An expedient synthesis strategy to the 1,4-dihydropyridines and pyrido[1,2-a]quinoxalines: iodine catalyzed one-pot four-component domino reactions

Article abstract of DOI:10.1016/j.tet.2016.08.049

Another aspect concerning enaminone chemistry leading to the one-pot synthesis of functionalized novel 1,4-dihydropyridines and pyrido[1,2-a]quinoxalines has been described. By highly efficient, one-pot, iodine-catalyzed four-component reactions, combinin

Full text of DOI:10.1016/j.tet.2016.08.049

Accepted Manuscript
An expedient synthesis strategy to the 1,4-dihydropyridines and pyrido[1,2-
a]quinoxalines: iodine catalyzed one-pot four-component domino reactions
Atieh Rezvanian
PII:
S0040-4020(16)30825-0
10.1016/j.tet.2016.08.049
TET 28030
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 June 2016
Revised Date: 4 August 2016
Accepted Date: 15 August 2016
Please cite this article as: Rezvanian A, An expedient synthesis strategy to the 1,4-dihydropyridines
and pyrido[1,2-a]quinoxalines: iodine catalyzed one-pot four-component domino reactions, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.08.049.
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ACCEPTED MANUSCRIPT
Leave this area blank for abstract info.
An Expedient Synthesis Strategy to the
1,4-Dihydropyridines and Pyrido[1,2-a]quinoxalines:
Iodine Catalyzed One-Pot Four-Component Domino
Reactions
Atieh Rezvanian*
Department of Physics & Chemistry, Alzahra University, P.O. Box 1993891176, Tehran, Iran
H
N
H2N
NH2
O
O
Ar
CHO
Ar
R'O2C
R'O2C
CO2R'
Ar
R
NH2
OH
O
N
+
O
HO
I2 (10 mol %)
MeCN, 6 h
I2 (10 mol %)
MeCN, 8 h
N
R
R'O2C
CO2R'
OH
O

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2
An Expedient Synthesis Strategy to the
1,4-Dihydropyridines and Pyrido[1,2-a]quinoxalines:
Iodine Catalyzed One-Pot Four-Component Domino
Reactions
Atieh Rezvanian*
Department of Physics & Chemistry, Alzahra University, P.O. Box 1993891176, Tehran, Iran
Abstract—Another aspect concerning enaminone chemistry leading to the one-pot synthesis of
functionalized novel 1,4-dihydropyridines and pyrido[1,2-a]quinoxalines has been described. By
highly efficient, one-pot, iodine-catalyzed four-component reactions, combining one set of
enamine intermediates and arylidene pyruvic acid (APA) in two procedures, heterocyclic skeletal
diversity can be achieved. The synthesis involves reaction of the intermediates formed by the 1:1
interaction between primary amines (or o-phenylenediamine) and dialkyl acetylenedicarboxylate
with
pyruvic
acid
and
benzaldehyde
through
an
iodine-catalyzed
Knoevenagel/Michael/cyclization sequence. The reaction is particularly attractive due to the
following advantages: atom economy, optimum convergence, high bond-forming efficiency, and
avoidance of tedious workup and purification of products. Significantly, the presence of an
acidic group at the 9 position on the products make these compounds excellent precursors for
further synthetic modifications to meet the need for diverse chemical inputs.
Keywords: 1,4-Dihydropyridines, Pyrido[1,2-a]quinoxalines, o-Phenylenediamine, Pyruvic acid, Dialkyl
acetylenedicarboxylate, Four-component reaction
Corresponding author, Tel.: +98 21 88041344; fax: +98 21 88041344; e-mail: Rezvaniana@alzahra.ac.ir

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3
1. Introduction
1,4-Dihydropyridines (1,4-DHPs) present ubiquitous structural motifs, which are frequently
found in natural products and in compounds for the pharmaceutical, agrochemical, and other
chemical industries.1,2 1,4-DHPs are a very important class of heterocyclic compounds due to a
variety of biological activities3 such as antihypertensive,4 antianginal,4,5 anti-inflammatory,6,7
antitubercular,8 analgesic,9 antithrombotic,10,11 vasodilation,12 anticonvulsant,13 stress protective
effect,14 and cardio depressant activity.15 It is shown that the presence of ester groups in the
structure of 1,4-DHPs and their positions of substitution
has an important role in
antihypertensive activity.16 Researchers have long been fascinated by the biological activity of
1,4-dihydropyridines (I), tacrine (II) and their derivatives (Fig. 1). Initially, these compounds
were found to be calcium channel modulators, and were developed as cardiovascular and
antihypertensive drugs, which include felodipine, amlodipine, nifedipine (III) and nicardipine.17
Quinoxalines belong to a class of excellent heterocyclic scaffolds owing to their wide biological
properties and diverse therapeutic applications in medicinal research. Recent updates showed
that the chemistry of quinoxaline has attracted considerable attention18 due to its diverse
chemical reactivities,19-21 application in materials science22-23 and wide spectrum of biological
activities.24,25 The quinoxaline motif is known to represent a class of medicinally important
compounds which are effective as antibacterial,18 antifungal,22 anticancer,25 antitumor,26
antiamoebic,27 antiepileptic,28 anticonvulsant,29 antitubercular,30 antiproliferative,31 anti-HCV32
and anti-inflammatory33 agents among others. Compounds with quinoxaline cores are used as
allosteric dual Akt1 and Akt2 inhibitors, human cytomegalovirus polymerase inhibitors34 SRPK-
1 inhibitors35 and monoamine oxidase A inhibitors.36 Reports have shown recently that
pyrrolo[1,2-a]quinoxaline derivatives are potent and selective 5-HT3 ligands.22 Furthermore, the

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4
quinoxaline nucleus is a common substructure of many biologically and pharmacologically
active compounds.37 In view of this, some coded quinoxaline derivatives such as CNQX and
YM872 (Fig. 1) have been reported as potent AMPA receptor antagonists and were projected as
good candidates for neuro-pharmacological screening.29 The known biological properties and the
huge potential in drug discovery of these heterocyclic compounds necessitates the development
of facile and efficient methodologies for their selective and diverse synthesis.
O
O
Ar
O
O
Ar
NH2
N
NO2
R
MeO2C
CO2Me
EtO
EtO
EtO
EtO
N
NH2
N
N
H
Ar
Ar
II
I
III
CO2H
N
H
N
NC
O
N
N
O
O
N
H
O
O2N
O2N
N
H
CNQX
YM872
Fig 1. Some biologically important 1,4-dihydropyridines and quinoxalines
Multicomponent reactions (MCRs) offer a wide range of possibilities for the construction of
pre-defined highly complex molecules in a single step with high atom economy, minimum time,
labor, cost, and straight forward experimental procedures.38 These benefits are highlights for
multicomponent cascade reactions, which involve in situ production of an intermediate with a
strategic reactive site for subsequent transformations.39 In the past decade, a lot of
multicomponent reactions have been reported,40 yet developing novel MCRs that meet almost all
of advantages above is still in the burgeoning phase.

