Synthesis of new 1,3,4-oxadiazol, thiadiazole, 1,2,4-triazole, and arylidene hydrazide derivatives of 4-oxo-1,4-dihydroquinoline with antimicrobial evaluation

Article abstract of DOI:10.1002/jhet.1005

A series of substituted 1,3,4-oxadiazole, 1,2,4-triazole, and 1,3,4-thiadiazole derivatives of the substituted 3-carboethoxy-1,4-dihydro-4- oxoquinoline have been synthesized through the reaction of the key intermediate thiosemicarbazide derivatives with different reagents. N′-Arylidene-4-oxo- 1,4-dihydroquinoline-3-carbohydrazides were also synthesized through the condensation reaction of the corresponding hydrazides with the appropriate aldehydes. Antimicrobial activity of some of the synthesized compounds was evaluated.

Full text of DOI:10.1002/jhet.1005

February 2013
Synthesis of New 1,3,4-Oxadiazol, Thiadiazole, 1,2,4-Triazole, and
Arylidene Hydrazide Derivatives of 4-Oxo-1,4-dihydroquinoline with
Antimicrobial Evaluation
E1
a
b
*
*
Farag A. El-Essawy and Wael A. El-Sayed
aChemistry Department, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
bPhotochemistry Department, National Research Center, El-Dokki, Cairo, Egypt
*
E-mail: farag.eleswi@science.menofia.edu.eg or waelshendy@gmail.com
Received January 18, 2011
DOI 10.1002/jhet.1005
Published online 2 April 2013 in Wiley Online Library (wileyonlinelibrary.com).
A series of substituted 1,3,4-oxadiazole, 1,2,4-triazole, and 1,3,4-thiadiazole derivatives of the substituted
3-carboethoxy-1,4-dihydro-4-oxoquinoline have been synthesized through the reaction of the key intermediate
thiosemicarbazide derivatives with different reagents. N0-Arylidene-4-oxo-1,4-dihydroquinoline-3-carbohydra-
zides were also synthesized through the condensation reaction of the corresponding hydrazides with the
appropriate aldehydes. Antimicrobial activity of some of the synthesized compounds was evaluated.
J. Heterocyclic Chem., 50, E1 (2013).
INTRODUCTION
significant anti-inflammatory activity [13–22]. Recently,
some 1,2,4-triazole derivatives incorporating Shiff base
structure were synthesized as antitumor agents [23]. In view
of these facts and in continuation of our research program
on the synthesis of new heterocyclic compounds to shed
some light on their biological studies [24–32], we report
herein the synthesis of some newer heterocyclic systems
containing 1,2,4-triazoles, 1,3,4-oxadiazoles, 1,3,4-thiadia-
zoles, and arylidene hydrazides linked with 3-carboethoxy-
1,4-dihydro-4-oxoquinoline.
Quinoline derivatives represent the major class of hetero-
cycles, and a number of preparations have been known
since the late 1800s. The quinoline ring system occurs in
various natural products, especially in alkaloids. The quino-
line skeleton is often used for the design of many synthetic
compounds with diverse pharmacological properties [1].
Despite its relatively low efficacy and tolerability, quinine
still plays an important role in the treatment of multiresistant
malaria [2]. Nalidixic acid 1-ethyl-7-methyl-4-oxo-[1,8]
naphthyridine-3-carboxylic acid was developed as an anti-
bacterial for the treatment of urinary tract infections [3].
The presence of quinoline nucleus in the framework of
various pharmacologically active compounds with anti-
asthmatic [4], antibacterial [5], antifungal [6], antimalarial
[7], antiviral [8], antitumor [9], and anti-inflammatory [10]
activities continues to promote their synthetic efforts. In
addition, the hydrazones derived from the a-(N)-acetylqui-
nolines inhibited in vitro antitumor activity, and other related
compounds were effective inhibitors of leukemia, colon, and
ovarian cancer cells [11]. The novel quinoline-quinone strep-
tonigrin is an antitumor antibiotic that has activity against a
broad range of tumors [12]. Furthermore, their synthesis is
performed in the ordinary organic solvent. On the other
hand, it has been reported that certain compounds bearing
1,3,4-oxa-, thiadiazole, and 1,2,4-triazole nuclei possess
RESULTS AND DISCUSSION
The starting materials quinolone derivatives 3a,b were
synthesized by the treatment of commercially available
o-toluidines and p-toluidines with diethyl ethoxymethylene
malonate (EMME), according to the reported method [33],
to afford diethyl methylanilinomethylenemalonates 2a,b,
which were then subjected to cyclization in refluxing
diphenylether affording 3-carboethoxy-8-methyl-1,4-dihy-
dro-4-oxoquinoline (3a) and 3-carboethoxy-6-methyl-1,
4-dihydro-4-oxoquinoline (3b) in 90% and 80% yields,
respectively. The respective hydrazides 4a,b were obtained
by refluxing quinolone esters 3a,b with hydrazine in etha-
nol. Their IR spectra showed a characteristic C═O absorp-
1
tion at 1642–1669 cmꢀ1, and their H NMR spectra agree
with the structures that showed a characteristic broad band
© 2013 HeteroCorporation

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F. A. El-Essawy and W. A. El-Sayed
Vol 50
1
for NHNH2 at d 4.58 and 4.56 ppm for 4a and 4b, respec-
tively. On the other hand, treating of 1b with EMME
in AcOH at reflux temperature afforded ethyl 3-[(4-methyl-
phenyl)amino]-2-{[(4-methylphenyl)amino]carbonyl}acry-
late (6), and the expected product 5, according to the report
of Anderson [34], was not obtained at all on the basis of
the spectral data. The structural assignment of 6 is based
of 7 is based on its H NMR spectrum, which revealed the
disappearance of the ethyl group and the presence of a singlet
at d 2.24 and 2.29ppm corresponding to the two methyl
groups. Besides, the MS spectrum revealed the molecular
ion peak at 292, indicating the molecular weight of the deriv-
ative 7 (Scheme 1).
