Synthesis of new pyrimidinylthio-substituted 1,3,4-oxa(thia)diazoles and 1,2,4-triazoles

Article abstract of DOI:10.1080/17415993.2012.692790

Novel 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones bearing the pyrimidinylthio-moiety were synthesized by cyclization of a substituted-thiosemicarbazide precursor under different conditions. The thiosemicarbazide intermediates were easily accessed from reaction of biologically active 2-(4,6-dimethylpyrimidin-2-ylthio)acetohydrazide and 2-(2-dimethylamino-6-methyl pyrimidin-4-ylthio)acetohydrazide with cyclohexyl or phenyl isothiocyanate. The compounds are characterized by ¹H, ¹³C NMR, IR spectroscopy and analytical data.

Full text of DOI:10.1080/17415993.2012.692790

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Synthesis of new pyrimidinylthio-
substituted 1,3,4-oxa(thia)diazoles and
1,2,4-triazoles
Milda M. Burbuliene a , Aliona Simkus a & Povilas Vainilavicius a
a Department of Organic Chemistry, Faculty of Chemistry , Vilnius
University , Naugarduko 24, LT-03225 , Vilnius , Lithuania
Published online: 07 Jun 2012.
To cite this article: Milda M. Burbuliene , Aliona Simkus & Povilas Vainilavicius (2012) Synthesis
of new pyrimidinylthio-substituted 1,3,4-oxa(thia)diazoles and 1,2,4-triazoles, Journal of Sulfur
Chemistry, 33:4, 403-411, DOI: 10.1080/17415993.2012.692790
To link to this article: http://dx.doi.org/10.1080/17415993.2012.692790
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Journal of Sulfur Chemistry
Vol. 33, No. 4, August 2012, 403–411
Synthesis of new pyrimidinylthio-substituted
1,3,4-oxa(thia)diazoles and 1,2,4-triazoles
Milda M. Burbuliene*, Aliona Simkus and Povilas Vainilavicius
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, LT-03225
Vilnius, Lithuania
(Received 28 March 2012; final version received 9 May 2012)
Novel 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones bearing the pyrimidinylthio-
moiety were synthesized by cyclization of a substituted-thiosemicarbazide precursor under different
conditions. The thiosemicarbazide intermediates were easily accessed from reaction of biologically
active 2-(4,6-dimethylpyrimidin-2-ylthio)acetohydrazide and 2-(2-dimethylamino-6-methyl pyrimidin-4-
ylthio)acetohydrazide with cyclohexyl or phenyl isothiocyanate. The compounds are characterized by 1H,
13C NMR, IR spectroscopy and analytical data.
H
N
N
O
Pyr-S-CH2CNHNHCNH-R
N
N
NHR
NHR
S
S
O
S
Pyr
Pyr
S
N
R
Pyr
N
N
S
R = cyclohexyl, phenyl
Pyr = 4,6-dimethylpyrimidin-2-yl-
2-dimethylamino-6-methylpyrimidin-4-yl-
S
Keywords: pyrimidine; thiosemicarbazide; 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-triazole
1. Introduction
Heterocyclic compounds form the basis of pharmaceutical and agrochemical products. Azoles
including 1,2,4-triazoles, 1,3,4-oxadiazoles and 1,3,4-thiadiazoles are in particular an important
class of compounds of considerable biological and technological interest that are appearing in an
increasing number of publications. These azoles potentially possess a variety of valuable prop-
erties including antitubercular (1, 2), antimicrobial (2–8), anticancer (9–11), anti-inflammatory,
analgetic(12, 13), antibacterial(14, 15), anticonvulsant(16, 17)andtyrosinase(18)ormonoamine
oxidase (19) inhibitory activity. 1,3,4-Oxadiazoles are also extensively investigated as promising
materials for application in electronic technologies as photosensitizers, liquid crystals and organic
*Corresponding author. Email: milda.burbuliene@chf.vu.lt
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.692790
http://www.tandfonline.com

404 M.M. Burbuliene et al.
light emitting diodes (20–22). The synthetic approaches to these heterocycles therefore are widely
reported and are receiving considerable attention. Several review articles have been published that
discuss the most frequently used, as well as uncommon synthetic methods, for the synthesis of
1,2,4-triazoles and 1,3,4-oxa(thia)diazoles (1, 23–31). An excellent strategy for the synthesis of
these azoles is the cyclization of substituted thiosemicarbazides, respectively (8, 32, 33).
