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we wish to report an efficient and practical procedure for the Initially, reaction between (E)-3-(4-bromophenyl)-1-(3-
synthesis of 2-pyrazolines using heterocyclic analogues of methylpyrazin-2-yl) prop-2-en-1-one (3c) and phenyl hydrazine
chalcones and substituted hydrazines in sodium acetate-acetic hydrochloride was chosen as a model reaction for optimization
acid aqueous solution at room temperature under ultrasound of reaction conditions. For this, equal molar ratio (1 mmol) of
irradiation (Scheme 1). reactants and 0.2 mmol sodium acetate were used and produced
79 % yield in 90 min at room temperature under ultrasonication
(Table 1, entry 1). The reaction using 2 mmol and 3 mmol of
2 | New J. Chem., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 2012
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accelerates instantaneous high temperature and pressure. The >C=O stretching of (4d) and (4e) due to carbonyl group
difference in yields and reaction times as comparison to attached to pyrazoline, observed at 1650 and 1668 respectively.
conventional method may be a consequence of the specific A band at 3344 and 3297 cm-1 owing to –NH2 of (4f-4l)
effects of ultrasound on molecules attributed to cavitation, a observed. Positive mode ESI-MS spectra of the synthesized
physical process that produces, extends, and collapses gaseous compounds (4a-4l) displayed the protonated molecular ion
and vaporous cavities in an irradiated liquid, thus enhancing the peaks, [M+H]+ respectively, confirming their molecular masses.
mass transfer28 and allowing chemical reactions to occur. The 1H NMR spectra showed an H abx pattern of protons of
ring and –CH3 and –C2H5 at 3-position of pyrazine. Probable methylenic protons (Ha and Hb) as dd, clearly postulates the
mechanism for 2-pyrazolines synthesis is illustrated in Fig. 1. magnetic non-equivalence of these two protons, which have
chemical shift at δ 3.2-3.6 ppm and δ 3.4-4.0 ppm with J = 5.0-
6.0 Hz and 11.5-13.5 Hz, respectively. The H x proton as dd
appeared at δ 5.2-6.0 ppm with J = 5.0-6.0 Hz. The alkyl
protons (-CH3 and -C2H5) appear at upper filed due to higher
shielding effect. The two broad singlet of NH’s proton for
compounds (4f-4l) were observed at δ 6.17-6.25 ppm and δ
6.95-7.03 ppm. These spectral data unequivocally proved the 2-
pyrazolines structure. For compounds (4a-4l), the aromatic
protons appear as multiplet in the desired range.
The 13C NMR spectra of compounds provided final
structure of 2-pyrazolines. Chemical shift a value of the
methylpyrazine (4a-4i) carbons appears at δ 24.5-25.5 ppm,
while in ethylpyrazine (4j-l) appears at δ 12.1-12.2 ppm. The
Figure 1. Plausible reaction mechanism of 2-pyrazolines synthesis chemical shifts at δ 22.05 ppm, δ 30.01 ppm and δ 44.39 ppm
are due to –CH2 of aliphatic carbon attached to pyrazine ring
Table 2. Ultrasound assisted (US) synthesis of substituted 2- (4j-4l), -CH3 of carbonyl (4d and 4e) and –CH3 of –N(CH3)2 of
pyrazolines in aqueous medium at room temperature a compound (4i) respectively.
a
room temperature 30-33 0C, bisolated yield.
