from Knoevenagel condensation of
Fig. 2 The investigation of the recycling of L-proline
aromatic aldehyde 4 with benzo[a]phenazin-5-ol 3. On the
other hand, NH3 resulting from ammonium acetate and
ethyl acetoacetate by L-proline yields enamine 9. Subse-
quently, the reaction between olefin 8 and enamine 9 gives
the corresponding intermediate 10. Tautomerization of
intermediate 10 affords intermediate 11 which suffers an
intramolecular nucleophilic attack of the NH2 group to the
123

L-Proline catalyzed domino cyclization for the green synthesis of novel 1,4-dihydrobenzo[a]…
Scheme 2
activated carbonyl group providing intermediate 12. At the
end, dehydration of this intermediate yields the desired
target molecules 7.
75 MHz for 13C analysis. 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 procedure for the synthesis of novel 1,4-dihy-
drobenzo[a]pyrido[2,3-c]phenazine derivatives 7a–7k
At first, 2-hydroxynaphthalene-1,4-dione (1, 1 mmol),
Conclusions
In summary, we have developed a green procedure for
the facile synthesis of various potentially biologically
active polyfunctionalized 1,4-dihydrobenzo[a]pyrido[2,3-c]
phenazines in high yields, using novel five-component
domino reactions under conventional heating in solvent-free
conditions. This single-pot condensation reaction was car-
ried out in the presence of L-proline as an efficient, non-
toxic, reusable, and bifunctional organocatalyst. This new,
environmentally friendly protocol with excellent green
chemistry credentials, such as use of the low loading of
reusable, nontoxic, easy to handle catalyst, shorter reaction
time without any byproduct, avoidance of hazardous organic
solvents and easy workup, may find a wide range of
applications.
benzene-1,2-diamine
2
(1 mmol)
and
L-proline
(30 mol%) were mixed at 80 °C (solvent-free) until in
less than 5 min an orange solid of benzo[a]phenazin-5-ol 3
was formed. Then, aryl aldehyde 4 (1 mmol), ammonium
acetate (2 mmol), and ethyl acetoacetate (1.5 mmol) were
added to the above reaction mixture which was heated
further at same temperature for an appropriate time as
shown in Table 2. Upon completion of the reaction,
monitored by TLC, the reaction mixture was allowed to
cool to room temperature. Then, 10 cm3 of water was
added to the mixture and the crude solid product was
filtered and washed with H2O (2 9 5 cm3). The L-proline
was removed from the reaction media by washing with
H2O. Since the catalyst is soluble in water, the catalyst was
recovered by evaporation of the water and washed with
diethyl ether and reused for the subsequent catalytic runs.
The solid crude product subsequently recrystallized from
hot ethanol to give the pure product 7.
Experimental
All melting points were determined on an Electrothermal
9100 apparatus. 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
Iranian Central Research of Petroleum Company. Mass
spectra were recorded on an Agilent Technology (HP)
spectrometer operating at an ionization potential of 70 eV.
Ethyl 1-(4-chlorophenyl)-3-methyl-1,4-dihydrobenzo[a]-
pyrido[2,3-c]phenazine-2-carboxylate
(7a, C29H22ClN3O2)
Yellow powder; yield 0.417 g (87%); m.p.: 275–277 °C;
ꢀ
IR (KBr): m = 3411, 3287, 3210, 3045, 2948, 1693, 1630,
1591, 1531, 1475, 1402, 1325, 1298, 1209, 1156, 1051,
1
1
The H nuclear magnetic resonance (NMR) and 13C NMR
955, 757 cm-1; H NMR (300 MHz, CDCl3): d = 1.31 (t,
3H, J = 7.2 Hz, OCH2CH3), 2.19 (s, 3H, CH3), 4.54 (q,
spectra were recorded in CDCl3 on a Bruker DRX-300
1
spectrometer operating at 300 MHz for H analysis and
2H, J = 7.2 Hz, OCH2CH3), 5.02 (s, 1H, CH), 5.97 (s, 1H,
123

A. Yazdani-Elah-Abadi et al.
NH), 7.21 (d, 2H, J = 8.1 Hz, Ar–H), 7.35 (d, 2H,
J = 8.1 Hz, Ar–H), 7.61–7.66 (m, 2H, Ar–H), 7.76–7.81
(m, 3H, Ar–H), 8.11–8.15 (m, 2H, Ar–H), 9.30–9.33 (m,
1H, Ar–H) ppm; 13C NMR (75 MHz, CDCl3): d = 14.6,
18.8 (2 CH3), 36.6 (CH), 61.8 (OCH2), 101.7, 112.2, 120.6,
122.4, 125.1, 128.6, 128.8, 129.0, 129.1, 129.6, 129.9,
130.0, 130.3, 131.4, 132.7, 133.0, 140.3, 141.6, 142.5,
145.7, 152.2 (Colefinic and Carom), 167.1 (C=O) ppm; MS:
m/z (%) = 479 (M?, 6).
