Synthesis and antimicrobial activity of new piperazine-based heterocyclic compounds

Article abstract of DOI:10.1515/hc-2016-0125

The hydrazide 5, that was obtained from 1-(4-fluorophenyl)piperazine (1), was converted to the corresponding carbothioamides 6a-c by the reaction with alkyl(aryl) isothiocyanates. The synthesis of conazole analogs 10a-f was performed via the intermediary

Full text of DOI:10.1515/hc-2016-0125

Heterocycl. Commun. 2017; aop
Serap Basoglu Ozdemir, Yıldız Uygun Cebeci, Hacer Bayrak, Arif Mermer, Sule Ceylan,
Ahmet Demirbas, Sengul Alpay Karaoglu and Neslihan Demirbas*
Synthesis and antimicrobial activity of new
piperazine-based heterocyclic compounds
DOI 10.1515/hc-2016-0125
In recent years, the concept of hybrid molecules
Received August 12, 2016; accepted October 12, 2016
which contain two or more pharmacophore groups bound
together covalently in one molecular framework has been
introduced. It has been suggested that such compounds
may inhibit two or more conventional targets simultane-
ously. This multiple target strategy has already resulted
in the development of a number of bioactive hybrid
molecules [9].
Abstract: The hydrazide 5, that was obtained from
1-(4-fluorophenyl)piperazine (1), was converted to the cor-
responding carbothioamides 6a–c by the reaction with
alkyl(aryl) isothiocyanates. The synthesis of conazole
analogs 10a–f was performed via the intermediary of
triazoles 7a–c. The condensation of triazoles 7a–c with
several heterocyclic amines in the presence of formalde-
hyde afforded the corresponding N-aminoalkylated tria-
zoles 11–14. The effect of different catalysts and solvents
on conventional and microwave (MW)-prompted reac-
tions was examined. The synthesized compounds were
screened for their antimicrobial activities.
Multicomponent reactions with at least three com-
ponents in the one-pot process to give a single product
represent a unique strategy leading to the formation of
various bioactive molecules, due to their convergence,
low energy consumption, minimum waste production,
facile execution, high selectivity and productivity [10–12].
On the other hand, microwave (MW) techniques are more
Keywords: antimicrobial activity; conazole; Mannich dynamic and effective than the conventional methods
base; microwave; piperazine.
[13–16]. The success of combinatorial chemistry aiming
at the discovery of new drug candidates depends on the
advances in the one-pot multicomponent reactions with
ecofriendly procedures. Solvent is one of the key factors
when it is used in large quantities [11]. Most organic sol-
vents are toxic, and they should be used in minimum
quantities as far as possible or should be replaced with
nontoxic alternatives, preferably with water [17–23].
A piperazine ring is a core structure of many mar-
keted drugs including fluoroquinolone antibiotics such as
norfloxacin, ciprofloxacin and levofloxacin [24–29]. Sub-
stituted piperazines often show increased antimicrobial
activity probably by enhancing lipophilicity of the mol-
ecule [30]. In biologically active products, piperazine is
often present as a fused or oxidized form [31] or is substi-
tuted with an azole (1,2,4-triazole and/or imidazole) [32].
Introduction
During the past few years, the excessive use of common
antimicrobial drugs has caused the emergence of resistant
bacteria leading to diminished efficiency of these drugs
[1–5]. This rapid emergence of drug resistance has now
become a serious public health problem [6, 7]. The increas-
ing resistance problem has prompted the synthesis of new
chemical entities in an effort to come up with new drugs
with better therapeutic properties including better toler-
ability, less side effects and low tendency to resistance [8].
*
Corresponding author: Neslihan Demirbas, Karadeniz Technical
University, Department of Chemistry, 61080 Trabzon, Turkey,
e-mail: neslihan@ktu.edu.tr
Serap Basoglu Ozdemir, Yıldız Uygun Cebeci, Arif Mermer and
Ahmet Demirbas: Karadeniz Technical University, Department of
Chemistry, 61080 Trabzon, Turkey
Results and discussion
Hacer Bayrak: Karadeniz Technical University, Department of
Chemistry and Chemical Processing Technology, 61080 Trabzon,
Turkey
Sule Ceylan: Artvin Coruh University, Department of Occupational
Health and Safety, Artvin, Turkey
Sengul Alpay Karaoglu: Recep Tayyip Erdoğan University,
Department of Biology, Rize, Turkey
Chemistry
Synthesis of the target compounds was carried out as
illustrated in Schemes 1 and 2. The key substrate 5 was
prepared from 1-(4-fluorophenyl)piperazine (1) by con-
ventional and also MW-assisted methods in four steps.
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ꢁꢁꢁꢂ
2ꢀ ꢀS. Basoglu Ozdemir et al.: New piperazine based heterocyclic compounds
i
ii
F
N
NH
F
N
N
NO2
F
N
N
NH2
1
F
F
2
3
iii
O
H
N
iv
F
N
N
NH
O
F
N
N
NHNH2
F
OEt
F
5
4
v
O
N
NH
H
N
H
N
H
vi
H
N
F
N
N
N
F
N
N
N
R
N
S
H
S
F
F
R
6
8
a–c
O
N
N
N
vii
H
Cl
N
F
N
N
N
H
N
N
SH
F
N
N
N
S
F
R
a–c
R
7a–c
F
Z
Y
viii
X
N
HO
S
O
Cl
N
N
Cl
H
N
ix
N
H
N
F
N
N
F
N
N
N
N
S
R
F
R
F
9
a–c
10a–i
6a–9a, 10a–c: R=Ph
6b–9b, 10d–f: R=Bn
6c–9c, 10g–i: R=Et
10a: X=Y=H; Z=Cl
10b: X=Z=Cl; Y=H
10c: X=Y=Cl; Z=H
10d: X=Y=H; Z=Cl
10e: X=Z=Cl; Y=H
10f: X=Y=Cl; Z=H
Scheme 1ꢁSynthetic route for compounds 2–10. (i): 3,4-difluoronitrobenzene, NaHCO ; (ii): H NNH , Pd-C; (iii): BrCH COOEt, Et3N;
3
2
2
2
(
iv): H NNH , EtOH; (v): isothiocyanate, DCM; (vi): 2N NaOH, H Oꢂ+ꢂEtOH; (vii): 4-ClC H COCH Br, Na, EtOH; (viii): NaBH4; (ix): NaH, THF,
2 2 2 6 4 2
substituted benzyl chloride.
The treatment of 5 with phenyl, benzyl or ethyl isothio- tautomeric form and this conclusion is also true for com-
cyanate generated the corresponding carbothioamide pounds 7a–c. On the basis of analysis of the spectral data
derivatives 6a–c. The reactions were conducted in dichlo- (see Experimental section), it can be suggested that 7a,b
romethane at room temperature and under MW irradia- and 7c exist preferentially in the respective thione and
tion in the attempts to maximize the yields of the products thiol forms.
and minimize the reaction times. The reaction time for
Alkylation of compounds 7a–c with 2-bromo-1-(4-chlo-
complete consumption of starting materials was lowered rophenyl)ethanone in ethanol afforded the corresponding
from 24 h for a conventional heating to a remarkable 8 min compounds 8a–c. Compared with a conventional heating,
using MW irradiation. The optimal MW power in terms of MW irradiation decreased the reaction time from 22 h to
yield and product stability was assessed at 150 W at 125°C 25 min and increased the yields from 22%–35% to 52%–
in a closed vessel without any solvent. Products 6a–c 75%. The best yields were obtained at 150°C for 25 min at
were obtained in yields of 91%–97%.
150 W maximum power. Compounds 7a–c can, in princi-
The treatment of compounds 6a–c with a base yielded ple, be alkylated at the sulfur or nitrogen atom. The struc-
1
,2,4-triazole derivatives 7a–c. The ring closure reactions tures of the resultant products 8a–c were suggested (see
1
leading to compounds 7a–c were identified with IR, H Experimental) based on the spectral data but additional
13
NMR, C NMR, mass spectral and elemental analyses. Our work is needed to support this analysis. The reduction
previous studies [5, 24, 30, 33–35] have demonstrated that of carbonyl group with NaBH in 8a–c to alcohol gave
4
the 3-mercapto-1,2,4-triazoles can exist in a thione or thiol compounds 9a–c which, again, was achieved using both
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S. Basoglu Ozdemir et al.: New piperazine based heterocyclic compoundsꢀꢂꢁꢁꢁꢀ3
O
O
F
OH
N
N
Norfoxacin for 11a–c
Ciprofloxacin for 12a–c
N
R′
H
N N
F
N
N
N
HCHO, DMF
N
R
S
F
1
1a–c, 12a–c
1
1
1
1a, 12a: R=Ph
1b, 12b, 13a: R=Bn
1c, 12c, 13b: R=Et
Thiomorpholine
HCHO, DMF
7a–c
F
N
N
NH
N
N
N
11a–c: R′=Et
S
1
2a–c: R′=cyclopropyl
F
N
S
1
3a,b
R
1
-phenylpiperazine
HCHO, DMF
F
N
N
NH
N
N
N
N
N
F
S
1
4
Scheme 2ꢁ
classical heating and MW irradiation. For MW-prompted the presence of different Lewis and Bronsted acid catalysts
reactions leading to the formation of compounds 9a–c, the such as p-TSA, FeCl , InCl and HCl. The effects of various
3
3
reduction of compound 9a was selected as model and the reaction parameters, including temperature, catalyst,
effects of various reaction parameters, including solvent, solvent, MW power and time were examined. In all cases,
temperature, time and MW power were examined. The completion of the reaction was monitored by the thin-layer
results showed that the best yield was obtained in ethanol chromatography (TLC) analysis. The solvent-free reaction
with MW irradiation at 100 W and 100°C for 20 min. The with HCl as a catalyst constituted the optimal method yield-
synthesis of compounds 10a–f was achieved by treatment ing the desired product 11a within 20 min at 70 W with the
of compounds 9a–c with substituted benzyl chlorides, yield of 83%. The spectral analysis of products 11–14 (see
namely 4-chloro-, 2,4-dichloro- and 2,6-dichlorobenzyl Experimental section) strongly suggested the N-alkylated
chlorides in the presence of NaH under MW-mediated thione structure in all cases as shown in Scheme 2.
and conventional conditions. In order to improve the MW
Mannich bases have been used previously as poten-
conditions, the reaction leading to the formation of 10a tially useful prodrug candidates for imides, amides,
was selected as a model reaction and the effects of several amines, hydantoin and urea derivatives. It is believed that
parameters including time, power and solvent were exam- the N-alkyl group in Mannich bases increases the lipophi-
ined. After optimization of the conditions for the prepa- licity of the parent amines at physiological pH values by
ration of 10a, the synthesis of the remaining compounds decreasing their protonation that results in enhancement
1
0b–i was carried out. Again, it should be noted that the of absorption through biomembranes [33].
structural assignments for products 9a–c and 10a–i are
tentative and additional work is needed to show the N- or
S-alkylation site (Scheme 1).
Biological activity
The aminoalkylation of compounds 7a–c with several
secondary amines, namely norfloxacin (for 11a–c), cipro- All compounds were tested for their antimicrobial activi-
floxacin (for 12a–c), thiomorpholine (for 13a,b) and phe- ties, and the results for active derivatives are presented
nylpiperazine (for 14) in the presence of formaldehyde in Table 1. Compounds of low activity are not included.
was conducted under the MW-assisted Mannich reaction No clear structure-activity relationships can be detected,
conditions (Scheme 2). Initially, to optimize the conditions indicating that the antibacterial activity is significantly
for this one-pot three-component reaction, compound 11a affected by the nature of the compound. It is evident from
was selected as a model product, and the model reactions Table 1 that the aminoalkylation of triazoles 7a–c with
were performed in polar solvents and without solvent in fluoroquinolones namely norfloxacin and ciprofloxacin
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ꢁꢁꢁꢂ
4ꢀ ꢀS. Basoglu Ozdemir et al.: New piperazine based heterocyclic compounds
Table 1ꢁScreening for antimicrobial activity.
obtained on a Quattro GC-MS (70 eV) instrument. MW-assisted reac-
tions were performed in a CEM Discovery reactor.
Comp.
No
Ec
Yp
Pa
Sa
Ef
Bc
Ms
1
-(2-Fluoro-4-nitrophenyl)-4-(4-fluorophenyl)-
8
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
b
–
–
–
–
ꢃꢄꢄ
–
ꢅꢆꢃ
ꢅꢃ.ꢈ
ꢄ.ꢉ9
ꢅꢆꢃ
ꢅꢆꢃ
–
ꢇ.9ꢅ
ꢂa
ꢁa
ꢁb
ꢁc
ꢃa
ꢃb
ꢃc
ꢅꢃ.ꢈ
ꢃꢄꢄ piperazine (2)
<ꢂꢄ.ꢆꢉ
ꢄ.ꢆꢉ
–
ꢄ.ꢉ9
ꢄ.ꢉ9
ꢅ.9
ꢅ.9ꢃ
ꢄ.9ꢊ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ
ꢄ.9ꢊ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ
ꢅ.9ꢃ <ꢂꢄ.ꢆꢉ
ꢅ.9
ꢅ.9ꢃ
Method 1ꢁA mixture of 1-(4-fluorophenyl)-piperazine (10 mmol),
ꢅ.9
ꢄ.ꢉ9
–
ꢅ.9
ꢇ.9
3
,4-difluoronitrobenzene (10 mmol) and NaHCO (30 mmol) in ace-
3
<ꢂꢄ.ꢆꢉ
<ꢂꢄ.ꢆꢉ
–
ꢄ.ꢉ9
ꢄ.9ꢊ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ
ꢄ.9ꢊ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ
tonitrile (50 mL) was heated under reflux for 8 h. Concentration
ꢄ.ꢉ9 <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ
under reduced pressure resulted in the formation of a yellow solid
that was treated with water, filtered off and crystallized from ethyl
acetate to give the target yellow compound in a 64% yield.