On treatment of hydrazides 4a,b with phenyl isothiocya-
nate in absolute ethanol, under reflux, the thiosemicarba-
zide derivatives 8a,b were obtained in 88% and 89%
yields, respectively. The latter thiosemicarbazides 8a,b
showed a characteristic absorption band for C═S at
1193–1153 cmꢀ1. Oxidative cyclization of 8a,b by elimi-
nation of H2S using I2 and KI in ethanolic NaOH afforded
3-[2-phenylamino-1,3,4-oxadiazoles]-8 and/or 6-methyl-
quinoline-4(1H)-one (9a,b), respectively. The 1H NMR
spectra of compounds 9a,b showed a singlet at d 10.55
and 10.56 ppm for NHPh proton and a broad singlet at
d 12.41 and 11.76 ppm for the NH of quinoline. On heating
1
on H NMR spectroscopy and its conversion to 6-methyl-
N-(4-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxa-
mide (7) through its thermal cyclization in refluxing diphenyl
1
ether. The H NMR spectrum of 6 revealed two singlet
signals at d 2.24 and 2.26 ppm corresponding to the two
methyl groups of tolyl groups, a triplet at d 1.39 and quartet
at 4.31ppm indicating the presence of only one ester group, a
doublet at d 8.55 indicative of the vinylic proton (Hb) adja-
cent to NH, a singlet at d 12.31 corresponding to the CONH,
and a doublet at d 10.88 ppm, indicative of the typical NH
adjacent to the vinylic proton. Also, the structural assignment
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis of New 1,3,4-Oxadiazol, Thiadiazole, 1,2,4-Triazole, and Arylidene
Hydrazide Derivatives of 4-Oxo-1,4-dihydroquinoline with Antimicrobial Evaluation
E3
of 8a,b with 2N NaOH in ethanol, they underwent smooth
cyclization through dehydration to afford (4,5-dihydro-4-
phenyl-5-thioxo-1H-1,2,4-triazol-3-yl)-8-methylquinolin-4
(1H)-one and/or (4,5-dihydro-4-phenyl-5-thioxo-1H-1,2,4-
triazol-3-yl)-6-methylquinolin-4(1H)-one (10a,b),
the corresponding arylidene carbohydrazide derivatives
15a–d. In the 1H NMR and 13C NMR spectra of
compounds 15a–d, the signals corresponding to benzylidene
group were observed at aromatic region, whereas the signals
of the –NH2 disappeared. Additionally, the 1H NMR spectra
confirmed the presence of N═CH proton in the range d 8.67–
8.80 ppm, besides the increase of aromatic protons as a result
of the insertion of aryl group of the appropriate aldehydes at
the range d 7.42–8.51 ppm. The signal corresponding to the
amide proton became downfield at the range d 13.17–
13.35 ppm (Scheme 3).
Antimicrobial activity. The synthesized compounds were
evaluated for their antimicrobial action against three different
bacterial species, namely, Pseudomonas sp. (Gram-negative
bacterium), Bacillus subtilis (Gram-positive bacterium), and
Streptomyces sp. (one of the important actinomycetes). All
the tested compounds exhibited different degrees of
antibacterial activities or inhibitory actions. The most
susceptible organisms were the two Gram-positive and
Gram-negative bacteria (B. subtilis and Pseudomonas sp.)
followed by Streptomyces sp., whereas the lowest inhibitory
effect was encountered in the case of Pseudomonas sp. The
highest degrees of inhibition were recorded for compounds
9a, 11b, and 14a followed by 8a, 9b, 11a, 12b, 14b, and
15c, whereas the lowest degree of inhibition was recorded
for 4a, 4b, 8b, 10a, 10b, and 12a (Table 1).
1
respectively. Their H NMR spectra showed a singlet at
d 11.05–12.97 ppm for the NH groups. 3-[5-Phenylamino-
1,3,4-thiadiazole]-8-methylquinoline-4(1H)-one and/or
3-[5-phenylamino-1,3,4-thiadiazole]-6-methylquinoline-
4(1H)-one (11a,b) were obtained by cyclization of 8a,b
after its treatment with cold concentrated H2SO4. The IR
data of compounds 11a,b showed carbonyl frequencies at
1631–1635 cmꢀ1 and a broad NH absorption in the region
1
3336–3366 cmꢀ1. Their H NMR spectra showed broad
singlets at d 10.65 and 10.66 ppm corresponding to the
NHPh proton (Scheme 2).
Reaction of the hydrazides 4a,b with CS2 in alcoholic
KOH at reflux temperature afforded the corresponding sub-
stituted oxadiazole derivatives 12a,b. The 1H NMR spectra
showed a broad singlet at d 11.68–13.49 ppm for the NH
groups. Treatment of the acid hydrazides 4a,b with CS2
in the presence of alc. KOH solution at room temperature
gave the crude potassium salts 13a,b. Their cyclization
upon treatment with equivalent amount of N2H4.H2O at
reflux temperature afforded 3-(4-amino-5-thioxo-4,5-dihy-
dro-1H-1,2,4-triazol-3-yl)-8-methylquinolin-4(1H)-one and/
or 3-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-
6-methylquinolin-4(1H)-one (14a,b) after neutralization by
3N HCl. The 1H NMR spectra of the substituted 1,2,4-tria-
zoles 14a,b showed broad singlets at d 5.80 and 5.90 ppm
corresponding to the NH2 and a singlet at d 10.68–13.58 ppm
for the NH groups. Also, the acid hydrazides 4a,b were
condensed with different aldehydes under reflux to afford
EXPERIMENTAL
Melting points were recorded using Kofter block instrument.
