Efficient synthesis of 3,4-dihydro-1H-quinoxalin-2-ones and 1H-quinolin-2-ones and evaluation of their anti-bacterial activity

Article abstract of DOI:10.3184/174751914X13987604216112

Economical and environmentally friendly syntheses of three 3,4-dihydro-1H-quinoxalin-2-ones and six 1H-quinolin-2-ones have been developed by a 1 : 1 reaction of o-, m-, or p-phenylenediamine with dialkyl acetylenedicarboxylates under solvent-free conditions. Some of the products were antibacterial towards both Gram positive and Gram negative microorganisms.

Full text of DOI:10.3184/174751914X13987604216112

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 JUNE, 337–340
RESEARCH PAPER 337
Efficient synthesis of 3,4-dihydro-1H-quinoxalin-2-ones and 1H-quinolin-2-
ones and evaluation of their anti-bacterial activity
Elham Zarenezhada*, Mohammad Hossein Mosslemina, Alireaza Alborzib,
Hossein Anaraki-Ardakanic, Nasim Shamsa, Mehdi Mard Khoshnoodd and Ali Zarenezhadd
aDepartment of Chemistry, Yazd Branch, Islamic Azad University, PO Box 89195-155, Yazd, Iran
bDepartment of Chemistry, Firoozabad Branch, Islamic Azad University, Firoozabad, Iran
cDepartment of Chemistry, College of Chemistry, Mahshahr Branch, Islamic Azad University, Mahshahr, Iran
dDepartment of Medicine, Fasa Medical Sciences, Fasa, Iran
Economical and environmentally friendly syntheses of three 3,4-dihydro-1H-quinoxalin-2-ones and six 1H-quinolin-2-ones have
been developed by a 1:1 reaction of o-, m-, or p-phenylenediamine with dialkyl acetylenedicarboxylates under solvent-free
conditions. Some of the products were antibacterial towards both Gram positive and Gram negative microorganisms.
Keywords: phenylenediamines, 3,4-dihydro-1H-quinoxalin-2-ones, 1H-quinolin-2-ones, dialkyl acetylenedicarboxylates, solvent-
free synthesis
The development of simple synthetic routes for widely used
organic compounds from readily available reagents is one
of the major tasks in organic synthesis.1 Solvent-free and
one-pot multi-component condensations are powerful green
chemical technology procedures from both economical and
synthetic points of view and may be the instrument to perform
a near-ideal synthesis.2–4 Due to the growing concern over the
influence of the organic solvent on the environment as well
as on the human body, organic reactions without the use of
conventional organic solvents have attracted the attention of
synthetic organic chemists. Although a number of modern
solvents, such as fluorous media, ionic liquids and water have
been extensively studied, not using a solvent at all would be the
best option. Development of solvent-free organic reactions is
thus gaining prominence.5,6
antitumour, anthelmintic, antibacterial, antiasthmatic, and
antiplatelet activities continue to justify their synthesis.9–11
Due to these useful pharmacophoric properties, they have
been extensively studied.12 In view of the emerging importance
of N-heterocyclic compounds13–15 and our general interest in
solvent-less chemical process,13–15 we envisioned expediting
the synthesis of quinoxaline and quinoline derivatives from
the reaction of phenylenediamines, and dialkylacetylene
dicarboxylates under catalyst- and solvent-free conditions.
All the synthesised compounds have been evaluated for their
antibacterial activity towards two Gram positive and two Gram
negative bacteria.
Results and discussion
We report here an efficient and rapid method for the preparation
of 3,4-dihydro-1H-quinoxalin-2-ones and 1H-quinolin-2-ones
that involves grinding of o-, m-, or p-phenylenediamine and
three dialkyl acetylenedicarboxylates using a pestle and mortar
(Schemes 1 and 2). This solvent-free approach requires only a
few minutes of reaction time. This type of reaction is expected
Heterocyclic compounds containing nitrogen heteroatoms
are common in nature, and derivatives feature in many
pharmaceuticals as well as agrochemicals.7,8 The presence of
a nitrogen heterocyclic nucleus in the framework of various
pharmacologically active compounds with antimalarial,
H
O
O
NH2
NH2
N
O
RO
R
C C
OR
+
H
N
a: Me
b: Et
c: t-bu
H
O
OR
1a
2
3
Scheme 1 Reaction between o-phenylenediamine 1a and dialkyl acetylenedicarboxylates 3.