<ꢂꢅ
ꢅꢊ >ꢂꢅꢆꢊ
<ꢂꢅ
<ꢂꢅ
ꢅꢄ
–
ꢇꢃ
<ꢂꢅ
ꢅꢃ
<ꢂꢅ
–
Amp.
Norf.
Cip.
ꢅꢄ
<ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ
<ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ <ꢂꢄ.ꢆꢉ
Method 2ꢁA mixture of 1-(4-fluorophenyl)-piperazine (1 mmol),
Strep.
ꢉ
NaHCO (3 mmol) and 3,4-difluoronitrobenzene (1 mmol) was irra-
3
diated in a MW reactor with pressure control at 125°C, 150 W for
Ec, Escherichia coli ATCC 25ꢋ22; Yp, Yersinia pseudotuberculosis
ATCC ꢋ11; Pa, Pseudomonas aeruginosa ATCC 43288; Sa, Staphy-
lococcus aureus ATCC 25ꢋ23; Ef, Enterococcus faecalis ATCC 2ꢋ212;
Bc, Bacillus cereus 702 Roma; Ms, M. smegmatis ATCC607; Amp.,
Ampicillin; Strep., streptomycin; Norf., Norloxacin; Cip., Ciprofloxa-
cin; –, no activity.
3
0 min. The yellow solid obtained was treated with water, filtered
off and crystallized from ethyl acetate to give the target yellow com-
pound in a 90% yield; mp 95–96°C; IR: ν 3081 (aromatic CH),
max
975 (aliphatic CH), 1503 and 1337 cmꢀ (NO ); H NMR: δ 3.23 (brs,
−ꢀ1
1
2
2
4
H, 2CH ), 3.42 (brs, 4H, 2CH ), 6.99–7.02 (m, 2H, ArH), 7.05–7.10 (m,
2
2
1
3
2
H, ArH), 7.21 (t, 1H, ArH, Jꢀ=ꢀ8.8 Hz), 8.02 (d, 2H, ArH, Jꢀ=ꢀ11.2 Hz); C
NMR: δ 49.4 (2CH ), 49.5 (CH ), 49.5 (CH ), Aryl-C: [112.6 and 112.8
2
2
2
(
(
d, CH, Jꢀ=ꢀ20 Hz), 115.7 and 115.9 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.9 and 118.0
d, 2CH, Jꢀ=ꢀ10 Hz), 118.5 and 118.6 (d, CH, Jꢀ=ꢀ10 Hz), 121.7 (CH),
gives rise to the excellent activity of the resultant prod-
ucts 11a–c and 12a–c toward the test bacteria with the
minimum inhibitory concentration (MIC) values between
1
39.9 and 140.0 (d, C, Jꢀ=ꢀ10 Hz), 145.5 and 145.6 (d, C, Jꢀ=ꢀ10 Hz),
48.0 (C), 151.3 and 153.8 (d, C, JCꢀ−ꢀFꢀ=ꢀ250 Hz), 155.6 and 157.9 (d,
1
0
.24 and 1.9 μg/mL. It can be suggested that excellent activ-
+
+
C, JC−Fꢀ=ꢀ230 Hz)]; MS: m/z 360.57 ([Mꢀ+ꢀ2ꢀ+ꢀK]ꢀ , 93), 321.45 ([Mꢀ+ꢀ2]ꢀ ,
ity of these compounds is due to the presence of a fluoro- 33), 193.14 (42), 150.94 (49), 135.03 (100), 117.04 (55%). Anal. Calcd
for C H F N O : C, 60.18; H, 4.73; N, 13.16. Found: C, 60.58; H, 4.65;
quinolone core in their structures. In fact, the MIC values
of compounds 11a–c are similar to the MIC values of nor-
floxacine and ciprofloxacine. Among the aminoalkylated
triazoles, especially the ones containing an aromatic
substituent at the position 4 of a 1,2,4-triazole ring, com-
pounds 11a,b and 12a,b are the most active. Compounds
16 15
2
3
2
N, 13.01.
3
-Fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]aniline (3)
Method 1ꢁPd/C catalyst (5 mmol) and hydrazine hydrate (50 mmol)
2
–9 except 8b and 10a did not exhibit noteworthy activity were added to the solution of compound 2 (10 mmol) in 1-butanol
toward the test microorganisms.
(50 mL) and the mixture was heated under reflux for 15 h and then
the catalyst was removed by filtrating the hot mixture on celite. Con-
centration under reduced pressure resulted in the formation of an
oily mass that was crystallized from ethanol to give the target white
compound in a 53% yield.
Experimental
Chemistry
Method 2ꢁPd/C (5 mmol) catalyst and hydrazine hydrate (5 mmol)
were added to the solution of compound 2 (10 mmol) in 1-butanol
and the mixture was irradiated in a MW reactor with pressure con-
The chemicals were purchased from Fluka Chemie AG (Buchs, Swit- trol at 150°C, 200 W for 50 min. Then, the catalyst was separated by
zerland) and used without purification. Melting points were deter- filtration and the solvent was evaporated under reduced pressure.
mined in open capillaries on a Büchi B-540 melting point apparatus The white solid obtained was crystallized from ethanol to give the
and are uncorrected. Reactions were monitored by TLC on silica target compound in a 71% yield; mp 156–157°C; IR: ν 3500 and
max
ꢀ−ꢀ1
1
gel 60 F254 aluminum sheets. The mobile phase was ethyl acetate/ 3407 (NH ), 3060 (aromatic CH), 2972 cm (aliphatic CH); H NMR:
2
diethyl ether (1ꢀ:ꢀ1) and detection was made using UV light. Fourier δ 2.96 (brs, 4H, 2CH ), 3.17 (brs, 4H, 2CH ), 5.02 (s, 2H, NH ), 6.32–6.78
2
2
2
transformꢀinfraredꢀ(FT-IR) spectra were recorded using a Perkin (m, 2H, ArH), 6.80 (t, 1H, ArH, Jꢀ=ꢀ9.2 Hz), 6.95–6.98 (m, 2H, ArH),
1
13
13
Elmer 1600 series spectrometer. H NMR and C NMR spectra were 7.03–7.07 (m, 2H, ArH); C NMR: δ 49.8 (2CH ), 51.7 (2CH ), Aryl-C:
2
2
registered in DMSO-d on a Bruker Avene II 400 NMR spectrometer [102.3 and 102.5 (d, CH, Jꢀ=ꢀ20 Hz), 110.05 (CH), 115.6 and 115.8 (d,
6
1
13
(
400 MHz for H and 100 MHz for C). The elemental analysis was 2CH, Jꢀ=ꢀ20 Hz), 117.7 and 117.8 (d, 2CH, Jꢀ=ꢀ10 Hz), 121.1 (CH), 129.4 and
performed on a Costech Elemental Combustion System CHNS-O 129.5 (d, C, Jꢀ=ꢀ10 Hz), 145.9 and 146.0 (d, C, J= 10 Hz), 148.4 (C), 155.4
elemental analyzer. The electron ionization (EI) mass spectra were and 157.7 (d, C, JC−Fꢀ=ꢀ230 Hz), 155.6 and 158.0 (d, C, JC−Fꢀ=ꢀ240 Hz)]; MS:
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S. Basoglu Ozdemir et al.: New piperazine based heterocyclic compoundsꢀꢂꢁꢁꢁꢀ5
+
m/z 290.38 ([Mꢀ+ꢀ1]ꢀ , 21), 181.26 (100), 138.18 (79%). Anal. Calcd for (d, C, Jꢀ=ꢀ10 Hz), 145.9 and 146.0 (d, C, Jꢀ=ꢀ10 Hz), 153.5 and 155.4 (d,
C H F N : C, 66.42; H, 5.92; N, 14.52. Found: C, 66.58; H, 5.85; N, 14.31. C, JC−Fꢀ=ꢀ190 Hz), 155.6 and 158.0 (d, C, JC−Fꢀ=ꢀ240 Hz)], 159.6 (C=O); MS:
1
6
17
2
3
+
m/z 362.35 ([Mꢀ+ꢀ1]ꢀ , 100), 290.33 (42), 174.27 (40), 155.19 (47%). Anal.
Calcd for C H F N O: C, 59.82; H, 5.86; N, 19.38. Found: C, 60.00; H,
1
8
21
2
5
5.65; N, 19.01.
Ethyl 2-{3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]
phenyl}amino)acetate (4)
General method for synthesis of compounds 6a–c
Method 1ꢁA mixture of compound 3 (10 mmol) and triethylamine
(
15 mmol) in dry tetrahydrofuran (50 mL) was treated dropwise at
0
–5°C with ethyl bromoacetate (10 mmol). Then, the mixture was Method 1ꢁAlkyl(aryl) isothiocyanate (10 mmol) was added to a solu-
allowed to reach room temperature and was stirred for an additional tion of compound 5 (10 mmol) in dichloromethane and the mixture
2
4 h. The precipitated triethylammonium salt was removed by filtra- was stirred at room temperature for 24 h. The resultant solid was col-
tion. Concentration under reduced pressure resulted in the formation lected by filtration and crystallized from acetone/diethyl ether (1ꢀ:ꢀ2).
of a brown solid that was crystallized from ethanol/water (1ꢀ:ꢀ3) to
give the target compound in a 47% yield.
Method 2ꢁA mixture of compound 5 (1 mmol) and alkyl(aryl) iso-
thiocyanate (1 mmol) was irradiated in a MW reactor with pressure
Method 2ꢁTriethylamine (1.5 mmol) was added dropwise at 0–5°C control at 125°C, 150 W for 8 min without any solvent. The resultant
to the mixture of compound 3 (1 mmol) and ethyl bromoacetate solid product was crystallized from acetone/diethyl ether (1ꢀ:ꢀ2).
(
1 mmol). Then, the mixture was irradiated in a MW reactor with pres-
sure control at 70°C, 70 W for 8 min. Water was added and the result- 2-{2-[3-Fluoro-4-(4-[4-fluorophenyl]piperazin-1-yl)phenyl]
ant solid was filtered off and crystallized from ethanol/water (1ꢀ:ꢀ3) to amino)acetyl}-N-phenylhydrazinecarbothioamide (6a)ꢁYield
give the target brown compound in a 88% yield; mp 131–132°C; IR: 75%, method 1); 97%, method 2; mp 130–133°C; IR: ν 3341 (NH),
max
νmax 3384 (NH), 3084 (aromatic CH), 1721 cmꢀ−ꢀ1 (C=O); H NMR: δ 1.19 3295 (NH), 3229 (2NH), 3042 (aromatic CH), 1673 (C=O), 1243 cm
1
ꢀ−ꢀ1
1
(
t, 3H, CH , Jꢀ=ꢀ7.2 Hz), 2.95 (brs, 4H, 2CH ), 3.17 (brs, 4H, 2CH ), 3.86 (C=S); H NMR: δ 2.98 (brs, 2H, CH ), 3.14 (brs, 2H, CH ), 3.19 (s, 2H,
3
2
2
2
2
(
d, 2H, CH , Jꢀ=ꢀ8.0 Hz), 4.11 (q, 2H, CH , Jꢀ=ꢀ6.8 Hz), 5.03 (brs, 1H, NH), CH ), 3.35 (s, 2H, CH ), 3.79 (s, 2H, CH ), 6.99–7.16 (m, 7H, ArH), 7.15 (t,
2
2
2
2
2
6
.31–6.39 (m, 2H, ArH), 6.81 (t, 1H, ArH, Jꢀ=ꢀ8.0 Hz), 6.96–6.99 (m, 2H, 1H, ArH, Jꢀ=ꢀ8.0 Hz), 7.32–7.35 (m, 2H, ArH), 7.42–7.48 (m, 2H, ArH), 9.67
13
13
ArH), 7.03–7.08 (m, 2H, ArH); C NMR: δ 14.6 (CH ), 45.4 (CH ), 46.3 (s, 1H, NH), 9.78 (s, 2H, 2NH), 10.10 (s, 1H, NH); C NMR: δ 45.8 (CH ),
3
2
2
(CH ), 49.9 (CH ), 51.6 (CH ), 54.4 (CH ), 60.7 (CH ), Aryl-C: [100.9 and 49.7 (CH ), 49.9 (CH ), 50.7 (CH ), 51.6 (CH ), Aryl-C: [112.4 and 112.6
2
2
2
2
2
2
2
2
2
1
1
1
01.2 (d, CH, Jꢀ=ꢀ20 Hz), 102.3 and 102.5 (d, CH, Jꢀ=ꢀ20 Hz), 115.6 and (d, CH, Jꢀ=ꢀ20 Hz), 115.6 and 115.7 (d, CH, Jꢀ=ꢀ10 Hz), 115.8 and 115.9 (d,
15.8 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.6 and 117.7 (d, CH, Jꢀ=ꢀ10 Hz), 117.7 and 2CH, Jꢀ=ꢀ10 Hz), 117.36 and 117.7 (d, 2CH, Jꢀ=ꢀ40 Hz), 119.3 and 119.4 (d,
17.8 (d, 2CH, Jꢀ=ꢀ10 Hz), 129.5 and 129.9 (d, C, Jꢀ=ꢀ40 Hz), 145.5 and CH, Jꢀ=ꢀ10 Hz), 128.6 (2CH), 128.8 (2CH), 128.9 (CH), 139.8 and 139.9 (d,
1
45.6 (d, C, Jꢀ=ꢀ10 Hz), 145.9 and 146.0 (d, C, Jꢀ=ꢀ10 Hz), 148.4 and 155.4 C, Jꢀ=ꢀ10 Hz), 141.7 (2C), 145.8 (C), 148.3 and 153.9 (d, C, JC−Fꢀ=ꢀ560 Hz),
(
d, C, JC−Fꢀ=ꢀ700 Hz), 155.6 and 158.0 (d, C, JC−Fꢀ=ꢀ240 Hz)], 171.6 (C=O); 148.4 and 155.8 (d, C, JC−Fꢀ=ꢀ740 Hz)], 157.83 (C=O), 180.01 (C=S); MS:
+
+
MS: m/z 376.36 ([M]ꢀ , 12), 188.22 (99), 160.19 (100%). Anal. Calcd for m/z 497.32 ([Mꢀ+ꢀ1]ꢀ , 12), 425.30 (18), 309.20 (48), 174.15 (100%). Anal.
