Microwave-Assisted Synthesis, Antioxidant, and Antimicrobial Evaluation of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives

Article abstract of DOI:10.1002/jhet.3336

Azole derivatives (10a–f) obtained starting from 1-(4-fluorohenyl)piperazine were converted to the corresponding Mannich bases (7a–d, 12a,b, and 16a,b) containing β-lactame or flouroquinolone core via a one-pot three-component reaction. The synthesis of c

Full text of DOI:10.1002/jhet.3336

Month 2018 Microwave-Assisted Synthesis, Antioxidant, and Antimicrobial Evaluation
of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives
a
a
Ahmet Demirbas,a Faik Ahmet Ayaz,b and Nesrin Çolakb
*
Serap Basoglu Ozdemir, Neslihan Demirbas,
aDepartment of Chemistry, Faculty of Science, Karadeniz Technical University, Trabzon, Turkey
bDepartment of Biology, Faculty of Science, Karadeniz Technical University, Trabzon, Turkey
*E-mail: neslihan@ktu.edu.tr
Received May 2, 2018
DOI 10.1002/jhet.3336
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Azole derivatives (10a–f) obtained starting from 1-(4-fluorohenyl)piperazine were converted to the corre-
sponding Mannich bases (7a–d, 12a,b, and 16a,b) containing β-lactame or flouroquinolone core via a one-
pot three-component reaction. The synthesis of conazole analogues was carried out starting from triazole by
three steps. Reactions were carried out under conventional-mediated and microwave-mediated conditions.
All the newly synthesized compounds were screened for their antimicrobial, antioxidant activity, and most
of them displayed good–moderate activity.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
has been a most referenced building blocks in the
pharmaceutical research areas [11].
The increasing incidence of bacterial and fungal
resistance to a large number of antimicrobial agents in
both community and hospital acquired infections has
been a serious and global health problem with nearly 15
million deaths every year, because currently available
drugs will be no longer effective on resistant infections,
as a result of pathogenic microorganisms adopt diverse
strategies to enhanced ability to survive in the presence
of antibiotics [1–5]. This unwanted event has prompted
medicinal chemists to study on the development of new
antimicrobial compounds with fewer tendencies to drug
resistance. For the rational design of new biologically
active compounds, the molecular manipulation or
conjugation of promising lead compounds with
recognized pharmacophoric units derived from known
bioactive molecules has become a major strategy of
approach [6–10]. Due to the excellent selectivity with
versatile biological activities and low toxicity, the
chemistry of nitrogen containing heterocyclic compounds
As one of the five-membered nitrogen-containing
heterocycles, 1,2,4-triazole derivatives exhibit a wide-
range spectrum of biological activities including
antibacterial [12–14], anti-inflammatory [15], anticancer
[16–18], antifungal [19], antioxidant [20], enzyme
inhibition [21,22], insecticidal [23], and plant growth
regulating activities [24]. Beside this, piperazine ring
constitutes another important heterocyclic unit that has
preferred properties including a wide-range biological
activity and low toxicity [25–27]. Piperazine ring forms
multiple hydrogen bonds or ionic bonds easily.
Moreover, it has functional effect that modulating drug
lipid water partition coefficient and acid–base equilibrium
constant [19]. In biologically active products, piperazine
is often present as a fused or oxidized form or is
substituted with an azole (1,2,4-triazole and/or imidazole)
[28]. Highly substituted piperazines can be expected to
increase antimicrobial activity probably by enhancing
lipophilicity of molecule [29]. Mainly, piperazine nucleus
© 2018 Wiley Periodicals, Inc.

S. Basoglu Ozdemir, N. Demirbas, A. Demirbas, F. A. Ayaz, and N. Çolak
Vol 000
constitutes an active part of fluoroquinolone class
antibacterial drugs such as ciprofloxacin, enoxacine,
pefloxacine, fleroxacine, ofloxacine, and grepafloxacine
[30–34]. In some of our previous studies, some 1,2,4-
triazole-N-substituted piperazine conjugates have been
obtained as antibacterial and/or antifungal agents [35–37].
However, the increase of opportunistic fungal infections
and the emergence of azole resistance strains have led the
medicinal and organic chemists to design and
synthesize of new compounds with new mechanism of
action [38–41]. 1,3,4-Oxadiazole ring has been
extensively used as another pharmacophore, because
some superior properties of it, such as being a good
bioisostere of amides and esters, which can contribute
significant pharmacokinetic properties by increasing the
lipophilicity and the ability of drugs to reach their
targets by transmembrane diffusion [42]. The application
of microwave techniques for organic synthesis has
attracted considerable interest in recent years.
Microwave-assisted organic synthesis has proven to be a
valuable technique for reducing reaction times, giving
cleaner reactions, improving yields, simplifying work-up,
and designing energy-saving protocols [43]. Moreover,
with the development of “green chemistry,” the focus
has now shifted to less cumbersome solvent-free
methods, undergoing facile reactions to provide high
yields of pure products, thus eliminating or minimizing
the use of organic solvents [44–46]. In light of these
considerations, as the continuation of our ongoing efforts
endowed with the discovery of new compounds with
biological activity, we reported here the microwave
irradiated and conventional synthesis and antimicrobial
activity screening studies of new azole class antifungals.
Moreover,
the
synthesis
of
piperazine-azole-
fluoroquinolone hybrids were intended as well, based on
molecular conjugation. Piperazine scaffold was selected
as the key prototype structural unit and the integration of
piperazine skeleton, azole, and fluoroquinolone
pharmacophores with different mode of action in the one
molecular frame was performed with the aim to prepare
new antibacterial agents with preferably therapeutic
profile having fewer tendencies to antibacterial resistance.
RESULT AND DISCUSSION
In the present study, microwave-assisted green
synthesis, antimicrobial, enzyme inhibition, and
antioxidant activity screening studies of novel
heterocyclic molecules were intended. Microwave
irradiation was applied in addition to traditional methods
to find more efficient synthetic conditions for these
reactions. The synthetic strategies adopted to obtain the
target compounds are depicted in Schemes 1–3.
Scheme 1. Synthetic route of compounds 2–7. Reagent and conditions. (i): BrCH2COOEt, Et3N, THF, rt of Mw; (ii): H2NNH2, EtOH reflux or Mw; (iii):
C6H5NCO,DCM, rt or Mw; (iv): NaOAc, BrCH2COOEt, EtOH, reflux or Mw; (v): NaOH, reflux or Mw; (vi–viii): suitable amine, HCHO, DMF, rt or
MW; Mw conditions were given in Table 1.
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Month 2018
Synthesis of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives
Scheme 2. Synthetic route of compounds 8–10. Reagent and conditions: (i): NaOEt, 2-bromo-1-(4-chlorophenyl)ethanone (for 8a) and 2,2,4-
trichloroacetophenone (for 8b) reflux or Mw; (ii): NaBH4, reflux or Mw; (iii): NaH, suitable benzyl chloride, THF, reflux or Mw; Mw conditions were
given in Table 1.
Scheme 3. Reagents and Conditions: (i): CS2, KOH, EtOH, reflux or Mw; (ii): HCHO, DMF, suitable amine, rt or Mw; (iii): NaOEt, 2-bromo-1-(4-
chlorophenyl)ethanone (for 13a) and 2,2,4-trichloroacetophenone (for 13b) reflux or Mw; (iv): H2NNH2.H2O, EtOH, reflux or Mw; (v): 4-
nitrobenzaldehyde, EtOH, reflux or Mw; (vi): HCHO, DMF, suitable amine, rt or Mw; Mw conditions were given in Table 1.
The treatment of compound 2 with hydrazine hydrate by
conventional and microwave-assisted techniques afforded
the corresponding hydrazide 3. The reaction was
investigated in ethanol under reflux conditions as well as
under microwave irradiation conditions with a view to
maximizing the yield of the product and minimizing the
reaction time. Thus, the yield of the reaction was
improved to good level (91%); however, more
Journal of Heterocyclic Chemistry
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S. Basoglu Ozdemir, N. Demirbas, A. Demirbas, F. A. Ayaz, and N. Çolak
Vol 000
significantly, the reaction time for complete consumption
of starting materials was lowered from 27 h with
conventional heating to a remarkable 30 min using MW
irradiation. The optimal MW power in terms of yields
and product stability was assessed at 125 W and 125°C
in the closed vessel that afforded 96% yield (Table 1).
The hydrazide 3 was characterized by the presence of
three strong bands at 3166 (NH), 3295, and 3255 cmꢀ1
(NH2) in the FT IR spectrum. This group was recorded at
8.04–9.59 ppm in the 1H NMR spectra as D2O
exchangeable singlet. In the 13C NMR spectra of these
compounds, C═O function resonated at 169.51 ppm. The
structures of this compound was also elucidated by the
appearance of [M + 1] ion peak at the corresponding m/z
values confirming their molecular masses and also have
given elemental analysis results consistent with the
proposed structure.
The cyclocondensation of compound 4 with ethyl
bromoacetate produced the corresponding hybrid
compound incorporating 1,3-oxazole nucleus linked to
the 1-(4-fluorophenylpiperazine) skeleton via an
acetohydrazide linkage. Compared with a conventional
heating, MW irradiation decreased the reaction time from
17 h to 30 min and increased the yields from 65% to
77%. The best yields were obtained at 150 W maximum
powers. Compound 5 was characterized by the presence
of additional strong band at 1712 cmꢀ1 in the FT IR
spectrum corresponding to second carbonyl function that
arose from ring closure. This was considered as a
confirmation of oxazolidin nucleus formation.
1
4.28 (NH2) and 8.94 (NH) ppm in the H NMR spectrum
as D2O exchangeable singlets. This compound gave mass
fragmentation and elemental analysis results consistent
with the assigned structure.
The nucleophilic addition of compound
3 with
phenyl isocyanate yielded the corresponding
hydrazinecarboxamide (4), which are considered as useful
intermediates for further cyclization reactions (Scheme 1).
The synthesis of compound 4 was examined after
microwave irradiation at 150 W for 7 min. Compared
with conventional thermal heating, microwave irradiation
decreased the reaction time from 24 h to 7 min. FT IR
spectra of compound 4 revealed the presence of ─C═O
group 1703 cmꢀ1. Another evidence for the formation of
carboxamide was the presence of three ─NH signals at
Another piece of evidence for cyclocondensation is the
appearance of a singlet signal at 3.39 ppm in the 1H
NMR spectrum integrating for two protons, which
apparently are the C5 protons of oxazolidin nucleus. This
carbon has resonated at 60.54 ppm in the 13C NMR
spectrum. Moreover, the elemental analyses and mass
spectral data of were compatible with the suggested
structure.
Table 1
Time, power, and yield data for compounds 3–16.
Conventional
Microwave irradiation method
method
The synthesis of compound 6 was performed by the
intramolecular cyclization of compound 4 in basic media
with conventional and also MW-mediated methods with
the aim to introduce the 1,2,4-triazole nucleus into
piperazine skeleton, because it is well known that more
efficacious bioactive compounds can be designed by
joining two or more biologically active heterocyclic
systems together in a single molecular framework
[7,36,37]. Moreover, it is well known that the presence of
fluorinated units in organic compounds may dramatically
modify the physicochemical profile of organic molecules.
Thus, the heterocyclic compounds containing fluorine
atom have been attracting much interest due to their
potent biological activities and their role in the
development of new drug candidates [29]. In addition,
type of compound 6 can be considered as useful tolls
having active NH group for further one-pot three-
component amino alkylation reactions leading to the
formation of new bioactive compounds (Scheme 1).