H
NH2
R1
R2
N
O
O
O
RO
R
C C
OR
+
R2
R1
a: Me
b: Et
c: t-bu
O
OR
1b (R1 = NH2, R2 = H)
1c (R1 = H, R2 = NH2)
4 (R1 =NH2, R2 = H)
5 (R1 = H, R2 = NH2)
2
Scheme 2 Reaction between m- and p-phenylenediamine 1b,c and dialkyl acetylenedicarboxylates 3.
* Correspondent. E-mail: elham.zarenezhad2014@gmail.com

338 JOURNAL OF CHEMICAL RESEARCH 2014
1
to be the most economical method since neither catalyst nor
solvent is used. The products were characterised by their IR,
1H and 13C NMR spectra along with their elemental analyses.
Thewhollysymmetricalisomers, o-and p-phenylenediamine,
as expected, yielded a single product. Thus, a 1:1 reaction
of o-phenylenediamine 1a with dimethyl, diethyl or di-tert-
butyl acetylenedicarboxylate 2a–c yielded (Z)-alkyl 2-(3-oxo-
3,4-dihydroquinoxalin-2(1H)-ylidene)acetates 3a–c in an
excellent yield (94–97%) (Scheme 1). Also, a 1:1 reaction
of p-phenylenediamine 1c and dimethyl, diethyl or di-t-butyl
acetylenedicarboxylates 2a–c afforded alkyl 6-amino-2-oxo-
1,2-dihydroquinoline-4-carboxylates 4a–c in a very good
yield (85–89%) (Scheme 2). In theory, a 1:1 reaction between
m-phenylenediamine 1b and dialkyl acetylenedicarboxylates
2a–c could have afforded two products A and B (Scheme 3),
but again, only one product, alkyl 7-amino-2-oxo-1,2-
dihydroquinoline-4-carboxylate 5a–c was formed, again in an
excellent yield (91–96%) (Scheme 2).
Thus, in the simple H NMR spectrum of compound 4b,
the vicinal protons of the benzene ring form an AX system
featuring a doublet at 7.59 (J=8.8 Hz) and a doublet of doublets
at 6.24 (J=8.8, 2 Hz), the latter also coupling with the proton
located between the N atoms which appears as a doublet at 6.22
(J=2 Hz). This pattern of peaks is only possible for compound
4b and not the other isomer B which has four vicinal aromatic
protons.
The formation of products 3a–c can be rationalised by a
Michael-type addition, with initial formation of intermediate
5 followed by cyclisation to 7 and elimination of RO– products
3a–c (Scheme 4).
We believe that the formation of the quinoline derivatives
4a–c, 5a–c proceeds by the pathways illustrated in Scheme 5.
m- or p-Phenylenediamine 1b,c reacts with dialkyl
acetylenedicarboxylate 2 to generate intermediate 8 which
cyclises to afford the intermediate 9 which can undergo
intramolecular nucleophilic substitution to afford the
corresponding quinolines 4a–c and 5a–c.
Finally, all synthesised compounds were screened for
antimicrobial activity against two Gram-positive bacteria
(Pseudomonas aeruginosa PTCC 1077, Escherichia coli PTCC
1330) and two Gram-negative bacteria (Staphylococcus aureus
PTCC 1133, Bacillus cereus PTCC 1015) and their activity
Regioselectivity
The regioselectivity observed leading to structure A is
probably due to steric hindrance which attacks at the 2-position
of m-phenylenediamine 1b. NMR spectroscopy demonstrated
that the major product was indeed compound A.
O
O
NH2
1
2
HN
HN
O
O
H2N
R
O
R
O
H2N
NH2
B
A
Scheme 3 The two possible products of reaction from m-phenylenediamine 1b and dialkyl acetylenedicarboxylates 2.
OR
OR
O
H
N
NH2
NH2
OR
O-
NH2
C
C
O
H
+
3 (a-c)
N
H
O
N
H
O
OR
2
O
OR
1a
7
6
Scheme 4 Suggested mechanism for the synthesis of (Z)-alkyl 2-(3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene)acetate 3a–c.
