A green method for synthesis of 7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives catalyzed by N-methylpyrrolidone hydrosulfate ([Hnmp]HSO 4) ionic liquid

Article abstract of DOI:10.1007/s00706-013-1009-4

An efficient and green approach for the synthesis of 7H-thiazolo[3,2-b][1, 2,4]triazin-7-one derivatives is described via one-pot, three-component condensation of arylpyruvic acids, thiosemicarbazide, and 2-bromoacetophenones in the presence of N-methylpyrrolidone hydrosulfate ([Hnmp]HSO₄) ionic liquid as the catalyst and solvent. This green catalyst can be recycled several times without any substantial decrease in the yields and reaction rates. The catalyst loadings are high. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1009-4

Monatsh Chem
DOI 10.1007/s00706-013-1009-4
ORIGINAL PAPER
A green method for synthesis of 7H-thiazolo[3,2-b][1,2,4]-
triazin-7-one derivatives catalyzed by N-methylpyrrolidone
hydrosulfate ([Hnmp]HSO4) ionic liquid
•
Sijie Liu Lanxiang Shi Jingyu He
•
•
•
Hongkun Yue Ran Zhou
Received: 27 January 2013 / Accepted: 26 April 2013
Ó Springer-Verlag Wien 2013
Abstract An efficient and green approach for the syn-
thesis of 7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives
is described via one-pot, three-component condensation of
arylpyruvic acids, thiosemicarbazide, and 2-bromoace-
tophenones in the presence of N-methylpyrrolidone
hydrosulfate ([Hnmp]HSO4) ionic liquid as the catalyst and
solvent. This green catalyst can be recycled several times
without any substantial decrease in the yields and reaction
rates. The catalyst loadings are high.
further enhances the versatility of ionic liquids. Moreover,
task-specific ionic liquids which contain acidic functional
groups were introduced as good catalysts for a series of
chemical transformations such as the Claisen rearrange-
ment [2, 3], Biginelli reaction [4, 5], Knoevenagel
condensation [6, 7], Pechmann reaction [8], Beckmann
rearrangement [9], Diels–Alder reaction [10, 11], Friedel–
Crafts reaction [12, 13], and Mannich reaction [14].
In our foregoing work, we designed and synthesized 7H-
thiazolo[3,2-b][1,2,4]triazin-7-ones which showed inhibi-
tory activity against acetylcholinesterase [15–18]. In
continuation of our interest in developing new multi-com-
ponent reactions and environmentally friendly methods, we
utilized the acidic ionic liquid N-methylpyrrolidone hydro-
sulfate ([Hnmp]HSO4) as catalyst and solvent for the
synthesis of 7H-thiazolo[3,2-b][1,2,4]triazin-7-ones.
Keywords 7H-Thiazolo[3,2-b][1,2,4]triazin-7-one Á
[Hnmp]HSO4 ionic liquid Á Multi-component reaction Á
Green chemistry Á Cyclization
Introduction
The green chemistry movement began more than two
decades ago. Specifically, the challenge in chemistry is to
develop new products, processes, and services that achieve
the societal, economic, and environmental benefits that are
required now and tomorrow, and the need for alternative
solvents for reactions has been one of the major issues we
have faced [1].
Results and discussion
In the initial stage of the experiment, we studied the synthesis
of 6-arylmethyl-3-aryl-7H-thiazolo[3,2-b][1,2,4]triazin-7-
ones by using sodium hydroxide for the first cyclization and
acetic acid for the second cyclization [15]. In the course of
this study, we developed green chemistry by one-pot syn-
theses of the target molecules in the presence of
[Hnmp]HSO4 (Scheme 1). The reaction of phenylpyruvic
acid, thiosemicarbazide, and 2-bromoacetophenone was
selected as a model reaction to optimize the reaction tem-
perature for the synthesis of 4a. The results are summarized
in Table 1. According to our results, as the temperature
increases, the reaction rate speeds up and the yields improve.
