Syntheses of diheterocyclic compounds based on 2-thioacetohydrazide-5,7- dimethyl-1,2,4-triazolo[1,5-a]-pyrimidine

Article abstract of DOI:10.3390/molecules13061353

The syntheses of some diheterocyclic compounds from 2-thioacetohydrazide-5, 7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (1) are described. Compound 1 can be converted into triazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles. The structures of the intermediates and the target compounds were confirmed by ¹H-NMR, MS and elemental analyses.

Full text of DOI:10.3390/molecules13061353

Molecules 2008, 13, 1353-1360; DOI: 10.3390/molecules13061353
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molecules
ISSN 1420-3049
www.mdpi.org/molecules
Article
Syntheses of Diheterocyclic Compounds Based on
2-Thioacetohydrazide-5,7-dimethyl-1,2,4-triazolo[1,5-a]-
pyrimidine
Zu-Ming Liu, Qiong Chen, Chao-Nan Chen, Hai-Yang Tu * and Guang-Fu Yang
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, P. R. China; http://klpcb.ccnu.edu.cn/
* Author to whom correspondence should be addressed; E-mail: haiytu@mail.ccnu.edu.cn
Received: 6 May 2008; in revised form: 26 May 2008 / Accepted: 26 May 2008 / Published: 13 June
2008
Abstract: The syntheses of some diheterocyclic compounds from 2-thioacetohydrazide-
5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (1) are described. Compound 1 can be
converted into triazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles. The structures of the
1
intermediates and the target compounds were confirmed by H-NMR, MS and elemental
analyses.
Keywords: 1,2,4-Triazolo[1,5-a]pyrimidine, triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazoles
Introduction
The study of nitrogen-containing heterocycles is currently a hot topic in pesticide chemistry [1-7].
In particular the chemistry of 1,2,4-triazolo[1,5-a]pyrimidine derivatives has been of considerable
interest for many years [8]. In 1935, 5-methyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine was found to
be an excellent stabilizer for photographic emulsions. Since then, various derivatives of 1,2,4-
triazolo[1,5-a]pyrimidine have found applications in pharmaceutical and agricultural chemistry and
other areas [9-10]. On the other hand, a wide range of biological activities have been attributed to
compounds containing 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole and

Molecules 2008, 13
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1,2,4-triazole rng systems [11-14]. If these heterocycles are introduced into the 1,2,4-triazolo[1,5-a]-
pyrimidine ring, the linked diheterocyclic compounds might display interesting biological activity, so
as a part of our research work aimed at searching for novel agrochemicals, our interest in
diheterocyclic compounds containing 1,2,4-triazolo[1,5-a]pyrimidine moieties lead us to study the
syntheses of the some diheterocyclic compounds based on the use of 2-thioacetohydrazide-5,7-
dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (1) as the starting material.
Results and Discussion
2-Thioacetohydrazide-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (1) was prepared according to
our previous procedure [5]. At room temperature, compound 1 reacted with CS2 in ethanol in the
presence of potassium hydroxide, followed by treatment with hydrazine hydrate at reflux to afford
1
compound 2. The structure of 2 was confirmed by its H-NMR spectrum and elemental analysis. The
NMR spectrum showed the methylene, amino and mercapto group protons as three singlets, at δ 4.56
ppm (SCH2), 5.66 ppm (NH2) and 13.67 ppm (SH), respectively.
Alkylation of 2 with alkyl halides afforded compounds 3 in good yields, whose structures were
confirmed by their 1H-NMR spectra and elemental analysis. In ethanol solution and in the presence of
HCl, 2 reacted with aromatic aldehydes to give a difused heterocyclic compound 4. The pH value of
the reaction solution influenced the yield of the product and experimental results showed that the best
1
pH value was 4~6. In the H-NMR spectrum of compound 4, the signals of the NH and methenyl
(SCH) groups were observed as two singlets at δ 13.7~14.0 ppm (NH) and 9.50~ 10.90 ppm (SCH),
respectively. The presence of these NH and SCH signals demonstrated the formation of 5,6-
dihydrogen-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole moiety.