As a continuation of our research in the synthesis of new heterocycles of potential
biological importance, we report here the synthesis of substituted (2-pyrimidinyl)- and
(4-pyrimidinyl)thiosemicarbazides and their cyclization products. Our interest was to develop effi-
cientproceduresforthesynthesisofnovel1,3,4-oxadiazoles, 1,3,4-thiadiazolesand1,2,4-triazoles
linked by sulfur to a pyrimidine moiety.
2. Results and discussion
Biologically active hydrazides 1 and 2 were used for the synthesis of azoles. (4,6-Dimethyl-
pyrimidin-2-ylthio)acethydrazide (1) and its derivatives were previously found to inhibit
monoamino oxidase activity (34), while derivatives of (2-dimethylamino-6-methylpyrimidin-
4-ylthio)acethydrazide (2) showed anti-inflammatory activity (35). In this context, it was
worthwhile to utilize these hydrazides for the synthesis of new potentially active biologically
heterocyclic systems.
Substituted thiosemicarbazides 5a and b and 6a and b were readily prepared by acylation of
hydrazides 1 and 2 in absolute ethanol with cyclohexyl or phenyl isothiocyanate as shown in
Scheme 1. Compounds 5 and 6 precipitated from the reactions mixtures in good yield as white
solids of excellent purity. The 1H NMR spectra of thiosemicarbazides 5 and 6 displayed three sets
of singlets between 6.48 and 10.27 ppm due to three NH group protons. The pyrimidine 5-CH
N
O
i
v
O
N
H
H
NHR
NH2
S
N
N
S
S
Pyr
N
R
Pyr
N
S
Pyr
H
H
S
1, 2
5a, b - 6a, b
9a, b - 10a, b
ii
iv
iii
H
N
N
S
N
N
N
N
S
N
Pyr
NH2
NHR
S
S
O
O
R
Pyr
Pyr
3, 4
7a, b - 8a, b
11a, b - 12a, b
CH3
i: R-NCS, C2H5OH, reflux, 2 h
N
N
Pyr =
H3C
1, 3, 5, 7, 9, 11
ii: C6H5OCN, toluene/2-PrOH, 55-60 °C, 3 h
N(CH3)2
N
N
H3C
iii: (CH3COO)2Hg, C2H5OH, reflux, 2 h
iv: 10% NaOH, reflux, 2 h (room temp. for 11b)
v: conc. H2SO4, 0-3 oC, 1 h, NH4OH
2, 4, 6, 8, 10,12
R = cyclohexyl (a), phenyl (b)
Scheme 1. Reagents and reaction conditions for the synthesis of compounds 3–12.

Journal of Sulfur Chemistry 405
singlet was observed between 6.37 and 6.98 ppm and the SCH2 group protons between 3.86 and
3.99 ppm. In addition, the signals for the cyclohexyl and phenyl group protons as well as the
pyrimidine ring substituents (CH3 and N(CH3)2) were compatible with structures 5 and 6. The
IR spectra displayed characteristic carbonyl frequencies at 1702–1662 cm−1 and NH bands at
3336–3140 cm−1
.
Thiosemicarbazides 5 and 6 can be cyclized under different conditions to the correspond-
ing azoles. The cyclodesulfurization to form 1,3,4-oxadiazoles have been conducted by treating
thiosemicarbazides with iodine in the presence of a base (32), either with mercury (II) hydroxide
(36) or acetate (32, 37). For the synthesis of oxadiazoles 7 and 8, several attempts were made to
ascertain the optimal reaction conditions. It was found that the use of mercury (II) acetate provided
shorter reaction time, simple work-up procedure and yields comparable to the other procedures.
Thus, compounds 5 and 6 were heated at reflux in ethanol in the presence of mercury (II) acetate
for 2 h. After filtration of by-products and concentration of the solvent, the 2-amino-substituted
1,3,4-oxadiazoles 7 and 8 crystallized in 75–88% yield. Treatment of the starting hydrazides 1 and
2 with phenyl cyanate at 55–60◦C in anhydrous conditions in a mixture of toluene and 2-propanol
gave the 2-amino-1,3,4-oxadiazoles 3 and 4 directly.