The -C3 carbon of pyrazoline ring appears in the range of δ
Structures of 2-pyrazoline derivatives were elucidated with 62.0 ppm to δ 63.0 ppm of compounds (4a-4c and 4f-4l), while
their FTIR, mass spectra, 1H and 13C NMR. The ring closure in compounds (4d and 4e) appears at δ 58.86 ppm and δ 58.92
reaction of chalcones was established by the FTIR spectra of ppm. The -C4 and -C5 carbons of pyrazoline ring appears in the
(4a-4l), which clearly showed the absence of >C=O bond range of δ 43.4 ppm to δ 44.7 ppm and δ 147 ppm to 156 ppm
stretching in region of 1650 cm-1 of chalcone backbone. A peak respectively. The phenyl ring carbons of compounds (4a-4l)
at 1596 cm-1 is corresponding to –C=N confirms the formation appear in their desired aromatic region. The peaks at δ 169.32
of –C=N bond and also due to pyrazine –C=N- bonds, while ppm and δ 177.5 ppm are of >C=O group (4d and 4e) and
peak at 1560 to 1568, 1522 and 1490 cm -1 are due to –C=C– >C=S group (4f-4l) carbons respectively. (See ESI†)
bond. In addition, the peaks at 1124 to 1211 cm-1 were Electronic spectra of the cyclized pyrazoline analogues (4a-
attributed to the (-C-N) vibrations, which also confirm the 4l) were studied in the UV region at molar concentration of 40
formation of desired pyrazoline ring in all the compounds. The μg/mL in ethanol and compounds exhibits different intense
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absorption band due to different functionality on 2-position of Table 3. Onset temperature, enthalpy and melting point of
pyrazolines as illustrated in Fig. 2. Compounds (4a-4c) showed synthesized compounds.
two spectral bands, whose maxima were located in the range Comp. Heat flow endothermic m.p.
between 240 nm to 260 nm, and a broad band larger than 350 Onset (0C) ΔH(J/g) (0C)
4a 114.01 38.32 113-115
nm.
4b 150.66 90.54 149-151
3.0 4c 152.66 67.81 151-153
4a 4b 4d 107.65 63.27 108-111
1.5
4k 179.28 104.18 179-181
4l 181.12 131.79 182-184
1.0
Antibacterial study
0.5
The in vitro antibacterial activities of compounds (4a–4l)
0.0 were investigated against the human pathogenic gram-positive
200 250 300 350 400 450 500 S. aureus (NCIM 2079) and gram-negative E. coli (NCIM
Wavelength (nm) 2109) bacterial strain. The minimum inhibitory concentration
(MIC) was evaluated by the broth tube dilution method.32
Figure 2. UV absorption spectra of compounds (4a-l) in ethanol Nutrient agar microbiological media used for bacteria (S.
aureus and E. coli), obtained from Hi-media (India) and its
The shorter bands were attributed to →* transition, while composition (grams per litre) has sodium chloride, 5.0; beef
the longer wavelength band were correspondence to extract 10.0; peptone 10.0 (pH 7.2). Stock solution of 1000 μg
intramolecular charge transfer transition owing to two nitrogen mL-1 of each compound prepared in DMSO. Serial dilutions of
of pyrazoline29 and additional phenyl ring at 2-position of the test compounds, already dissolved in DMSO, were prepared
pyrazolines. Compounds (4d) and (4e) showed a broad band in to final concentrations of 512, 256, 128, 126, 64 and 32 μg mL-
the range of 290 nm to 340 nm due to →* transitions. In 1
. The MIC which inhibits the visible growth was determined
carbothioamide containing pyrazolines (4f-4l) three absorption visually after incubation for 24 h, at 37 0C and pH 7.4.
bands in range 210-230 nm, 240-260 nm and 335-355 nm were
owing to n→σ*, →* and n→* transitions, respectively. The Table 4. MIC values (μg/mL) for (4a–4l) against S. aureus, and
band at 335-355 nm assigned to the n→* transition involving E. coli bacterial strains.a,b
the thione portion (-C=S) of thiocarboxamide group. The two Comp. S. aureus E. coli
other absorption bands at 240-260 and 210-230 nm were owing 4a >512 >512
to →* transition of phenyl ring and n→σ* transition of 4b >512 >512
pyrazine ring nitrogen respectively.30 4c >512 >512
4d >512 >512
4e >512 >512
Thermal stability of 2-pyrazolines was studied with DSC, 4f 256 >512
their onset and enthalpy data are given Table 3. The DSC 4g 256 >512
measurements provide quantitative and qualitative information 4h >512 >512
4i 256 >512
about physical and chemical changes that involve endothermic 4j 256 >512
or exothermic processes, or changes in heat capacity. This may 4k 256 >512
result to provide a significant impact on the chemical stability 4l 256 >512
Chloramphenicol <16 <16
and shelf life of the drug products. During the standard heating a
Data are the mean values of three replicates for each concentration.