Compared with conventional thermal heating, microwave
irradiation decreased the reaction time from 5 h to 15 min
and increased the yields from 83% to 90% (Table 1).
The synthesis of compounds 7a–d and 16a,b was
carried out by the treatment of compounds 6 and 15 with
several amines, namely, norfloxacin, ciprofloxacin, 7-
Comp.
No
Time
(min)
Power
(W)
Yield
(%)
Time
(h)
Yield
(%)
3
4
5
6
7a
7b
7c
7d
8a
8b
9a
9b
10a
10b
10c
10d
10e
10f
11
12a
12b
13a
13b
14
30
7
30
15
6
125
150
150
150
100
150
100
150
125
125
100
100
120
120
120
120
120
120
125
100
100
125
125
125
150
100
100
96
87
77
90
80
84
49
70
89
84
72
75
45
50
40
60
55
61
78
55
85
87
70
77
94
58
55
27
24
17
5
24
24
24
24
14
14
15
15
8
10
10
12
12
12
10
24
24
14
14
16
3
91
50
65
83
65
72
25
54
75
76
60
60
24
32
15
42
47
43
53
25
78
70
50
54
75
45
32
15
6
15
40
40
12
12
25
25
25
25
25
25
20
8
8
40
40
20
10
8
15
16a
16b
24
24
8
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Month 2018
Synthesis of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives
aminocephalosporanic acid, and thiomorpholine, in the
presence of formaldehyde. This idea originated from the
intend to introduce a fluoroquinolone, cephalosporin,
which are the known antibiotics or thiomorpholine core
to the azole skeleton. Two methods were applied for this
treatment including conventional-assisted and microwave-
assisted techniques. In comparison with the long
refluxing time, microwave irradiation provided more
efficient and green way for one-pot Mannich type
condensation with higher product yield. For MW-
mediated reactions leading to the formation of these
Mannich bases (7a–d and 16a,b), the production of
compound 7a was selected as model and the effects of
various reaction parameters, including temperature, time,
and MW power, were examined on the model reaction,
and the results are summarized in Table 1.
The treatment of 6 and 11 with 2-bromo-1-(4-
chlorophenyl)ethanone and 2,2,4-trichloroacetophenone
produced the corresponding ethenone derivatives (8a,b
and 13a,b). Compared with a conventional heating, MW
irradiation decreased the reaction time from 14 h to
40 min and increased the yields from 50–76% to 70–89%
(Table 1). In the 1H NMR and 13C NMR spectra,
additional signals corresponding to the substituted
phenylethanone moiety were recorded at the related
chemical shift values, while the spectra of these
compounds (8a,b and 13a,b) showed the disappearance
of the characteristic bands of triazole or oxadiazole–NH
(Scheme 2).
to 4-{[(4-nitrophenyl)methylene]amino}-2,4-dihydro-3H-
1,2,4-triazole-3-thione (15) derivative via the
treatment of 11 with hydrazine hydrate and 4-
nitrophenylbenzaldehyde, respectively, in the
conventional-mediated and also microwave-mediated
conditions. The structure of 15 was elucidated on the basis
of spectroscopic data and elemental analysis results
(Scheme 3).
Biological activity. Antimicrobial activity.
All the
newly synthesized compounds were screened for their
antimicrobial activity, and the results obtained were
presented in Table 2. Among these, compounds 7a,b,
12a,b, and 16a,b that contain a fluoroquinolone nucleus
linked to the 1,2,4-triazole or 1,3,4-oxadiazole core
exhibited excellent antibacterial and antimycobacterial
(on Micobacterium Smegmatis) activity with the minimal
inhibition concentration values varying between 0.24 and
3.9 μg/mL. It can be suggested that excellent activity of
these compounds is due to the presence of
a
fluoroquinolone core in their structures. Compounds 10a–
d exhibited Gram (+) bacteria, Staphylococcus aureus
(Sa), Enterococcus faecalis (Ef), Bacillus cereus (Bc),
and micobacteria Micobacterium smegmatis (Ms). In fact,
the activity of compounds 10a–d on Sa was better than
standard drug ampicillin. On the other hand, although
these compounds (10a–d) were designed as new
analogues of azole class antifungals, they did not show
activity on Saccharomyces cerevisiae (Sc) and Candida
albicans (Ca), yeast like fungy. The remaining
compounds displayed slight activities on some of the test
microorganisms.
Antioxidant activity. Principal component analysis.
The three sets of antioxidant capacity (AC) values
representing 40 measurements were modeled on a
principal component (PC) analysis to visualize possible
variation and correlation patterns of the AC values of the
synthesized compounds (Fig. 1). The AC values
compared in Table 3 have revealed two PCs accounted
totally 97.26% (PC1; 67.31% and PC2; 29.95%). Data
exhibited strong positive loadings at the right upper and
lower quadrants on PC1 with the five compounds (5,
12b, 12a, 4, and 11), respectively. They all were
associated, but only the AC values obtained from the
compounds 11 and 5 are unique and significantly strong
correlated (r = 0.887, P < 0.05). The remaining 10
compounds shared more or less the same AC values,
closing to the center on the PC that negatively located at
the upper and lower quadrant on PC2 with variation
29.95%. They all were closely associated and
The reduction of carbonyl group of compounds 8a,b to
alcohol afforded compounds 9a,b that, again, was
achieved using both classical heating and MW irradiation.
1
These compounds gave H NMR, 13C NMR, FT IR, and
mass spectroscopic data and elemental analysis results
compatible with the proposed structures. The synthesis of
compounds 10a–f that can be considered as new
analogues of azole class antifungals was achieved by
treatment of compounds 9a,b with substituted benzyl
chlorides in the presence of NaH. Two methods were
applied for this treatment including conventional-assisted
and microwave-assisted techniques. In comparison with
the long refluxing time, microwave irradiation provided
more efficient and green way for one-pot Mannich type
condensation with higher product yield. The most
1
important evidence in the FT-IR and H NMR spectra of
compounds 10a–f are the disappearance of the signal
originated from hydroxyl group. The appearance of
additional signals belonging to (di)chlorobenzyl group
supported the formation of new conazole derivatives.
Furthermore, the mass spectral data and elemental analysis
results are in accordance with their structures.
insignificantly low correlated (r
=
0.144, 0.372,
P < 0.05) with the three AC assays (Fig. 1).
The cyclization of hydrazide (3) with carbon disulfide in
basic media produced the corresponding 1,3,4-oxadiazole
derivative (11), then this compound was converted
Compounds given in Table 3 exhibited different AC
values using the three different assays (2,2-Diphenyl-1-
picrylhydrazyl [DPPH], ferric reducing ability of plasma
Journal of Heterocyclic Chemistry
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S. Basoglu Ozdemir, N. Demirbas, A. Demirbas, F. A. Ayaz, and N. Çolak
Vol 000
Table 2
Screening for the activity of compounds 4–16.
Microorganisms and minimal inhibition concentration
No
Ec
125
–
125
<0.24
<0.24
125
–
Yp
Pa
Sa
Ef
Bc
Ms
Ca
Sc
4
5
6
7a
7b
7c
7d
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
125
62.5
<0.24
<0.24
–
125
–
–
125
125
125
–
125
500
125
–
<0.24
<0.24
125
–
<0.24
<0.24
250
–
<0.24
<0.24
125
–
<0.24
<0.24
–
–
<0.24
<0.24
250
–
–
8a
8b
9a
9b
–
–
–
–
–
625
–
–
–
–
–
–
–
–
–
–
500
–
–
–
–
–
–
–
–
<0.24
<0.24
–
–
125
–
<1
3.9
125
>128
–
250
–
–
–
–
–
–
–
–
62.5
–
–
250
–
250
250
–
–
–
–
125
<0.24
<0.24
500
125
–
–
–
–
500
–
–
–
–
–
–
–
62.5
–
–
–
–
–
–
62.5
–
–
–
–
–
10a
10b
10c
10d
11
12a
12b
13a
13b
14
31.25
31.25
31.25
31.25
–
<0.24
<0.24
–
125
–
250
1.9
3.9
–
31.25
31.25
31.25
31.25
–
<0.24
<0.24
62.5
500
–
31.25
31.25
125
31.25
–
<0.24
<0.24
–
–
–
–
1.9
1.9
500
15
125
125
125
125
125
<0.24
<0.24
62.5
62.5
–
–
125
<0.24
<0.24
–
125
–
<0.24
<0.24
–
–
–
15
–
–
–
–
–
–
–
<1
1.9
125
16a
16b
DMSO
Amp.
Strep.
Flu
<1
<1
125
10
<1
3.9
125
18
35
10
4
<8
<8
Amp., Ampicillin; Bc, Bacillus cereus 702 Roma; Ca, Candida albicans ATCC 60193; Ec, Escherichia coli ATCC 25922; Ef, Enterococcus faecalis
ATCC 29212; Ms, Micobacterium smegmatis ATCC607; Pa, Pseudomonas aeruginosa ATCC 43288; Sa, Staphylococcus aureus ATCC 25923; Sc,
Saccharomyces cerevisiae RSKK 251; Strep., streptomycin; Yp, Yersinia pseudotuberculosis ATCC 911; –, no activity.
Table 3
Antioxidant capacity (*μmol TE/g, AC) values of synthesized 15 novel
compounds.
No
DPPH*
FRAP*
CUPRAC*
4
5
6
20.64 1.09b 1698.33 35.51k
629.54 17.08v 2049.26 4.18o
8.13 0.06a 1415.15 13.42g-j
1607.33 54.23v
1497.06 81.16u
263.46 7.59c
7a
7b
7c
7d
8a
8b
9a
9b
n.d.
n.d.
1795.63 82.70L
1952.46 146.90n
421.72 10.82fg
456.69 10.74gh
629.35 16.51kL
483.92 6.52gh
67.95 0.84a
63.78 2.25f 1870.72 56.75Lm
n.d.
n.d.
2982.27 56.66p
338.45 10.67a
3.76 0.11a 1293.84 32.56ef
343.52 23.15de
216.29 10.21BC
249.51 13.08de
4673.21 95.69x
1156.58 9.28p
n.d.
1896.68 42.91mn
43.52 4.40c 1618.45 53.94k
11 161.61 0.12s 9826.25 44.42r
12a 119.96 0.09op 1682.58 81.90k
12b 154.75 0,05r 1434.53 128.19gh–j 1501.14 23.02u
Figure 1. Principal component (PC) analysis applied to the antioxidant
capacity (AC) values of the synthesized 15 novel compounds listed in
Table 3. [Color figure can be viewed at wileyonlinelibrary.com]
14 151.49 5.24r
894.88 93.53b
684.42 32.28Lm
Values represent the mean SD of three determinations. An analysis of
variance (SPSS version 11.5. one-way analysis of variance) was used for
comparisons among the means. The values with the same letter at super-
scripts within a column are not significantly different at P < 0.05, n.d., not
detected. CUPRAC, cupric ion reducing antioxidant capacity; DPPH, 2,2-
diphenyl-1-picrylhydrazyl; FRAP, ferric reducing ability of plasma.