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2. Results and discussion
As part of our ongoing research program for the development of new environmentally benign
methodologies for the synthesis of useful precursors in the field of biology, industry, and key
intermediates for multistep synthesis,41 during a previous investigation38a it was discovered that
molecular iodine can be applied as a good catalyst for the activation of the carbonyl group of
benzaldehyde.42 Utilising this result imidazo[1,2-a]pyridines were successfully prepared based
on the reaction of nitro ketene aminals (NKAs) and the Knoevenagel adduct from pyruvic acid
and benzaldehyde in the presence of a catalytic amount of molecular iodine.
Accordingly, and in continuation of this study, it was questioned whether this Knoevenagel
adduct could be trapped by the enaminone generated in situ from a primary amine and a dialkyl
acetylenedicarboxylate to give a cascade reaction product. The addition of amines to dialkyl
acetylenedicarboxylates has been extensively studied and the desired dialkyl
acetylenedicarboxylate-primary amine adducts (enaminones) as a mixture of E and Z isomers
have been used as efficient starting materials for the synthesis of heterocyclic skeletons.43 It is
believed that the two ester groups pendent to the enaminone decrease its nucleophilicity.
At first, the reaction was evaluated in a four-component manner according to the previously
reported procedure.26a The reaction was carried out by the sequential addition of reagents:
alkylamine 1, dialkyl acetylenedicarboxylate 2, pyruvic acid and benzaldehyde 3 in one flask
under the same reaction conditions (Scheme 1). Thus, in a pilot reaction, propylamine and
dimethyl acetylenedicarboxylate (DMAD) under solvent-free conditions at room temperature
were combined. The resultant reaction mixture was stirred to complete the reaction as monitored
by thin-layer chromatography (TLC). After the formation of enaminone (10 min), pyruvic acid
and 4-chlorobenzaldehyde with catalytic amount of I2 (10 mol%) were introduced and the

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reaction was heated at reflux in acetonitrile for 6 hours. After workup, the expected 1,4-
dihydropyridine 4a was obtained in excellent yield.
Once the feasibility of the proposed pathway had been validated, the scope and robustness of
this one-pot, four-component 1,4-dihydropyridine synthesis was evaluated by employing a range
of the primary amines 1, dialkyl acetylenedicarboxylates 2 and benzaldehydes 3 component
(Table 1, entry 1-9). A variety of electron-poor and electron-rich aromatic aldehydes and amines
were found to react very smoothly to provide the analogous 1,4-dihydropyridines 4 in
satisfactory yields (85-70%) as shown in Table 1.
O
OH
O
Ar
R'O2C
R'O2C
CHO
Ar
R
I2 (10 mol %)
+
NH2
1
O
reflux, 6 h
MeCN
N
R
4
3
OH
R'O2C
CO2R'
2
Scheme 1. Iodine-mediated 4-component reaction for the synthesis of 1,4-DHPs
After this successful endeavor with the synthesis of 1,4-DHPs 4 using the enaminone
intermediate and Knoevenagel adduct, our attention turned to the use of dihydroquinoxalines
derived from o-phenylenediamine and dialkyl acetylenedicarboxylates to evaluate the formation
of pyrido[1,2-a]quinoxalines. For this aim, initially the reaction of o-phenylenediamine and
dimethyl acetylenedicarboxylate was performed in acetonitrile at room temperature. As
expected, the reaction produced dihydroquinoxaline 5 in excellent yield (Scheme 2). In the next
stage, the two-component reaction of dihydroquinoxaline 5 and Knoevenagel adduct 6 was
performed in acetonitrile at room temperature. Unfortunately, the reaction did not proceed at all
even at high temperature and extended reaction times, and the starting materials remained

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7
completely unconsumed (Scheme 2). Next, the above reaction was carried out under similar
conditions in the presence of I2 (10 mol%). In this case, fortunately the desired reaction took
place successfully to afford a series of pyrido[1,2-a]quinoxaline derivatives 7 in acetonitrile
under reflux. It was therefore suggested that a halogen bond between the carbonyl oxygen and
iodine molecule plays a key role in the remarkable catalytic effect of iodine observed in this
reaction.44 A halogen bond is defined as the intermolecular non-covalent interaction between a
halogen atom and electron-donor atom such as O or N (similar to a hydrogen bond).45
H
MeCN
reflux, 24 h
N
O
H2N
NH2
MeCN
No Product
CO2R'
catalyst free
+
r.t., 30 min
N
H
5
R'O2C
CO2R'
H
N
2
O
+
Ar
CO2R'
Ar
O
N
O
OH
I2 (10 mol %)
I2 (10 mol %)
CHO
Ar
+
HO
reflux, 5 h
MeCN
reflux, 2 h
MeCN
CO2H
O
3
O
7
6
Scheme 2. Two step procedure for the synthesis of pyrido[1,2-a]quinoxalines 7 (Procedure 1
)
Despite the success in the synthesis of pyrido[1,2-a]quinoxalines 7 using the above two-
components per reaction, two step procedure (Procedure 1), a one-pot four-component reaction
procedure (Procedure 2) for the synthesis of 7 was evaluated. Procedure 2 avoids the isolation of
the intermediates and should save execution and solvent, and might afford better yields. With the
optimized conditions in hand, a one-pot, four-component reaction was performed with o-
phenylenediamine, dimethyl acetylenedicarboxylate, pyruvic acid and 4-chlorobenzaldehyde.
Surprisingly, the reaction proceeds smoothly in acetonitrile under reflux to produce pyrido[1,2-
a]quinoxaline 8 in 80% yield after 8 h (Scheme 2).