Compound 1 was also refluxed with carbon disulfide in ethanol in the presence of potassium
1
hydroxide with subsequent treatment with hydrochloric acid. The H-NMR spectrum and elemental
analysis data of the isolated product were consistent with the 1,3,4-oxadiazole structure 5. Compound
5 reacted with alkyl halides in the presence of sodium hydroxide to afford compounds 6. The reaction
of 5 with alkyl halides is a typical nucleophilic substitution process and the experimental results
indicated that the reactivity of the alkyl halide determined the reaction time and the yields. For
example, intermediate 5 reacted with p-nitrobenzyl chloride under basic conditions at room
temperature to give compound 6a in yield 56% after 2 hours, but no product was observed when
intermediate 5 reacted with 1-bromocyclohexane under the same conditions. Interestingly, compound
2 can also be obtained in 42% yield by refluxing compound 5 with hydrazine hydrate in methanol.
Heating compound 1 with benzoic acid in the presence of phosphoryl chloride afforded
1
diheterocyclic compound 7 in 66% yield. The structure of 7 was established by H-NMR and
elemental analysis. For example, the proton spectrum showed two methyl protons as two singlets at δ
2.64 ppm (5-CH3) and 2.73 (7-CH3), respectively. The SCH2 group protons and 6-protons in the 1,2,4-
triazolo-[1,5-a]pyrimidine moiety displayed two singlets at δ 4.82 ppm (SCH2) and 6.76 ppm (6-H),
respectively. The phenyl protons displayed a multiplet at δ 7.47-8.01 ppm (C6H5).
Furthermore, 2-thioacetohydrazide-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine 1 can react with
carbon disulfide in ethanol in presence of potassium hydroxide at room temperature with subsequent
treatment with concentrated H2SO4 to afford a cyclization product 8 containing a 1,3,4-thiadiazole

Molecules 2008, 13
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moiety, which was then alkylated with alkyl halides to give the corresponding compounds 9 in good
yields. The factors affecting the yields and the reaction time for these alkylations of 8 were similar to
those of the reaction of 5 with alkyl halides.
Scheme 1. Synthesis of diheterocyclic compounds based on compound 1.
CH3
CH3
CH3
N
N
N
S
N
N
N
S
N
N
N
N
N
N
N
N
N
N
i
SCH2
8
SCH2
SCH2
H3C
N
SH
H3C
N
SR
H3C
N
SR
NH2
9a~c
3a~c
a, R = C6H5CH2
b, R = p-NO2C6H4CH2
c, R = p-ClC6H4CH2
a, R = C6H5CH2
b, R = p-NO2C6H4CH2
c, R = p-ClC6H4CH2
b
h
CH3
CH3
CH3
O
N
N
N
O
N
N
N
N
N
N
g
N
N
N
N
N
a
e
SCH2C
NHNH2
SCH2
7
SCH2
2
H3C
N
H3C
N
Ph
H3C
N
SH
1
NH2
d
c
CH3
CH3
CH3
N
N
N
O
N
N
N
N
N
N
N
N
N
N
f
SCH2
SCH2
SCH2
N
O
N
N
H3C
N
SR
H3C
N
SH
H3C
N
S
HN
6a~b
5
4a~c
Ar
a, R = p-CH3OC6H4
b, R = p-CH3C6H4
c, R = o-FC6H4
a, R = p-NO2C6H4CH2
b, R = o-ClC6H4CH2
a: (i) CS2, KOH, r.t; (ii) NH2NH2.H2O, reflux; b: RX, NaOH, r.t; c: ArCHO, HCl,
reflux; d: CS2, KOH, reflux; e: NH2NH2.H2O, reflux; f: RX, NaOH, r.t; g: PhCOOH,
POCl3, reflux; h: (i) CS2, KOH, r.t; (ii) H2SO4 (conc.); i: RX, NaOH, r.t.
Experimental
General
Melting points were measured with a Buchi melting point apparatus and are uncorrected. TLC was
performed on Merck 60 F254 silica gel-coated aluminum sheets and spots were detected by UV light
1
(254 nm).The H-NMR spectra were recorded on a Varian MERCURY-PLUS 400 instrument using
the indicated solvents and TMS as an internal standard. MS spectra were recorded on a Hewlett-
Packard 5988A instrument. Elemental analyses were performed on a Vario El III CHNS instrument.
All solvents and materials were reagent grade and purified as required. 2-Thioacetohydrazide-5,7-
dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (1) was prepared as described in our published procedure [5].

Molecules 2008, 13
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4-Amino-3-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-1,2,4-triazol-5-thiol (2)
Method A: To a solution of potassium hydroxide (5.0 g, 0.09 mol) and 2-thioacetohydrazide-5,7-
dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (1, 15.1 g, 0.06 mol) in ethanol (450 mL), carbon disulfide
(10 mL, 0.16 mol) was added dropwise over a period of half hour at room temperature. The resulting
mixture was stirred for 10 hours at room temperature and the precipitate formed was collected by
filtration. After washing with ethanol and ethyl ether, the salt formed was dissolved in a solution of
ethanol (300 mL) and hydrazine hydrate (85%, 15 mL, 0.26 mol), and then refluxed for 4 hours. After
cooling, the mixture was filtered and the filtrate was poured into water (100 mL), acidified with HCl,
and the precipitate thus formed was filtered off and crystallized from ethanol to give pure product 2 as
a white solid in 38% yield, m.p. 228~229 oC. 1H-NMR δ (DMSO-d6): 2.56 (s, 3H, CH3), 2.67 (s, 3H,
CH3), 4.56 (s, 2H, SCH2), 5.66 (s, 2H, NH2), 7.12 (s, 1H, CH), 13.67 (s, 1H, SH); Anal. calcd. for
C10H12N8S2 (308.37): C, 38.96; H, 3.90; N, 36.36. Found: C, 38.69; H, 3.77; N, 36.52.
Method B: Compound 5 (0.01 mol, 2.94 g), prepared as indicated below, was refluxed with an
equimolar amount of 80% hydrazine hydrate in methanol (25 mL) for 2 hours. The solution was
partially concentrated and cooled and the precipitate formed was filtered off and recrystallized from
ethanol, yield: 27%.
5-Alkylthio-4-amino-3-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-1,2,4–triazoles
3a~c
A mixture of RX (5.6 mmol) and methanol (or DMF, 5 mL) was added dropwise to a stirred
solution of compound 2 (1.6 g, 5.0 mmol) and sodium hydroxide (0.2 g, 5.6 mmol) in water (15 mL).
The resulting mixture was stirred at room temperature for 2 hours. The precipitate formed was filtered
off and recrystallized from ethanol to give the pure title compounds in good yields.
3a: (R = C6H5CH2): m.p. 114~115 oC; yield 82%; 1H-NMR δ(CDCl3): 2.60 (s, 3H, CH3), 2.70 (s, 3H,
CH3), 4.29(s, 2H, SCH2), 4.55(s, 2H, SCH2), 6.71(s, 2H, NH2), 7.18(s, 1H, CH), 7.21 (m, 5H, C6H5);
Anal. calcd. for C17H18N8S2 (398.50): C, 51.19; H, 4.52; N, 28.11; Found: C, 51.42; H, 4.37; N, 28.40.
3b: (R = p-NO2C6H4CH2): m.p. 227~228 oC; yield 78%; 1H-NMR δ (CDCl3): 2.53 (s, 3H, CH3), 2.62
(s, 3H, CH3), 4.47 (s, 2H, SCH2), 4.56 (s, 2H, SCH2), 6.09 (s, 2H, NH2), 7.07 (s, 1H, CH), 7.59~8.08
(m, 4H, C6H4); Anal. calcd. for C17H17N9O2S2 (443.50): C, 45.99; H, 3.83; N, 28.41; Found: C, 45.67;
H, 4.02; N, 28.76.
o
1
3c: (R = p-ClC6H4CH2): m.p. 175~176 C; yield 82.5%; H-NMR δ (CDCl3): 2.62 (s, 3H, CH3), 2.71
(s, 3H, CH3), 4.31 (s, 2H, SCH2), 4.56 (s, 2H, SCH2), 5.05 (s, 2H, NH2), 7.07 (s, 1H, CH), 7.19~7.27
(m, 4H, C6H4); Anal. calcd. for C17H17N8ClS2 (432.94): C, 47.12; H, 3.93; N, 25.87; Found: C, 46.88;
H, 3.77; N, 26.24.

Molecules 2008, 13
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3-(5,7-Dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-6-aryl-5,6-dihydrogen-1,2,4-triazolo-
[3,4-b]-1,3,4-thiadiazoles 4a-c
The appropriate aryl aldehyde (3.3 mmol) was added to a solution of 2 (1.0 g, 3.3 mmol) and
ethanol (60 mL) and the pH value of the mixture was then adjusted to 4~6 with an ethanol solution
saturated with HCl gas. The resulting mixture was refluxed for 6~7 hours. After cooling, the
precipitate was filtered off and crystallized from DMF/ethanol to give pure products as white solids in
excellent yields.
4a (Ar = p-CH3OC6H4): m.p. 246~247 oC; yield 80%; 1H-NMR δ (DMSO-d6): 2.51 (s, 3H, CH3), 2.55
(s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.66 (s, 2H, SCH2), 7.01 (s, 1H, CH), 6.88~7.65 (m, 4H, C6H4), 9.56
(s, 1H, SCH), 13.84(s, 1H, NH); Anal. calcd. for C18H18N8OS2 (426.51): C, 50.64; H, 4.22; N, 26.26;
Found: C, 50.49; H, 3.97; N, 26.50.
o
1
4b (Ar = p-CH3C6H4): m.p. 240~241 C; yield 86%; H-NMR δ (DMSO-d6): 2.50 (s, 3H, CH3), 2.52
(s, 3H, CH3), 2.54 (s, 3H, CH3), 4.66 (s, 2H, SCH2), 6.99 (s, 1H, CH), 7.12~7.56 (m, 4H, C6H4), 9.69
(s, 1H, SCH), 13.83 (s, 1H, NH); Anal. calcd. for C18H18N8S2 (410.51): C, 52.62; H, 4.38; N, 27.28;
Found: C, 52.83; H, 4.59; N, 27.61.
4c (Ar = o-FC6H4): m.p. 237~239 oC; yield 83.7%; 1H-NMR δ (DMSO-d6): 2.51 (s, 3H, CH3), 2.59 (s,
3H, CH3), 4.70 (s, 2H, SCH2), 7.02 (s, 1H, CH), 7.15~7.90 (m, 4H, C6H4), 10.43 (s, 1H, SCH),
13.91(s, 1H, NH); Anal. calcd. for C17H15N8FS2 (414.47): C, 49.22; H, 3.62; N, 27.02; Found: C,
49.50; H, 3.89; N, 27.33.
2-(5,7-Dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-1,3,4-oxadiazol-5-thiol (5)
Compound 1 (5.0 g, 0.02 mol) was added to a solution of KOH (1.3 g, 0.024 mol) in anhydrous
EtOH (160 mL). A solution of CS2 (2.0 g, 0.03 mol) in anhydrous EtOH (40 mL) was then added
dropwise to the vigorously stirred mixture, which was refluxed for 6 hours. The solvent was removed
under reduced pressure and the residue was dissolved in water (100 mL). After acidification to pH 5~6
with glacial acetic acid the crude product was isolated by filtration and recrystallized from
1
ethanol/petroleum ether to afford 5.5 g of pure 5 as white crystals; m.p. 203-204 °C; yield: 94%; H-
NMR δ (CDCl3): 2.50 (s, 1H, SH), 2.55 (s, 3H, 5-CH3), 2.65 (s, 3H, 7-CH3), 4.65 (s, 2H, SCH2), 7.15
(s, 1H, 6-H); Anal. calcd. for C10H10N6OS2 (294.34): C, 40.82; H, 3.40; N, 28.57; Found: C, 40.67; H,
3.51; N, 28.68.
2-(5,7-Dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-5-alkylthio-1,3,4-oxadiazoles 6a~b
To a stirred solution of 5 (1.5 g, 5.1 mmol) and sodium hydroxide (0.2 g, 5.6 mmol) in water (15
mL), a mixture of a substituted benzyl chloride (5.6 mmol) and methanol (5 mL) was added dropwise.
The resulting mixture was stirred at room temperature for 2 hours. The precipitate formed was filtered
off and recrystallized from petroleum ether/acetone to give 6 in good yields.

Molecules 2008, 13
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o
1
6a: (R = p-NO2C6H4CH2): m.p. 132~133 C; yield 56.3%; H-NMR δ (CDCl3): 2.58 (s, 3H, 5-CH3),
2.65 (s, 3H, 7-CH3), 4.41 (s, 2H, CH2C6H4), 4.64 (s, 2H, SCH2), 6.72 (s, 1H, 6-H), 7.51-8.08 (q, 4H,
Ar-H); MS (m/z): 429 (M+, 1), 293 (4), 262 (15), 261 (100), 221 (3), 219 (7), 193 (11), 180 (6), 149
(5), 148 (2), 136 (4), 108 (23), 107 (14); Anal. calcd. for C17H15N7O3S2 (429.47): C, 47.55; H, 3.50; N,
22.84; Found: C, 48.34; H, 3.96; N, 22.97.
6b: (R = o-ClC6H4CH2): m.p. 133~135 oC; yield 75%; 1H-NMR δ (CDCl3): 2.65 (s, 3H, 5-CH3), 2.72
(s, 3H, 7-CH3), 4.38 (s, 2H, CH2C6H4), 4.72 (s, 2H, SCH2), 6.77 (s, 1H, 6-H), 7.23-7.39 (q, 4H, Ar-H);
Anal. calcd. for C17H15N6OClS2 (418.91): C, 48.69; H, 3.58; N, 20.05; Found: C, 48.81; H, 3.75; N,
20.43.
2-(5,7-Dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-5-phenyl-1,3,4-oxadiazole (7)
A mixture of 1 (1.0g, 4.0 mmol), benzoic acid (0.55 mL, 6 mmol) and POCl3 (5 mL) was refluxed
for 6 hours. After cooling to room temperature, the mixture was poured into crushed ice and filtered.
The solid was washed with sodium hydroxide solution (5%) and water (x 3) and recrystallized from
EtOH to afford yellow crystals (0.9 g, 66% yield); m.p. 171-173 oC; 1H-NMR δ (CDCl3): 2.64 (s, 3H,
5-CH3), 2.73 (s, 3H, 7-CH3), 4.82 (s, 2H, SCH2), 6.76 (s, 1H, 6-H), 7.47-8.01 (m, 5H, Ar-H); Anal.
calcd. for C16H14N6OS: C, 56.80; H, 4.14; N, 24.85; Found: C, 57.13; H, 3.87; N, 24.69.
2-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-1,3,4-thiadiazol-5-thiol (8)
To a solution of potassium hydroxide (4.68 g, 0.08 mol) and 2-thioacetohydrazide-5,7-dimethyl-
1,2,4-triazolo[1,5-a]pyrimidine (1, 15.1 g, 0.09 mol) in ethanol (250 mL), carbon disulfide (10 mL,
0.16 mol) was added dropwise at room temperature over a period of half an hour. The resulting
mixture was stirred for 12 hours at room temperature and the precipitate formed was collected by
filtration. After washing with ethanol and ethyl ether, the salt formed was added to concentrated
H2SO4 (90 mL). The mixture was stirred at room temperature for 4 hours, poured into crushed ice (250
g) and the precipitate formed was filtered off and dissolved in NaOH solution (250 mL, 2.4 g). After
filtration the filtrate was acidified with HCl, and the precipitate thus formed was filtered off and
o
1
crystallized from ethanol to give pure 8 as yellow crystals (42%); m.p. 217~219 C; H-NMR δ
(CD3COCD3): 2.60 (s, 3H, CH3), 2.76 (s, 3H, CH3), 4.67 (s, 2H, SCH2), 7.09 (s, 1H, CH), 13.89 (s,
1H, SH); Anal. calcd. for C10H10N6S3 (310.40): C, 38.66; H, 3.22; N, 27.06; Found: C, 38.43; H, 3.51;
N, 27.40.
2-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-5-alkylthio-1,3,4-thiadiazoles 9a~c
To a stirred solution of 8 (1.6 g, 5.1 mmol) and sodium hydroxide (0.2 g, 5.6 mmol) in water (15
mL), a mixture of substituted benzyl chloride (5.1 mmol) in methanol (5 mL) was added dropwise.
The resulting mixture was stirred at room temperature for 2.5 hours. The precipitate formed was
filtered off and recrystallized from petroleum ether/acetone to give 9 in fair to good yields.

Molecules 2008, 13
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9a (R = C6H5CH2): m.p. 118~120 oC; yield 86%; 1H-NMR δ (CDCl3): 2.65 (s, 3H, CH3), 2.73 (s, 3H,
CH3), 4.50 (s, 2H, SCH2), 4.84 (s, 2H, SCH2), 6.78 (s, 1H, CH), 7.25~7.38 (m, 5H, C6H5); MS (m/z):
400 (M+, 9), 309 (1), 237 (8), 181 (11), 180 (7), 149 (9), 148 (9), 91 (100), 67 (17); Anal. calcd. for
C17H16N6S3 (400.53): C, 50.93; H, 3.99; N, 17.98; Found: C, 51.17; H, 4.26; N, 27.65.
o
1
9b (R = p-NO2C6H4CH2): m.p. 145~146 C; yield 68%; H-NMR δ (CDCl3): 2.65 (s, 3H, CH3), 2.72
(s, 3H, CH3), 4.56 (s, 2H, SCH2), 4.83 (s, 2H, SCH2), 6.78 (s, 1H, CH), 7.56~8.14 (m, 4H, C6H4); MS
(m/z): 446 (M+, 7), 309 (10), 237 (25), 219 (12), 149 (26), 148 (20), 136 (15), 107 (60), 46 (24), 32
(100); Anal. calcd. for C17H15N7O2S3 (445.53): C, 45.79; H, 3.37; N, 21.99. Found: C, 45.97; H, 3.65;
N, 22.33.
1
9c (R = p-ClC6H4CH2): m.p. 146~147oC; yield 44%; H-NMR δ (CDCl3): 2.65 (s, 3H, CH3), 2.72 (s,
3H, CH3), 4.45 (s, 2H, SCH2), 4.84 (s, 2H, SCH2), 6.78 (s, 1H, CH), 7.24~7.34 (m, 4H, C6H4); MS
(m/z): 435 (M+, 7), 309 (4), 237 (10), 193 (3), 181 (19), 125 (100), 108 (14), 107 (25); Anal. calcd. for
C17H15N6ClS3 (434.97): C, 46.89; H, 3.45; N, 19.31; Found: C, 46.61; H, 3.23; N, 19.64.
Acknowledgements
This work was supported by National Natural Science Foundation of China (No. 20572030,
20432010, 20528201, and 20672044), Key project of Ministry of Education (Nos. 103116 and
104205), Program for New Century Excellent Talents in University of China and Program for
Excellent Research Group of Hubei Province (No. 2004ABC002)
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Sample Availability: Samples of the compounds are available from the authors.
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