Design and synthesis of novel quinoline derivatives bearing oxadiazole, isoxazoline, triazolothiadiazole, triazolothiadiazine, and piperazine moieties

Article abstract of DOI:10.1002/jhet.3907

A new series of 2,3-disubstituted quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2-chloroquinoline-3-carbaldehyde 1, which was transformed to 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 by reaction with 4-phenylpiperazine in DMF-containing anhydrous K₂CO₃; then, compound 2 was oxidized by iodine in methanol, and methyl 2-(4-phenylpiperazin-1-yl)quinoline-3-carboxylate 3 was synthesized. The key intermediate 4, 4-amino-5-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 6a-c, respectively. Moreover, compound 2 condensed with o-phenylenediamine to give 2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimidazole 7. Interaction of 7 and 2-chloromethyl-5-aryl-1,3,4-oxadiazoles in the presence of K₂CO₃ led to the title compounds 8a-c. Furthermore, 4,5-dihydroisoxazoline derivatives 9a-c were obtained by the reaction of readily accessible starting materials including 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2, 1-phenyl-2-(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et₃N. The hydrazone intermediates 10a-c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3-acetyl-5-aryl-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazoles 11a-c. Structures of these compounds were established by their elemental analysis, IR, ¹H NMR, and mass spectral data.

Full text of DOI:10.1002/jhet.3907

Received: 26 March 2019
DOI: 10.1002/jhet.3907
Revised: 9 January 2020
Accepted: 9 January 2020
A R T I C L E
Design and synthesis of novel quinoline derivatives bearing
oxadiazole, isoxazoline, triazolothiadiazole,
triazolothiadiazine, and piperazine moieties
Zhiren Tang | Yang Peng | Fangming Liu
College of Materials and Chemical
Abstract
Engineering, Hangzhou Normal
University, Hangzhou, China
A new series of 2,3-disubstituted quinoline derivatives were synthesized from
2-chloroquinoline-3-carbaldehyde. In the reaction sequence, acetanilide was
cyclized to give 2-chloroquinoline-3-carbaldehyde 1, which was transformed to
Correspondence
Fangming Liu, College of Materials and
Chemical Engineering, Hangzhou Normal
University, Hangzhou 311121, China.
Email: fmliu859@sohu.com
2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde
2
by reaction with
4-phenylpiperazine in DMF-containing anhydrous K2CO3; then, compound
2 was oxidized by iodine in methanol, and methyl 2-(4-phenylpiperazin-1-yl)
quinoline-3-carboxylate 3 was synthesized. The key intermediate 4, 4-amino-
5-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, was pre-
pared using the ester 3 by a series of step. Reaction of 5 with various aromatic
carboxylic acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b][1,3,4]
thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 6a-c, respectively.
Moreover, compound
2 condensed with o-phenylenediamine to give
2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimidazole 7. Interaction of
7 and 2-chloromethyl-5-aryl-1,3,4-oxadiazoles in the presence of K2CO3 led to
the title compounds 8a-c. Furthermore, 4,5-dihydroisoxazoline derivatives 9a-
c were obtained by the reaction of readily accessible starting materials includ-
ing 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2, 1-phenyl-2-(tripheny
lphosphoranylidene)ethanone and hydroximoyl chlorides under mild condi-
tions in the presence of Et3N. The hydrazone intermediates 10a-c were
obtained by the condensation of 2 with aroylhydrazides in ethanol, then,
refluxing in acetic anhydride yielded 3-acetyl-5-aryl-2-[2-(4-phenylpiperazin-
1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazoles 11a-c. Structures of these
1
compounds were established by their elemental analysis, IR, H NMR, and
mass spectral data.
1 | INTRODUCTION
structural modifications might exhibit multiple activities.
Hence, considerable interest has been created in the chemis-
The quinoline skeleton is one of the most prevalent motifs,
found in a large variety of naturally occurring compounds,
especially alkaloids and pharmacologically active sub-
stances.[1] Quinoline scaffold is versatile and capable of bind-
ing to multiple receptor targets, and consequently, its
try of quinoline derivatives because of their various thera-
peutic activities such as antiviral,[2] antimalarial,[3]
antitubercular,[4] anticancer,[5] anti-inflammatory, and
antihypertensive,[6,7] tyrokinase platelet-derived growth fac-
tor receptor tyrosine kinase (PDGF-RTK)-inhibiting agents[8]
J Heterocyclic Chem. 2020;1–9.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
TANG ET AL.
and anti-HIV.[9] On the other hand, there are much sound
reports expressing that isoxazoline, benzimidazole,
1,3,4-oxadiazole, triazolothiadiazole, and triazolothiadiazine
derivatives are vital heterocycles with a wide spectrum of
biological effects.[10–14] Meanwhile, the pharmacophore
hybridization approach for the synthesis of new chemical
entities is an effective strategy for the discovery of new drugs
since the presence of two pharmacophores in a single mole-
cule may synergize their biological effects.[15,16] Literature
survey reveals that the compounds having heterocyclic ring-
containing nitrogen and oxygen tethered with quinoline
nucleus have showed enhanced biological and pharmacolog-
ical properties on account of the molecular hybridization of
different pharmacophores.[17,18]
triazolothiadiazine, that are incorporated at the third posi-
tion of quinoline ring, with the intension to improve bio-
logical profile by combination of diverse pharmacophores
in hybrid molecules in single skeleton.