OR
O
OR
OR
NH
R1
R2
NH2
R1
R2
NH2
+
R1
R2
C
C
O
O
4 (a-c)
5 (a-c)
H
C
CH
CH
C
O
COOR
COOR
OR
1b (R1 = NH2, R2 = H)
1c (R1 = H, R2 = NH2)
2
8
9
Scheme 5 Suggested mechanism for the synthesis of 1H-quinolin-2-ones 4a–c and 5a–c.

JOURNAL OF CHEMICAL RESEARCH 2014 339
(Z)-Methyl 2-(3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene)acetate
(3a): Yellow powder, 0.212 g, yield 97%; m.p. 225–227 °C; IR (νmax):
3211, 3164, 3046, 3010, 2945, 2874, 2783, 1688, 1647, 1619, 1443 cm–1;
1H NMR (CDCl3): 3.80 (s, 3H, OCH3), 5.86 (s, 1H, C=C–H), 6.96–7.27
(m, 4H, arom), 8.88 (s, 1H, NH exchangeable with D2O), 11.14 (s, 1H,
NH exchangeable with D2O); 13C NMR (CDCl3 +DMSO (3%)): 51.2,
84.9, 114.7, 116.1, 122.8, 124.1, 125.5, 125.6, 144.6, 156.9, 171.3. Anal.
calcd for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84; found: C, 60.45; H,
4.78; N, 12.69%.
(Z)-Ethyl 2-(3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene)acetate
(3b): Yellow powder, 0.220 g, yield 94%; m.p. 218 °C; IR (νmax): 3210,
3164, 3046, 3010, 2878, 2781, 1687, 1646, 1619, 1463; 1H NMR (CDCl3):
1.14 (t, J=7.1, 3H, CH3), 4.03 (q, J=7.1, 2H, O–CH2), 5.55 (s,1H,
C=C–H), 6.79–6.94 (m, 4H, arom), 10.98 (s, 1H, NH exchangeable
with D2O), 11.17 (s, 1H, NH exchangeable with D2O); 13C NMR
(CDCl3 +DMSO (3%)): δ 14.7, 59.9, 85.3, 114.7, 116.1, 122.7, 124.0,
125.5, 125.6, 144.5, 156.9, 171.0. Anal. calcd for C12H12N2O3: C, 62.06;
H, 5.21; N, 12.06; found: C, 61.55; H, 5.40; N, 12.14%.
compared with gentamycin and ampicillin as reference drugs
for Gram-negative and Gram-positive bacteria, respectively.
The minimum inhibitory concentration (MIC) of the
synthesised compounds and reference drugs were determined
by the microdilution method.16 As can be seen from Table 1,
good antibacterial activity was observed for 5c against all
species of Gram-positive and Gram-negative bacteria, and
compounds 3a–c showed good antibacterial activity against
two Gram-positive bacteria. Indeed, 3a was found to have the
same activity against S. aureus as ampicillin, and compounds
3b–c, 4f and 5c have the same activity against B. cereus as
ampicillin.
Table 1 Evaluation of the antibacterial activity of 3,4-dihydro-1H-
quinoxalin-2-ones 3a–c and 1H-quinolin-2-ones 4a–c, 5a–c using the
microdilution method16
Compound
MIC/mg mL–1
(Z)-tert-butyl 2-(3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene)
acetate (3c): Yellow powder, 0.452 g, yield 96%; m.p. 187–190 °C; IR
(νmax): 3434, 3257, 3162, 3044, 3008, 2969, 2923, 2880, 2785, 2736,
1683, 1643, 1625, 1480; 1H NMR (CDCl3): 1.58 (s, 9H, C(CH3)3), 5.82 (s,
1H, C=C–H), 7.04–7.30 (m, 4H, arom) 10.34 (s, 1H, NH exchangeable
with D2O), 11.152 (s, 1H, NH exchangeable with D2O); 13C NMR
(CDCl3 +DMSO (5%)): 28.5, 79.7, 86.9, 114.5, 115.8, 122.2, 123.7,
125.3, 125.4, 143.7, 156.7, 170.4. Anal. calcd for C14H16O3N2: C, 64.60;
H, 6.20; N, 10.76; found: C, 64.77; H, 6.23; N, 10.83%.