[FRAP], and cupric ion reducing antioxidant capacity
[CUPRAC]). Among the 15 novel synthesized
compounds, only the compounds 8a, 9a, 7a, 7b, and 7d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives
did not show any AC values in the DPPH assay, while the
90% (method 2); mp 54–55°C. FT IR (νmax, cmꢀ1): 3015
(Aromatic CH), 2986 (Aliphatic CH), 1736 (C═O). H
1
other had. Compounds 5 (629.54
(8.13 0.06) in DPPH, 11 (9826.25
17.08) and 8b
44.4) and 8a
NMR (DMSO-d6, δ ppm): 1.19 (t, 3H, CH3, J = 6.8 Hz),
2.65 (t, 4H, 2CH2, J = 4.8 Hz), 3.06 (d, 4H, 2CH2,
J = 5.2 Hz), 3.27 (s, 2H, CH2), 4.09 (q, 2H, CH2,
J = 7.2 Hz), 6.91–6.95 (m, 2H, arH), 7.00–7.05 (m, 2H,
arH). 13C NMR (DMSO-d6, δ ppm): 14.58 (CH3), 49.38
(2CH2), 52.38 (2CH2), 58.78 (CH2), 60.33 (CH2), arC:
[115.57 and 115.79 (d, 2CH, J = 22.0 Hz), 117.59 and
117.67 (d, 2CH, J = 8.0 Hz), 148.34 and 148.35 (d, C,
J = 1.0 Hz), 155.30 and 157.64 (d, C, JC-F = 234.0 Hz)],
170.29 (C═O). EI MS m/z (%): 267.23 ([M + 1]+, 100),
193.14 (39), 188.18 (39), 160.19 (34). Elemental analysis
for C14H19FN2O2, calculated (%): C, 63.14; H, 7.19; N,
10.52. Found: C, 63.47; H, 7.29; N, 10.55.
2-[4-(4-Fluorophenyl)piperazin-1-yl]acetohydrazide (3).
Method 1: Hydrazine hydrate (30 mmol) was added to the
solution of compound 2 (10 mmol) in absolute ethanol, and
the mixture was refluxed for 27 h. Then, the solvent was
removed under reduced pressure and the obtained oily
mass was recrystallized from ethyl acetate:diethyl ether
(1:3) to give the target compound. [48]. Yield 91%, mp
155–156°C.
(338.45 10.67) in FRAP and 11 (4673.21 95.69) and
8a (67.95 0.84) in CUPRAC had the highest and the
lowest AC values, respectively (Table 3).
MATERIAL AND METHODS
All the chemicals were purchased from Fluka Chemie
AG Buchs (Switzerland) and used without further purifica-
tion. Melting points were determined in open capillaries on
a Büchi B-540 melting point apparatus and are uncor-
rected. Reactions were monitored by thin-layer chromatog-
raphy on silica gel 60 F254 aluminum sheets. The mobile
phase was ethyl acetate:diethyl ether (1:1), and detection
was made using UV light. FT-IR spectra were recorded
1
using a Perkin Elmer 1600 series FT IR spectrometer. H
NMR and 13C NMR spectra were registered in DMSO-d6
on a BRUKER AVENE II 400 MHz NMR spectrometer
(400.13 MHz for 1H and 100.62 MHz for 13C).
Microwave-assisted syntheses were carried out using
monomode CEM-Discover microwave apparatus. The
chemical shifts are given in ppm relative to Me4Si as an in-
ternal reference; J values are given in Hz. The elemental
analysis was performed on a Costech Elemental Combus-
tion System CHNS-O elemental analyzer. All the com-
pounds gave C, H, and N analysis within 0.4% of the
theoretical values. The mass spectra were obtained on a
Quattro GC–MS (70 eV) instrument. Compound 2 was
prepared by the way reported earlier [47].
Method 2: The mixture of hydrazine hydrate (2.5 mmol)
and compound 2 (1 mmol) was irradiated in closed vessels
with the pressure control at 125°C, 125 W for 30 min. The
product obtained was recrystallized from ethyl acetate:
diethyl ether (1:3) to give the pure compound. Yield
96%. FT IR (νmax, cmꢀ1): 3295 and 3255 (NH2), 3166
(NH), 3051 (Aromatic CH), 2962 (Aliphatic CH), 1666
1
(C═O). H NMR (DMSO-d6, δ ppm): 2.56 (t, 4H, 2CH2,
J = 4.8 Hz), 2.96 (s, 2H, CH2), 3.08 (t, 4H, 2CH2,
J = 4.4 Hz), 4.28 (brs, 2H, NH2), 6.91–6.95 (m, 2H,
ArH), 7.00–7.05 (m, 2H, ArH), 8.94 (s, 1H, NH). 13C
NMR (DMSO-d6, δ ppm): 49.31 (2CH2), 53.20 (2CH2),
60.26 (CH2), arC: [115.57 and 115.79 (d, 2CH,
J = 22.0 Hz), 117.49 and 117.57 (d, 2CH, J = 8.0 Hz),
148.36 (C), 155.44 and 157.58 (d, C, JC-F = 214.0 Hz)],
168.57 (C═O). EI MS m/z (%): 293.30 (43), 193.18
(100), 178.16 (20), 150.13 (62), 138.11 (37).
EXPERIMENTAL
Ethyl[4-(4-fluorophenyl)piperazin-1-yl]acetate (2).
Method 1: Ethyl bromoacetate (10 mmol) was added to
the solution of 1-(4-fluorophenyl)piperazine (10 mmol) in
tetrahydrofuran (THF) drop wise, and the mixture was
stirred at room temperature in the presence of
triethylamine (15 mmol) for 24 h. The solid formed was
removed by filtration, and the solvent was evaporated
under reduced pressure. The oily crude product was
recrystallized from ethanol to afford the desired compound.
Method 2: The mixture of ethyl bromoacetate
(1.5 mmol), 1-(4-fluorophenyl)piperazine (1.0 mmol) and
trimethylamine (3.0 mmol) in THF was stirred at room
temperature for 5 min and then irradiated in closed
vessels with the pressure control at 110°C for 15 min
(hold time) at 150 W maximum power. The precipitate
was removed by filtration, and the resulting solution was
evaporated under reduced pressure to dryness. The oily
crude recrystallized from ethanol. Yield: 75% (method 1),
2-{[4-(4-Fluorophenyl)piperazin-1-yl]acetyl}-N-
phenylhydrazinecarboxamide (4).
Method 1: Phenyl
isocyanate (20 mmol) was added to the solution of
compound 3 (10 mmol) in dichloromethane, and the
mixture was stirred at room temperature for 24 h. After
evaporating the solvent, a solid appeared. This solid was
recrystallized from acetone:diethyl ether (1:2).
Method 2: The solution of the corresponding aryl
isothiocyanate (2 mmol) in dichloromethane (DCM) was
added to the solution of compound 3 (1 mmol). Then, the
reaction mixture was irradiated in microwave reactor in
closed vessels with the pressure control at 100°C, for
7 min at 150 W. After evaporating the solvent under
reduced pressure,
a
solid appeared. This was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Basoglu Ozdemir, N. Demirbas, A. Demirbas, F. A. Ayaz, and N. Çolak
Vol 000
recrystallized from acetone:diethyl ether (1:2) to give the
desired product. Yield 50% (method 1), 87% (method 2);
mp 151–152°C. FT IR (νmax, cmꢀ1): 3379 (NH), 3307
(2NH), 3091 (Aromatic CH), 2882, (Aliphatic CH), 1713
acidified to pH 5 with 37% HCl. The precipitate formed
was filtered and washed with water. This compound
recrystallized from ethyl acetate.
Method 2: The mixture of compound 4 (1 mmol) and
2 mol/L NaOH (2 mmol) in water (10 mL) was irradiated
in monomode microwave reactor in closed vessel with
the pressure control at 120°C for 15 min at 150 W. Then,
the resulting solution was cooled to room temperature
and acidified to pH 5 with 37% HCl. The precipitate
formed was filtered off, wash with water, and
recrystallized from ethanol. Yield: 83% (method 1), 90%
(method 2); mp 200–201°C. FT IR (νmax, cmꢀ1): 3175
(NH), 3067 (Aromatic CH), 2940 (Aliphatic CH), 1694
(C═O). 1H NMR (DMSO-d6, δ ppm): 2.42 (s, 4H,
2CH2), 2.90 (s, 4H, 2CH2), 3.34 (s, 2H, CH2), 6.85–6.89
(m, 2H, ArH), 7.00 (t, 2H, ArH, J = 8.0 Hz), 7.48 (s, 5H,
ArH), 11.78 (brs, 1H, NH). 13C NMR (DMSO-d6, δ
ppm): 49.34 (2CH2), 52.35 (2CH2), 52.86 (CH2), arC:
[115.55 and 115.77 (d, 2CH, J = 22.0 Hz), 117.52 and
117.60 (d, 2CH, J = 8.0 Hz), 127.56 (CH), 128.59
(2CH), 129.34 (2CH), 133.93 (C), 144.44 (C), 155.27
and 157.61 (d, C, JC-F = 234.0 Hz)], 148.24 (triazole C-
3), 154.88 (triazole C-5). EI MS m/z (%): 377.37
([M + 1 + Na]+, 21), 376.36 ([M + Na]+, 100). Elemental
analysis for C19H20FN5O, calculated (%): C, 64.57; H,
5.70; N, 19.82. Found: C, 64.87; H, 5.55; N, 19.59.
1
(C═O), 1662 (C═O). H NMR (DMSO-d6, δ ppm): 2.66
(s, 4H, 2CH2), 3.11 (s, 4H, 2CH2), 3.38 (s, 2H, CH2),
6.93–6.96 (m, 3H, ArH), 7.02–7.06 (m, 2H, ArH), 7.25
(t, 2H, ArH, J = 8.0 Hz), 7.45 (d, 2H, ArH, J = 8.0 Hz),
8.04 (s, 1H, NH), 8.79 (s, 1H, NH), 9.59 (s, 1H, NH).
13C NMR (DMSO-d6, δ ppm): 49.24 (2CH2), 53.12
(2CH2), 60.12 (CH2), arC: [115.58 and 115.80 (d, 2CH,
J = 22.0 Hz), 117.50 and 117.58 (d, 2CH, J = 8.0 Hz),
124.62 (CH), 129.12 (2CH), 129.27 (2CH), 140.08 (C),
148.34 (C), 155.26 and 157.60 (d, C, JC-F = 234.0 Hz)],
155.69 (C═O), 169.51 (C═O). EI MS m/z (%): 372.36
([M + 1]+, 100), 253.29 (77), 193.23 (48). Elemental
analysis for C19H22FN5O2, calculated (%): C, 61.44; H,
5.97; N, 18.86. Found: C, 61.87; H, 6.09; N, 18.55.
2-[4-(4-Fluorophenyl)piperazin-1-yl]-N0-[(2Z)-4-oxo-3-
phenyl-1,3-oxazolidin-2-ylidene]acetohydrazide (5). Method
1: Ethyl bromo acetate (10 mmol) was added to the solution
of compound 4 (10 mmol) in ethanol. The mixture was
refluxed for 17 h in the presence of dry sodium acetate
(50 mmol). After evaporating the solvent under reduced
pressure, a solid was occurred and washed with water. This
crude product crystallized from ethanol:water (1:3).
Method 2: The mixture of compound 4 (1 mmol) and
ethyl bromoacetate (1 mmol) and sodium acetate (5 mmol)
in ethanol was irradiated in microwave reactor in closed
vessels with the pressure control at 150°C, 150 W for
30 min. After evaporating the solvent under reduced
pressure, a solid was occurred and washed with water. This
crude product crystallized from ethanol:water (1:3). Yield
65% (method 1), 77% (method 2); mp 135–137°C. FT IR
(νmax, cmꢀ1): 3306 (NH), 3038 (Aromatic CH), 2919
(Aliphatic CH), 1712 (C═O), 1662 (C═O), 1509 (C═N).
