A microwave-assisted solid-state synthesis and characterization of diheterocyclic thioureas

Article abstract of DOI:10.1002/hc.20193

In this study, a number of new diheterocyclic thioureas have been synthesized under microwave irradiation coupled with solvent-free condition, which proves to be simple and efficient. The structures of the prepared compounds are characterized by elemental

Full text of DOI:10.1002/hc.20193

Heteroatom Chemistry
Volume 17, Number 2, 2006
A
Microwave-Assisted Solid-State Synthesis
and Characterization of Diheterocyclic
Thioureas
Jianping Li, Chunming Ma, and Guirong Qu
College of Chemistry and Environmental Science, The Key Laboratory of Environmental
Pollution Control of Henan Province, Henan Normal University, Xinxiang, Henan 453007,
People’s Republic of China
Received 10 July 2005; revised 15 September 2005
N-heterocyclic compounds (such as antipyrine) have
ABSTRACT: In this study, a number of new dihete-
been found to exhibit wide physiological activ-
rocyclic thioureas have been synthesized under mi-
ity [9]. Meanwhile, 4-aminoantipyrine is a versa-
crowave irradiation coupled with solvent-free condi-
tile reagent, which has been extensively utilized
tion, which proves to be simple and efficient. The
in heterocyclic synthesis. It has been found that
structures of the prepared compounds are character-
antipyrine and its derivatives possess antibacte-
1
13
ized by elemental analysis, IR, H NMR, and C NMR
rial [10] and anti-inflammatory properties [11].
spectra. ꢀC 2006 Wiley Periodicals, Inc. Heteroatom Chem
Some N-antipyrinyl compounds, such as N,N-
diantipyrinyl thiourea and N-allyl-N -antipyrinyl
1
7:148–151, 2006; Published online in Wiley InterScience
ꢁ
(
www.interscience.wiley.com). DOI 10.1002/hc.20193
thiourea, could be used for extracting copper,
silver, gold, and platinum and for determining
the micropalladium [12]. Therefore, particularly
intense interest has been directed toward their
synthesis.
Recently, we prepared 4-antipyrinyl isothio-
cyanate [13–15] (Scheme 1) and studied the reac-
tion of 4-antipyrinyl isothiocyanate and heterocyclic
amines assisted by microwave. A series of dihetero-
cyclic thioureas containing 4-antipyrinyl framework
were obtained with excellent yields.
INTRODUCTION
It is now well known that, with the development
of microwave ovens, solvent-free reactions have be-
come easier due to their short reaction time, uni-
form heating, high yields, high efficiency, and con-
venient work-up conditions [1]. Meanwhile, it also
leads to increase in safety and environmental aspects
[2]. All these merits are in accordance with the green
production’s requests of energy saving and high effi-
ciency [3]. Today, it has been widely used in a variety
of organic reactions [4].
RESULTS AND DISCUSSION
Heterocyclic thiourea compounds are known
to exhibit antiviral [5], antituberculous [6], fungi-
cidal [7], and herbicidal activities [8]. Some
As shown in Scheme 1, 4-antipyrinyl isothio-
cyanate 2 was prepared from the reaction of
4-aminoantipyrine with carbon disulfide and ethyl
chlorocarbonate in the presence of triethylamine as
a catalyst. The structure of compound 2 was con-
Correspondence to: Jianping Li; e-mail: jpli@henannu.edu.cn.
Contract grant sponsor: Natural Science Foundation of China.
Contract grant number: 20372018.
+
firmed by MS spectra-245 (M ), elemental analysis,
−
1
1
IR spectra (N C S, 2038 cm ), and H NMR spec-
tra (the signals of no NH protons).
ꢀ
c 2006 Wiley Periodicals, Inc.
1
48

A Microwave-Assisted Solid-State Synthesis and Characterization of Diheterocyclic Thioureas 149
The synthesis of diheterocyclic thioureas 4a–e
was readily achieved according to the following
solvent-free procedure (Scheme 2). Heterocyclic
amine 3a–e and 4-antipyrinyl isothiocyanate 2 was
mixed thoroughly in a mortar, which was then
placed into a household microwave oven and then
irradiated for the specified time under solvent-free
condition. When the reaction was placed in a fo-
SCHEME 1
A number of different amines were chosen to
cused microwave oven, several experiments were
performed at various powers and irradiation times
in order to find the most appropriate conditions. As
shown by the results in Table 1, the use of focused
microwave irradiations without solvent gave high
yields under very mild conditions in a short reaction
assess the scope of the reaction. The synthetic results
are presented in Table 1. Generally speaking, this re-
action gives very good yields with primary amines
allowing us to obtain the corresponding thiourea as
the only product.
TABLE 1 Reaction Time, Melting Point, and Yields of Diheterocyclic Thioureas 4
Irradiation
Melting
Point ( C)
◦
Entry
Amine (3)
Product (4)
Time (min)
Yield (%)
a
15
248–250
212–214
216–218
224–226
245–247
90
b
c
5a
15
15
10
98
90
95
98
d
e
f
40
40
–
–
0
0
g
aIrradiation power: 300 W.