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8
O
CHO
CO2Me
HN
CO2Me
O
NH2
NH2
I2 (10 mol %)
OH
+
Cl
N
+
+
MeCN, 8 h
reflux
O
CO2Me
HO2C
Cl
8
2
Scheme 3. Outcome of the one-pot 4CR synthesis of pyrido[1,2-a]quinoxaline (Procedure 2)
Then, various aldehydes with different substituents and dialkyl acetylenedicarboxylates were
utilized under the same one-pot four-component reaction conditions to examine the scope and
limitations of the procedure. It was found that only aldehydes carrying electron-withdrawing
groups (Cl and Br) showed similar reactivity and react efficiently to yield the desired products
(Table 1, entries10-13). Application of substituted aldehydes with an electron-donating group
such as OMe or Me (Entries 14, 15) did not lead to the desired product at all. In these cases, after
the appropriate time, dihydroquinoxaline intermediates and the related Knoevenagel adduct were
recovered unchanged.
The molecular structure of all synthetic compounds 4a-i and 7a-d were deduced from their
elemental analysis, IR, and high-field 1H, 13C NMR spectra. The mass spectrum of 4a displayed
the molecular ion peak at m/z 393, which is in agreement with the proposed structure. The IR
spectrum of this compound showed absorption bands due to the C=O groups stretching
1
frequency at 1761, 1722 and 1708 cm–1. The H NMR spectrum of 4a showed one triplet and
two sharp singlets for three CH3 groups (δ = 0.75 ppm with 3JHH = 7.3 Hz, 3.62 and 3.87 ppm),
three multiplets for two CH2 groups, because these protons are diastereotopic (δ = 1.45-1.50,
3.04-3.10 and 3.56-3.62 ppm), two doublets for CH groups (δ = 4.68 and 6.12 ppm, 3JHH = 5.5
Hz), and one singlet for the OH group (δ = 13.11 ppm). Also, four aromatic hydrogens gave rise
to characteristic signals in the aromatic region of the spectrum. Observation of 17 distinct signals

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9
H2N
NH2
H
N
O
Ar
CO2R'
R'O2C
R'O2C
O
CO2R'
Ar
R
NH2
CHO
Ar
N
+
+
O
CO2H
I2 (10 mol %)
reflux, 8 h
MeCN
I2 (10 mol %)
N
R
HO
CO2R'
reflux, 8 h
MeCN
OH
3
7
O
4
2
Entry
1
Products 4,7
R
R'
Ar
Yield %
85
80
78
82
77
74
76
70
72
80
77
70
72
-
n-Propyl
n-Propyl
n-Butyl
n-Butyl
i-Butyl
Me
Et
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Me-C6H4
4-Me-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4
4a
4b
4c
4d
4e
4f
2
3
Me
Et
4
5
Me
Et
6
i-Butyl
7
n-Propyl
n-Propyl
n-Butyl
Me
Me
Me
4g
4h
4i
8
9
10
11
12
13
14
15
o-phenylenediamine Me
o-phenylenediamine Et
o-phenylenediamine Me
o-phenylenediamine Et
o-phenylenediamine Me
o-phenylenediamine Me
7a
7b
7c
7d
7e
7f
-
Table 1. One-pot domino synthesis of 1,4-dihydropyridines 4a-i and pyrido[1,2-a]quinoxalines
7a-d
1
13
in the H-decoupled C NMR spectrum of 4a is in agreement with the proposed structure. The
most important region of the spectrum is related to resonances due to, CH, CCO and CO which
appear at δ = 121.4, 127.1 and 170.4 ppm.
The mass spectrum of 7a displayed the molecular ion peak at m/z = 410 with low intensity. In
the IR spectrum, the stretching frequency of NH group appears at 3271 cm−1. Absorption bands

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10
at 1766, 1697 and 1660 cm−1 are related to two C=O and C=N groups, respectively, and indicate
1
the most important functional groups of the product. The H NMR spectrum of 7a exhibited
three singlets at δ = 3.64, 8.14, and 13.09 ppm and were assigned as CH3, NH and OH protons.
Observation of 19 distinct signals in the 1H-decoupled 13C NMR spectrum of 7a is in agreement
with the proposed structure.
Although no detailed mechanistic studies have been carried out at this point, a mechanistic
rationale for both of the one-pot reactions is outlined in Scheme 4. At first, addition of the
alkylamine to the dialkyl acetylenedicarboxylate gives the key intermediate enamino ester 9.
Second, under the catalysis of iodine Knoevenagel condensation of benzaldehyde 3 with the enol
form of pyruvic acid resulted in arylidene pyruvic acid (APA) 6. Third, Michael addition of the
enamino ester intermediate 9 to APA 6 (activated by I2) yielded the addition intermediate 10,
which transformed to intermediate 11 through proton transfer. Finally the intramolecular
nucleophilic addition of the secondary amino group to the carbonyl group followed by loss of
one equiv. of H2O affords product 4.
On the other hand, in the presence of o-phenylenediamine, dihydroquinoxaline 5 readily
prepared in situ from the addition of a 1:1 ratio of o-phenylenediamine and dialkyl
acetylenedicarboxylate by loss of one equiv. of ROH. Compound 5 possesses enamine character
and thus reacts with arylidene pyruvic acid 6 to generate the intermediate 12 which transformed
to intermediate 13 through tautomerization. Finally, the ketonic C=O moiety is still highly
reactive in intermediate 13, an intramolecular cyclization process followed by loss of one equiv.
of H2O leads to the formation of pyrido[1,2-a]quinoxaline product 7 (Scheme 4). The role of
iodine may be attributed to its inherent mild Lewis acidity, which could activate carbonyl groups

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11
throughout the whole condensation and thus facilitate cyclization and promote the formation of
the final structures.
3. Conclusion
In summary, a novel and efficient synthesis of multisubstituted 1,4-dihydropyridines and
pyrido[1,2-a]quinoxaline derivatives has been developed via two I2-mediated four-component
one-pot reactions. Both one-pot procedures proceed through domino Knoevenagel
condensation/Michael addition/cyclization reactions that lead to the formation of three and four
chemical bonds in 1,4-dihydropyridines and pyrido[1,2-a]quinoxalines respectively. Cheap and
easily available I2 worked efficiently as a Lewis acid with a range of amines and substituted
benzaldehydes. The reaction is particularly attractive due to the following advantages: atom
economy, optimum convergence, high bond-forming efficiency, and operational simplicity. Also,
the optimized one-pot procedure is noteworthy, when compared to the stepwise procedure,
because of its ease of execution, and substantial minimization of waste, labor, time, and cost. To
the best of our knowledge this is the first example of a pyrido[1,2-a]quinoxaline synthesis via
one-pot multi-component reactions catalyzed by iodine. From the structural viewpoint, the
products are fully substituted compounds that will be suitable for further elaboration.

