Silica phosphoric acid (SPA) as a highly active, reusable, heterogeneous catalyst for the synthesis of 2-amino/anilino-5-aryl-1,3,4-thiadiazine bromide derivatives

Article abstract of DOI:10.1080/10426500903486714

Silica phosphoric acid has been found to be an efficient catalyst for the synthesis of 2-amino/anilino-5-aryl-1,3,4-thiadiazine bromide derivatives from the reaction of thiosemicarbazide and α-bromoketones in acetonitrile at room temperature. The catalyst

Full text of DOI:10.1080/10426500903486714

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Silica Phosphoric Acid (SPA) as a Highly
Active, Reusable, Heterogeneous
Catalyst for the Synthesis of 2-Amino/
Anilino-5-ARYL-1,3,4-Thiadiazine
Bromide Derivatives
Shahnaz Rostamizadeh a , Ali Mohammad Amani a & Nasrin Shadjou a
a Department of Chemistry, K. N. Toosi University of Technology,
Tehran, Iran
Version of record first published: 05 Jan 2012.
To cite this article: Shahnaz Rostamizadeh , Ali Mohammad Amani & Nasrin Shadjou (2012): Silica
Phosphoric Acid (SPA) as a Highly Active, Reusable, Heterogeneous Catalyst for the Synthesis of 2-
Amino/Anilino-5-ARYL-1,3,4-Thiadiazine Bromide Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 187:2, 238-244
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Phosphorus, Sulfur, and Silicon, 187:238–244, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903486714
SILICA PHOSPHORIC ACID (SPA) AS A HIGHLY ACTIVE,
REUSABLE, HETEROGENEOUS CATALYST FOR THE
SYNTHESIS OF 2-AMINO/ANILINO-5-ARYL-1,3,4-
THIADIAZINE BROMIDE DERIVATIVES
Shahnaz Rostamizadeh, Ali Mohammad Amani,
and Nasrin Shadjou
Department of Chemistry, K. N. Toosi University of Technology, Tehran, Iran
Silica phosphoric acid has been found to be an efficient catalyst for the synthesis of 2-
amino/anilino-5-aryl-1,3,4-thiadiazine bromide derivatives from the reaction of thiosemicar-
bazide and α-bromoketones in acetonitrile at room temperature. The catalyst can be reused
for four times without any significant loss of catalytic activity. The experimental procedure is
simple, and the products are obtained in high yield.
Keywords Heterogeneous catalyst; phenacyl bromide; silica phosphoric acid (SPA); 1,3,4-
thiadiazine; thiosemicarbazide
INTRODUCTION
In the last few decades, the use of reusable heterogeneous catalysts has received
considerable attention in organic synthesis because of their environmental, economical, and
industrial aspects.1,2 Therefore, one of the most important objectives now is directed toward
the heterogenization of homogeneous catalysts so that such an attachment of homogeneous
catalysts to insoluble supports allows the easy separation and recycling of the catalyst
from the reaction mixture. Consequently, simpler reaction procedures are needed. This
continues to drive chemists to develop novel catalysts that can efficiently help access
unexplored regions of chemical spaces, in which silica-supported reagents have attracted
considerable attention for 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, 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.
Silica phosphoric acid (SPA) (I) is a versatile catalyst that makes reaction processes
convenient, more economic, and environmentally benign. Owing to the numerous advan-
tages associated with this cheap and nonhazardous reagent, SPA has been explored as a
powerful catalyst for some organic transformations under mild conditions.3 This catalyst
Received 13 September 2009; accepted 13 November 2009.
Address correspondence to Shahnaz Rostamizadeh, Department of Chemistry, K. N. Toosi University of
Technology, P.O. Box 15875-4416, Tehran, Iran. E-mail: rostamizadeh@yahoo.com
238