The most satisfactory result was obtained at the temperature
of 80 °C in the presence of the ionic liquid. To find the
optimal catalyst loading for the model reaction, the amount
Owing to their unique properties such as good solvating
ability, negligible vapor pressure, variable polarity, non-
flammability, and recyclability, ionic liquids have been
widely used as catalysts and reaction media. It has been
widely reported that the use of task-specific ionic liquids
S. Liu (&) Á L. Shi Á J. He Á H. Yue Á R. Zhou
College of Chemical Engineering, Shijiazhuang University,
Shijiazhuang 050035, People’s Republic of China
e-mail: liusijie1982@yahoo.com.cn
123

S. Liu et al.
Scheme 1
R3
R4
O
O
Br
S
[Hnmp]HSO4
OH
N
N
+
+
H2NCNHNH2
N
R3
O
R1
R1
O
S
R4
R2
R2
1
2
3
4
Table 3 One-pot synthesis of 7H-thiazolo[3,2-b][1,2,4]triazin-7-
ones in 0.4 equiv. [Hnmp]HSO4 at 80 °C
Table 1 Effect of the reaction temperature on the synthesis of 4a in
[Hnmp]HSO4
Entry
R1
R2
R3
R4
Product
Yield/%
Entry
Temp/°C
[Hnmp]HSO4/equiv.
Time/h
Yield/%
1
H
H
H
H
4a
4b
4c
4d
4e
4f
88
87
91
89
87
92
87
91
87
88
87
86
1
2
3
4
30
60
1
1
1
1
4
4
4
4
43
61
91
86
2
H
H
Br
H
3
H
H
Cl
H
80
4
H
OCH3
OCH3
H
Br
H
100
5
H
Cl
H
6
OCH3
OH
OH
Cl
OH
OH
OH
Cl
H
Table 2 Effect of the amount of [Hnmp]HSO4 on the synthesis of 4a
in the solvent-free condensation at 80 °C
7
H
H
4g
4h
4i
8
H
CH3
H
Entry
[Hnmp]HSO4/equiv.
Time/h
Yield/%
9
H
10
11
12
Cl
H
OH
OH
OH
CH3
H
4j
1
2
3
4
5
0.05
0.2
0.4
0.6
0.8
4
4
4
4
4
9
70
88
86
89
OH
OH
OCH3
OCH3
4k
4l
CH3
The recyclability of the catalyst was investigated using
the same reaction and scale. Upon the completion of
the reaction, the product was readily isolated by filtra-
tion, washed with water, and dried under vacuum without
further separation, whereas the filtrate containing
[Hnmp]HSO4 was dried to remove water at 60 °C under
vacuum. The recovered ionic liquid was reused in the
subsequent reactions. As shown in Table 4, for the prepa-
ration of 4a, the ionic liquid [Hnmp]HSO4 could be
recycled three times without considerable decrease of
activity.
of [Hnmp]HSO4 was reduced from 0.8 to 0.05 equivalents.
The results are summarized in Table 2. The reactivity for the
lower loading of [Hnmp]HSO4 (0.05 equiv.) was very low.
Increasing the amount of [Hnmp]HSO4 from 0.4 to
0.8 equiv. did not improve the yield in contrast to our
expectations. Thus, we chose 0.4 equiv. as the optimal
amount of catalyst for further experiments.
To explore the scope and limitations of this reaction, we
extended it to various substituted arylpyruvic acids 1, thi-
osemicarbazide (2), and 2-bromoacetophenones 3 in the
presence of [Hnmp]HSO4. As indicated in Table 3, the
reaction proceeds efficiently with all of them. A mecha-
nism for the [Hnmp]HSO4-catalyzed formation of products
Conclusion
7H-thiazolo[3,2-b][1,2,4]triazin-7-ones
4 is shown in
Scheme 2. Although we could not isolate any intermediate,
the reaction may involve the initial formation of interme-
diate 5 between arylpyruvic acids 1 and thiosemicarbazide,
which undergoes reaction with 2-bromoacetophenones 3 to
produce 7H-thiazolo[3,2-b][1,2,4]triazin-7-ones 4. It was
suggested that [Hnmp]HSO4 will act as an organic acid and
activate arylpyruvic acids and 2-bromoacetophenones,
which in turn promotes the condensation reaction.
We have found a practical and green synthesis procedure
for preparing 7H-thiazolo[3,2-b][1,2,4]triazin-7-ones by
one-pot, three-component condensation of arylpyruvic
acids, thiosemicarbazide, and 2-bromoacetophenones in the
presence of ionic liquid [Hnmp]HSO4. The main advanta-
ges of this methodology are the simple catalyst system,
higher yields, lack of organic solvent, and the easy syn-
thetic procedure.