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12
I-I
Ar
O
CO2R'
Ar
R
OH
R'O2C
R'O2C
-H2O
Cyclization
H2N
+
1
O
O
O
R'O2C
CO2R'
N
R
NH
R'O2C
2
R
OH
11
4
Tautomerism
H
R'O2C
R'O2C
NR
H
R'O2C
R'O2C
H
NR
Ar
R'O2C
O
9
OH
R'O2C
I-I
O
I-I
N
R
O
Michael
addition
+
+
Ar
I2 (10 mol %)
Condensation
OH
10
Ar
O
CO2H
O
+
O
O
H
CO2R'
Ar
O
OH
Ar CHO
6
CO2R'
Ar
HN
HN
3
O
N
NH
HO
I-I
Michael
addition
H
N
12
O
OH
O
CO2R'
O
O
N
H
Tautomerism
I-I
O
5
O
CO2R'
Ar
H
N
-R'OH
CO2R'
HN
-H2O
CO2R'
Ar
O
NH
N
I-I
NH2
Cyclization
HO
O
+
OH
O
NH2
13
7
CO2R'
2
Scheme 4. Proposed mechanism for one-pot domino synthesis of 4 and 7
4. Experimental
The primary amines, o-phenylenediamine, dialkyl acetylenedicarboxylates, aldehydes, and
pyruvic acid were obtained from Merck (Germany) and Fluka (Switzerland) and were used
without further purification. Elemental analyses for C, H and N were performed using a Heraeus
CHN–O–Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MATT 8430 mass
1
13
spectrometer operating at an ionization potential of 70 eV. H NMR (400 MHz) and C NMR
(100 MHz) spectra were obtained using Bruker DRX-300 AVANCE and Bruker DRX-400

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13
AVANCE spectrometers. IR spectra were recorded as KBr pellets on a NICOLET FT-IR 100
spectrometer, Melting points were measured on an Electrothermal 9100 apparatus.
4.1. Typical synthesis procedure: (for example 4a)
A mixture of propylamine (0.06 g, 0.083 mL, 1 mmol) and dimethyl acetylenedicarboxylate
(0.14 g, 0.12 mL, 1 mmol) was mixed in a 50 mL round bottom (RB) flask at room temperature.
After 10 min a mixture of pyruvic acid (0.08 g, 0.07 mL, 1 mmol), 4-chlorobenzaldehyde (0.14
g, 1 mmol) and 10 mol% iodine (0.013 g, 0.1 mmol) in 5 mL acetonitrile was added to the RB
flask. The reaction mixture was heated at reflux for 6 h. The completion of the reaction was
monitored using thin layer chromatography (TLC). After completion of the reaction the mixture
was cooled to room temp, diluted with a 20% solution of sodium thiosulfate (3 mL) and
extracted with ethyl acetate (3
×
5 mL). The organic layers were collected, combined, dried over
Na2SO4, filtered and concentrated under vacuum. Finally, to the remained mixture ethanol (3
mL) was added and the precipitated product was produced that was filtered and washed with
cold ethanol to afford the pure yellow product 4a.
4.1.1. 4-(4-Chlorophenyl)-5,6-bis(methoxycarbonyl)-1-propyl-1,4-dihydropyridine-2-
carboxylic acid (4a). Yellow powder, mp = 168-170 °C (decomp.), 334.7 g, yield: 85%. IR
(KBr) (νmax, cm-1): 1722 and 1708 (CO2Me), 1761 (C=O), 1652 (NC=C), 1258 (C-N), 1135 (C-
O) cm−1. Anal. Calcd for C19H20ClNO6: C, 57.95; H, 5.12; N, 3.56. Found C, 57.90; H, 5.15; N,
3.54. MS (EI, 70 eV): m/z (%) = 393 (M+, 4), 378 (10), 358 (19), 348 (87), 237 (28), 282 (100),
3
200 (39), 136 (27). δH (300 MHz, DMSO-d6): 0.75 (3H, t, JHH = 7.3 Hz, CH2CH3), 1.45-1.50
(2H, m, CH2CH3), 3.04-3.10 (1H, m, NCH2), 3.56-3.62 (1H, m, NCH2), 3.62 (3H, s, OMe), 3.87
(3H, s, OMe), 4.68 (1H, d, 3JHH = 5.5 Hz, CH), 6.12 (1H, d, 3JHH = 5.5 Hz, CH), 7.16 (2H, d, 3JHH