1H NMR (DMSO-d6, δ ppm): 2.64 (s, 4H, 2CH2), 3.08 (s,
4H, 2CH2), 3.39 (s, 4H, 2CH2), 6.94–6.96 (m, 3H, ArH),
7.01–7.06 (m, 2H, ArH), 7.23 (t, 2H, ArH, J = 8.4 Hz),
7.46 (d, 2H, ArH, J = 6.8 Hz), 9.63 (s, 1H, NH). 13C NMR
(DMSO-d6, δ ppm): 49.28 (2CH2), 53.13 (2CH2), 60.22
(CH2), 60.54 (CH2), arC: [115.57 and 115.79 (d, 2CH,
J = 22.0 Hz), 117.49 and 117.56 (d, 2CH, J = 7.0 Hz),
122.73 (CH), 129.03 (2CH), 129.15 (2CH), 140.49 (2C),
155.24 and 157.58 (d, C, JC-F = 234.0 Hz)], 148.39
(C═N), 169.46, (C═O), 175.81 (C═O). EI MS m/z (%):
411.36 ([M+], 25), 394.33 (68), 193.04 (100). Elemental
analysis for C21H22FN5O3, calculated (%): C, 61.30; H,
5.39; N, 17.02. Found: C, 61.37; H, 5.09; N, 17.15.
General procedure for the synthesis of compounds 7a–d,
12a,b, and 16a,b.
Method 1: To a solution of
corresponding compounds 6, 11, and 15 (10 mmol) in
dimethylformamide (DMF) containing suitable primary or
secondary amine (10 mmol) was added, and the mixture
was stirred at room temperature in the presence of
formaldehyde (50 mmol) for 24 h. The solid precipitated
was filtered off and recrystallized from dimethyl
sulfoxide:water (1:1) for compounds (7a,b, 12a,b, and
16a,b) and ethyl acetate for compounds (7c,d).
Method 2: The mixture of compounds 6, 11, and 15
(1 mmol), suitable amine (1 mmol), HCl (5 mmol), and
formaldehyde (5 mmol) in DMF was irradiated in the
microwave reactor in the closed vessel with pressure
control (physical parameters were given Table 1). The
solid formed after the mixture was poured to ice-water
was filtered off and purified by recrystallization from
dimethyl sulfoxide:water (1:3).
1-Ethyl-6-fluoro-7-{4-[(3-{[4-(4-fluorophenyl)piperazin-1-yl]
methyl}-5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)
methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (7a).
Yield: 65% (method 1), 80%
(method 2); mp >260°C. FT IR (νmax, cmꢀ1): 3067
(Aromatic CH), 2920 (Aliphatic CH), 1708 (C═O), 1627
(2C═O). 1H NMR (DMSO-d6, δ ppm): 1.41 (s, 3H,
CH3), 2.41 (s, 4H, 2CH2), 2.73 (s, 4H, 2CH2), 2.89 (s,
4H, 2CH2), 3.38 (s, 6H, 3CH2), 4.57 (s, 2H, CH2), 4.72
(s, 2H, CH2), 6.82 (brs, 2H, ArH), 6.98 (brs, 2H, ArH),
5-{[4-(4-Fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-
2,4-dihydro-3H-1,2,4-triazol-3-one (6).
Method 1: A
solution of the corresponding compound 4 (10 mmol) in
refluxed in the presence 2% NaOH solution for 5 h.
Then, solution was cooled to room temperature and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives
7.15 (brs, 1H, ArH), 7.52 (s, 4H, ArH), 7.85 (s, 1H, ArH),
7.95 (s, 1H, ArH), 8.91 (s, 1H, quinolone CH), 15.32 (s,
1H, OH). 13C NMR (DMSO-d6, δ ppm): 14.79 (CH3),
49.28 (CH2), 49.49 (2CH2), 49.75 (CH2), 49.89 (CH2),
51.06 (CH2), 52.36 (2CH2), 52.64 (CH2), 66.15 (CH2),
79.95 (CH2), 107.51 (C), arC: [106.18 (CH), 111.46 and
111.69 (d, CH, J = 23.2 Hz), 115.51 and 115.73 (2CH),
117.44 and 117.52 (2CH), 119.52 and 119.59 (d, C,
J = 7.0 Hz), 127.55 (CH), 128.86 (2CH), 129.41 (2CH),
133.87 (C), 137.58 (C), 143.30 (C), 145.71 and 145.81
(d, C, J = 10.0 Hz), 148.13 and 151.98 (d, C,
(OH), 3045 (Aromatic CH), 2933 (Aliphatic CH), 1766
(C═O), 1713 (2C═O), 1647 (C═O). H NMR (DMSO-
1
d6, δ ppm): 2.02 (s, 3H, CH3), 2.43 (s, 4H, 2CH2), 2.73
(s, 4H, 2CH2), 2.89 (s, 4H, 2CH2), 4.65 (d, 1H, CH,
J = 10.4 Hz), 4.79 (d, 1H, CH, J = 11.6 Hz), 4.89–5.07
(m, 4H, 2CH2), 6.88 (s, 2H, ArH), 7.01 (s, 2H, ArH),
7.46 (s, 5H, ArH). 13C NMR (DMSO-d6, δ ppm): 25.89
(CH3), 49.32 (2CH2), 52.35 (CH2), 52.68 (CH2), 52.85
(CH2), 59.21 (CH), 59.28 (CH2), 63.20 (CH2), 67.66
(CH2), 68.90 (CH), arC: [115.55 and 115.77 (d, 2CH,
J = 22.0 Hz), 117.52 and 117.60 (d, 2CH, J = 8.0 Hz),
127.56 (CH), 128.61 (2CH), 129.35 (2CH), 143.43 and
143.56 (d, C, JC-F = 13.0 Hz), 144.47 (C), 153.29 and
155.28 (d, C, JC-F = 199.0 Hz)], 133.80 (C), 134.01 (C),
148.22 (triazole C-3), 157.62 (triazole C-5), 170.66
(3C═O). EI MS m/z (%): 660.48 ([M + Na]+, 24), 638.40
([M + 1]+, 100). Elemental analysis for C30H32FN7O6S,
calculated (%): C, 56.50; H, 5.06; N, 15.38. Found: C,
56.17; H, 5.01; N, 15.66.
JC-F
=
385.0 Hz), 154.10 and 157.60 (d, C,
JC-F = 350.0 Hz)], 148.78 (CH), 154.46 (triazole C-3),
162.77 (triazole C-5), 166.54 (C═O), 176.53 (C═O). EI
MS m/z (%): 723.04 ([M
+
K]+, 29), 708.16
([M + 1 + Na]+, 43), 707.28 ([M + Na]+, 100), 685.31
([M + 1]+, 32). Elemental analysis for C36H38F2N8O4,
calculated (%): C, 63.15; H, 5.59; N, 16.36. Found: C,
63.17; H, 5.51; N, 16.56.
1-Cyclopropyl-6-fluoro-7-{4-[(3-{[4-(4-fluorophenyl)
piperazin-1-yl]methyl}-5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-
triazol-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-
5-{[4-(4-Fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2-
(thiomorpholin-4-ylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
(7d). Yield: 54% (method 1), 70% (method 2); mp. 151–
153°C. FT IR (νmax, cmꢀ1): 3063 (Aromatic CH), 1706
3-carboxylic acid (7b).
Yield: 72% (method 1), 84%
(method 2); mp >280°C. FT IR (νmax, cmꢀ1): 3065
(Aromatic CH), 2950 (Aliphatic CH), 1711 (C═O), 1626
(2C═O). 1H NMR (DMSO-d6, δ ppm): 1.18 (s, 2H,
CH2), 1.32 (s, 2H, CH2), 2.42 (s, 2H, CH2), 2.50 (s, 2H,
CH2), 2.73 (s, 2H, CH2), 2.89 (s, 4H, 2CH2), 3.34 (s, 8H,
4CH2), 3.82 (s, 1H, CH), 4.72 (s, 2H, CH2), 6.83–6.86
(m, 2H, ArH), 6.99 (t, 2H, ArH, J = 8.8 Hz), 7.49–7.57
(m, 5H, ArH), 7.87 (d, 1H, ArH, J = 13.2 Hz), 7.95 (s,
1H, ArH), 8.65 (d, 1H, quinolone CH, J = 4.8 Hz), 15.19
(s, 1H, OH). 13C NMR (DMSO-d6, δ ppm): 8.02 (2CH2),
36.29 (CH), 48.38 (CH2), 49.30 (CH2), 49.73 (CH2),
49.85 (CH2), 51.08 (2CH2), 52.37 (2CH2), 52.65 (CH2),
66.17 (CH2), 107.21 (C), arC: [106.87 (CH),111.26 and
111.51 (d, CH, J = 25.0 Hz), 115.51 and 115.54 (d, 2CH,
J = 3.0 Hz), 117.48 and 117.56 (d, 2CH, J = 8.0 Hz),
118.97 and 119.05 (d, C, J = 7.5 Hz), 127.58 (CH),
128.88 (2CH), 129.35 (2CH), 133.88 (2C), 139.60 and
139.64 (d, C, J = 4.1 Hz), 145.49 (C), 145.59 and 148.16
1
(C═O), 1507 (C═N). H NMR (DMSO-d6 δ ppm): 2.42
(s, 6H, 3CH2), 2.61 (s, 4H, 2CH2), 2.89 (s, 4H, 2CH2),
3.38 (s, 4H, 2CH2), 4.61 (s, 2H, CH2), 6.88 (s, 2H, ArH),
7.00 (s, 2H, ArH), 7.51 (s, 5H, ArH). 13C NMR (DMSO-
d6, δ ppm): 27.65 (CH2), 49.32 (2CH2), 52.37 (2CH2),
52.47 (2CH2), 52.66 (2CH2), 67.76 (CH2), arC: [115.55
and 115.77 (d, 2CH, J = 22.0 Hz), 117.53 and 117.61 (d,
2CH, J = 8.0 Hz), 127.55 (2CH), 129.41 (CH), 129.47
(2CH), 133.90 (C), 148.18 and 148.20 (d, C, J = 2.0 Hz),
154.04 and 157.63 (d, C, JC-F = 359.0 Hz)], 143.19
(triazole C-3), 155.29 (triazole C-5). EI MS m/z (%):
470.48 ([M + 2]+, 24), 325.01 (100). Elemental analysis
for C24H29FN6OS, calculated (%): C, 61.52; H, 6.24; N,
17.93. Found: C, 61.77; H, 6.56; N, 17.56.
General procedure for the synthesis of compounds 8a,b
and 13a,b. Method 1: The solution of the corresponding
compound 6 or 11 (10 mmol) in ethanol was refluxed in
the presence of sodium ethoxide (10 mmol) for 2 h.
Then, 2-bromo-1-(4-chlorophenyl)ethanone (for 8a, 13a)
and 2,2,4-trichloroacetophenone (for 8b, 13b) (10 mmol)
was added into it, and the mixture was refluxed for
additional 12 h. After evaporating the solvent, a solid
appeared. This crude product was recrystallized from
acetone:water (1:3) to give the target compound.
Method 2: The solution of the corresponding compound
6 or 11 (1 mmol) in ethanol was irradiated in microwave
reactor in the closed vessel with pressure control at
125°C, 120 W for 10 min in the presence of metallic
sodium (1 mmol). Then, 2-bromo-1-(4-chlorophenyl)
ethanone (1 mmol) was added into it and the reaction
mixture was irradiated at 125°C, 120 W for 30 min.