TLC was performed on plastic plates Silica Gel 60F254
(E. Merck, Darmstadt, Germany; layer thickness 0.2 mm). NMR
spectra were recorded on a Bruker AC 250 FT NMR spectrometer
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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F. A. El-Essawy and W. A. El-Sayed
Vol 50
Scheme 3
Madison, WI). Mass spectra were measured on a Kratos 50 TC
spectrometer (Kratos, Manchester, UK). The microanalyses were
performed at the microanalytical unit, Cairo University, Egypt,
and were found to agree favorably with the calculated values. Anti-
microbial activity of the synthesized compounds was evaluated at
the Botany Department, Faculty of Science, Menoufia University,
Shebin El-Koam, Egypt.
General procedure for the synthesis of compounds 3a,b. A
suspension of methylenemalonates 2a,b (1.11 g, 4 mmol) in diphenyl
ether (10 mL) was heated in an oil bath for 5–10 min at 220–250ꢁC
using a short air condenser to remove the liberated ethanol. After
cooling, the reaction mixture was digested with diethyl ether, and the
obtained precipitate was filtered, washed with diethyl ether, and
recrystallized from ethanol to give compounds 3a,b.
Ethyl 8-methyl-4-oxo-1,4-dihydroquinolin-3-carboxylate (3a).
White crystal (0.84 g, 90%). mp 259–260ꢁC; IR (KBr) n: 3246 (NH),
1726 (C═O), 1644 (C═O) cmꢀ1. 1H NMR (DMSO-d6, 300 MHz): d
1.28 (t, J=7.2Hz, 3H, CH3CH2O), 2.21 (s, 3H, CH3), 4.22 (q,
J= 7.2 Hz, 2H, CH3CH2O), 7.30 (t, J= 7.2 Hz, 1H, ArH-6), 7.55 (d,
J= 6.0 Hz, 1H, ArH-7), 8.03 (d, J= 6.9 Hz, 1H, ArH-5), 8.39 (s, 1H,
ArH-2), 11.62 (bs, 1H, NH). 13C NMR (DMSO-d6, 75MHz): d
15.25 (CH3CH2O), 19.82 (CH3), 60.57 (OCH2CH3), 110.16, 124.54,
125.23, 127.09, 128.41, 134.21, 138.34, 145.45 (C–Ar), 165.67,
174.5 (2 CO). MS m/z (I, %): 231 (M+, 45), 185 (100), 159 (10),
129 (41). Anal. Calcd for C13H13NO3: C, 67.52; H 5.67; N 6.06.
Table 1
Antimicrobial activity of the tested compounds.
Compound
Bacillus
subtilis
Pseudomonas
aeruginosa
Streptomyces
sp.
4a
4b
8a
8b
9a
9b
10a
10b
11a
11b
12a
12b
14a
14b
15c
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
+
+
ꢀ
+++
ꢀ
++
ꢀ
++++
+++
ꢀ
+++
+
+
ꢀ
ꢀ
ꢀ
+
++
ꢀ
ꢀ
+++
++++
ꢀ
++
+++
ꢀ
+
+++
++++
+++
++
ꢀ
++
+++
+
+
+
+
ꢀ
ꢀ No antimicrobial effect; + low antimicrobial effect (4mm); ++ moderate
antimicrobial effect (8–10mm); +++ high antimicrobial effect (12–18 mm);
++++ potent antimicrobial effect (20–22mm).
Found: C 67.61; H 5.72; N 6.12.
Ethyl 6-methyl-4-oxo-1,4-dihydroquinolin-3-carboxylate (3b).
(Bruker UK, Coventry) at 300MHz for 1H NMR and at 75.5 and
62.5MHz for 13C NMR with TMS as an internal standard. IR spec-
tra were recorded on a Nicolet FTIR spectrophotometer (Nicolet,
White crystals (0.74 g, 80%). mp 268–270ꢁC; IR (KBr) n: 3152–2981
1
(OH/NH), 1724 (C═O), 1641 (C═O) cmꢀ1. H NMR (DMSO-d6,
300 MHz): d 1.27 (t, J = 7.2 Hz, 3H, CH3CH2O), 2.23 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis of New 1,3,4-Oxadiazol, Thiadiazole, 1,2,4-Triazole, and Arylidene
Hydrazide Derivatives of 4-Oxo-1,4-dihydroquinoline with Antimicrobial Evaluation
E5
CH3), 4.21 (q, J = 7.2 Hz, 2H, CH3CH2O), 7.52 (m, 2H, ArH-7,8),
7.95 (s, 1H, ArH-5), 8.49 (s, 1H, ArH-2), 12.20 (bs, 1H, NH). 13C
NMR (DMSO-d6, 75MHz): d 16.12 (CH3CH2O), 19.08 (CH3),
62.07(OCH2CH3), 112.12, 125.12, 126.24, 129.55, 129.94,
136.31, 139.24, 147.56 (C–Ar), 168.04, 174.5 (2 CO). MS m/z
(I, %): 231 (M+, 42), 186 (100), 159 (30); Anal. Calcd for
C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.56; H,
5.55; N, 5.98.
compound 7 (0.85 g, 73%). mp 220–222ꢁC; IR (KBr) n:
1
3315–3264 (NH), 1661 (C═O), 1640 (C═O) cmꢀ1. H NMR
(DMSO-d6, 300 MHz): d 2.24 (s, 3H, p-CH3), 2.29 (s, 3H,
CH3), 7.16 (d, J = 8.1 Hz, 2H, ArH-30,50), 7.21 (d, 2H,
J = 8.1 Hz, H–Ar-20,60), 7.44 (m, 2H, ArH-7,8), 8.11 (s, 1H,
ArH-5), 8.81 (s, 1H, ArH-2), 12.43 (s, 1H, CONH), 12.93
(bs, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): d 21.13, 21.25
(2 CH3), 116.09, 118.58, 120.85, 121.33, 123.55, 126.22,
130.66, 135.07, 136.33, 136.78, 138.66, 139.36, 140.43,
163.17 (C–Ar), 165.51, 170.89 (2 CO). MS m/z (I, %): 292
(M+, 60), 277 (100), 185 (30), 158 (20), 143 (15). Anal.
Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C,
73.98; H, 5.64; N, 9.67.
General procedure for the synthesis of compounds 8a,b. To a
solution of acid hydrazides 4a,b (2.17 g, 10 mmol) in absolute
ethanol (15 mL), phenyl isothocyanate (1.35 g, 10mmol) was
added. The reaction mixture was heated under reflux for 3–5 h.
The product that separated on cooling was filtered off, washed
with ethanol, and dried well to afford thiosemicarbazides 8a,b,
which were recrystallized from methanol.
General procedure for the synthesis of compounds 4a,b. A
mixture of quinolone esters 3a,b (1.50 g, 6.5 mmol) and
N2H4ꢂH2O (1.25 g, 25 mmol) in ethanol (20 mL) was heated
under reflux for 4–6 h. The excess of ethanol was removed
under reduced pressure, and the resulting precipitate was filtered
off, washed with ethanol, and recrystallized from DMF.
8-Methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (4a).
White crystals (1.28 g, 91%). mp >330ꢁC; IR (KBr) n: 3295–3067
1
(NHNH2), 1667 (C═O), 1644 (C═O) cmꢀ1. H NMR (DMSO-d6,
300 MHz): d 2.28 (s, 3H, CH3), 4.58 (bs, 2H, NH2), 7.34–7.39 (m,
1H, ArH-6), 7.60–762 (m, 1H, ArH-7), 8.11–814 (d, J= 7.8 Hz, 1H,
ArH-5), 8.60 (s, 1H, ArH-2), 10.68 (s, 1H, CONH), 11.97 (bs, 1H,
NH). 13C NMR (DMSO-d6, 75MHz): d 19.51 (CH3), 114.77, 122.44,
124.98, 125.15, 126.42, 131.66, 137.33 143.18 (ArC), 165.77, 175.61
(2 CO). MS m/z (I, %): 217 (M+, 100), 202 (30), 188(10), 161 (15);
Anal. Calcd for C11H11N3O2: C, 60.82; H, 5.10; N, 19.34. Found: C,
60.87; H, 5.18; N, 19.45.
6-Methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (4b).
White crystals (1.14 g, 81%). mp >300ꢁC; IR (KBr) n: 3316–3043
(NHNH2), 1669 (C═O), 1642 (C═O). 1H NMR (DMSO-d6,
300 MHz): d 2.24 (s, 3H, CH3), 4.56 (bs, 2H, NH2), 7.59 (m, 2H,
ArH-7,8), 8.04 (s, 1H, ArH-5), 8.68 (s, 1H, ArH-2), 10.74 (s, 1H,
CONH), 12.13 (bs, 1H, NH). MS m/z (I, %): 217 (M+, 100), 202 (18),
188 (21), 161 (33), 131 (50). Anal. Calcd for C11H11N3O2: C, 60.82;
H, 5.10; N, 19.34. Found: C, 60.64; H, 5.16; N, 19.52.
Ethyl (3-[(4-methylphenyl)amino]-2-{[(4-methylphenyl)amino]-
carbonyl}acrylate (6). A mixture of p-toluidine (0.54 g, 5 mmol)
and EMME (1.18 g, 5.5 mmol) was refluxed for 7 h in glacial acetic
acid (30 mL). The solvent was removed under reduced pressure,
and the residue was co-evaporated with anhydrous toluene
(3 ꢃ 10 mL). The residue was triturated with diethyl ether (30 mL),
and the separated solid product was collected by filtration, dried,
and recrystallized from ethanol to afford the pale yellow crystals of
6 (1.45 g, 85%). mp 139–140ꢁC; IR (KBr) n: 3289–3150 (NH),
1726 (C═O), 1641 (C═O) cmꢀ1. 1H NMR (DMSO-d6, 300MHz):
d 1.39 (t, J= 7.1 Hz, 3H, OCH2CH3), 2.24 (s, 3H, CH3), 2.26 (s,
3H, CH3), 4.31 (q, J= 7.1 Hz, 2H, OCH2CH3), 7.06 (d, J=8.5Hz,
2H, ArH-3,5), 7.27 (d, J= 8.2 HZ, 2H, ArH-30,50), 7.51 (d,
J= 8.5 Hz, 2H, ArH-2,6), 8.55 (d, J= 8.2 Hz, 2H, ArH-20,60), 10.88
(s, 1H, CONH), 12.31 (bs, 1H, NH). 13C NMR (DMSO-d6,
75 MHz): d 12.89 (CH3CH2), 19.21, 19.81 (2 CH3), 49.51
(CH2CH3), 116.18, 120.55, 120.91, 124.61, 125.20, 132.13,
135.19, 137.09, 138.51, 140.12, 141.83, 142.44, 143.55, 163.89
(C–Ar), 165.51, 177.54 (2 CO). MS m/z (I, %): 338 (M+, 5), 232
(60), 186 (80), 187 (25), 107 (100). Anal. Calcd for C20H22N2O3:
C, 70.99; H, 6.55; N, 8.28. Found: C, 71.08; H, 6.71; N, 8.33.
6-Methyl-N-(4-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-
carboxamide (7). A suspension of compound 6 (1.35 g,
4 mmol) in diphenyl ether (10 mL) was heated in an oil bath
for 5–10 min at 220–250ꢁC using a short air condenser to
remove the liberated ethanol. After cooling, the reaction
mixture was digested with diethyl ether; the obtained
precipitate was filtered, washed with diethyl ether, and
recrystallized from methanol to afford a white crystal of
2-[(8-Methyl-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]-N-phenyl
thiosemicarbazide (8a). White crystals (3.11 g, 88%). mp 220–
222ꢁC; IR (KBr) n: 3316–3225 (NH), 1660 (C═O), 1641 (C═O),
1193 (C═S) cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 2.54
.
