Synthesis and evaluation of antimicrobial activity of some new hetaryl-azoles derivatives obtained from 2-aryl-4-methylthiazol-5- carbohydrazides and isonicotinic acid hydrazide

Article abstract of DOI:10.1002/jhet.1060

A series of new 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives have been synthesized starting from 2-aryl-4-methylthiazol-5-carbohydrazides and isonicotinic acid hydrazide. All the newly synthesized compounds were characterized by IR, ^1<

Full text of DOI:10.1002/jhet.1060

November 2012
Synthesis and Evaluation of Antimicrobial Activity of Some New
Hetaryl-Azoles Derivatives Obtained from 2-Aryl-4-
1407
methylthiazol-5-carbohydrazides and Isonicotinic Acid Hydrazide
a
a
b
a
*
Brînduşa Tiperciuc, Valentin Zaharia, Ioana Colosi, Cristina Moldovan,
Ovidiu Crişan,a Adrian Pîrnau,c Laurian Vlase,a Mihaela Duma,d
and Ovidiu Onigaa
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy,
400010 Cluj-Napoca, Romania
bDepartment of Microbiology, Faculty of Medicine, University of Medicine and Pharmacy,
400010 Cluj-Napoca, Romania
cNational Institute for Research and Development of Isotopic and Molecular Technologies,
400293 Cluj-Napoca, Romania
dState Veterinary Laboratory for Animal Health and Food Safety, 400572 Cluj-Napoca, Romania
*
E-mail: brandu32@yahoo.com
Received April 5, 2011
DOI 10.1002/jhet.1060
View this article online at wileyonlinelibrary.com.
A series of new 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives have been synthesized starting
from 2-aryl-4-methylthiazol-5-carbohydrazides and isonicotinic acid hydrazide. All the newly synthesized
compounds were characterized by IR, 1H NMR, 13C NMR, and mass spectrometry. The synthesized
compounds were screened for their antibacterial and antifungal activity, assessed as growth inhibition
diameter. Some of them showed good antibacterial activity against gram positive Staphylococcus aureus,
while the antibacterial activity against Listeria monocytogenes, Escherichia coli, and Salmonella typhymurium
and antifungal activity against Candida albicans was modest. None of the tested compounds showed inhibitory
activity against gram positive bacteria Enterococcus faecalis and Bacillus cereus and against gram negative
bacteria Pseudomonas aeruginosa.
J. Heterocyclic Chem., 49, 1407 (2012).
INTRODUCTION
of new antimicrobial agents, with novel mechanisms and
a broadened spectrum of activity. In the past years, some
azole derivatives were developed as new antimicrobial
agents, for instance, Linezolid and Eperezolid are currently
used for the treatment of multidrug-resistant gram positive
The problem of multidrug resistant microorganisms has
reached an alarming level around the world in the past
decades, and represents a challenge for the development
© 2012 HeteroCorporation

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B. Tiperciuc, V. Zaharia, I. Colosi, C. Moldovan, O. Crisan, A. Pîrnau, L. Vlase, M. Duma,
and O. Oniga
Vol 49
Scheme 1
infections [1–3]. There is some important antifungal drugs
containing thiazole or 1,2,4-triazole ring in their structures,
such as Ravuconazole, Fluconazole, Voriconazole, and
Itraconazole, [4]. Also, thiazole derivatives are found to
be associated with various biological activities such as
antibacterial [5], antifungal [6], antiinflammatory [7], anti-
hypertensive [8], anti-HIV [9], antitumor [10–13], antifilar-
ial [12, 13], anticonvulsant [14], herbicidal, insecticidal,
schistosomicidal, and anthelmintic [15]. Heterocyclic
compounds containing 1,3,4-oxadiazole, 1,3,4-thiadiazole
or 1,2,4-triazole moiety present a wide spectrum of biological
activities such as antimicrobial, antiviral, anti-inflammatory,
and antitumoral [16–21]. Acid hydrazides were documented
as important compounds, due to their high reactivity in hetero-
cycles synthesis, as key starting materials for 1,2,4-triazole,
1,3,4-oxadiazole or 1,3,4-thiadiazole synthesis [22, 23].
1,3,4-oxadiazole or 1,3,4-thiadiazole rings, using 2-aryl-
4-methylthiazol-5-carbohydrazides and isonicotinic acid
hydrazide as starting materials. The compounds were
designed to investigate the effect of such structural varia-
tion on the anticipated antimicrobial activities.
RESULTS AND DISCUSSION
Chemistry. The reaction sequences used for the synthesis of
target compounds are shown in Schemes 1–3. The structures
of the newly synthesized compounds were confirmed by
analytical and spectral data (IR, 1H NMR, 13C NMR, and MS).
The key intermediates 2-aryl-4-methylthiazol-5-carbo-
hydrazides 1a–c (X H, CH3, and Br) were prepared by
the reaction of ethyl-2-aryl-4-methylthiazol-5-carboxylates
(A–C) with hydrazine hydrate in absolute ethanol, according
to the literature [27] (Scheme 1).
In view of the wide interest in the biological activity of
these compounds and as a continuation of our research in
this area [24–26], our aim was to synthesize new isolated
heterocyclic systems, as antimicrobial agents, that com-
prise both the thiazole/pyridine and the 1,2,4-triazole,
The 1,3,4-oxadiazole derivatives 2a–d were obtained in
good yield, by the reaction of the carbohydrazides 1a–c
and isonicotinic acid hydrazide 1d with CS2 and KOH in
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012 Synthesis and Evaluation of Antimicrobial Activity of Some New Hetaryl-Azoles Derivatives
Obtained from 2-Aryl-4-methylthiazol-5-carbohydrazides and Isonicotinic Acid Hydrazide
1409
Scheme 3
refluxing ethanol, followed by hydrochloric acid work up.
Reaction of 1a–b, respectively, 1d with CS2 and KOH in
absolute ethanol below 10°C resulted in the formation of
potassium dithiocarbazates 3a–c. Dehydrative cyclization
of compounds 3a–c using sulfuric acid at room temperature
yielded the 1,3,4-thiadiazoles 4a–c (Scheme 2).
crystal structures of the compounds correspond to the thione
form. The mass spectra of the prepared compounds showed
the correct molecular ions (M+ or M + 1) as suggested by
their molecular formulas.
Antibacterial and antifungal activity. The newly synthesized
compounds were tested for their antimicrobial activity, at a
concentration of 10 mg/mL, against four gram positive
bacterial strains: Staphylococcus aureus (ATCC 49444),
Enterococcus faecalis (ATCC 29211), Bacillus cereus
(ATCC 11778), Listeria monocytogenes (ATCC 13076);
three gram negative bacterial strains: Escherichia coli
(ATCC 25922), Salmonella typhymurium (ATCC
14028), Pseudomonas aeruginosa (ATCC 27853); and
one fungal strain: Candida albicans (ATCC 10231), by
the cup-plate agar diffusion method [28]. Each
microorganism was suspended in Mueller Hinton (MH)
broth and diluted approximately to 106 colony forming
unit (cfu)/mL. They were “flood inoculated” onto the
surface of MH agar and MH dextroxe agar (MDA) and
then dried. For C. albicans, MDA was used. Six
millimeter diameter wells were cut from the agar using a
sterile cork-borer, and 10 μL of each compound solution
were delivered into the wells. The plates were incubated
at 37°C, and the diameters of the growth inhibition zones
were measured after 24 h in case of bacteria and after 48
h in case of C. albicans. Stock solution of each
compound (10 mg/mL) was prepared in dimethyl
sulfoxide (DMSO; Merck, Germany). Gentamicin (10 μg per
well) and Fluconazole (25 μg per well) were used as standard
drugs. The controls were performed with only sterile broth
and with only overnight culture and 10 μL of DMSO.