(d, C, JC-F = 257.0 Hz), 152.18 and 154.10 (d, C, JC-F
=
192.0 Hz)], 143.33 (triazole C-3), 148.37 (CH), 155.27
(triazole C-5), 166.36 (C═O), 176.78 (C═O). EI MS m/z
(%): 720.21 ([M + 1 + Na]+, 48), 719.21 ([M + Na]+,
100), 697.18 ([M + 1]+, 59), 398.24 (34), 376.21 (37).
Elemental analysis for C37H38F2N8O4, calculated (%): C,
63.78; H, 5.50; N, 16.08. Found: C, 63.67; H, 5.41; N,
16.06.
(6R,7R)-3-[(Acetyloxy)methyl]-7-{[(3-{[4-(4-fluorophenyl)
piperazin-1-yl]methyl}-5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-
triazol-1-yl)methyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
2-ene-2-carboxylic acid (7c). Yield: 25% (method 1), 49%
(method 2); mp 208–211°C. FT IR (νmax, cmꢀ1): 3400
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Basoglu Ozdemir, N. Demirbas, A. Demirbas, F. A. Ayaz, and N. Çolak
Vol 000
After evaporating the solvent under reduced pressure, a
solid appeared. This was washed with water and
recrystallized from acetone to afford the desired
evaporating the solvent, a solid appeared. This crude
product was washed with water and recrystallized from
acetone:water (1:3) to yield the target product.
2-[2-(4-Chlorophenyl)-2-hydroxyethyl]-5-{[4-(4-
compound.
fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2,4-dihydro-3H-
2-[2-(4-Chlorophenyl)-2-oxoethyl]-5-{[4-(4-fluorophenyl)
piperazin-1-yl]methyl}-4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-
one (8a). Yield: 75% (method 1), 89% (method 2); mp
1,2,4-triazol-3-one (9a).
Yield: 60% (method 1), 72%
(method 2); mp141–142°C. FT IR (νmax, cmꢀ1): 3428
156–158°C. FT IR (νmax, cmꢀ1): 3071 (Aromatic CH),
2964 (Aliphatic CH), 1716 (C═O), 1693 (C═O), 1509
(OH), 3050 (Aromatic CH), 2958 (Aliphatic CH), 1679
1
(C═O), 1512 (C═N). H NMR (DMSO-d6, δ ppm): 2.35
1
(C═N). H NMR (DMSO-d6, δ ppm): 2.41 (s, 2H, CH2),
(s, 4H, 2CH2), 2.89 (s, 4H, 2CH2), 3.34 (s, 2H, CH2),
3.77–4.97 (m, 2H, CH2), 4.98 (t, 1H, CH, J = 8.0 Hz),
5.78 (brs, 1H, OH), 6.89–6.91 (m, 2H, ArH), 7.00–7.02
(m, 2H, ArH), 7.38–7.49 (m, 9H, ArH). 13C NMR
(DMSO-d6, δ ppm): 49.33 (CH2), 52.26 (2CH2), 52.36
(CH2), 52.52 (CH2), 56.34 (CH2), 70.07 (CH), arC:
[115.58 and 115.80 (d, 2CH, J = 22.0 Hz), 117.51 and
117.59 (d, 2CH, J = 8.0 Hz), 127.42 (CH), 128.52
(2CH), 128.62 (2CH), 128.80 (2CH), 129.42 (2CH),
132.33 (C), 133.89 (C), 142.01 (C), 142.90 (C), 153.31
and 155.29 (d, C, JC-F = 198.0 Hz)], 148.23 (triazole C-
3), 157.64 (triazole C-5). EI MS m/z (%): 532.17 (36),
530.17 ([M + Na]+, 100), 376.25 (31). Elemental analysis
for C27H27ClFN5O2, calculated (%): C, 63.84; H, 5.36;
2.90 (s, 4H, 2CH2), 3.35 (s, 4H, 2CH2), 5.45 (s, 2H,
CH2), 6.89 (brs, 2H, ArH), 7.02 (brs, 2H, ArH), 7.34–
7.53 (m, 5H, ArH), 7.67 (d, 2H, ArH, J = 7.2 Hz), 8.07
(d, 2H, ArH, J = 7.2 Hz). 13C NMR (DMSO-d6, δ ppm):
49.32 (CH2), 52.79 (2CH2), 52.61 (CH2), 56.35 (CH2),
64.36 (CH2), arC: [115.56 and 115.77 (d, 2CH,
J = 21.0 Hz), 117.54 and 117.61 (d, 2CH, J = 7.0 Hz),
127.40 (CH), 128.01 (2CH), 128.91 (2CH), 129.52
(2CH), 130.53 (2CH), 133.49 (C), 133.84 (C), 139.43
(C), 153.96 and 157.64 (d, C, JC-F = 368.0 Hz)], 148.21
(triazole C-3), 155.30 (triazole C-5), 192.98 (C═O). EI
MS m/z (%): 528.16 ([M + Na]+, 45), 506.33 ([M + 1]+,
9), 448.52 (29), 447.58 (100). Elemental analysis for
C27H25ClFN5O2, calculated (%): C, 64.09; H, 4.98; N,
13.84. Found: C, 64.17; H, 4.56; N, 13.56.
N, 13.79. Found: C, 63.99; H, 5.51; N, 13.86.
2-[2-(2,4-Dichlorophenyl)-2-hydroxyethyl]-5-{[4-(4-
fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2,4-dihydro-3H-
2-[2-(2,4-Dichlorophenyl)-2-oxoethyl]-5-{[4-(4-fluorophenyl)
piperazin-1-yl]methyl}-4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-
one (8b). Yield: 76% (method 1), 84% (method 2); mp
1,2,4-triazol-3-one (9b).
Yield: 60% (method 1), 75%
(method 2); mp 98–100°C. FT IR (νmax, cmꢀ1): 3255
165–166°C. FT IR (νmax, cmꢀ1): 3088 (Aromatic CH),
2921 (Aliphatic CH), 1698 (2C═O), 1508 (C═N). 1H
NMR (DMSO-d6, δ ppm): 2.41 (s, 2H, CH2), 2.89 (s,
4H, 2CH2), 3.34 (s, 6H, 3CH2), 6.88 (s, 2H, ArH), 7.01
(s, 2H, ArH), 7.43 (s, 8H, ArH). 13C NMR (DMSO-d6, δ
ppm): 48.06 (CH2), 49.34 (CH2), 52.17 (2CH2), 52.35
(CH2), 52.85 (CH2), arC: [115.56 and 115.77 (d, 2CH,
J = 21.0 Hz), 117.52 and 117.60 (d, 2CH, J = 8.0 Hz),
127.56 (2CH), 128.61 (CH), 129.35 (2CH), 130.59
(2CH), 133.90 (CH), 144.47 (2C), 148.22 (2C), 154.89
(2C)], 155.27 (triazole C-3), 157.62 (triazole C-5),
195.37 (C═O). EI MS m/z (%): 564.21 ([M + 1 + Na]+,
(OH), 3009 (Aromatic CH), 2987 (Aliphatic CH), 1680
(C═O), 1512 (C═N). H NMR (DMSO-d6, δ ppm): 2.41
1
(s, 4H, 2CH2), 2.90 (s, 4H, 2CH2), 3.33 (s, 5H,
CH + 2CH2), 6.88 (brs, 2H, ArH), 7.01 (brs, 2H, ArH),
7.49 (brs, 8H, ArH). 13C NMR (DMSO-d6, δ ppm):
49.31 (CH2), 52.20 (2CH2), 52.66 (CH2), 52.92 (CH2),
56.90 (CH2), 70.08 (CH), arC: [115.68 and 115.90 (d,
2CH, J = 22.0 Hz), 117.51 and 117.58 (d, 2CH,
J = 7.0 Hz), 127.42 (2CH), 128.62 (2CH), 128.69 (CH),
128.84 (2CH), 129.40 (2CH), 132.30 (C), 133.79 (C),
142.03 (C), 142.99 (C), 153.33 and 155.31 (d, C,
JC-F = 198.0 Hz)], 150.34 (triazole C-3), 157.68 (triazole
C-5). EI MS m/z (%): 542.46 ([M]+, 70), 451.09 (100),
176.15 (31). Elemental analysis for C27H26Cl2FN5O2,
calculated (%): C, 59.78; H, 4.83; N, 12.91. Found: C,
59.98; H, 4.54; N, 12.86.
76),
562.21
(100).
Elemental
analysis
for
C27H24Cl2FN5O2, calculated (%): C, 60.01; H, 4.48; N,
12.96. Found: C, 60.10; H, 4.51; N, 12.86.
General procedure for the synthesis of compounds 9a,b.
Method 1: A solution of the corresponding compound 8
(10 mmol) in ethanol was refluxed in the presence of
NaBH4 (30 mmol) for 15 h. After evaporating the
solvent, an oily mass appeared. This crude product was
recrystallized from acetone:water (1:3) to afford the
desired product.
Method 2: The mixture of compound 8 (1 mmol) and
NaBH4 (3 mmol) in ethanol (10 mL) was irradiated in
monomode microwave reactor in closed vessel with the
pressure control at 100°C for 12 min at 100 W. After
General procedure for the synthesis of compounds
10a–f.
Method 1: NaH (10 mmol) was added to the
solution of the corresponding compound 9 (10 mmol) in
THF, and the mixture was refluxed for 2 h. Then, the
suitable benzyl chloride (30 mmol) was added and the
mixture was refluxed for an additional 8–12 h. After
evaporating the solvent, an oily mass formed. This was
extracted with 15 mL of ethyl acetate for three times in
the presence of K2CO3, and the organic layer was dried
on Na2SO4. After the removal of solvents at a reduced
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives
pressure, a solid or an oily product was obtained, which
was recrystallized from acetone (for 10a, 10c) or purified
by column chromatography (ethyl acetate/n-hexane) (3/7)
for (10b, 10d–f).
133.17 (2CH), 134.55 (C), 134.72 (C), 134.85 (C),
137.83 (C), 140.33 (C), 141.62 and 141.96 (d, C,
J = 34.0 Hz), 153.27 (C), 155.99 and 157.78 (d, C, JC-
= 179.0 Hz)], 152.90 (triazole C-3), 155.42 (triazole C-
F
Method 2: The mixture of NaH (1 mmol) and the
corresponding compound 9 (1 mmol) in the THF were
irradiated in microwave reactor in the closed vessel with
pressure control at 70°C, 100 W for 5 min. Then, suitable
benzylchloride (3 mmol) was added and the irradiation
was continued for 20 min at 100°C, 120 W. After
evaporating the solvent under reduced pressure, an oily
mass formed. This was extracted with 15 mL of ethyl
acetate for three times in the presence of K2CO3, and the
organic layer was dried on Na2SO4. After the removal of
solvents at a reduced pressure, a solid or an oily product
was obtained, which was recrystallized from acetone (for
10a, 10c) or purified by column chromatography (ethyl
5). EI MS m/z (%): 668.09 ([M + 1]+, 100), 143.87 (51).
Elemental analysis for C34H31Cl3FN5O2, calculated (%):
C, 61.22; H, 4.68; N, 10.50. Found: C, 61.29; H, 4.53;
N, 10.86.