P. aeruginosa
q
B. cereus
S. aureus
3a
3b
3c
4a
4b
4c
5a
5b
>100
>100
>50
>50
>25
>50
>25
>25
> 12.5
–
>50
>50
>25
>100
>100
>50
>25
> 12.5
> 12.5
>100
>50
>100
>25
>50
> 12.5
12.5 >
–
> 3.125
>6.5
>6.5
>50
>25
>50
>25
>25
>6.25
3.125>
–
>50
> 12.5
>6.25
–
5c
Methyl 7-amino-2-oxo-1,2-dihydroquinoline-4-carboxylate (4a):
Yellow powder, 0.198 g, yield 90%; m.p. 201–203 °C; IR (νmax): 3447,
Ampicillinb
Gentamycinc
6.25>
6.25>
1
3339, 3218, 3218, 3097, 2998, 2957, 1725, 1669, 1623, 1474; H NMR
aExamined bacteria: Staphylococcus aureus (PTCC 1133), Bacillus cereus
(PTCC 1015), Pseudomonas aeruginosa (PTCC 1077) and Escherichia coli
(PTCC 1330).
(CDCl3): 3.43 (s, 3H, OCH3), 4.77 (s, 2H, NH2 exchangeable with D2O),
6.09 (s, 1H, C=C–H), 6.02–7.34 (m, 3J=8.8, 4J=2.0, 3H, arom), 11.08
(s, 1H, NH exchangeable with D2O); 13C NMR (DMSO): 53.5, 97.4,
107.0, 112.2, 116.9, 127.6, 141.0, 142.6, 152.5, 162.4, 167.1. Anal. calcd
for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84; found: C, 60.46; H, 4.59; N,
12.89%.
bReference drug for Gram-positive bacteria.
cReference drug for Gram-negative bacteria.
Ethyl 7-amino-2-oxo-1,2-dihydroquinoline-4-carboxylate (4b):
Yellow powder, 0.232 g, yield 91%; m.p. 208 °C; IR (νmax): 3427, 3367,
3323, 3046, 3215, 3087, 2981, 2927, 2866, 1709, 1672, 1623, 1471; H
Conclusions
1
We have described a simple, one-pot, two-component reaction
between dialkyl acetylene dicarboxylates and all three isomers
of phenylenediamine which gave very good to excellent yields
of medicinally important nitrogen heterocycles. The advantages
of the reported method are readily available starting materials,
short reaction time, simple work-up, neutral reaction conditions
and high yields. Nearly all the compounds exhibited moderate
to good antibacterial activity against all four of the tested
strains.
NMR (CDCl3): 1.09 (t, J=7.1, 3H, CH3), 4.07 (q, J=7.1, 2H, OCH2),
3
4.62, 6.36 (s,1H, C=C–H), 6.22–7.60 (m, J=8.8,4J=2.1, 3H, arom),
δ 11.23 (s,1H, NH exchangeable with D2O); 13C NMR (CDCl3): 14.8,
62.3, 97.4, 107.0, 112.2, 116.6, 127.5, 141.3, 142.6, 152.5, 162.5, 166.6.
Anal. calcd for C12H12N2O3: C, 62.06; H, 5.21; N, 12.06; found: C, 61.96;
H, 5.11; N, 12.18%.
tert-Butyl 7-amino-2-oxo-1,2-dihydroquinoline-4-carboxylate (4c):
Yellow powder, 0.210 g, yield 86%; m.p. 202–204 °C; IR (νmax): 3467,
3365, 3296, 3197, 3093, 3027, 2925, 2860, 1725, 1669, 1622, 1475; 1H
NMR (CDCl3): 1.53 (s, 9H, C(CH3)3), 4.56 (2H, NH2 exchangeable with
3
4
Experimental
D2O), 6.30 (s, 1H, C=C–H), 6.39–7.06 (m, 3H, J=8, J=1.3, arom),
11.53 (s, 1H, NH exchangeable with D2O);13C NMR (DMSO): 28.0,
80.4, 96.9, 108.4, 112.3, 116.2, 128.1, 141.1, 142.6, 152.0, 162.8, 167.9.