1587, 1533, 1469, 1415, 1335, 1265, 1195, 1133, 1029,
1
927, 762 cm-1; H NMR (300 MHz, CDCl3): d = 1.25 (t,
3H, J = 7.5 Hz, OCH2CH3), 2.28 (s, 3H, CH3), 4.12 (q,
2H, J = 7.5 Hz, OCH2CH3), 4.96 (s, 1H, CH), 5.89 (s, 1H,
NH), 7.07–7.12 (m, 2H, Ar–H), 7.32 (d, 1H, J = 7.8 Hz,
Ar–H), 7.64 (d, 2H, J = 8.1 Hz, Ar–H), 7.65–7.68 (m, 2H,
Ar–H), 7.73–7.79 (m, 2H, Ar–H), 8.18–8.23 (m, 2H, Ar–
H), 9.31–9.33 (m, 1H, Ar–H) ppm; 13C NMR (75 MHz,
CDCl3): d = 14.2, 18.7 (2 CH3), 36.6 (CH), 61.5 (OCH2),
99.8, 114.7, 121.6, 122.7, 124.9, 128.5, 128.9, 129.3,
129.4, 129.6, 130.0, 130.2, 130.3, 131.7, 132.2, 132.8,
140.1, 141.0, 142.7, 145.7, 151.9 (Colefinic and Carom),
167.4 (C=O) ppm; MS: m/z (%) = 479 (M?, 3).
Ethyl 3-methyl-1-(4-nitrophenyl)-1,4-dihydrobenzo[a]-
pyrido[2,3-c]phenazine-2-carboxylate
(7b, C29H22N4O4)
Yellow powder; yield 0.416 g (85%); m.p.: 269–271 °C;
ꢀ
IR (KBr): m = 3432, 3262, 3201, 3107, 2969, 1690, 1626,
1592, 1535, 1492, 1410, 1325, 1272, 1216, 1122, 1081,
Ethyl 3-methyl-1-(3-nitrophenyl)-1,4-dihydrobenzo[a]-
pyrido[2,3-c]phenazine-2-carboxylate (7e, C29H22N4O4)
Orange powder; yield 0.407 g (83%); m.p.: 264–265 °C;
1
992, 761 cm-1; H NMR (300 MHz, CDCl3): d = 1.42 (t,
ꢀ
3H, J = 7.2 Hz, OCH2CH3), 2.17 (s, 3H, CH3), 4.32 (q,
2H, J = 7.2 Hz, OCH2CH3), 5.07 (s, 1H, CH), 6.11 (s, 1H,
NH), 7.35 (d, 2H, J = 7.8 Hz, Ar–H), 7.52 (d, 2H,
J = 8.1 Hz, Ar–H), 7.65–7.68 (m, 2H, Ar–H), 7.80–7.86
(m, 2H, Ar–H), 7.95–7.98 (m, 1H, Ar–H), 8.24–8.28 (m,
2H, Ar–H), 9.22–9.25 (m, 1H, Ar–H) ppm; 13C NMR
(75 MHz, CDCl3): d = 14.5, 19.3 (2 CH3), 36.5 (CH), 61.5
(OCH2), 99.8, 115.3, 120.8, 121.5, 122.2, 124.5, 127.3,
128.5, 129.2, 129.8, 129.9, 130.1, 130.4, 130.8, 131.4,
132.9, 133.5, 140.8, 141.5, 142.5, 144.9, 153.0 (Colefinic and
IR (KBr): m = 3428, 3290, 3213, 3138, 2892, 1691, 1623,
1593, 1537, 1475, 1422, 1338, 1259, 1223, 1105, 1077,
1
985, 757 cm-1; H NMR (300 MHz, CDCl3): d = 1.22 (t,
3H, J = 7.2 Hz, OCH2CH3), 2.21 (s, 3H, CH3), 4.19 (q,
2H, J = 7.2 Hz, OCH2CH3), 5.14 (s, 1H, CH), 6.27 (s, 1H,
NH), 7.51–7.55 (m, 2H, Ar–H), 7.78–8.01 (m, 7H, Ar–H),
8.31 (dd, 1H, J = 7.8 Hz, 2.1 Hz, Ar–H), 8.57 (s, 1H, Ar–
H), 9.13–9.15 (m, 1H, Ar–H) ppm; 13C NMR (75 MHz,
CDCl3): d = 14.0, 17.8 (2 CH3), 36.8 (CH), 60.7 (OCH2),
102.6, 116.7, 121.1, 121.5, 122.6, 123.8, 127.6, 128.5,
129.2, 129.9, 130.0, 130.6, 130.7, 131.2, 132.5, 133.0,
140.4, 140.8, 141.8, 142.8, 152.7 (Colefinic and Carom),
167.5 (C=O) ppm; MS: m/z (%) = 490 (M?, 4).
