Synthesis and biological activity studies of some new hybrid compounds derived from antipyrine

Article abstract of DOI:10.1515/hc-2016-0002

N-Benzyl-N'-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)urea (1) was obtained from antipyrine. The reaction of 1 with ethyl bromoacetate produced the 1,3-oxazole derivative 2. Compounds 5a-c were obtained from antipyrine by three steps via in

Full text of DOI:10.1515/hc-2016-0002

Heterocycl. Commun. 2016; aop
SSeyrpnil Dtehmeircsi*is and biological activity studies of some
new hybrid compounds derived from antipyrine
could be beneficial for the treatment of microbial infec-
tious [4–6].
DOI 10.1515/hc-2016-0002
Received January 10, 2016; accepted February 17, 2016
Antipyrine (AP) was first synthesized by Knorr [7]
in 1883 and there has been a continuous interest in the
studies of antipyrine derivatives (APDs). Broad bioactivi-
ties of APDs have been investigated including antitumor
[8], antimicrobial [9], antiviral [10], analgesic, and anti-
inflammatory effects [11]. APDs have been accepted as
important model compounds in the biological systems [12].
A triazole scaffold is a lead structure for the synthesis of
antimicrobial agents. It has been reported that the primary
structural requirement for the antimicrobial azole class is a
weakly basic imidazole or triazole ring bonded by a nitro-
gen-carbon linkage to the rest of the structure [13]. Selected
antifungal agents of this type are given in Figure 1 [14].
This report deals with the synthesis of novel thiourea
and 1,2,4-triazol derivatives that incorporate antipyrine
moiety, The newly synthesized compounds were evalu-
ated as potential antimicrobial agents against Gram
positive and Gram negative bacteria and fungi [15, 16].
Abstract:
N-Benzyl-N′-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl)urea (1) was obtained from
antipyrine. The reaction of 1 with ethyl bromoacetate pro-
duced the 1,3-oxazole derivative 2. Compounds 5a–c were
obtained from antipyrine by three steps via intermediary
of the ester 3 and hydrazide 4. The microwave supported
cyclocondensation of 5a–c with 4-chlorophenacyl bro-
mide and ethyl bromoacetate afforded the corresponding
1,3-thiazoles 6 or 1,3-thia(oxa)zolidines 7. The intramolec-
ular cyclization of 5a–c in the presence of NaOH produced
the corresponding triazoles 8a–c. The synthesis of the
hybrid compound 9 containing a penicillin skeleton was
carried out by the treatment of 8a with (+)-6-aminopeni-
cillanic acid (6-apa) in the presence of formaldehyde. The
structural assignments of new compounds were based
on their elemental analysis and spectral (IR, 1H-NMR, 13C-
NMR and LC-MS) data. All compounds except 1 and 7b
show moderate antimicrobial activity.
Keywords: antimicrobial activity; antipyrine; Mannich
reaction; microwave.
Results and discussion
The synthetic chemistry is outlined in Scheme 1. The
treatment of antipyrine with benzyl isocyanate produced
the urea derivative 1. The synthesis of compound 2 was
Introduction
The development of drug resistance is becoming a world- achieved by condensation of compound 1 and ethyl bro-
wide concern with rapid increases in multidrug resistant moacetate. Product 2 is a hybrid molecule containing anti-
bacteria [1, 2]. Literature survey has revealed that more pyrine and a 1,3-oxazole ring. The synthesis of compound
than one-third of the world populations are infected by 3 was performed by the reaction of antipyrine with ethyl
bacterial pathogens and nearly two million people per bromoacetate in tetrahydrofuran in the presence of tri-
year die due to these infections [3]. Therefore, the design ethylamine at room temperature. Then, compound 3 was
and synthesis of new and potent antibacterial agents heated under reflux with hydrazine hydrate in ethanol to
without cross resistance with the present antibacterial give the hydrazide 4. The treatment of hydrazide 4 with
agents is a crucial task for the effective treatment of bac- several isocyanates and isothiocyanates produced the key
terial infections. A molecule that includes more than one intermediate products 5a–c. Compounds 5a–c exhibit
pharmacophore, each with a different mode of action, spectral and elemental analysis data consistent with the
proposed structures.