Results were obtained in duplicate. The results of the
antimicrobial screening are summarized in Table 1.
4-Alkyl/aryl-1-(2-aryl-4-methylthiazol-5-carbonyl)-thiose-
micarbazides 5a–i and 4-alkyl/aryl-1-(pyridin-4-carbonyl)-
thiosemicarbazide 5j–l were obtained from hydrazides 1a–d
and the corresponding alkyl/arylisothiocyanates. The thiose-
micarbazides 5a–l, on heating with NaOH 2 N in ethanol,
underwent cyclization through dehydration to afford 4-
alkyl/aryl-3-(2-aryl-4-methylthiazol-5-yl)-1H-1,2,4-triazol-5
(4H)-thiones 6a–i and 4-alkyl/aryl-3-(pyridin-4-yl)-1H-
1,2,4-triazol-5(4H)-thiones 6j–l (Scheme 3), respectively.
IR spectra of thiosemicarbazides 5a–l displayed absorp-
tion peaks at 3115–3308 cm−1 for NH, 1650–1682 cm−1
for C O, and 1214–1265 cm−1 corresponding to C S
1
stretching vibrations. H NMR spectra showed the three
signals for the CONH, CSNH, and NH protons, as singlets
at 10–10.3, 9.3–9.85, and 8.1–8.8 ppm, respectively,
confirming the formation of thiosemicarbazide.
IR spectra of 2a–d, 4a–c, and 6a–l exhibited NH bands
in 3448–3463, 3438–3400, and 3070–3187 cm−1, respectively.
The absorption bands at 1597–1616, 1541–1599, and
1538–1614 cm−1 are due to the presence of C N stretch
of the oxadiazole, thiadiazole, and triazole ring system,
respectively. The absence of the C O absorption in 2a–d,
4a–c, and 6a–l provided strong evidences for the formation
of the new products. Also, the presence of bands for the
C S group in the 1232–1275, 1242–1258, and 1214–1286
cm−1 proved that the compounds were in thione form in the
1
solid state. In the H NMR spectra of 1a–c, the NH proton
All the tested compounds were inactives against E. faecalis,
B. cereus, and P. aeruginosa. Some of the compounds are ac-
tive and showed moderate-to-good activity against S. aureus:
thiazolyl-1,3,4-oxadiazoles 2a–c, potassium dithiocarbazates
3a–c, thiazolyl-1,3,4-tiadiazoles 4a–b, and thiazolyl-thiosemi-
carbazides 5a–d and 5g–h. As it can be seen in Table 1,
appeared in the 9.56–9.72 ppm region, whereas in
compounds 2a–d, 3a–c, and 6a–l, the NH signal was shifted
to 14.1–14.4 ppm, indicating the thiol–thione tautomerism in
solution. In the 13C NMR spectra of 2a–d, 3a–c, and 6a–l,
the C S gave a peak at 169.9–172.9, 182.9–183.6,
168.6–171.4 ppm, respectively, indicating that the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1410
B. Tiperciuc, V. Zaharia, I. Colosi, C. Moldovan, O. Crisan, A. Pîrnau, L. Vlase, M. Duma,
and O. Oniga
Vol 49
Table 1
Antimicrobial activity of the synthesized compounds.a
Gram positive bacteria
L. monocytogenes
Gram negative bacteria
E. coli S. typhymurium
Fungi
Compound
S. aureus
C. albicans
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
‐
‐
‐
16
20
22
15
15
20
7
15
7
10
9
6
‐
‐
6
6
4
4
‐
‐
‐
5
4
4
3
3
4
3
3
4
4
4
4
3
4
4
4
5
4
4
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
18
‐
10
12
‐
‐
‐
‐
6
‐
9
‐
‐
‐
‐
‐
‐
15
10
‐
‐
‐
‐
‐
3
‐
3
4
4
4
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
22
‐
3
3
3
3
3
3
3
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
4
19
‐
6g
6h
6i
‐
‐
25
Gentamicin
Fluconazole
18
‐
Gentamycin (10 μg per well) and Fluconazole (25 μg per well) were used as standard drugs.
‐ Indicates the compound has no activity.
aZones of inhibition in millimeter.
EXPERIMENTAL
oxadiazole derivatives 2a–c were more active than the
thiadiazole derivatives 4a–b. The most active compound
was 2c with a 4-bromophenyl group in position 2 of the
thiazole ring, the inhibitory activity being more powerful
than that of Gentamicin (10 μg per well), used as standard
drug. All the synthesized compounds were slightly sensitive
against gram positive B. cereus and L. monocytogenes and
gram negative bacteria E. coli. The antifungal screening data
reveal that most of the new compounds are inactive, only
six compounds displayed weak inhibitory activity against
C. albicans: acid hydrazides 1a, 1b, potassium dithiocarba-
zates 3a, 3c, and thiazolyl-thiosemicarbazides 5e, 5f.
In conclusion, a series of new thiazolo/pyridin-1,3,4-oxadia-
zole, thiazolo/pyridin-1,3,4-thiadiazole, and thiazolo/pyridin-
1,2,4-triazole derivatives have been synthesized starting from
2-aryl-4-methylthiazol-5-carbohydrazides and isonicotinic acid
hydrazide and evaluated for their antibacterial and antifungal
activity against various gram positive, gram negative bacteria,
and C. albicans.
Reagents were commercial grade and were used as supplied.
Thin layer chromatography was used to analyze the reaction
progress and purity of the synthesized compounds and was
carried out on precoated Silica Gel 60F254 sheets using heptan–
ethyl acetate 1:1 system and ultraviolet light for visualization.
Melting points were determined in open glass capillary method
with an electrothermal melting point meter and were uncorrected.
IR spectra were obtained in KBr disks on a Nicolet 210 FT-IR
spectrometer. The 1H NMR spectra were recorded at room
temperature on a Bruker Avance NMR spectrometer (500 MHz)
using TMS as internal standard. The samples were prepared by
dissolving the compounds in DMSO-d6 (δH = 2.51ppm) as
solvent and the spectra were recorded using a single excitation
pulse of 12 μs. 13C NMR spectra were recorded on Bruker
spectrometer (125 MHz) in DMSO-d6. Mass spectra were
recorded by Agilent 1100, type SL spectrometer (positive ionization)
and with a Varian MAT CH-5 spectrometer (70 eV). Elemental
analysis was registered with a Vario El CHNS instrument, results
were found to be in good agreement ( 0.4%) with the calculated
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012 Synthesis and Evaluation of Antimicrobial Activity of Some New Hetaryl-Azoles Derivatives
Obtained from 2-Aryl-4-methylthiazol-5-carbohydrazides and Isonicotinic Acid Hydrazide
1411
values. The hydrazides 1a–c were already published [27], but they
were characterized only by elemental analysis and melting points.
2-Aryl-4-methylthiazol-5-carbohydrazides (1a–c) [27]. To a
solution of ethyl 2-aryl-2-methylthiazol-5-carboxylates A–C (58.7
mmol) in absolute ethanol (100 mL), hydrazine hydrate (5.87 g,
117.4 mmol) was added and the resulting mixture was heated to
100°C for 4 h. The mixture was concentrated under reduced
pressure. Water was added to the residue and the resulting solid was
filtered, washed with water, and recrystallized from ethanol to give
compounds 1a–c, as white crystals.