SILICA PHOSPHORIC ACID AS CATALYST
239
was prepared by our research group, and the formation of a new covalent bond between
P O and SiO2 has been proven, which gives this new catalyst several advantages such as
reusability, ease of handling, low cost, and high catalytic activity (Scheme 1).
O
O
-H2O
SiO2
OH
+
NH4 O
P
OH
SiO2
NH
O
P
OH
+
3
OH
OH
I (SPA)
Scheme 1
In continuation to our general interest in the synthesis of heterocyclic compounds,4
we have the opportunity to further explore the catalytic activity of SPA for the synthesis
of 1,3,4-thiadiazines, which are some of the most thoroughly investigated isomers out of
the six theoretically possible thiadiazines.5 During recent years, interest in the chemistry of
1,3,4-thiadiazines has increased due to their high biological activity such as antibacterial,
antiviral,6 analgesic, muscle-relaxant,7 anthelmintic,8 and the broad-spectrum action of
their derivatives.9
The main synthetic approach to these heterocycles involves condensation of thiosemi-
carbazides with α-haloketones. 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.9–11 It has also been
reported that in concentrated mineral acids, rearrangement to a five-membered heterocycle
occurs, especially for those thiadiazines with an aliphatic substituent at the 5-position.12
Recently, solid phase synthesis of 2-amino-1,3,4-thiadiazines has been reported in the lit-
erature.12 For useful pharmacological activity and novelty of these heterocycles, and a few
drawbacks reported in the literature such as long reaction time, harsh refluxing conditions,
formation of more than one product,10 and lower product yields, we are encouraged to
develop a simple and efficient method for the preparation of these compounds.
RESULTS AND DISCUSSION
In this article, 2-amino/anilino-5-aryl-1,3,4-thiadiazine bromide derivatives 4 were
prepared, from the reaction of thiosemicarbazides 1 and α-bromoketones 2 in acetonitrile
at room temperature in the presence of SPA as catalyst (Scheme 2, Table I).
S
O
R2
N
N
Br
SPA
_
R1HN
+
NHNH2
+ R2
CH3CN, r.t
NH2R1Br
S
1
2
3
Scheme 2
Since in this new kind of methodology, there is a great challenge to find new solid,
Brønsted-type acid catalysts able to perform the reactions with high activities, we considered

240
S. ROSTAMIZADEH ET AL.
Table 1 SPA-catalyzed synthesis of 5-aryl-(N-phenyl)-6H-1,3,4-thiadiazin-2-aminium salts
Compound
R1
R2
Time (min)
Yield (%)a
Mp (◦C) (Lit. mp [Ref.])
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
4-MeO-C6H4-
4-Br-C6H4-
4-Cl-C6H4-
4-NO2-C6H4-
C6H5-
170
90
90
80
90
80
87
85
81
90
80
90
80
88
80
184–185 (—)
200–201 (—)
189–190 (—)
188.5–189.5 (—)
174 (176 [15])
90
155
120
90
90
100
60
2,4-Cl2-C6H3-
C6H5-
186–187 (186 [7])
196–198 (206 [13])
188–189 (185 [13])
216–217 (218 [13])
226–227 (228 [13])
169–170 (170–172 [14])
168.5–169.5 (172 [11])
4-MeO-C6H4-
4-Br-C6H4-
4-NO2-C6H4-
2,4-Cl2-C6H3-
CH3-
3j
3k
3l
150
120
H
aIsolated yield.
SPA as a potential promoter due to its good features for such a transformation. During our
investigation, at first, we chose the reaction of thiosemicarbazide (1.2 mmol) and phenacyl
bromide (1 mmol) as model reactants and examined the effect of the different amounts of
SPA. When above model reactants were conducted in acetonitrile (5 mL) in the presence
of 0, 50, 100, 150, 200, and 250 mg of silica phosphoric acid separately. the best result
was obtained using 200 mg of catalyst (yield = 90%). Using lower amounts of catalyst
resulted in lower yields, while higher amounts of catalyst did not affect the reaction times
and yields. In the absence of catalyst, the product was not formed (Table II). It is significant
to mention that in the presence of SPA, we did not observe any byproduct, while, by
the previous reports, in the presence of some protic acids such as (HBr, HOAc, PTSA
etc.), some byproducts, along with 1,3,4-thiadiazine, had been obtained,9–11 which shows
a significant and privileged aspect of our new catalyst (Scheme 3, Table II).
O
N
S
Br
N
SPA
_
+
+
H2N
NHNH2
S
NH2Br
CH3CN, r.t
1
2
3
Scheme 3
To find out whether this new catalyst gives a better result compared with some other
selected Lewis acids, such as zirconium (II), and zinc salts, the progress of the above model
reaction in the presence of these catalysts at room temperature was studied for 4 h, hence
obtaining 1,3,4-thiadiazine salts in low yield, which further proves the superior catalytic
activity of SPA in this transformation.
In order to evaluate the effect of the solvent, the reaction of thiosemicarbazide and
phenacyl bromide in the presence of SPA was performed in various solvents such as CH3CN,
DMF, EtOH, and a mixture of EtOH and H2O, in which the best result was obtained in