C H F N O : C, 63.99; H, 6.18; N, 11.19. Found: C, 63.78; H, 6.15; N, 11.01. Calcd for C H F N OS: C, 60.47; H, 5.28; N, 16.92. Found: C, 60.16; H,
2
0
23
2
3
2
25 26
2
6
5.00; N, 16.61.
N-Benzyl-2-{2-[3-fluoro-4-(4-[4-fluorophenyl]piperazin-1-yl)phe-
nyl]amino)acetyl}hydrazinecarbothioamide (6b)ꢁYield 70%,
2
-{3-Fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]-
phenylamino}acetohydrazide (5)
method 1, 96%, method 2; mp 160–161°C; IR: ν 3399 (NH), 3251
max
(
2NH), 3146 (NH), 1667 (C=O), 1220 cmꢀ (C=S); H NMR: δ 2.99 (brs, 2H,
−ꢀ1
1
Method 1ꢁHydrazine hydrate (25 mmol) was added to a solution of
compound 4 (10 mmol) in ethanol and the mixture was heated under
reflux for 10 h. Concentration under reduced pressure resulted in the
formation of a white solid that was crystallized from ethyl acetate to
give the target compound in a 72% yield.
CH ), 3.13 (brs, 2H, CH ), 3.20 (s, 2H, CH ), 3.34 (s, 2H, CH ), 3.74 (s, 2H,
2
2
2
2
CH ), 4.74 (s, 2H, CH ), 7.04 (d, 2H, ArH, Jꢀ=ꢀ16.0 Hz), 7.67 (d, 3H, ArH,
2
2
Jꢀ=ꢀ4.0 Hz), 7.29–7.34 (m, 7H, ArH), 8.16 (s, 1H, NH), 8.42 (s, 1H, NH),
13
9
(
.42 (s, 1H, NH), 9.59 (s, 1H, NH); C NMR: δ 48.2 (CH ), 49.7 (CH ), 49.9
2
2
CH ), 50.7 (CH ), 50.8 (CH ), 51.6 (CH ), Aryl-C: [115.6 and 115.7 (d, 2CH,
2 2 2 2
Jꢀ=ꢀ10 Hz), 115.8 and 115.9 (d, CH, Jꢀ=ꢀ10 Hz), 117.6 (CH), 117.7 and 117.8
Method 2ꢁA mixture of hydrazine hydrate (2.5 mmol) and com- (d, 2CH, Jꢀ=ꢀ10 Hz), 117.8 and 117.9 (d, CH, Jꢀ=ꢀ10 Hz), 127.3 (CH), 127.4
pound 4 (1 mmol) was irradiated in a MW reactor with pressure con- (2CH), 128.0 (2CH), 134.4 (C), 139.4 and 139.7 (d, C, Jꢀ=ꢀ30 Hz), 145.6 and
trol at 150°C, 125 W for 30 min. The product was crystallized from 145.7 (d, C, Jꢀ=ꢀ10 Hz), 145.6 and 145.7 (d, C, Jꢀ=ꢀ10 Hz), 148.3 and 153.5
ethyl acetate to give white compound in a 95% yield; mp 146–148°C; (d, C, Jꢀ=ꢀ520 Hz), 148.4 and 155.4 (d, C, Jꢀ=ꢀ700 Hz), 158.0 (C=O), 181.3
ꢀ
−ꢀ1
1
+
IR: νmax 3500 and 3406 (NH ), 3304 (2NH), 1631 cm (C=O); H NMR: δ (C=S); MS: m/z 511.28 ([Mꢀ+ꢀ1]ꢀ , 27), 402.40 (31), 332.32 (29), 323.38
2
2
.97 (brs, 4H, 2CH ), 3.17 (brs, 4H, 2CH ), 3.59 (d, 2H, CH , Jꢀ=ꢀ8.0 Hz), (100), 267.19 (39), 193.29 (90%). Anal. Calcd for C H F N OS: C, 61.16;
2
2
2
2
6
2
8
2
6
5
1
.02 (brs, 2H, NH ), 5.89 (s, 1H, NH), 6.33–6.42 (m, 2H, ArH), 6.80 (t, H, 5.53; N, 16.46. Found: C, 61.11; H, 5.19; N, 16.51.
2
1
3
H, ArH, Jꢀ=ꢀ8.8 Hz), 6.83–7.08 (m, 4H, ArH), 9.11 (s, 1H, NH); C NMR:
δ 45.4 (CH ), 46.5 (CH ), 49.8 (2CH ), 51.6 (CH ), Aryl-C: [100.9 and 101.2 N-Ethyl-2-{2-[3-fluoro-4-(4-[4-fluorophenyl]piperazin-1-yl)phe-
2
2
2
2
(
(
(
d, CH, Jꢀ=ꢀ20 Hz), 102.3 and 102.5 (d, CH, Jꢀ=ꢀ20 Hz), 115.6 and 115.8 nyl]amino)acetyl}hydrazinecarbothioamide (6c)ꢁYield 70%,
d, 2CH, Jꢀ=ꢀ20 Hz), 117.6 and 117.7 (d, CH, Jꢀ=ꢀ10 Hz), 117.7 and 117.8 method 1, 91%, method 2; mp 175–177°C; IR: ν 3303 (2NH), 3272
max
d, 2CH, Jꢀ=ꢀ10 Hz), 129.5 and 129.9 (d, C, Jꢀ=ꢀ40 Hz), 145.6 and 145.7 (NH), 3156 (NH), 3002 (aromatic CH), 2880 (aliphatic CH), 1634
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ꢁꢁꢁꢂ
6ꢀ
ꢀS. Basoglu Ozdemir et al.: New piperazine based heterocyclic compounds
1
(
(
C=O), 1240 cmꢀ−ꢀ1 (C=S); H NMR: δ 1.05 (t, 3H, CH , Jꢀ=ꢀ6.8 Hz), 2.97 and 157.7 (d, C, JC−Fꢀ=ꢀ230 Hz)], 168.3 (triazole C-3), 181.4 (triazole C-5);
3
+
+
brs, 4H, 2CH ), 3.18 (brs, 4H, 2CH ), 3.36 (s, 2H, CH ), 3.59 (s, 2H, MS: m/z 516.34 ([Mꢀ+ꢀ1ꢀ+ꢀNa]ꢀ , 30), 515.34 ([Mꢀ+ꢀNa]ꢀ , 91), 512.46 (100),
2
2
2
+
CH ), 4.51 (brs, 2H, 2NH), 5.89 (s, 1H, NH), 6.81–6.90 (m, 2H, ArH), 493.32 ([Mꢀ+ꢀ1]ꢀ 11), 461.34 (70), 447.45 (31), 360.54 (52%). Anal. Calcd
2
1
3
6
.98–7.06 (m, 5H, ArH), 9.12 (s, 1H, NH); C NMR: δ 14.8 (CH ), 45.9 for C H F N S: C, 63.40; H, 5.32; N, 17.06. Found: C, 63.36; H, 5.09;
3 26 26 2 6
(
CH ), 49.1 (CH ), 49.7 (CH ), 49.9 (CH ), 50.8 (CH ), 51.6 (CH ), Aryl-C: N, 16.81.
2 2 2 2 2 2
[
100.9 and 101.2 (d, CH, Jꢀ=ꢀ20 Hz), 102.3 and 102.5 (d, CH, Jꢀ=ꢀ20 Hz),
1
08.3 (CH), 115.6 and 115.8 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.7 and 117.8 (d, 2CH, 4-Ethyl-5-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phe-
Jꢀ=ꢀ10 Hz), 129.9 and 130.0 (d, C, J= 10 Hz), 142.9 (C), 145.7 and 145.8 nyl}amino)methyl]-4H-1,2,4-triazole-3-thiol (7c)ꢁYield 52%,
(
d, C, Jꢀ=ꢀ10 Hz), 148.4 and 151.5 (d, C, JC−F= 310 Hz), 155.4 and 158.0 (d, method 1, 90%, method 2; mp 177–180°C; IR: ν 3385 (NH), 3060
max
ꢀ−ꢀ1
1
C, JC−F= 260 Hz)], 157.7 (C=O), 169.7 (C=S); MS: m/z 393.27 (18), 392.27 (aromatic CH), 2850 (SH), 2954 (aliphatic CH), 1506 cm (C=N); H
96), 348.34 (100), 330.32 (40), 290.34 (67), 153.00 (76%). Anal. Calcd NMR: δ 1.10 (t, 3H, CH , Jꢀ=ꢀ7.2 Hz), 3.18 (brs, 4H, 2CH ), 3.35 (brs,
(
3
2
for C H F N OS: C, 56.23; H, 5.84; N, 18.74. Found: C, 56.16; H, 5.90; 4H, 2CH ), 4.01 (q, 2H, CH , Jꢀ=ꢀ7.2 Hz), 4.34 (d, 2H, CH , Jꢀ=ꢀ5.6 Hz),
2
1
26
2
6
2
2
2
1
3
N, 18.61.
6.99–7.09 (m, 7H, ArH), 13.63 (s, 1H, SH); C NMR: δ 14.63 (CH ),
9.73 (2CH ), 49.85 (CH ), 50.75 (CH ), 51.50 (2CH ), Aryl-C: [101.0 and
3
4
2 2 2 2
1
1
01.2 (d, CH, Jꢀ=ꢀ20 Hz), 108.6 (CH), 115.6 and 115.7 (d, 2CH, Jꢀ=ꢀ10 Hz),
15.8 and 115.9 (d, 2CH, Jꢀ=ꢀ10 Hz), 117.8 (CH), 134.8 and 136.4 (d, C,
General method for synthesis of compounds 7a–c
Jꢀ=ꢀ160 Hz), 144.9 and 145.0 (d, C, Jꢀ=ꢀ10 Hz), 148.3 (C), 150.4 and 155.5
d, C, JC−Fꢀ=ꢀ510 Hz), 153.5 and 157.9 (d, C, JC−Fꢀ=ꢀ440 Hz)], 155.9 (triazole
(
Method 1ꢁA solution of compound 6 (10 mmol) in water was heated
under reflux in the presence of 2M NaOH (50 mL) for 6 h, then cooled
to room temperature and acidified to pH 4 with 37% HCl. The result-
ant precipitate was filtered off, washed with water and crystallized
from dimethyl sulfoxide/water (1ꢀ:ꢀ4).
+
+
C-3), 180.0 (triazole C-5); MS: m/z 432.24 ([Mꢀ+ꢀ2]ꢀ , 26), 431.24 ([Mꢀ+ꢀ1]ꢀ ,
00), 377.24 (26), 332.13 (24), 289.21 (36), 152.93 (24%). Anal. Calcd for
C H F N S: C, 58.89; H, 5.62; N, 19.52. Found: C, 59.00; H, 5.70; N,
1
2
1
24
2
6
1
9.61.
Method 2ꢁA solution of 6 (1 mmol) in 2N NaOH (5 mL) was irradiated
in a MW reactor with pressure control at 150°C, 200 W for 15 min,
then cooled to room temperature and acidified to pH 4 with 37% HCl.
The resultant precipitate was filtered off, washed with water and
crystallized from dimethyl sulfoxide/water (1ꢀ:ꢀ4).
General method for synthesis of compounds ꢄa–c
Method 1ꢁA solution of compound 7 (10 mmol) and sodium ethoxide
prepared from metallic sodium (10 mmol) and ethanol was heated
under reflux for 2 h. Then, 2-bromo-1-(4-chlorophenyl)ethanone
(
10 mmol) was added and the mixture was heated under reflux for an
5
-[({3-Fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phenyl}
additional 20 h and then concentrated and the residue was treated
with water. The resultant solid was crystallized from acetone to give
an orange product.
amino)methyl]-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione
(
7a)ꢁYield 58%, method 1, 89%, method 2; mp 154–156°C; IR: ν
max
−ꢀ1
1
3
367 (NH), 3044 (aromatic CH), 1507 (C=N), 1226 cmꢀ (C=S); H NMR:
δ 2.97 (brs, 2H, CH ), 3.23 (brs, 4H, 2CH ), 3.34 (s, 4H, 2CH ), 6.99–7.08
2
2
2
(
(
m, 6H, ArH), 7.33 (t, 1H, ArH, Jꢀ=ꢀ8.0 Hz), 7.42–7.48 (m, 3H, ArH), 7.54 Method 2ꢁA solution of compound 7 (1 mmol) in ethanol was irradi-
t, 2H, ArH, Jꢀ=ꢀ7.6 Hz), 9.55 (brs, 2H, NH); 1 C NMR: δ 49.7 (2CH ), 49.8 ated at 125°C, 150 W for 5 min in the presence of sodium methoxide.
