An efficient synthesis of [1,3,4]thiadiazolo[2,3-c ][1,2,4] triazin-4-ones

Article abstract of DOI:10.1080/17415993.2012.744408

A three-component reaction between 4-amino-6-methyl-3-thioxo-3,4-dihydro- 2H-[1,2,4]triazin-5-one, ammonium thiocyanate and aroyl chlorides in the presence of N-methylimidazole to afford the [1,3,4]thiadiazolo[2,3-c][1,2,4] triazin-4-ones in excellent yields is described.

Full text of DOI:10.1080/17415993.2012.744408

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An efficient synthesis of
[1,3,4]thiadiazolo[2,3-c][1,2,4]
triazin-4-ones
Razieh Mohebat a , Masoumeh Tabatabaee a & Mohammad Ashrafi
Bafghi a
a Department of Chemistry , Islamic Azad University , Yazd Branch,
PO Box 89195-155, Yazd , Iran
Published online: 27 Nov 2012.
To cite this article: Razieh Mohebat , Masoumeh Tabatabaee & Mohammad Ashrafi Bafghi (2013) An
efficient synthesis of [1,3,4]thiadiazolo[2,3-c][1,2,4] triazin-4-ones, Journal of Sulfur Chemistry,
34:4, 377-382, DOI: 10.1080/17415993.2012.744408
To link to this article: http://dx.doi.org/10.1080/17415993.2012.744408
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Journal of Sulfur Chemistry, 2013
Vol. 34, No. 4, 377–382, http://dx.doi.org/10.1080/17415993.2012.744408
An efficient synthesis of [1,3,4]thiadiazolo[2,3-c][1,2,4]
triazin-4-ones
Razieh Mohebat*, Masoumeh Tabatabaee and Mohammad Ashrafi Bafghi
Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
(Received 12 September 2012; final version received 25 October 2012)
A three-component reaction between 4-amino-6-methyl-3-thioxo-3,4-dihydro-2H-[1,2,4]triazin-5-one,
ammonium thiocyanate and aroyl chlorides in the presence of N-methylimidazole to afford the
[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-ones in excellent yields is described.
N
NH2
O
N
O
N
H3C
N
S
S
O
H
N
CH3
N
NH4 SCN
+
+
O
NH
Ar
Cl
N
Solvent-free,r.t.
N
N
H3C
Ar
Keywords: N-methylimidazole; aroyl chlorides; ammonium thiocyanate; AMTTO; three-component
reaction
1. Introduction
Triazines and their derivatives are important groups of heterocyclic compounds. They have
attracted considerable interest because of their exceptional biological antitumor (1, 2), anti-HIV
(3), antiviral (4), antimalarial (5), antibacterial (6), antifungal (7), and antioxidant activities (8).
Triazines have also found wide applications as herbicides (9, 10) and pesticides (11) in the field
of agriculture. In addition, a number of thiadiazole derivatives exhibit a broad range of biological
−
activities due to the presence of the NCS moiety (12). Bartlett et al. described 1,2,4-triazinones
as anti-inflammatory agents with immune modulating properties (13). They reported that these
compounds are effective not only in preventing, but also curing established arthritic disorders in
rats. They also reported that these compounds effectively inhibited the carrageenan-induced paw
edema, attenuated the activeArthus reaction, and demonstrated antierythema as well as antipyretic
activity. Part of the anti-inflammatory effects of these compounds is most probably related to their
*Corresponding author. Email: rozitakalami@yahoo.com
© 2013 Taylor & Francis