C
arom), 167.8 (C=O) ppm; MS: m/z (%) = 490 (M?, 1).
Ethyl 1-(4-cyanophenyl)-3-methyl-1,4-dihydrobenzo[a]-
pyrido[2,3-c]phenazine-2-carboxylate
(7c, C30H22ClN4O2)
Yellow powder; yield 0.376 g (80%); m.p.: 254–255 °C;
Ethyl 3-methyl-1-(p-tolyl)-1,4-dihydrobenzo[a]pyrido[2,3-
c]phenazine-2-carboxylate (7f, C30H25N3O2)
ꢀ
IR (KBr): m = 3427, 3272, 3226, 3009, 2969, 2206, 1690,
1621, 1591, 1529, 1480, 1421, 1330, 1269, 1209, 1112,
Yellow powder; yield 0.390 g (85%); m.p.: 282–284 °C; IR
ꢀ
(KBr): m = 3419, 3314, 3257, 3025, 2892, 1690, 1618,
1587, 1536, 1486, 1408, 1332, 1275, 1223, 1137, 1089, 968,
1091, 938, 752 cm-1
;
1H NMR (300 MHz, CDCl3):
1
d = 1.40 (t, 3H, J = 7.2 Hz, OCH2CH3), 2.23 (s, 3H,
CH3), 4.61 (q, 2H, J = 7.2 Hz, OCH2CH3), 5.18 (s, 1H,
CH), 6.00 (s, 1H, NH), 7.55 (d, 2H, J = 7.8 Hz, Ar–H),
7.74 (d, 2H, J = 8.1 Hz, Ar–H), 7.80–7.91 (m, 5H, Ar–H),
8.14 (d, 1H, J = 8.4 Hz, Ar–H), 8.26 (d, 1H, J = 8.4 Hz,
Ar–H), 9.14–9.16 (m, 1H, Ar–H) ppm; 13C NMR
(75 MHz, CDCl3): d = 14.1, 19.0 (2 CH3), 37.3 (CH),
61.7 (OCH2), 100.9, 109.7, 113.7, 117.5 (CN), 121.7,
126.3, 127.9, 128.2, 129.3, 129.5, 129.6, 129.9, 130.5,
130.7, 131.2, 132.5, 133.7, 141.3, 141.8, 142.3, 144.2,
152.6 (Colefinic and Carom), 167.7 (C=O) ppm; MS:
m/z (%) = 470 (M?, 5).
759 cm-1; H NMR (300 MHz, CDCl3): d = 1.15 (t, 3H,
J = 7.2 Hz, OCH2CH3), 2.15, 2.27 (s, 6H, 2 CH3), 3.98 (q,
2H, J = 7.2 Hz, OCH2CH3), 5.07 (s, 1H, CH), 6.19 (s, 1H,
NH), 7.10 (d, 2H, J = 7.8 Hz, Ar–H), 7.21 (d, 2H,
J = 7.8 Hz, Ar–H), 7.59–7.67 (m, 5H, Ar–H), 8.14–8.20
(m, 2H, Ar–H), 9.27–9.30 (m, 1H, Ar–H) ppm; 13C NMR
(75 MHz, CDCl3): d = 14.4, 19.1, 21.3 (3 CH3), 36.5 (CH),
59.7 (OCH2), 104.2, 114.5, 119.6, 120.6, 124.4, 125.5,
127.3, 128.8, 129.2, 129.3, 129.4, 129.7, 130.0, 130.2, 131.3,
132.5, 132.8, 141.2, 141.6, 142.8, 145.1, 152.5 (Colefinic and
C
arom), 167.1 (C=O) ppm; MS: m/z (%) = 459 (M?, 1).