(s, 3H, CH3), 6.54–6.91 (m, 3H, ArH), 7.55–7.92 (m, 4H, ArH),
8.41 (m, 2H, ArH), 9.45 (bs, 1H, PhNH), 9.71 (bs, 1H, CSNH),
10.65 (bs, 1H, CONH), 12.12 (bs, 1H, NH). 13C NMR (DMSO-
d6, 75MHz): d 21.03 (CH3), 109.08, 118.56, 118.99, 121.32,
122.36, 124.08, 130.89, 134.66, 135.15, 135.91, 136.04, 137.18,
139.41, 159.43 (C–Ar), 166.03, 175.05 (2 CO), 181.33 (C═S).
MS m/z (I, %): 353 (M+, 10), 352 (M+, 5), 217 (45), 186 (41),
135 (96), 103 (32), 51 (100). Anal. Calcd for C18H16N4O2S: C,
61.35; H, 4.58; N, 15.90. Found: C, 61.44; H, 4.66; N, 15.97
2-[(6-Methyl-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]-N-phenyl
thiosemicarbazide (8b). White crystals (3.14 g, 89%). mp 238–240ꢁC;
IR (KBr) n: 267–3169 (NH), 1661 (C═O), 1640 (C═O), 1153 (C═S)
1
cmꢀ1. H NMR (DMSO-d6, 300MHz): d 2.50 (s, 3H, CH3), 6.53–
6.91 (m, 3H, ArH), 7.55–7.92 (m, 4H, ArH), 8.40 (m, 2H, ArH), 9.60
(bs, 1H, PhNH), 9.83 (bs, 1H, CSNH), 10.65 (bs, 1H, CONH), 12.63
(bs, 1H, NH). MS m/z (I, %): 352 (M+, 3), 217 (42), 185 (36), 136
(13), 93 (45), 50 (100). Anal. Calcd for C18H16N4O2S: C, 61.35; H,
4.58; N, 15.90. Found: C, 61.51; H, 4.62; N, 15.95.
General procedure for the synthesis of compounds 9a,b. A
suspension of thiosemicarbazides 8a,b (1.41 g, 4 mmol) in
absolute ethanol (50 mL) was dissolved in 5N aqueous NaOH
with cooling and stirring, resulting in the formation of a clear
solution. To this, 5% I2 in KI solution was added dropwise with
stirring till the color of iodine persisted at room temperature. The
reaction mixture was then refluxed for 7 h on water bath. It was
then concentrated and cooled, and the solid separated out was
filtered, dried, and recrystallized with methanol to afford the
oxadiazole derivatives 9a,b.
3-[2-Phenylamino-1,3,4-oxadiazoles]-8-methylquinoline-4(1H)-
one (9a). Pale yellow powder (1.17 g, 92%). mp 270–272ꢁC; IR
1
(KBr) n: 3211 (NH), 1638 (C═O), 1608 (C═N) cmꢀ1. H NMR
(DMSO-d6, 300 MHz): d 2.32 (s, 3H, CH3), 6.99 (t, J= 7.4 Hz, 1H,
Ar–H), 7.31–7.54 (m, 5H, Ar–H), 7.59 (m, 1H, Ar–H), 8.10
(d, J= 8.1 Hz, 1H, ArH), 8.38 (s, 1H, ArH-2), 10.55 (s, 1H, NHPh),
11.76 (bs, 1H, NH). 13C NMR (DMSO-d6, 75MHz): d 19.89 (CH3),
105.26, 116.08, 116.73, 121.09, 121.44, 123.20, 124.04, 126.90,
128.86, 128.99, 133.10, 134.15, 138.85, 140.37, (C–Ar), 165.50
(oxadiazolyl C-5), 168.55 (oxadiazolyl C-2), 174.22 (CO). MS m/z
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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F. A. El-Essawy and W. A. El-Sayed
Vol 50
(I, %): 319 (M+ + 1, 25), 318 (M+, 98), 317 (31), 262 (3), 186 (28), 184
(51), 118 (26), 77 (100). Anal. Calcd for C18H14N4O2: C, 67.91; H,
4.43; N, 17.60. Found: C, 67.99; H, 4.71; N, 17.75.
MS m/z (I, %): 334 (M+, 12), 332 (36), 159 (100). Anal. Calcd for
C18H14N4OS: C, 64.65; H, 4.22; N, 16.75. Found: C, 64.77; H,
4.50; N, 16.81.
3-[2-Phenylamino-1,3,4-oxadiazoles]-6-methylquinoline-4(1H)-
3-[5-Phenylamino-1,3,4-thiadiazole]-6-methylquinoline-4(1H)-
one (11b). Yellow crystal (1.17 g, 70%). mp >300ꢁC; IR (KBr) n:
3366 (NH), 1635 (C═O), 1604 (C═N) cmꢀ1. 1H NMR (DMSO-d6,
300 MHz): d 2.30 (s, 3H, CH3), 7.37–7.56 (m, 4H, Ar–H), 7.62–
7.86 (m, 3H, Ar–H), 8.05 (s, 1H, ArH-5), 8.88 (s, 1H, ArH-2),
10.66 (bs, 1H, NHPh), 12.79 (bs, 1H, NH). 13C NMR (DMSO-d6,
75MHz): d 20.60 (CH3), 107.18, 112.39, 123.22, 123.21 125.40,
125.86, 126.09, 129.55, 128.45, 128.79, 133.33, 138.07, 139.16,
146.55 (C–Ar), 160.31 (thiadiazolyl C-2), 169.89 (thiadiazolyl
C-5), 174.60 (CO). MS m/z (I, %): 334 (M+, 30), 243 (25), 210
(26), 159 (100). Anal. Calcd for C18H14N4OS: C, 64.65; H, 4.22;
N, 16.75. Found: C, 64.69; H, 4.31; N, 16.55.