2-Amino-substituted 1,3,4-thiadiazoles 9 and 10 were synthesized by cyclodehydration reac-
tions of 5 and 6 in acidic media. Thiosemicarbazides 5 and 6 were treated with concentrated
sulfuric acid at ∼ 0◦C and upon neutralization of the reaction mixture with ammonium hydroxide
the products 9 and 10 were isolated as white solids in 52–65% yield. The structural assign-
ments for 3, 4 and 7–10 were made by examination of IR and NMR data. In the IR spectra of
compounds 3, 4 and 7–10, absorption bands at 1609–1500 cm−1 were observed for C N and
=
−1
=
C C and between 3303 and 3120 cm for the NH and NH2 groups. Compounds 3 and 4 also
displayed peaks at 1664–1663 cm−1 arising from bending vibrations of the N H bonds. Note-
worthy in the H NMR spectra, the SCH2 singlets were shifted downfield by at least 0.5 ppm
−
1
in comparison to the shifts observed in the starting compounds 5 and 6. The NH protons for
the compounds with the cyclohexyl substituent (7a, 8a, 9a and 10a) appeared as doublets at
7.51–7.55 ppm, while those with the phenyl group (7b, 8b, 9b and 10b) displayed singlets at
10.24–10.48 ppm.
Thiosemicarbazides 5 and 6 on treatment with aqueous sodium hydroxide undergo smooth
cyclodehydration to give 1,2,4-triazoles 11 and 12 in 87–95% yields. Conversion of 5b to 11b
occurred at room temperature while the other compounds required heating of the reaction mix-
tures at reflux. The IR spectra of triazole-3-thiones 11 and 12 displayed absorption bands at
3091–3099 cm−1 for NH. The stretchings at 1585–1551, 1501–1494 cm−1 are attributable to
−1
=
=
=
the C N and C C bonds and the absorptions at 1342–1331 cm arise from C S vibrations.
The characteristic triazole NH proton singlet appeared in the 1H NMR spectra in the downfield
between 13.10 and 13.86 ppm and the SCH2 singlets upfield between 4.34 and 4.49 ppm. The
chemical shifts of the pyrimidine and triazole ring substituents are also consistent with their
structures.
3. Conclusions
We have developed concise and efficient procedures for the synthesis of novel 1,3,4-oxadiazoles,
1,3,4-thiadiazoles and 1,2,4-triazoles bearing 4-pyrimidinylthio- and 2-pyrimidinylthio moi-
eties. The target compounds were obtained from the acylation reaction of biologically active
(2-dimethylamino-6-methylpyrimidin-4-ylthio)acetohydrazide and (4,6-dimethylpyrimidin-2-
ylthio)acetohydrazide with isothiocyanates followed by intramolecular cyclization of substituted
thiosemicarbazides intermediates. All the compounds prepared are under evaluation for their
antimicrobial activity and the results will be published later.

406 M.M. Burbuliene et al.
4. Experimental
Melting points were determined in open capillaries using digital melting point IA9100 series
apparatus (Fisher Scientific) and are uncorrected. 1H and 13C NMR spectra were recorded on a
UnityVarian INOVA spectrometer (300 and 75 MHz, respectively) using residual solvents signals
as the internal standard. The IR spectra were recorded on a Spectrum BX FT-IR (Perkin-Elmer) in
KBr discs. The reactions and purities of the compounds were monitored by TLC on Silica gel 60
F254 aluminum plates (Merck). Visualization was accomplished by UV light. Elemental analyses
were performed at the Microanalyses Laboratory of the Department. Reagents and solvents were
purchased from commercial sources.
2-(4,6-Dimethylpyrimidin-2-ylthio)acetohydrazide (1) and (2-dimethylamino-6-methyl-
pyrimidin-4-ylthio)acetohydrazide (2) were synthesized as earlier reported (34, 35).
4.1. Synthesis of 2-amino-1,3,4-oxadiazoles 3 and 4
Hydrazide 1 or 2 (5 mmol) was suspended in a mixture of dry toluene (10 ml) and 2-propanol
(4 ml). Phenyl cyanate (0.61 g, 0.56 ml, 5.1 mmol) was added dropwise to this suspension and the
reaction mixture was stirred at 55–60◦C for 3 h. The precipitate was filtered, washed with ethanol
and ether, dried and recrystallized from 2-ethoxyethanol to give colorless crystals of 3 or 4.