4-Methyl-2-phenylthiazol-5-carbohydrazide (1a). Yield 13 g,
55.8 mmol, (95%), mp 168–169°C [27]; IR (KBr): ν 1620 (C N),
1670 (C O) cm−1; 1H NMR (DMSO-d6): δ 2.77 (s, 3H, CH3), 4.21
(s, 2H, NH2), 7.46–7.96 (m, 5H, Ar H), 9.72 (s, 1H, NH) ppm; MS:
m/z (%) 233 (M+, 100). Anal. Calcd. for C11H11N3OS: C, 56.63; H,
4.75; N, 18.01; S, 13.74. Found: C, 56.59; H, 4.77; N, 17.94; S,
13.67.
IR (KBr): ν 1156 (C O C), 1275 (C S), 1608 (C N), 3452 (NH) cm−1;
1H NMR (DMSO-d6): δ 2.68 (s, 3H, CH3), 7.73–7.96 (m, 4H, Ar H),
14.93 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ 17.63 (CH3), 114.3
(C), 125.45 (CH), 128.89 (CH), 131.42 (C), 132.9 (C), 156.2 (C),
156.9 (C), 167.2.5 (C), 183.9 (C S) ppm; MS: m/z (%) 354 (M + 1,
100). Anal. Calcd. for C12H8BrN3OS2: C, 40.69; H, 2.28; N,
11.86; S, 18.1. Found: C, 40.68; H, 2.27; N, 11.83; S, 18.02.
5-(Pyridin-4-yl)-1,3,4-oxadiazol-2(3H)-thione (2d) [29]. Yield
1.46 g, 7.49 mmol, (75% ); mp 264–265°C; IR (KBr): ν 1232
(C S), 1352 (C O C), 1616 (C N), 3450 (NH) cm−1; 1H NMR
(DMSO-d6): δ 7.63 (dd, 2H, J = 5, 3-Py), 8.76 (dd, 2H, J = 5, 2–
Py), 14.73 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ 121.9
(2CH), 139.8 (C), 149.1 (C), 150.1 (2CH), 182.7 (C S) ppm; MS:
m/z (%) 179 (M+, 20). Anal. Calcd. for C7H5N3OS: C, 46.92; H,
2.81; N, 23.45; S, 17.89. Found: C, 46.78; H, 2.70; N, 23.25; S,
17.76.
Potassium 2-(2-aryl-4-methylthiazol-5-carbonyl)-
hydrazinecarbodithioate (3a–c). To a solution of 1a–b and 1d
(20 mmol) in 40 mL ethanol refrigerated below 10°C, a solution
of 1.68 g potassium hydroxide (30 mmol) in 60 mL ethanol and
3.04 g carbon disulfide (30 mmol) were added and the reaction
mixture was refrigerated 3 h. The resulting solid was filtered,
washed with ether, and dried to afford compounds 3a–c as
yellow–orange solids.
4-Methyl-2-p-tolylthiazol-5-carbohydrazide (1b). Yield 13.63g,
55.18 mmol, (94%), mp 186–187°C (Ref. [27] 182–183°C); IR
1
(KBr): ν 1625 (C N), 1675 (C O) cm−1; H NMR (DMSO-d6): δ
2.36 (s, 3H, CH3), 2.59 (s, 3H, CH3), 4.64 (s, 2H, NH2), 7.32–7.83
(m, 4H, Ar H), 9.56 (s, 1H, NH) ppm; MS: m/z (%) 247 (M+, 100).
Anal. Calcd. for C12H13N3OS: C, 58.28; H, 5.30; N, 16.99; S,
12.97. Found: C, 58.21; H, 5.33; N, 16.92; S, 12.95.
2-(4-Bromophenyl)-4-methylthiazol-5-carbohydrazide (1c).
Yield 16.85g, 54 mmol, (92%), mp 218–219°C (Ref. [27] 215–216°
C; IR (KBr): ν 1615 (C N), 1677 (C O) cm−1; 1H NMR (DMSO-d6):
δ 2.7 (s, 3H, CH3), 4.13 (s, 2H, NH2), 7.68–7.73 (m, 4H, Ar H), 9.67
(s, 1H, NH) ppm; MS: m/z (%) 312 (M+, 100). Anal. Calcd. for
C11H10BrN3OS: C, 42.32; H, 3.23; N, 13.46; S, 10.27. Found: C,
42.35; H, 3.28; N, 13.41; S, 10.22.
5-(2-Aryl-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2(3H)-thione
(2a–c); 5-(pyridin-4-yl)-1,3,4-oxadiazol-2(3H)-thione (2d). To a
solution of 1a–d (10 mmol) in absolute ethanol (100 mL), carbon
disulfide (20 mmol) and potassium hydroxide (12.5 mmol) were
added and the resulting solution was heated to reflux for 24 h.
The reaction mixture was concentrated and the residue was
dissolved in water and acidified with diluted hydrochloric acid.
The resulting solid was filtered, dried, and recrystallized from
ethanol to afford compounds 2a–d as yellow solids.
Potassium 2-(4-methyl-2-phenylthiazol-5-carbonyl)-
hydrazinecarbodithioate (3a). Yield 4.6 g, 13.3 mmol, (66.5%);
IR (KBr): ν 3444, 3228 (2NH), 1647 (C O) cm−1.
Potassium 2-(4-methyl-2-p-tolylthiazol-5-carbonyl)-
hydrazinecarbodithioate (3b). Yield 6.6 g, 18.28 mmol, (91.4%);
IR (KBr): ν 3443, 3223 (2NH), 1652 (C O) cm−1.
Potassium pyridin-4-carbonyl-hydrazinecarbodithioate
(3c). Yield 3.91 g, 15.57 mmol, (78%); IR (KBr): ν 3370, 3309
(2NH), 1675 (C O) cm−1.
5-(2-Aryl-4-methylthiazol-5-yl)-1,3,4-tiadiazol-2(3H)-thione
(4a–b); 5-(pyridin-4-yl)-1,3,4-thiadiazol-2(3H)-thione (4c).
Potassium hydrazinecarbodithioates 3a–c (10 mmol) were added
portion wise to 98% sulfuric acid (25 mL) and the resulted clear
solution was stirred at room temperature for 24 h. The mixture was
cautiously added to crushed ice, stirred for 1h, refrigerated for 4 h,
and the separated precipitate was filtered, washed with water, and
dried and crystallized from ethanol to afford compounds 4a–c, as
yellow solids.
5-(4-Methyl-2-phenylthiazol-5-yl)-1,3,4-oxadiazol-2(3H)-
thione (2a). Yield 2.13 g, 7.73 mmol, (77.3%), mp 243–244°C;
IR (KBr): ν 1155 (C O C), 1271 (C S), 1612 (C N), 3448 (NH)
5-(4-Methyl-2-phenylthiazol-5-yl)-1,3,4-tiadiazol-2(3H)-thione
(4a). Yield 1.98 g, 6.8 mmol, (68.1%), mp 204–205°C; IR
1
cm−1; H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 7.54–8.0 (m,
5H, Ar H), 14.17 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ
17.01 (CH3), 115.8 (CH), 126.17 (CH), 129.71 (CH), 132.3 (C),
134.7 (C), 144.5 (C), 156.9 (C), 167.5 (C), 169.9 (C S) ppm;
MS: m/z (%) 276 (M + 1, 100). Anal. Calcd. for C12H9N3OS2:
C, 52.34; H, 3.29; N, 15.26; S, 23.29. Found: C, 52.32; H,
3.26; N, 15.24; S, 23.26.