one (9b). Pale yellow powder (1.10 g, 85%). mp 240–243ꢁC; IR
1
(KBr) n: 3212 (NH), 1635 (C═O), 1610 (C═N) cmꢀ1. H NMR
(DMSO-d6, 300MHz): d 2.28 (s, 3H, CH3), 6.99 (m, 1H, Ar–H),
7.32–7.37 (m, 2H, ArH), 7.57–7.63 (m, 4H, ArH), 8.01 (s, 1H,
ArH), 8.50 (s, 1H, ArH), 10.56 (s, 1H, NHPh), 12.41 (bs, 1H,
NH). 13C NMR (DMSO-d6, 75MHz): d 19.75 (CH3), 104.06,
116.78, 116.12, 121.01, 121.31, 123.19, 123.54, 126.71, 128.43,
128.78, 132.65, 134.20, 137.81, 139.85, 163.15 (Ar + oxadiazolyl
C-5), 165.71 (oxadiazolyl C-2), 173.61 (CO). MS m/z (I, %): 319
(M+ + 1, 22), 318 (M+, 98), 184 (54), 118 (20), 77 (100). Anal.
Calcd for C18H14N4O2: C, 67.91; H, 4.43; N, 17.60. Found: C,
67.88; H, 4.31; N, 17.38.
General procedure for the synthesis of compounds 10a,b. A
suspension of thiosemicarbazides 8a,b (1.76 g, 5 mmol) in
absolute ethanol (50mL) was dissolved in 2N NaOH resulting in
the formation of a clear solution. The reaction mixture was
refluxed for 6 h on water bath, concentrated, cooled, and filtered.
The pH of the filtrate was adjusted at 5–6 with AcOH and kept
aside for 1–2 h. The solid separated out was filtered, washed with
water, dried, and recrystallized with methanol to give the 1,2,4-
triazole derivatives 10a,b.
General procedure for the synthesis of compounds 12a,b. A
mixture of acid hydrazides 4a,b (2.17 g, 10 mmol) and CS2
(0.6mL, 10 mmol) was added to a solution of KOH (0.56 g,
10mmol) in H2O (50 mL) and ethanol (50mL). The reaction
mixture was heated under reflux for 6 h. After evaporating the
reaction to dryness in vacuo, a solid was obtained, which was
then dissolved in H2O (50mL) and acidified with concentrated
HCl. The precipitate was filtered off, washed with H2O, and
recrystallized from methanol to afford the oxadiazole derivatives
12a,b.
3-(4,5-Dihydro-4-phenyl-5-thioxo-1H-1,2,4-triazol-3-yl)-8-
methylquinolin-4(1H)-one (10a). Yellow powder (1.59 g, 95%).
mp 202–203ꢁC; IR (KBr) n: 3485–3318 (NH), 1639 (C═O), 1605
3-(4,5-Dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)-8-methylquinolin-
4(1H)-one (12b). White crystal (1.74 g, 67%). mp 160–163ꢁC; IR
1
(KBr) n: 3424–3254 (NH), 1641 (C═O), 1609 (C═N) cmꢀ1. H
(C═N) cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 2.29 (s, 3H,
.
NMR (DMSO-d6, 300MHz):
d 2.26 (s, 3H, CH3), 7.35
CH3), 7.19 (m, 1H, ArH), 7.30–7.36 (m, 3H, ArH), 7.51 (d,
J = 7.5Hz, 1H, ArH), 7.74 (m, 2H, ArH), 7.81 (d, J = 7.5 Hz, 1H,
ArH), 8.47 (s, 1H, ArH), 11.05 (bs, 1H, NH), 12.97 (bs, 1H, NH).
13C NMR (DMSO-d6, 75MHz): d 19.19 (CH3), 107.19, 122.81,
123.73, 125.26, 126.79, 127.79, 128.27, 128.86, 129.05, 133.05,
134.49, 137.99, 141.61, 141.86 (ArC), 166.48 (triazolyl C-2),
174.02 (C═O), 181.05 (C═S). MS m/z (I, %): 335 (M+ +1, 29),
334 (M+, 46), 333 (26), 185 (20), 184 (20), 149 (26), 103 (51), 51
(100). Anal. Calcd for C18H14N4OS: C, 64.65; H, 4.22; N, 16.75.
Found: C, 64.43; H, 4.13; N, 16.58.
(t, J = 7.5 Hz, 1H, ArH-6), 7.60 (d, J =6.9 Hz, 1H, ArH-7), 8.04
(d, J = 7.5Hz, 1H, ArH-5), 8.31 (s, 1H, ArH-2), 11.88 (bs, 1H,
NH), 13.18 (bs, 1H, NH). MS m/z (I, %): 260 (M+ + 1, 15), 259
(M+, 36), 186 (100). Anal. Calcd for C12H9N3O2S: C 55.59; H
3.50; N, 16.21. Found: C, 55.64; H, 3.62; N, 16.31.
3-(4,5-Dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)-6-methylquinolin-
4(1H)-one (12a). White crystal (2.20 g, 85%). mp 139–141ꢁC; IR
1
(KBr) n: 3431–3081 (NH), 1639 (C═O), 1605 (C═N) cmꢀ1. H
NMR (DMSO-d6, 300MHz): d 2.31 (s, 3H, CH3), 7.53–7.67 (m,
2H, ArH-6,7), 7.97 (s, 1H, ArH-5), 8.49 (s, 1H, ArH-2), 11.68
(bs, 1H, NH), 13.49 (bs, 1H, SH). 13C NMR (DMSO-d6,
75MHz): d 19.23 (CH3), 105.05, 117.64, 123.55, 125.93, 133.78,
134.44, 136.97, 141.12 (C–Ar), 159.20 (oxadiazolyl C-2), 171.65
(CO), 180.16 (C═S). MS m/z (I, %): 260 (M+ + 1), 259 (M+, 33)
186 (70), 88 (55), 77 (100). Anal. Calcd for C12H9N3O2S: C,
55.59; H, 3.50; N, 16.21. Found: C, 55.63; H, 3.57; N, 16.09.
