Facile synthesis of some novel 6-alkyl or aryl-7H-tetrazolo[5,1-b][1,3,4] thiadiazine

Article abstract of DOI:10.3184/174751914X14001496962946

New bis-heterocyclic thiadiazine derivatives containing a tetrazole nucleus have been synthesised by simple, high yielding routes and characterised by FT-IR, 1H NMR, 13C NMR and mass spectral analysis. The key step in the construction of the sixsubstituted 7H-tetrazolo[5,1-b][1,3,4]thiadiazine derivatives involved the cyclocondensation of sodium 1-amino-1H-tetrazole-5- thiolate with a-haloketones. The radical scavenging activity of the new tetrazolothiadiazines was also investigated.

Full text of DOI:10.3184/174751914X14001496962946

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 JUNE, 365–367
RESEARCH PAPER 365
Facile synthesis of some novel 6‑alkyl or aryl‑7H‑tetrazolo[5,1‑b][1,3,4]
thiadiazine
Melika Eftekhar, Hossein Eshghi*, Mohammad Rahimizadeh, Mehdi Bakavoli and Sattar Saberi
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
New bis-heterocyclic thiadiazine derivatives containing a tetrazole nucleus have been synthesised by simple, high yielding
routes and characterised by FT-IR, 1H NMR, 13C NMR and mass spectral analysis. The key step in the construction of the six-
substituted 7H-tetrazolo[5,1-b][1,3,4]thiadiazine derivatives involved the cyclocondensation of sodium 1-amino-1H-tetrazole-5-
thiolate with α-haloketones. The radical scavenging activity of the new tetrazolothiadiazines was also investigated.
Keywords: tetrazolo nucleus, thiadiazine, α‑haloketones, heterocyclisation, radical scavenging activity
Thiadiazine derivatives are an important class of
pharmacologically active compounds.1–4 Syntheses of
1,3,4‑thiadiazines have attracted widespread attention due to
their diverse applications as antibacterial, 5,6 antimycobacterial,7,8
antimycotic,9,10 antifungal11,12 and antidepressant agents.13
For example, the fused heterocyclic compounds I and II
(triazolothiadiazines) have been reported as novel analgesic
and antibacterial compounds (Scheme 1).14,15 In addition,
compounds incorporating tetrazole rings have attracted
attention due to their diverse pharmacological properties. For
example angiotensin II receptor blockers, such as losartan16
and candesartan, contain tetrazoles.17 In view of the biological
potential of the above pharmacophores and in continuation of
our efforts to develop novel routes to heterocyclic derivatives
of thiadiazine with potential biological activity, we considered
the synthesis of novel 6‑alkyl or aryl‑7H‑tetrazolo[5,1b][1,3,4]
thiadiazines. In view of the biological importance of these
heterocycles, we decided to synthesise the tetrazole thiadiazine
compounds wherein the biologically active thiadiazine moiety
is fused to potent tetrazole ring at the 4,5 positions. We now
report the details of the synthesis of novel 6‑alkyl or aryl‑7H‑
tetrazolo[5,1‑b][1,3,4]thiadiazines. Their ability at scavenging
free radicals were measured by DPPH (2,2′‑diphenyl‑1‑
picrylhydrazyl) reduction spectrophotometric assay.
Result and discussion
The amino and mercapto groups are nucleophilic centres for the
synthesis of condensed heterocyclic rings. The required sodium
1‑amino‑1H‑tetrazole‑5‑thiolate was prepared as previously
reported in 80% yield (Scheme 2). We found that the one‑pot
cyclocondensation of the tetrazole with α‑haloketones can be
carried out in high yields by the reaction of sodium 1‑amino‑
1H‑tetrazole‑5‑thiolate with the α‑halocarbonyl compounds
(Scheme 3). The structures of all the products were confirmed
by 1H NMR, 13C NMR, FTIR and mass spectral data and
elemental analysis. In their 1H NMR spectra, the absence of the
peaks corresponding to the NH2 protons of compound 2 clearly
confirmed the formation of tetrazolothiadiazine ring. In the 1H
NMR spectra of compounds (4a–g), the signal due to the –S–
CH2– protons of tetrazolothiadiazine ring gave rise to a singlet
peak at 3.7–4.7 ppm. The FT‑IR spectra of these compounds
lacked the absorption corresponding to the NH2 of compound
2 and the carbonyl group of the α‑halocarbonyl compounds
confirmed the formation of the tetrazolothiadiazine ring. The
mechanism must involve two straightforward steps, namely
the nucleophilic substitution by the sulfur of the chlorine and
cyclisation through direct attack of the amino group on the
carbonyl group. First we report the details of the synthesis of
novel 6‑alkyl or aryl‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine.
N
N
N
N
N
N
S
S
N
N
N
I
II
Scheme 1 Compounds reported as anti-inflammatory/analgesic agents.
S
O
S
O
H2N
+
CS2
NH2-NH2
+
MeO
OMe
N
S
H
1
NH2
N
S
Ethanol/Water
Reflux
N
N
SNa+
H2N
+
NaN3
N
S
N
H
2
Scheme 2 Synthesis of sodium 1-amino-1H-tetrazole-5-thiolate.
* Correspondent. E‑mail: heshghi@um.ac.ir
JCR1402383_FINAL.indd 365
10/06/2014 09:37:25

366 JOURNAL OF CHEMICAL RESEARCH 2014
S-Na+
S
H
C
3
N
N
ClCH2COCH3
CH OH Reflux
N
N
N
N NH2
N
N
N
,
3
a
3
2
O
S
+
X
-
S Na
Br
X
H2C
C
N
N
N
N
N
N
N NH2
N
ACOH,Reflux
N
a-
4
g
2
4a) X=H
4b) X=Cl
4c) X=Ph
4e) X=NO2
4f) X=CH3
4g) X=Br
4d) X=OCH3
Scheme 3 Synthesis of 6-alkyl or aryl-7H-tetrazolo[5,1-b][1,3,4 ]thiadiazine.
NH2); IR (KBr disc): νmax 3424, 3272, 1657, 1607 cm−1. The product
was also characterised by conversion to the free thiol by careful
acidification with dilute H2SO4 to give 1‑amino‑1H‑tetrazole‑5‑thiol,
m.p. 160–161 °C (dec.).21
Interest in the fused tetraazolo[3,4‑b][1,3,4]thiadiazine
systems is stimulated by their broad biological activity. In
a simple and fast evaluation of their biological activity, we
determined the radical scavenging activity of these compounds.
Since free radicals are believed to play an important role in
many pathological states, radical scavenging compounds have
received increased attention in medicinal research. Recently,
interest in the application of antioxidants to medical treatment
has been stimulated by links between the development of
human diseases and oxidative stress.18 Free radicals play a
role in the pathogenesis of chronic degenerative diseases
including cancer, autoimmune, inflammatory, cardiovascular
and neurodegenerative diseases and ageing. It is also known
that oxidative stress can be induced by a wide range of
environmental factors including UV stress, pathogen invasion,
pesticide action and oxygen shortage. Consequently, synthetic
and natural compounds with potential antioxidant activity have
received increased attention in biological research, medicine
and pharmacy. There are many ways to evaluate the free radical
scavenging activity of tested compounds. One of the most
widely used detection procedures, which facilitates analysis of
various antioxidants, is based on 2,2′‑diphenyl‑1‑picrylhydrazyl
radical (DPPH) bleaching.19 The tetrazolo compounds 4b and
4e showed good antioxidant activity.
Synthesis of 6‑methyl‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine (3a)
A mixture of 2 (1 mmol) and chloroacetone (1 mmol) in methanol
(5 mL) was refluxed for about 4 h. The progress of the reaction was
monitored by TLC using chloroform: methanol (20:1). After the
completion of the reaction, the mixture was concentrated and the
resultant precipitates were collected by filtration. The precipitate was
recrystallised from ethanol to give crystals; m.p. 92–94°C, yield 90%;
1
IR (KBr) νmax (cm−1): 1624 (C=N), 1266 (C–S). H NMR (100 MHz,
CDCl3, 25°C, ppm) δ 3.72 (s, 2H, CH2), 2.48 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3, ppm) δ 158.01, 142.49, 26.46, 24.00. EI‑MS m/z: 156.
Anal. calcd for C4H5N5S: C, 30.96; H, 3.25; N, 45.13; S, 20.66; found: C,
31.23; H, 3.37; N, 46.45; S, 20.34%.
Synthesis of substituted‑6‑phenyl‑[1,2,4]tetrazolo‑[5,1‑b][1,3,4]
thiadiazines (4a–g); general procedure
A mixture of 2 (1 mmol) and the substituted phenacyl bromide
(1 mmol) in acetic acid (5 mL) was refluxed for about 4 h. The
progress of the reaction was monitored by TLC using chloroform:
methanol (20:1). After the completion of the reaction, the mixture was
concentrated and the resultant precipitates were collected by filtration.
The precipitate was recrystallised from ethanol to give the crystalline
products.
Experimental
6‑Phenyl‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine (4a): M.p. 165–167 °C;
yield 90%; IR (KBr) νmax (cm−1): 1589 (C=N), 1269 (C–S). H NMR
Melting points were recorded on an Electrothermal type 9100 melting
point apparatus and are uncorrected. The IR spectra were obtained
1
(DMSO‑d6): δ (ppm), 8.02 (dd, 2H, J1 = 8 H z, J2 =1.2 Hz), 7.67 (tt, 1H,
J1 = 7.2 H z, J2 =1.6 Hz), 7.59 (dt, 2H, J1 = 8 H z, J2 =1.6 Hz), 4.17 (s,
2H, CH2). 13C NMR (100 MHz, CDCl3, ppm) δ154.31, 142.96, 133.13,
132.30, 129.38, 127.83, 23.93. EI‑MS m/z: 217. Anal. calcd for C9H7N5S:
C, 49.76; H, 3.25; N, 32.24; S, 14.76; found: C, 49.95; H, 3.33; N, 32.83;
S, 14.64%.
1
on an Avatar 370 FT‑IR Thermo‑Nicolet spectrometer. The H NMR
(100 MHz) spectra were recorded on a Bruker AC 400 spectrometer.
The mass spectra were scanned on a Varian Mat CH‑7 at 70 eV.
Elemental analysis was performed on a Thermo Finnigan Flash EA
microanalyser.
6‑(4‑Chlorophenyl)‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine (4b):
M.p. 176–178 °C; yield 85%; IR (KBr) νmax (cm−1): 1655 (C=N), 1270
(C–S). 1H NMR (DMSO‑d6): δ (ppm), 7.80 (d, 2H, J=8.8 Hz), 7.99 (d,
2H, J=8.8 Hz), 4.60 (s, 2H, CH2). 13C NMR (100 MHz, DMSO‑d6, ppm)
δ156.44, 144.53, 132.72, 132.09, 130.037, 127.26, 24.08. EI‑MS m/z:
251. Anal. calcd for C9H6ClN5S: C, 42.95; H, 2.40; N, 27.82; S, 12.74;
found: C, 43.26; H, 2.51; N, 28.14; S, 12.49%.
6‑([1,1′‑Biphenyl]‑4‑yl)‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine (4c):
M.p. 201–203°C; yield 78%; IR (KBr νmax (cm−1): 1650 (C=N), 1265
(C–S). 1H NMR (DMSO‑d6): δ (ppm) 8.10 (d, 2H, J=8.2 Hz), 7.8
Synthesis of sodium 1‑amino‑1H‑tetrazole‑5‑thiolate (2)
Methyl dithiocarbazate 1 (27.5 g, 225 mmol)20 and sodium azide
97% (15.1 g, 225 mmol) were added to a mixture of ethanol (300 mL)
and water (80 mL), then the mixture was refluxed for 17 h. After
the reaction, the mixture was evaporated at 45 °C under reduced
pressure to remove solvent. Then, ethanol (150 mL) was added to the
residue, and the resultant precipitate was collected by filtration. The
precipitate was washed with ethanol and then dried to give sodium
1‑amino‑1H‑tetrazole‑5‑thiolate 2 (26.6 g, 85%) as a white powder;
1
m.p. 88–90 °C; H NMR (100 MHz, DMSO‑d6‑d6): δ 10.1 (br. s, 2H,
JCR1402383_FINAL.indd 366
10/06/2014 09:37:26

JOURNAL OF CHEMICAL RESEARCH 2014 367
Table 1 DPPH bleaching IC50 of the synthetic compounds
concentration. Ethanol was used as control solution. After 30 min
at room temperature, the absorbance was recorded at 517 nm and
compared to NDGA (nordihydroguaiaretic acid). DPPH bleaching
IC50 of the synthetic compounds is shown in Table 1. Our results were
compared with ascorbic acid and 4‑MNPB (pyrimido[4,5‑b][1,4]
benzothiazine)22. Tetrazolothiadiazines 4b and 4e showed good anti‑
oxidant activity.
Compound name
IC50 (µM) SD
3a
4a
4b
4c
283.8 13.9
87.2 4.3
32.2 2.4
>1000
4d
4e
4f
4g
114.5 4.8
31.9 11.1
98.7 4.1
528.2 12
96.3 3.9
22.5 1.81
We are grateful to the Department of Chemistry, Ferdowsi
University of Mashhad, Iran for financial support.
4-MNPB
Ascorbic acid
Received 6 January 2014; accepted 25 April 2014
Paper 1402383 doi: 10.3184/174751914X14001496962946
Published online: 10 June 2014
(d, 2H, J=8.2 Hz), 7.68 (dd, 2H, J1 = 7.2 H z, J2 =1.2 Hz), 7.52 (dt, 2H,
J1 = 7.2 H z, J2 =1.2 Hz), 7.45 (tt, H, J1 = 7.2 H z, J2 =1.2 Hz), 4.18 (s, 2H,
CH2). EI‑MS m/z: 293. Anal. calcd for C15H11N5S: C, 61.42; H, 3.78, N,
23.87; S, 10.93; found: C, 61.63; H, 3.87; N, 24.26; S, 10.81%.
6‑(4‑Methoxyphenyl)‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine (4d):
M.p. 150–152°C; yield 85%; IR (KBr) νmax (cm−1): 1687 (C=N), 1264
(C–S). 1H NMR (DMSO‑d6/CDCl3): δ (ppm) 3.93 (s, 3H, OCH3), 7.03
(d, 2H, J=8.8 Hz), 7.97 (d, 2H, J=8.8 Hz), 4.09 (s, 2H, CH2). 13C NMR
(100 MHz, DMSO‑d6, ppm) δ163.41, 155.44, 143.68, 130.20, 124.59,
114.67, 55.73, 23.91. EI‑MS m/z: 247. Anal. calcd for C10H9N5OS: C,
48.57; H, 3.67; N, 28.32; S, 12.97; found: C, 48.95; H, 3.77; N, 28.66; S,
12.61%.
6‑(4‑Nitrophenyl)‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine (4e):
M.p. 200–202°C; yield 90%; IR (KBr) νmax (cm−1): 1645 (C=N), 1270
(C–S). 1H NMR (DMSO‑d6): δ (ppm) 7.98 (d, 2H, J=9.2 Hz), 8.10 (d,
2H, J=9.2 Hz), 4.702 (s, 2H, CH2). EI‑MS m/z: 262. Anal. calcd for
C9H6N6O2S: C, 41.22; H, 2.31; N, 32.05; S, 12.23; found: C, 41.40; H,
2.41; N, 32.53; S, 12.10%.
6‑(p‑Tolyl)‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine (4f): M.p.
146–148 °C; yield 70%; IR (KBr) νmax (cm−1): 1630 (C=N), 1260 (C–S).
1H NMR (DMSO‑d6): δ (ppm) 2.09 (3H,s,CH3), 6.95 (d, 2H, J= 7.6 H z),
7.13 (d, 2H, J=7.6 Hz), 4.41 (s, 2H, CH2). EI‑MS m/z: 231. Anal. calcd
for C10H9N5S: C, 51.93; H, 3.92; N, 30.28; S, 13.86; found: C, 52.12; H,
4.08; N, 30.69; S, 13.71%.
6‑(4‑Bromophenyl)‑7H‑tetrazolo[5,1‑b][1,3,4]thiadiazine (4g): M.p.
183–185 °C; yield 80%; IR (KBr) νmax (cm−1): 1640 (C=N), 1272 (C–S).
1H NMR (DMSO‑d6‑d6): δ (ppm) 7.50–8.00 (m, 4H), 4.45 (s, 2H, CH2).
EI‑MS m/z: 296. Anal. calcd for C9H6BrN5S: C, 36.50; H, 2.04; N, 23.65;
S, 10.83; found: C, 36.69; H, 2.12; N, 24.16; S, 10.70%.
References
1
2
3
4
M.D. Altıntop, Z.A. Kaplancıklı, G.T. Zitounia, A. Özdemira, G. Iscan, G.
Akalın and S.U. Yıldırım, Euro. J. Med. Chem., 2011, 46, 5562.
M. Bakavoli, S.M. Seyedi, A. Shiri, S. Saberi, M. Gholami and H.
Sadeghian, J. Chem. Res., 2013, 37, 48.
M. Wujec, M. Pitucha, M. Dobosz, U. Kosikowska and A. Malm, Acta
Pharm., 2004, 54, 251.
M. Heravi, M. Bakherad, M. Rahimizadeh and M. Bakavoli, Phosphorous
Sulfur Silicon., 2003, 177, 2403.
5
6
7
C.S. Reddy, L.S. Rao and A. Nagaraj, Acta Chim. Slov., 2010, 57, 726.
M.A.H. Abd. El. Gawaad Awas, Acta Chim. Slov., 2008, 55, 492.
M.G. Mamolo, V. Falagiani, D. Zampieri, L. Vio and E. Banfi, Farmaco.,
2001, 56, 587.
8
9
M. Wujec, M. Pitucha, M. Dobosz, U. Kosikowska and A. Malm, Acta
Pharm., 2004, 54, 251.
K. Zamani, K. Faghifi, I. Tefighi and M.R. Sharlatzadeh, Turk. J. Chem.,
2004, 28, 95.
10 H. Chen, Z. Li and Y. Han, J. Agric. Food Chem., 2000, 48, 5312.
11 X.J. Zou, G.Y. Jin and Z.X. Zhang, J. Agric. Food Chem., 2002, 50, 1461.
12 X.J. Zou, L.H. Lai, G.Y. Jin and Z.X. Zhang, J. Agric. Food Chem., 2002,
50, 3757.
13 F. Clerici, D. Pocar, M. Guido, A. Loche, V. Perlini and M. Brufani, J. Med.
Chem., 2001, 44, 931.
14 S. Peri Aytac, B. Tozkoparan, F. Betul Kaynak, G. Aktay, O. Goktas and S.
Unuvar, Eur. J. Med. Chem., 2009, 44, 4528.
15 M.A. Hussein, R.M. Shaker, M.A. Ameen and M.F. Mohammed, Arch.
Pharm. Res., 2011, 34, 1239.
16 D.J. Carini, J.V. Duncia and P.C.B. Wong, U.S. Patent, 1992, 5, 138.
17 K. Kubo, Y. Kohara, E. Imamiya, Y. Sugiura, Y. Inada, Y. Furukawa, K.
Nishikawa and T. Naka, J. Med. Chem., 1993, 36, 2182.
18 A. Jabbari, M. Davoodnejad, M. Alimardani, A. Assadieskandar, A.
Sadeghian, H. Safdari, J. Movaffagh and H. Sadeghian, Bioorg. Med.
Chem., 2012, 20, 5518.
Determination of DPPH bleaching
19 A. Assadieskandar, M. Amini, M. Salehi, H. Sadeghian, M. Alimardani,
A. Sakhteman, H. Nadri and A. Shafiee, Bioorg. Med. Chem., 2012, 20,
7160.
20 W. Hu, Bioorg. Med. Chem. Lett., 2006, 16, 2213.
21 H. Eshghi, M. Rahimizadeh, S. Saberi, K. Abnous and M. Bakavoli, J.
Chem. Res., 2013, 37, 553.
The radical scavenging activity of the new series of tetrazolo
thiadiazine was also determined. The ability of scavenging free
radicals was measured by DPPH reduction spectrophotometric
assay. 25 μM solution of DPPH in absolute ethanol was prepared.
This solution was added to an equal volume of the solution of
the test compounds (dissolved in ethanol) to obtain the desired
22 M. Bakavoli, M. Nikpour, M. Rahimizadeh, M.R. Saberi and H. Sadeghian,
Bioorg. Med. Chem., 2007, 15, 2120.
JCR1402383_FINAL.indd 367
10/06/2014 09:37:26

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.