3
2
(
CH ), 50.7 (CH ), 51.5 (CH ), Aryl-C: [101.1 and 101.3 (d, CH, Jꢀ=ꢀ20 Hz), Then, 2-bromo-1-(4-chlorophenyl)ethanone (1 mmol) was added and
2
2
2
1
08.4 (CH), 115.8 and 115.9 (d, 2CH, Jꢀ=ꢀ10 Hz), 117.7 and 117.8 (d, CH, the mixture was irradiated in a MW reactor with pressure control
Jꢀ=ꢀ10 Hz), 117.8 and 117.9 (d, 2CH, Jꢀ=ꢀ10 Hz), 128.5 (CH), 128.9 (2CH), at 150°C, 150 W for 20 min. Concentration under reduced pressure
1
29.8 (2CH), 139.8 (2C), 144.9 and 145.0 (d, C, Jꢀ=ꢀ10 Hz), 148.3 and 148.4 resulted in the formation of an orange solid that was treated with
(
d, C, Jꢀ=ꢀ10 Hz), 150.7 and 155.4 (d, C, JC−Fꢀ=ꢀ470 Hz), 153.4 and 157.8 water, filtered off and crystallized from acetone.
(
4
d, C, JC−Fꢀ=ꢀ440 Hz)], 168.6 (triazole C-3), 180.0 (triazole C-5); MS: m/z
+
79.43 ([Mꢀ+ꢀ1]ꢀ , 23), 447.52 (41), 391.45 (26), 360.61 (100), 332.39 (30), 1-(4-Chlorophenyl)-2-{3-[({3-fluoro-4-[4-(4-fluorophenyl)pip-
2
88.27 (30), 195.29 (60%). Anal. Calcd for C H F N S: C, 62.74; H, erazin-1-yl]phenyl}amino)methyl]-4-phenyl-5-thioxo-4,5-di-
2
5
24
2
6
5
.05; N, 17.56. Found: C, 62.67; H, 5.00; N, 17.60.
hydro-1H-1,2,4-triazol-1-yl}ethanone (8a)ꢁYield 35%, method 1,
5%, method 2; mp 140–142°C; IR: ν 3285 (NH), 3067 (aromatic
7
max
−ꢀ1
ꢀ
1
4
-Benzyl-5-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl] CH), 1698 (C=O), 1508 (C=N), 1225 cm (C=S); H NMR: δ 2.95 (brs,
phenyl}amino)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione 4H, 2CH ), 3.17 (brs, 4H, 2CH ), 4.17 (s, 2H, CH ), 4.86 (s, 2H, CH ),
2
2
2
2
(
7b)ꢁYield 68%, method 1, 85%, method 2; mp 171–173°C; IR: ν
5.91 (brs, 1H, NH), 6.98 (s, 5H, ArH), 7.46 (s, 8H, ArH), 8.01 (s, 3H,
max
1
3
3
251 (NH), 3087 (aromatic CH), 2953 (aliphatic CH), 1509 (C=N), ArH); C NMR: δ 38.8 (CH ), 49.7 (CH ), 49.8 (2CH ), 50.9 (CH ), 51.5
2 2 2 2
−ꢀ1
1
1
245 cmꢀ (C=S); H NMR: δ 2.97 (brs, 4H, 2CH ), 3.22 (brs, 4H, 2CH ), (CH ), Aryl-C: [101.0 and 101.2 (d, CH, Jꢀ=ꢀ20 Hz), 108.5 (CH), 115.6
2
2
2
4
.15 (d, 2H, CH , Jꢀ=ꢀ5.6 Hz), 5.33 (s, 2H, CH ), 6.37 (s, 1H, ArH), 6.83 (t, and 115.8 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.7 and 117.8 (d, 2CH, Jꢀ=ꢀ10 Hz),
2
2
1
H, ArH, Jꢀ=ꢀ9.2 Hz), 6.96–7.07 (m, 5H, ArH), 7.28–7.34 (m, 5H, ArH), 118.7 (CH), 127.5 (2CH), 129.4 (2CH), 130.0 (2CH), 130.3 (2CH), 130.4
3
9
.66 (brs, 2H, NH); 1 C NMR: δ 46.1 (CH ), 47.2 (CH ), 49.7 (CH ), 49.8 (CH), 133.2 (C), 134.5 (2C), 139.1 (2C), 145.2 (C), 148.3 and 154.2 (d,
2
2
2
(
CH ), 50.8 (CH ), 51.5 (CH ), Aryl-C: [101.1 and 101.3 (d, CH, Jꢀ=ꢀ20 Hz), C, JC−Fꢀ=ꢀ590 Hz), 150.6 and 155.4 (d, C, JC−Fꢀ=ꢀ480 Hz)], 157.8 (triazole
2
2
2
+
1
08.5 (CH), 115.6 and 115.7 (d, CH, Jꢀ=ꢀ10 Hz), 115.8 and 115.9 (d, 2CH, C-3ꢀ+ꢀtriazole C-5), 192.7 (C=O); MS: m/z 655.30 ([Mꢀ+ꢀ1ꢀ+ꢀNa]ꢀ , 32),
+
Jꢀ=ꢀ10 Hz), 117.7 and 117.8 (d, 2CH, Jꢀ=ꢀ10 Hz), 127.6 (2CH), 127.8 (CH), 654.36 ([Mꢀ+ꢀNa]ꢀ , 46), 484.43 (89), 447.71 (48), 431.45 (100%). Anal.
1
28.7 (2CH), 130.3 and 130.4 (d, C, Jꢀ=ꢀ10 Hz), 136.2 (C), 139.5 (C), 144.8 Calcd for C H ClF N OS: C, 62.80; H, 4.63; N, 13.32. Found: C, 62.66;
33 29 2 6
and 144.9 (d, C, Jꢀ=ꢀ10 Hz), 150.6 and 155.4 (d, C, JC−Fꢀ=ꢀ480 Hz), 155.4 H, 4.40; N, 13.61.
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S. Basoglu Ozdemir et al.: New piperazine based heterocyclic compoundsꢀꢂꢁꢁꢁꢀ7
4
-Benzyl-3-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phe- 128.3 (2CH), 128.5 (CH), 130.3 (2CH), 130.4 (2CH), 130.0 and 130.1 (d, C,
nyl}amino)methyl]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}- Jꢀ=ꢀ10 Hz), 132.2 (C), 133.3 (C), 143.2 (C), 145.2 and 145.3 (d, C, Jꢀ=ꢀ10 Hz),
1
-(4-chlorophenyl)ethanone (8b)ꢁYield: 32%, method 1), 52%, 148.3 and 148.4 (d, C, J= 10 Hz), 151.6 and 155.4 (d, C, JC−Fꢀ=ꢀ380 Hz),
method 2; mp 190–192°C; IR: ν 3377 (NH), 3000 (aromatic CH), 2955 152.9 and 157.7 (d, C, JC−Fꢀ=ꢀ480 Hz)], 154.1 (triazole C-3), 155.4 (triazole
max
ꢀ−ꢀ1
1
+
+
(
aliphatic CH), 1683 (C=O), 1506 (C=N), 1226 cm (C=S); H NMR: δ C-5); MS: m/z 657.13 ([Mꢀ+ꢀ2ꢀ+ꢀNa]ꢀ , 51), 655.18 ([Mꢀ+ꢀNa]ꢀ , 100%). Anal.
2
.99 (brs, 4H, 2CH ), 3.22 (brs, 6H, 3CH ), 5.33 (s, 4H, 2CH ), 6.17 (s, 3H, Calcd for C H ClF N OS: C, 62.60; H, 4.94; N, 13.27. Found: C, 62.50;
2 2 2 33 31 2 6
ArH), 6.73 (t, 2H, ArH, Jꢀ=ꢀ8.0 Hz), 6.90–7.17 (m, 5H, ArH), 7.28–7.94 (m, H, 5.04; N, 13.31.
H, ArH), NH was not observed; 1 C NMR: δ 47.2 (CH ), 49.7 (CH ), 49.9
3
6
2
2
(
2CH ), 51.5 (3CH ), Aryl-C: [108.5 (2CH), 115.6 and 115.7 (d, CH, Jꢀ=ꢀ10 Hz), 4-Benzyl-2-[2-(4-chlorophenyl)-2-hydroxyethyl]-5-[({3-fluoro-
2
2
1
15.4 and 116.0 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.7 and 117.8 (d, 2CH, Jꢀ=ꢀ10 Hz), 123.8 4-[4-(4-fluorophenyl)piperazin-1-yl]phenyl}amino)methyl]-
(
2CH), 126.0 (CH), 127.6 (2CH), 127.8 (2CH), 129.0 (2CH), 130.3 and 130.4 (d, 2,4-dihydro-3H-1,2,4-triazole-3-thione (9b)ꢁYield 48%, method
2
C, Jꢀ=ꢀ10 Hz), 136.2 (C), 139.5 (2C), 144.8 and 144.9 (d, C, Jꢀ=ꢀ10 Hz), 150.6 1, 68%, method 2; mp 180–182°C; IR: ν 3357 (OH), 3025 (aromatic
max
ꢀ
−ꢀ1
1
and 155.4 (d, C, JC−Fꢀ=ꢀ480 Hz), 155.5 and 157.7 (d, C, JC−Fꢀ=ꢀ200 Hz)], 158.3 CH), 3122 (NH), 2953 (aliphatic CH), 1505 (C=N), 1235 cm (C=S); H
+
(triazole C-3), 165.4 (triazole C-5), 185.3 (C=O); MS: m/z 646.89 ([Mꢀ+ꢀ1]ꢀ , NMR: δ 3.11 (s, 2H, CH ), 3.12 (brs, 4H, 2CH ), 3.18 (brs, 4H, 2CH ),
2
2
2
3
4), 458.00 (100), 234.09 (76%). Anal. Calcd for C H ClF N OS: C, 63.30; 3.34 (s, 4H, 2CH ), 5.05 (s, 1H, CH), 6.35 (brs, 1H, OH), 6.75–6.78 (m,
34
31
2
6
2
H, 4.84; N, 13.03. Found: C, 63.13; H, 5.00; N, 13.21.
2H, ArH), 6.99–7.09 (m, 5H, ArH), 7.19–7.37 (m, 7H, ArH), 7.41–7.51 (m,
1
3
2
H, ArH), 9.07 (brs, 1H, NH); C NMR: δ 40.6 (2CH ), 44.1 (2CH ), 50.1
2
2
1
-(4-Chlorophenyl)-2-({4-ethyl-5-[({3-fluoro-4-[4-(4-fluorophe- (3CH ), 70.1 (CH), Aryl-C: [106.2 (2CH), 108.2 (2CH), 110.2 (2CH), 116.8
2
nyl)piperazin-1-yl]phenyl} amino)methyl]-4H-1,2,4-triazol-3-yl} and 116.9 (d, 2CH, Jꢀ=ꢀ10 Hz), 118.43 and 118.54 (d, 2CH, Jꢀ=ꢀ11 Hz),
thio)ethanone (8c)ꢁYield 22%, method 1, 65%, method 2; mp 144– 120.2 (CH), 125.5 (CH), 127.8 (CH), 129.3 (2CH), 130.0 (CH), 132.4
1
47°C; IR: ν 3370 (NH), 3054 (aromatic CH), 2951 (aliphatic CH), (2C), 133.8 (2C), 135.2 and 135.4 (d, 2C, Jꢀ=ꢀ20 Hz), 151.6 and 154.4 (d,
max
ꢀ−ꢀ1
1
1
692 (C=O), 1507 cm (C=N); H NMR: δ 1.10 (t, 3H, CH , Jꢀ=ꢀ6.4 Hz), 2C, JC−Fꢀ=ꢀ280 Hz)], 155.2 (triazole C-3), 162.7 (triazole C-5); MS: m/z
3
+
2
.99 (brs, 2H, CH ), 3.19 (brs, 8H, 4CH ), 4.02 (d, 2H, CH , Jꢀ=ꢀ6.8 Hz), 671.31 ([Mꢀ+ꢀ1ꢀ+ꢀK]ꢀ , 28), 605.17 (100), 555.21 (35%). Anal. Calcd for
.38 (s, 2H, CH ), 4.92 (s, 1H, NH), 7.00–7.08 (m, 7H, ArH), 7.53 (d, 2H, C H ClF N OS: C, 63.10; H, 5.14; N, 12.99. Found: C, 63.00; H, 5.34;
2
2
2
4
2
3
4
3
3
2
6
ArH, Jꢀ=ꢀ8.0 Hz), 7.61 (t, 1H, ArH, Jꢀ=ꢀ7.6 Hz), 8.02 (d, 1H, ArH, Jꢀ=ꢀ8.0 Hz); N, 12.88.
1
3
C NMR: δ 15.4 (CH ), 49.8 (2CH ), 49.9 (2CH ), 50.8 (2CH ), 51.6 (CH ),
3
2
2
2
2
Aryl-C: [100.9 (CH), 108.7 (CH), 115.7 and 115.9 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.8 1-(4-Chlorophenyl)-2-({4-ethyl-5-[({3-fluoro-4-[4-(4-fluorophe-
and 117.9 (d, 2CH, Jꢀ=ꢀ10 Hz), 120.6 (CH), 129.4 (2CH), 130.8 (2CH), 134.5 nyl)piperazin-1-yl]phenyl}amino)methyl]-4H-1,2,4-triazol-
(
2C), 139.1 (2C), 148.2 (C), 149.5 and 153.8 (d, 2C, JC−Fꢀ=ꢀ430 Hz)], 155.5 3-yl}thio)ethanol (9c)ꢁYield 40%, method 1, 71%, method 2); mp
+
(
triazole C-3 and triazole C-5), 192.8 (C=O); MS: m/z 583.21 ([M]ꢀ , 71), 166–168°C; IR: ν 3321 (OH), 3051 (aromatic CH), 2953 (aliphatic
max
71.25 (47), 569.24 (100%). Anal. Calcd for C H ClF N OS: C, 59.73; H, CH), 1507 cmꢀ (C=N); H NMR: δ 1.23 (brs, 3H, CH ), 2.97 (brs, 2H,
−ꢀ1
1
5
5
2
9
29
2
6
3
.01; N, 14.41. Found: C, 60.00; H, 5.09; N, 14.31.
CH ), 3.12 (brs, 2H, CH ), 3.18 (s, 2H, CH ), 3.23 (s, 2H, CH ), 3.34 (s,
2
2
2
2
4
H, 2CH ), 3.94 (s, 2H, CH ), 4.37 (s, 1H, CH), 4.88 (brs, 1H, OH), 6.26
2
2
(
s, 1H, NH), 6.80 (d, 1H, ArH, Jꢀ=ꢀ8.0 Hz), 7.00–7.07 (m, 6H, ArH),
1
3
General method for synthesis of compounds 9a–c
7.39–7.52 (m, 2H, ArH), 7.58 (d, 2H, ArH, Jꢀ=ꢀ7.6 Hz); C NMR: δ 15.4
CH ), 49.7 (CH ), 49.8 (2CH ), 50.9 (2CH ), 51.5 (2CH ), 70.8 (CH),
(
3
2
2
2
2
Aryl-C: [100.9 and 101.2 (d, CH, Jꢀ=ꢀ30 Hz), 108.6 (CH), 109.5 and
Method 1ꢁCompound 8 (10 mmol) was stirred in the presence of
NaBH (30 mmol) in absolute ethanol (40 mL) at room temperature for
1
1
09.7 (d, CH, Jꢀ=ꢀ20 Hz), 115.6 and 115.8 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.7 and
17.8 (d, 2CH, Jꢀ=ꢀ30 Hz), 128.4 (2CH), 128.5 (2CH), 130.5 (C), 132.2
4
2
4 h (for 9a and 9c) or heated under reflux for 18 h (for 9b). Concen-
(
2C), 134.5 (C), 138.8 (C), 143.2 and 148.3 (d, C, JC−Fꢀ=ꢀ510 Hz), 150.4
tration under reduced pressure resulted in the formation of a white
solid that was washed with water and crystallized from acetone.
and 153.6 (d, C, JC−Fꢀ=ꢀ320 Hz)], 153.4 (triazole C-3), 158.9 (triazole
+
C-5); MS: m/z 609.20 ([Mꢀ+ꢀ1ꢀ+ꢀNa]ꢀ , 56), 607.25 (100%). Anal. Calcd
for C H ClF N OS: C, 59.53; H, 5.34; N, 14.36. Found: C, 59.67; H,
2
9
31
2
6
Method 2ꢁA solution of compound 8 (1 mmol) and NaBH (3 mmol)
4
5.16; N, 14.01.
in ethanol was irradiated at 100°C, 100 W for 20 min. Concentration
under reduced pressure resulted in the formation of a white solid that
was washed with water and crystallized from acetone.
General method for synthesis of compounds 10a–i
2
-[2-(4-Chlorophenyl)-2-hydroxyethyl]-5-[({3-fluoro-4-[4-(4-
fluorophenyl)piperazin-1-yl]phenyl}amino)methyl]-4-phenyl- Method 1ꢁNaH (10 mmol) was added to a solution of compound
2
,4-dihydro-3H-1,2,4-triazole-3-thione (9a)ꢁYield 45%, method 9 (10 mmol) in tetrahydrofuran and the mixture was heated under
1
, 75%, method 2; mp 153–155°C; IR: ν 3298 (OH), 3049 (aromatic reflux for 6 h. Then, the corresponding benzyl chloride was added
max
ꢀ−ꢀ1
1
CH), 2920 (aliphatic CH), 1508 (C=N), 1223 cm (C=S); H NMR: δ 2.96 and the mixture was heated under reflux for an additional 8–12 h.
(
brs, 4H, 2CH ), 3.16 (brs, 4H, 2CH ), 3.22 (s, 2H, CH ), 4.17 (d, 2H, CH , After concentration under reduced pressure, the resultant oily mass
2
2
2
2
Jꢀ=ꢀ8.0 Hz), 4.85 (q, 1H, CH, Jꢀ=ꢀ4.4 Hz), 5.89 (brs, 1H, OH), 6.96–7.08 (m, was treated with K CO (10 mmol) solution and the mixture was
2
3
7
H, ArH), 7.29–7.45 (m, 6H, ArH), 7.56 (t, 3H, ArH, Jꢀ=ꢀ4.0 Hz), signal for extracted with ethyl acetate (3ꢀ×ꢀ15 mL). The organic layer was dried
13
NH was not observed; C NMR: δ 38.8 (CH ), 41.0 (CH ), 49.7 (CH ), with Na SO and concentrated under reduced pressure. The residue
2
2
2
2
4
4
9.8 (CH ), 51.0 (CH ), 51.5 (CH ), 70.7 (CH), Aryl-C: [101.0 and 101.2 (d, was crystallized from acetone (10a–d, 10g) or purified by silica gel
2 2 2
CH, Jꢀ=ꢀ20 Hz), 106.9 and 107.2 (d, CH, Jꢀ=ꢀ30 Hz), 108.5 (CH), 115.8 and column chromatography eluting with ethyl acetate/n-hexane (3ꢀ:ꢀ7,
15.9 (d, 2CH, Jꢀ=ꢀ10 Hz), 117.7 and 117.8 (d, 2CH, Jꢀ=ꢀ10 Hz), 127.6 (2CH), 10e, 10f, 10h, 10i).
1
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ꢄꢀꢁꢁꢁꢂꢀS. Basoglu Ozdemir et al.: New piperazine based heterocyclic compounds
Method 2ꢁNaH (1 mmol) was added to a solution of compound 9 4.84 (s, 7H, 3CH ꢀ+ꢀCH), 7.09 (brs, 4H, ArH), 7.27–7.34 (m, 6H, ArH),
2
1
3
(
1
1 mmol) in THF (10 mL) and the mixture was irradiated at 80°C, 7.34–7.54 (m, 9H, ArH), 8.98 (brs, 1H, NH); C NMR: δ 41.3 (2CH ),
2
00 W for 10 min. Then, the corresponding benzyl chloride (3 mmol) 58.8 (2CH ), 60.2 (3CH ), 70.3 (CH), Aryl-C: [108.2 and 108.4 (d, CH,
2
2
was added, and heating was continued for 20 min at 100°C at 150 Jꢀ=ꢀ20 Hz), 116.2 (2CH), 117.2 and 117.4 (d, 2CH, Jꢀ=ꢀ20 Hz), 118.3 and
W. After concentration the crude product was treated with K CO
118.4 (d, 2CH, Jꢀ=ꢀ10 Hz), 128.4 (CH), 128.5 (CH), 128.8 (CH), 128.9
10 mmol) solution and the mixture was extracted with ethyl acetate (CH), 129.1 (CH), 129.6 (CH), 129.7 (2CH), 130.3 (2CH), 131.6 (2CH), 133.2
2
3
(
(
3ꢀ×ꢀ15 mL). The extract was dried with Na SO concentrated under (2C), 135.6 (2C), 136.0 (2C), 136.5 (2C), 136.7 (C), 152.1 and 155.2 (d, 2C,
2
4,
a reduced pressure and the residue was crystallized from acetone JC−F ꢀ=ꢀ31.0 Hz)], 157.6 (triazole C-2), 161.1 (triazole C-5); MS: m/z 810.90
+
(
10a–d, 10g) or purified by silica gel column chromatography elut- ([Mꢀ+ꢀH O]ꢀ , 12), 456.90 (100%). Anal. Calcd for C H Cl F N OS: C,
2
40 35
3
2
6
ing with ethyl acetate/n-hexane, (3ꢀ:ꢀ7, 10e, 10f, 10h, 10i).
60.65; H, 4.45; N, 10.61. Found: C, 60.78; H, 4.36; N, 10.50.
2
-[2-(4-Chlorophenoxy)-2-(4-chlorophenyl)ethyl]-5-[({3-fluoro- 4-Benzyl-2-[2-[(4-chlorobenzyl)oxy]-2-(4-chlorophenyl)
4
-[4-(4-fluorophenyl)piperazin-1-yl]phenyl}amino)methyl]- ethyl]-5-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phe-
-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (10a)ꢁThis nyl}amino)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione
4
compound was obtained from 9a and 4-chlorobenzyl chloride; yield (10d)ꢁThis compound was obtained from 9b and 4-chlorobenzyl
ꢀ−ꢀ1
2
5%, method 1, 70%, method 2; mp 58–60°C; IR: ν , cm ): 3263 chloride; yield 31%, method 1, 55%, method 2; mp 42–44°C; IR:
max
(
NH), 3056 (aromatic CH), 2919 (aliphatic CH), 1507 (C=N), 1227 (C=S), νmax 3120 (NH), 3092 (aromatic CH), 2918 (aliphatic CH), 1588 (C=N),
089 cmꢀ (C-O); H NMR: δ 3.04 (brs, 4H, 2CH ), 3.24 (brs, 6H, 3CH ), 1237 cm (C=S); H NMR: δ 3.11 (brs, 4H, 2CH ), 3.21 (brs, 4H, 2CH ),
−ꢀ1
1
ꢀ−ꢀ1
1
1
3
2
2
2
2
.46 (s, 2H, CH ), 4.19 (s, 2H, CH ), 4.76 (brs, 1H, CH), 6.87–6.94 (m, 3.40 (s, 6H, 3CH ), 4.40 (brs, 1H, CH), 5.05 (s, 2H, CH ), 6.37 (s, 1H,
2
2
2
2
1H, ArH), 7.09 (s, 5H, ArH), 7.38–7.56 (m, 11H, ArH), 7.57 (d, 3H, ArH, ArH), 6.75–6.78 (m, 2H, ArH), 7.06–7.09 (m, 8H, ArH), 7.21–7.29 (m, 5H,
13
Jꢀ=ꢀ7.2 Hz), NH was not observed; C NMR: δ 40.6 (CH ), 41.0 (CH ), ArH), 7.34 (d, 2H, ArH, Jꢀ=ꢀ8.0 Hz), 7.47 (d, 2H, ArH, Jꢀ=ꢀ8.0 Hz), 11.10
2
2
1
3
4
5.6 (CH ), 50.1 (CH ), 50.8 (CH ), 51.5 (CH ), 62.6 (CH ), 70.7 (CH), Aryl- (s, 1H, NH); C NMR: δ 48.2 (2CH ), 49.7 (3CH ), 51.0 (3CH ), 90.9 (CH),
2 2 2 2 2
2
2
2
C: [100.9 and 101.2 (d, CH, Jꢀ=ꢀ20 Hz), 108.6 (CH), 115.8 and 116.0 (d, Aryl-C: [109.4 and 109.5 (d, CH, J= 10 Hz), 111.2 (CH), 115.7 and 115.8
CH, Jꢀ=ꢀ20 Hz), 118.5 (2CH), 127.6 (CH), 128.3 (2CH), 128.4 (2CH), 128.5 (d, 2CH, Jꢀ=ꢀ10 Hz), 117.2 and 117.3 (d, 2CH, Jꢀ=ꢀ10 Hz), 117.8 and 117.9 (d,
(
CH), 128.6 (CH), 128.8 (CH), 128.9 (CH), 129.1 (CH), 129.1 (CH), 129.2 CH, Jꢀ=ꢀ10 Hz), 119.2 (2CH), 126.9 (2CH), 127.5 (2CH), 128.5 (2CH), 128.9
(
2CH), 130.3 (2CH), 130.4 (C), 131.2 (C), 132.2 (2C), 137.2 (C), 137.7 (C), (CH), 129.2 (2CH), 130.2 (C), 130.9 (2CH), 134.5 (2C), 136.8 (2C), 137.6
1
43.2 (2C), 151.8 and 153.4 (d, C, JC−Fꢀ=ꢀ160 Hz), 151.9 and 154.0 (d, C, (2C), 138.8 (C), 139.9 (C), 140.1 (C)], 148.3 (triazole C-3), 159.6 (triazole
JC−Fꢀ=ꢀ210 Hz)], 155.4 (triazole C-3), 157.8 (triazole C-5); MS: m/z 780.21 C-5); MS: m/z 732.19 (9), 461.27 (100), 177.90 (52%). Anal. Calcd for
+
(
[Mꢀ+ꢀNa]ꢀ , 24), 612.09 (54), 555.90 (15), 498.00 (100%). Anal. Calcd C H Cl F N OS: C, 63.81; H, 4.96; N, 10.89. Found: C, 63.69; H, 4.78;
41
38
2
2
6
for C H Cl F N OS: C, 63.40; H, 4.79; N, 11.09. Found: C, 63.34; H, N, 10.99.
4
0
36
2
2
6
4
.99; N, 11.31.
4
-Benzyl-2-{2-(4-chlorophenyl)-2-[(2,4-dichlorobenzyl)oxy]
2
-[2-(4-Chlorophenyl)-2-(2,4-dichlorophenoxy)ethyl]-5-[({3- ethyl}-5-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phe-
fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phenyl}amino) nyl}amino)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione
methyl]-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (10e)ꢁThis compound was obtained from 9b and 2,4-dichlorobenzyl
(
10b)ꢁThis compound was obtained from 9a and 2,4-chlorobenzyl chloride; yield 30%, method 1, 55%, method 2; yellow oil; IR: ν
max
chloride; yield 32%, method 1, 55%, method 2; mp 150–152°C; IR: 3092 (aromatic CH), 2963 (aliphatic CH), 1588 (C=N), 1508 (C=N),
νmax 3263 (NH), 3066 (aromatic CH), 2917 (aliphatic CH), 1507 (C=N), 1228 cmꢀ (C=S); H NMR: δ 2.50 (brs, 4H, 2CH ), 3.04 (s, 2H, CH ),
−ꢀ1
1
2
2
227 (C=S), 1144 cmꢀ (C-O); H NMR: δ 2.50 (s, 2H, CH ), 2.97 (s, 2H, 3.24 (brs, 4H, 2CH ), 3.43 (s, 4H, 2CH ), 4.81 (brs, 3H, CHꢀ+ꢀCH ), 7.08
−ꢀ1
1
1
2
2
2
2
CH ), 3.18 (brs, 4H, 2CH ), 3.36 (brs, 4H, 2CH ), 4.17 (s, 2H, CH ), 4.85 (brs, 3H, ArH), 7.31–7.37 (m, 5H, ArH), 7.46–7.48 (m, 5H, ArH), 7.64–7.68
2
2
2
2
1
3
(
6
t, 1H, CH, Jꢀ=ꢀ7.2 Hz), 6.30 (d, 1H, ArH, Jꢀ=ꢀ8.4 Hz), 6.41 (s, 5H, ArH), (m, 6H, ArH), 9.12 (brs, 1H, NH); C NMR: δ 40.6 (3CH ), 43.3 (3CH ),
2
2
.83 (t, 2H, ArH, Jꢀ=ꢀ8.8 Hz), 6.99–7.43 (m, 7H, ArH), 7.56 (s, 4H, ArH), 49.9 (2CH ), 60.2 (CH), Aryl-C: [116.5 (2CH), 126.9 (2CH), 127.1 (2CH),
2
.98 (brs, 1H, NH); 1 C NMR: δ 40.6 (CH ), 40.9 (CH ), 44.8 (CH ), 49.9 127.6 (CH), 128.2 and 128.3 (d, CH, Jꢀ=ꢀ10 Hz), 128.5 (CH), 128.6 (CH),
3
8
2
2
2
(
CH ), 50.2 (CH ), 51.5 (2CH ), 70.7 (CH), Aryl-C: [101.0 and 101.2 (d, CH, 129.1 (2CH), 129.2 (2CH), 129.4 (2CH), 129.7 (2CH), 129.8 (CH), 131.9 (C),
2
2
2
Jꢀ=ꢀ20 Hz), 108.5 (CH), 115.6 and 115.8 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.8 and 117.9 132.2 (2C), 132.3 (C), 133.3 (C), 134.5 and 134.9 (d, 2C, Jꢀ=ꢀ40 Hz), 136.7
(
d, 2CH, Jꢀ=ꢀ20 Hz), 121.0 (2CH), 127.6 (2CH), 128.3 (2CH), 128.5 (2CH), (C), 139.3 (C), 150.4 and 154.2 (d, 2C, JC−F =380 Hz)], 153.6 (triazole C-3),
+
1
28.6 (CH), 130.3 (2CH), 130.4 (2CH), 132.2 (2C), 133.3 (2C), 141.3 (2C), 158.9 (triazole C-5); MS: m/z 807.13 ([Mꢀ+ꢀ1]ꢀ , 56), 775.54 (100), 665.00
1
43.2 (2C), 145.5 (C), 154.1 and 157.7 (d, 2C, JC−F = 360 Hz)], 151.6 (tria- (21%).
+
zole C-3), 157.9 (triazole C-5); MS: m/z 793.45 ([Mꢀ+ꢀ1]ꢀ , 56), 605.25 (68),
5
51.21 (20), 321.98 (100%). Anal. Calcd for C H Cl F N OS: C, 60.65; 4-Benzyl-2-{2-(4-chlorophenyl)-2-[(2,6-dichlorobenzyl)oxy]
4
0
35
3
2
6
H, 4.45; N, 10.61. Found: C, 60.69; H, 4.31; N, 10.31.
ethyl}-5-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phenyl}
amino)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (10f)ꢁThis
2
-[2-(4-Chlorophenyl)-2-(2,6-dichlorophenoxy)ethyl]-5-[({3- compound was obtained from 9b and 2,6-chlorobenzyl chloride; yield
fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phenyl}amino) 42%, method 1, 67%, method 2, yellow oil; IR: ν 3063 (aromatic CH),
max
methyl]-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione 2924 (aliphatic CH), 1508 (C=N), 1226 cmꢀ (C=S); H NMR: δ 3.03 (brs,
−ꢀ1
1
(
10c)ꢁThis compound was obtained from 9a and 2,6-chlorobenzyl 4H, 2CH ), 3.13 (brs, 4H, 2CH ), 3.22 (s, 4H, 2CH ), 3.39–3.45 (m, 2H,
2
2
2
chloride; yield 24%, method 1, 58%, method 2; mp 126–127°C; IR: CH ), 4.90 (s, 3H, CHꢀ+ꢀCH ), 7.03–7.08 (m, 5H, ArH), 7.27–7.42 (m, 7H,
2
2
13
νmax 3083 (aromatic CH), 2956 (aliphatic CH), 1508 (C=N), 1226 (C=S), ArH), 7.50–7.55 (m, 7H, ArH), 9.24 (brs, 1H, NH); C NMR: δ 40.4 (3CH ),
1
2
091 cmꢀ (C-O); H NMR: δ 3.17 (brs, 4H, 2CH ), 3.28 (brs, 4H, 2CH ), 41.4 (3CH ), 50.1 (2CH ), 58.7 (CH), Aryl-C: [116.3 (CH), 126.9 (2CH), 127.0
−ꢀ1
1
2
2
2
2
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S. Basoglu Ozdemir et al.: New piperazine based heterocyclic compoundsꢀꢂꢁꢁꢁꢀ9
2CH), 127.4 (CH), 128.2 and 128.4 (d, 2CH, Jꢀ=ꢀ20 Hz), 128.5 (CH), 128.9 General method for synthesis of compounds 11–14
(
CH), 131.6 (C), 131.9 (C), 133.3 (2C), 135.6 (2C), 135.9 (2C), 136.7 (C), 152.2
Method 1ꢁTo a solution of corresponding compound 7 (10 mmol)
in DMF containing HCl (50% mmol), norfloxacin (for 11a–c), cipro-
floxacin (for 12a–c), thiomorpholine (for 13a,b) or phenylpiperazine
and 156.2 (d, 2C, JC−Fꢀ=ꢀ400 Hz)], 155.2 (triazole C-3), 162.7 (triazole C-5);
MS: m/z 824.56 ([Mꢀ+ꢀH O]ꢀ , 34), 778.09 (100%).
+
2
(
for 14) (10 mmol) was added and the mixture was stirred at room
N-[(5-{[2-(4-Chlorophenoxy)-2-(4-chlorophenyl)ethyl]thio}-4-
ethyl-4H-1,2,4-triazol-3-yl)methyl]-3-fluoro-4-[4-(4-fluorophe-
nyl)piperazin-1-yl]aniline (10g)ꢁThis compound was obtained crystallized from DMSO/water (1ꢀ:ꢀ3).
from 9c and 4-chlorobenzyl chloride; yield 33%, method 1, 66%,
method 2; mp 94–95°C; IR: ν 3407 (NH), 3056 (aromatic CH), 2955
temperature in the presence of formaldehyde (50 mmol) for 24 h. The
solid obtained was collected by filtration, washed with water and
max
Method 2ꢁA solution of 7 (1 mmol), norfloxacin (for 11a–c), cipro-
aliphatic CH), 1507 cmꢀ (C=N); H NMR: δ 1.18 (brs, 3H, CH ), 2.98 (s, floxacin (for 12a–c), thiomorpholine (for 13a,b) or phenylpiperazine
−ꢀ1
1
(
3
2
2
H, CH ), 3.05 (brs, 4H, 2CH ), 3.13–3.19 (m, 4H, 2CH ), 3.20 (brs, 4H, (for 14) (1 mmol), HCl (50% mmol) and formaldehyde (5 mmol) was
CH ), 3.98 (q, 2H, CH , Jꢀ=ꢀ6.8 Hz), 4.79 (s, 1H, CH), 6.59–6.99 (m, 3H, irradiated in a MW reactor with pressure control at 50°C, 70 W for
2
2
2
2
2
ArH), 7.00–7.07 (m, 5H, ArH), 7.08 (d, 4H, ArH, Jꢀ=ꢀ5.2 Hz), 7.38 (d, 3H, 20 min. The resultant solid was washed with water and crystallized
ArH, Jꢀ=ꢀ9.6 Hz), 10.42 (brs, 1H, NH); 13C NMR: δ 14.0 (CH ), 34.4 (CH ), from DMSO/water (1ꢀ:ꢀ3).
3
2
4
9.7 (2CH ), 49.8 (CH ), 49.9 (CH ), 50.8 (CH ), 51.2 (CH ), 63.9 (CH ), 70.8
2 2 2 2 2 2
1
-Ethyl-6-fluoro-7-[4-({3-[({3-fluoro-4-[4-(4-fluorophenyl)
piperazin-1-yl]phenyl}amino)methyl]-4-phenyl-5-thioxo-
,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)piperazin-1-yl]-4-oxo-
(
CH), Aryl-C: [105.6 and 105.8 (d, CH, Jꢀ=ꢀ20 Hz), 109.1 (CH), 113.6 (CH),
1
1
1
15.7 and 115.9 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.8 and 117.9 (d, 2CH, Jꢀ=ꢀ10 Hz),
19.7 (2CH), 120.9 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH), 128.9 (CH),
29.5 (CH), 130.1 (C), 133.8 (2C), 136.9 (2C), 148.2 (2C), 154.9 and 157.8
4
1
,4-dihydroquinoline-3-carboxylic acid (11a)ꢁThis compound
was obtained from 7a and norfloxacin; yield 56%, method 1, 83%,
method 2; mp 103–105°C; IR: ν 3359 (OH), 3060 (aromatic CH),
(
d, C, JC−Fꢀ=ꢀꢀ=ꢀ290 Hz), 155.5 and 157.3 (d, C, JC−Fꢀ=ꢀ180 Hz)], 161.6 (tria-
+
max
zole C-3), 164.7 (triazole C-5); MS: m/z 710.65 ([Mꢀ+ꢀ1]ꢀ , 56), 651.20 (43),
ꢀ
−ꢀ1
2
920 (aliphatic CH), 1710 (C=O), 1659 (C=O), 1508 (C=N), 1226 cm
6
00.21 (100), 554.32 (13%). Anal. Calcd for C H Cl F N OS: C, 60.93;
36 36 2 2 6
1
(
C=S); H NMR: δ 1.41 (brs, 3H, CH ), 2.50 (s, 2H, CH ), 2.73 (s, 2H, CH ),
3
2
2
H, 5.11; N, 11.84. Found: C, 60.88; H, 5.31; N, 11.91.
2
2
.89 (s, 2H, CH ), 3.00 (brs, 4H, 2CH ), 3.37 (brs, 8H, 4CH ), 4.14 (s,
2 2 2
H, CH ), 4.58 (s, 2H, CH ), 6.99–7.03 (m, 7H, ArH), 7.20 (brs, 2H, ArH),
2
2
N-[(5-{[2-(4-Chlorophenyl)-2-(2,4-dichlorophenoxy)ethyl]thio}-
-ethyl-4H-1,2,4-triazol-3-yl)methyl]-3-fluoro-4-[4-(4-fluorophe-
7
.32 (s, 1H, ArH), 7.44 (s, 2H, ArH), 7.56 (s, 2H, ArH), 7.95 (s, 1H, ArH),
4
13
8
.95 (s, 1H, quinolone CH), 15.36 (s, 1H, OH); C NMR: δ 14.8 (CH ),
3
nyl)piperazin-1-yl]aniline (10h)ꢁThis compound was obtained
from 9c and 2,4-chlorobenzyl chloride; yield 39%, method 1, 51%,
3
1.2 (CH ), 47.9 (CH ), 49.4 (CH ), 49.6 (CH ), 49.7 (CH ), 49.8 (CH ), 50.7
2 2 2 2 2 2
(
CH ), 51.1 (CH ), 51.3 (CH ), 51.5 (2CH ), 107.5 (C), Aryl-C: [106.2 (CH),
2 2 2 2
method 2; brown oil; IR: ν 3063 (aromatic CH), 2925 (aliphatic CH),
max
111.6 and 111.8 (d, CH, Jꢀ=ꢀ20 Hz), 115.6 and 115.9 (d, CH, Jꢀ=ꢀ30 Hz),
508 (C=N), 1098 cmꢀ (C-O); H NMR: δ 1.06 (brs, 3H, CH ), 3.10 (brs, 117.4 and 117.5 (d, 2CH, Jꢀ=ꢀ10 Hz), 117.8 and 117.9 (d, 2CH, Jꢀ=ꢀ10 Hz),
−ꢀ1
1
1
4
3
H, 2CH ), 3.26 (brs, 4H, 2CH ), 4.77 (s, 9H, 4CH ꢀ+ꢀCH), 7.08 (s, 4H, 118.9 (CH), 119.7 (C), 121.9 (CH), 128.5 (CH), 129.3 (2CH), 129.9 (2CH),
2
2
2
ArH), 7.39–7.41 (m, 5H, ArH), 7.59 (t, 5H, ArH, Jꢀ=ꢀ8.4 Hz), 9.65 (brs, 134.4 (C), 134.7 (C), 136.2 (C), 136.3 (2C), 137.6 (C), 141.4 (C), 147.1 (C),
1
3
1
(
H, NH); C NMR: δ 18.9 (CH ), 43.3 (CH ), 49.9 (CH ), 52.3 (2CH ), 56.5 149.3 (C)], 149.0 (CH), 162.8 (triazole C-3), 166.6 (triazole C-5), 176.6 and
3 2 2 2
2CH ), 60.2 (2CH ), 70.7 (CH), Aryl-C: [116.2 and 116.4 (d, CH, Jꢀ=ꢀ20 Hz), 181.7 2(C=O); MS: m/z 680.45 (26), 386.38 (25), 288.27 (100%). Anal.
2
2
Calcd for C H F N O S: C, 62.29; H, 5.23; N, 15.56. Found: C, 62.49; H,
5
1
1
1
27.5 (2CH), 128.2 (2CH), 128.5 and 128.6 (d, CH, Jꢀ=ꢀ10 Hz), 128.9 (2CH),
29.6 and 129.7 (d, 2CH, Jꢀ=ꢀ10 Hz), 131.3 (CH), 131.5 (CH), 132.2 (C),
32.3 (C), 133.2 (2CH), 134.6 (2C), 134.7 (C), 134.8 (2C), 139.3 (C), 154.3
42 42
3
9
3
.31; N, 15.31.