run, we have observed one endothermic thermograms and the
Concentration in μg mL-1 in DMSO.
b
onset point of endothermic thermograms is noted as solid–
liquid transition or melting transition (T M) and the peak as
liquid-liquid transition (TL-L) for each compounds.31 The The lowest concentration, which showed no visible growth, was
enthalpy (ΔH) values of compounds (4a-e) were found in the considered as an end point for MIC. The MIC level of
range of ΔH = 38.32 J/g to 90.54 J/g, while compounds compounds (4a–4l) against these organisms is given in Table 4.
containing thiocarboxamide groups (4f-l) fall in the range of It is evident from the MIC data that the compounds (4a-4e) and
99.03 J/g to 195 J/g. Compounds having thiocarboxamide (4h) showed MIC value more than 512 μg mL -1 having phenyl
group are more thermally stable than of the phenyl and and ethanone functionality at 2-position of pyrazoline ring,
ethanone functionality containing pyrazolines. while rest of the compounds having –CSNH2 functionality on 2-
position of pyrazoline increase 50% activity against S. aureus
as compared to phenyl and ethanone group with MIC 256 μg
4 | New J. Chem., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 2012
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80 4j 4k 4l 600 Comp.+Dye
AA (4b)
70
500
60
DNA binding (ng/mL)
50 400
40
300
30
20 200
20 40 60 80 100
Concentration (μg mL-1 ) 100
Figure 3. Percentage antioxidant or scavenging activities of
compounds (4a–4l) in μg mL-1 determined with DPPH free 0
DD
3b
3d
3g
4b
4d
4g
4h
4i
3a
3c
3e
4a
4c
4e
4j
4k
4l
3f
4f
DPPH radical scavenging activity of the compounds was found Figure 4. (a) Standard DNA calibration curve and (b) dsDNA
to be good-to-moderate as compared to the standard AA. binding affinity of compounds in the presence of fluorescence
Compounds (4a-4l) showed an increase in % antioxidant dye
activity within the range of 29.26% to 68.86% with an increase
in concentration. An increasing trend of antioxidant activity is From the data it was evident that chalcones and pyrazolines
have structural binding affinity towards the DNA molecule
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(Figure 4b) and increase two to three folds concentration of The results revealed that all compounds are within the range set by
DNA, while they produce negligible fluorescence in Lipinski rule of five as per Table 5. It was also found that none of
conjugation with dye (Figure 4b). When the compounds were the compounds have toxicity risk in terms of mutagenic,
added to the DNA-Dye (DD) conjugate, increase in tumorigenic, irritant and reproductive effect. Thus, synthesized
fluorescence was observed, which on result increase DNA compounds could be considered as potent lead compounds in drug
concentration in the range of 229-570 ng/mL, due to discovery.
intercalation and minor groove binding mechanisms with
6 | New J. Chem., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 2012
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showed good to moderate antioxidant (36-69%) and dsDNA interval. On completion of the reaction (5-7 min), the mixture
binding activities. Thus, synthesized compounds could be was cooled to ambient temperature and the product was
considered as potent lead compounds in bioorganic chemistry. extracted with ethyl acetate and concentrated under vacuum
using a Buchi rotary evaporator or poured over the crushed ice
Experimental and filter, washed with water and dried under vacuum. The
overall yields of synthesized compounds were obtained as 90–
Hydrazine monohydrate, phenylhydrazine hydrochloride, 95%. The compounds were recrystallized in ethanol/methanol
performed at 30 KHz using an Oscar ultrasonic cleaner (model compounds 4a–4l by conventional method
FP-108FX). The reaction progress was monitored with TLC
(Merck, silica GF257), and spots were visualized under UV In a 50 mL round bottom flask, a mixture of pyrazine
light (RICO Scientific Industries, Model RSUV-5). Melting bearing chalcones (4a-g, 1 mmol) and substituted hydrazines (2
points were determined on a Stuart SMP 40 apparatus and mmol) were charged into a 10 mL ethanol and dissolved on
found uncorrected. Elemental analysis was made with Euro reflux. To this clear solution, a solution of potassium hydroxide
Vector elemental analyser. FT-IR spectra were recorded in KBr (2 mmol dissolved in 10 mL ethanol) added drop wise, and
pellets with a Perkin Elmer spectrum-65 FT-IR refluxed for a completion of the reaction (Table 2). The
spectrophotometer, and wavenumbers are given in cm −1. Mass obtained solid was filtered, washed with water; dry under
spectral analysis (m/z) was obtained using Agilent vacuum and gives 58-75% yields (Table 2). For compound (4d)
Technologies G6520B LCMS-QTOF mass spectrometry with and (4e) catalytic amount of acetic acid was added. The
positive electron spray ionization (+ESI) method. The mobile substituted 2-pyrazolines (4a-l) were recrystallized in ethanol
phase containing 2% trifloroacetic acid in water and acetonitrile or methanol.