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
Synthetic strategies adopted to obtain the target com-
pounds are depicted in Scheme 1. IR, 1H NMR, and mass
spectral data are in agreement with the proposed struc-
tures of all the synthesized compounds.
In view of these observations and with a view to fur-
ther explore the pharmacological profile of this class of
compounds, we report here new type of quinoline deriva-
tives in which active pharmacophores, viz, isoxazoline,
benzimidazole, 1,3,4-oxadiazole, triazolothiadiazole, and
The 2-chloroquinoline-3-carbaldehyde 1 was chosen as
starting material to design the target compounds. Acetani-
lide was treated with DMF-POCl3 complex (Vilsmeier-Haack
reagent) to obtain the key aldehyde intermediate 1, upon
treatment with 4-phenylpiperazine in the presence of K2CO3
SCHEME 1 Synthetic pathway for the target compounds

TANG ET AL.
3
furnished 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde
2; then, compound 2 was oxidized by iodine in methanol,
and methyl 2-piperazinylquinoline-3-carboxylate 3 was syn-
thesized. The key intermediate 4, 4-amino-5-[2-(2-
piperazinyl-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, can
be achieved from compound 3 via a three-step protocol
including hydrazidation, salt formation, and cyclization in
good yield. Reaction of 4 with various aromatic carboxylic
acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b]
[1,3,4]thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]
thiadiazines 6a-c, respectively. The appearance of new
stretching bands and disappearance of characteristic peaks
for SH and NH2 in the IR spectra of 5a-c and 6a-c indicated
to form the α,β-unsaturated compound, which upon
1,3-dipolar cyclization reaction with hydroximoyl chlo-
rides in the presence of Et3N base gave the final prod-
ucts in excellent yields. The progress of the reaction
was monitored by thin-layer chromatography (TLC).
The IR spectrum of 9a exhibit C O stretching at
1678 cm−1 and C N stretching at 1604 cm−1 bands.
The 1H NMR spectrum of compound 9a is in agree-
ment with the proposed structure. Two singlets at 6.20
and 5.74 ppm readily recognized as two CH hydrogen
atoms of the isoxazoline ring. The mass spectrum of
compound 9a displays an (M+) ion peak at m/z 538 for
molecular formula C35H30N4O2, indicating formation of
4,5-dihydroisoxazoline heterocycle ring. Finally, the
structure of 9b was unambiguously confirmed by X-ray
diffraction analysis. The crystal data and structure
refinement are shown in Table 1. Selected bond lengths
and angles are listed in Table 2 and the hydrogen bond
geometry in Table 3. The crystal structure of the com-
pound 9b is shown in Figures 1, and a perspective view
of the crystal packing in the unit cell is tabulated in
Figures 2.
Condensation reaction of compound 2 with equimo-
lar amounts of aroylhydrazides in boiling ethanol
afforded N-arylidenearoylhydrazides 10a-c. In turn, the
heterocyclization of hydrazones 10a-c in the presence of
acetic anhydride afforded the desired 1,3,4-oxadiazoline
derivatives 11a-c. IR spectra of 11a-c had different char-
acteristics as they showed no N H stretching bands and
only C O bands in the 1167 to 1169 cm−1 region, which
were attributed to the C O stretching of acetyl group. 1H
NMR spectra of 11a-c showed a signal at 2.47 to 2.48 ppm
attributable to the CH3CO group and a singlet signal at
7.46 to 7.53 ppm for O CHR N of 1,3,4-oxadiazoline
ring. The mass spectrum of compound 11a exhibited a
molecular ion peak at m/z 477 (M+) that is compatible
with the formula (C29H27N5O2).
1
the formation of conjugated scaffolds. H NMR spectra of
intermediate compound 4 showed a downfield broad singlet
at 13.86 ppm (NH), whereas the NH2 group appeared as a
singlet at 5.62 ppm, which are D2O exchangeable. The
absence of signals for NH2 and NH protons confirms that
the triazole has been converted into triazolothiadiazole
derivatives 5a-c and triazolothiadiazine derivatives 6a-c. In
1
the H NMR spectra of all compounds 6a-c, the signal
because of the S CH2 protons of triazolothiadiazine ring
gave rise to a singlet peak at 5.4 to 5.42 ppm, clearly indicat-
ing that ring closure reaction occurred. All other protons
were seen at the expected chemical shifts and integral values
(see Section 4). Additionally, the mass spectrum of com-
pounds 5a and 6a displays an (M+) ion peak at m/z 489 and
503 for molecular formula C28H23N7S and C29H25N7S,
respectively, indicating formation of triazolothiadiazine and
triazolothiadiazole heterocycle ring.