ACCEPTED MANUSCRIPT
14
3
= 8.1 Hz, 2 CH of Ar), 7.28 (2H, d, JHH = 8.1 Hz, 2 CH of Ar), 13.11 (1H, brs, OH). δC (75
MHz, DMSO-d6): 10.2 (CH2CH3), 20.1 (CH2CH3), 41.3 (CH), 44.0 (CH2N), 51.5 (OCH3), 52.6
(OCH3), 106.7 (CCH), 121.4 (CH), 127.1 (CCO), 128.2 (CH of Ar), 129.6 (CH of Ar), 131.5
(Cipso-Ar), 142.3 (Cipso-Ar), 142.7 (NC), 163.4 (CO2Me), 165.0 (CO2Me), 170.4 (CO2H).
4.1.2. 4-(4-Chlorophenyl)-5,6-bis(ethoxycarbonyl)-1-propyl-1,4-dihydropyridine-2-
carboxylic acid (4b). Yellow powder, mp = 169-171 °C (decomp.), 337.4 g, yield: 80%. IR
(KBr) (νmax, cm-1): 1719 and 1702 (CO2Et), 1772 (C=O), 1659 (NC=C), 1280 (C-N), 1132 (C-O)
cm−1. Anal. Calcd for C21H24ClNO6: C, 59.79; H, 5.73; N, 3.32. Found C, 59.8; H, 5.71; N, 3.35.
3
3
δH (300 MHz, DMSO-d6): 0.82 (3H, t, JHH = 7.2 Hz, CH2CH3), 1.32 (3H, t, JHH = 7.1 Hz,
3
OCH2CH3) 1.36 (3H, t, JHH = 7.1 Hz, OCH2CH3), 1.48-1.63 (2H, m, CH2CH3), 3.15-3.20 (1H,
m, NCH2), 3.59-3.64 (1H, m, NCH2), 4.15-4.22 (2H, m, OCH2CH3), 4.26-4.35 (2H, m,
OCH2CH3), 4.83 (1H, d, 3JHH = 5.6 Hz, CH), 6.08 (1H, d, 3JHH = 5.6 Hz, CH), 7.04 (2H, d, 3JHH
3
= 8.1 Hz, 2 CH of Ar), 7.22 (2H, d, JHH = 8.1 Hz, 2 CH of Ar), 13.15 (1H, brs, OH). δC (75
MHz, DMSO-d6): 10.7 (OCH2CH3), 13.4 (CH2CH3), 13.4 (OCH2CH3), 21.7 (CH2CH3), 41.5
(CH), 46.1 (CH2N), 60.6 (OCH2CH3), 61.6 (OCH2CH3), 106.2 (CCH), 121.5 (CH), 127.4
(CCO), 128.3 (CH of Ar), 129.7 (CH of Ar), 131.5 (Cipso-Ar), 142.4 (Cipso-Ar), 142.7 (NC),
163.4 (CO2Et), 165.0 (CO2Et), 170.4 (CO2H).
4.1.3. 1-Butyl-4-(4-chlorophenyl)-5,6-bis(methoxycarbonyl)-1,4-dihydropyridine-2-
carboxylic acid (4c). Yellow powder, mp = 168-170 °C (decomp.), 318.1 g, yield: 78%. IR
(KBr) (νmax, cm-1): 1732 and 1710 (CO2Me), 1729 (C=O), 1673 (NC=C), 1249 (C-N), 1127 (C-
O) cm−1. Anal. Calcd for C20H22ClNO6: C, 58.90; H, 5.44; N, 3.43. Found C, 58.92; H, 5.41; N,
3
3.44. δH (300 MHz, DMSO-d6): 0.86 (3H, t, JHH = 7.1 Hz, CH2CH3), 1.26-1.35 (2H, m,
CH2CH3), 1.39-1.47 (2H, m,CH2CH2CH3), 3.18-3.24 (1H, m, NCH2), 3.42-3.48 (1H, m, NCH2),

ACCEPTED MANUSCRIPT
15
3
3.72 (3H, s, OMe), 3.89 (3H, s, OMe), 4.57 (1H, d, JHH = 5.4 Hz, CH ), 6.19 (1H, d, 3JHH = 5.4
Hz, CH), 7.17 (2H, d, 3JHH = 8.0 Hz, 2 CH of Ar), 7.30 (2H, d, 3JHH = 8.0 Hz, 2 CH of Ar), 13.07
(1H, brs, OH). δC (75 MHz, DMSO-d6): 13.5 (CH3), 20.1 (CH2CH3), 25.3 (CH2CH2CH3), 41.3
(CH), 44.1 (CH2N), 51.5 (OCH3), 52.6 (OCH3), 106.4 (CCH), 121.3 (CH), 127.1 (CCO), 128.1
(CH of Ar), 129.5 (CH of Ar), 131.5 (Cipso-Ar), 142.2 (Cipso-Ar), 142.7 (NC), 163.6 (CO2Me),
165.2 (CO2Me), 170.1 (CO2H).
4.1.4. 1-Butyl-4-(4-chlorophenyl)-5,6-bis(ethoxycarbonyl)-1,4-dihydropyridine-2-
carboxylic acid (4d). Yellow powder, mp = 172-174 °C (decomp.), 357.4 g, yield: 82%. IR
(KBr) (νmax, cm-1): 1724 and 1710 (CO2Et), 1757 (C=O), 1619 (NC=C), 1261 (C-N), 1126 (C-O)
cm−1. Anal. Calcd for C22H26ClNO6: C, 60.62; H, 6.01; N, 3.21. Found C, 6.63; H, 5.98; N, 3.24.
3
3
δH (300 MHz, DMSO-d6): 0.76 (3H, t, JHH = 7.3 Hz, CH2CH3), 1.16 (3H, t, JHH = 7.1 Hz,
3
OCH2CH3) 1.27 (3H, t, JHH = 7.1 Hz, OCH2CH3), 1.36-1.45 (4H, m, CH2CH3 and
CH2CH2CH3), 3.09-3.14 (1H, m, NCH2), 3.55-3.61 (1H, m, NCH2), 4.05-4.11 (2H, m,
3
3
OCH2CH3), 4.19-4.27 (2H, m, OCH2CH3), 4.77 (1H, d, JHH = 5.5 Hz, CH ), 6.1 (1H, d, JHH
=
3
3
5.5 Hz, CH), 7.13 (2H, d, JHH = 8.1 Hz, 2 CH of Ar), 7.29 (2H, d, JHH = 8.1 Hz, 2 CH of Ar),
13.09 (1H, brs, OH). δC (75 MHz, DMSO-d6): 10.8 (OCH2CH3), 13.3 (CH3), 13.4 (OCH2CH3),
19.8 (CH2CH3), 25.6 (CH2CH2CH3), 41.7 (CH), 44.6 (CH2N), 60.9 (OCH2CH3), 62.2
(OCH2CH3), 106.4 (CCH), 121.9 (CH), 127.2 (CCO), 128.3 (CH of Ar), 129.7 (CH of Ar), 131.8
(Cipso-Ar), 142.3 (Cipso-Ar), 142.5 (NC), 163.2 (CO2Et), 165.9 (CO2Et), 170.3 (CO2H).
4.1.5. 4-(4-Chlorophenyl)-1-isobutyl-5,6-bis(methoxycarbonyl)-1,4-dihydropyridine-2-
carboxylic acid (4e). Yellow powder, mp = 174-176 °C (decomp.), 314.0 g, yield: 77%. IR
(KBr) (νmax, cm-1): 1732 and 1728 (CO2Me), 1764 (C=O), 1651 (NC=C), 1272 (C-N), 1136 (C-
O) cm−1. Anal. Calcd for C20H22ClNO6: C, 58.90; H, 5.44; N, 3.43. Found C, 58.88; H, 5.43; N,