Ethyl 1-(4-methoxyphenyl)-3-methyl-1,4-dihydrobenzo[a]-
pyrido[2,3-c]phenazine-2-carboxylate (7g, C30H25N3O3)
Yellow powder; yield 0.380 g (80%); m.p.: 258–259 °C;
Ethyl 1-(2-chlorophenyl)-3-methyl-1,4-dihydrobenzo[a]-
pyrido[2,3-c]phenazine-2-carboxylate
ꢀ
(7d, C29H22ClN3O2)
Orange powder; yield 0.393 g (82%); m.p.: 236–238 °C;
IR (KBr): m = 3440, 3275, 3221, 3117, 2932, 1692, 1627,
1592, 1527, 1485, 1402, 1361, 1270, 1215, 1102, 1056,
1
IR (KBr): m = 3440, 3332, 3271, 3035, 2964, 1692, 1627,
975, 757 cm-1; H NMR (300 MHz, CDCl3): d = 1.19 (t,
ꢀ
123

L-Proline catalyzed domino cyclization for the green synthesis of novel 1,4-dihydrobenzo[a]…
3H, J = 7.2 Hz, OCH2CH3), 2.17 (s, 3H, CH3), 3.66 (s,
3H, OCH3), 4.51 (q, 2H, J = 7.2 Hz, OCH2CH3), 5.24 (s,
1H, CH), 5.91 (s, 1H, NH), 6.83 (d, 2H, J = 8.4 Hz, Ar–
H), 7.27 (d, 2H, J = 8.1 Hz, Ar–H), 7.53–7.57 (m, 2H, Ar–
H), 7.75–7.84 (m, 3H, Ar–H), 8.12–8.17 (m, 2H, Ar–H),
9.18–9.21 (m, 1H, Ar–H) ppm; 13C NMR (75 MHz,
CDCl3): d = 14.7, 18.7 (2 CH3), 35.8 (CH), 55.4
(OCH3), 61.2 (OCH2), 98.6, 111.6, 113.5, 120.1, 121.6,
121.7, 124.5, 128.3, 128.7, 129.4, 129.8, 129.9, 130.0,
130.2, 130.4, 131.7, 132.2, 132.8, 140.3, 141.5, 142.7,
145.2, 153.3 (Colefinic and Carom), 168.3 (C=O) ppm; MS:
m/z (%) = 475 (M?, 7).
1591, 1534, 1462, 1423, 1357, 1244, 1206, 1155, 1054,
1
948, 757 cm-1; H NMR (300 MHz, CDCl3): d = 1.23 (t,
3H, J = 7.2 Hz, OCH2CH3), 2.19, 2.41, 2.43 (s, 9H, 3
CH3), 4.15 (q, 2H, J = 7.2 Hz, OCH2CH3), 5.04 (s, 1H,
CH), 5.99 (s, 1H, NH), 7.20 (d, 2H, J = 7.8 Hz, Ar–H),
7.38 (d, 2H, J = 7.8 Hz, Ar–H), 7.77–7.84 (m, 3H, Ar–H),
8.22–8.26 (m, 2H, Ar–H), 9.18–9.21 (m, 1H, Ar–H) ppm;
13C NMR (75 MHz, CDCl3): d = 14.3, 18.1, 20.6, 20.9 (4
CH3), 37.3 (CH), 60.7 (OCH2), 101.3, 112.4, 115.3, 120.3,
121.6, 125.7, 128.2, 129.0, 129.2, 129.6, 129.9, 130.2,
130.3, 131.6, 133.0, 133.5, 140.2, 141.6, 142.5, 145.5,
153.6 (Colefinic and Carom), 168.5 (C=O) ppm; MS:
m/z (%) = 508 (M?, 5).