123

A green method for synthesis of 7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives
Scheme 2
O
HO
O
S
O
OH
H2NCNHNH2
OH
OH
NH2
+
H
R1
OH
2
R1
O
NHCNH2
S
R1
R2
-H2O
R2
R2
1
O
OH
-H
N
N
OH
N
OH
-H2O
NH
SH
NH
H
N
R1
N
R1
R1
O
NHCNH2
S
R1
O
N
S
-H
R2
NHCNH2
S
R2
H
R2
R2
OH
5
R3
Br
3
R4
R3
R3
R4
R4
HO
NH
N
N
N
N
-H2O
-H
N
R1
O
S
R1
O
S
R2
R2
4
2-bromoacetophenone 3 (1.1 mmol) were added. Upon the
completion of the reaction, the reaction mixture was
poured into water and the precipitate of 7H-thiazolo-[3,2-
b][1,2,4]triazin-7-one 4 was filtered, washed, and crystal-
lized from ethanol. The residue solution containing [Hnmp]
HSO4 was reused for subsequent reactions.
Table 4 Recycling performance of 0.4 equiv. [Hnmp]HSO4
Run
Temp/°C
Time/h
Yield/%
1
2
3
4
80
80
80
80
4
4
4
4
88
85
84
79
6-Benzyl-3-phenylthiazolo[3,2-b][1,2,4]triazin-7-one
(4a, C18H13N3OS)
M.p.: 179–181 °C (Ref. [15] 179–181 °C).
Experimental
6-Benzyl-3-(4-bromophenyl)-7H-thiazolo[3,2-
Reagents and solvents were purchased from common
commercial suppliers and were used without further puri-
fication. All melting points were corrected and measured
on a X-4 digital melting point instrument. The NMR
spectra were recorded in CDCl3 or DMSO-d6 solutions,
using Bruker 300 MHz or 600 MHz spectrometers. The
mass spectra (MS) were obtained by electrospray (ESI) in a
Waters spectrometer at 3.5 kV spray voltage; acetonitrile
was used as the solvent. The IR spectra were obtained
using a Perkin-Elmer 298 spectrometer (Perkin-Elmer,
Norwalk, CT, USA). All the products (except 4a, 4f, 4g,
and 4i) are new compounds, which were characterized by
b][1,2,4]triazin-7-one (4b, C18H12BrN3OS)
M.p.: 229–230 °C; 1H NMR (600 MHz, DMSO-d6):
d = 7.63 (d, J = 8.4 Hz, 2H, Ar), 7.59 (d, J = 8.4 Hz,
2H, Ar), 7.58 (s, 1H, S-CH), 7.24–7.32 (m, 5H, Ar), 3.74
(s, 2H, Ar-CH2) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 165.1, 159.4, 158.9, 138.2, 136.8, 133.4, 130.9, 130.2,
128.9, 127.1, 119.1, 115.8, 104.5, 37.3 ppm; ESI-MS:
m/z = 397.9 ([M ? H]?), 817.1 ([2M ? Na]?); IR (KBr):
ꢀ
m = 3,100, 2,924, 1,639, 1,574, 1,481, 1,399, 1,385, 1,314,
1,188, 1,113, 818, 756, 710 cm-1
.
6-Benzyl-3-(4-chlorophenyl)-7H-thiazolo[3,2-
1
IR, H NMR, 13C NMR, and MS.
b][1,2,4]triazin-7-one (4c, C18H12ClN3OS)
M.p.: 237–239 °C; 1H NMR (300 MHz, CDCl3): d = 7.46
(d, J = 8.4 Hz, 2H, Ar), 7.38 (d, J = 8.4 Hz, 2H, Ar),
7.26–7.33 (m, 5H, Ar), 6.83 (s, 1H, S-CH), 4.13 (s, 2H, Ar-
CH2) ppm; 13C NMR (75 MHz, CDCl3): d = 164.2, 161.1,
159.6, 136.7, 135.2, 133.1, 131.7, 129.6, 126.1, 125.6,
118.7, 117.4, 103.9, 36.9 ppm; ESI-MS: m/z = 353.9
General procedure for synthesis of 7H-thiazolo[3,2-
b][1,2,4]triazin-7-ones 4a–4l
Arylpyruvic acid 1 (1 mmol) and thiosemicarbazide (2,
1.1 mmol) were mixed together in the presence of
[Hnmp]HSO4, then stired at 80 °C. An hour later,
?