378 R. Mohebat et al.
antioxidative activity, as well as to the inhibition of lipoxygenase metabolites (13). As a result,
many efforts have been devoted to the development of new methodologies for efficient synthesis
of 1,2,4-triazinones (14, 15).
A few years ago, several substituted 4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-ones were
prepared by refluxing a solution of 4-amino-6-methyl-3-thioxo-3,4-dihydro-2H-[1,2,4]triazin-5-
one (AMTTO) and aroyl chlorides with potassium thiocyanate in acetonitrile for 4 h (16). Unlike
previously reported methods, the present method does not require toxic organic solvents and also
the experimental results show that the reaction times are shorter and the yields of the products
are higher under solvent-free conditions to produce the [1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-
4-one derivatives. As part of an ongoing development of efficient protocols for the preparation
of biologically active sulfur-containing heterocycles (17–24), we report here an efficient one-
pot synthesis of the [1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-ones, employing readily available
starting materials.
2. Results and discussion
Reaction of AMTTO 1 and aroyl chlorides 2 with ammonium thiocyanate 3 in the presence of N-
methylimidazole affords [1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-one derivatives 4 in excellent
yields (Scheme 1).
N
NH2
O
N
O
N
H3C
N
S
S
O
H
N
N
CH3
NH4SCN
3
+
+
O
NH
Ar
Cl
N
Solvent-free,r.t.
N
N
H3C
Ar
1
2
4
*
Ar
%Yield
2, 4
a
b
c
phenyl
80
83
o-CH3 C6H4
m-CH3 C6H4
p-Cl C6H4
p-Br C6H4
88
88
87
92
d
e
f
m-NO2 C6H4
yields
*
Isolated
Scheme 1. Three-component reaction between AMTTO, ammonium thiocyanate and aroyl
chlorides in the presence of N-methylimidazole.
Structures of compounds 4a–4f were confirmed by IR, 1H NMR, 13C NMR, and mass spectral
data. For example, the 1H NMR spectrum of 4b shows two sharp signals (δ = 2.42 and 2.45 ppm)
corresponded to the protons of the methyl groups. The aromatic protons resonated between 7.35–
8.04 ppm and a singlet signal was observed at δ = 13.75 ppm for an NH proton which disappears
after addition of a few drops of D2O to a DMSO solution of 4b.

Journal of Sulfur Chemistry 379
The 13C NMR spectrum of compound 4b shows 13 distinct signals, which is consistent with
the proposed structure. The mass spectrum of 4b displayed the molecular ion peak at m/z = 301.
The IR spectrum of compound 4b also supported the suggested structure, and strong absorption
bands were observed at 3200, 1700, and 1681 cm−1, respectively, for the NH and carbonyl groups.
A tentative mechanism for this transformation is proposed in Scheme 2.
N
N
S
O
O
_
N
+
N
1
CH3
2
3
+
Ar
Ar
N
N
C
S
CH3
N
_
6
5
O
Ar
NH
NH2
N
_
S
O
NH2
N
S
O
S
+
N
N
CH3
CH3
_
O
S
N
N
Ar
N
_
H
N
H3C
7
N
N
H3C
8
9
O
Ar
SH
HN
H
N
-H2S
S
O
N
4
N
N
H3C
Scheme 2. Suggested mechanism for the formation of compound 4.
It is conceivable that the reaction starts with the formation of aroyl thiocyanate 5, followed by
the formation of the 1:1 adducts 6 and its subsequent protonation by AMTTO to produce 7. Then,
the positively charged ion 7 is attacked by the anion of AMTTO 8. Intermediate 9 undergoes a
cyclization reaction and elimination of H2S to produce 4.
In conclusion, the reaction AMTTO and aroyl chlorides with ammonium thiocyanate in the
presence of N-methylimidazole led to [1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-one derivatives.
The present procedure has advantages such as shorter reaction times and simple work-up, and
affords excellent yields.
3. Experimental
Melting points were determined with an Electrothermal 9100 apparatus. Elemental analyses were
performed using a Costech ECS 4010 CHNS-O analyzer at analytical laboratory of Islamic Azad
University Yazd Branch. Mass spectra were recorded on an FINNIGAN-MAT 8430 mass spec-
trometer operating at an ionization potential of 70 eV. IR spectra were recorded on a Shimadzu
1
IR-470 spectrometer. H and 13C NMR spectra were recorded on a Bruker DRX-400 Avance
spectrometer. The chemicals used in this work were purchased from Fluka (Buchs, Switzerland)
and were used without further purification. Compound AMTTO 1 was prepared as previously
described in the literature (25).

380 R. Mohebat et al.
3.1. General procedure
Aroyl chloride (2 mmol) was added to ammonium thiocyanate (2 mmol) in a 50 ml flask at room
temperature (rt). The reaction mixture was stirred in a water bath at about 90 ◦C for 5 min. Then,
AMTTO (2 mmol) was added at this temperature. The reaction mixture was allowed to cool to
room temperature. Finally, N-methylimidazole (0.032 g) (10 mol%) was added via syringe. The
resulting mixture was stirred at rt for 2 h. The progress of the reaction was monitored by TLC.
After completion of the reaction, 15 ml distilled water was added for more than 5 min to the
reaction mixture. The resulting precipitate was collected by filtration on a Buchner funnel and
washed with 10 ml of cold diethyl ether to afford the pure title compounds.
3.1.1. N-(3-methyl 4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)benzamide (4a)
White powder; m.p. > 290 ◦C, IR (KBr) (νmax cm−1): 3205, 2980, 1702, 1670, 1599, 1564, 1374.
Analyses: Calcd for C12H9N5O2S: C, 50.17; H, 3.16; N, 24.38%. Found: C, 50.35; H, 3.03; N,
1
24.50. MS (m/z, %): 287 (M+, 5). H NMR (400 MHz, DMSO-d6): δ 2.44 (3H, s, CH3), 7.60
(2H, t, 3JHH = 7.6 Hz, 2CH of C6H5), 7.72 (1H, d, 3JHH = 7.6 Hz, 1CH of C6H5), 8.15 (2H, d,
3JHH = 7.6 Hz, 2CH of C6H5), 13.75 (1H, s, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 17.2
(CH3), 128.3, 129.1, 130.7, and 133.06 (phenyl moiety), 147.9 (C), 151.9 (C), 153.5 (C), 161.7
=
and 167.3 (2C O) ppm.
3.1.2. N-(3-methyl 4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)
2-methylbenzamide (4b)
White powder; m.p. > 270 ◦C, IR (KBr) (νmax cm−1): 3200, 2975, 1700, 1681, 1600, 1566, 1375.
Analyses: Calcd for C13H11N5O2S: C, 51.82; H, 3.68; N, 23.24%. Found: C, 51.73; H, 3.81; N,
1
23.15. MS (m/z, %): 301 (M+, 10). H NMR (400 MHz, DMSO-d6): δ 2.42 and 2.45 (6H, 2s,
2CH3), 7.35–7.38 (2H, m, 2 CH of C6H4CH3), 7.78 (1H, t, 3JHH = 7.6 Hz, 1CH of C6H4CH3),
3
8.04 (2H, d, JHH = 7.6 Hz, 2CH of C6H4CH3), 13.76 (1H, s, NH) ppm. 13C NMR (100 MHz,
DMSO-d6): δ 17.4 and 21.6 (2CH3), 126.9, 129.3, 130.2, 132.3, 134.9, and 138.8 (aryl moiety),
=
148.0 (C), 148.6 (C), 151.7 (C), 161.6 and 167.7 (2C O) ppm.
3.1.3. N-(3-methyl 4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)
3-methylbenzamide (4c)
White powder; m.p. > 280 ◦C, IR (KBr) (νmax cm−1): 3200, 2975, 1705, 1666, 1587, 1564, 1374.
Analyses: Calcd for C13H11N5O2S: C, 51.82; H, 3.68; N, 23.24%. Found: C, 51.93; H, 3.55;
1
N, 23.30. MS (m/z, %): 301 (M+, 7). H NMR (400 MHz, DMSO-d6): δ 2.43 and 2.49 (6H,
2s, 2CH3), 7.48 (2H, t, 3JHH = 7.6 Hz, 2CH of C6H4CH3), 7.54 (1H, d, 3JHH = 7.5 Hz, 1CH of
3
C6H4CH3), 7.91 (2H, d, JHH = 7.6 Hz, 2CH of C6H4CH3), 7.97 (1H, s, 1CH of C6H4CH3),
13.76 (1H, s, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 17.5 and 21.7 (2CH3), 126.9, 129.3,
130.2, 132.3, 134.9, and 138.8 (aryl moiety), 148.0 (C), 148.5 (C), 151.8 (C), 161.6 and 167.6
=
(2C O) ppm.
3.1.4. N-(3-methyl 4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)
4-chlorobenzamide (4d)
White powder; m.p. > 300 ◦C, IR (KBr) (νmax cm−1): 3250, 2965, 1705, 1666, 1587, 1551, 1374.
Analyses: Calcd for C12H8ClN5O2S: C, 44.80; H, 2.51; N, 21.77%. Found: C, 44.93; H, 2.61; N,

Journal of Sulfur Chemistry 381
21.59. MS (m/z, %): 321 (M+, 11). 1H NMR (400 MHz, DMSO-d6): δ 2.43 (3H, s, CH3), 7.83
3
3
(2H, d, JHH = 8.4 Hz, 2CH of C6H4Cl), 8.11 (2H, d, JHH = 8.4 Hz, 2CH of C6H4Cl), 13.77
(1H, s, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 17.4 (CH3), 128.7, 129.9, 134.1, and 139.1
=
(aryl moiety), 148.1 (C), 148.5 (C), 151.6 (C), 161.8 and 168.6 (2C O) ppm.
3.1.5. N-(3-methyl 4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)
4-bromobenzamide (4e)
White powder; m.p. > 300 ◦C, IR (KBr) (νmax cm−1): 3250, 2980, 1707, 1665, 1589, 1556, 1376.
Analyses: Calcd for C12H8BrN5O2S: C, 39.36; H, 2.20; N, 19.12%. Found: C, 39.20; H, 2.14;
N, 19.26. MS (m/z, %): 366 (M+, 5). 1H NMR (400 MHz, DMSO-d6): δ 2.43 (3H, s, CH3), 7.93
3
3
(2H, d, JHH = 8.4 Hz, 2CH of C6H4Br), 8.06 (2H, d, JHH = 8.4 Hz, 2CH of C6H4Br), 13.76
(1H, s, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 17.4 (CH3), 126.7, 129.8, 132.1, and 136.1
=
(aryl moiety), 148.2 (C), 148.6 (C), 151.5 (C), 161.8 and 168.7 (2C O) ppm.
3.1.6. N-(3-methyl 4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)
3-nitrobenzamide (4f)
White powder; m.p. > 310 ◦C, IR (KBr) (νmax cm−1): 3230, 1697, 1675, 1596, 1524, 1497, 1457,
1378. Analyses: Calcd for C12H8N6O4S: C, 43.37; H, 2.43; N, 25.29%. Found: C, 43.51; H, 2.30;
N, 25.48. MS (m/z, %): 332 (M+, 9). 1H NMR (400 MHz, DMSO-d6): δ 2.43 (3H, s, CH3), 7.76
(2H, t, 3JHH = 7.6 Hz, 2CH of C6H4NO2), 8.32 (1H, d, 3JHH = 8.0 Hz, 1CH of C6H4NO2), 8.51
(2H, d, 3JHH = 7.6 Hz, 2CH of C6H4NO2), 8.89 (1H, s, 1CH of C6H4NO2), 13.76 (1H, s, NH)
ppm. 13C NMR (100 MHz, DMSO-d6): δ 17.6 (CH3), 123.2, 125.7, 130.2, 134.9, 140.0, and 148.2
=
(aryl moiety), 148.4 (C), 151.1 (C), 153.8 (C), 161.9 and 169.1 (2C O) ppm.
Acknowledgement
We gratefully acknowledge financial support from the Research Council of Islamic Azad University of Yazd of Iran.
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