4.1.1. 2-Amino-5-[(4,6-dimethylpyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole (3)
1
Yield 65%, mp 219–220◦C. IR, ν, cm−1: 3332, 3228, 1663 (NH2), 1578, 1535 (C N, C C). H
NMR (DMSO-d6) δ: 2.37 (s, 6H, CH3), 4.49 (s, 2H, SCH2), 7.03 (s br, 3H, CH-pyrimidine +
NH2); 13C NMR (DMSO-d6) δ: 24.03, 24.42, 117.23, 157.08, 164.61, 168.06, 168.47.Anal. calcd.
for C9H11N5OS (237.28): C, 45.56; H, 4.67; N, 29.51%. Found: C, 45.37; H, 4.70; N, 29.45%.
=
=
4.1.2. 2-Amino-5-[(2-dimethylamino-6-methylpyrimidin-4-ylthio)methyl]-1,3,4-oxadiazole (4)
Yield 70%, mp 193–194◦C. IR, ν, cm−1: 3302, 3118, 1664 (NH2), 1573, 1552 (C N, C C).
1H NMR (DMSO-d6) δ: 2.20 (s, 6H, CH3), 3.11 (s, 6H, N(CH3)2), 4.49 (s, 2H, SCH2), 6.47 (s,
1H, CH-pyrimidine), 7.03 (s, 2H, NH2); 13C NMR (DMSO-d6) δ: 22.46, 24.31, 105.76, 157.08,
161.37, 164.58, 166.38, 166.67. Anal. calcd. for C10H14N6OS (266.32): C, 45.10; H, 5.30; N,
31.56%. Found: C, 45.15; H, 5.13; N, 31.61%.
=
=
4.2. Synthesis of substituted thiosemicarbazides 5a and b and 6a and b
Hydrazide 1 or 2 (5 mmol) was dissolved in abs. ethanol (∼30 ml) and cyclohexyl (or phenyl)
isothiocyanate (5.5 mmol) was added. The reaction mixture was stirred at reflux for 2 h and cooled.
The resultant solid was filtered off, dried and recrystallized.
4.2.1. 4-Cyclohexyl-1-[(4,6-dimethylpyrimidin-2-ylthio)acetyl]thiosemicarbazide (5a)
Yield 74% (2-propanol), mp 156–158◦C (acetone–water). IR, ν, cm−1: 3296, 3238 (NH), 1686
1
=
=
=
=
(C O), 1584, 1546 (C N, C C), 1341 (C S). H NMR (CDCl3) δ: 1.17–1.26, 1.37–1.41, 1.67–
1.79, 1.98–2.01 (4m, 10H, CH2-cyclohexyl), 2.51 (s, 6H, CH3), 3.86 (s, 2H, SCH2), 4.03–4.07
(m, 1H, CH-cyclohexyl), 6.82 (s, 1H, CH-pyrimidine), 6.94 (s br, 1H, CSNH), 9.31 (s br, 1H,
NHCS), 10.19 (s br, 1H, CONH); 13C NMR (CDCl3) δ: 24.28, 24.86, 25.61, 25.71, 32.75, 53.27,

Journal of Sulfur Chemistry 407
117.13, 166.29, 168.30, 169.45, 178.63. Anal. calcd. for C15H23N5OS2 (353.51): C, 50.96; H,
6.56; N, 19.81%. Found: C, 51.11; H, 6.58; N, 19.93%.
4.2.2. 1-[(4,6-Dimethylpyrimidin-2-ylthio)acetyl]-4-phenylthiosemicarbazide (5b)
Yield 91% (ethanol–acetone), mp 175–176◦C. IR, ν, cm−1: 3270, 3210 (NH), 1662 (C O), 1584,
=
1
=
=
=
1561, 1498 (C C, C N), 1340 (C S). H NMR (DMSO-d6) δ: 2.36 (s, 6H, CH3), 3.99 (s, 2H,
SCH2), 6.98 (s, 1H, CH-pyrimidine), 7.16–7.21 (m, 1H, Ph-H), 7.32–7.42 (m, 4H, Ph-H), 9.59
(s br, 1H, CSNH), 9.74 (s br, 1H, NHCS), 10.27 (s br, 1H, CONH); 13C NMR (DMSO-d6) δ:
24.05, 33.60, 116.86, 125.88, 126.59, 128.83, 139.68, 167.85, 168.30, 169.78, 181.49.Anal. calcd.
for C15H17N5OS2 (347.46): C, 51.85; H, 4.93; N, 20.16%. Found: C, 51.66; H, 5.01; N, 20.24%.