(KBr): ν 1242 (C S), 1541 (C N), 3438 (NH) cm−1; H NMR
1
(DMSO-d6): δ 2.6 (s, 3H, CH3), 7.5–8.1 (m, 5H, Ar H), 14.2
(s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ 17.2 (CH3), 120.1
(CH), 126.2 (CH), 128.9 (CH), 133.3 (C), 143.7 (C), 153.6
(C), 156.7 (C), 161.2 (C), 182.9 (C S) ppm; MS: m/z (%) 292
(M + 1, 100). Anal. Calcd. for C12H9N3S3: C, 49.46; H,
3.11; N, 14.42; S, 33.01. Found: C, 49.42; H, 3.10; N,
14.41; S, 33.04.
5-(4-Methyl-2-p-tolylthiazol-5-yl)-1,3,4-oxadiazol-2(3H)-thione
(2b). Yield 2.46 g, 8.52 mmol, (85.2%), mp 247–248°C; IR (KBr): ν
1158 (C O C), 1267 (C S), 1596 (C N), 3463 (NH) cm−1; 1H NMR
(DMSO-d6): δ 2.37 (s, 3H, CH3), 2.43 (s, 3H, CH3), 7.3–7.8 (m,
4H, Ar H), 14.26 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ 16.9
(Th CH3), 21.38 (Ar CH3), 117.4 (CH), 126.5 (CH), 129.7 (C),
131.6 (C), 141.5 (C), 144.3 (C), 156.9 (C), 167.5 (C), 172.9 (C S)
ppm; MS: m/z (%) 290 (M + 1, 100). Anal. Calcd. for
C13H11N3OS2: C, 53.96; H, 3.83; N, 14.52; S, 22.16. Found: C,
53.93; H, 3.81; N, 14.49; S, 22.15.
5-(4-Methyl-2-p-tolylthiazol-5-yl)-1,3,4-tiadiazol-2(3H)-thione
(4b). Yield 2.9 g, 5.28 mmol, (52.8%), mp 250–251°C; IR
1
(KBr): ν 1243 (C S), 1558 (C N), 3410 (NH) cm−1; H NMR
(DMSO-d6): δ 2.44 (s, 3H, CH3), 2.58 (s, 3H, CH3), 7.32–7.92
(m, 4H, Ar H), 14.92 (s, 1H, NH) ppm; 13C NMR (DMSO-d6):
δ 17.67 (Th CH3), 21.55 (Ar CH3), 120.8 (CH), 126.7 (CH),
126.9 (C), 129.8 (C), 130.3 (C), 141.9 (C), 154.8 (C), 167.8
(C), 183.6 (C S) ppm; MS: m/z (%) 306 (M + 1, 100). Anal.
Calcd. for C13H11N3S3: C, 51.12; H, 3.63; N, 13.76; S, 31.49.
Found: C, 51.13; H, 3.61; N, 13.76; S, 31.50.
5-(2-(4-Bromophenyl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2
(3H)-thione (2c). Yield 2.99 g, 8.45 mmol, (84.5%), mp 255–257°C;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1412
B. Tiperciuc, V. Zaharia, I. Colosi, C. Moldovan, O. Crisan, A. Pîrnau, L. Vlase, M. Duma,
and O. Oniga
Vol 49
5-(Pyridin-4-yl)-1,3,4-thiadiazol-2(3H)-thione (4c). Yield
1.10g, 5.63 mmol (56.5%); mp 280–282°C; IR (KBr): ν 1258
(C S), 1599 (C N), 3400 (NH) cm−1 1H NMR (DMSO-d6): δ
7.66 (dd, 2H, J = 5, 3-Py), 8.78 (dd, 2H, J = 5, 2-Py), 14.68 (s,
1H, NH) ppm; 13C NMR (DMSO-d6): δ122.1 (2CH), 139.7 (C),
148.8 (C), 150.5 (2CH), 183.1 (C S) ppm; MS: m/z (%)
195 (M+, 36). Anal. Calcd. for C7H5N3S2: C, 43.06; H,
2.58; N, 21.52; S, 32.84. Found: C, 43.19; H, 2.54; N,
21.44; S, 32.64.
4-Alkyl/aryl-1-(2-aryl-4-methylthiazol-5-carbonyl)-
thiosemicarbazides (5a–i); 4-alkyl/aryl-1-(pyridin-4-yl-carbonyl)-
thiosemicarbazides (5j–). To a solution of 4 mmol 1a–d in 30 mL
ethanol, 4 mmol of the appropriate isothiocyanate were added. The
resulting mixture was heated under reflux for 3 h. After cooling the
precipitate was separated and recrystallized from methanol/acetone
to afford thiosemicarbazides 5a–l.
1-(4-Methyl-2-phenylthiazol-5-carbonyl)-4-phenyl-
thiosemicarbazide (5a). This was obtained as yellow crystal; Yield
1.35 g, 3.68 mmol, (92%), mp 184–185°C; IR (KBr): ν 1231 (C S),
1532 (C N), 1672 (C O), 3115 (NH) cm−1; 1H NMR (DMSO-d6): δ
2.67 (s, 3H, CH3), 7.16–7.32 (m, 5H, Ar H), 7.95–7.97 (m, 5H,
Ar H), 8.3 (s,1H, NH C S), 9.6 (s, 1H, NH C S), 10.13 (s, 1H,
NH C O) ppm; 13C NMR (DMSO-d6): δ 17.9 (CH3), 123.1 (2CH),
126.2 (4CH), 129.6 (4CH), 130.3 (C), 131.5 (C), 132.7 (C), 157.8
(C O), 160.7 (C), 167.1 (C), 182.9 (C S) ppm; MS: m/z (%) 369
(M + 1, 100). Anal. Calcd. for C18H16N4OS2: C, 58.67; H, 4.38; N,
15.21; S, 17.4. Found: C, 58.65; H, 4.36; N, 15.18; S, 17.38.
1-(4-Methyl-2-p-tolylthiazol-5-carbonyl)- 4-phenyl-
thiosemicarbazide (5b). This was obtained as yellow solid; Yield 1.4
g, 3.66 mmol, (91%), mp 179–180°C; IR (KBr): ν 1234 (C S), 1534
(C N), 1615 (C O), 3317 (NH) cm−1; 1H NMR (DMSO-d6): δ 2.37 (s,
3H, CH3), 2.69 (s, 3H, CH3), 7.24–7.52 (m, 5H, Ar H), 7.35 (d, 2H,
J = 8.5 Hz, Ar), 7.85 (d, 2H, J = 8.5 Hz, Ar), 8.7 (s,1H, NH C S), 9.8
(s, 1H, NH C S), 10.3 (s, 1H, NH C O) ppm; 13C NMR (DMSO-d6):
δ 17.95 (Th CH3), 21.5 (Ar CH3), 126.7 (4CH), 127.2 (CH), 128.5
(4CH), 130.2 (C), 130.4 (C), 139.7 (C), 141.6 (C), 160.4 (C O),
167.1 (C), 182.1 (C S) ppm; MS: m/z (%) 383 (M + 1, 100). Anal.
Calcd. for C19H18N4OS2: C, 59.66; H, 4.74; N, 14.65; S, 16.77.
Found: C, 59.63; H, 4.71; N, 14.63; S, 16.78.
C13H14N4OS2: C, 50.96; H, 4.61; N, 18.29; S, 20.93. Found: C,
50.92; H, 4.59; N, 18.24; S, 20.90.