General procedure for the synthesis of compounds 14a,b.
Potassium hydroxide (0.84 g, 15 mmol) in absolute ethanol
(10 mL) and acid hydrazides 4a,b (2.17 g, 10mmol) were mixed
together until the solution became clear. To the clear solution, CS2
(1.32 g, 30 mmol) was added. The solution was stirred for 3 h at
25ꢁC, and then diethyl ether (30 mL) was added to form a
precipitate. The precipitate was mixed with N2H4ꢂH2O (1.6 g,
32mmol) and H2O (1mL). The solution was refluxed for 2 h until
the color of the solution became clear green. After cooling to
room temperature, ice water (10mL) was added to the reaction
mixture, which was then neutralized with 3N HCl to form a
precipitate. The precipitate was isolated by filtration and purified
by recrystallization from methanol to afford the triazole
derivatives 14a,b.
3-(4,5-Dihydro-4-phenyl-5-thioxo-1H-1,2,4-triazol-3-yl)-6-
methylquinolin-4(1H)-one (10b). Yellow powder (1.50 g, 90%).
mp 292–293ꢁC; IR (KBr) n: 3436–3300 (NH), 1641 (C═O), 1610
(C═N) cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 2.29 (s, 3H,
.
CH3), 7.24–7.38 (m, 4H, ArH), 7.42 (m, 1H, ArH), 7.46–7.58 (m,
2H, ArH), 7.73 (1H, s, ArH-5), 8.24 (1H, s, ArH-2), 11.26 (bs,
1H, NH), 12.96 (bs, 1H, NH). MS m/z (I, %): 334 (M+, 55), 185
(43), 149 (25), 125 (23), 103 (55), 51 (100). Anal. Calcd for
C18H14N4OS: C, 64.65; H, 4.22; N, 16.75. Found: C, 64.71; H
4.41; N, 16.61.
General procedure for the synthesis of compounds 11a,b. The
thiosemicarbazides 8a,b (1.76 g, 5 mmol) was added gradually with
stirring to cooled concentrated H2SO4 (10 mL) during 10 min. The
mixture was further stirred for another 5 h in an ice bath. It was
then poured over crushed ice with stirring. The solid separated out
was filtered, washed with water, dried, and recrystallized from
methanol to afford the thiadiazole derivatives 11a,b.
3-[5-Phenylamino-1,3,4-thiadiazole]-8-methylquinoline-4(1H)-
one (11a). Yellow crystal (1.47 g, 88%). mp >300ꢁC; IR (KBr)
1
n: 3336–3353 (NH), 1631 (C═O), 1607 (C═N) cmꢀ1. H NMR
(DMSO-d6, 300MHz): d 2.24 (s, 3H, CH3), 7.42–7.59 (m, 4H,
Ar–H), 7.68–7.94 (m, 3H, Ar–H), 8.10–8.15 (m, 1H, ArH-5),
8.83 (s, 1H, ArH-2), 10.65 (bs, 1H, NHPh), 12.18 (bs, 1H, NH).
3-(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-8-
methylquinolin-4(1H)-one (14a). Pale yellow crystals (1.99 g, 73%).
mp 165–168ꢁC; IR (KBr) n: 3422–3154 (NH, NH2), 1637 (C═O),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis of New 1,3,4-Oxadiazol, Thiadiazole, 1,2,4-Triazole, and Arylidene
Hydrazide Derivatives of 4-Oxo-1,4-dihydroquinoline with Antimicrobial Evaluation
E7
1608 (C═N) cmꢀ1. 1H NMR (DMSO-d6, 300 MHz): d 2.25 (s, 3H,
CH3), 5.80 (bs, 2H, NH2), 7.33–7.39 (m, 1H, Ar–H6), 6.61 (d,
J= 7.5 Hz, 1H, ArH-7), 8.12 (d, J= 7.5 Hz, 1H, ArH-5), 8.59 (s,
1H, ArH-2), 10.68 (bs, 1H, NH), 12.57 (bs, 1H, NH). 13C NMR
(DMSO-d6, 75MHz): d 19.15 (CH3), 116.81, 122.13, 125.22,
126.30, 128.19, 133.14, 140.10, 141.32 (C–Ar), 160.15 (triazolyl
C-2), 175.08 (CO), 180.14 (C═S). MS m/z (I, %): 273 (M+, 12),
217 (45), 186 (100). Anal. Calcd for C12H11N5OS: C, 52.73; H,
4.06; N, 25.62. Found: C, 52.61; H, 3.98; N, 25.51.
N0-(4-Methoxybenzylidene)-6-methyl-4-oxo-1,4-dihydro-
quinoline-3-carbohydrazide (15d). White crystals (1.60 g, 96%).
mp: 290–291ꢁC; IR (KBr) n: 3272 (NH), 1670 (C═O),
1638 (C═O) cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 2.24
.
(s, 3H, CH3), 3.79 (s, 3H, OCH3), 6.70 (d, J = 8.6 Hz, 2H, ArH),
7.61–7.70 (m, 4H, ArH), 8.05 (m, 1H, ArH,), 8.33 (s, 1H, ArH-2),
8.78 (s, 1H, N═CH), 12.30 (bs, 1H, NH), 13.25 (s, 1H, CONH).
MS m/z (I, %): 336 (M+ + 1, 11), 335 (M+, 30), 185 (35), 158
(25), 129 (26), 115 (12), 107 (100). Anal. Calcd. For
C19H17N3O3: C, 68.05; H, 5.11; N, 12.53. Found: C, 68.10; H,
5.14; N, 12.41.