ACCEPTED MANUSCRIPT
16
3
3
3.45. δH (300 MHz, DMSO-d6): 0.86 (3H, d, JHH = 7.1 Hz, CH3), 0.91 (3H, d, JHH = 7.1 Hz,
CH3), 2.19-2.26 (1H, m, CH(Me)2), 3.03-3.08 (1H, m, NCH2), 3.61-.3.68 (1H, m, NCH2), 3.66
3
3
(3H, s, OMe), 3.82 (3H, s, OMe), 4.73 (1H, d, JHH = 5.5 Hz, CH ), 6.23 (1H, d, JHH = 5.5 Hz,
3
3
CH), 7.19 (2H, d, JHH = 8.3 Hz, 2 CH of Ar), 7.31 (2H, d, JHH = 8.3 Hz, 2 CH of Ar), 13.17
(1H, brs, OH). δC (75 MHz, DMSO-d6): 19.2 (CHCH3), 19.3 (CHCH3), 25.1 (CH), 41.6 (CH),
50.7 (CH2N), 51.5 (OCH3), 52.5 (OCH3), 105.6 (CCH), 122.1 (CH), 127.2 (CCO), 128.3 (CH of
Ar), 129.4 (CH of Ar), 131.3 (Cipso-Ar), 142.3 (Cipso-Ar), 142.7 (NC), 163.3 (CO2Me), 164.9
(CO2Me), 170.3 (CO2H).
4.1.6. 5,6-Bis(ethoxycarbonyl)-1-isobutyl-4-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid
(4f). Yellow powder, mp = 176-178 °C (decomp.), 307.5 g, yield: 74%. IR (KBr) (νmax, cm-1):
1720 and 1709 (CO2Et), 1776 (C=O), 1650 (NC=C), 1271 (C-N), 1124 (C-O) cm−1. Anal. Calcd
for C23H29NO6: C, 66.49; H, 7.03; N, 3.37. Found C, 66.48; H, 7.05; N, 3.35. δH (300 MHz,
3
3
DMSO-d6): 0.84 (6H, t, JHH = 7.3 Hz, CH2CH3), 1.27 (3H, t, JHH = 7.0 Hz, OCH2CH3) 1.38
3
(3H, t, JHH = 7.0 Hz, OCH2CH3), 2.18 (3H, s, CH3), 2.2-2.25 (1H, m, CH), 3.64-3.69 (1H, m,
NCH2), 3.72-3.78 (1H, m, NCH2), 4.17-4.22 (2H, m, OCH2CH3), 4.29-4.38 (2H, m, OCH2CH3),
4.80 (1H, d, 3JHH = 5.3 Hz, CH), 6.18 (1H, d, 3JHH = 5.3 Hz, CH), 7.12-7.15 (4H, br, 4 CH of Ar),
13.12 (1H, brs, OH). δC (75 MHz, DMSO-d6): 13.4 (OCH2CH3), 13.6 (OCH2CH3), 19.2
(CHCH3), 19.2 (CHCH3), 20.0 (CH3), 25.1 (CH(Me)2), 41.7 (CH), 50.7 (CH2N), 60.6
(OCH2CH3), 61.8 (OCH2CH3), 106.7 (CCH), 121.9 (CH), 126.9 (CCO), 127.3 (CH of Ar), 129.6
(CH of Ar), 135.9 (Cipso-Ar), 140.7 (Cipso-Ar), 142.6 (NC), 162.8 (CO2Et), 164.5 (CO2Et), 170.3
(CO2H).
4.1.7. 5,6-bis(methoxycarbonyl)-1-propyl-4-(p-tolyl)-1,4-dihydropyridine-2-carboxylic
acid (4g). Yellow powder, mp = 170-172 °C (decomp.), 283.7 g, yield: 76%. IR (KBr) (νmax, cm-

ACCEPTED MANUSCRIPT
17
1): 1723 and 1711 (CO2Me), 1764 (C=O), 1660 (NC=C), 1258 (C-N), 1135 (C-O) cm−1. Anal.
Calcd for C20H23NO6: C, 64.33; H, 6.21; N, 3.75. Found C, 64.35; H, 6.17; N, 3.78. δH (300
MHz, DMSO-d6): 0.72-0.77 (3H, m, CH2CH3), 1.39-1.44 (2H, m, CH2CH3), 2.19 (3H, s, CH3),
3.11-3.16 (1H, m, NCH2) , 3.51-3.58 (1H, m, NCH2), 3.63 (3H, s, OMe), 3.81 (3H, s, OMe),
3
3
4.71 (1H, d, JHH = 5.7 Hz, CH ), 6.23 (1H, d, JHH = 5.7 Hz, CH), 7.24-7.27 (4H, m, 4 CH of
Ar), 13.14 (1H, brs, OH). δC (75 MHz, DMSO-d6): 10.7 (CH2CH3), 20.0 (CH3), 20.3 (CH2CH3),
41.5 (CH), 44.1 (CH2N), 51.5 (OCH3), 52.6 (OCH3), 106.7 (CCH), 121.1 (CH), 127.1 (CCO),
127.6 (CH of Ar), 129.0 (CH of Ar), 135.5 (Cipso-Ar), 141.3 (Cipso-Ar), 142.9 (NC), 163.2
(CO2Me), 165.1 (CO2Me), 170.3 (CO2H).
4.1.8. 5,6-Bis(methoxycarbonyl)-4-(4-methoxyphenyl)-1-propyl-1,4-dihydropyridine-2-
carboxylic acid (4h). Yellow powder, mp = 174-176 °C (decomp.), 272.5 g, yield: 70%. IR
(KBr) (νmax, cm-1): 1719 and 1704 (CO2Me), 1739 (C=O), 1659 (NC=C), 1248 (C-N), 1115 (C-
O) cm−1. Anal. Calcd for C20H23NO7: C, 61.69; H, 5.95; N, 3.60. Found C, 61.68; H, 5.93; N,
3.63. δH (300 MHz, DMSO-d6): 0.82-0.86 (3H, m, CH2CH3), 1.42-46 (2H, m, CH2CH3), 3.11-
3.15 (1H, m, NCH2), 3.42-3.50 (1H, m, NCH2), 3.62 (3H, s, OMe), 3.69 (3H, s, OCH3), 3.86
3
3
(3H, s, OMe), 4.73 (1H, d, JHH = 5.4 Hz, CH ), 6.22 (1H, d, JHH = 5.4 Hz, CH), 6.91 (2H, d,
3JHH = 8.0 Hz, 2 CH of Ar), 7.17 (2H, d, 3JHH = 8.0 Hz, 2 CH of Ar), 13.26 (1H, brs, 1 H, OH). δC
(75 MHz, DMSO-d6): 10.8 (CH2CH3), 20.9 (CH2CH3), 41.3 (CH), 44.1 (CH2N), 51.5 (OCH3),
52.7 (OCH3), 55.4 (OCH3), 105.0 (NC=C), 110.1 (CH of Ar), 121.1 (CH), 127.1 (CCO), 129.7
(CH of Ar), 135.5 (Cipso-Ar), 142.7 (NC), 157.5 (Cipso-Ar), 163.4 (CO2Me), 165.1 (CO2Me),
170.3 (CO2H).
4.1.9. 1-Butyl-5,6-bis(methoxycarbonyl)-4-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid

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(4i). Yellow powder, mp = 175-177 °C (decomp.), 290.4 g, yield: 72%. IR (KBr) (νmax, cm-1:
1727 and 1714 (CO2Me), 1745 (C=O), 1638 (NC=C), 1262 (C-N), 1132 (C-O) cm−1. Anal.
Calcd for C21H25NO7: C, 62.52; H, 6.25; N, 3.47. Found C, 62.55; H, 6.25; N, 3.44. δH (300
3
MHz, DMSO-d6): 0.86 (3H, t, JHH = 7.1 Hz, CH2CH3), 1.24-1.30 (2H, m, CH2CH3), 1.37-1.44
(2H, m, CH2CH2CH3), 3.03-3.08 (1H, m, NCH2), 3.64-3.71 (1H, m, NCH2), 3.65 (3H, s, OMe),
3
3.81 (3H, s, OMe), 3.92 (3H, s, OMe), 4.81 (1H, d, JHH = 5.4 Hz, CH ), 6.09 (1H, d, 3JHH = 5.4
Hz, CH), 6.84 (2H, d, 3JHH = 8.1 Hz, 2 CH of Ar), 7.11 (2H, d, 3JHH = 8.1 Hz, 2 CH of Ar), 13.14
(1H, brs, OH). δC (75 MHz, DMSO-d6): 13.4 (CH3), 20.5 (CH2CH3), 25.6 (CH2CH2CH3), 41.3
(CH), 44.6 (CH2N), 51.3 (OCH3), 52.4 (OCH3), 55.7 (OCH3), 104.8 (NC=C), 110.5 (CH of Ar),
121.3 (CH), 127.4 (CCO), 129.5 (CH of Ar), 135.5 (Cipso-Ar), 143.0 (NC), 157.4 (Cipso-Ar),
163.5 (CO2Me), 165.2 (CO2Me), 170.5 (CO2H).
4.2. Typical synthesis procedure: (for example 7a)
A mixture of o-phenylenediamine (0.10 g, 1 mmol) and dimethyl acetylenedicarboxylate (0.14
g, 1 mmol) was mixed in a 50 mL round bottom (RB) flask at room temperature in 5 mL of
acetonitrile. After 30 min a mixture of pyruvic acid (0.08 g, 1 mmol), 4-chlorobenzaldehyde
(0.14 g, 1 mmol) and 10 mol% iodine (0.013 g, 0.1mmol) was added to the RB flask. The
reaction mixture was heated at reflux for 7 h. The completion of the reaction was monitored
using thin layer chromatography (TLC). After completion of the reaction the mixture was cooled
to room temp, diluted with a 20% solution of sodium thiosulfate (3 mL) and extracted with ethyl
acetate (3
×
5 mL). The organic layers were collected, combined, dried over Na2SO4, filtered and
concentrated under vacuum. Finally, to the remained mixture ethanol (3 mL) was added and the

ACCEPTED MANUSCRIPT
19
precipitated product was produced that was filtered and washed with cold ethanol to afford the
pure yellow product 7a.
4.2.1.
8-(4-Chlorophenyl)-7-(methoxycarbonyl)-6-oxo-6,8-dihydro-5H-pyrido[1,2-
a]quinoxaline-10-carboxylic acid (7a). Yellow powder, mp = 188-190 °C (decomp.), 328.6 g,
yield: 80%. IR (KBr) (νmax, cm-1): 3271 (NH), 1766 (C=O), 1697 (CO2Me), 1660 (NC=O)
cm−1. Anal. Calcd for C21H15ClN2O5: C, 61.40; H, 3.68; N, 6.82. Found C, 61.37; H, 3.70; N,
6.84. m/z (%) = 410 (M+, 2), 365 (26), 351 (42), 358 (19), 334 (42), 306 (56), 299 (100), 255
3
(37), 91 (76). δH (300 MHz, DMSO-d6): 3.64 (3H, s, OMe), 4.62 (1H, d, JHH = 5.6 Hz, CH),
6.19 (1H, d, 3JHH = 5.6 Hz, CH), 7.17–7.21 (2H, m, 2 CH of Ar), 7.27 (2H, d, 3JHH = 8.0 Hz, 2
CH of Ar), 7.36 (2H, d, 3JHH = 8.0 Hz, 2 CH of Ar), 7.49 (1H, t, 3JHH = 7.7 Hz, CH of Ar), 7.62
3
(1H, d, JHH = 7.7 Hz, 1 CH of Ar), 8.14 (1H, s, NH), 13.09 (1H, brs, OH). δC (75 MHz,
DMSO-d6): 42.4 (CH), 52.5 (OCH3), 115.5 (C=CN), 121.4 (CH), 123.5 (CH of Ar), 126.4 (CH
of Ar), 127.1 (CCO), 127.5 (CH of Ar), 128.3 (CH of Ar), 128.4 ( 2 CH of Ar), 129.0 (2 CH of
Ar), 131.5 (Cipso-Ar), 131.9 (Cipso-of Ar), 138.8 (Cipso-of Ar), 142.3 (Cipso-Ar), 142.7 (NC),
154.3 (NCO), 164.7 (CO2Me), 170.4 (CO2H).
4.2.2.
8-(4-Chlorophenyl)-7-(ethoxycarbonyl)-6-oxo-6,8-dihydro-5H-pyrido[1,2-
a]quinoxaline-10-carboxylic acid (7b).Yellow powder, mp=190-192°C (decomp.), 327.1 g,
yield: 77%. IR (KBr) (νmax, cm-1): 3280 (NH), 1751 (C=O), 1681 (CO2Et), 1635 (NC=O) cm−1.
Anal. Calcd for C22H17ClN2O5: C, 62.20; H, 4.03; N, 6.59. Found C, 62.23; H, 4.04; N, 3.55. δH
3
(300 MHz, DMSO-d6): 1.18 (3H, t, JHH = 7.1 Hz, OCH2CH3), 4.12 (2H, m,OCH2CH3), 4.53
3
3
(1H, d, JHH = 5.4 Hz, CH), 6.37 (1H, d, JHH = 5.4 Hz, CH), 7.18–7.23 (2H, m, 2 CH of Ar),
3
3
7.28 (2H, d, JHH = 8.0 Hz, CH of Ar), 7.39 (2H, d, JHH = 8.0 Hz, 2 CH of Ar), 7.51 (1H, d,
3JHH = 7.7 Hz, CH of Ar), 7.6 (1H, d, 3JHH = 7.7 Hz, 1 CH of Ar), 8.13 (1H, s, NH), 13.11 (1H,