;
1-(4-Methyl-2-p-tolylthiazol-5-carbonyl)- 4-methyl-
thiosemicarbazide (5e). This was obtained as white solid; Yield
1.2 g, 3.75 mmol, (64.5%), mp 208–209°C; IR (KBr): ν 1233
(C S), 1540 (C N), 1650 (C O), 3315 (NH) cm−1; 1H NMR
(DMSO-d6): δ 2.43 (s, 3H, CH3), 2.58 (s, 3H, CH3), 2.9 (d, 3H,
J = 4.5 Hz, NCH3), 7.54 (d, 2H, J = 8.5 Hz, Ar), 7.97 (d, 2H,
J = 8.5 Hz, Ar), 8.81 (s,1H, NH C S), 9.85 (s, 1H, NH C S),
10.31 (s, 1H, NH C O) ppm; 13C NMR (DMSO-d6): δ17.7
(Th CH3), 21.4 (Ar CH3), 31.24 (NCH3), 124.5 (2CH), 127.3
(2CH), 131.5 (C), 136.6 (C), 138.8 (C), 159.9 (C O), 161.2
(C), 166.7 (C), 182.1 (C S) ppm; MS: m/z (%) 321 (M + 1,
100). Anal. Calcd. for C14H16N4OS2: C, 52.48; H, 5.03; N,
17.48; S, 20.01. Found: C, 52.47; H, 5.04; N, 17.45; S, 20.05.
1-(2-(4-Bromophenyl)-4-methylthiazol-5-carbonyl)-4-methyl-
thiosemicarbazides (5f). This was obtained as yellow solid; Yield
1.25 g, 3.25 mmol, (81.2%), mp 220–221°C; IR (KBr): ν 1232
(C S), 1567 (C N), 1658 (C O), 3307 (NH) cm−1; 1H NMR
(DMSO-d6): δ 2.43 (s, 3H, CH3), 2.88 (d, 3H, J = 4.5 Hz, NCH3),
7.48 (d, 2H, J = 8.5 Hz, Ar), 7.90 (d, 2H, J = 8.5 Hz, Ar), 8.4
(s,1H, NH C S), 9.5 (s, 1H, NH C S), 10.2 (s, 1H, NH C O) ppm;
13C NMR (DMSO-d6): δ 17.61 (CH3), 31.14 (NCH3), 126.2
(2CH), 129.1 (2CH), 133.4 (C), 138.2 (C), 139.8 (C), 160.1 (C O),
163.4 (C), 168.2 (C), 181.9 (C S) ppm; MS: m/z (%) 386 (M + 1,
100). Anal. Calcd. for C13H13BrN4OS2: C, 40.52; H, 3.40; N,
14.54; S, 16.64. Found: C, 40.49; H, 3.41; N, 14.52; S, 16.6.
4-Allyl-1-(4-methyl-2-phenylthiazol-5-carbonyl)-thiosemicarbazide
(5g). This was obtained as white solid; Yield 1.22 g, 3.68 mmol,
(92%), mp 185–188°C; IR (KBr): ν 1235 (C S), 1530 (C N), 1660
(C O), 3302 (NH) cm−1; 1H NMR (DMSO-d6): δ 2.7 (s, 3H, CH3),
4.11 (m, 2H, CH2), 5.06 (d, 2H, CH2), 5.8 (m, 1H, CH ), 7.17–7.36
(m, 5H, Ar H), 8.3 (s,1H, NH C S), 9.4 (s, 1H, NH C S), 10.1 (s,
1H, NH C O) ppm; 13C NMR (DMSO-d6): δ 17.9 (CH3), 46.3
(CH2), 114.9 ( CH2), 125.7 (CH), 126.6 (2CH), 128.4 (CH ), 129.4
(2CH), 130.1 (C), 131.9 (C), 132.6 (C), 157.4 (C O), 161.2 (C),
166.9 (C), 181.8 (C S) ppm; MS: m/z (%) 333 (M + 1, 100). Anal.
Calcd. for C15H16N4OS2: C, 54.19; H, 4.85; N, 16.85; S, 19.29.
Found: C, 54.16; H, 4.84; N, 16.81; S, 19.27.
1-(2-(4-bromophenyl)-4-methylthiazol-5-carbonyl)-4-phenyl-
thiosemicarbazides (5c). This was obtained as yellow crystal;
Yield 1.7 g, 3.8 mmol, (95%), mp 254–256°C; IR (KBr): ν 1214
(C S), 1567 (C N), 1670 (C O), 3300 (NH) cm−1; 1H NMR
(DMSO-d6): δ 2.5 (s, 3H, CH3), 7.17–7.36 (m, 5H, Ar H), 7.74
(d, 2H, J = 9 Hz, ar), 7.90 (d, 2H, J = 8.5 Hz, ar), 8.3 (s,1H,
NH C S), 9.5 (s, 1H, NH C S), 10.1 (s, 1H, NH C O) ppm; 13C
NMR (DMSO-d6): δ 17.4 (Th CH3), 124.7 (C), 128.2 (2CH),
129.4 (C), 129.9 (3CH), 130.5 (2CH), 131.2 (2CH), 132.6 (C),
134.3 (C), 156.1 (C), 159.9 (C O), 164 (C),180.8 (C S) ppm; MS:
m/z (%) 448 (M + 1, 100). Anal. Calcd. for C18H15BrN4OS2: C,
48.33; H, 3.38; N, 12.52; S, 14.33. Found: C, 48.32; H, 3.36; N,
12.49; S, 14.34.
4-Allyl-1-(4-methyl-2-p-tolylthiazol-5-carbonyl)-thiosemicarbazide
(5h). This was obtained as white solid; Yield 1.06 g, 3.07 mmol,
(76.7%), mp 199–200°C; IR (KBr): ν 1226 (C S), 1545 (C N),
1662 (C O), 3125 (NH) cm−1; 1H NMR (DMSO-d6): δ 2.38 (s, 3H,
CH3), 2.69 (s, 3H, CH3), 4.1 (m, 2H, CH2), 5.05 (d, 2H, CH2),
5.82 (m, 1H, CH ), 7.41 (d, 2H, J = 8 Hz, Ar), 7.89 (d, 2H, J = 8
Hz, Ar), 8.4 (s,1H, NH C S), 9.3 (s, 1H, NH C S), 10.06 (s, 1H,
NH C O) ppm; 13C NMR (DMSO-d6): δ 17.4 (Th CH3), 21.25
(Ar CH3), 46.1 (CH2), 115.2 ( CH2), 124.6 (C), 124.4 (2CH), 128.9
(2CH), 128.7 (CH ), 131.2 (C), 132.2 (C), 136.7 (C O), 161.9 (C),
165.9 (C), 181.7 (C S) ppm; MS: m/z (%) 347 (M + 1, 100). Anal.
Calcd. for C16H18N4OS2: C, 55.47; H, 5.24; N, 16.17; S, 18.51.
Found: C, 55.44; H, 5.22; N, 16.14; S, 18.46.