2-{2-(4-Chlorophenyl)-2-[(2,6-dichlorobenzyl)oxy]ethyl}-5-
{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2,4-
dihydro-3H-1,2,4-triazol-3-one (10c). Yield: 15% (method
1), 40% (method 2); mp 163–165°C. FT IR (νmax, cmꢀ1):
3063 (Aromatic CH), 2975 (Aliphatic CH), 1681 (C═O),
1
1510 (C═N). H NMR (DMSO-d6, δ ppm): 2.35 (s, 4H,
2CH2), 2.89 (s, 4H, 2CH2), 3.34 (s, 6H, 3CH2), 3.77–
3.81 (m, 1H, CH), 6.87–6.91 (m, 3H, ArH), 7.00–7.05
(m, 3H, ArH), 7.36–7.48 (m, 7H, ArH), 7.49 (s, 3H,
ArH). 13C NMR (DMSO-d6, δ ppm): 49.33 (2CH2),
52.26 (2CH2), 52.36 (CH2), 52.52 (CH2), 65.37 (CH2),
70.07 (CH), arC: [115.59 and 115.81 (d, 2CH,
J = 22.0 Hz), 117.51 and 117.59 (d, 2CH, J = 8.0 Hz),
127.43 (3CH), 128.53 (3CH), 128.63 (2CH), 128.80
(2CH), 129.42 (2CH), 132.33 (C), 133.90 (2C), 142.01
(C), 142.91 (2C), 148.22 and 148.24 (d, C, J = 22.0 Hz),
153.32 (C)], 155.30 (triazole C-3), 157.64 (triazole C-5).
EI MS m/z (%): 667.09 ([M]+, 56), 400.54 (100), 341.09
(75). Elemental analysis for C34H31Cl3FN5O2, calculated
(%): C, 61.22; H, 4.68; N, 10.50. Found: C, 61.28; H,
acetate/n-hexane) (3/7) for (10b, 10d–f).
2-[2-[(4-Chlorobenzyl)oxy]-2-(4-chlorophenyl)ethyl]-5-{[4-
(4-fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2,4-dihydro-
3H-1,2,4-triazol-3-one (10a). Yield: 24% (method 1), 45%
(method 2); mp 120–122°C. FT IR (νmax, cmꢀ1): 3054
(Aromatic CH), 2956 (Aliphatic CH), 1706 (C═O), 1508
(C═N). 1H NMR (DMSO-d6, δ ppm): 2.32 (s, 4H,
2CH2), 2.82 (s, 4H, 2CH2), 3.33 (s, 6H, 3CH2), 3.90 (brs,
1H, CH), 6.87 (d, 2H, ArH, J = 3.2 Hz), 7.02 (s, 2H,
ArH), 7.29 (s, 2H, ArH), 7.39–7.49 (m, 11H, ArH).13C
NMR (DMSO-d6, δ ppm): 45.63 (CH2), 49.26 (2CH2),
50.47 (2CH2), 52.22 (CH2), 69.67 (CH2), 78.21 (CH),
arC: [115.59 and 115.80 (d, 2CH, J = 21.0 Hz), 117.49
and 117.56 (d, 2CH, J = 7.0 Hz), 127.35 (2CH), 128.66
(2CH), 129.06 (2CH), 129.37 (2CH), 129.42 (2CH),
129.48 (2CH), 132.44 (CH), 133.28 (C), 133.79 (C),
137.61 (C), 138.18 (C), 142.00 (C), 143.09 (C), 153.34
and 155.29 (d, C, JC-F = 195.0 Hz)], 148.17 (triazole C-
3), 157.63 (triazole C-5). EI MS m/z (%): 632.27 ([M]+,
4.43; N, 10.78.
2-[2-[(4-Chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-5-
{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2,4-
dihydro-3H-1,2,4-triazol-3-one (10d). Yield: 42% (method
1), 60% (method 2); brown oil. FT IR (νmax, cmꢀ1): 3014
(Aromatic CH), 2956 (Aliphatic CH), 1709 (C═O), 1491
(C═N). 1H NMR (DMSO-d6, δ ppm): 2.88 (s, 2H,
CH2), 3.36 (s, 8H 4CH2), 4.76 (s, 2H, CH2), 4.96 (brs,
1H, CH), 6.88 (d, 2H, ArH, J = 4.4 Hz), 7.00 (d, 2H,
ArH, J = 8.4 Hz), 7.43–7.48 (m, 12H, ArH). 13C NMR
(DMSO-d6, δ ppm): 40.22 (CH2), 40.39 (CH2), 40.42
(CH2), 40.60 (CH2), 45.63 (CH2), 49.31 (CH2), 52.34
(CH2), 70.15 (CH), arC:[115.57 (2CH), 117.62 (2CH),
127.58 (2CH), 129.11 (3CH), 129.38 (3CH), 130.02
(2CH), 131.18 (2CH), 133.42 (3C), 134.87 (2C), 137.19
(3C)], 155.57 (triazole C-3), 158.64 (triazole C-5). EI
MS m/z (%): 668.11 ([M + 1]+, 100), 524.75 (56).
Elemental analysis for C34H31Cl3FN5O2, calculated (%):
C, 61.22; H, 4.68; N, 10.50. Found: C, 61.48; H, 4.73;
68),
178.28
(100).
Elemental
analysis
for
C34H32Cl2FN5O2, calculated (%): C, 64.56; H, 5.10; N,
11.07 Found: C, 64.66; H, 5.11; N, 11.16.
2-{2-(4-Chlorophenyl)-2-[(2,4-dichlorobenzyl)oxy]ethyl}-5-
{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2,4-
dihydro-3H-1,2,4-triazol-3-one (10b). Yield: 32% (method
1), 50% (method 2); brown oil. FT IR (νmax, cmꢀ1): 3002
(Aromatic CH), 2958 (Aliphatic CH), 1712 (C═O), 1473
(C═N).1H NMR (DMSO-d6, δ ppm): 2.39 (s, 2H, CH2),
2.89 (s, 2H, CH2), 3.31 (s, 2H, CH2), 3.44 (s, 2H, CH2),
3.62 (s, 1H, CH),4.78 (s, 6H, 3CH2), 6.85 (brs, 2H,
ArH), 6.99 (d, 2H, ArH, J = 8.0 Hz), 7.38–7.41 (m, 5H,
ArH), 7.56–7.61 (m, 7H, ArH). 13C NMR (DMSO-d6, δ
ppm): 43.28 (CH2), 52.22 (CH2), 56.34 (CH2), 56.56
(CH2), 60.26 (CH2), 64.43 (CH2), 65.89 (CH2), 70.11
(CH), arC: [115.55 and 115.77 (d, 2CH, J = 22.0 Hz),
117.61 (2CH), 127.95 (CH), 128.20 (2CH), 128.48 (CH),
128.55 (2CH), 129.05 (2CH), 129.57 (CH), 129.91 (CH),
N, 10.88.
2-[2-[(2,4-Dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-
5-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2,4-
dihydro-3H-1,2,4-triazol-3-one (10e). Yield: 47% (method
1), 55 (method 2); brown oil. FT IR (νmax, cmꢀ1): 3063
(Aromatic CH), 2956 (Aliphatic CH), 1712 (C═O), 1508
(C═N). 1H NMR (DMSO-d6, δ ppm): 2.41 (brs, 4H,
2CH2), 2.88 (brs, 4H, 2CH2), 3.00–3.44 (m, 2H, CH2),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Basoglu Ozdemir, N. Demirbas, A. Demirbas, F. A. Ayaz, and N. Çolak
Vol 000
4.77 (s, 4H, 2CH2), 5.04 (s, 1H, CH), 6.82–6.96 (m, 2H,
ArH), 6.98–7.00 (m,2H, ArH), 7.38 (s, 4H, ArH), 7.38–
7.48 (m, 2H, ArH), 7.50–7.61 (m, 5H, ArH). 13C NMR
(DMSO-d6, δ ppm): 43.29 (CH2), 46.05 (CH2), 49.31
(CH2), 52.26 (CH2), 52.32 (CH2), 60.29 (CH2), 60.50
(CH2), 78.28 (CH), arC:[115.51 and 115.73 (d, 2CH,
J = 22.0 Hz), 117.50 and 117.57 (d, 2CH, J = 7.0 Hz),
127.39 (CH), 127.50 (2CH), 127.95 (CH), 128.21 (2CH),
129.03 (CH), 129.33 (CH), 129.41 (2CH), 129.59 (CH),
133.49 (C), 133.66 (C), 133.70 (C), 134.56 (2C), 134.73
acidified to pH 4 with acetic acid. On cooling the
mixture in cold overnight, a solid obtained. The crude
product was filtered off and recrystallized from ethyl
acetate to yield to pure compound. Yield: 53% (method
1), 78% (method 2); mp 190–192°C.FT IR (νmax, cmꢀ1):
3079 (NH), 3019 (Aromatic CH), 2988 (Aliphatic CH),
1
1509 (C═N), 1226 (C═S). H NMR (DMSO-d6, δ ppm):
2.62 (d, 4H, 2CH2, J = 4.0 Hz), 3.07 (d, 4H, 2CH2,
J = 4.4 Hz), 3.71 (s, 2H, CH2), 6.91–6.95 (m, 2H, ArH),
7.01–7.05 (m, 2H, ArH). 13C NMR (DMSO-d6, δ ppm):
49.38 (2CH2), 51.65 (CH2), 52.44 (CH2), arC: [115.59
and 115.81 (d, 2CH, J = 21.0 Hz), 117.72 and 117.79
(d, 2CH, J = 7.0 Hz), 148.27 (C), 155.36 and 157.70 (d,
C, JC-F = 234.0 Hz)], 161.12 (triazole C-3), 178.65
(triazole C-5). EI MS m/z (%): 294.34 ([M]+,12), 293.40
(C), 134.86 (C), 153.27 and 155.36 (d, C, JC-F
=
209.0 Hz), 148.08 (C)], 153.36 (triazole C-3), 157.70
(triazole C-5). EI MS m/z (%): 701.67 ([M]+, 45), 500.50
(100). Elemental analysis for C34H30Cl4FN5O2,
calculated (%): C, 58.22; H, 4.31; N, 9.98. Found: C,
58.48; H, 4.55; N, 9.88.
2-[2-[(2,6-Dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-
5-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-4-phenyl-2,4-
(71),
193.14
(100).
Elemental
analysis
for
C13H15FN4OS, calculated (%): C, 53.05; H, 5.14; N,
19.03. Found: C, 53.40; H, 5.50; N, 19.18.
1-Ethyl-6-fluoro-7-(4-{[5-{[4-(4-fluorophenyl)piperazin-1-yl]
methyl}-2-thioxo-1,3,4-oxadiazol-3(2H)-yl]methyl}piperazin-1-
yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (12a).
dihydro-3H-1,2,4-triazol-3-one
(10f).
Yield:
43%
(method 1), 61% (method 2); orange oil. FT IR (νmax
,
cmꢀ1): 3073 (Aromatic CH), 2925 (Aliphatic CH), 1713
1
(C═O), 1508 (C═N). H NMR (DMSO-d6, δ ppm): 2.32
Yield: 25% (method 1), 55% (method 2); mp 210–211°C.