SILICA PHOSPHORIC ACID AS CATALYST
241
Table 2 Optimization of the reaction conditiona
Entry
Amount of SPA (mg)
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
0
50
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
5
5
5
2
1.5
1.5
5
5
5
Other products
40
54
77
90
91
Other products
Other products
Other products
100
150
200
250
200
200
200
EtOH
H2O/EtOH
aReaction was performed with thiosemicarbazide (1.2 mmol), phenacyl bromide (1 mmol)in acetonitrile.
bIsolated yield.
acetonitrile (Table II, entries 5 and 7–9); thus we chose it as the solvent for all further
reactions.
We then continued our study to examine the reusability and recoverability of the
catalyst as an additional important factor. To achieve it, the same model reaction was
performed at room temperature in acetonitrile using 0.2 g of the catalyst. After completion
of the reaction, the solvent was removed in vacuo, and MeOH (25 mL) was added to
the residue and stirred for 10 min. The catalyst was then filtered, washed with methanol,
dried, and reused for the subsequent run. Due to the good stability of SPA, the recycled
catalyst was used without any significant loss of catalytic activity after full extraction of
the product with 25 mL methanol per extraction for four additional runs. Subsequently, the
SPA was then applied to the synthesis of 2-amino/anilino-5-aryl-1,3,4-thiadiazine salts as
summarized in Table III.
Based on the above observations, SPA was found to be the best catalyst for performing
this reaction. As demonstrated here, selecting a solvent in combination with a catalyst is
the main factor in controlling the direction of the reaction. Under optimal conditions, the
reaction between thiosemicarbazides 1 and α-bromoketones 2 proceeds via the formation
of the intermediate 3, yielding 2-amino/anilino-5-aryl (alkyl)1,3,4-thiadiazine bromide
derivatives 4 in high yield (Scheme 1), using a low cost, heterogeneous, and reusable
catalyst. And since the mixture has not been heated, no byproducts are formed. Short
reaction time, easy work-up, and formation of only one product (without any rearranged
product) for both aliphatic and aromatic substituents at the 5-position, are advantages of
this new methodology and make it attractive for large scale operation.
Table 3 The recycling of SPAa
Entry
Time (min)
Yield (%)b
1
2
3
4
90
90
90
90
90
90
87
85
aReaction was performed with thiosemicarbazide (1.2 mmol), phenacyl bromide
(1 mmol) in acetonitrile, and 0.2 g catalyst.
bIsolated yield.

242
S. ROSTAMIZADEH ET AL.
In conclusion, the synthetic protocol allows the formation of biologically significant
1,3,4-thiadiazine salts exclusively using SPA as a new heterogeneous catalyst in acetonitrile
in high yields.
EXPERIMENTAL
Melting points were recorded on a Buchi B-540 apparatus and are uncorrected. IR
spectra were recorded on an ABB Bomem Model FTLA200–100 instrument. 1H and 13
C
NMR spectra were measured with a Bruker DRX-500 Avance spectrometer at 300 and
75 MHz using TMS as an internal standard. Chemical shifts are reported (δ) relative to
TMS, and coupling constants (J) are reported in Hertz (Hz). Mass spectra were recorded
on Shimadzu QP 1100 EX mass spectrometer with 70 eV ionization potential. Elemental
analysis of new compounds was done with a Vario EL III 0 Serial No. 11024054 instrument,
and the results favorably agreed with calculated values. Chemicals were obtained from
Merck and Sigma-Aldrich and were used without further purification.
General Procedure for the Synthesis of
5-Aryl-(N-phenyl)-6H-1,3,4-thiadiazin-2-aminium Salts Using Silica
Phosphoric Acid (Compounds 4a–4i)
To the stirred suspension of α-bromoketone (2) (1 mmol) and thiosemicarbazide (1)
(1.2 mmol) in acetonitrile (5 mL), silica phosphoric acid (200 mg) was added at room tem-
perature. After complete conversion(Table I, 90 min), as indicated by TLC (EtOAc/MeOH),
the solvent was removed in vacuo, and MeOH (25 mL) was added to the residue and stirred
for 10 min. The solids 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 compounds 3a and
3b, which were identified by IR, 1H NMR, 13C NMR, MS, and CHN analysis.
5-(4-Methoxyphenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-
aminium Bromide (3a)
This compound was obtained as cream needles (MeOH/EtOAc), IR (KBr): 3339,
3302, 3146, 1598, 1523 cm−1; 1H NMR CDCl3 (δ-ppm): δ = 3.88 (s, 5H), 6.90–7.00(d, 2H,
J = 8.88), 7.27–7.48 (m, 5H), 7.79–7.82(d, 2H, J = 8.88), 12.70 (br, 2H); 13C NMR CDCl3
(δ-ppm): δ = 22.9, 55.6, 114.6, 124.0, 124.2, 127.2, 129.4, 129.5, 136.9, 152.0, 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 (3b)
This compound was obtained as colorless needles (MeOH/EtOAc), IR (KBr): 3137,
1
2968, 2819, 1668, 1602, 1561, 1494, 1319, 1217, 1073, 1011, 837, 759 cm−1; H NMR
CDCl3 (δ-ppm): δ = 3.90 (s, 2H), 7.20–7.30 (m, 2H), 7.31–7.66 (m, 5H), 13.43 (br, 2H);
13C NMR CDCl3 (δ-ppm): δ = 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),