ACCEPTED MANUSCRIPT
20
brs, OH). δC (75 MHz, DMSO-d6): 13.6 (OCH2CH3), 42.4 (CH), 61.2 (OCH2CH3), 115.3
(C=CN), 121.4 (CH), 123.6 (CH of Ar), 126.1 (CH of Ar), 127.1 (CCO), 127.3 (CH of Ar),
128.3 (CH of Ar), 128.5 (2 CH of Ar), 129.1 (2 CH of Ar), 131.5 (Cipso-Ar), 131.7 (Cipso-Ar),
139.0 (Cipso-Ar), 142.4 (Cipso-Ar), 142.6 (NC), 154.3 (NCO), 164.7 (CO2Me), 170.2 (CO2H).
4.2.3.
8-(4-Bromophenyl)-7-(methoxycarbonyl)-6-oxo-6,8-dihydro-5H-pyrido[1,2-
a]quinoxaline-10-carboxylic acid (7c). Yellow powder, mp = 194-196 °C (decomp.), 318.7 g,
yield: 70%. IR (KBr) (νmax, cm-1): 3266 (NH), 1758 (C=O), 1661 (CO2Me), 1629 (NC=O)
cm−1. Anal. Calcd for C21H15BrN2O5: C, 55.40; H, 3.32; N, 6.15. Found C, 55.42; H, 3.29; N,
3
3.6.17. δH (300 MHz, DMSO-d6): 3.65 (3H, s, OMe), 4.52 (1H, d, JHH = 5.7 Hz, CH), 6.27
3
(1H, d, JHH = 5.7 Hz, CH), 7.14–7.19 (2H, m, 2 CH of Ar), 7.25-7.33 (4 H, m, 4 CH of Ar),
3
3
7.46 (1H, d, JHH = 7.8 Hz, CH of Ar), 7.56 (1H, d, JHH = 7.8 Hz, 1 CH of Ar), 8.16 (1H, s,
NH), 13.17 (1H, brs, OH). δC (75 MHz, DMSO-d6): 39.8 (CH), 52.6 (OCH3), 115.3 (C=CN),
121.3 (CH), 123.9 (CH of Ar), 126.4 (CH of Ar), 127.1 (CCO), 127.5 (CH of Ar), 128.3 (CH
of Ar), 128.4 (2 CH of Ar), 129.3 (2 CH of Ar), 130.2 (Cipso-Ar), 131.9 (Cipso-Ar), 138.8 (Cipso
Ar), 142.1 (Cipso-Ar), 142.9 (NC), 154.2 (NCO), 164.3 (CO2Me), 170.3 (CO2H).
-
4.2.4.
8-(4-Bromophenyl)-7-(ethoxycarbonyl)-6-oxo-6,8-dihydro-5H-pyrido[1,2-
a]quinoxaline-10-carboxylic acid (7d). Yellow powder, mp = 195-197 °C (decomp.), 337.9 g,
yield: 72%. IR (KBr) (νmax, cm-1): 3284 (NH), 1743 (C=O), 1670 (CO2Me), 1636 (NC=O) cm−1.
Anal. Calcd for C22H17BrN2O5: C, 56.31; H, 3.65; N, 5.97. Found C, 56.29; H, 3.66; N, 5.99. δH
3
(300 MHz, DMSO-d6): 1.13 (3H, t, JHH = 7.0 Hz, OCH2CH3), 4.16-4.20 (2H, m, OCH2CH3),
3
3
4.76 (1H, d, JHH = 5.6 Hz, CH), 6.13 (1H, d, JHH = 5.6 Hz, CH), 7.12–7.20 (2H, m, 2 CH of
3
Ar), 7.26-7.32 (4H, m, 4 CH of Ar), 7.48 (1H, d, JHH = 7.8 Hz, CH of Ar), 7.59 (1H, d, 3JHH
=
7.8 Hz, CH of Ar), 8.14 (1H, s, NH), 13.19 (1H, brs, OH). δC (75 MHz, DMSO-d6): 13.7

ACCEPTED MANUSCRIPT
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(OCH2CH3), 61.3 (OCH2CH3), 115.8 (C=CN), 121.4 (CH), 123.8 (CH of Ar), 126.5 (CH of Ar),
127.1 (CCO), 127.6 (CH of Ar), 128.2 (CH of Ar), 128.5 ( 2 CH of Ar), 129.7 (2 CH of Ar),
130.1 (Cipso-Ar), 132.0 (Cipso-Ar), 138.6 (Cipso-Ar), 142.3 (Cipso-Ar), 143.1 (NC), 153.9 (NCO),
165.4 (CO2Et), 170.8 (CO2H).
Acknowledgements
Financial support of this research from Alzahra University, Iran is gratefully acknowledged.
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