Condensed
2 with o-phenylenediamine to give
2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimida
zole 7. Interaction of 7 and 2-chloromethyl-5-aryl-1,
3,4-oxadiazoles in the presence of K2CO3 led to the title
compounds 8a-c. In the IR spectra of compound
7 showed an absorption band at 3568 cm−1 assigned to
N H bond, which was absent in the spectra of com-
pounds 8a-c because of the alkylation of benzimidazole
nitrogen atom. IR spectra of compounds 8a-c also dis-
played absorption bands of C O C stretching of the
oxadiazole ring around 1108 to 1271 cm−1 and C N
3 | CONCLUSION
1
bonds at 1600 to 1605 cm−1. In the H NMR spectra of
In summary, we have reported a convenient and effi-
compound 7 showed a broad singlet at d 11.79 ppm
because of NH proton of the benzimidazole ring. In the
spectra of compounds 8a-c, such signal was not
observed. The CH2 protons of compounds 8a-c were
represented as a singlet at 5.56 ppm. The mass spec-
trum of 8a displays an (M+) ion peak at m/z 563 for
molecular formula C35H29N7O, further strengthened the
assigned structure.
cient
protocol
for
the
synthesis
of
new
2,3-disubstituted quinoline derivatives from easily
available intermediate 2-chloroquinoline-3-carbalde
hyde. The simplicity of experimental procedure,
catalyst-free conditions, and ready availability of
starting materials render this strategy as an attractive
method for the synthesis of new 2,3-disubstituted quin-
oline derivatives. Full characterization of these com-
pounds is reported. The new synthesized compounds
are interesting for their potential pharmacological and
biological activities.
The
synthesis
of
the
title
compounds
4,5-dihydroisoxazoline derivatives 9a-c involves the
reaction of the aldehyde moiety with a Wittig reagent

4
TANG ET AL.
TABLE 1 Crystal and experimental data for 9b
TABLE 2 Selected bond lengths (Å), bond angles (ꢀ), and
torsion angles (ꢀ) for compound 9b
CCDC
1 039 308
C36H32N4O3
568.66
N(1) C(9)
1.316 (3)
1.447 (2)
1.424 (3)
1.357 (2)
1.285 (2)
1.424 (3)
1.357 (2)
1.424 (2)
1.316 (3)
1.451 (3)
Empirical formula
Formula weight
Crystal system
Space group
a, Å
O(1) C(36)
O(3) C(35)
Triclinic
P-1
O(3) C(31)
C(28) N(4)
10.833 (3)
11.042 (3)
12.847 (3)
1479.7 (6)
2
O(3) C(35)
b, Å
O(3) C(31)
c, Å
V, Å3
O(1) N(4)
N(2) C(9)
Z
Dc, MgÁm−3
F(000)
1.276
N(2) C(10)
Bond angles (ꢀ)
600
C(9) N(2) C(10)
C(10) N(2) C(12)
C(9) N(1) C(4)
N(4) O(1) C(35)
C(31) O(3) C(35)
C(15) N(3) C(11)
N(1) C(9) N(2)
Torsion angles (ꢀ)
N(4) O(1) C(36) C(26)
C(35) O(3) C(31) C(30)
C(35) O(3) C(31) C(32)
C(9) N(1) C(4) C(5)
C(4) N(1) C(9) N(2)
C(10) N(2) C(9) N(1)
C(10) N(2) C(9) C(8)
C(12) N(2) C(9) C(8)
C(22) N(4) C(25) C(23)
116.44 (16)
108.56 (16)
118.86 (18)
107.95 (14)
118.28 (18)
116.09 (17)
118.83 (18)
Absorpt_coefficient μ,
0.082
mm−1
α, ꢀ
76.594
β, ꢀ
83.939
γ, ꢀ
82.545
Crystal size, mm3
0.100 × 0.100 × 0.100
296
T(K)
θ range of data collection,
ꢀ
1.90ꢀ≦ θ ≦ 27.55ꢀ
96.10 (19)
6.5 (3)
Index ranges
−13 ≦ h ≦ 13, −14 ≦ k ≦ 14,
−16 ≦ l < =16
−173.82 (19)
−178.5 (2)
−177.40 (18)
22.7 (3)
Total reflections collected
Independent reflection
Refinement method
18 756
6769
Full-matrix least-square on F2
Data/restraints/parameters
Final R indices [I > 2σ(I)]
Goodness of fit on F2
Refine method
6769 / 0 / 389
−153.04 (18)
77.1 (2)
R1 = 0.0518, wR2 = 0.1532
1.030
Full-matrix least-squares on F2
174.5 (2)
R indices (all data)
R1 = 0.0477, wR2 = 0.1405
TABLE 3 Intermolecular interactions (Å) in the compound 9b
D–Hf…A
C(20) H(20)…N(4)
D–H
0.9
H…A
2.56
2.42
D…A
D–H…A
153
4 | EXPERIMENTAL
3.421 (3)
2.931 (3)
C(26) C(23) O(1)
0.9
115
4.1 | Reagents and techniques
All chemical reagents were obtained from a commer-
cial source and used without further purification.