Anal. calcd for C14H16O2N2: C, 64.60; H, 6.20; N, 10.76; found: C, 64.48;
H, 6.11; N, 10.69%.
Melting points were determined with an Electrothermal 9100
apparatus. Elemental analyses were performed using a Heraeus
CHN-O-Rapid analyser. IR spectra were recorded on a Shimadzu
IR-470 spectrometer. NMR spectra were obtained on a Bruker DRX-
500 Avance spectrometer (1H NMR at 500 Hz, 13C NMR at 125 Hz)
in CDCl3 or in CDCl3/DMSO-d6 using TMS as internal standard.
Chemical shifts (d) are given in ppm and coupling constants (J) in Hz.
The chemicals used in this work were purchased from Fluka (Buchs,
Switzerland) and were used without further purification.
Methyl 6-amino-2-oxo-1,2-dihydroquinoline-4-carboxylate (5a):
Yellow oil, (0.189 g, yield 85%; IR (νmax): 3445, 3367, 3323, 3215, 3110,
3000, 2875, 1721, 1642, 1600, 1495; 1H NMR (CDCl3): 3.56 (s, 2H, NH2
exchangeable with D2O), 4.25 (s, 3H, OCH3), 6.61–6.81 (m, 4H, 3J=8.4
arom, C=CH,), 9.56 (s, 1H, NH exchangeable with D2O); 13C NMR
(CDCl3): 53.5 (OCH3), 98.8 (C=C–H), δ 109.5, 115.0, 121.2, 127.6,
140.0, 141.0, 153.6, 163.4, 166.1. Anal. calcd for C11H10N2O3:C, 60.55; H,
4.62; N, 12.84;; found: C, 60.45; H, 4.52; N, 12.75%.
Synthesis of compounds 3a–c, 4a–c, 5a–c; general procedure
A mixture of o-, m- or p-phenylenediamine (2 mmol) and dialkyl
acetylenedicarboxylate (2 mmol) was crushed for 2 min using a pestle
and mortar. The reaction takes place almost immediately. The mixture
was treated with dichloromethane (5 mL), filtered and the filtrate
evaporated to give the product. In the case of the products 5a–c, the
residue was purified by silica gel column chromatography using
hexane and ethyl acetate as the eluents.
Ethyl 6-amino-2-oxo-1,2-dihydroquinoline-4-carboxylate (5b):
Yellow oil, 0.20 g, yield 86%; IR (νmax): 3432, 3383, 3351, 3215, 3087,
1
2957, 2925, 2860, 1725, 1669, 1623, 147; H NMR (CDCl3): 1.157 (t,
J=7.1, 3H, CH3), 3.65 (s, 2H, NH2 exchangeable with D2O), 4.16 (q,
J=7.1, 2H, OCH2) 6.61–6.87 (m, 4H, 3J=8.4, arom, C=CH) 9.56 (s,1H,
NH exchangeable with D2O); 13C NMR (CDCl3): 14.7, 59.9, 98.3, 109.5,

340 JOURNAL OF CHEMICAL RESEARCH 2014
5
6
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C12H12N2O3: C, 62.06; H, 5.21; N, 12.06; found: C, 62.22; H, 5.11; N,
12.26%.
7
tert-Butyl 6-amino-2-oxo-1,2-dihydroquinoline-4-carboxylate (5c):
Yellow oil, 0.21 g, yield 89%; IR (νmax): 3444, 3383, 3281, 2972, 2931,
1737, 1659, 1607, 1475; 1H NMR (CDCl3): 1.53 (s, 9H, C)CH3)3), 3.61(s,
2H, NH2 exchangeable with D2O), 6.63–6.90 (m, 4H, 3J=8.5, C=C–H,
arom), 9.49 (s, 1H, NH exchangeable with D2O); 13C NMR (CDCl3):
δ 28.0, 80.1, 97.5, 109.3, 115.8, 121.3, 127.0, 141.0,142.6, 153.292, 164.0,
167.2. Anal. calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76; found: C,
64.74; H, 6.10; N, 10.59%.
8
9
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Received 3 February 2014; accepted 23 March 2014
Paper 1402444 doi: 10.3184/174751914X13987604216112
Published online: 10 June 2014
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