?
ꢀ
([M ? H] ), 730.7 ([2M ? Na] ); IR (KBr): m = 3,102,
123

S. Liu et al.
2,920, 1,641, 1,574, 1,482, 1,404, 1,383, 1,360, 1,315,
1,187, 1,113, 1,092, 1,012, 849, 820, 756, 722, 704 cm-1
6-(4-Chlorobenzyl)-3-(4-hydroxy-3-methylphenyl)-7H-
.
thiazolo[3,2-b][1,2,4]triazin-7-one (4j, C19H14ClN3O2S)
M.p.: 214–217 °C; 1H NMR (600 MHz, DMSO-d6):
d = 9.82 (s, 1H, OH), 7.35 (d, J = 8.4 Hz, 2H, Ar), 7.32
(d, J = 8.4 Hz, 2H, Ar), 7.29 (m, 2H, Ar), 7.26 (s, 1H, Ar),
6.79 (s, 1H, S-CH), 3.99 (s, 2H, Ar-CH2), 2.10 (s, 3H, CH3)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 164.2, 159.1,
158.3, 154.2, 138.1, 137.7, 133.1, 129.5, 128.5, 128.2,
121.9, 121.6, 115.4, 111.4, 106.5, 56.2, 36.2, 25.3 ppm;
ESI-MS: m/z = 383.9 ([M ? H]?), 790.7 ([2M ? Na]?);
3-(4-Bromophenyl)-6-(3-methoxybenzyl)-7H-thiazolo[3,2-b]-
[1,2,4]triazin-7-one (4d, C19H14BrN3O2S)
M.p.: 201–203 °C; 1H NMR (600 MHz, DMSO-d6):
d = 7.59–7.63 (m, 5H, Ar), 7.22 (t, 1H, Ar), 6.87 (s, 1H,
S-CH), 6.85 (d, 1H, Ar), 6.82 (d, 1H, Ar), 3.94 (s, 2H, Ar-
CH2), 3.71 (s, 3H, OCH3) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 164.4, 159.1, 158.2, 153.0, 137.4, 137.2,
130.1, 129.6, 128.6, 128.2, 123.4, 121.6, 115.0, 111.9,
ꢀ
IR (KBr): m = 3,114, 1,748, 1,626, 1,475, 1,406, 1,385,
1,353, 1,278, 1,195, 1,122, 1,091, 1,015, 929, 867, 808,
106.1, 54.8, 36.4 ppm; ESI-MS: m/z = 428.1 ([M ? H]?),
?
ꢀ
450.3 ([M ? Na] ); IR (KBr): m = 3,101, 2,950, 1,635,
1,576, 1,480, 1,384, 1,322, 1,296, 1,259, 1,152, 1,113,
724 cm-1
.
1,047, 1,007, 818, 784, 754 cm-1
.
6-(4-Hydroxy-3-methoxybenzyl)-3-(4-hydroxyphenyl)-7H-
thiazolo[3,2-b][1,2,4]triazin-7-one (4k, C19H15N3O4S)
M.p.: 258–260 °C; 1H NMR (600 MHz, DMSO-d6):
d = 9.95 (s, 1H, OH), 8.82 (s, 1H, OH), 7.50 (d,
J = 7.8 Hz, 2H, Ar), 7.33 (s, 1H, Ar), 6.88 (s, 1H,
S-CH2), 6.80 (d, J = 7.8 Hz, 2H, Ar), 6.67 (m, 2H, Ar),
3.86 (s, 2H, Ar-CH2), 3.72 (s, 3H, OCH3) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 164.5, 159.5, 158.3, 155.6,
153.9, 151.7, 136.5, 134.2, 131.6, 127.9, 127.6, 121.6,
115.5, 114.3, 106.6, 54.2, 36.1 ppm; ESI-MS: m/z = 381.9
3-(4-Chlorophenyl)-6-(3-methoxybenzyl)-7H-thiazolo[3,2-b]-
[1,2,4]triazin-7-one (4e, C19H14ClN3O2S)
M.p.: 213–214 °C; 1H NMR (300 MHz, CDCl3): d = 7.48
(d, J = 8.6 Hz, 2H, Ar), 7.40 (d, J = 8.6 Hz, 2H, Ar), 7.22
(t, 1H, Ar), 6.90 (d, 2H, Ar), 6.83 (s, H, S-CH), 6.80 (m,
1H, Ar), 4.10 (s, 2H, Ar-CH2), 3.77 (s, 3H, OCH3) ppm;
13C NMR (75 MHz, CDCl3): d = 164.8, 159.7, 157.4,
153.5, 138.1, 137.7, 133.1, 129.5, 128.5, 128.2, 121.9,
121.6, 115.4, 111.4, 105.9, 55.2, 36.9 ppm; ESI-MS:
m/z = 284.2 ([M ? H]?), 589.3 ([2M ? Na]?); IR
?