Melting points were recorded on an X-5 micro melt-
ing point apparatus, and temperature was
uncorrected. The IR spectra were recorded from KBr
on a Bruker Tensor 27 spectrophotometer. The 1H
NMR spectra were recorded on a Varian Inova-400
spectrophotometer using tetramethylsilane (TMS) as
a standard. Electron ionization-mass spectroscopy
(EI-MS) was recorded on an Agilent 5975 mass
selective detector. X-ray diffraction data were
obtained on a Hitachi F-4500 R-AXIS SPDER diffrac-
tometer (Hitachi, Japan). Element analyses were per-
formed on
a Perkin-Elmer 240 CHN analyzer.
2-chloroquinoline-3-carbaldehyde 1, 2-(4-phenylpiper
azin-1-yl)quinolin-3-carbaldehyde 2, 2-chloromethyl-
5-aryl-1,3,4-oxadiazole, 1-phenyl-2-(triphenylphospho
ranylidene)ethanone, and hydroximoyl chloride were
prepared using literature reported methods.[19–23]

TANG ET AL.
5
6 hours. After completion the reaction according to TLC
detection, the mixture was cooled to room temperature
and quenched with sat. aqueous Na2S2O3 (50 mL). The
resulted solid was collected by filtration and washed with
water, then dried under vacuum to afford compound 3.
The crude product was characterized and was pure
enough for further use.
Yellow solid; yield: 86%; mp: 168ꢀC to 170ꢀC; IR
(KBr): νmax: 3058, 2978 (CH), 1736 (C O), 1589
1
(C N) cm−1; H NMR (CDCl3): 3.46 (t, J = 4.8 Hz, 4H,
CH2 N); 3.53 (t, J = 4.8 Hz, 4H, CH2 N),3.95 (s, 3H,
OCH3), 8.15-7.75(m, 9H, ArH), 8.31 (s, 1H, quinoline-H4)
ppm; MS (EI): m/z 347 (M+); anal. calcd. for
C21H21N3O2: C, 72.62; H, 6.05; N, 12.10; found: C,
72.58; H, 6.13; N, 12.03.
FIGURE 1 The structure of crystal 9b
4.1.2 | Synthesis and analytical data of
4-amino-5-[2-(4-phenylpiperazin-1-yl)
quinolin-3-yl]-4H-1,2,4-triazole-3-thiol 4
To
an
ethanolic
solution
of
methyl
2-(4-phenylpiperazin-1-yl)quinoline-3-carboxylate 3 (10,
mmol), hydrazine hydrate (98%) (30 mmol) was added,
and the mixture was refluxed for 3 hours. After comple-
tion of the reaction, the mixture was cooled to room
temperature, and precipitate was filtered and dried to
give the arylhydrazide product. To a solution of KOH
(15 mmol) in absolute ethanol (30 mL), the
arylhydrazide (10 mmol) was added. Then, to this
stirred solution, CS2 (15 mmol) was added dropwise,
and the reaction mixture was left overnight at room
temperature, then 15 mL of anhydrous ether was added.
The solid product of potassium dithiocarbazinate was
filtered, washed with chilled ethanol, and dried. It was
directly used for next step without purification. The
above potassium dithiocarbazinate was taken in water
(10 mL) and hydrazine hydrate (4 mL, 85%, 11 mmol)
and refluxed for 4 to 5 hours. Upon completion, the
mixture was poured into cold water (150 mL) and acidi-
fied to pH = 3-5 by slow addition of 1M HCl. The
white precipitated solid was filtered, washed with cold
water, and recrystallized from DMF/ethanol to give
compound 4.
FIGURE 2 The molecular packing of crystal 9b
Off-white solid; yield: 63%; mp: 220ꢀC to 225ꢀC; IR
(KBr): νmax: 3464, 3387 (NH2, NH), 3046, 2984 (CH),
4.1.1 | Procedure for synthesis of methyl
2-(4-phenylpiperazin-1-yl)quinoline-
3-carboxylate 3
2578 (SH), 1603 (C N) cm−1 1H NMR (DMSO-d6):
;
13.86 (s, 1H, SH), 8.28 (s, 1H, quinoline-H4), 8.05-7.75
(m, 9H, ArH), 5.62 (s, 2H, NH2)，3.47 (t, J = 4.8 Hz,
4H, CH2 N); 3.56 (t, J = 4.8 Hz, 4H, CH2 N) ppm;
MS (EI): m/z 403 (M+); anal. calcd. for C21H21N7S: C,
62.57; H, 5.23; N, 24.32; found: C, 62.49; H,
5.21; N, 24.38.