1-(4-Methyl-2-phenylthiazol-5-carbonyl)- 4-methyl-
thiosemicarbazide (5d). This was obtained as white solid; Yield
0.95 g, 2.58 mmol, (64.5%), mp 205–207°C; IR (KBr): ν 1265
(C S), 1527 (C N), 1660 (C O), 3113 (NH) cm−1; 1H NMR
(DMSO-d6): δ 2.6 (s, 3H, CH3), 2.8 (d, 3H, J = 4.5 Hz, NCH3),
7.11–7.28 (m, 5H, Ar H), 8.1 (s,1H, NH C S), 9.7 (s, 1H, NH C S),
10.11 (s, 1H, NH C O) ppm; 13C NMR (DMSO-d6): δ 17.9 (CH3),
31.48 (NCH3), 125.2 (CH), 126.8 (2CH), 129.9 (2CH), 130.7 (C),
131.6 (C), 132.8 (C), 157.9 (C O), 161.6 (C), 167.2 (C), 183.4
(C S) ppm; MS: m/z (%) 307 (M + 1, 100). Anal. Calcd. for
4-Allyl-1-(2-(4-bromophenyl)-4-methylthiazol-5-carbonyl)-
thiosemicarbazides (5i). This was obtained as yellow solid;
Yield 1.35 g, 3.28 mmol, (82%), mp 224–225°C; IR (KBr): ν
1264 (C S), 1558 (C N), 1668 (C O), 3173 (NH) cm−1 1H
;
NMR (DMSO-d6): δ 2.67 (s, 3H, CH3), 4.12 (m, 2H, CH2),
5.12 (d, 2H, CH2), 5.8 (m, 1H, CH ), 7.74 (d, 2H, J = 9 Hz,
Ar), 7.9 (d, 2H, J = 9 Hz, Ar), 8.36 (s,1H, NH C S), 9.48 (s,
1H, NH C S), 10.19 (s, 1H, NH C O) ppm; 13C NMR (DMSO-
d6): δ 17.89 (CH3), 46.4 (CH2), 115.7 ( CH2), 124.2 (C), 124.9
(2CH), 128.3 (2CH), 128.6 (CH ), 131.9 (C), 132.9 (C), 135.9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012 Synthesis and Evaluation of Antimicrobial Activity of Some New Hetaryl-Azoles Derivatives
Obtained from 2-Aryl-4-methylthiazol-5-carbohydrazides and Isonicotinic Acid Hydrazide
1413
(C O), 161.4 (C), 165.8 (C), 183.9 (C S) ppm; MS: m/z (%) 412
(M + 1, 100). Anal. Calcd. for C15H15BrN4OS2: C, 43.80; H,
3.68; N, 13.62; S, 15.59. Found: C, 43.81; H, 3.66; N, 13.59; S,
15.55.
3-(2-(4-Bromophenyl)-4-methylthiazol-5-yl)-4-phenyl-1H-
1,2,4-triazol-5(4H)-thione (6c). Yield 1.39 g, 3.24 mmol,
(92.5%), mp 295–296°C; IR (KBr): ν 1268 (C S), 1515 (C N),
1
1557 (C N), 3172 (NH) cm−1; H NMR (DMSO-d6): δ 2.45 (s,
4-Phenyl-1-(pyridin-4-yl-carbonyl)-thiosemicarbazide (5j).
This was obtained as white solid; Yield 0.84 g, 3.10 mmol
(81%); mp 187–189°C (Ref. [30] 120°C); MS: m/z (%) 272
(M+, 18). Anal. Calcd. for C13H12N4OS: C, 57.33; H, 4.44; N,
20.57; S, 11.77. Found: C, 57.44; H, 4.28; N, 20.65; S, 11.35.
4-Methyl-1-(pyridine-4-yl-carbonyl)-thiosemicarbazide (5k).
This was obtained as white solid; Yield 0.68 g, 3.22 mmol (80.5%);
mp 265–267°C; IR (KBr): ν 1252(C S), 1553(C N), 1673(C O),
2971, 2975, 3114, 3263(3NH) cm−1; 1H NMR (DMSO-d6): δ 2.8
(d, 3H, J = 5 Hz, NCH3), 7.78 (dd, 2H, J = 5, 3-Py), 8.79 (dd,
2H, J = 5, 2-Py), 8.40 (s, 1H, NH C S), 9.48 (s, 1H, NH C S),
10.57 (s, 1H, NH C O) ppm; 13C NMR (DMSO-d6): δ 32.2
(NCH3), 121.8 (2CH), 138.6 (C), 148.9 (2CH), 164.7 (C O),
180.9 (C S) ppm; MS: m/z (%) 210 (M+, 40). Anal. Calcd. for
C8H10N4OS: C, 45.70; H, 4.79; N, 26.65; S, 15.25. Found: C,
45.94; H, 4.53; N, 26.32; S, 15.10.
3H, CH3), 7.44–7.56 (m, 5H, Ar H), 7.67 (d, 2H, J = 9 Hz, Ar),
7.7 (d, 2H, J = 9 Hz, Ar), 14.37 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6): δ 17.42 (CH3), 115.9 (C), 124.7 (C), 128.4
(2CH), 129.5 (3CH), 129.9 (2CH), 130.5 (2CH), 131.5 (C),
132.8 (C), 134.0 (C), 144.85 (C), 156.5 (C), 168.72 (C S) ppm;
MS: m/z (%) 429 (M+, 100). Anal. Calcd. for C18H13BrN4S2:
C, 50.33; H, 3.02; N, 13.01; S, 14.89. Found: C, 50.35; H,
3.05; N, 13.05; S, 14.94.
4-Methyl-3-(4-methyl-2-phenylthiazol-5-yl)-1H-1,2,4-triazol-
5(4H)-thione (6d). Yield 0.92 g, 3.19 mmol, (91%), mp 228–229°C;
IR (KBr): ν 1280 (C S), 1488 (C N), 1541 (C N), 3070 (NH) cm−1;
1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 3.48 (s, 3H, NCH3),
7.54–7.99 (m, 5H, Ar H), 14.17 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6): δ 17.04 (CH3), 31.8 (NCH3), 115.1 (C), 126.8 (CH),
129.9 (2CH), 131.6 (2CH), 132.6 (C), 144.8 (C), 156.3 (C), 167.9
(C), 168.8 (C S) ppm; MS: m/z (%) 289 (M + 1, 100). Anal. Calcd.
for C13H12N4S2: C, 54.14; H, 4.19; N, 19.43; S, 22.24. Found: C,
54.13; H, 4.18; N, 19.39; S, 22.19.
4-Methyl-3-(4-Methyl-2-p-tolylthiazol-5-yl)-1H-1,2,4-triazol-5
(4H)-thione (6e). Yield 0.84 g, 2.77 mmol, (79%), mp 278–279°C;
IR (KBr): ν 1279 (C S), 1522 (C N), 1540 (C N), 3092 (NH) cm−1;
1H NMR (DMSO-d6): δ 2.37 (s, 3H, CH3), 2.69 (s, 3H, CH3), 3.42
(s, 3H, NCH3), 7.35 (d, 2H, J = 8 Hz, Ar), 7.86 (d, 2H, J = 9 Hz,
Ar), 14.31 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ 17.2
(Th CH3), 21.38 (Ar CH3), 31.6 (NCH3), 116.2 (C), 124.7 (C),
126.6 (2CH), 129.7 (2CH), 131.9 (C), 138.6 (C), 144.8 (C), 154.9
(C), 169.7 (C S) ppm; MS: m/z (%) = 303 (M + 1, 100). Anal.
Calcd. for C14H14N4S2: C, 55.6; H, 4.67; N, 18.53; S, 21.21.
Found: C, 55.58; H, 4.65; N, 18.49; S, 21.18.
4-Allyl-1-(pyridine-4-yl-carbonyl)-thiosemicarbazide (5l).