FT IR (νmax
,
cmꢀ1): 3075 (Aromatic CH), 2945
(s, 2H, CH2), 2.82 (s, 2H, CH2), 3.29 (s, 2H, CH2), 3.38
(s, 2H, CH2), 4.88 (s, 6H, 3CH2), 5.17 (s, 1H, CH),
6.81–6.90 (m, 2H, ArH), 6.98–7.00 (m, 2H, ArH), 7.40–
7.42 (m, 5H, ArH), 7.51 (d, 6H, ArH, J = 7.6 Hz).13C
NMR (DMSO-d6, δ ppm): 41.48 (CH2), 44.29 (CH2),
49.24 (2CH2), 52.16 (2CH2), 52.34 (CH2), 75.39 (CH),
arC: [115.51 and 115.56 (d, 2CH, J = 5.0 Hz), 117.55
(2CH), 127.33 (2CH), 127.46 (2CH), 127.97 (CH),
128.83 (CH), 129.00 (CH), 129.14 (CH), 129.30 (2CH),
129.43 (CH), 130.28 (C), 131.20 (C), 131.85 (C), 133.29
(C), 133.87 (C), 135.61 (C), 136.32 (C), 136.53 (C),
152.98 and 155.33 (d, C, J = 235.0 Hz)], 148.14 (triazole
C-3), 157.64 (triazole C-5). EI MS m/z (%): 702.07
([M + 1]+, 10), 514.25 (67), 512.24 (100), 332.20 (27),
159.07 (43). Elemental analysis for C34H30Cl4FN5O2,
calculated (%): C, 58.22; H, 4.31; N, 9.98. Found: C,
58.42; H, 4.33; N, 10.09.
(Aliphatic CH), 1725 (C═O), 1625 (C═O), 1505 (C═N),
1
1217 (C═S). H NMR (DMSO-d6, δ ppm): 1.40 (t, 3H,
CH3, J = 6.8 Hz), 2.65 (s, 4H, 2CH2), 2.93 (s, 4H,
2CH2), 3.06 (d, 4H, 2CH2), 3.33 (s, 4H, 2CH2), 3.77 (s,
2H, CH2), 4.56 (d, 2H, CH2, J = 6.8 Hz), 5.05 (s, 2H,
CH2), 6.88–6.91 (m, 2H, ArH), 6.98–7.03 (m, 2H, ArH),
7.13 (d, 1H, ArH, J = 7.2 Hz), 7.85 (d, 1H, ArH,
J = 13.2 Hz), 8.91 (s, 1H, quinolone CH), 15.30 (s, 1H,
OH). 13C NMR (DMSO-d6, δ ppm): 14.78 (CH3), 49.38
(2CH2), 49.50 (2CH2), 49.81 (CH2), 51.05 (CH2), 51.62
(CH2), 52.43 (2CH2), 68.93 (2CH2), 107.54 (C), arC:
[106.33 (CH), 111.50 and 111.73 (d, CH, J = 23.2 Hz),
115.56 and 115.78 (d, 2CH, J = 22.0 Hz), 117.67 and
117.75 (d, 2CH, J = 8.0 Hz), 119.64 and 119.72 (d, C,
J = 7.7 Hz), 137.58 (C), 145.64 and 145.74 (d, C,
J
JC-F
=
10.0 Hz), 151.99 and 154.47 (d, C,
= 248.0 Hz), 157.69 and 159.44 (d, C,
5-{[4-(4-Fluorophenyl)piperazin-1-yl]methyl}-1,3,4-
oxadiazole-2(3H)-thione (11). Method 1: The solution of
JC-F = 175.0 Hz), 155.35 (C)], 148.19 (oxadiazole C-2),
148.84 (CH), 166.52 (C═O), 176.56 (C═O), 178.49
(C═S). EI MS m/z (%): 625.36 ([M]+, 16), 302.24 (33),
276.19 (56), 256.31 (23), 233.15 (100). Elemental
analysis for C30H33F2N7O4S, calculated (%): C, 57.59; H,
5.32; N, 15.67. Found: C, 57.40; H, 5.51; N, 15.88.
1-Cyclopropyl-6-fluoro-7-(4-{[5-{[4-(4-fluorophenyl)
piperazin-1-yl]methyl}-2-thioxo-1,3,4-oxadiazol-3(2H)-yl]
methyl}piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
KOH (10 mmol) in water was added to the solution of
compound 3 in ethanol, and the mixture was refluxed in
the presence of CS2 (20 mmol) for 10 h. Then, ethanol
was evaporated and the aqueous solution acidified to pH
4 with acetic acid. On cooling the mixture in cold
overnight, a solid obtained. The crude product was
filtered off and recrystallized from ethyl acetate to yield
to pure compound.
carboxylic acid (12b).
Yield: 78% (method 1), 85%
Method 2: The solution of KOH (1 mmol) in water was
added to the solution of compound 3 in ethanol, and the
mixture was irradiated in closed vessels with the
pressure control 125°C, 125 W for 20 min. Then,
ethanol was evaporated and the aqueous solution
(method 2); mp 185–186°C. FT IR (νmax, cmꢀ1): 3661
(OH), 3020 (Aromatic CH), 2970 (Aliphatic CH), 1726
(C═O), 1675 (C═O), 1449 (C═N), 1252 (C═S).1H NMR
(DMSO-d6, δ ppm): 1.16 (s, 2H, CH2), 1.31 (d, 2H, CH2,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives
J = 6.4 Hz), 2.65 (s, 4H, 2CH2), 2.73 (s, 2H, CH2), 2.89 (s,
2H, CH2), 2.95 (s, 4H, 2CH2), 3.06 (s, 4H, 2CH2), 3.77 (s,
3H, CH2 + CH), 5.06 (s, 2H, CH2), 6.89–6.92 (m, 2H,
ArH), 6.99–7.04 (m, 2H, ArH), 7.53 (d, 1H, ArH,
J = 8.8 Hz), 7.85 (d, 1H, ArH, J = 13.2 Hz), 8.62 (s, 1H,
quinolone CH), 15.17 (s, 1H, OH). 13C NMR (DMSO-d6,
δ ppm): 8.03 (2CH2), 36.28 (CH), 49.38 (2CH2), 49.74
(2CH2), 51.61 (2CH2), 52.43 (2CH2), 69.91 (2CH2),
107.21 (C), arC: [106.96 (CH), 111.28 and 111.51 (d,
CH, J = 23.0 Hz), 115.57 and 115.79 (d, 2CH,
J = 22.0 Hz), 117.68 and 117.76 (d, 2CH, J = 8.0 Hz),
119.02 and 119.09 (d, C, J = 7.0 Hz), 139.56 (C), 145.36
and 145.46 (d, C, J = 10.0 Hz), 148.20 and 152.15 (d, C,
JC-F = 363.0 Hz), 154.63 (C), 155.36 and 159.45 (d, C,
JC-F = 385.0 Hz)], 148.36 (CH), 162.76 (C), 166.33
(C═O), 176.77 (C═O), 178.49 (C═S). EI MS m/z (%):
MA = 637.70 ([M]+ 12), 632.61 (14), 332.32 (100).
Elemental analysis for C31H33F2N7O4S, calculated (%):
C, 58.39; H, 5.22; N, 15.38. Found: C, 58.40; H, 5.21;
132.24 (C), 135.29 (C), 137.57 (C), 148.22 (C), 155.37
and 157.72 (d, C, J = 235.0 Hz)], 165.14 (oxadiazole C-
2), 178.52 (oxadiazole C-5), 193.88 (C═O). EI MS m/z
(%): 481.18 ([M]+, 22), 193.17 (100), 181.15 (23).
Elemental analysis for C21H19Cl2FN4O2S, calculated (%):
C, 52.40; H, 3.98; N, 11.64. Found: C, 52.60; H, 3.71;
N, 11.48.
4-Amino-5-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-2,4-
dihydro-3H-1,2,4-triazole-3-thione (14).
Method 1: The
solution of compound 11 (10 mmol) in ethanol was
added to hydrazine hydrate and the mixture was refluxed
for 16 h. After evaporating the solvent, a solid appeared.
This crude product was recrystallized from ethyl acetate
to yield the target product.
Method 2: The solution of compound 11 (mmol) in
ethanol was added to hydrazine hydrate and the mixture
was irradiated in closed vessels with the pressure control
125°C, 125 W for 20 min. After evaporating the solvent,
a solid appeared. This crude product was recrystallized
from ethyl acetate to yield the target product. Yield: 54%
(method 1), 77% (method 2); mp 167–169°C. FT IR
(νmax, cmꢀ1): 3312 and 3215 (NH2), 3109 (NH), 3061
(Aromatic CH), 1254 (C═S).1H NMR (DMSO-d6, δ
ppm): 2.60 (s, 4H, 2CH2), 3.06 (s, 4H, 2CH2), 3.65 (s,
2H, CH2), 5.57 (s, 2H, NH2), 6.94 (d, 2H, ArH,
J = 4.4 Hz), 7.02 (d, 2H, ArH, J = 8.8 Hz), 7.13 (s, 1H,
NH).13C NMR (DMSO-d6, δ ppm): 49.34 (CH2), 49.37
(CH2), 50.76 (CH2), 50.88 (CH2), 52.66 (CH2), arC:
[115.58 and 115.80 (d, 2CH, J = 22.0 Hz), 117.55 and
117.68 (d, 2CH, J = 13.0 Hz), 148.33 and 148.92 (d, C,
N, 15.78.
1-(4-Chlorophenyl)-2-[5-{[4-(4-fluorophenyl)piperazin-1-yl]
methyl}-2-thioxo-1,3,4-oxadiazol-3(2H)-yl]ethanone (13a).
Yield: 70% (method 1), 87% (method 2); mp 108–110°C.
FT IR (νmax
,
cmꢀ1): 3089 (Aromatic CH), 2921
(Aliphatic CH), 1682 (C═O), 1488 (C═N), 1218 (C═S).
1H NMR (DMSO-d6, δ ppm): 2.58 (s, 4H, 2CH2), 3.04
(t, 4H, 2CH2, J = 4.0 Hz), 3.84 (s, 2H, CH2), 5.07 (d,
2H, CH2, J = 13.6 Hz), 6.89–6.93 (m, 2H, ArH), 7.00–
7.05 (m, 2H, ArH), 7.63 (d, 2H, ArH, J = 8.4 Hz), 8.06
(d, 2H, ArH, J = 8.4 Hz). 13C NMR (DMSO-d6, δ ppm):
49.36 (2CH2), 51.29 (CH2), 51.87 (CH2), 52.38 (CH2),
52.51 (CH2), arC: [115.58 and 115.79 (d, 2CH,
J = 21.0 Hz), 117.67 and 117.75 (d, 2CH, J = 8.0 Hz),
129.56 (2CH), 130.82 (2CH), 134.20 (C), 139.39 (C),
148.22 and 148.24 (d, C, J = 2.0 Hz), 155.35 and 157.70
(d, C, J = 235.0 Hz)], 163.97 (oxadiazole C-2), 165.12
(oxadiazole C-5), 192.04 (C═O). EI MS m/z (%): 294.34
([M]+, 12), 293.40 (71), 193.14 (100). Elemental analysis
for C21H20ClFN4O2S, calculated (%): C, 56.44; H, 4.51;
N, 12.54. Found: C, 56.60; H, 4.71; N, 12.48.
J = 59.0 Hz), 155.27 and 157.61 (d, C, JC-F
=
234.0 Hz)], 162.36 (triazole C-3), 166.19 (triazole C-5).
EI MS m/z (%): 309.65 ([M]+, 43), 181.15 (100), 171.20
(78). Elemental analysis for C13H17FN6S, calculated (%):
C, 50.63; H, 5.56; N, 27.25. Found: C, 50.60; H, 5.71;
N, 27.40.