4.2.3. 4-Cyclohexyl-1-[(2-dimethylamino-6-methylpyrimidin-4-ylthio)acetyl]
thiosemicarbazide (6a)
Yield 88%, mp 178–180◦C (ethanol). IR, ν, cm−1: 3306, 3140 (NH), 1701 (C O), 1580, 1548
=
1
=
=
=
(C N, C C), 1315 (C S). H NMR (CDCl3) δ: 1.02–1.20, 1.32–1.43, 1.59–1.69, 1.93–1.96
(4m, 10H, CH2-cyclohexyl), 2.30 (s, 3H, CH3), 3.20 (s, 6H, N(CH3)2), 3.87 (s, 2H, SCH2), 4.09–
4.12 (m, 1H, CH-cyclohexyl), 6.37 (s, 1H, CH-pyrimidine), 6.48 (s br, 1H, CSNH), 8.48 (s br, 1H,
NHCS), 9.64 (s br, 1H, CONH); 13C NMR (CDCl3) δ: 24.35, 24.87, 25.65, 31.17, 32.52, 37.49,
53.36, 106.07, 161.74, 165.83, 167.07, 168.09, 180.23. Anal. calcd. for C16H26N6OS2 (382.55):
C, 50.23; H, 6.85; N, 21.97%. Found: C, 50.09; H, 6.88; N, 22.09%.
4.2.4. 1-[(2-Dimethylamino-6-methylpyrimidin-4-ylthio)acetyl]-4-
phenylthiosemicarbazide (6b)
Yield 73%, mp 165–167◦C. IR, ν, cm−1: 3336, 3142 (NH), 1686 (C O), 1605, 1560, 1498 (C N,
=
=
1
=
=
C C), 1317 (C S). H NMR (DMSO-d6) δ: 2.20 (s, 3H, CH3), 3.08 (s, 6H, N(CH3)2), 3.99 (s,
2H, SCH2), 6.46 (s, 1H, CH-pyrimidine), 7.18–7.20 (m, 1H, Ph-H), 7.32–7.37 (m, 4H, Ph-H),
9.50 (s br, 1H, CSNH), 9.73 (s br, 1H, NHCS), 10.23 (s br, 1H, CONH); 13C NMR (DMSO-d6)
δ: 24.35, 31.63, 37.23, 105.68, 125.90, 126.9, 126.43, 128.85, 139.65, 161.55, 166.15, 167.87,
181.55. Anal. calcd. for C16H20N6OS2 (376.50): C, 51.04; H, 5.35; N, 22.32%. Found: C, 51.16;
H, 5.41; N, 22.33%.
4.3. Synthesis of 1,3,4-oxadiazoles 7a and b and 8a and b
To a stirred solution of thiosemicarbazide 5 or 6 (1 mmol) in ethanol (15 ml), mercury (II) acetate
(0.32 g, 1 mmol)wasaddedinportion.Thereactionmixturewasheatedatrefluxfor2 handfiltered.
The filtrate was concentrated, cooled and the precipitate formed was collected by filtration and
recrystallized.
4.3.1. 2-Cyclohexylamino-5-[(4,6-dimethylpyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole (7a)
1
Yield 75%, mp 191–192◦C (ethyl acetate). IR, ν, cm−1: 3189 (NH), 1604, 1584 (C N, C C). H
NMR (DMSO-d6) δ: 1.18–1.28, 1.51–1.60, 1.65–1.73, 1.87–1.89 (4m, 10H, CH2-cyclohexyl),
2.37 (s, 6H, CH3), 3.25–3.36 (m, 1H, CH-cyclohexyl), 4.50 (s, 2H, SCH2), 7.03 (s, 1H, CH-
pyrimidine), 7.52 (d, J = 7.5 Hz, 1H, NH); 13C NMR (DMSO-d6) δ: 24.03, 24.42, 25.05, 25.83,
32.89, 52.41, 117.23, 157.05, 163.64, 168.04, 168.45. Anal. calcd. for C15H21N5OS (319.43): C,
56.40; H, 6.63; N, 21.92%. Found: C, 56.46; H, 6.51; N, 21.89%.
=
=

408 M.M. Burbuliene et al.
4.3.2. 5-[(4,6-Dimethylpyrimidin-2-ylthio)methyl]-2-phenylamino-1,3,4-oxadiazole (7b)
Yield 76%, mp 166–168◦C (benzene). IR, ν, cm−1: 3178, (NH), 1602, 1578, 1504 (C N, C C).