(30:70 v/v) was run on Agilent zorbax 300 SB-C18 column (3.5
μm, 4.6×50 mm) with flow rate 0.6 mL/min. 1H and 13C NMR Method B: General procedure for the synthesis of
spectra were recorded at r.t. in 5 mm tube using Bruker Avance compounds 4a–4l by ultrasound irradiation method
III 500 MHz spectrometer in deuterated chloroform (CDCl3) or
DMSO-d6 and tetramethylsilane (TMS) as internal standard. A mixture of respective pyrazine bearing chalcones (3a-g, 1
The chemical shifts are given in ppm and coupling constants mmol) and substituted hydrazines (3 mmol) were taken into a
J in Hz. Splitting patterns are described as singlet (s), doublet 50 mL capacity Elmer flask. To this mixture added a solution of
(d), double doublet (dd), triplet (t), quartet (q), broad (br) and sodium acetate (0.3 mmol) in 15 mL acetic acid–water (10:5
multiplet (m). The absorption transition (λmax) was recorded in v/v), and sonicated for a completion of the reaction. The
ethanol at r.t. ranging from 200–600 nm using Analytical UV progress of the reaction was monitored by TLC. After
spectro 2060 plus. The equilibrium transition temperatures and completion of the reaction (Table 2), the mixture was poured on
enthalpies were noted using differential scanning calorimetry crushed ice and stirred vigorously. The obtained solid was
(DSC) with DSC-6000 Perkin Elmer instrument under nitrogen filtered, washed with water and recrystallize in ethanol or
(flow rate 20 mL/min) and at heating rate of 5 0C/min. for 30- methanol to afford compound 4a-l with 85 to 93 % yield. Their
300 0C and aluminum pan was used as reference. The DSC was structures were confirmed with 1H NMR, 13C NMR, FTIR,
calibrated with indium provided by Perkin Elmer as standard mass and elemental analysis.