Ethyl 11,12-dichloro-1-(4-chlorophenyl)-3-methyl-1,4-di-
hydrobenzo[a]pyrido[2,3-c]phenazine-2-carboxylate
(7h, C29H20Cl3N3O2)
Ethyl 3,11,12-trimethyl-1-(4-nitrophenyl)-1,4-dihydrobenzo-
[a]pyrido[2,3-c]phenazine-2-carboxylate
Yellow powder; yield 0.438 g (80%); m.p.: 306–308 °C;
(7k, C31H26N4O4)
Yellow powder; yield 0.420 g (81%); m.p.: 288–291 °C;
ꢀ
IR (KBr): m = 3427, 3342, 3262, 3045, 2914, 1687, 1627,
1576, 1525, 1482, 1440, 1332, 1275, 1236, 1107, 1050,
ꢀ
IR (KBr): m = 3430, 3285, 3221, 3045, 2940, 1692, 1630,
1591, 1534, 1462, 1423, 1357, 1244, 1206, 1155, 1054,
1
955, 759 cm-1; H NMR (300 MHz, CDCl3): d = 1.20 (t,
1
3H, J = 7.5 Hz, OCH2CH3), 2.25 (s, 3H, CH3), 4.07 (q,
2H, J = 7.5 Hz, OCH2CH3), 5.06 (s, 1H, CH), 6.10 (s, 1H,
NH), 7.19 (d, 2H, J = 8.1 Hz, Ar–H), 7.28 (d, 2H,
J = 8.1 Hz, Ar–H), 7.72–7.78 (m, 3H, Ar–H), 8.07–8.10
(m, 2H, Ar–H), 9.28–9.31 (m, 1H, Ar–H) ppm; 13C NMR
(75 MHz, CDCl3): d = 14.4, 19.3 (2 CH3), 36.2 (CH), 59.9
(OCH2), 102.4, 114.5, 119.2, 121.8, 122.0, 124.3, 125.6,
128.2, 128.8, 129.1, 129.4, 129.9, 130.0, 130.2, 130.8,
132.7, 133.3, 140.8, 142.1, 142.6, 143.8, 152.8 (Colefinic and
948, 757 cm-1; H NMR (300 MHz, CDCl3): d = 1.21 (t,
3H, J = 7.5 Hz, OCH2CH3), 2.17 (s, 3H, CH3), 2.44 (s,
6H, 2 CH3), 4.08 (q, 2H, J = 7.5 Hz, OCH2CH3), 5.11 (s,
1H, CH), 6.05 (s, 1H, NH), 7.22 (d, 2H, J = 7.8 Hz, Ar–
H), 7.34 (d, 2H, J = 7.8 Hz, Ar–H), 7.81–7.90 (m, 3H, Ar–
H), 8.08–8.13 (m, 2H, Ar–H), 9.23–9.26 (m, 1H, Ar–H)
ppm; 13C NMR (75 MHz, CDCl3): d = 14.7, 17.9, 20.4,
20.6 (4 CH3), 36.8 (CH), 61.4 (OCH2), 101.8, 113.1, 115.5,
120.6, 121.3, 125.5, 128.2, 128.7, 129.2, 129.8, 129.9,
130.3, 130.8, 132.4, 133.1, 133.7, 141.3, 141.8, 142.4,
145.8, 152.7 (Colefinic and Carom), 167.8 (C=O) ppm; MS:
m/z (%) = 518 (M?, 2).
C
arom), 167.8 (C=O) ppm; MS: m/z (%) = 548 (M?, 3).
Ethyl 11,12-dichloro-3-methyl-1-(p-tolyl)-1,4-dihydrobenzo-
[a]pyrido[2,3-c]phenazine-2-carboxylate
(7i, C30H23Cl2N3O2)
Yellow powder; yield 0.401 g (76%); m.p.: 315–318 °C; IR
Acknowledgements We gratefully acknowledge 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, Iran.
ꢀ
(KBr): m = 3432, 3275, 3212, 3025, 2915, 1692, 1624, 1575,
1532, 1482, 1414, 1327, 1275, 1245, 1148, 1083, 975,
1
760 cm-1; H NMR (300 MHz, CDCl3): d = 1.18 (t, 3H,
J = 7.2 Hz, OCH2CH3), 2.22, 2.37 (s, 6H, 2 CH3), 4.12 (q,
2H, J = 7.2 Hz, OCH2CH3), 5.25 (s, 1H, CH), 6.07 (s, 1H,
NH), 7.14 (d, 2H, J = 7.8 Hz, Ar–H), 7.36 (d, 2H,
J = 7.8 Hz, Ar–H), 7.59–7.65 (m, 3H, Ar–H), 7.99–8.04
(m, 2H, Ar–H), 9.18–9.22 (m, 1H, Ar–H) ppm; 13C NMR
(75 MHz, CDCl3): d = 14.7, 19.1, 21.5 (3 CH3), 35.7 (CH),
60.8 (OCH2), 101.5, 116.7, 119.2, 121.7, 124.1, 125.0, 128.2,
128.7, 129.0, 129.3, 129.5, 129.8, 130.1, 130.2, 130.8, 132.6,
133.1, 141.4, 142.3, 142.8, 144.8, 151.9 (Colefinic and Carom),
168.2 (C=O) ppm; MS: m/z (%) = 528 (M?, 1).
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