1H NMR (DMSO-d6) δ: 2.39 (s, 6H, CH3), 4.63 (s, 2H, SCH2), 7.06 (s, 1H, CH-pyrimidine), 7.0
(t, J = 8 Hz, 1H, Ph-H), 7.33 (t, J = 8 Hz, 2H, Ph-H), 7.52 (d, J = 8 Hz, 2H, Ph-H), 10.48 (s,
1H, NH); 13C NMR (CDCl3) δ: 24.06, 24.39, 117.30, 117.57, 122.48, 129.75, 139.36, 157.94,
160.67, 168.11, 168.42. Anal. calcd. for C15H15N5OS (313.38): C, 57.49; H, 4.82; N, 22.35%.
Found: C, 57.59; H, 4.67; N, 22.49%.
=
=
4.3.3. 2-Cyclohexylamino-5-[(2-dimethylamino-6-methylpyrimidin-4-ylthio)methyl]-1,3,4-
oxadiazole (8a)
1
Yield 76%, mp 144–146◦C. IR, ν, cm−1: 3241 (NH), 1580, 1555 (C N, C C). H NMR (DMSO-
d6) δ: 1.18–1.28, 1.52–1.60, 1.62–1.72, 1.90–1.94 (4m, 10H, CH2-cyclohexyl), 2.20 (s, 1H, CH3),
3.11 (s, 6H, N(CH3)2), 3.30–3.40 (m, 1H, CH-cyclohexyl), 4.50 (s, 2H, SCH2), 6.48 (s, 1H,
CH-pyrimidine), 7.49 (d, J = 7.5 Hz, 1H, NH); 13C NMR (DMSO-d6) δ: 22.46, 24.37, 25.07,
25.86, 32.91, 37.22, 52.43, 105.80, 157.11, 161.53, 163.69, 166.52. Anal. calcd. for C16H24N6OS
(348.47): C, 55.15; H, 6.94; N, 24.12%. Found: C, 55.37; H, 6.79; N, 24.14%.
=
=
4.3.4. 5-[(2-Dimethylamino-6-methylpyrimidin-4-ylthio)methyl]-2-phenylamino-1,3,4-
oxadiazole (8b)
1
Yield 88%, mp 194–195◦C. IR, ν, cm−1: 3248 (NH), 1571, 1550, 1500 (C N, C ). H NMR
(DMSO-d6) δ: 2.21 (s, 1H, CH3), 3.11 (s, 6H, N(CH3)2), 4.62 (s, 2H, SCH2), 6.51 (s, 1H, CH-
pyrimidine), 6.99 (t, J = 8 Hz, 1H, Ph-H), 7.32 (t, J = 8 Hz, 2H, Ph-H), 7.50 (d, J = 8 Hz, 2H,
Ph-H), 10.46 (s, 1H, NH); 13C NMR (DMSO-d6) δ: 22.43, 24.32, 37.25, 105.83, 117.59, 122.48,
129.74, 139.34, 157.99, 160.64, 161.44, 162.28, 166.49. Anal. calcd. for C16H18N6OS (342.42):
C, 56.12; H, 5.30; N, 24.54%. Found: C, 56.07; H, 5.17; N, 24.48%.
=
=
4.4. Synthesis of 1,3,4-thiadiazoles 9a and b and 10a and b
Thiosemicarbazide 5 or 6 (1 mmol) was added gradually with stirring to conc. sulfuric acid (5 ml)
at 0–3◦C. The reaction mixture was then stirred for 2 h at room temperature, poured over crushed
ice and neutralized with ammonium hydroxide to pH ∼ 7. The precipitate thus formed was filtered
off, washed with water, dried and recrystallized.
4.4.1. 2-Cyclohexylamino-5-[(4,6-dimethylpyrimidin-2-ylthio)methyl]-1,3,4-thiadiazole (9a)
1
Yield 65%, mp 185–187◦C (2-propanol). IR, ν, cm−1: 3185 (NH), 1586, 1520 (C N, C C). H
NMR (DMSO-d6) δ: 1.17–1.27, 1.52–1.60, 1.62–1.67, 1.91–1.94 (4m, 10H, CH2-cyclohexyl),
2.40 (s, 6H, CH3), 3.50 (s br, 1H, CH-cyclohexyl), 4.52 (s, 2H, SCH2), 7.05 (s, 1H, CH-
pyrimidine), 7.54 (d, J = 7.2 Hz, 1H, NH); 13C NMR (DMSO-d6) δ: 23.97, 24.92, 25.94, 29.63,
32.74, 53.88, 117.15, 155.22, 168.08, 169.01, 169.07. Anal. calcd. for C15H21N5S2 (335.49): C,
53.70; H, 6.31; N, 20.87%. Found: C, 53.79; H, 6.27; N, 20.64%.
=
=
4.4.2. 5-[(4,6-Dimethylpyrimidin-2-ylthio)methyl]-2-phenylamino-1,3,4-thiadiazole (9b)
Yield 62%, mp 196–197◦C (2-propanol). IR, ν, cm−1: 3261 (NH), 1609, 1578, 1556, 1508 (C N,
=
1
=
C C). H NMR (DMSO-d6) δ: 2.42 (s, 6H, CH3), 4.63 (s, 2H, SCH2), 6.99 (t, J = 8 Hz, 1H, Ph-
H), 7.07 (s, 1H, CH-pyrimidine), 7.33 (t, J = 8 Hz, 2H, Ph-H), 7.57–7.60 (m, 2H, Ph-H), 10.24 (s,

Journal of Sulfur Chemistry 409
1H, NH); 13C NMR (DMSO-d6) δ: 23.98, 29.51, 117.26, 118.03, 122.48, 129.77, 141.29, 157.81,
165.70, 168.17, 168.95. Anal. calcd. for C15H15N5S2 (329.45): C, 54.69; H, 4.59; N, 21.26%.
Found: C, 54.78; H, 4.66; N, 21.48%.
4.4.3. 2-Cyclohexylamino-5-[(2-dimethylamino-6-methylpyrimidin-4-ylthio)methyl]-1,3,4-
thiadiazole (10a)
1
Yield 52%, mp 203–205◦C (ethanol). IR, ν, cm−1: 3307 (NH), 1547, 1519 (C N, C C). H
NMR (DMSO-d6) δ: 1.18–1.28, 1.54–1.58, 1.60–1.70, 1.90–1.94 (4m, 10H, CH2-cyclohexyl),
2.21 (s, 1H, CH3), 3.15 (s, 6H, N(CH3)2), 3.47 (s br, 1H, CH-cyclohexyl), 4.59 (s, 2H, SCH2), 6.47
(s, 1H, CH-pyrimidine), 7.54 (d, J = 7.2 Hz, 1H, NH); 13C NMR (DMSO-d6) δ: 24.37, 24.92,
25.96, 27.46, 32.74, 37.31, 53.83, 106.09, 155.82, 161.53, 166.55, 166.75, 168.92. Anal. calcd.
for C16H24N6S2 (364.53): C, 52.72; H, 6.64; N, 23.05%. Found: C, 52.67; H, 6.70; N, 23.15%.
=
=
4.4.4. 5-[(2-Dimethylamino-6-methylpyrimidin-4-ylthio)methyl]-2-phenylamino-1,3,4-
thiadiazole (10b)
Yield 59%, mp 193–195◦C (ethyl acetate). IR, ν, cm−1: 3280 (NH), 1606, 1547, 1507 (C N,
=
1
=
C C). H NMR (DMSO-d6) δ: 2.23 (s, 6H, CH3), 3.17 (s, 6H, N(CH3)2), 4.70 (s, 2H, SCH2),
6.54 (s, 1H, CH-pyrimidine), 6.99 (t, J = 8 Hz, 1H, Ph-H), 7.35 (t, J = 8.4 Hz, 2H, Ph-H), 7.59
(d, J = 8.4 Hz, 2H, Ph-H), 10.25 (s, 1H, NH); 13C NMR (DMSO-d6) δ: 28.76, 32.19, 42.24,
110.96, 118.03, 122.76, 127.23, 134.52, 145.98, 156.99, 163.14, 165.62, 170.31, 170.65, 172.08.
Anal. calcd. for C16H18N6S2 (358.49): C, 53.61; H, 5.06; N, 23.44%. Found: C, 53.87; H, 4.93;
N, 23.53%.
4.5. Synthesis of 1,2,4-triazole-3(4H)-thiones 11a and b and 12a and b
Thiosemicarbazide 5 or 6 (1 mmol) was suspended in 10% sodium hydroxide solution (10–15 ml)
and stirred at room temperature (for 5b) or heated gently at reflux for 2 h. The cooled mixture
was poured over crushed ice and then neutralized with acetic acid to pH 7. The precipitate was
filtered off, washed with water and recrystallized.