calibration sample. DNA interaction study was performed using
dsDNA HS assay kit with the Qubit 2.0 Fluorometer. 2-(5-(4-fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-
yl)-3-methylpyrazine (4a)
Synthesis
Chemical formula: C20H17FN4; Color: Pale yellow; Rf : 0.53;
Microwave assisted solvent free synthesis of (E)-3-aryl-1-(3- m.p.: 113-115 0C; Elemental analysis (%): Calculated: C 72.27,
alkyl-2-pyrazinyl)-2-propenones (3a-3g)27 H 5.16, N 16.86; Found: C, 72.24, H 5.18, N 16.90; FTIR (KBr,
cm-1): νmax 3051, 2999 (Ar, -CH str.); 2961, 2928, 2856 (-CH
A mixture of 2-acetyl-3-alkylpyrazine (1a-1b, 0.01 mol), str., -CH3); 1585 (-C=N), 1596, 1569, 1551, 1524 (-C=C); 1H
and substituted aromatic aldehyde (2a–2d, 0.01 mol), was NMR (500 MHz, CDCl3): δ 3.05 (s, 3H, -CH3, pyrazine ring),
mixed in ethyl acetate (5 mL), absorbed on anhy. K2CO3 and 3.36 (dd, 1H, J = 5.0, 5.0 Hz, Hb), 4.00 (dd, 1H, J = 13.0, 13.0
taken in teflon reaction vessels, dried in air and irradiated at Hz, Ha), 5.32 (dd, 1H, J = 7.0, 6.5 Hz, H x), 7.27-6.85 (m, 9H,
300 W, infrared red (IR) temperature 70C and a maximum Ar rings), 8.32 (s, 1H, pyrazine), 8.35 ppm (s, 1H, pyrazine);
13
pressure of 20 bar inside the vessels for completion of C NMR (125 MHz, CDCl3): δ 24.63 (-CH3, pyrazine ring),
reactions. The progress of the reaction was monitored by TLC 43.41, 61.94 (pyrazoline ring), 112.63, 115.15, 119.10, 126.44,
using ethyl acetate: hexane (2:8 v/v) as eluents after each 30 sec 128.08, 136.81, 139.81(Ar rings), 142.69, 144.87, 146.46
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(pyrazine ring), 152.20 (pyrazoline), 160.13 (pyrazine ring), (pyrazoline), 127.16, 129.06, 133.48, 140.06 (-CH=CH-, Ar
162.09 ppm (Ar ring); +ESI-MS (m/z): calculated for ring), 141.19, 142.91, 144.52 (pyrazine ring), 153.98
C20H18FN4+ 333.1437 [M+1]+, found 333.1521. (pyrazoline), 154.99 (pyrazine ring), 169.32 ppm (>C=O);
+ESI-MS (m/z): calculated for C16H16ClN4O+ 315.0934
2-(5-(4-chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3- [M+1]+, found 315.1029.
yl)-3-methylpyrazine (4b)
1-(5-(4-bromophenyl)-3-(3-methylpyrazin-2-yl)-4,5-
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(dd, 1H, J = 12.0, 11.5 Hz, Ha), 5.98 (dd, 1H, J = 5.0, 5.0 Hz, 4.90, N 21.26; Found: C 58.30, H 4.95, N 21.30; FTIR (KBr,
Hx), 6.25, 6.99 (br 2s, 2H, -NH2), 7.32-7.16 (m, 4H, Ar rings), cm-1): νmax 3250, 3145 (-NH2), 3045, 3028 (Ar, -CH str.); 2988,
8.45, 8.47 ppm (2s, 2H, pyrazine ring); 13C NMR (125 MHz, 2939, 2879 (-CH str., -CH2CH3), 1584 (-C=N), 1551, 1532,
CDCl3): δ 25.30 (-CH3, pyrazine ring), 44.36, 62.33 (pyrazoline 1510, 1480 (-C=C), 1374, 872 (-C=S); 1H NMR (500 MHz,
ring), 126.96, 129.11, 133.45, 140.14 (Ar ring), 141.50, 143.50, CDCl3): δ 1.40 (t, 3H, J = 7.5 Hz, -CH2CH3), 3.32 (q, 2H, J =
143.92 (pyrazine ring), 153.91 (pyrazoline ring), 156.92 7.5 Hz, -CH2CH3), 3.47 (dd, 1H, J = 5.0, 5.0 Hz, Hb), 3.98 (dd,
(pyrazine ring), 177.58 ppm (-C=S); +ESI-MS (m/z): 1H, J = 12.0, 11.5 Hz, Ha), 5.99 (dd, 1H, J = 5.0, 5.0 Hz, Hx),
1H-pyrazole-1-carbothioamide (4h) ring), 115.91, 127.32, 137.44 (Ar ring), 141.30, 143.67, 156.65
(pyrazine ring), 158.37 (pyrazoline ring), 161.15 (pyrazine
Chemical formula: C15H14BrN5S; Color: white; Rf : 0.60; m.p.: ring), 163.11 (-C-F, Ar ring), 177.54 ppm (-C=S); +ESI-MS
239-241 0C; Elemental analysis (%): Calculated: C 47.88, H (m/z): Calculated for C16H17FN5S+ 330.1110 [M+1]+, found
3.75, N 18.61; Found: C 47.90, H 3.78, N 18.64; FTIR (KBr, 330.1230.
cm-1): νmax 3250, 3137 (-NH2), 3051 (Ar, -CH str.); 2987, 2913
(-CH str., -CH3); 1584 (-C=N), 1524, 1487, 1480 (-C=C-), 5-(4-chlorophenyl)-3-(3-ethylpyrazin-2-yl)-4,5-dihydro-1H-
1364, 832 (-C=S); 1H NMR (500 MHz, CDCl3): δ 2.94 (s, 3H, - pyrazole-1-carbothioamide (4k)
CH3, pyrazine ring), 3.47 (dd, 1H, J = 5.0, 5.0 Hz, Hb), 3.97
(dd, 1H, J = 12.0, 11.5 Hz, Ha), 5.98 (dd, 1H, J = 5.0, 5.0 Hz, Chemical formula: C16H16ClN5S; Color: white; Rf : 0.60; m.p.:
Hx), 6.25, 6.99 (br 2s, 2H, -NH2), 7.47-7.10 (m, 4H, Ar rings), 179-181 0C; Elemental analysis (%): Calculated: C 55.56, H
8.44 (s, 1H, pyrazine ring), 8.48 ppm (s, 1H, pyrazine ring); 13C 4.66, N 20.25; Found: C 55.51, H 4.70, N 20.30; FTIR (KBr,
NMR (125 MHz, CDCl3): δ 25.29 (-CH3, pyrazine ring), 44.31, cm-1): νmax 3250, 3145 (-NH2), 3040, 3025 (Ar, -CH str.); 2987,
62.39 (pyrazoline ring), 121.55, 127.29, 132.05, 140.68 (Ar 2947, 2909 (-CH str., -CH2CH3), 1584 (-C=N), 1551, 1528,
ring), 141.50, 143.50, 143.91 (pyrazine ring), 153.91 1494, 1476 (-C=C), 1375, 843 (-C=S); 1H NMR (500 MHz,
(pyrazoline ring), 156.91 (pyrazine ring), 177.58 ppm (-C=S); CDCl3): δ 1.40 (t, 3H, J = 7.5 Hz, -CH2CH3), 3.31 (q, 2H, J =
+ESI-MS (m/z): Calculated for C15H15BrN5S+ 376.0153 7.5 Hz, -CH2CH3), 3.45 (dd, 1H, J = 5.0, 5.0 Hz, Hb), 3.99 (dd,
[M+1]+, found 376.0262. 1H, J = 12.0, 11.5 Hz, Ha), 5.98 (dd, 1H, J = 5.0, 5.0 Hz, Hx),
6.25, 6.97 (br 2s, 2H, -NH2), 7.32-7.16 (m, 4H, Ar ring), 8.44
5-(4-(dimethylamino)phenyl)-3-(3-methylpyrazin-2-yl)-4,5- (s, 1H, pyrazine ring), 8.52 ppm (s, 1H, pyrazine ring); 13C
dihydro-1H-pyrazole-1-carbothioamide (4i) NMR (125 MHz, CDCl3): δ 12.17 (-CH3, -CH2CH3), 30.00 (-
CH2, -CH2CH3), 44.58 (pyrazoline ring), 62.26 (pyrazoline
Chemical formula: C17H20N6S; Color: pale yellow; Rf : 0.58; ring), 126.94, 129.10, 133.44, 140.12 (Ar ring), 141.28, 143.48,
m.p.: 189-191 0C; Elemental analysis (%): Calculated: C 59.97, 143.68, (pyrazine ring), 156.62 (pyrazoline ring), 158.36
H 5.92, N 24.69; Found: C 59.94, H 5.96, N 24.65; FTIR (KBr, (pyrazine ring), 177.53 ppm (-C=S); +ESI-MS (m/z):
cm-1): νmax 3270, 3149 (-NH2), 3069, 3028 (Ar, -CH str.); 2992, Calculated for C16H17ClN5S+ 346.0815 [M+1]+, found
2891 (-CH str., -CH3), 1589 (-C=N), 1617, 1553, 1528, 1472 (- 346.0938.