This was obtained as white solid; Yield 0.80 g, 3.4 mmol
(85.8%); mp 210–211°C; IR (cm−1): ν 1229 (C S), 1526
(C N), 1676 (C O), 3219, 3268, 3308 (3NH) cm−1 1H NMR
;
(DMSO-d6): δ 4.11 (d, 2H, CH2 ), 5.14 (dd, 2H, CH2), 5.82
(m, 1H, CH ), 7.83 (dd, 2H, J = 5, 3-Py), 8.77 (dd, 2H, J = 5,
2-Py), 8.42 (s, 1H, NH C S), 9.51 (s, 1H, NH C S), 10.69 (s,
1H, NH C O) ppm; 13C NMR (DMSO-d6): δ 46.4 (CH2),
115.7 ( CH2), 122.1 (2CH), 135.4 (CH ), 140.0 (C), 150.6
(2CH), 164.9 (C O), 182.0 (C S) ppm; MS: m/z (%) 237
(M + 1, 100). Anal. Calcd. for C10H12N4OS: C, 50.83; H,
5.12; N, 23.71; S, 13.57. Found: C, 50.99; H, 5.4.87; N,
23.40; S, 13.31.
4-Alkyl/aryl-3-(2-aryl-4-methylthiazol-5-yl)-1H-1,2,4-triazol-5
(4H)-thione (6a–i); 4-alkyl/aryl-3-(pyridin-4-yl)-1H-1,2,4-triazol-
5(4H)-thione (6j–l). A solution of corresponding thiosemicarbazide
5a–l (3.5 mmol) in 20 mL NaOH 2N was refluxed for 2 h. The
resulting solution was cooled to room temperature, diluted with
water, and acidified to pH 5–6. The precipitate was filtered, washed
with water, and recrystallized from ethanol to afford the triazolyl–
thiones 6a–l as white solids.
3-(4-Methyl-2-phenylthiazol-5-yl)-4-phenyl-1H-1,2,4-triazol-5
(4H)-thione (6a). Yield 1.18 g, 3.4 mmol, (97%), mp 272–274°C;
IR (KBr): ν 1265 (C S), 1531 (C N), 1570 (C N), 3110 (NH) cm−1;
1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 7.44–7.56 (m, 5H,
Ar H), 7.6–7.99 (m, 5H, Ar H), 14.1 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6): δ 17.04 (CH3), 115.1 (C), 126.1 (CH), 126.3 (3CH),
129.9 (4CH), 131.2 (2CH), 132.3 (C), 142.5 (C), 144.5 (C), 156.8
(C), 160.7 (C), 165.1 (C), 168.9 (C S) ppm; MS: m/z (%) 350 (M+,
100). Anal. Calcd. for C18H14N4S2: C, 61.69; H, 4.03; N, 15.99; S,
18.30. Found: C, 61.65; H, 4.01; N, 15.94; S, 18.27.
3-(4-Methyl-2-p-tolylthiazol-5-yl)-4-phenyl-1H-1,2,4-triazol-5
(4H)-thione (6b). Yield 0.92 g, 2.62 mmol, (75%), mp 267–269°C;
IR (KBr): ν 1257 (C S), 1520 (C N), 1538 (C N), 3102 (NH) cm−1;
1H NMR (DMSO-d6): δ 2.38 (s, 3H, CH3), 2.44 (s, 3H, CH3),
7.45–7.55 (m, 5H, Ar H), 7.34 (d, 2H, J = 8 Hz, Ar), 7.86 (d, 2H,
J = 9 Hz, Ar), 14.2 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ
16.9 (Th CH3), 21.5 (Ar CH3), 117.2 (C), 124.8 (C), 126.2 (2CH),
127.8 (3CH), 128.8 (2CH), 132.1 (2CH), 130.4 (C), 140.1 (C),
142.6 (C), 144.4 (C), 157.1 (C), 170.2 (C S) ppm; MS: m/z (%)
364 (M+, 100). Anal. Calcd. for C19H16N4S2: C, 62.61; H, 4.42; N,
15.37; S, 17.59. Found: C, 62.58; H, 4.41; N, 15.32; S, 17.53.
3-(2-(4-Bromophenyl)-4-methylthiazol-5-yl)-4-methyl-1H-
1,2,4-triazol-5(4H)-thione (6f). Yield 1.24 g, 3.4 mmol, (97%),
mp 283–285°C; IR (KBr): ν 1280 (C S), 1521 (C N), 1541
1
(C N), 3095 (NH) cm−1; H NMR (DMSO-d6): δ 2.46 (s, 3H,
CH3), 3.5 (s, 3H, NCH3), 7.6 (d, 2H, J = 9 Hz, Ar), 7.7 (d, 2H,
J = 9 Hz, Ar), 14.37 (s, 1H, NH) ppm; 13C NMR (DMSO-d6):
δ 17.4 (Th CH3), 31.9 (NCH3), 115.6 (C), 124.9 (C), 128.2
(2CH), 129.4 (2CH), 131.2 (C), 132.9 (C), 144.5 (C), 156.5
(C), 171.4 (C S) ppm; MS: m/z (%) 367 (M+, 100). Anal.
Calcd. for C13H11BrN4S2: C, 42.51; H, 3.02; N, 15.25; S,
17.46. Found: C, 42.52; H, 3.02; N, 15.21; S, 17.42.
4-Allyl-3-(4-methyl-2-phenylthiazol-5-yl)-1H-1,2,4-triazol-5
(4H)-thione (6g). Yield 1.03 g, 3.3 mmol, (94%), mp 214–216°C;
IR (KBr): ν 1267 (C S), 1533 (C N), 1573 (C N), 3099 (NH) cm−1
;
1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 4.65 (m, 2H, CH2),
4.85–5.16 (dd, 2H, CH2), 5.82 (m, 1H, CH ), 7.55–7.99 (m, 5H,
Ar H), 14.21 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ 17.7
(CH3), 46.2 (CH2), 113.7 ( CH2), 115.9 (C), 126.6 (CH), 129.8
(2CH), 130.3 (2CH), 131.7 (CH ), 140.2 (C), 144.4 (C), 156.2
(C), 162.9 (C), 170.8 (C S) ppm; MS: m/z (%) 314 (M + 1, 100).
Anal. Calcd. for C15H14N4S2: C, 57.30; H, 4.49; N, 17.82; S,
20.40. Found: C, 57.27; H, 4.47; N, 17.78; S, 20.36.
4-Allyl-3-(4-Methyl-2-p-tolylthiazol-5-yl)-1H-1,2,4-triazol-5
(4H)-thione (6h). Yield 1.1 g, 3.3 mmol, (94%), mp 185–186°C;
IR (KBr): ν 1279 (C S), 1522 (C N), 1540 (C N), 3187 (NH) cm−1
;
1H NMR (DMSO-d6): δ 2.37 (s, 3H, CH3), 2.44 (s, 3H, CH3), 4.66
(m, 2H, CH2), 4.86–5.17 (dd, 2H, CH2), 5.87 (m, 1H, CH ), 7.34
(d, 2H, J = 8 Hz, Ar), 7.86 (d, 2H, J = 9 Hz, Ar), 14.26 (s, 1H, NH)
ppm; 13C NMR (DMSO-d6): δ 16.97 (Th CH3), 21.48 (Ar CH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1414
B. Tiperciuc, V. Zaharia, I. Colosi, C. Moldovan, O. Crisan, A. Pîrnau, L. Vlase, M. Duma,
and O. Oniga
Vol 49
[3] Weidner-Wells, M. A.; Boggs, C. M.; Foleno, B. D.; Melton, J.;
Bush, K.; Goldschmidt, R; Hlasta, D. J. Bioorg Med Chem 2002, 10, 2345.
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M.; Lewandowski, F. A.; Zhou, Z.; Sharp, C.; Maguire, D.; Grasberger, B.;
DesJarlais, R. L.; Spurlino, O. J Bioorg Med Chem Lett 2001, 11, 915.