SILICA PHOSPHORIC ACID AS CATALYST
243
183(36.5), 224(10), 313(4), 347(40.9), 420(1.5), 421(0.33), 425(0.01), 427(0.005) [M+],
429(0.00025). Anal. Calcd. For C15H13BrN3S: C, 42.18; H, 3.07; N, 9.8. Found: C, 42.13;
H, 2.88; N, 9.8.
5-(4-Chlorophenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-aminium
Bromide (3c)
IR (KBr): 3329, 1623, 1602, 1575 cm−1; 1H NMR CDCl3 (δ-ppm): δ = 3.90 (s, 2H),
7.03 (t, 1H, J = 7.3), 7.14 (d, 2H, J = 4.8), 7.29 (t, 2H, J = 7.6), 7.51 (d, 2H, J = 8.5), 7.86 (d,
2H, J = 8.5), 8.70 (br, 2H, NH2); 13C NMR CDCl3 (δ-ppm): δ = 22.9, 122.0, 123.8, 128.7,
129.5, 129.6, 134.9,135.0, 145.9, 160.0. MS (EI): m/z (%) = 77(37), 109(9), 136(100),
188(27.3), 301(57), 381(0.4) [M+], 383(0.25).Anal. Calcd. For C15H13BrClN3S: C, 47.08;
H, 3.42; N, 10.98. Found: C, 47.11; H, 3.48; N, 10.97.
5-(4-Nitrophenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-aminium
Bromide (3d)
IR (KBr): 3330, 3173, 1620, 1601 cm−1; 1H NMR CDCl3 (δ-ppm): δ = 4.37 (s, 2H),
7.35–7.36 (m, 1H), 7.37–7.4 (d, 2H, J = 7.8), 7.49–7.50 (t, 2H, J = 7.8), 8.17 (d, 2H, J
= 8.9), 8.34 (d, 2H, J = 8.9), 10.69 (br, 2H, NH2); 13C NMR CDCl3 (δ-ppm): δ = 23.6,
118.9, 122.6, 124.9, 125.4, 128.3, 129.1, 130.4, 138.4, 140.1, 161.2. MS (EI): m/z (%)
= 51(13.3), 77(32), 82(100), 136(65), 163(3.2), 312(42), 392(0.5) [M+], 394(0.3). Anal.
Calcd. For C15H13BrN4S: C, 45.81; H, 3.33; N, 14.25. Found: C, 45.80; H, 3.28; N, 14.24.
5-(Phenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-aminium Bromide (3e15)
1
IR (KBr, cm−1): 1576, 1581, 1617, 2895, 3137; H NMR (δ-ppm): δ 3.91 (s, 2H),
7.27 (s, 1H), 7.34 (d, 2H, J = 6.50Hz), 7.44–7.55 (m, 5H), 7.84 (d, 2H, J = 6.90 Hz), 12.95
(s, 1H, NH), 13.56 (s, 2H, NH).
5-(2,4-Dichlorophenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-
aminium Bromide (3f7)
IR (KBr, cm−1): 1555, 1617, 1880, 2972, 3132, 3250; 1H NMR (δ-ppm): δ 4.01 (s,
2H), 7.25 (m, 3H), 7.39–7.42 (m, 2H), 7.44 (s, 2H), 7.50–7.80 (m, 2H), 7.81 (s, 2H),
6.00–9.00 (br, 2H, NH2).
2-Amino-5-(phenyl)-6H-1,3,4-thiadiazine Hydrobromide (3g13)
1
IR (KBr, cm−1):1550, 1632, 2669, 2752, 2972; H NMR (δ-ppm): δ 4.29 (s, 2H,
CH2), 7.49–7.57 (m, 3H), 7.87–7.91 (m, 2H), 8.05–10.50 (br, 2H, NH2).
2-Amino-5-(4-methoxyphenyl)-6H-1,3,4-thiadiazine
Hydrobromide (3h13)
IR (KBr, cm−1): 1570, 1606, 1642, 2885; 1H NMR (δ-ppm): δ 3.82 (s, 3H), 4.23 (s,
2H), 7.05–7.10 (d, 2H, J = 8.97 Hz), 7.82–7.87 (d, 2H, J = 8.97 Hz), 9.00–10.00 (br, 2H,
NH2).

244
S. ROSTAMIZADEH ET AL.
2-Amino-5-(4-Bromophenyl)-6H-1,3,4-thiadiazine Hydrobromide (3i13)
1
IR (KBr, cm−1): 1563, 1630, 2668, 3033, 3147; HN MR (δ-ppm): δ 4.28 (s, 2H),
7.73–7.76 (d, 2H, J = 8.65 Hz), 7.85 (d, 2H, J = 8.65 Hz), 9.00–10.00 (br, 2H, NH2),
13.00–14.01 (br, 1H, NH).
2-Amino-5-(4-nitrophenyl)-6H-1,3,4-thiadiazine Hydrobromide (3j13)
IR (KBr, cm−1): 857, 1149, 1350, 1514, 1560, 1632, 1606, 2906.
2-Amino-5-(2,4-dichlorophenyl)-6H-1,3,4-thiadiazine Hydrobromide
(3k14)
IR (KBr, cm−1): 800, 826, 923, 1093, 1380, 1576, 1632, 2911; 1H NMR (δ-ppm): δ
4.17 (s, 2H), 7.55 (t, 2H, J = 9.00 Hz), 7.83 (s, 1H), 9.05–11.03 (br, 2H, NH2), 13.00–14.00
(br, 1H, NH).
2-Amino-5-(aceto)-6H-1,3,4-thiadiazine Hydrobromide (3l11)
1
IR (KBr, cm−1): 1509, 1622, 3070, 3142, 3272; H NMR (δ-ppm): δ 2.22 (s, 3H),
6.16 (s, 2H), 6.56 (s, 1H, NH), 9.47 (br, 2H, NH2).
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