C=C), 1359, 869 (-C=S); 1H NMR (500 MHz, CDCl3): δ 2.92
(s, 6H, -N(CH3)2, 2.94 (s, 3H, -CH3), 3.50 (dd, 1H, J = 5.0, 5.0 5-(4-bromophenyl)-3-(3-ethylpyrazin-2-yl)-4,5-dihydro-1H-
Hz, Hb), 3.92 (dd, 1H, J = 11.5, 11.5 Hz, Ha), 5.93 (dd, 1H, J = pyrazole-1-carbothioamide (4l)
5.0, 5.0 Hz, Hx), 6.17, 6.95 (br 2s, 2H, -NH2), 6.67-7.11 (m,
4H, Ar rings), 8.44 (s, 1H, pyrazine ring), 8.45 ppm (s, 1H, Chemical formula: C16H16BrN5S; Color: white; Rf : 0.57; m.p.:
pyrazine ring); 13C NMR (125 MHz, CDCl 3): δ 25.34 (-CH3, 183-185 0C; Elemental analysis (%): Calculated: C 49.24, H
pyrazine ring), 40.53 (pyrazoline ring), 44.39 (-N(CH3)2), 62.61 4.13, N 17.94; Found: C 49.20, H 4.15, N 17.97; FTIR (KBr,
(pyrazoline ring), 112.59, 126.54, 129.27 (Ar rings), 141.47, cm-1): νmax 3254, 3142 (-NH2), 3045, 3023 (Ar, -CH str.); 2982,
143.23, 144.34 (pyrazine ring), 150.02 (Ar ring), 153.82 2941, 2907 (-CH str., -CH2CH3), 1586 (-C=N), 1548, 1530,
(pyrazoline ring), 157.20 (pyrazine ring), 177.45 ppm (-C=S); 1493, 1474 (-C=C), 1373, 845 (-C=S); 1H NMR (500 MHz,
+ESI-MS (m/z): Calculated for C17H21N6S+ 341.1470 [M+1]+, CDCl3): δ 1.40 (t, 3H, J = 7.5 Hz, -CH2CH3), 3.31 (q, 2H, J =
found 341.1601. 7.5 Hz, -CH2CH3), 3.45 (dd, 1H, J = 5.0, 5.0 Hz, Hb), 3.99 (dd,
1H, J = 12.0, 11.5 Hz, Ha), 5.96 (dd, 1H, J = 5.0, 5.0 Hz, Hx),
3-(3-ethylpyrazin-2-yl)-5-(4-fluorophenyl)-4,5-dihydro-1H- 6.23, 6.97 (br 2s, 2H, -NH2), 7.47-7.10 (m, 4H, Ar ring), 8.44
pyrazole-1-carbothioamide (4j) (s, 1H, pyrazine ring), 8.52 ppm (s, 1H, pyrazine ring); 13C
NMR (125 MHz, CDCl3): δ 12.18 (-CH3, -CH2CH3), 30.01 (-
Chemical formula: C16H16FN5S; Color: white; Rf : 0.58; m.p.: CH2, -CH2CH3), 44.54 (pyrazoline ring), 62.33 (pyrazoline
176-178 0C; Elemental analysis (%): Calculated: C 58.34, H ring), 121.56, 127.28, 132.06 140.65 (Ar ring), 141.30, 143.48,
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ARTICLE New Journal of Chemistry
143.70 (pyrazine ring), 156.62 (pyrazoline ring), 158.37 18 T. Eicher, S. Hauptmann, The chemistry of heterocycles, Wiley-
(pyrazine ring), 177.54 ppm (-C=S); +ESI-MS (m/z): VCH GmbH and Co. KGaA, Weinheim, 2003.
Calculated for C16H17BrN5S+ 390.0310 [M+1]+, found 19 S. Sarveswari and V. Vijayakumar, J. Chin. Chem. Soc., 2012, 59,
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