In a round bottom flask, 2-(4-phenylpiperazin-1-yl)
quinolin-3-carbaldehyde 2 (20 mmol), I2 (50 mmol),
methanol (40 mL), and K2CO3 (50 mmol) were added.
The suspension was heated to reflux with stirring for 5 to

6
TANG ET AL.
4.1.3 | Synthetic procedure and
analytical data of 6-substituted-
3-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5a-c)
containing DMF (10 + 1 mL), and the resulting mixture
was heated under reflux for about 5 to 6 hours. Upon
completion, the mixture was poured into crushed ice and
neutralized with sodium bicarbonate. Solid product
obtained was filtered, washed with water, dried, and rec-
rystallized from DMF/ethanol to afford conjugated prod-
ucts 6a-c.
A mixture of 4-amino-5-[2-(4-phenylpiperazinyl)quinolin-
3-yl]-1,2,4-triazole-3-thiol 4 (1 mmol) and substituted aro-
matic acids (1.1 mmol) in POCl3 (5 mL) was refluxed for
6 to 7 hours. The reaction mixture was slowly poured into
crushed ice with stirring and neutralized with sodium
bicarbonate. Solid material was filtered, washed with cold
water, dried, and recrystallized from DMF/ethanol to
afford 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 5a-c.
6-Phenyl-3-[2-(4-phenylpiperazin-1-yl)lquinolin-3-yl]-
7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (6a)
Light yellow solid; yield: 67%; mp: 270ꢀC to 272ꢀC; IR
(KBr): νmax: 3013(Ar H), 2946 (CH2), 1613 (C N)
1
cm−1; H NMR (DMSO-d6): 8.28 (s, 1H, quinoline-H4),
7.80-8.25(m, 14H, Ar H), 5.42 (s, 2H, SCH2), 3.67(t,
J = 4.8 Hz, 4H, CH2 N); 3.42 (t, J = 4.8 Hz, 4H,
CH2 N) ppm; MS (EI): m/z 503 (M+); anal. calcd. for
C29H25N7S: C, 69.18; H, 4.97; N, 19.48; found: C,
69.21; H, 4.92; N, 19.53.
6-Phenyl-3-[2-(4-phenylpiperazin-1-yl)lquinolin-3-yl]-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (5a)
Yellow solid; yield: 78%; mp: 249ꢀC to 251ꢀC; IR (KBr):
νmax: 3052, 2987 (CH), 1608 (C N) cm−1 1H NMR
;
(DMSO-d6): 8.28 (s, 1H, quinoline-H4), 8.05-7.75(m, 14H,
Ar H), 3.46 (t, J = 4.8 Hz, 4H, CH2 N); 3.53 (t,
J = 4.8 Hz, 4H, CH2 N) ppm; MS (EI): m/z 489 (M+);
anal. calcd. for C28H23N7S: C, 68.71; H, 4.70; N, 20.04;
found: C, 68.69; H, 4.75; N, 20.13.
6-(4-Methoxyphenyl)-3-[2-(4-phenylpiperazin-1-yl)
lquinolin-3-yl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (6b)
Light yellow solid; yield: 60%; mp: 258ꢀC to 260ꢀC; IR
(KBr): νmax: 3015 (Ar H), 2957 (CH2), 1609 (C N)
1
6-(4-Methoxyphenyl)-3-[2-(4-phenylpiperazin-1-yl)
lquinolin-3-yl]-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazole (5b)
cm−1; H NMR (DMSO-d6): 8.24 (s, 1H, quinoline-H4),
7.31-8.16 (m, 13H, Ar H), 5.40 (s, 2H, SCH2), 3.96 (s, 3H,
OCH3), 3.65 (t, J = 4.8 Hz, 4H, CH2 N); 3.41 (t,
J = 4.8 Hz, 4H, CH2 N) ppm; MS (EI): m/z 533 (M+);
anal. calcd. for C30H27N7OS: C, 67.54; H, 5.07; N, 18.39;
found: C, 67.49; H, 5.03; N, 18.45.
Yellow solid; yield: 78%; mp: 248ꢀC to 250ꢀC; IR (KBr):
νmax: 3051, 2983 (CH), 1604 (C N) cm−1 1H NMR
;
(DMSO-d6): 8.31 (s, 1H, quinoline-H4), 7.63-8.13 (m,
13H, Ar H), 3.93 (s, 3H, OCH3), 3.48 (t, J = 4.8 Hz, 4H,
CH2 N); 3.56 (t, J = 4.8 Hz, 4H, CH2 N) ppm; MS (EI):
m/z 519 (M+); anal. calcd. for C29H25N7OS: C, 67.03; H,
4.85; N, 18.87; found: C, 67.10; H, 4.80; N, 18.76.