7
-[4-({4-Benzyl-3-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]
and 157.2 (d, C, JC−Fꢀ=ꢀ290 Hz), 156.2 and 157.8 (d, C, JC−Fꢀ=ꢀ160 Hz)], 160.2
+
phenyl}amino)methyl]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-
(
(
triazole C-3), 165.0 (triazole C-5); MS: m/z 744.90 ([M]ꢀ , 23), 701.26
100), 556.09 (67), 501.21 (43%).
1
-yl}methyl)piperazin-1-yl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-
quinoline-3-carboxylic acid (11b)ꢁThis compound was obtained
from 7b and norfloxacin; yield 45%, method 1), 82%, method 2; mp
N-[(5-{[2-(4-Chlorophenyl)-2-(2,6-dichlorophenoxy)ethyl]thio}-
-ethyl-4H-1,2,4-triazol-3-yl)methyl]-3-fluoro-4-[4-(4-fluorophe-
2
04–206°C; IR: ν 3307 (OH), 3065 (aromatic CH), 2920 (aliphatic
4
max
ꢀ−ꢀ1
1
CH), 1723 (C=O), 1668 (C=O), 1507 (C=N), 1226 cm (C=S); H NMR:
δ 1.37 (t, 3H, CH , Jꢀ=ꢀ6.8 Hz), 2.50 (s, 2H, CH ), 2.70 (s, 2H, CH ), 2.81
nyl)piperazin-1-yl]aniline (10i)ꢁThis compound was obtained
from 9c and 2,6-chlorobenzyl chloride; yield 44%, method 1), 62%,
3
2
2
(
brs, 4H, 2CH ), 3.13 (brs, 2H, CH ), 3.18 (brs, 2H, CH ), 3.22 (s, 2H, CH ),
2
2
2
2
method 2; brown oil; IR: ν 3056 (aromatic CH), 2924 (aliphatic
max
3
.26 (s, 2H, CH ), 3.35 (s, 2H, CH ), 4.56 (s, 2H, CH ), 5.20 (s, 2H, CH ),
CH), 1508 (C=N), 1091 cmꢀ (C-O); H NMR: δ 1.04–1.06 (m, 3H, CH ),
−ꢀ1
1
2
2
2
2
3
5
.39 (s, 2H, CH ), 6.28 (brs, 1H, NH), 6.67–6.76 (m, 2H, ArH), 6.92–7.07
2
3
.27 (brs, 8H, 4CH ), 4.36 (brs, 6H, 3CH ), 4.85 (brs, 3H, CH ꢀ+ꢀCH),
2
2
2
(m, 5H, ArH), 7.27–7.33 (m, 6H, ArH), 7.91 (s, 1H, ArH), 8.90 (s, 1H, qui-
13
7.37–7.53 (m, 14H, ArH), 9.02 (brs, 1H, NH); C NMR: δ 15.9 (CH ), 43.7
13
3
nolone CH), 15.31 (brs, 1H, OH); C NMR: δ 14.8 (CH ), 47.2 (CH ), 48.4
3
2
(
2CH ), 49.9 (2CH ), 50.2 (CH ), 51.8 (CH ), 58.7 (2CH ), 101.0 (CH), Aryl-
2 2 2 2 2
(CH ), 49.5 (CH ), 49.7 (2CH ), 50.0 (2CH ), 50.7 (2CH ), 51.2 (2CH ), 68.8
2 2 2 2 2 2
C: [108.5 (CH), 116.1 (CH), 116.2 (CH), 116.3 (2CH), 119.9 (CH), 128.9
(
CH ), 107.6 (C), Aryl-C: [106.3 (CH), 108.7 (CH), 111.5 and 111.7 (d, CH,
2
(
(
1
2CH), 129.1 (2CH), 129.2 (2CH), 129.3 (2CH), 130.6 (2C), 130.8 (C), 131.9
Jꢀ=ꢀ20 Hz), 115.4 and 115.6 (d, CH, Jꢀ=ꢀ20 Hz), 115.9 (CH), 117.3 and 117.4
2C), 133.3 (C), 135.6 (C), 136.1 (C), 153.6 and 155.5 (d, 2C, JC−F= 190 Hz)], (d, 2CH, Jꢀ=ꢀ10 Hz), 117.8 and 117.9 (d, 2CH, Jꢀ=ꢀ10 Hz), 119.5 and 119.7 (d,
+
57.9 (triazole C-3), 164.7 (triazole C-5); MS: m/z 767.23 ([Mꢀ+ꢀNa]ꢀ , 24), C, Jꢀ=ꢀ20 Hz), 127.9 (CH), 128.7 (2CH), 129.01 (2CH), 130.4 (C), 135.9 (C),
4
20.00 (100), 389.92 (75%).
137.6 (C), 139.4 (C), 144.3 (C), 148.1 and 148.3 (d, C, Jꢀ=ꢀ20 Hz), 146.1 and
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1
0ꢀꢁꢁꢁꢂꢀS. Basoglu Ozdemir et al.: New piperazine based heterocyclic compounds
1
54.6 (d, C, JC−Fꢀ=ꢀ850 Hz), 149.3 and 155.3 (d, C, JC−Fꢀ=ꢀ600 Hz), 152.2 and 7-[4-({4-Benzyl-3-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]
1
57.6 (d, C, JC−Fꢀ=ꢀ540 Hz)], 148.8 (CH), 166.5 (triazole C-3), 169.3 (triazole phenyl}amino)methyl]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-
+
C-5), 176.6 (C=O), 181.3 (C=O); MS: m/z 824.48 ([Mꢀ+ꢀ1]ꢀ , 10), 798.39 (15), 1-yl}methyl)piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-di-
7
76.62 (19), 749.40 (25), 739.51 (28), 724.50 (53), 723.49 (100), 718.64 hydroquinoline-3-carboxylic acid (12b)ꢁThis compound was
(
65%). Anal. Calcd for C H F N O S: C, 62.68; H, 5.38; N, 15.30. Found: obtained from 7b and ciprofloxacin; yield 50%, method 1, 90%,
43
44
3
9
3
C, 62.59; H, 5.39; N, 15.61.
method 2; mp 170–172°C; IR: ν 3297 (OH), 3065 (aromatic CH), 2919
max
ꢀ−ꢀ1
(
aliphatic CH), 1721 (C=O) and 1667 (C=O), 1508 (C=N), 1225 cm (C=S);
1
H NMR: δ 1.08 (s, 2H, CH ), 1.18 (s, 2H, CH ), 2.73 (brs, 4H, 2CH ), 2.89
1
-Ethyl-7-[4-({4-ethyl-3-[({3-fluoro-4-[4-(4-fluorophenyl)piper-
2
2
2
(
brs, 4H, 2CH ), 3.22 (brs, 4H, 2CH ), 3.34 (brs, 6H, 3CH ), 3.79 (brs, 1H,
2 2 2
azin-1-yl]phenyl}amino)methyl]-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-1-yl}methyl)piperazin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-
quinoline-3-carboxylic acid (11c)ꢁThis compound was obtained
from 7c and norfloxacin; yield 47%, method 1, 77%, method 2); mp
CH), 5.20 (s, 2H, CH ), 5.39 (s, 2H, CH ), 6.73–6.77 (m, 1H, ArH), 6.94–
2
2
7
.07 (m, 5H, ArH), 7.34 (brs, 7H, ArH), 7.93 (s, 1H, ArH), 8.65 (s, 1H, qui-
13
nolone CH), 9.26 (brs, 1H, NH), 15.15 (s, 1H, OH); C NMR: δ 8.0 (2CH ),
2
3
6.2 (CH), 47.2 (CH ), 48.4 (CH ), 49.5 (CH ), 49.7 (CH ), 49.8 (CH ), 49.9
1
52–154°C; IR: ν 3500 (OH), 3060 (aromatic CH), 2944 (aliphatic
2 2 2 2 2
max
ꢀ
−ꢀ1
1
(CH ), 50.7 (CH ), 51.1 (CH ), 51.3 (2CH ), 68.7 (CH ), 107.3 (C), Aryl-C:
CH), 1724 (C=O), 1666 (C=O), 1508 (C=N), 1235 cm (C=S); H NMR: δ
2 2 2 2 2
[
106.8 (CH), 108.7 (CH), 111.3 and 111.5 (d, CH, Jꢀ=ꢀ20 Hz), 115.5 and 115.7
d, CH, Jꢀ=ꢀ20 Hz), 117.3 and 117.4 (d, 2CH, J= 10 Hz), 117.8 and 117.9 (d,
CH, Jꢀ=ꢀ10 Hz), 119.1 (C), 120.6 (CH), 127.9 (2CH), 128.7 (2CH), 129.1 (CH),
1
.22 (brs, 3H, CH ), 1.39 (brs, 3H, CH ), 2.73 (brs, 6H, 3CH ), 3.01 (brs,
3
3
2
(
6
H, 3CH ), 3.19 (brs, 8H, 4CH ), 4.06 (s, 2H, CH ), 4.58 (s, 2H, CH ),
2 2 2 2
.14 (brs, 1H, NH), 7.05 (brs, 8H, ArH), 7.95 (s, 1H, ArH), 8.96 (s, 1H,
2
5
13
130.4 (C), 135.9 (2C), 139.4 and 139.5 (d, C, Jꢀ=ꢀ10 Hz), 144.4 (C), 145.8
and 149.4 (d, C, JC−Fꢀ=ꢀ360 Hz), 148.0 and 148.2 (d, C, Jꢀ=ꢀ20 Hz), 152.0
and 155.3 (d, C, JC−Fꢀ=ꢀ330 Hz), 154.8 and 157.7 (d, C, JC−F ꢀ=ꢀ290 Hz)], 148.3
quinolone CH), 15.33 (s, 1H, OH); C NMR: δ 13.5 (CH ), 14.8 (CH ),
3
3
3
6.2 (CH ), 39.3 (CH ), 48.4 (CH ), 49.5 (CH ), 49.7 (CH ), 49.8 (CH ), 50.0
2 2 2 2 2 2
(
[
CH ), 50.8 (CH ), 51.1 (CH ), 51.2 (2CH ), 79.9 (CH ), 107.6 (C), Aryl-C:
2 2 2 2 2
(
CH), 166.2 (triazole C-3), 169.4 (triazole C-5), 176.7 and 181.3 2(C=O);
106.4 (CH), 111.5 and 111.7 (d, CH, Jꢀ=ꢀ20 Hz), 113.5 (CH), 115.5 (CH),
+
MS: m/z 868.34 (52), 858.39 ([Mꢀ+ꢀNa]ꢀ , 35), 850.63 (32), 849.63 (28),
1
1
1
15.6 and 115.8 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.3 and 117.4 (d, 2CH, Jꢀ=ꢀ10 Hz),
17.8 and 117.9 (d, C, Jꢀ=ꢀ10 Hz), 120.2 (CH), 129.4 (C), 133.1 (C), 136.4 (C),
37.6 (C), 144.8 (C), 149.1 and 155.4 (d, C, JC−Fꢀ=ꢀ630 Hz), 153.4 and 157.2
+
+
8
37.43 ([Mꢀ+ꢀ2]ꢀ , 50), 836.31 ([Mꢀ+ꢀ1]ꢀ ,100), 827.42 (31%). Anal. Calcd for
C H F N O S: C, 63.22; H, 5.31; N, 15.08. Found: C, 63.60; H, 5.07; N,
44 44
3
9
3
1
5.01.
(
d, C, JC−Fꢀ=ꢀ380 Hz), 154.7 and 157.77(d, 2C, JC−Fꢀ=ꢀ300 Hz)], 148.9 (CH),
62.1 (triazole C-3), 166.5 (C=O), 166.6 (C=O), 168.2 (triazole C-5); MS:
1
+
+
+
1-Cyclopropyl-7-[4-({4-ethyl-3-[({3-fluoro-4-[4-(4-fluorophenyl)
piperazin-1-yl]phenyl} amino)methyl]-5-thioxo-4,5-dihydro-1H-
m/z 785.25 ([Mꢀ+ꢀ1ꢀ+ꢀNa]ꢀ , 56), 784.25 ([Mꢀ+ꢀNa]ꢀ , 84), 763.16 ([Mꢀ+ꢀ2]ꢀ ,
+
4
2), 762.35 ([Mꢀ+ꢀ1]ꢀ , 85), 750.46 (43), 749.21 (100%). Anal. Calcd for
1
,2,4-triazol-1-yl}methyl)piperazin-1-yl]-6-fluoro-4-oxo-1,4-di-
C H F N O S: C, 59.91; H, 5.56; N, 16.55. Found: C, 59.60; H, 5.67; N,
3
8
42
3
9
3
hydroquinoline-3-carboxylic acid (12c)ꢁThis compound was
obtained from 7c and ciprofloxacin; yield 78%, method 1, 94%,
1
6.61.