With the aim to obtain hybrid compounds contain-
*Corresponding author: Serpil Demirci, Giresun University,
ing antipyrine and 1,3-thiazole moieties together, 6a,b,
Kadir Karabas School of Applied Sciences, Department of Crop
the carbo(thio)amides 5a, 5c were heated under reflux in
the presence 4-chlorophenacyl bromide and anhydrous
Production and Technologies, 28000, Bulancak, Giresun, Turkey,
e-mail: demirciserpil17@gmail.com
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ꢀꢀꢀꢁ
2ꢀ ꢀS. Demirci: New hybrid compounds derived from antipyrine
N
N
N
N
N N
O
S
H
Cl
O
N
N
O
HO
N
N
N
N
O
O
O
Cl
O
N
F
N
N
O
N
N N
HO
F
Tazobactam
Fluconazole
Itraconazole
N
N
OH
N
O
N
O
F
O
N
N
N
N
F
Posaconazole
Figure 1ꢀSelected antifungal imidazoles and triazoles.
sodium acetate. Other hybrid compounds 7a–c incorpo- against Gram negative bacteria Escherichia coli (Ec), Yers-
rating antipyrine and 1,3-oxa(thia)zolidine moieties in inia pseudotuberculosis (Yp) and Pseudomonas aeruginosa
the molecular framework were obtained by the reaction (Pa). Compounds 5c, 6a, 7c, 8a, 8c and 9 display moder-
of compounds 5a–c with ethyl bromoacetate in ethanolic ate antimicrobial activity against Gram positive bacteria
solution in the presence of sodium acetate. The treat- Staphylococcus aureus (Sa), Enterococcus faecalis (Ef),
ment of intermediate products 5a–c with sodium hydrox- Bacillus cereus (Bc), Micobacterium smegmatis (Ms), an
ide afforded derivatives 8a–c. The idea was to merge atypical tuberculosis factor, and Candida albicans (Ca)
two bioactive nuclei namely antipyrine and triazole in a and Saccaromyces cerevisiae (Sc), yeast-like fungi.
1
single molecule. Elemental analysis and FT-IR, H-NMR,
13C NMR, LC-MS spectral data were obtained for all these
products. In particular, in the 13C NMR spectra of com-
Conclusion
pounds 8a–c, the chemical shifts of C-3 and C-5 carbon
atoms belonging to 1,2,4-triazole nucleus are consistent
This study reports the synthesis of some new antipyrine
with the literature values for related compounds [17–19]. It
derivatives incorporating several other heterocyclic moie-
is known that compounds 8a and 8c can exist as thioxo-
ties having importance for biological activity in a single
mercapto tautomeric forms, while type 8b compounds are
structure. The structures of new compounds were con-
generally ketones [20].
firmed by IR, 1H NMR, 13C NMR, MS and elemental analysis
The synthesis of compound 9 was performed by
techniques. The synthesized compounds were screened
Mannich reaction between compound 8a and (+)-6-amin-
for antimicrobial activities. Compounds, 5c, 6a, 7c, 8a, 8c
openicillanic acid (6-apa) at room temperature. The aim
and 9 exhibit moderate activities against some of the test
was to join the antipyrine nucleus with a penicillin skele-
microorganisms.
ton which belongs to β-lactam class antibiotics. β-Lactam
derivatives constitute a class of important antibacterial
agents in the current clinical regimen. Besides their appli-
cations as antibacterials, β-lactams are increasingly used Experimental
as inhibitors of other medicinally important targets [21].
All chemicals were purchased from Fluka Chemie AG Buchs
Compound 9 display spectral data and elemental analysis
(Switzerland) and used without further purification. Melting
results consistent with the assigned structure.
points were determined in open capillaries on a Büchi B-540 melt-
ing point apparatus and are uncorrected. Reactions were moni-
tored by thin-layer chromatography (TLC) on silica-gel 60 F254
aluminum sheets. The mobile phase was ethanol/ethyl ether,
1:1, and detection was made using UV light. FT-IR spectra were
The newly synthesized compounds were evaluated
in vitro for their antimicrobial activities and the results
are shown in Table 1 (only positive results are presented).