?
ꢀ
([M ? H] ), 784.8 ([2M ? Na] ); IR (KBr): m = 3,243,
1,611, 1,513, 1,472, 1,384, 1,353, 1,262, 1,243, 1,176,
ꢀ
(KBr): m = 3,103, 2,932, 1,636, 1,577, 1,482, 1,403,
1,384, 1,297, 1,258, 1,154, 1,115, 1,090, 1,050, 1,010,
1,126, 1,036, 882, 834, 813, 767, 746 cm-1
.
846, 819, 785, 767, 756 cm-1
.
6-(4-Hydroxy-3-methoxybenzyl)-3-(4-hydroxy-3-methyl-
phenyl)-7H-thiazolo[3,2-b][1,2,4]triazin-7-one
3-(4-Hydroxyphenyl)-6-(4-methoxybenzyl)-7H-thiazolo-
[3,2-b][1,2,4]triazin-7-one (4f, C19H15N3O3S)
M.p.: 188–189 °C (Ref. [15] 188–189 °C).
(4l, C20H17N3O4S)
M.p.: 249–251 °C; 1H NMR (600 MHz, DMSO-d6):
d = 9.84 (s, 1H, OH), 8.80 (s, 1H, OH), 7.35 (s, 1H, Ar),
7.32 (d, 1H, Ar), 7.29 (s, 1H, Ar), 6.87 (s, 1H, S-CH), 6.81
(d, 1H, Ar), 6.67 (t, 2H, Ar), 3.86 (s, 2H, Ar-CH2), 3.70 (s,
3H, OCH3), 2.10 (s, 3H, CH3) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 164.2, 159.1, 157.9, 154.7, 152.8, 151.9,
135.2, 133.7, 131.2, 128.3, 127.5, 123.4, 121.6, 115.1,
6-(4-Hydroxybenzyl)-3-(4-hydroxyphenyl)-7H-thiazolo-
[3,2-b][1,2,4]triazin-7-one (4g, C18H13N3O3S)
M.p.: 292–294 °C (Ref. [19] 292–294 °C).
6-(4-Hydroxybenzyl)-3-(4-hydroxy-3-methylphenyl)-7H-
thiazolo[3,2-b][1,2,4]triazin-7-one (4h, C19H15N3O3S)
M.p.: 187–189 °C; 1H NMR (300 MHz, CDCl3): d = 7.58
(m, 3H, Ar), 7.23 (d, H, Ar), 7.09 (d, 2H, Ar), 6.70 (s, H,
Ar), 6.66 (s, H, S-CH), 3.86 (s, 2H, Ar-CH2), 2.16 (s, 3H,
CH3) ppm; 13C NMR (75 MHz, CDCl3): d = 164.1, 158.5,
157.4, 153.4, 152.7, 133.4, 132.8, 129.6, 128.5, 128.1,
127.4, 126.3, 124.5, 115.9, 115.5, 106.6, 36.1, 23.4 ppm;
ESI-MS: m/z = 366.3 ([M ? H]?), 388.2 ([M ? Na]?);
114.6, 105.9, 53.9, 36.5, 24.1 ppm; ESI-MS: m/z = 395.9
?
ꢀ
([M ? H] ); IR (KBr): m = 3,206, 2,934, 1,621, 1,603,
1,514, 1,475, 1,405, 1,384, 1,342, 1,296, 1,258, 1,195,
1,155, 1,126, 1,047, 841, 786, 752, 709 cm-1
.
Acknowledgments We are grateful to Prof. Hu for discussions and
Mr. Hao ChE for measuring the MS and NMR spectra.
ꢀ
IR (KBr): m = 3,224, 3,108, 2,926, 2,646, 1,774, 1,710,
1,613, 1,534, 1,516, 1,493, 1,408, 1,384, 1,327, 1,264,
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