4.5.1. 4-Cyclohexyl-5-[(4,6-dimethylpyrimidin-2-ylthio)methyl]-2H-1,2,4-triazole-3(4H)-
thione (11a)
Yield 95%, mp 212–213◦C (methanol). IR, ν, cm−1: 3091 (NH), 1582, 1551, 1494 (C N,
=
1
=
=
C C), 1339 (C S). H NMR (DMSO-d6) δ: 1.16–1.19, 1.59–1.69, 1.76–1.81 (3m, 10H, CH2-
cyclohexyl), 2.38 (s, 6H, CH3), 4.43 (s br, 1H, CH-cyclohexyl), 4.66 (s, 2H, SCH2), 7.06 (s, 1H,
CH-pyrimidine), 13.60 (s, 1H, NH); 13C NMR (DMSO-d6) δ: 24.05, 24.25, 25.47, 26.15, 29.54,
56.77, 117.26, 150.08, 167.19, 168.06, 168.47. Anal. calcd. for C15H21N5S2 (335.49): C, 53.70;
H, 6.31; N, 20.87%. Found: C, 53.61; H, 6.39; N, 20.91%.
4.5.2. 5-[(4,6-Dimethylpyrimidin-2-ylthio)methyl]-4-phenyl-2H-1,2,4-triazole-3(4H)-
thione (11b)
Yield 87%, mp 198–201◦C (2-propanol). IR, ν, cm−1: 3099 (NH), 1585, 1500 (C N, C C),
=
=
1
=
1332 (C S). H NMR (DMSO-d6) δ: 2.29 (s, 6H, CH3), 4.34 (s, 2H, SCH2), 6.95 (s, 1H, CH-
pyrimidine), 7.43–7.53 (m, 5H, Ph-H), 13.86 (s, 1H, NH); 13C NMR (DMSO-d6) δ: 23.98, 24.97,

410 M.M. Burbuliene et al.
117.09, 129.11, 129.98, 130.19, 134.01, 135.23, 150.31, 167.79, 168.14, 168.82. Anal. calcd. for
C15H5N5S2 (329.45): C, 54.69; H, 4.59; N, 21.26%. Found: C, 54.53; H, 4.61; N, 20.99%.
4.5.3. 4-Cyclohexyl-5-[(2-dimethylamino-6-methylpyrimidin-4-ylthio)methyl]-2H-1,2,4-
triazole-3-(4H)-thione (12a)
Yield 87%, mp 243–246◦C (2-propanol). IR, ν, cm−1: 3094 (NH), 1562, 1496 (C N, C C), 1342
=
=
1
=
(C S). H NMR (DMSO-d6) δ: 1.05–1.15, 1.58–1.60, 1.62–1.78 (3m, 10H, CH2-cyclohexyl),
2.22 (s, 3H, CH3), 3.13 (s, 6H, N(CH3)2), 4.32 (s br, 1H, CH-cyclohexyl), 4.69 (s, 2H, SCH2), 6.50
(s, 1H, CH-pyrimidine), 13.58 (s, 1H, NH); 13C NMR (DMSO-d6) δ: 22.99, 24.37, 25.25, 26.09,
29.25, 37.25, 56.93, 106.01, 149.91, 161.47, 166.15, 166.77, 167.19.Anal. calcd. for C16H24N6S2
(364.53): C, 52.72; H, 6.64; N, 23.05%. Found: C, 52.55; H, 6.88; N, 22.89%.
4.5.4. 5-[(2-Dimethylamino-6-methylpyrimidin-4-ylthio)methyl]-4-phenyl-2H-1,2,4-
triazole-3-(4H)-thione (12b)
Yield 88%, mp 205–206◦C (2-propanol). IR, ν, cm−1: 3099 (NH), 1560, 1501 (C N, C C),
=
=
1
=
1331 (C S). H NMR (CDCl3) δ: 2.26 (s, 3H, CH3), 3.11 (s, 6H, N(CH3)2), 4.41 (s, 2H, SCH2),
6.19 (s, 1H, CH-pyrimidine), 7.34–7.36 (m, 3H, Ph-H), 7.47–7.49 (m, 2H, Ph-H), 12.10 (s br,
1H, NH); 13C NMR (CDCl3) δ: 22.30, 24.19, 37.17, 105.78, 128.44, 129.92, 130.32, 133.25,
150.57, 161.26, 165.07, 166.30, 169.33. Anal. calcd. for C16H18N6S2: 358.49, C, 53.61; H, 5.06;
N, 23.44%. Found: C, 53.56; H, 5.11; N, 23.49%.
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