None of the tested compounds, except 9, display activity
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ꢁꢀꢀꢀ
S. Demirci: New hybrid compounds derived from antipyrineꢂ
ꢂ3
O
NH
N
O
N
H2N
HN
N
i
ii
O
N
N
O
O
O
N
N
N
2
Ph
1
Ph
Ph
iii
X
H
N
H
N
EtO
v
iv
NH
H2N
NH
HN
R
HN
NH
O
O
O
N
N
N
O
O
O
N
N
N
Ph
Ph
Ph
3
4
5a–c
Cl
vi
H
N
X
viii
vii
N
NH
N
O
N
R
O
N
6a,b
Ph
H
N
X
N
N
NH
N
NH
a: R = CH2Ph; X=S
b: R = CH2Ph; X=O
c: R = Ph; X= S
N
O
N
O
HX
N
N
O
R
O
R
N
N
8a–c
7a–c
Ph
Ph
ix
H
N
N
S
N
NH
N
N
O
S
N
Et
O
N
Et HNOOC
Et
Ph
9
Scheme 1ꢀSynthesis of compounds 1–9.
i: PhCH2NCO, 13 h, reflux, ii: BrCH2CO2Et, CH3COONa, CHCl3, 18 h, reflux. iii: BrCH2CO2Et, TEA, in THF, 24 h, rt., iv: H2NNH2, in EtOH, 15 h,
reflux, v: RNCX, in EtOH, reflux (5 h for 5a) (16 h for 5b and 5c), vi: BrCH2COC6H4Cl, CH3COONa, in EtOH, MW (15 min., 150 W for 6a) (15 min.,
200 W for 6b), vii: BrCH2COOEt, CH3COONa, MW (20 min., 150 W for 7a and 7b) (5 min., 200 W for 7c), viii: NaOH, EtOH-water, 3 h, reflux,
ix: 6-apa, HCOH, DMF, 4 h, rt.,
recorded using a Perkin Elmer 1600 series FT-IR spectrometer using using mono-mode CEM-Discover microwave apparatus. The elemen-
1
KBr pellets. H-NMR and 13C-NMR spectra were registered in DMSO- tal analysis was performed on a Costech Elemental Combustion Sys-
d6 on a Bruker Avene II 400 NMR spectrometer (400 MHz for 1H and tem CHNS-O elemental analyzer. The mass spectra were obtained
100 MHz for 13C). Microwave-assisted syntheses were carried out on a Quattro LC-MS (70 eV) instrument.
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ꢀꢀꢀꢁ
4ꢀ ꢀS. Demirci: New hybrid compounds derived from antipyrine
Table 1ꢀAntimicrobial activity of selected compounds. See the text
for definitions of microorganisms.
Ethyl N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)glycinate (3)
No
Microorganisms and inhibition zone (mm)
To the mixture of antipyrine (10 mmol) and triethylamine (10 mmol)
in dry tetrahydrofuran, ethyl bromoacetate (10 mmol) was added
dropwise at 0–5°C. Then, the mixture was allowed to reach room tem-
perature and stirred for 12 h (the progress of the reaction was moni-
tored by TLC). The precipitated triethylammonium salt was removed
by filtration and the solution was concentrated under reduced pres-
sure. The obtained yellow solid was crystallized from ethyl acetate/n-
hexane (2:1) to give the desired product: yield 92%; mp 72–73°C; IR:
Ec
Yp
Pa
Sa
Ef
Bc
Ms
Ca
Sc
5c
–
–
–
–
–
–
12
10
6
6
–
6
6
16
–
10
7
15
12
6
6a
7c
–
–
–
6
6
–
6
8a
–
–
–
6
–
–
–
–
–
8
13
–
35
–
6
10
6
–
–
25
6
8c
–
–
–
9
20
8
–
–
9
15
10
–
10
18
–
–
15
35
–
10
10
–
10
15
–
1
3251, 3062, 1729, 1117 cm-1; H NMR: δ 1.13 (t, 3H, J ꢀ=ꢀ 7.0 Hz), 2.13 (s,
Amp.
Strep.
Flu.
18
–
3H,), 2.76 (s, 3H), 3.85 (d, 2H, J ꢀ=ꢀ 5.4 Hz), 4.03 (q, 2H, J ꢀ=ꢀ 7.0 Hz), 7.22
(bs, 1H, NH D2O exchangeable), 7.39–7.46 (m, 5H); 13C NMR: δ 10.8,
14.8, 19.2, 47.0, 60.7, 120.5, 122.9, 125.8, 126.1, 129.5, 136.0, 162.0, 172.7;
–
–
–
–
–
–
ꢃ>ꢃ25
+
+
LC-MS m/z (%): 328.41 ([M+K] 10), 312.43 ([M+Na] 13), 304.44 (100),
Ec, Escherichia coli ATCC 25922; Yp, Yersinia pseudotubercu-
losis ATCC 911; Pa, Pseudomonas aeruginosa ATCC 43288; Sa,
Staphylococcus aureus ATCC 25923; Ef, Enterococcus faecalis ATCC
29212; Bc, Bacillus cereus 702 Roma; Ms, Mycobacterium smegma-
tis ATCC607; Ca, Candida albicans ATCC 60193; Sc, Saccharomyces
cerevisiae RSKK 251; Amp.: ampicillin, Strep.: streptomycin, Flu.:
fluconazole; –, no activity of test concentrations.
+
289.48 ([M] 10). Anal. Calcd for C15H19N3O3: C, 62.27; H, 6.62; N, 14.52.
Found: C, 62.26; H, 6.67; N, 14.51.
2-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)aminoaceto hydrazide (4)
Hydrazine hydrate (25 mmol) was added to the solution of compound
3 (10 mmol) in ethanol and the mixture was heated under reflux for
15 h and then cooled. The resultant white crystals were filtered off and
crystallized from ethyl acetate: yield 82%; mp 52–53°C; IR: 3371, 3047,
1704 cm-1; 1H NMR: δ 2.13 (s, 3H), 2.77 (s, 3H), 3.59 (s, 2H), 3.98 (bs, 2H,
NH2, D2O exchangeable), 7.23–7.26 (m, 2H, 2NH, D2O exchangeable),
7.379–7.47 (m, 5H); 13C NMR: δ 10.7, 37.6, 48.8, 119.7, 123.1, 123.6, 126.5,
N-Benzyl-N′-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-yl)urea (1)
A solution of antipyrine (10 mmol) and benzyl isocyanate (10 mmol)
in absolute ethanol (10 mL) was heated under reflux for 13 h. On
cooling the mixture to room temperature, a solid was formed. This
crude product was collected by filtration and crystallized from ethyl
acetate/n-hexane (2:1) to give the target product: yield 92%; mp
188–189°C; FT-IR: 3274, 3077, 1765 cm-1; 1H NMR: δ 2.14 (s, 3H), 3.00 (s,
3H), 4.23 (bs, 2H, J ꢀ=ꢀ 5.8 Hz), 6.75 (s, 2H, NH, D2O exchangeable), 7.24
(bs, 2H), 7.29 (d, 2H, J ꢀ=ꢀ 5.0 Hz), 7.36 (bs, 2H), 7.46 (d, 4H, J ꢀ=ꢀ 7.0 Hz);
13C NMR: δ 14.1, 35.2, 61.3, 116.2, 125.8, 127.5, 129.5, 130.0, 131.2, 134.3,
+
129.8, 135.5, 162.6, 171.2; LC-MS m/z (%): 275.41 ([M] 10), 257.43 ([M-
+
H2O] 13), 165.10 (100). Anal. Calcd for C13H17N5O2: C, 56.71; H, 6.62; N,
25.44. Found: C, 56.80; H, 6.64; N, 25.41.
Synthesis of compounds 5a–c
+
140.3, 152.6; LC-MS m/z (%): 355.21 ([M+1+H2O] 45), 321.11 (100).
Anal. Calcd for C19H20N4O2: C, 67.84; H, 5.99; N, 16.66. Found: C, 67.79;
H, 5.98; N, 16.62.
The mixture of compound 4 (10 mmol) and iso(thio)cyanate
(10 mmol) in absolute ethanol was heated under reflux for 5 h (for
5a), 15 h (for 5b) and 16 h (for 5c) with the progress of the reaction
monitored by TLC. Upon cooling the resultant white solid was filtered
and crystallized from ethanol to afford the desired compound.
3-Benzyl-2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihy-
dro-1H-pyrazol-4-yl)imino]-1,3-oxazolidin-4-one (2)
N-Benzyl-2-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zol-4-yl)amino]acetylhydrazine carbothioamide (5a)ꢁYield
A mixture of compound 1 (10 mmol) and ethyl bromoacetate in dry 66%, mp 290°C; IR: 3353, 3328, 3293, 3241, 3061, 1650, 1284 cm-1; H
chloroform was heated under reflux in the presence of dried sodium NMR: δ 2.14 (s, 3H), 2.80 (s, 3H), 3.63 (s, 2H), 4.60 (bs, 2H), 7.20 (s, 2H),
acetate (50 mmol) for 18 h. Then, the mixture was cooled to room 7.27 (bs, 6H), 7.37 (d, 2H, J ꢀ=ꢀ 7.0 Hz), 8.65 (s, 2H, NH, D2O exchange-
temperature and the precipitated salt was separated by filtration. The able), 9.31 (s, 1H, NH, D2O exchangeable), 9.98 (s, 1H, NH, D2O
filtrate was concentrated under reduced pressure and the resultant exchangeable); 13C NMR: δ 10.6, 37.9, 41.5, 46.3, 118.9, 126.3, 127.8, 127.9,
solid was crystallized from ethyl acetate to give the target product: 129.1, 129.3, 129.7, 135.9, 136.6, 145.2, 151.6, 162.7, 168.2; LC-MS m/z (%):
1
1
+
yield 27%; mp 177–178°C; IR: 3076, 1770, 1628 cm-1; H NMR: 2.14 (s, 424.62 ([M] 18), 251.48 (100). Anal. Calcd for C21H24N6O2S: C, 59.41; H,
3H), 3.00 (s, 3H), 3.34 (s, 2H), 4.25 (d, 2H, J ꢀ=ꢀ 5.8 Hz), 6.75 (t, 1H, J ꢀ=ꢀ 5.70; N, 19.80. Found: C, 59.39; H, 5.64; N, 19.81.
5.6 Hz), 7.25–7.32 (m, 6H), 7.37 (s, 1H), 7.48 (t, 2H, J ꢀ=ꢀ 7.8 Hz); 13C NMR:
14.1, 35.4, 56.3, 61.3, 118.2, 125.9, 127.2, 129.8, 131.0, 131.8, 132.3, 134.6, N-Benzyl-2-{2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
+
140.3, 148.9, 152.6, 167.0; LC-MS m/z (%): 393.14 ([M+1] 50), 385.22 pyrazol-4-yl)amino]acetyl}hydrazine carboxamide (5b)ꢁYield
(100). Anal. Calcd for C19H20N4O2S: C, 64.27; H, 5.14; N, 14.28. Found: 32%, mp 241–242°C; IR: 3325, 3267, 3052, 1702, 1649 cm-1; H NMR: δ
1
C, 64.29; H, 5.18; N, 14.22.
2.12 (s, 3H), 3.00 (s, 3H), 3.71 (bs, 2H), 4.22 (d, 2H, J ꢀ=ꢀ 5.2 Hz), 7.19–7.34
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ꢁꢀꢀꢀ
ꢂ5
S. Demirci: New hybrid compounds derived from antipyrineꢂ
(m, 8H), 7.47 (m, 2H); 13C NMR: δ 12.0, 35.2, 61.2, 63.0, 106.2, 125.9, 127.5, N′-[3-Benzyl-4-oxo-1,3-thiazolidin-2-ylidene]-2-[(1,5-dimethyl-
+
129.0, 130.0, 134.3, 140.4, 152.7; LC-MS m/z (%): 429.24 ([M+2+Na] , 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]acetohy-
50), 399.23 (100). Anal. Calcd for C21H24N6O3: C, 61.75; H, 5.92; N, 20.58. drazide (7a)ꢁYield 75%; mp 140°C; IR: 3289, 3287, 3058, 1702, 1689,
Found: C, 61.77; H, 5.94; N, 20.51.
1599 cm-1; 1H NMR: δ 1.89 (s, 3H), 2.87 (s, 3H), 3.37 (s, 2H), 4.01 (s, 2H),
4.77 (s, 2H), 7.32 (m, 10H); 13C NMR: δ 10.0, 24.6, 32.6, 45.6, 51.4, 120.1,
2-{[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) 123.0, 127.9, 128.6, 129.3, 134.4, 136.0, 149.9, 155.7, 160.0; LC-MS m/z (%):
+
+
amino]acetyl}-N-phenylhydrazine carbothioamide (5c)ꢁYield 487.55 ([M+Na] , 100), 464.06 ([M] , 25). Anal. Calcd for C23H24N6O3S:
42%; mp 168–169°C; IR: 3264, 3014, 1657, 1288 cm-1; H NMR: δ 1.94 C, 59.47; H, 5.21; N, 18.09. Found: C, 59.37; H, 5.21; N, 18.01.
1
(s, 3H), 2.77 (s, 3H), 4.08 (s, 2H), 7.28–7.48 (m, 10H), 9.71 (s, 1H, NH,
D2O exch.), 9.98 (s, 1H, NH, D2O exchangeable), 10.71 (s, 1H, NH, D2O N′-[3-Benzyl-4-oxo-1,3-oxazolidin-2-ylidene]-2-[(1,5-dimethyl-
exchangeable), 13.89 (s, 1H, NH, D2O exchangeable); 13C NMR: δ 7. 5, 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]acetohy-
9.7, 54.0, 116.0, 116.7, 120.9, 122.4, 125.5, 128.0, 128.3, 133.4, 144.0, 151.0, drazide (7b)ꢁYield 77%; mp 177–178°C; IR: 3158, 3021, 1713, 1702,
+
155.5, 161.6; LC-MS m/z (%): 443.27 (100), 449.21 ([M+K] 10), 429.26 1593 cm-1; 1H NMR: δ 2.14 (s, 3H), 2.99 (s, 3H), 3.46 (s, 4H), 4.24 (s, 2H,
+
([M+1+H2O] , 45). Anal. Calcd for C20H22N6O2S: C, 58.52; H, 5.40; N, J ꢀ=ꢀ 5.0 Hz), 6.74 (bs, 2H), 7.30–7.34 (m, 10H); 13C NMR: δ 10.0, 24.6,
20.47. Found: C, 58.57; H, 5.44; N, 20.50.
32.6, 45.6, 51.4, 120.1, 123.0, 127.9, 128.6, 129.3, 134.4, 136.0, 149.9, 155.7,
+
+
160.0; LC-MS m/z (%): 487.55 ([M+Na] , 100), 464.06 ([M] , 25). Anal.
Calcd for C23H24N6O3S: C, 59.47; H, 5.21; N, 18.09. Found: C, 59.37; H,
5.21; N, 18.01.
Synthesis of compounds 6a,b
2-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)
amino]-N′-(4-oxo-3-phenylthiazolidin-2-ylidene)acetohydrazide
(7c)ꢁYield 71%; mp 118–119°C; IR: 3235, 3278, 3093, 1727, 1722, 1589
A mixture of compound 5 (10 mmol) and dried sodium acetate
(20 mmol) in absolute ethanol was stirred at room temperature for
15 min. Then, 4-chlorophenacyl bromide (15 mmol) was added and
the mixture irradiated in a closed vessel with the pressure control at
124°C for 10 min (hold time) at 150 W (for 6a) and 160°C for 15 min
(hold time) at 200 W (for 6b) maximum power. The solution was
poured into ice water and the resultant white solid was collected
by filtration and crystallized from butylacetate/diethylether (1:2) to
afford the target compound.
1
cm-1; H NMR: δ 1.91 (s, 3H), 2.77 (s, 3H), 4.01–4.16 (m, 4H), 6.92 (t,
1H, J ꢀ=ꢀ 6.0 Hz), 7.24 (s, 2H), 7.30 (d, 2H, J ꢀ=ꢀ 7.8 Hz), 7.44 (s, 1H), 7.53
(m, 4H), 9.86 (s, 2H, NH, D2O exchangeable); 13C NMR: δ 14.5, 34.6,
37.2, 62.2, 105.0, 117.5, 127.6, 129.0, 129.7, 130.0, 130.6, 130.8, 133.2, 135.5,
+
141.6, 156.5, 163.2, 168.8; LC-MS m/z (%): 450.00 ([M] , 10), 321.11
(100). Anal. Calcd for C22H22N6O3S: C, 58.65; H, 4.92; N, 18.65. Found:
C, 58.67; H, 4.94; N, 18.61.
N′-[3-Benzyl-5-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]-2-
[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)
amino]acetohydrazide (6a)ꢁYield 45%; mp 180°C; IR: 3381, 3227,
3056, 1721, 1588 cm-1;. 1H NMR: δ 2.00 (s, 3H), 2.80 (s, 3H), 4.10 (s, 2H),
4.31 (bs, 1H), 5.38 (s, 2H), 7.31–7.45 (m, 14H); 13C NMR: δ 10.5, 37.6, 46.3,
58.2, 104.5, 118.4, 123.5, 126.6, 127.8, 128.4, 129.0, 129.3, 129.7, 130.8,
Synthesis of compounds 8a–c
A solution of compound 5 (10 mmol) and NaOH (0.4 g, 10 mmol)
in ethanol-water (10 mL, 1:1), was heated under reflux for 3 h, then
cooled to room temperature and acidified to pH 4 with 37% HCl. The
precipitate formed was filtered off, washed with water, and crystal-
lized from ethanol to give the target product.
+
135.7, 136.4, 139.5, 145.7, 151.6, 162.8, 169.5; LC-MS m/z (%): 559.55 ([M]
+
45), 541.06 ([M-H2O] , 25), 321.41 (100). Anal. Calcd for C29H27ClN6O2S:
C, 62.30; H, 4.87; N, 15.03. Found: C, 62.37; H, 5.81; N, 15.01.
N′-[5-(4-Chlorophenyl)-3-phenyl-1,3-thiazol-2(3H)-ylidene]-
2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)
amino]acetohydrazide (6b)ꢁYield 70%; mp 140–141°C; IR: 3279,
3227, 3056, 1702, 1589 cm-1; 1H NMR: δ 1.76 (s, 3H), 1.88 (s, 3H), 3.35 (s,
2H), 6.56 (s, 1H), 7.11–7.36 (m, 14H); 13C NMR: δ18.9, 25.0, 44.2, 109.3, 120.0,
128.1, 129.0, 129.4, 130.3, 130.6, 133.5, 138.5, 159.9, 166.5; LC-MS m/z (%):
4-{[(4-Benzyl-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]amino}-
1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (8a)ꢁYield
1
73%; mp 139–140°C; IR: 3325, 3033, 2767, 1649 cm-1; H NMR: δ 2.00
(s, 3H), 2.80 (s, 3H), 4.81 (s, 2H), 4.11 (s, 2H), 5.37 (s, 1H), 7.32 (m, 8H),
7.43 (d, 2H, J ꢀ=ꢀ 6.6 Hz), 13.07 (s, 1H); 13C NMR: δ 10.5, 37.5, 46.3, 54.2,
105.6, 123.5, 126.6, 127.5, 127.8, 128.4, 129.0, 129.3, 129.7, 130.1, 135.6,
+
+
568.05 ([M+1+Na] , 100), 545.06 ([M] , 25). Anal. Calcd for C28H25ClN6O2S:
+
136.4, 145.8, 151.6, 162.8; LC-MS m/z (%): 443.21 ([M-2+K] 100), 429.03
C, 61.70; H, 4.62; N, 15.42. Found: C, 61.77; H, 4.64; N, 15.41.
+
+
+
([M+Na] , 61), 424.13 ([M+H2O] , 25), 406.37 ([M] , 21). Anal. Calcd for
C21H24N6OS: C, 62.05; H, 5.45; N, 20.67. Found: C, 62.39; H, 5.54; N,
20.81.
Synthesis of compounds 7a–c
4-{[(4-Benzyl-5-hydroxy-4H-1,2,4-triazol-3-yl)methyl]amino}-
A mixture of compound 5 (15 mmol) and dried sodium acetate 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (8b)ꢁYield
1
(20 mmol) in absolute ethanol was stirred at room temperature for 95%; mp 256–257°C; IR: 3521, 3287, 3098, 1712 cm-1; H NMR: δ 2.48
15 min. Then, ethyl bromoacetate (15 mmol) was added and the (bs, 3H), 3.56 (bs, 3H), 4.21 (d, 4H, J ꢀ=ꢀ 5.6 Hz), 7.01 (s, 1H, NH, D2O
mixture was irradiated in a closed vessel with the pressure control exchangeable), 7.25 (bs, 10H), 7.81 (s, 1H, OH, D2O exchangeable); 13
C
at 125°C for 20 min (hold time) at 150 W (for 7a and 7b) and 160°C NMR: δ 14.5, 34.5, 43.3, 44.2, 108.5, 123.5, 125.6, 127.6, 127.6, 128.6, 129.0,
+
for 5 min (hold time) at 200 W (for 7c) maximum power. The solution 131.6, 135.7, 137.9, 146.6, 156.6, 162.8; LC-MS m/z (%): 390.21 ([M] , 70),
+
poured into ice water and the resultant white solid was collected by fil- 372.26 ([M-H2O] , 45), 241 (100). Anal. Calcd for C21H22N6O2: C, 64.60;
tration and crystallized from ethyl acetate to give the target compound. H, 5.68; N, 21.52. Found: C, 64.57; H, 5.69; N, 21.50.
Unauthenticated
Download Date | 5/12/16 10:20 PM

ꢀꢀꢀꢁ
6ꢀ ꢀS. Demirci: New hybrid compounds derived from antipyrine
4-{[(5-Mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methyl]amino}-
1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (8c)ꢁYield
57%; mp 239–240°C; IR: 3267, 3056, 2651, 1721 cm-1; 1H NMR: δ 1.94 (s,
3H), 2.77 (s, 3H), 4.07 (s, 2H), 7.33–7.48 (m, 10H), 13.87 (s, 1H); 13C NMR:
δ 10.4, 37.4, 41.6, 118.1, 123.5, 125.6, 128.7, 129.7, 130.0, 134.0, 135.5, 145.5,
154.1, 162.5; LC-MS m/z (%): 415.07 (([M+Na] , 25), 393.09 ([M+1] ,
100). Anal. Calcd for C20H20N6OS: C, 61.20; H, 5.14; N, 21.41. Found: C,
61.27; H, 5.14; N, 21.41.
Acknowledgments: This work was supported by Karadeniz
Technical University, BAP, Turkey (Ref. No. 8663 and 8623).
+
+
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6-Apa (10 mmol) was added to a solution of compound 8a (10 mmol) in
DMF and the mixture was stirred at room temperature in the presence
of formaldehyde (37%, 7.4 mL) for 4 h. Then, water was added and the
mixture kept overnight at 0oC. The solid separated was collected by
filtration and crystallized from ethyl acetate/petroleum ether (1:2) to
give the target product: yield 70%; mp 129–130°C; IR: 3203, 3060, 1763,
1
1728, 1215 cm-1; H NMR: δ 1.12 (t, 9H, J ꢀ=ꢀ 7.8 Hz), 1.45 (s, 3H), 1.53 (s,
3H), 2.24 (s, 3H), 2.51 (s, 2H), 2.91 (q, 6H, J ꢀ=ꢀ 7.2 Hz), 3.06 (s, 3H), 4.06
(s, 1H), 4.47 (s, 2H), 4.52 (s, 1H), 4.67 (d, 2H, J ꢀ=ꢀ 5.8 Hz), 5.32 (d, 1H, J ꢀ=ꢀ
3.4 Hz), 7.19–7.28 (m, 5H), 7.33 (m, 2H), 7.47 (t, 3H, J ꢀ=ꢀ 7.8 Hz), 9.52 (s, 2H,
2NH, D2O exchangeable); 13C NMR: δ 9.2, 14.2, 27.4, 30.2, 34.2, 46.3, 47.9,
50.3, 51.3, 59.3, 62.3, 64.3, 75.5, 107.3, 124.9, 127.6, 128.8, 130.0, 131.8,
133.0, 134.6, 140.1, 148.9, 163.6, 165.3, 167.0, 171.9; LC-MS m/z (%): 734.14
+
([M-1] , 70), 585.22 (100). Anal. Calcd for C36H49N9O4S2: C, 58.75; H, 6.71;
N, 17.13. Found: C, 58.69; H, 6.78; N, 17.12.
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ꢂ7
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