6-(4-Chlorophenyl)-3-[2-(4-phenylpiperazin-1-yl)
lquinolin-3-yl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (6c)
Light yellow solid; yield: 69%; mp: 266ꢀC to 267ꢀC; IR
(KBr): νmax: 3019 (Ar H), 2986 (CH2), 1601
(C N) cm−1; 1H NMR (DMSO-d6): 8.36 (s, 1H,
quinoline-H4), 7.53-8.19 (m, 13H, Ar H), 5.42 (s, 2H,
SCH2), 3.70 (t, J = 4.8 Hz, 4H, CH2 N); 3.31 (t, J = 4.8 Hz,
4H, CH2 N) ppm; MS (EI): m/z 537 539 (M+); anal.
calcd. for C29H24N7SCl: C, 64.80; H, 4.47; N, 18.25;
found: C, 64.76; H, 4.43; N, 18.32.
6-(4-Chlorophenyl)-3-[2-(4-phenylpiperazin-1-yl)
lquinolin-3-yl]-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazole (5c)
Yellow solid; yield: 78%; mp: 258ꢀC to 261ꢀC; IR (KBr):
νmax: 3047, 2963 (CH), 1596 (C N) cm−1; 1H NMR
(DMSO-d6): 8.36 (s, 1H, quinoline-H4), 7.73-8.23(m, 13H,
Ar H), 3.45 (t, J = 4.8 Hz, 4H, CH2 N); 3.58 (t, J = 4.8 Hz,
4H, CH2 N) ppm; MS (EI): m/z 523, 525 (M+); anal. calcd.
for C28H22N7SCl: C, 64.24; H, 4.21; N, 18.74; found: C,
64.29; H, 4.25; N, 18.65.
4.1.5 | Synthesis of
2-[2-(4-phenylpiperazin-1-yl)lquinolin-3-yl]-
1H-benzimidazole 7
4.1.4 | Synthetic procedure and
analytical data of 6-substituted-
3-[2-(4-phenylpiperazin-1-yl)lquinolin-3-yl]-
7H-[1,2,4]triazolothiadiazines (6a-c)
A
mixture of 2-(4-phenylpiperazin-1-yl)quinoline-
3-carbaldehyde 2 (10 mmol) and o-phenylenediamine
(10 mmol) was heated at 100ꢀC in DMF (20 mL) con-
taining TsOH (2 mmol) for 4 to 5 hours. The progress of
the reaction was monitored by TLC. The reaction mixture
A mixture of 5 (1 mmol) and substituted phenacyl bro-
mides (1.2 mmol) were dissolved in anhydrous ethanol

TANG ET AL.
7
was poured into ice water, and the resulting precipitate
was filtered, washed with water, and dried. The crude
product was purified by flash column chromatography
using dichloromethane/ethyl acetate (8:1) as eluent.
Yield: 76% (yellow crystal); mp: 245ꢀC to 248ꢀC; IR
(KBr): νmax: 3568 (NH), 3023 (Ar H), 2981 (CH2), 1596
1-{[5-(4-5 Chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-
1H-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]
benzimidazole (8c)
Light yellow crystal; yield 69%; mp: 265ꢀC to 268ꢀC; IR
(KBr): νmax: 3031 (Ar H), 2961 (CH2), 1600 (C N),
1
1276, 1108 (C O C) cm−1; H NMR (DMSO-d6): δ 8.39
1
(C N) cm−1; H NMR (DMSO-d6): δ 11.79 (s, 1H, NH),
(s, 1H, quinoline-H4), 7.23-8.28 (m, 17H, Ar H),5.56 (s,
2H, NCH2 ), 3.67 (t, J = 4.8 Hz, 4H, CH2 N); 3.31 (t,
J = 4.8 Hz, 4H, CH2 N)ppm; MS (EI): m/z 597 599 (M+);
anal. calcd. for C35H28N7OCl: C, 70.35; H, 4.69; N, 16.42;
found: C, 70.39; H, 4.71; N, 16.39.
8.38 (s, 1H, quinoline-H4), 8.01-7.72 (m, 13H, Ar H),
3.68 (t, J = 4.8 Hz, 4H, CH2 N); 3.32 (t, J = 4.8 Hz, 4H,
CH2 N) ppm; MS (EI): m/z 405(M+); anal. calcd. for
C26H23N5: C, 77.04; H, 5.68; N, 17.28; found: C, 77.08; H,
5.71; N, 17.35.
4.1.7 | General procedure for the
synthesis of {3-aryl-4-[2-(4-phenylpiperazin-
1-yl)quinolin-3-yl]-4,5-dihydroisoxazol-5-yl}
phenylmethanones (9a-c)
4.1.6 | General procedure for the
preparation of 1-[(5-aryl-1,3,4-oxadiazol-
2-yl)methyl]-1H-2-[2-(4-phenylpiperazin-
1-yl)quinolin-3-yl]benzimidazole
derivatives (8a-c)
The 2-(4-phenylpiperazin-1-yl)quinoline-3-carbaldehyde
2
(1 mmol),1-phenyl-2-(triphenylphosphoranylidene)
KOH (0.13 g, 2 mmol) was added to a mixture of the
benzimidazole 7 (2 mmol) and 2-chloromethyl-5-aryl-1,-
3,4-oxadiazole (2 mmol) in DMF (5 mL). The reaction
mixture was stirred at room temperature for 4 to 5 hours.
After completion of reaction, the reaction mixture was
poured onto crushed ice. The solid that separated was fil-
tered off, washed with water, and dried. The residue was
purified by column chromatography using ethyl acetate/
petroleum ether (1:3) as eluent.
ethanone (1 mmol) and hydroximoyl chlorides (1 mmol)
were combined in a vessel in DCM (10 mL) as solvent,
then a solution of TEA (1 mmol, in 5 mL DCM) was
slowly added over 1 hours. The resulting reaction mixture
was stirred at room temperature for 3 to 5 hours. The
product was obtained after purification by column chro-
matography on silica gel using ethyl acetate/petroleum
ether (1:9) as eluent to give the corresponding pure
product.
1-[(5-Phenyl-1,3,4-oxadiazol-2-yl)methyl]-1H-
2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]
benzimidazole (8a)
{3-Phenyl-4-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-
4,5-dihydroisoxazol-5-yl}phenylmethanone (9a)
Pale yellow crystal; yield 57%; mp: 169ꢀC to 170ꢀC; IR
1
Light yellow crystal; yield 67%; mp: 253ꢀC to 255ꢀC; IR
(KBr): νmax: 3029 (Ar H), 2962 (CH2), 1608 (C N),
(KBr): νmax: 1678 (C O), 1604 (C N) cm−1; H NMR
(DMSO-d6):δ 8.38(s, 1H, quinoline-H4), 6.71-8.20 (m,
19H, Ar H), 6.20 (d,1H, N O CH, J = 4.6 Hz), 5.74(d,
1H, CH C O, J = 4.6 Hz), 3.63 (t, J = 4.8 Hz, 4H,
CH2 N); 3.50 (t, J = 4.8 Hz, 4H, CH2 N) ppm; MS (EI):
m/z 538(M+); anal. calcd. for C35H30N4O2: C, 78.07; H,
5.58; N, 10.41; found: C, 78.09; H, 5.65; N, 10.43.
1
1274, 1105 (C O C) cm−1; H NMR (DMSO-d6): δ 8.39
(s, 1H, quinoline-H4), 7.23-8.28 (m, 18H, Ar H), 5.56 (s,
2H, NCH2 ), 3.67(t, J = 4.8 Hz, 4H, CH2 N); 3.31 (t,
J = 4.8 Hz, 4H, CH2 N) ppm; MS (EI): m/z 563 (M+);
anal. calcd. for C35H29N7O: C, 74.60; H, 5.15; N, 17.41;
found: C, 74.65; H, 5.11; N, 17.37.
{3-(4-Methoxyphenyl)-4-[2-(4-phenylpiperazin-1-yl)
quinolin-3-yl]-4,5-dihydroisoxazol-5-yl}
phenylmethanone (9b)
1-{[5-(4-5 Methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-
1H-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]
benzimidazole (8b)
Pale yellow crystal; yield 57%; mp: 195ꢀC to 197ꢀC; IR
1
Light yellow crystal; yield 63%; mp: 259ꢀC to 261ꢀC; IR
(KBr): νmax: 3027 (Ar H), 2963 (CH2), 1605 (C N),
(KBr): νmax: 1668 (C O), 1607 (C N) cm−1; H NMR
(DMSO-d6): δ 8.36 (s, 1H, quinoline-H4), 6.78-8.18 (m,
18H, Ar H), 6.21 (d, 1H, N O CH, J = 4.6 Hz), 5.76
(d,1H, CH C O, J = 4.6 Hz), 3.87 (s,3H, OCH3), 3.65
(t, J = 4.8 Hz, 4H, CH2 N); 3.50 (t, J = 4.8 Hz, 4H,
CH2 N) ppm; MS (EI): m/z 568(M+); anal. calcd. for
C36H32N4O3: C, 76.06; H, 5.63; N, 9.86; found: C,
76.13; H, 5.58; N, 9.93.