Antimicrobial testing. The inhibition zones were measured
using the agar cup diffusion technique [35]. Nutritive agar plates
seeded with the test organisms (three plates for each organism)
were allowed to solidify, and then 5-mm-diameter holes were
formed in the plates using a cork borer. Each hole was filled with
one drop of the DMF of the tested compound, whereas the hole in
the center of the plate was filled with one drop of DMF. The
plates were separately incubated at 30ꢁC for 24h. Inhibition zones
(zones with no growth) around the holes were measured.
3-(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-6-
methylquinolin-4(1H)-one (14b). Pale yellow crystals (2.18 g,
80%). mp 140–143ꢁC; IR (KBr) n: 3460–3215 (NH, NH2), 1641
1
(C═O), 1612 (C═N) cmꢀ1. H NMR (DMSO-d6, 300MHz): d
2.24 (s, 3H, CH3), 5.90 (bs, 2H, NH2), 7.34–8.61 (m, 4H, ArH),
11.40 (brs, 1H, NH), 13.58 (bs, 1H, NH). MS m/z (I, %): 274
(M+, 45), 273 (M+, 25), 218 (17), 217 (66), 186 (100). Anal.
Calcd for C12H11N5OS: C, 52.73; H, 4.06; N, 25.62. Found, %:
C, 52.78; H, 4.14; N, 25.44.
General procedure for the synthesis of compounds 15a–d. A
solution of the acid hydrazides 4a,b (1.08 g, 5 mmol) in absolute
ethanol (15 mL) was treated with appropriate aldehydes (10mmol)
in presence of a few drops of piperidine. The mixture was boiled
under reflux for 3–5 h (TLC). The excess of ethanol was removed
under reduced pressure, and the solid separated was collected by
filtration, washed with ethanol, dried, and recrystallized from
methanol to afford the arylidene derivatives 15a–d.
REFERENCES AND NOTES
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N0-Benzylidene-8-methyl-4-oxo-1,4-dihydroquinoline-3-carbo-
hydrazide (15a). White crystals (1.31 g, 86%). mp 310–313ꢁC; IR
1
(KBr) n: 3172 (NH), 1665 (C═O), 1642 (C═O) cmꢀ1; H NMR
(DMSO-d6, 300MHz): d 2.24 (s, 3H, CH3), 7.42–7.50 (m, 3H,
ArH)), 7.70–7.94 (m, 3H, (ArH)), 8.22–8.51 (m, 3H, ArH), 8.78
(s, 1H, N═CH), 12.30 (bs, 1H, NH), 13.21 (bs, 1H, NH). 13C
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125.07, 126.10, 127.13, 127.26, 128.83, 129.12, 130.31, 133.91,
134.15, 143.19, 147.90, 154.33 (C–Ar), 160.24 (C═N), 162.99,
171.33 (2 CO). MS m/z (I, %): 306 (M+ + 1, 18), 305 (M+, 55),
228 (62), 186 (100). Anal. Calcd. for C18H15N3O2: C, 70.81; H,
4.95; N, 13.76. Found: C, 70.93; H, 5.03; N, 13.81.
N0-Benzylidene-6-methyl-4-oxo-1,4-dihydroquinoline-3-carbo-
hydrazide (15b). White crystals (1.23 g, 81%). mp 323–325ꢁC; IR
1
(KBr) n: 3210 (NH), 1650 (C═O), 1641 (C═O) cmꢀ1. H NMR
(DMSO-d6, 300MHz): d 2.25 (s, 3H, CH3), 7.42–7.46 (m, 3H,
ArH), 7.61–7.77 (m, 4H, ArH), 8.15–8.41 (m, 2H, ArH), 8.80
(s, 1H, N═CH), 12.33 (bs, 1H, NH), 13.35 (bs, 1H, NH). MS m/z
(I, %): 305 (M+, 40), 228 (30), 186 (100), 158 (42), 143 (52), 131
(12). Anal. Calcd. For C18H15N3O2: C, 70.81; H, 4.95; N, 13.76.
Found: C, 70.90; H, 5.01; N, 13.45.
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N0-(4-Methoxybenzylidene)-8-methyl-4-oxo-1,4-dihydroqui-
noline-3-carbohydrazide (15c). White crystals (1.40 g, 84%).
mp >330ꢁC; IR (KBr) n: 3250 (NH), 1666 (C═O), 1642 (C═O)
[15] Amir, M.; Khan, M. S. Y.; Zaman, M. S. Ind J Chem 2004,
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1
cmꢀ1. H NMR (DMSO-d6, 300MHz): d 2.26 (s, 3H, CH3), 3.79
(s, 3H, OCH3), 6.99–7.01 (d, J= 8.6 Hz, 2H, ArH), 7.41 (m, 1H,
ArH), 7.63 (d, J= 8.7 Hz, 1H, ArH-7), 7.69 (d, J=8.6Hz, 2H,
ArH), 8.15 (d, J= 8.6Hz, 1H, ArH-5), 8.35 (s, 1H, ArH-2),
8.67 (s, 1H, N═CH), 12.15 (bs, 1H, NH), 13.17 (bs, 1H, NH).
13C NMR (DMSO-d6, 75MHz): d 21.07 (CH3), 55.67 (OCH3),
110.99, 117.22, 123.15, 126.14, 127.23, 127.76, 128.14, 128.85,
129.07, 131.63, 132.53, 141.11, 144.44, 155.09 (C–Ar), 160.14
(C═N) 166.45, 176.61 (2 CO). MS m/z (I, %): 336
(M+ + 1, 45), 335 (M+, 33), 228 (62), 185 (60), 158 (25),
103 (22), 51 (100). Anal. Calcd. For C19H17N3O3: C, 65.05;
H, 5.11; N, 12.53. Found: C, 65.13; H, 5.17; N, 12.61.
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F. A. El-Essawy and W. A. El-Sayed
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