[7] Haviv, F.; Ratajczyk, R. J.; DeNet, R. W.; Kerdesky, F. A.;
Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young, P. R.; Carter, G.
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[8] Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J.; Taylor,
D. Jr.; Connolly, C. J.; Doherty, A. M.; Klutchko, S. R.; Sircar, I. J Med Chem
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[9] Bell, F. W.; Cantrell, A. S.; Hoegberg, M.; Jaskunas, S. R.;
Johansson, N. G.; Jordan, J.; Kinnick, M. D.; Lind, P.; Morin, J. M. Jr.
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46.27 (CH2), 113.9 ( CH2), 117.7 (C), 126.7 (2CH), 129.9 (2CH),
130.4 (C), 131.89 (CH ), 141.6 (C), 144.5 (C), 156.6 (C), 167.9
(C), 168.67 (C S) ppm; MS: m/z (%) 329 (M + 1, 100). Anal.
Calcd. for C16H16N4S2: C, 58.51; H, 4.91; N, 17.06; S, 19.52.
Found: C, 58.49; H, 4.90; N, 17.01; S, 19.49.
4-Allyl-3-(2-(4-bromophenyl)-4-methylthiazol-5-yl)-1H-1,2,4-
triazol-5(4H)-thione (6i). Yield 1.34 g, 3.4 mmol, (98%), mp
259–260°C; IR (KBr): ν 1286 (C S), 1533 (C N), 1558 (C N),
3108 (NH) cm−1 1H NMR (DMSO-d6): δ 2.7 (s, 3H, CH3),
;
4.13 (m, 2H, CH2), 5.05–5.17 (dd, 2H, CH2), 5.86 (m, 1H,
CH ), 7.66 (d, 2H, J = 9 Hz, Ar), 7.71 (d, 2H, J = 9 Hz, Ar),
14.4 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): δ 17.4
(Th CH3), 46.7 (CH2), 114 ( CH2), 116.7 (C), 128.9 (2CH),
131.2 (2CH), 131.9 (CH ), 133.2 (C), 143.9 (C), 144.9 (C),
156.8 (C), 164.7 (C), 168.7 (C S) ppm; MS: m/z (%) 393 (M+,
100). Anal. Calcd. for C15H13BrN4S2: C, 45.80; H, 3.33; N,
14.24; S, 16.30. Found: C, 45.77; H, 3.32; N, 14.22; S, 16.27.
4-Phenyl-3-(pyridin-4-yl)-1H-1,2,4-triazol-5(4H)-thione (6j).
Yield 0.66 g, 2.6 mmol (74.6%); mp 279–280°C (Ref. [30] 122°
C); MS: m/z (%) = 254 (M+, 100). Anal. Calcd. for C13H10N4S:
C, 61.39; H, 3.96; N, 22.03; S, 12.61. Found: C, 61.30; H, 3.65;
N, 21.86; S, 12.51.
[10] Gu, X. H.; Wan, X. Z.; Jiang, B. Bioorg Med Chem Lett 1999, 9,
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[12] Kumar, Y.; Green, R.; Borysko, K. Z.; Wise, D. S.; Wotring,
L. L.; Townsend, L. B. J Med Chem 1993, 36, 3843.
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L. B. J Med Chem 1993, 36, 3849.
[14] Medime, E.; Capan, G. Il Farmaco 1994, 49, 449.
[15] Metzger, J. V. Comprehensive Heterocyclic Chemistry I; Pergamon:
New York, NY, 1984;Vol.6, pp328.
[16] Amir, M.; Kumar, H.; Javed, S. A. Eur J Med Chem 2008, 43,
2056.
[17] Navidpour, L.; Shafaroodi, H.; Abdi, K.; Amini, M.; Ghahremani,
M. H.; Dehpourd, A. R.; Shafiee, A. Bioorg Med Chem 2006, 14, 2507.
[18] Tehranchian, S.; Akbarzadeh, T.; Fazeli, M. R.; Jamalifar, H.;
Shafiee, A. Bioorg Med Chem Lett 2005, 15, 1023.
[19] Holla, B. S.; Poorjary, N. K.; Rao, S. B.; Shivananda, M. K.
Eur J Med Chem 2002, 37, 511.
[20] Shiradkar, M. R.; Murahari, K. K.; Gangadasu, H. R.; Suresh,
T.; Kalyan, C. A.; Panchal, D.; Kaur, R.; Burange, P.; Ghogare, O. J
Bioorg Med Chem 2007, 42, 3997.
[21] Joshi, S. D.; Vagdevi, H. M.; Vaidya, V. P.; Gadaginamath, G.
S. Eur J Med Chem 2008, 43, 1989.
[22] Cansiz, A.; Koparir, M.; Demirdag, A. Molecules 2004, 9, 204.
[23] Rostom, S. A. F.; Shalaby, M. A.; EL-Demellawy, M. A. Eur J
Med Chem 2003, 38, 959.
[24] Oniga, O.; Grosu, I.; Mager, S.; Simiti, I. Monatsh Chem 1998,
129, 661.
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1995, 50, 12, 794.
4-Methyl-3-(pyridin-4-yl)-1H-1,2,4-triazol-5(4H)-thione (6k).
Yield 0.50 g, 2.62 mmol, (75%); mp 283–284°C; IR (KBr): ν 1226
(C S), 1571 (C N), 1609 (C N), 3271 (NH) cm−1; 1H NMR
(DMSO-d6): δ 3.45 (s, 3H, NCH3), 7.46 (dd, 2H, J = 5 Hz, 3-Py),
8.64 (dd, 2H, J = 5 Hz, 2-Py), 14.16 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6): δ 31.64 (NCH3), 123.1 (2CH), 133.6 (C), 149.5
(C N), 151.2 (2CH), 168.8 (C S) ppm; MS: m/z (%) 192 (M+,
100). Anal. Calcd. for C8H8N4S: C, 49.98; H, 4.09; N, 29.14; S,
16.68. Found: C, 50.11; H, 3.93; N, 29.48; S, 16.41.
4-Allyl-3-(pyridin-4-yl)-1H-1,2,4-triazol-5(4H)-thione (6l).
Yield 0.595 g, 2.73 mmol (78%); mp 210–212°C; IR (KBr): ν 1262
(C S), 1571 (C N), 1614 (C N), 3337 (NH) cm−1; 1H NMR (DMSO-
d6): δ 4.8 (d, 2H, CH2 ), 5.01 (dd, 2H, CH2), 5.86 (m, 2H, CH ), 7.66
(dd, 2H, J = 5 Hz, 3-Py), 8.77 (dd, 2H, J = 5 Hz, 2-Py), 14.26 (s, 1H,
NH) ppm; 13C NMR (DMSO-d6): δ 46.7 (CH2), 117.7 ( CH2), 122.6
(2CH), 130.4 (CH ), 133.8 (C), 149.7 (C N), 150.8 (2CH), 168.6
(C S) ppm; MS: m/z (%) 218 (M+, 25). Anal. Calcd. for
C10H10N4S: C, 55.02; H, 4.62; N, 25.67; S, 14.69. Found: C,
55.05; H, 4.34; N, 25.94; S, 14.47.
[26] Zaharia, V.; Ignat, A.; Palibroda, N.; Ngameni, B.; Kuete, V.;
Fokunang, K. N.; Moungang, M. L.; Ngadjui, B. T. Eur J Med Chem
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UK, 1983; p140.
Acknowledgments. This work was financially supported by the
National University Research Council, Romania (Project PNII-ID
No.1348/2008). This support is gratefully acknowledged.
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet