Synthesis of the new heterocyclic system 7,8-dihydro-6H-benzotetrazolothiadiazine and derivatives

Article abstract of DOI:10.1515/hc-2014-0111

New N,N-disubstituted 7,7-dimethyl-7,8-dihydro-6H-benzotetrazolothiadiazine-9-amines were synthesized from sodium 1-amino-1H-tetrazole-5-thiolate and 2-bromo-5,5-dimethylcyclohexane-1,3-dione in multiple steps. The compounds were characterized by ^13<

Full text of DOI:10.1515/hc-2014-0111

Heterocycl. Commun. 2014; 20(6): 339–341
Shima Rezaeian, Mohammad Rahimizadeh, Hossein Eshghi*, Mehdi Bakavoli,
Kamahldin Haghbin and Mohammad Saadatmandzadeh
Synthesis of the new heterocyclic system
7
,8-dihydro-6H-benzotetrazolothiadiazine and
derivatives
Abstract: New N,N-disubstituted 7,7-dimethyl-7,8-dihydro- structures. Therefore, in pursuit of our efforts to develop
6
H-benzotetrazolothiadiazine-9-amines were synthesized novel routes to heterocyclic derivatives of thiadiazine
from sodium 1-amino-1H-tetrazole-5-thiolate and 2-bromo- with potential biological activities [15, 16] and in view of
,5-dimethylcyclohexane-1,3-dione in multiple steps. The the possible biological activities of the tetrazole pharma-
5
13
1
compounds were characterized by C NMR, H NMR, IR, cophore, a synthetic route to the novel tricyclic system
MS, and elemental analysis.
of s-tetrazolobenzothiadiazine (compounds 6a–f) was
designed. This article reports the successful synthetic
Keywords: amines; 2-bromo-5,5-dimethylcyclohexane- approach to this novel heterocyclic system.
1,3-dione; nucleophilic substitution.
DOI 10.1515/hc-2014-0111
Received July 15, 2014; accepted October 20, 2014
Results and discussion
Strategies for the rapid synthesis and functionalization
of new classes of compounds are of considerable interest
to both academic and industrial researchers. Although
the synthesis of triazolothiadiazine derivatives has been
reported, the literature survey revealed that the syn-
thesis of tetrazolothiadiazine derivatives has not been
investigated.
Synthesis of 1,3,4-thiadiazines is based on cyclo-
condensation of heterocyclic amino thiols with an α-
halo carbonyl compound. In this research, cyclization
of the α-bromodimedone (2) with a 1-amino-1H-tetra-
zole-5-thiolate (3) [17] in methanol under reflux condi-
tion gave the 7,7-dimethyl-7,8-dihydro5H-tetrazolo[1,5-b]
Introduction
In recent years, the chemistry of 1,3,4-thiadiazines have
received considerable attention owing to their synthetic
and biological importance [1]. The fused derivatives
including 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine (triazolo-
thiadiazine) exhibit a broad spectrum of pharmacological
activities including antifungal [2], antibacterial [3], antivi-
ral [4], anti-Alzheimer [5], anti-HIV [6], antitumor [7], anti-
inflammatory [8], antidepressant [9, 10], central nervous
system depressant [11], and antioxidant [12] properties.
Tetrazole derivatives have also attracted some interest due
to their diverse pharmacological potential. For instance,
angiotensin II receptor blockers such as losartan [13] and
candesartan [14] contain a tetrazole ring in their chemical
[
4,1,2]benzothiadiazin-9(6H)-one (4), which was subse-
quently transformed to 9-chloro-7,7-dimethyl-7,8-dihy-
dro-6H-tetrazolo[1,5-b][4,1,2]benzothiadiazine (5) by the
reaction with phosphorous oxychloride. Reaction of com-
pound 5 with a secondary amine in ethanol in the pres-
ence of a catalytic amount of glacial acetic acid led to the
replacement of the chlorine atom and gave product 6. The
synthesis of 2-bromo-5,5-dimethylcyclohexane-1,3-dione
(2) was achieved by bromination of 5,5-dimethylcyclohex-
ane-1,3-dione (1) using a reported procedure [18].
*
Corresponding author: Hossein Eshghi, Department of Chemistry,
School of Sciences, Ferdowsi University of Mashhad, 91775-1436
Mashhad, Iran, e-mail: heshghi@um.ac.ir
Shima Rezaeian, Mohammad Rahimizadeh, Mehdi Bakavoli and
Mohammad Saadatmandzadeh: Department of Chemistry, School of
Sciences, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
Kamahldin Haghbin: National Institute of Genetic Engineering and
Biotechnology, 14155-6343 Tehran, Iran
The structural assignments of compounds 6a–f
were based on the spectral and microanalytical data. For
1
example, in H NMR spectra, the peaks of CH groups of
2
9-chloro-7,7-dimethyl-7,8-dihydro-6H-tetrazolo[1,5-b]
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40ꢀꢀꢀꢀꢁꢀS. Rezaeian et al.: 6H-Benzotetrazolothiadiazine
H N
2
Synthesis of 7,7-dimethyl-7,8-dihydro-5H-tetrazolo[1,5-b]
4,1,2]benzothiadiazin-9(6H)-one (4)
N
N
Br
N
[
O
O
O
O
N
NaS
Br2
3
Sodium 1-amino-1H-tetrazole-5-thiolate (2.8 g, 20 mmol), prepared
MeOH
by the reported method [17], was added to a solution of compound
1
2
2
(4.3 g, 20 mmol) in methanol (50 mL), and the mixture was stirred
H
N
overnight. The resulting precipitate was filtered off under reduced
N
S
N
N
N
N
POCl3
N
pressure to give 3.8 g (80%) of the title compound as a white solid;
N
N
1
mp: 255°C; H NMR (100 MHz): δ 1.10 (s, 6H, 2CH ), 2.20 (s, 2H,
N
3
S
PhNEt2
CH ), 2.3 (s, 2H, CH ), 5.12 (br s, 1H, NH); IR: ν 3301 (NH), 2955, 2929
2
2
O
Cl
4
5
-1
(
aliphatic H), 1655 cm (C ꢀ= ꢀO ); MS: m/z 237. Anal. Calcd for C H N OS:
9 11 5
C, 45.56; H, 4.67; N, 29.51; S, 13.51. Found: C, 45.50; H, 4.61; N, 29.41;
S, 13.43.
6
a: N(R)2 = morpholino
N
S
N
N
N
HN(R)2
EtOH
N
6b: N(R)2 = pyrrolidino
6c: N(R)2 = piperidino
6d: N(R)2 = 4-methylpiperazino
NR2
6e
: N(R)2 = 4-ethylpiperazino
6f: N(R)2 = 4-phenylpiperazino
Synthesis of 9-chloro-7,7-dimethyl-7,8-dihydro-
6
a-f
6H-tetrazolo[1,5-b][4,1,2]benzothiadiazine (5)
Scheme 1ꢂProtocol for synthesis of new heterocyclic system.
Phosphorous oxychloride (16 mL, 172 mmol) and N,N-dimethylani-
line (1.6 mL, 13.2 mmol) were added successively to compound 4
(
2.3 g, 9.7 mmol), and the mixture was heated at 106°C for 3 h, cooled,
[
4,1,2]benzothiadiazine and N,N-disubstituted 7,7-dime-
and poured into ice water. The resultant precipitate was filtered off
under reduced pressure to give the title compound as a yellowish
thyl-7,8-dihydro-6H-benzotetrazolothiadiazine-9-amine
appear at δ 2.6 and δ 2.4, respectively. The molecular ion
peak is present in the mass spectra of all products.
1
solid: mp 245°C; H NMR (400 MHz) δ 1.16 (s, 6H, 2CH ), 2.64 (s, 2H,
3
-1
CH ), 2.68 (s, 2H, CH ). IR: 2868,2956 (aliphatic H), 798 cm (Cl); MS:
2
2
m/z 255. Anal. Calcd for C H ClN S: C, 42.27; H, 3.94; N, 27.39; S, 12.54.
9
10
5
Found: C, 42.21; H, 3.85; N, 27.25; S, 12.49.
Conclusion
The synthesis of a family of compounds of the novel tri-
cyclic heterocyclic system, N,N-disubstituted 7,7-dime-
thyl-7,8-dihydro-6H-benzotetrazolothiadiazine-9-amine,
was accomplished.
General procedure for the synthesis of N,N-disubstituted
7
,7-dimethyl-7,8-dihydro-6H-tetrazolo[1,5-b][4,1,2]
benzothiadiazin-9-amines 6a–f
A mixture of a secondary amine (2 mmol) and compound 5 (0.5 g,
2
mmol) in ethanol (10 mL), was stirred and heated under reflux
for 3–4 h. Af er completion of the reaction, as monitored by TLC,
the mixture was cooled to room temperature and the resulting solid
was filtered and washed with ethanol and crystallized from ethyl
acetate.
Experimental
Melting points were recorded on an electrothermal type 9100 melting
point apparatus. The IR spectra (KBr pellets) were obtained on an AVA- 7,7-Dimethyl-9-morpholino-7,8-dihydro-6H-tetrazolo[1,5-b]
1
TAR 370FT-IR Thermo Nicolet spectrometer. The H NMR spectra were [4,1,2]benzothiadiazine (6a):ꢀTLC solvent: acetate/n-hexane 2:1,
1
recorded in CDCl on Bruker spectrometers. The EI mass spectra were yield 75%, powder, mp 94–96°C; H NMR (400 MHz): δ 1.10 (s, 6H,
3
scanned on a Varian Mat CH-7 instrument at 70 eV. Elemental analysis 2CH ), 2.37 (s, 2H, CH ), 2.51 (s, 2H, CH ), 3.0 (t, J ꢀ= ꢀ 4.4 Hz, 4H), 3.42
3
2
2
-1
-1
was performed on a Thermo Finnigan Flash EA microanalyzer.
(t, J ꢀ= ꢀ 4.4 Hz, 4H, 2CH O); IR: ν 2958 (CH ), 2900 cm (CH ), 1560 cm
2
3
2
(
2
C ꢀ= ꢀN ); MS: m/z 306. Anal. Calcd for C H N OS: C, 50.96; H, 5.92; N,
1
3
18
6
7.43; O, 5.22; S, 10.47. Found: C, 50.89; H, 5.87; N, 27.39; S, 10.41.
Synthesis of 2-bromo-5,5-dimethylcyclohexane-
7
,7-Dimethyl-9-pyrrolidino-7,8-dihydro-6H-tetrazolo[1,5-b]
1
,3-dione (2)
[
4,1,2]benzothiadiazine (6b):ꢀTLC solvent: acetate/n-hexane 2:1;
1
yield 70%; powder; mp 170–172°C; H NMR (400 MHz): 1.10 (s, 6H,
Bromine (0.51 mL, 10 mmol) was added dropwise to a solution of 2CH ), 1.9–2.0 (m, 4H, 2CH ), 2.40 (s, 2H, CH ), 2.43 (s, 2H, CH ), 3.54–
3
2
2
2
1
3
5
,5-dimethylcyclohexane-l,3-dione (1.4 g, 10 mmol) in acetic acid 3.6 (t, J ꢀ= ꢀ 6.8 Hz, 4H, 2CH N); C NMR (100 MHz): 160.7, 154.3, 77.5,
2
(
20 mL) at room temperature. The mixture was stirred for 2 h. The 77, 76.5, 64.9, 60.8, 51.3, 45.6, 45.3, 30.3, 27.9, 25.5; IR: ν 2970 (CH ),
3
-1
product was isolated by filtration, washed with ether (2 ꢀ× ꢀ1 00 mL), 2949 (CH ), 1543 cm (C ꢀ= ꢀN ); MS: m/z 290. Anal. Calcd for C H N S:
2
13 18
6
and dried under a reduced pressure: Yield 95%; mp 174–175°C C, 53.77; H, 6.25; N, 28.94; S, 11.04. Found: C, 53.71; H, 6.18; N, 28.87;
(mp 176°C) [19].
S, 10.98.
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S. Rezaeian et al.: 6H-Benzotetrazolothiadiazineꢂꢁꢀꢀꢀꢂ341
7
,7-Dimethyl-9-piperidino-7,8-dihydro-6H-tetrazolo[1,5-b][4,1,2]
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benzothiadiazine (6c):ꢀTLC solvent: acetate/n-hexane 2:1; yield
1
7
3%; powder; mp 187–188°C; H NMR (100 MHz): 1.10 (s, 6H, 2CH ),
3
1
.60–1.80 (m, 6H, 3CH ), 2.35 (s, 2H, CH ), 2.50 (s, 2H, CH ), 2.90–3.10
2
2
2
-1
(
m, 4H, 2CH N); IR: ν 2966 (CH ), 2936 (CH ), 1552 cm (C ꢀ= ꢀN ); MS:
2
3
2
m/z 304. Anal. Calcd for C H N S: C, 55.24; H, 6.62; N, 27.61; S, 10.53.
14
20
6
Found: C, 55.19; H, 6.58; N, 27.57; S, 10.47.
7
,7-Dimethyl-9-(4-methylpiperazino)-7,8-dihydro-6H-tetrazolo-
[
1,5-b][4,1,2] benzothiadiazine (6d):ꢀTLC solvent: acetate/n-hexane
1
2
:1; yield 68%; powder; mp 117–119°C; H NMR (100 MHz): 1.10 (s, 6H,
2
CH ), 2.40 (s, 5H, N-CH , and CH ), 2.50 (s, 2H, CH ), 2.50–2.70 (m, 4H,
3
3
2
2
-1
CH N), 2.90–3.01 (m, 4H, CH N); IR: ν 2960 (CH ), 2932 (CH ), 1557 cm
2
2
3
2
(C ꢀ= ꢀN ); MS: m/z 319. Anal. Calcd for C H N S: C, 52.64; H, 6.63; N, 30.69;
14 21 7
S, 10.04. Found: C, 52.58; H, 6.58; N, 30.62; S, 9.97.
9
-(4-Ethylpiperazino)-7,7-dimethyl-7,8-dihydro-6H-tetrazolo[1,5-
b][4,1,2] benzothiadiazine (6e):ꢀTLC solvent: acetate/n-hexane 2:1;
1
yield 70%; mp 145–147°C; H NMR (250 MHz): δ 1.22 (s, 6H, 2CH ), 1.25
3
(
t, 3H, CH3), 2.5 (s, 2H, CH ), 2.7 (s, 2H, CH ), 2.81–3.21 (m, 6H, 3CH ),
2
2
2
13
3
.31–3.41 (m, CH ). C NMR (100 MHz): 156.4, 154.7, 141.7, 77.5, 77.2, 77, [10] Brucato, A.; Coppola, A.; Gianquzza, S.; Provenzano, P. M.
2
7
6.5, 52.2, 47.7, 45.2, 41.1, 30.4, 27.8, 27.5, 11.3; IR: ν 2957 (CH ), 2809
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3
-1
(
CH ), 1562 cm (C ꢀ= ꢀN ); MS: m/z 333. Anal. Calcd for C H N S: C, 54.03;
2
1
5
2
3
7
H, 6.95; N, 29.40; S, 9.62. Found: C, 53.98; H, 6.91; N, 28.36; S, 9.58.
7
,7-Dimethyl-9-(4-phenylpiperazino)-7,8-dihydro-6H-tetrazolo[1,5- [12] Čačić, M.; Pavić, V.; Molnar, M.; Šarkanj, B.; Has-Schon, E.
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1
yield 68%; powder; mp 124–126°C; H NMR (250 MHz): 1.04 (s, 6H, 2CH ),
3
2
.33 (s, 2H, CH ), 2.43 (s, 2H, CH ), 3.00–3.40 (m, 8H, 4CH ), 6.75–7.5 (m,
2
2
2
-1
5
H, aromatic); IR: ν 3060 (aromatic H), 2958 (CH ), 2880 (CH ), 1599 cm
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3
2
13
(
C ꢀ= ꢀN ); C NMR (250 MHz): 156.3, 154.8, 150.7, 129.3, 116.6, 77.52, 77, 76.5,
4
9.5, 48.4, 45.2, 41.3, 30.5, 27.8; MS: m/z 381. Anal. Calcd for C H N S: C, [14] Kubo, K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.;
19 23 7
59.82; H, 6.08; N, 25.70; S, 8.41. Found: C, 59.78; H, 5.97; N, 25.69; S, 8.37.
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