1
1271, 1096 (C O C) cm−1; H NMR (DMSO-d6): δ 8.38
(s, 1H, quinoline-H4), 7.19-8.24 (m, 17H, Ar H), 5.56 (s,
2H, NCH2 ), 3.96 (s, 3H, OCH3), 3.68 (t, J = 4.8 Hz,
4H, CH2 N); 3.37 (t, J = 4.8 Hz, 4H, CH2 N) ppm; MS
(EI): m/z 593 (M+); anal. calcd. for C36H31N7O2: C,
72.85; H, 5.23; N, 16.53; found: C, 72.79; H, 5.27; N, 16.47.

8
TANG ET AL.
{3-(4-Chlorophenyl)-4-[2-(4-phenylpiperazin-1-yl)
quinolin-3-yl]-4,5-dihydroisoxazol-5-yl}
phenylmethanone (9c)
3-Acetyl-5-(4-chlorophenyl)-2-[2-(4-phenylpiperazin-
1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazole (11c)
White solid, yield: 86%; mp: 206ꢀC to 207ꢀC; IR (KBr):
1
Pale yellow crystal; yield 57%; mp: 153ꢀC to 154ꢀC; IR
νmax: 1669 (C O), 1599 (C N); H NMR (DMSO-d6): δ
1
(KBr): νmax: 1677 (C O), 1603 (C N) cm−1; H NMR
8.28 (s, 1H, quinoline, 4-H), 7.47 (s, 1H, oxadiazoline,
2-H), 7.38-7.95 (m, 13H, Ar H), 3.72 (t, J = 4.8 Hz, 4H,
CH2 N), 3.51 (t, J = 4.8 Hz, 4H, CH2 N), 2.47 (s, 3H,
CH3); MS (EI): m/z 511 513 (M+); anal. calcd. for
C29H26 N5O2Cl: C, 68.10; H, 5.09; N, 13.70; found: C,
68.11; H, 5.12; N, 13.77.
(DMSO-d6): δ 8.37(s, 1H, quinoline-H4), 6.71-8.25 (m,
18H, Ar H), 6.20 (d, 1H, N O CH, J = 4.6 Hz), 5.74
(d, 1H, CH C O, J = 4.6 Hz), 3.63 (t, J = 4.8 Hz, 4H,
CH2 N); 3.50 (t, J = 4.8 Hz, 4H, CH2 N) ppm; MS (EI):
m/z 572 574(M+); anal. calcd. for C35H29N4O2Cl: C,
73.43; H, 5.07; N, 9.79; found: C, 73.39; H, 5.11; N, 9.84.
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4.1.8 | General procedure for the
synthesis of compounds 11a-c
Equimolar
quantity
of
quinoline-3-carbaldehyde
2 (2 mmol) and different aroylhydrazine (2 mmol) were
refluxed in ethanol (20 mL) for 3 hours in presence of few
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White solid, yield: 87%; mp: 186ꢀC to 188ꢀC; IR (KBr):
1
νmax: 1667 (C O), 1602 (C N); H NMR (DMSO-d6): δ
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8.27 (s, 1H, quinoline, 4-H), 7.53 (s, 1H, oxadiazoline,
2H), 7.29-8.00 (m, 14H, Ar H), 3.75 (t, J = 4.8 Hz, 4H,
CH2 N), 3.55 (t, J = 4.8 Hz, 4H, CH2 N), 2.48 (s, 3H,
-CH3); MS (EI): m/z 477 (M+); anal. calcd. for
C29H27N5O2: C, 72.96; H, 5.66; N, 14.68; found: C,
72.91; H, 5.72; N, 14.61.
3-Acetyl-5-(4-methoxyphenyl)-2-[2-(4-phenylpiperazin-
1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazole (11b)
White solid, yield: 82%; mp: 177ꢀC to 178ꢀC; IR (KBr):
1
νmax: 1668 (C O), 1600 (C N); H NMR (DMSO-d6): δ
8.29 (s, 1H, quinoline, 4-H), 7.46 (s, 1H, oxadiazoline,
2H), 7.27-8.03 (m, 13H, Ar H), 3.84 (s, 3H, OCH3),
3.72 (t, J = 4.8 Hz, 4H, CH2 N), 3.51 (t, J = 4.8 Hz, 4H,
CH2 N), 2.47 (s, 3H, CH3); MS (EI): m/z 507 (M+);
anal. calcd. for C30H29N5O3: C, 71.01; H, 5.72; N, 13.81;
found: C, 70.97; H, 5.68; N, 13.89.
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9
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How to cite this article: Tang Z, Peng Y, Liu F.
Design and synthesis of novel quinoline derivatives
bearing oxadiazole, isoxazoline, triazolothiadiazole,
triazolothiadiazine, and piperazine moieties.
J Heterocyclic Chem. 2020;1–9. https://doi.org/10.
1002/jhet.3907
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