5-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-4-{[(4-
nitrophenyl)methylene]amino}-2,4-dihydro-3H-1,2,4-triazole-
3-thione (15). Method 1: The solution of compound 14
(10 mmol) in absolute ethanol was refluxed with 4-
nitrobenzaldehyde (10 mmol) for 3 h. On cooling the
reaction content to room temperature, a solid appeared.
This crude product was filtered off and recrystallized
from ethanol.
1-(2,4-Dichlorophenyl)-2-[5-{[4-(4-fluorophenyl)piperazin-1-
yl]methyl}-2-thioxo-1,3,4-oxadiazol-3(2H)-yl]
ethanone
(13b).
Yield: 50% (method 1), 70% (method 2); mp
165–166°C. FT IR (νmax, cmꢀ1): 3077 (Aromatic CH),
2988 (Aliphatic CH), 1687 (C═O), 1508 (C═N), 1226
Method 2: 4-nitrobenzaldehyde (1 mmol) was added to
the solution of compound 14 (1 mmol) in absolute
ethanol, and the reaction mixture was irradiated by
microwave at 150 W and 110°C for 10 min. After
removing in the solvent under reduced pressure, a solid
product obtained. This crude product was recrystallized
from ethanol. Yield 75% (method 1), 94% (method 2);
mp148–150°C. FT IR (νmax, cmꢀ1): 3365 (NH), 3085
(Aromatic CH), 2989 (aliphatic CH), 1543 (C═N), 1510
1
(C═S). H NMR (DMSO-d6, δ ppm): 2.63 (s, 4H, 2CH2),
3.07 (s, 4H, 2CH2), 3.73 (s, 2H, CH2), 3.85 (s, 2H, CH2),
6.94 (d, 2H, ArH, J = 3.6 Hz), 7.03 (t, 2H, ArH,
J = 8.0 Hz), 7.61 (d, 1H, ArH, J = 8.4 Hz), 7.78 (s, 1H,
ArH), 7.90 (d, 1H, ArH, J = 8.4 Hz). 13C NMR (DMSO-
d6, δ ppm): 42.70 (CH2), 49.35 (CH2), 51.27 (CH2),
51.56 (CH2), 52.41 (2CH2), arC: [115.59 and 115.81 (d,
2CH, J = 22.0 Hz), 117.73 and 117.81 (d, 2CH,
J = 8.0 Hz), 128.12 (CH), 130.75 (CH), 131.96 (CH),
and 1340 (NO2). 1H NMR (DMSO-d6,
δ ppm):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Basoglu Ozdemir, N. Demirbas, A. Demirbas, F. A. Ayaz, and N. Çolak
Vol 000
3.42–3.47 (m, 6H, 3CH2), 3.71–3.76 (m, 2H, CH2), 4.65
(s, 2H, CH2), 7.03 (t, 2H, ArH, J = 4.8 Hz), 7.11 (t, 2H,
ArH, J = 4.8 Hz), 8.03 (d, 2H, ArH, J = 7.2 Hz), 8.28 (d,
2H, ArH, J = 8.8 Hz), 11.20 (s, 1H, N═CH). 13C NMR
(DMSO-d6, δ ppm): 47.83 (CH2), 51.90 (CH2), 52.05
(CH2), 56.48 (CH2), 61.68 (CH2), arC: [115.88 and
116.10 (d, 2CH, J = 32.0 Hz), 118.32 and 118.40 (d,
2CH, J = 8.0 Hz), 124.41 (CH), 124.59 (CH), 128.18
(2CH), 130.05 (CH), 141.39 (C), 146.79 (C), 147.96 (C),
152.14 and 155.94 (d, C, JC-F = 380.0 Hz)], 148.62
(triazole C-3), 158.29 (triazole C-5). EI MS m/z (%):
442.65 ([M + 1]+, 67), 320.76 (100). Elemental analysis
for C20H20FN7O2S, calculated (%): C, 54.41; H, 4.57; N,
(CH), 46.63 (2CH2), 48.99 (2CH2), 50.09 (2CH2), 51.85
(CH2), 56.85 (2CH2), 66.24 (CH2), 106.07 (C), arC:
[107.31 (CH), 112.18 and 112.38 (d, 2CH, J = 20.0 Hz),
114.20 and 114.36 (d, 2CH, J = 16.0 Hz), 118.05 (CH),
120.02 and 120.20 (d, C, J = 18.0 Hz), 124.16 and
124.26 (d, C, J = 10.0 Hz), 126.05 (CH), 127.50 (2CH),
128.90 (CH), 133.45 (C), 135.65 (C), 141.38 (C), 142.63
(C), 147.95 (C), 152.14 and 155.94 (d, C,
JC-F = 380.0 Hz)], 148.47 (CH), 152.13 (N=CH), 148.54
(triazole C-3), 160.64 (triazole C-5), 166.38 (C═O),
173.34 (C═O). EI MS m/z (%): 785.65 ([M + 1]+, 34),
300.19 (100). Elemental analysis for C38H38F2N10O5S,
calculated (%): C, 58.15; H, 4.88; N, 17.85 Found: C,
58.18; H, 4.70; N, 17.99.
22.21. Found: C, 54.60; H, 4.71; N, 22.49.
1-Ethyl-5-fluoro-6-{4-[(3-{[4-(4-fluorophenyl)piperazin-1-yl]
methyl}-4-{[(4-nitrophenyl)methylene]amino}-5-thioxo-4,5-
dihydro-1H-1,2,4-triazol-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-
Biological activities. Antimicrobial activity.
The test
microorganisms were obtained from the Hifzissihha
Institute of Refik Saydam (Ankara, Turkey) and were as
follows: Escherichia coli (E. coli) ATCC35218, Yersinia
pseudotuberculosis (Y. pseudotuberculosis) ATCC911,
Pseudomonas aeruginosa (P. aerugi-nosa) ATCC43288,
Enterococcus faecalis (E. faecalis) ATCC29212, Staphylo-
coccus aureus (S. aureus) ATCC25923, Bacillus cereus
(B. cereus) 709 Roma, Mycobacterium smegmatis
(M. smegmatis) ATCC607, Candida albicans (C. albicans)
ATCC60193 and Saccharo-myces cerevisiae (S. cerevisia)
RSKK 251. All the newly synthesized compounds were
weighed and dissolved in dimethyl sulfoxide to prepare
extract stock solution of 20.000 microgram/milliliter
(mg/mL). The antimicrobial effects of the substances were
tested quantitatively in respective broth media by using dou-
ble micro-dilution and the minimal inhibition concentration
values (mg/mL) were determined. The antibacterial and anti-
fungal assays were performed in Mueller–Hinton broth
(Difco, Detroit, MI, USA) at pH 7.3 and buffered Yeast
Nitrogen Base (Difco, Detroit, MI) at pH 7.0, respectively.
The micro-dilution test plates were incubated for 18–24h at
35°C. Brain heart infusion broth (Difco, Detriot, MI) was
used for M. smegmatis and incubated for 48–72 h at 35°C
[49]. Ampicillin (10 mg) and fluconazole (5 mg) were used
as standard antibacterial and antifungal drugs, respectively.
Dimethyl sulfoxide with dilution of 1:10 was used as solvent
control. Only positive results were presented in Table 2.
dihydroquinoline-3-carboxylic acid (16a).
Yield: 45%
(method 1), 58% (method 2); mp 184–186°C. FT IR
(νmax, cmꢀ1): 3365 (OH), 3085 (Aromatic CH), 2989
(Aliphatic CH), 1705 (2C═O), 1510 (C═N), 1209 (C═S).
1H NMR (DMSO-d6, δ ppm): 1.40 (s, 3H, CH3), 2.09 (s,
2H, CH2), 2.50 (s, 4H, 2CH2), 2.73 (s, 6H, 3CH2), 3.35
(s, 8H, 4CH2), 4.58 (s, 2H, CH2), 7.00 (brs, 1H, ArH),
8.02 (brs, 4H, ArH), 8.30 (brs, 5H, ArH), 8.95 (s, 1H,
quinolone CH), 11.21 (s, 1H, N═CH), 15.38 (s, 1H, OH).
13C NMR (DMSO-d6, δ ppm): 14.87 (CH3), 46.65
(2CH2), 48.90 (2CH2), 50.01 (2CH2), 51.25 (2CH2),
56.65 (2CH2), 65.24 (CH2), 106.67 (C), arC: [107.21
(CH), 112.14 and 112.34 (d, 2CH, J = 20.0 Hz), 114.25
and 114.46 (d, 2CH, J = 21.0 Hz), 118.45 (CH), 120.12
and 120.20 (d, C, J = 8.0 Hz), 124.26 and 124.36 (d, C,
J = 10.0 Hz), 127.65 (2CH), 129.50 (2CH), 131.24 (C),
134.45 (C), 137.65 (2C), 141.54 and 141.64 (d, C,
J = 10.0 Hz), 152.14 and 155.94 (d, C, JC-F
=
380.0 Hz)], 148.31 (CH), 152.23 (N═CH), 149.54
(triazole C-3), 158.76 (triazole C-5), 165.25 (C═O),
172.34 (C═O). EI MS m/z (%): 772.65 ([M]+, 54),
300.15 (100). Elemental analysis for C37H38F2N10O5S,
calculated (%): C, 57.50; H, 4.96; N, 18.12. Found: C,
57.68; H, 4.77; N, 18.19.
1-cyclopropyl-5-fluoro-7-{4-[(3-{[4-(4-fluorophenyl)
piperazin-1-yl]methyl}-4-{[(4-nitrophenyl)methylene]amino}-5-
thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl]piperazin-1-yl}-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid (16b). Yield:
Antioxidant
activity. 2,2-Diphenyl-1-picrylhydrazyl
radical scavenging activity.
The scavenging activity of
32% (method 1), 55% (method 2); mp 175–178°C. FT IR
(νmax, cmꢀ1): 3226 (OH), 3078 (Aromatic CH), 2929
(Aliphatic CH), 1698 (C═O), 1661 (C═O), 1586 (C═N),
1508 and 1340 (NO2). 1H NMR (DMSO-d6, δ ppm):
1.17 (brs, 2H, CH2), 1.30 (brs, 2H, CH2), 2.72 (s, 4H,
2CH2), 2.88 (s, 4H, 2CH2), 3.34 (s, 12H, 6CH2), 3.79 (s,
1H, CH), 7.00 (brs, 1H, ArH), 7.57 (s, 1H, ArH), 8.03
(brs, 4H, ArH), 8.29 (brs, 4H, ArH), 8.65 (s, 1H,
quinolone CH), 11.20 (s, 1H, N═CH), 15.21 (brs, 1H,
OH). 13C NMR (DMSO-d6, δ ppm): 8.08 (2CH2), 36.23
the synthesized novel compounds was determined using
the free radical DPPH according to method of with slight
modifications. Blois [50]. In brief, a 100-μL compound
solution was mixed with 1 mL of freshly prepared
methanolic DPPH solution. The reaction mixture was
incubated for 30 min at room temperature in the dark
and then measured at 520 nm using a UV–VIS
spectrophotometer (Thermo, Evolution 100, and
England). The results were expressed as μmol Trolox
equivalent.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Piperazine-Azole-Fluoroquinolone Based 1,2,4-Triazole Derivatives
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Synthesis and antimicrobial activities of some new [1,2,4]triazolo[3,4-b]
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Basoglu Ozdemir, N. Demirbas, A. Demirbas, F. A. Ayaz, and N. Çolak
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet