A mild and highly efficient method for the synthesis of 5-aryl-(N-phenyl-)6H-1,3,4-thiadiazin-2-aminium salts using reusable heterogeneous catalysts

Article abstract of DOI:10.1002/jhet.5570450631

(Chemical Equation Presented) 5-Aryl-6H-1,3,4-thiadiazin-2-aminium and 5-aryl-N-phenyl-6H-1,3,4-thiadiazin-2-aminium salts have efficiently been synthesized from the reaction of thiosemicarbazide and α-haloketones in acetonitrile at room temperature using

Full text of DOI:10.1002/jhet.5570450631

Nov-Dec 2008
1761
A Mild and Highly Efficient Method for the Synthesis of 5-Aryl-(N-
phenyl-)6H-1,3,4-thiadiazin-2-aminium Salts Using Reusable
Heterogeneous Catalysts
Shahnaz Rostamizadeh,* Nasrin Shadjou, Ali M. Amani and Reza Aryan
Department of Chemistry, K.N.Toosi University of Technology P.O.Box 15875-4416; Tehran, Iran
rostamizadeh@hotmail.com
Received October 24, 2007
R2
N
S
O
S
N
SiO2-NaHSO4
_
X
+
+
NH2R1X
or SiO2-OSO3H, CH3CN
R2
NHNH2
R1NH
X=Br, Cl
5-Aryl-6H-1,3,4-thiadiazin-2-aminium and 5-aryl-N-phenyl-6H-1,3,4-thiadiazin-2-aminium salts have
efficiently been synthesized from the reaction of thiosemicarbazide and ꢀ-haloketones in acetonitrile at
room temperature using i) silica supported sodium hydrogen sulfate and ii) silica sulfuric acid as reusable
heterogeneous catalysts. The experimental procedure is simple and the products are obtained in high
yields.
J. Heterocyclic Chem., 45, 1761 (2008).
INTRODUCTION
higher catalytic activity than most other catalysts, which
are sensitive to moisture and also very expensive [11].
Moreover, silica sulfuric acid has been found to be a
superior proton source for preparation of organic
compounds and has been used in many types of reactions
such as oxidation, carbon-carbon bond formation and
cycloaddition [12].
With all the aforementioned in mind, it occurred to us
that silica supported sodium hydrogen sulfate (SiO2-
NaHSO4), as well as silica sulfuric acid (SiO2-OSO3H),
may be an effective, versatile and reusable catalysts for
the preparation of 1,3,4-thiadiazines.
As part of a continuing program of exploratory research
in heterocyclic chemistry [1], we turned our attention to
the 1,3,4-thiadiazines, which are one of the most
thoroughly investigated isomers out of the six
theoretically possible thiadiazines [2]. A literature survey
on 1,3,4-thiadiazine derivatives, revealed that compounds
with this moiety in their structure have shown anti-
inflammatory [3], analgesic [4,5], antimicrobial [6],
antiedematic [7], fungicidal [8,9], and muscle relaxant
activity [10].
In recent years, silica supported reagents have attracted
considerable attention because of their higher catalytic
activity due to a larger surface area and better selectivity.
Moreover, silica supported reagents have high mechanical
and thermal stability, ease of handling, low toxicity, non-
corrosiveness, easy separation of the catalyst after
completion of the reaction and reusability of the catalyst,
which make them promising for both academic and
industrial applications. Recently, it has been reported that
sodium hydrogen sulfate adsorbed on silica gel has a
The main synthetic approach to these heterocycles
involves condensation of thiosemicarbazides with ꢀ-
haloketones [3].
It has been mentioned that the reaction, however, can be
complex and the products are dependent on the nature of
the substituents in each of the reactants (in which an
aromatic substituent at the 5-position results in an increase
of ring stability), the polarity of the solvent used and the
reaction temperature [13-15]. It has also been reported that
in conc. mineral acids, rearrangement to five membered
Table 1
Synthesis of 5-Aryl-(N-phenyl-)6H-1,3,4-thiadiazin-2-aminium Salts
SiO2-NaHSO4 SiO2-OSO3H
Yield (%) Time(h)
Entry
R1
R2
Time (h)
Yield (%)
mp °C[lit. mp]
1
2
3
4
5
6
7
8
H
H
H
H
C6H5-
ꢀ
ꢁ
ꢁ
ꢁ
1
3
3
3
3
85
82
98
91
75
96
81
97
74
82
1.5
1
1
1
4
4
4
4
4
80
94
92
83
53
75
88
85
43
70
200.6-201[17]
188-189[17]
216-217[17]
228-228.5[17]
169-170[18]
172-173[19]
184.8- 185.5
199.5-200
4 - MeO- C6H4-
4 - Br - C6H4-
4 - NO2 - C6H4-
2,4 -di-Cl- C6H3-
C6H5-
4 - MeO- C6H4-
4 - Br - C6H4-
2,4 -di-Cl- C6H3-
CH3-
H
Ph
Ph
Ph
Ph
H
9
10
186-187[10]
168.5-169.5[14]
2
3

1762
S. Rostamizadeh, N. Shadjou, A. M. Amani and R. Aryan
Vol 45
heterocycles will occur; especially for those thiadiazines
with an aliphatic substituent at the 5-position [14].
methodology. We have also found out that the reaction
goes to completion using 1.2 mmol of thiosemicarbazide
per 1 mmol of ꢀ-haloketones. Finally, we further
investigated the best reaction conditions by using different
amounts of SiO2-NaHSO4, and 200 mg was found to be
the best amount and in the case of SiO2-OSO3H [20], 230
mg was the optimized amount.
Recently, solid phase synthesis of amino-1,3,4-
thiadiazines has been reported in the literature [16].
Because of the useful pharmacological activity and
novelty of these heterocycles, and as the previously
reported methods have a few drawbacks such as long
reaction times, harsh refluxing conditions, formation of
more than one product [13] and low product yields, we
were encouraged to develop a simple and efficient method
for the preparation of these compounds.
Table 2
Optimization of the Reaction Condition Using Different Catalysts
Reagent
Time (h) Condition Yield (%)
Intermediate
RESULTS AND DISCUSSION
_
5
R.T
formed
In this report, 5-aryl-(N-phenyl-)6H-1,3,4-thiadiazin-2-
aminium salts 4 were prepared, from the reaction of
thiosemicarbazides 1 and ꢀ-haloketones 2 in acetonitrile
at room temperature in the presence of solid supported
reagents, i) SiO2-NaHSO4 and ii) SiO2-OSO3H as catalysts
(Scheme 1,Table 1).
ZrCl4
5
R.T
R.T
R.T
R.T
R.T
not isolated
ZnCl2
AlCl3
24
2
50
40
85
80
SiO2-NaHSO4
SiO2-OSO3H
0.75
1.5
Thus, a range of 5-substituted 6H-1,3,4-thiadiazin-2-
aminium salts (entries 2-10) were prepared under the
optimized condition (Table 2), using i) SiO2-NaHSO4 and
ii) SiO2-OSO3H as catalysts.
Scheme 1
O
S
R2
N
S
SiO2-NaHSO4
or SiO2-OSO3H, CH3CN
N
X
+
In view of green chemistry, we then turned our
attention towards the reusability of the catalysts. In order
to achieve this, SiO2-NaHSO4 was prepared according to
the literature method [20]. Thus, the reaction of
thiosemicarbazide (1.2 mmol), phenacyl bromide (1
mmol) (entry 1, Table 1) and (200 mg) of SiO2-NaHSO4
was performed in acetonitrile (5 mL) at room temperature.
After completion of reaction the solvent was removed in
vacuo and to the residue MeOH (50 mL) was added and
stirred for 1 hr. The catalyst was separated by filtration,
washed with methanol, dried and reused for the
subsequent run. It was noticed that the catalyst could be
reused for at least four cycles (Table 3). SiO2-OSO3H was
next prepared according to the reported method [12a]. In a
similar experiment the reaction of thiosemicarbazide (1.2
mmol), phenacyl bromide (1 mmol), and SiO2-OSO3H
(230 mg) was performed in acetonitrile (5 mL) at room
temperature and as indicated in Table 3 the catalyst could
be reused for at least three cycles.
R2
_
X
NHNH2
+
R1NH
NH2R1
X=Br, Cl
1
2
4
-H2O
R2
O
NH2
+
HN
_
S
NHR1 X
3
In our research, in order to achieve optimized condition,
the reaction of thiosemicarbazide and phenacyl bromide
(entry 1, Table 1) was initially performed in different
solvents such as DMF, CH3CN, EtOH and a mixture of
EtOH, H2O under neutral, acidic and basic conditions at
room temperature, in which the best result was obtained
with CH3CN under acidic reagents such as (ZrCl4, ZnCl2,
AlCl3, SiO2-NaHSO4 and silica sulfuric acid) (Table 2).
We avoided using protic acids such as (HBr, HOAc,
PTSA etc.), since in the presence of such acids, unwanted
byproducts together with 1,3,4-thiadiazine will be formed
[13-15]. When ZrCl4 was used, the reaction went to
completion very well at room temperature but we had
difficulty in separating the ZrCl4 from the products (since
a small amount of ZrCl4 is also dissolved in methanol). In
the absence of any catalyst and in acetonitrile the
intermediate 3 was obtained. Based on the above
observations and as indicated in Table 2, SiO2-NaHSO4
and SiO2-OSO3H which are both reusable and inexpensive
catalysts were found to be the best catalysts for
performing this reaction. Therefore, it seems that, the
choice of the catalyst played an important role in this new
It should be mentioned that in the case of entry 6 the
free base has been isolated and it’s mp is reported.
Table 3
The Recycling of Silica Sulfuric Acid
SiO2-
NaHSO4
SiO2-
OSO3H
Time (h)
Entry
Yield(%)b
Yield (%)b
Time (h)
1
2
3
4
0.75
0.75
0.75
0.75
85
84
80
79
1.5
1.5
1.5
1.5
80
77
70
68
b Isolated Yield.

Nov-Dec 2008
A Mild and Highly Efficient Method for the Synthesis of
1763
5-Aryl-(N-phenyl-)6H-1,3,4-thiadiazin-2-aminium Salts
5-(4-Methoxyphenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-
aminium bromide (entry 7). This compound was obtained as
cream needles (MeOH/ EtOAc), mp = 184.8-185.5 ºC; IR (KBr):
CONCLUSION
In conclusion, we have developed a convenient, easy,
and mild method for the synthesis of 5-aryl-6H-1,3,4-
thiadiazin-2-aminium,5-aryl-N-phenyl-6H-1,3,4-thiadiaz-
in-2-aminium and 5-methyl-6H-1,3,4-thiadiazin-2-amin-
ium salts in high yield, using low cost i) SiO2-NaHSO4
and ii) SiO2-OSO3H heterogeneous and reuseable
catalysts without heating the mixture which usually
results in the formation of many by-products. Short
reaction time, easy workup, formation of only one product
(without any rearranged product) for both aliphatic and
aromatic substituents at 5-position, are advantages of this
new methodology and make it attractive for large scale
operation.
1
ꢁ
max= 3339, 3302, 3146, 1598, 1523 cm-1; H NMR (300MHz,
CDCl3): ꢀ = 3.88 (s, 5H), 6.9-7(d, 2H, J = 8.86), 7.27-7.48 (m,
5H),7.79-7.82(d, 2H, J = 8.87), 12.7(br, 2H); 13C NMR:
(125MHz, DMSO-D6):ꢀ = 22.9, 55.6, 114.6, 124.02, 124.2,
127.2, 129.4, 129.5, 136.9, 152.04, 160.3, 162.4; MS (EI): m/z
(%) = 51(7.22), 77(23.7), 133(100), 162(137.7), 297(65.4),
299(4.56), 375(0.15) 377 (for 79Br) and 379 (for 81Br) [M+].
Anal. Calcd. For C16H16N3OS: C, 50.80; H, 4.26; N, 11.11.
Found: C, 50.40; H, 4.05; N, 11.05.
5-(4-Bromophenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-
aminium bromide (entry 8). This compound was obtained as
colourless needles (MeOH/ EtOAc), mp = 199.5-200 ºC; IR
(KBr): ꢁmax =.3137, 2968, 2819, 1668, 1602, 1561, 1494, 1319,
1217, 1073, 1011, 837, 759cm-1; 1H NMR (500MHz, CDCl3): ꢀ
= 3.9 (s, 2H), 7.2-7.3 (m, 2H), 7.70-7.73 (d, 2H, J = 8.25), 7.31-
7.66 (m, 5H), 13.43(br, 2H); 13C NMR: (125MHz, DMSO-D6):
ꢀ = 22.4, 124.5, 124.9, 127.4, 128.9, 129.5, 131.9,132.1, 137.1,
150.3, 160.4; MS (EI): m/z (%) = 51(10), 77(29), 91(6),
102(46), 136(100), 183(36.5), 224(10), 313(4), 345(38),
347(40.9). Anal. Calcd. For C15H13BrN3S: C, 42.18; H, 3.07; N,
9.8. Found: C, 42.13; H, 2.88; N, 9.8.
EXPERIMENTAL
Melting points were determined on a Büchi B-540 instrument
in open capillary tubes and are uncorrected. IR spectra were
recorded on an ABB Bomem Model FTLA200-100 instrument.
1H and 13C NMR spectra were measured with a Bruker DRX -
300 Avance spectrometer at 300 and 75 MHz using TMS as an
internal standard. Chemical shifts are reported (ꢀ) relative to
TMS, and coupling constants (J) are reported in hertz (Hz).
Mass spectra were recorded on a High Resolution Agilent
Technology EX mass spectrometer. Elemental analysis of new
compounds was performed with a Vario EL III 0 Serial No.
11024054 instrument. All reactions were monitored by thin layer
chromatography, carried out on 0.2 mm silica gel 60 F-254
(Merck) plates using UV light (254 and 366 nm) for detection.
Chemicals were obtained from Merck and Sigma-Aldrich and
used without further purification.
Acknowledgment. We thank the K.N. Toosi research council
for their financial support.
REFERENCES
[1a] Rostamizadeh, Sh.; Tajik, H.; Yazdanfarahi, S. Synth.
Commun. 2003, 33, 113. [b] Rostamizadeh, Sh.; Sadeghi, K. Synth.
Commun. 2002, 32, 1899. [c] Rostamizadeh, Sh.; Housaini, A.Gh.
Tetrahedron Lett. 2004, 45, 8753. [d] Rostamizadeh, Sh.; Housaini,
A.Gh. Phosphorus, Sulfur, and Silicon, 2005, 180, 1321. [e]
Rostamizadeh, Sh.; Mollahousaini, K. Phosphorus , Sulfur, and Silicon,
2006, 181, 1839.
[2a] Elderfield, R.C. Heterocyclic compounds, John Wiley &
Sons, New York, London, 1961,Vol 7. [b] Katritzky, A.R.; Rees, C. W.
In Comprehensive Heterocyclic Chemistry, Scriven, E.F.V. Ed,
Pergamon Press, Oxford, 1996, Vol. 6, p.737.
[3] Bose, P.K. J. Indian Chem. Soc. 1924, 1, 51.
[4] Takamizawa, A.; Sato, H. Japan Pat. 6, 927, 896; Chem.
Abstr. 1970, 72, 55523q.
[5] Yoshida, N.; Tanaka K.; Lizuka, Y.; Wachi, K.; Nishimura,
T.; Yasuda, H. Japan Pat. 7,488,889; Chem. Abstr. 1975, 82, 57744t.
[6] Petersen, U.; Heitzer, H. German Pat. 2, 251, 683; Chem.
Abstr. 1974, 81, 13564j.
[7] Takamizawa, A.; Sato, H. Japan Pat. 6, 928, 103; Chem.
Abstr. 1970, 72, 43738a.
[8] Saikawa, I.; Takano, Sh. Japan Pat. 7, 041, 593; Chem. Abstr.
1971, 75, 5965b.
[9] Zenno, H.; Sugihara, A.; Ito, M. Japan Pat. 678, 033; Chem.
Abstr. 1967, 67, 54173k.
[10] Jones, W.D.; Miller, F.P. U.S. Pat. 4, 309, 426; Chem. Abstr.
1982, 96, 181317j.
[11a] Adharvana Chari, M.; Syamasundar, K. J. Mol. Cat. A. 2004,
221, 137. [b] Das, B.; Thirupathi, P.; Reddy, K. R.; Lingaiah Nagarapu,
B. R. Catal. Commun. 2007, 8, 535. [c] Ravikanth, B.; Laxminarayana,
K.; Vittal Rao, B. J. Mol. Catal. A. 2006, 253, 92 . [d] Das, B.; Banerjee,
J.; Ravindranath, N. Tetrahedron, 2004, 60, 8357. [e] Das, B.; Majhi, A.;
Banerjee, J. Tetrahedron Lett. 2006, 47, 7619. [f] Das, B.; Ravinder
Reddy, K.; Thirupathi, P. Tetrahedron Lett. 2006, 47, 5855. [g] Ramesh,
C.; Mahender, G.; Ravindranath, N.; Das, B. Tetrahedron Lett. 2003, 44,
General procedure for the synthesis of 5-aryl-(N-phenyl)-
6H-1,3,4-thiadiazine-2-aminium salts using silica supported
NaHSO4 (entries 1-10). To the stirred suspension of phenacyl
bromide (2) (1 mmole), thiosemicarbazide (1.2 mmole) in
acetonitrile (5 mL), SiO2-NaHSO4 (200 mg) was added at room
temperature. After complete conversion Table 1 (3/4 hr), as
indicated by TLC (EtOAc/MeOH), the solvent was removed in
vacuo and to the residue MeOH (50 mL) was added and stirred
for 1 hr. The catalyst was separated by filtration and the filtrate
was evaporated in vacuo. The solids formed were then collected
by filtration and recrystallized from methanol and ethyl acetate.
General procedure for the synthesis of 5-aryl-(N-phenyl)-
6H-1,3,4-thiadiazin-2-aminium salts using Silica Sulfuric
acid (entries 1-10). To the stirred suspension of phenacyl
bromide (2) (1 mmole), thiosemicarbazide (1) (1.2 mmole) in
acetonitrile (5 mL), silica sulfuric acid (230 mg) was added at
room temperature. After complete conversion, Table 1 (1/2
hr) as indicated by TLC (EtOAc / MeOH), the solvent was
removed in vacuo and to the residue MeOH (50 mL) was
added and stirred for 1 hr. The catalyst was separated by
filtration and the filtrate was evaporated in vacuo. The solids
formed were then collected by filtration and recrystallized
from methanol and ethyl acetate. All products are known
compounds and were characterized by comparison of their
spectral and physical data with those of known samples
except (entries 7,8) which were identified by IR, 1H NMR, 13
NMR, MS and CHN analysis.
C

1764
S. Rostamizadeh, N. Shadjou, A. M. Amani and R. Aryan
Vol 45
1465. [h] Das, B.; Mahender, G.; Sunil Kumar, V.; Chowdhury, N.
Tetrahedron Lett. 2004, 45, 6709.
Heterocycl. Comp. 1991, 1159.
[16] Kilburn, J.P.; Lau, J.; Jones, R.C.F. Tetrahedron Lett. 2002,
43, 3309.
[17] Schröder, J.; Henke, A.; Wenzel, H.; Brandstetter, H.;
Stammler, H.G.; Stammler, A.; Pfeiffer, W.D.; Tschesche, H. J. Med.
Chem. 2001, 44, 3231.
[12a] Zolfigol, M.A. Tetrahedron, 2001, 57, 9509. [b] Mirjalili, B.F.;
Zolfigol, M.A.; Bamoniri, A.; Zarei, A. J. Chin. Chem. Soc. 2004, 51, 509.
[c] Chen, W.Y.; Lu, J. Synlett , 2005, 19, 2293. [d] Salehi, P.; Dabiri, M.;
Zolfigol, M.A. and Baghbanzadeh, M. Tetrahedron Lett. 2005, 46, 7051.
[13] Beyer, H. Quart. Rep. Sulfur Chem. 1970, 5, 177.
[14] Busby, R.E.; Dominey, T.W. J. Chem. Soc. Perkin Trans, II
1980, 890.
[18] Davidson, C.M.R. Nl. Pat. 8006206; Chem. Abstr. 1982, 97,
216243g.
[19] Beyer, H. Z. Chem. 1969, 9, 61.
[15] Novikova, A.P.; Perova, N.M. and Chupakhin, O.N. Chem.
[20] Berton, G.W. J. Org .Chem. 1997, 62, 8952.