Synthesis and biological activity of 3-[4H-(1,2,4)-Triazolyl]-2,6-diaryl-1, 3,5-oxadiazine-4-thione

Article abstract of DOI:10.1080/10426500802487789

4-Amino-1,2,4-triazole (1) undergoes facile condensation with aromatic aldehydes to afford the corresponding 4-(arylidene-amino)-4H-[1,2,4]-triazole (2a-h) in good yield. Rearrangement of compounds (2a-h) with benzoyl isothiocyanate/4-chloro-benzoyl isoth

Full text of DOI:10.1080/10426500802487789

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Synthesis and Biological
Activity of 3-[4H-(1,2,4)-
Triazolyl]-2,6-diaryl-1,3,5-
oxadiazine-4-thione
Hasmukh S. Patel a & Ketan B. Patel a
a Department of Chemistry , Sardar Patel
University , Vallabh Vidyanagar, Gujarat, India
Published online: 04 Sep 2009.
To cite this article: Hasmukh S. Patel & Ketan B. Patel (2009) Synthesis and Biological
Activity of 3-[4H-(1,2,4)-Triazolyl]-2,6-diaryl-1,3,5-oxadiazine-4-thione, Phosphorus,
Sulfur, and Silicon and the Related Elements, 184:9, 2443-2452
To link to this article: http://dx.doi.org/10.1080/10426500802487789
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Phosphorus, Sulfur, and Silicon, 184:2443–2452, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802487789
Synthesis and Biological Activity of 3-[4H-(1,2,4)-
Triazolyl]-2,6-diaryl-1,3,5-oxadiazine-4-thione
Hasmukh S. Patel and Ketan B. Patel
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar,
Gujarat, India
4-Amino-1,2,4-triazole (1) undergoes facile condensation with aromatic aldehydes
to afford the corresponding 4-(arylidene-amino)-4H-[1,2,4]-triazole (2a–h) in good
yield. Rearrangement of compounds (2a–h) with benzoyl isothiocyanate/4-chloro-
benzoyl isothiocyanate/2,4-dichloro-benzoyl isothiocyanate yields corresponding
1,3,5-oxadiazine derivatives (3). Structural elucidation of these compounds was
based on elementary analysis and spectral data studies. The newly synthesized
compounds were evaluated for their antibacterial activities.
Keywords 4-Amino-1,2,4-triazole; antibacterial activity; 1,3,5-oxadiazine
INTRODUCTION
4-Amino-1,2,4-triazole1 and their condensed products2−5 are the start-
ing materials for the synthesis of a wide variety of heterocyclic deriva-
tives, which are of great importance in medicinal chemistry.6−8 Many
reports of the synthesis of N-arylideneamino-1,2,4-triazole derivatives
are currently known.9−11 These compounds display diverse biological
activity, including antibacterial, antifungicidal, analgesic, and anti-
inflammatory activity.12−14 These heterocyclic systems find wide use
in medicine, agriculture, and industry. The 1,3,5-oxadiazine deriva-
tives can be synthesized by 1,4-cycloaddition of benzoyl isothiocyanate
with a Schiff’s base.15,16 1,3,5-Oxadiazine derivatives act as a herbi-
cides, which was reported by Japanese scientists.17 The microwave-
assisted synthesis of 1,3,5-oxadiazine derivatives has been attempted
Received 21 May 2008; accepted 18 September 2008.
The authors are thankful to the Head, Department of Chemistry, for providing lab-
oratory facilities and Kemrock Industries and Exports Limited, Baroda, Gujarat, India
for providing necessary financial assistance.
Address correspondence to Hasmukh S. Patel, Department of Chemistry,
Sardar Patel University, Vallabh Vidyanagar, Gujarat, India 388 120. E-mail:
hsp13152@rediffmail.com
2443

2444
H. S. Patel and K. B. Patel
successfully.18 1,3,5-oxadiazine derivatives are employed as an additive
in textile finishing or cleaning.19 1,3,5-Oxadiazine derivatives are also
reported as pesticides or fungicides.20 Recently, the coumarin ring
containing 1,3,5-oxadiazine has been reported.21 Hence, the present
communication comprises the synthesis of 3-[4H-(1,2,4)-triazolyl]-2,6-
diaryl-1,3,5-oxadiazine-4-thione (3) and is shown in Scheme 1.
SCHEME 1 Where Ar = (a) C6H5, (b) 4-OH-C6H4, (c) 2-OH-C6H4, (d) 4-OCH3-
C6H4, (e) 4-OH-3-OCH3-C6H3, (f) 4-Cl-C6H4, (g) 2-NO2-C6H4, (h) 5-Br-2-OH-
C6H3. Ph = (x) C6H5, (y) 4-chloro-C6H4, (z) 2,4-di chloro-C6H3.
RESULTS AND DISCUSSION
The structures of 4-(arylidene-amino)-4H-[1,2,4]-triazoles (2a–h) were
confirmed by elemental analysis and IR spectra showing absorption
bands at 1620–1640 cm−1 (C N), ∼1040 cm−1 (N N of triazole), 3250–
3300 cm−1 (C H of triazole and C H of arylidene), 3030–3080 cm−1
(C H of Ar), 1475–1525 cm−1 (C C of Ar), 1575–1625 cm−1 (C C of
Ar), and additional peaks appear due to the substitution in the aromatic
ring showing absorption band at ∼1230 cm−1 (C O), 3450–3550 cm−1

Antibacterial Activity
2445
(O H), 2815–2850 cm−1 (C H of OCH3), ∼1095 cm−1 (C Cl), 1310–
1340 and 1490–1560 cm−1 ( NO2), ∼1075 cm−1 (C Br). All spectra
comprise the expected NMR signals, including 9.5–10.2 (t, 2H of CH N
of triazole and 1H of CH N of arylidene), 7.5–7.8 (m, aromatic proton),
whereas the additional signals appear due to substitution in the aro-
matic ring with signals at 5.1–5.3 (s, H of OH) and 3.7–3.9 (s, H of
OCH3). The C, H, N analysis and 1H NMR data of all compounds are
presented in Table I.
The structures assigned to 3-[4H-(1,2,4)-triazolyl]-2,6-diaryl-1,3,5-
oxadiazine-4-thione (3) were supported by the elemental analysis and
IR spectra showing same absorption bands as in (2a–h) with additional
bands at 1000–1400 cm−1 (C N of oxadiazine), 1350 cm−1 (C S of oxa-
diazine), 1300 cm−1 (C O C of oxadiazine). All the compounds show
the expected NMR signals for different kinds of protons at their re-
spective positions, which are same as in (2a–h) with additional NMR
signals: 4.3 (s, C2 H of oxadiazine), which confirmed the structures of
oxadiazine derivatives. The C, H, N, S analysis and 1H NMR data of all
compounds are presented in Tables II, III, and IV.
An examination of data reveals that the elemental contents are con-
sistent with the predicted structure (3) shown in Scheme 1. The IR and
NMR data also confirm the assignment of the predicted structure. The
final structure of all compounds is confirmed by LC-MS data of selected
samples. The LC-MS of selected samples 3ax and 3fx give molecular
ion peaks (m/z) at 337 and 370, respectively. These values correspond
to their molecular weights.
The antibacterial activity of series (3) was carried out against some
strains of bacteria. The results show that the prepared compounds are
toxic against the bacteria. The comparison of the antibacterial activ-
ity of these compounds with ampicillin (standard) shows that these
compounds have almost similar activity.
BIOLOGICAL SCREENING
Antibacterial Activities
The antibacterial activities of all the compounds were studied against
gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus)
and gram-negative bacteria (Escherichia coli, Salmonella typhi, and
Klebsiella pneumoniae) at a concentration of 50 µg/ML by the agar cup
plate method. A methanol system was used as control in this method.
Under similar conditions, ampicillin was used as a standard drug for
comparison. The area of inhibition zone is measured in centimeters.
Compounds 3fy, 3fz, and 3hz were found to be more active against the

2446

2447

2448

2449

2450
H. S. Patel and K. B. Patel
TABLE V Antibacterial Activity of Compounds (3a–h)
Zone of inhibition
Gram +Ve
Gram –Ve
Bacillus Staphylococcus
Klebsiella
pneumoniae
Salmonella
typhi
Escherichia
coli
Compounds
subtilis
aureus
3ax
3bx
3cx
3dx
3ex
3fx
3gx
3hx
3ay
3by
3cy
3dy
3ey
3fy
3gy
3hy
3az
3bz
3cz
3dz
3ez
3fz
05
09
10
07
11
15
12
14
07
07
09
07
15
17
17
15
05
09
12
10
12
19
16
18
19
06
08
09
06
10
13
11
12
05
08
09
06
11
15
12
13
07
11
12
09
13
21
15
19
15
04
06
07
05
08
09
09
10
04
06
07
05
09
13
10
12
05
11
10
07
11
14
12
13
20
06
08
09
07
10
14
12
13
02
04
05
03
07
12
09
11
04
08
09
05
10
13
11
14
21
08
12
13
09
12
15
13
14
02
07
09
03
10
14
12
13
06
09
07
04
09
18
10
16
17
3gz
3hz
Ampicillin
above microbes. Other compounds were found to be less or moderately
active compared to ampicillin (Table V).
CONCLUSION
The synthesis of compounds 3-[4H-(1,2,4)-triazolyl]-2,6-diaryl-1,3,5-
oxadiazine-4-thione (3) has been done successfully. Both the moi-
eties 1,2,4-triazole and 1,3,5-oxadiazine have important applications
in medicinal use; the compounds (3) produced may act as good biologi-
cal compounds.

Antibacterial Activity
2451
EXPERIMENTAL
Melting points were determined in open capillary tubes and are un-
corrected. The IR spectra were recorded in KBr pellets on a Nicolet
1
400D spectrometer and H NMR and spectra were recorded in DMSO
with TMS as internal standard on a Brucker spectrometer at 400 MHz.
LC-MS of selected samples taken on LC-MSD-Trap-SL-01046.
Preparation of 4-(Arylidene-amino)-4H-[1,2,4]-triazole (2a–h)
An equimolecular mixture of 4-amino-1,2,4-triazole (1), (0.84 g, 0.01
mol) and the aromatic aldehyde (a–h) in ethanol (15 mL) and conc.
H2SO4 (0.4 mL) was refluxed in a water bath for 1–2 h. The solid that
separated was collected by filtration, dried, and recrystallized from
ethanol. The yields, melting points, and other characterization data of
these compounds are given in Table I.
Preparation of 3-[4H-(1,2,4)-Triazolyl]-2,6-diaryl-1,3,5-
oxadiazine-4-thione (3)
A mixture of 4-(arylidene-amino)-4H-[1,2,4]-triazole (2a–h) (0.01
mol), benzoyl isothiocyanate22 (0.01 mol), and triethyl amine (three
drops) in 1,4-dioxane (20 mL) was refluxed for 2 h. The separated solid
that formed upon dilution with water (20 mL) was filtered, dried, and
recrystallized from xylene to give yellow crystals of product (3). All the
compounds were characterized by analytical and spectral data (Tables
II, III, and IV).
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