method 2); mp 192–194°C; IR: ν 3400 (OH), 3061 (aromatic CH),
1
-Cyclopropyl-6-fluoro-7-[4-({3-[({3-fluoro-4-[4-(4-fluorophenyl)
max
ꢀ−ꢀ1
1
2
925 (aliphatic CH), 1628 (2C=O), 1507 (C=N), 1217 cm (C=S); H
piperazin-1-yl]phenyl} amino)methyl]-4-phenyl-5-thioxo-4,5-di-
hydro-1H-1,2,4-triazol-1-yl}methyl)piperazin-1-yl]-4-oxo-1,4-di-
hydroquinoline-3-carboxylic acid (12a)ꢁThis compound was
obtained from 7a and ciprofloxacin; yield 56%, method 1), 89%,
NMR: δ 1.17 (brs, 5H, CH ꢀ+ꢀCH ), 1.31 (s, 2H, CH ), 2.25 (s, 2H, CH ),
3
2
2
2
2
.50 (brs, 4H, 2CH ), 2.73 (brs, 4H, 2CH ), 3.16 (brs, 6H, 3CH ), 3.32
2
2
2
(
brs, 4H, 2CH ), 3.45 (s, 1H, CH), 5.12 (s, 2H, CH ), 6.63 (s, 1H, ArH),
2
2
6
.99 (s, 6H, ArH), 7.56 (brs, 1H, ArH), 7.94 (s, 1H, ArH), 8.65 (brs, 1H,
method 2; mp 115–117°C; IR: ν 3356 (OH), 3065 (aromatic CH), 2949
max
1
3
ꢀ
−ꢀ1
quinolone CH), 9.09 (brs, 1H, NH), 15.20 (brs, 1H, OH); C NMR: δ
(
aliphatic CH), 1714 (C=O), 1659 (C=O), 1507 (C=N), 1224 cm (C=S);
1
8.0 (2CH ), 31.2 (CH ), 36.2 (CH), 48.4 (CH ), 49.7 (CH ), 49.8 (2CH ),
H NMR: δ 1.18 (s, 2H, CH ), 1.32 (s, 2H, CH ), 2.73 (brs, 4H, 2CH ), 3.00
2
3
2
2
2
2
2
2
5
0.8 (CH ), 51.1 (CH ), 68.0 (CH ), 79.9 (CH ), 81.7 (CH ), 82.4 (CH ), 82.5
2 2 2 2 2 2
(
brs, 6H, 3CH ), 3.14 (s, 2H, CH ), 3.17 (brs, 4H, 2CH ), 3.80 (brs, 1H,
2
2
2
(
CH ), 107.2 (C), Aryl-C: [104.0 and 104.2 (d, CH, Jꢀ=ꢀ20 Hz), 106.2 (CH),
CH), 4.16 (s, 2H, CH ), 5.21 (s, 2H, CH ), 5.81 (brs, 1H, NH), 6.77 (brs,
2
2
2
1
11.4 (CH), 113.5 (CH), 115.5 and 115.6 (d, 2CH, Jꢀ=ꢀ10 Hz), 117.7 and 117.8
1
H, ArH), 7.01–7.07 (m, 6H, ArH), 7.33 (s, 1H, ArH), 7.46 (s, 3H, ArH),
(
d, 2CH, Jꢀ=ꢀ10 Hz), 119.5 and 119.9 (d, CH, Jꢀ=ꢀ40 Hz), 131.7 (C), 132.5
7
.56 (s, 2H, ArH), 7.90 (s, 1H, ArH), 8.65 (s, 1H, quinolone CH), 15.22
1
3
(C), 133.1 (C), 139.6 (C), 141.3 (2C), 144.7 and 148.3 (d, C, JC−Fꢀ=ꢀ360 Hz),
54.5 and 156.1 (d, C, JC−Fꢀ=ꢀ160 Hz), 155.4 and 157.4 (d, C, JC−Fꢀ=ꢀ200 Hz)],
(
s, 1H, OH); C NMR: δ 8.1 (2CH ), 36.2 (CH), 47.9 (CH ), 49.2 (CH ),
2
2
2
1
4
9.6 (CH ), 49.7 (CH ), 49.8 (CH ), 49.9 (CH ), 50.7 (CH ), 51.1 (CH ), 51.3
2 2 2 2 2 2
1
40.6 (CH), 154.7 (triazole C-3), 157.8 (triazole C-5), 166.4 (2C=O); MS:
(
CH ), 51.5 (CH ), 107.2 (C), Aryl-C: [106.6 and 106.8 (d, CH, Jꢀ=ꢀ20 Hz),
2
2
+
m/z 774.17 ([Mꢀ+ꢀ1]ꢀ , 17), 398.26 (100%). Anal. Calcd for C H F N O S:
C, 60.53; H, 5.47; N, 16.29. Found: C, 60.60; H, 5.67; N, 16.51.
1
1
1
1
11.4 and 111.6 (d, CH, Jꢀ=ꢀ20 Hz), 115.6 and 115.7 (d, CH, Jꢀ=ꢀ10 Hz),
15.8 and 115.9 (d, 2CH, Jꢀ=ꢀ10 Hz), 117.7 and 117.8 (d, 2CH, Jꢀ=ꢀ10 Hz),
21.9 (CH), 125.7 (CH), 128.9 (2CH), 129.4 (2CH), 129.9 (CH), 134.4 (C),
36.6 and 136.9 (d, C, Jꢀ=ꢀ30 Hz), 139.6 and 139.7 (d, C, Jꢀ=ꢀ10 Hz), 141.4
39 42
3
9
3
4
-Benzyl-5-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phe-
nyl}amino)methyl]-2-(thiomorpholin-4-ylmethyl)-2,4-dihydro-
H-1,2,4-triazole-3-thione (13a)ꢁThis compound was obtained
from 7b and thiomorpholine; yield 67%, method 1, 88%, method 2;
mp 133–135ºC; IR: ν 3229 (NH), 3061 (aromatic CH), 2912 (aliphatic
(
C), 144.5 (C), 145.1 and 145.7 (d, C, Jꢀ=ꢀ60 Hz), 148.1 and 148.3 (d, C,
3
Jꢀ=ꢀ20 Hz), 151.9 and 154.8 (d, C, JC−Fꢀ=ꢀ290 Hz), 152.3 and 155.5 (d, C,
JC−Fꢀ=ꢀ320 Hz), 154.5 and 157.8 (d, C, JC−F ꢀ=ꢀ330 Hz)], 148.5 (CH), 162.8
(
triazole C-3), 169.6 (triazole C-5), 176.8 and 181.8 2(C=O); MS: m/z
max
ꢀ
−ꢀ1
1
+
CH), 1503 (C=N), 1223 cm (C=S); H NMR: δ 2.50 (brs, 4H, 2CH ),
2.73 (brs, 4H, 2CH ), 2.89 (brs, 4H, 2CH ), 3.18 (brs, 4H, 2CH ), 3.33
2 2 2
8
44.31 ([Mꢀ+ꢀNa]ꢀ , 79), 840.62 (56), 830.36 (79), 828.61 (55), 821.98
2
+
(
[M]ꢀ , 100), 815.85 (49), 811.40 (60), 804.15 (43), 794.38 (48%). Anal.
(
(
brs, 4H, 2CH ), 4.73 (s, 2H, CH ), 7.10–7.09 (m, 6H, ArH), 7.26–7.41
m, 6H, ArH), 9.58 (brs, 1H, NH); C NMR: δ 27.6 (CH ), 47.6 (2CH ),
Calcd for C H F N O S: C, 62.84; H, 5.15; N, 15.34. Found: C, 62.60;
2
2
4
3
42
3
9
3
1
3
H, 5.55; N, 15.61.
2
2
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S. Basoglu Ozdemir et al.: New piperazine based heterocyclic compoundsꢀꢂꢁꢁꢁꢀ11
4
9.7 (2CH ), 49.8 (2CH ), 50.7 (CH ), 50.8 (CH ), 52.7 (2CH ), Aryl-C: dimethyl sulfoxide to prepare a stock solution of 20.0 μg/mL. The
2
2
2
2
2
[
115.7 and 115.9 (d, 2CH, Jꢀ=ꢀ20 Hz), 117.7 and 117.8 (d, 2CH, Jꢀ=ꢀ10 Hz), antimicrobial effects of the compounds were tested quantitatively in
1
19.51and 119.6 (d, CH, Jꢀ=ꢀ10 Hz), 120.2 (CH), 127.3 and 127.4 (d, CH, respective broth media by using double microdilution and the MIC
Jꢀ=ꢀ10 Hz), 128.7 (2CH), 128.8 (CH), 129.1 (2CH), 134.4 and 134.5 (d, C, values (μg/mL) were determined. The antibacterial and antifungal
J= 10 Hz), 135.9 (C), 136.7 and 136.8 (d, C, J= 10 Hz), 148.3 and 148.4 assays were performed in Mueller-Hinton broth (MH) (Difco, Detroit,
(
(
d, C, Jꢀ=ꢀ10 Hz), 149.5 and 153.5 (d, C, JC−Fꢀ=ꢀ400 Hz), 155.5 and 157.8 MI, USA) at pH 7.3 and buffered Yeast Nitrogen Base (Difco, Detroit,
d, C, JC−Fꢀ=ꢀ230 Hz)], 155.9 (triazole C-3), 181.2 (triazole C-5); MS: m/z MI, USA) at pH 7.0, respectively. The microdilution test plates were
+
6
07.88 ([M]ꢀ , 45), 532.21 (65), 448.90 (31), 321.56 (76), 201.35 (100%). incubated for 18–24 h at 35°C. Brain Heart Infusion broth (BHI)
Anal. Calcd for C H F N S : C, 61.26; H, 5.80; N, 16.13. Found: C, (Difco, Detriot, MI, USA) was used for M. smegmatis and incubated
6
3
1
35
2
7 2
1.60; H, 5.77; N, 16.00.
for 48–72 h at 35°C [36]. Ampicillin (10 μg) and fluconazole (5 μg)
were used as the standard antibacterial and antifungal drugs,
4
-Ethyl-5-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]phe- respectively. DMSO with a dilution of 1ꢀ:ꢀ10 was used as a solvent
nyl}amino)methyl]-2-(thiomorpholin-4-ylmethyl)-2,4-dihydro- control.
3
H-1,2,4-triazole-3-thione (13b)ꢁThis compound was obtained
from 7c and thiomorpholine; yield 61% (Method 1), 86% (Method
Acknowledgments: The support provided by Scien-
2
); mp. 180–181°C; IR: ν 3059 (aromatic CH), 2915 (aliphatic CH),
max
507 (C=N), 1225 cmꢀ (C=S); H NMR: δ 1.10 (brs, 3H, CH ), 2.57 (brs,
−ꢀ1
1
tific and Technological Research Council of Turkey
1
3
4
H, 2CH ), 3.02 (brs, 6H, 3CH ), 3.19 (brs, 6H, 3CH ), 3.35 (brs, 4H, (TUBITAK, Project no: 113Z181) and Karadeniz Techni-
2
2
2
2
CH ), 4.80 (s, 2H, CH ), 6.98 (s, 3H, ArH), 7.05 (s, 4H, ArH), 9.42 (s,
2
2
cal University, BAP, Turkey (Ref. No. 8623) is gratefully
acknowledged.
1
3
1
H, NH); C NMR: δ 13.5 (CH ), 27.5 (CH ), 49.7 (2CH ), 50.7 (CH ), 51.1
3 2 2 2
(
2CH ), 51.6 (CH ), 52.2 (CH ), 53.4 (CH ), 68.0 (2CH ), Aryl-C:[106.2
2 2 2 2 2
and 106.4 (d, CH, Jꢀ=ꢀ20 Hz), 111.4 (CH), 113.5 (CH), 115.6 and 115.8 (d,
CH, J= 20 Hz), 117.8 and 117.8 (d, 2CH, Jꢀ=ꢀ10 Hz), 133.0 and 133.1 (d, C,
2
Jꢀ=ꢀ10 Hz), 144.7 and 144.8 (d, C, Jꢀ=ꢀ10 Hz), 148.3 (2C), 155.4 and 157.2
(
d, C, JC−F= 180 Hz)], 154.8 (triazole C-3), 157.8 (triazole C-5); MS: m/z
+
References
5
45.90 ([M]ꢀ , 56), 321.09 (100), 225.89 (57), 201.78 (98), 126.55 (45%).
Anal. Calcd for C H F N S : C, 57.22; H, 6.10; N, 17.97. Found: C, 57.60;
H, 6.23; N, 17.90.
2
6
33
2
7 2
[
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-Benzyl-5-[({3-fluoro-4-[4-(4-fluorophenyl)piperazin-1-yl]
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3%, method 2; mp 145–147°C; IR: νmax 3262 (NH), 3059 (aromatic
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(
2
2
2
2
7
-(pyridinium-3-yl)-carbonyl imidazo[5,1-b]thiazol-2-yl carbap-
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H, ArH, Jꢀ=ꢀ4.0 Hz), 7.02–7.09 (m, 7H, ArH), 7.20–7.38 (m, 9H, ArH),
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.87 (brs, 1H, NH); C NMR: δ 47.7 (CH ), 48.1 (CH ), 48.2 (CH ), 48.4
2
2
2
(
CH ), 48.7 (CH ), 49.7 (2CH ), 50.3 (CH ), 50.7 (CH ), 50.8 (CH ), 55.0
2 2 2 2 2 2
1
,2,4-triazole and 1,3,4-thiadiazole class bearing diphenylsul-
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2
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CH, Jꢀ=ꢀ10 Hz), 116.1 (CH), 117.8 and 117.9 (d, 2CH, J =10 Hz), 119.5 (CH),
27.3 (2CH), 127.4 (2CH), 127.9 (2CH), 128.7 (2CH), 129.4 (2CH), 134.4
and 134.5 (d, C, Jꢀ=ꢀ10 Hz), 136.7 and 136.7 (d, C, Jꢀ=ꢀ10 Hz), 139.4 (C),
48.3 (2C), 151.6 and 155.5 (d, C, JC−Fꢀ=ꢀ390 Hz), 153.5 and 157.8 (d, C,
1
[
[
1
JC−Fꢀ=ꢀ430 Hz)], 155.9 (triazole C-3), 181.3 (triazole C-5); MS: m/z 667.89
+
(
[Mꢀ+ꢀ1]ꢀ , 67), 600.21 (38), 556.90 (100), 431.21 (31%). Anal. Calcd for
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37
40
2
8
1
6.61.
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