1
50 Li, Ma, and Qu
chemistry and physiological activity is in progress in
our laboratory.
EXPERIMENTAL
Melting points were determined with a Kofler
micromelting point apparatus and were uncor-
rected. IR was recorded on a FTS-40 spectropho-
tometer using KBr pellets. H NMR and C NMR
spectra were measured on a Bruker DPX-400 spec-
trometer at 400 and 100 MHz, respectively, using
SCHEME 2
1
13
time (5–15 min). The reaction was monitored by
TLC.
TMS as internal standard and DMSO-d as sol-
6
It was observed that in the case of 2-amino-
pyridine 3a and 3-aminopyridine 3b, the corre-
sponding thioureas (4a, 4b) were obtained with
different rates; 3-aminopyridine reacted faster than
vent. Chemical shifts (δ) were expressed in ppm
downfield from internal standard TMS. Elemental
analyses were performed on PE-2400 CHN elemen-
tal analyzer. The experiment was carried out with
Galanz microwave oven (750 W).
2-aminopyridine, which show a regular chemical be-
havior according to the nucleophilic activity of the
amino group, that is, in the addition reaction, amines
with high nucleophilic activity can accelerate the re-
action, while those with low nucleophilic activity re-
sult in longer reaction time. It is also noteworthy that
in the case of cytosine and 6-chloro-2-purinamine,
the corresponding thioureas were obtained with very
long time and low yield, probably for their low
Microwave Irradiation Synthesis of Dihetero-
cyclic Thioureas 4a–e
A mixture of heterocyclic amine (1 mmol) and 4-
antipyrinyl isothiocyanate 2 was mixed thoroughly
in a mortar. The mixture was then placed into
a household microwave oven and then irradiated
for the specified time under solvent-free condition
(495 W or 300 W). The end of the reaction was mon-
itored by TLC. After the reaction was completed, the
crude products were recrystallized from ethanol, and
dried in vacuum to yield the pure products.
nucleophilic activity and very high melting point
◦
(
>300 C), which seemed no synthetic utility in these
conditions.
The simplicity of the experimental procedures
renders this method particularly attractive. In a sim-
ilar way, we have also studied the addition of 2 to
the secondary heterocyclic amines 5-methyluracil 3f
and 2,6-dichloropurine 3g in the same reaction con-
ditions. However, we did not obtain the desired com-
pounds and the starting materials were recovered
unchanged. The reaction seems to be very sensitive
to steric effects. Therefore, the scope of this reac-
tion seems to be limited to the primary heterocyclic
amines.
ꢁ
N-(4-Antipyrinyl)-N -(2-pyridyl) Thiourea 4a [14].
White crystals; IR (KBr) ν: 3218, 3175, 3105, 3037,
2997, 1687 (C O), 1631, 1603, 1539, 1487, 1293
−
1
1
(C S), 788, 752, 698 cm . H NMR (400 MHz,
DMSO-d ) δ: 2.21 (s, 3H, CH ), 3.11 (s, 3H, CH ),
8.28–7.09 (m, 9H, ArH), 10.94 (s, 1H, N H), 12.52
(s, 1H, N H). Anal. Calcd for C17 OS: C, 60.14;
6
3
3
H
17
N
5
H, 5.05; N, 20.63; Found: C, 60.25; H, 5.09; N, 20.51.
In conclusion, we have developed a very sim-
ple, efficient, and environment-friendly methodology
for the synthesis of diheterocyclic thioureas. This
methodology works under solvent-free conditions
assisted by microwave irradiation and affords in very
high yields the corresponding products, which re-
quire no organic solvent, catalyst, and complicated
instruments. No by-product is formed during the
reaction. The reaction works very well for primary
heterocyclic amines, while some low nucleophilic
with very high melting point amines and sterically
hindered secondary amines in general cannot be
used. The structures of the prepared compounds
ꢁ
N-(4-Antipyrinyl)-N -(3-pyridyl) Thiourea 4b [15].
White powder; IR (KBr) ν: 3260, 3230, 3105, 3046,
2933, 1633 (C O), 1601, 1580, 1565, 1531, 1295
−
1
1
(C S), 761, 713 cm . H NMR (400 MHz, DMSO-
) δ: 2.22 (s, 3H, CH ), 3.09 (s, 3H, CH ), 8.59–
7.33 (m, 9H, ArH), 9.12 (s, 1H, N H), 9.79 (s, 1H,
d
6
3
3
1
3
N H). C NMR (100 MHz, DMSO-d ) δ: 11.85,
36.57, 123.97, 125.03, 127.53, 130.00, 130.09, 136.00,
137.58, 146.47, 147.05, 162.58 (C O), 183.08 (C S).
N OS: C, 60.14; H, 5.05; N,
20.63; Found: C, 60.16; H, 5.00; N, 20.75.
6
Anal. Calcd for C17
H
17
5
1
ꢁ
were characterized by elemental analysis, IR, H
N-(4-Antipyrinyl)-N -(2-thiazole) Thiourea 4c.
1
3
NMR, and C NMR spectra. And more detailed work
about the application of the thioureas in analytical
Pale yellow crystals; IR (KBr) ν: 3225, 3202, 3102,
2993, 1643 (C O), 1599, 1562, 1493, 1290 (C S),

A Microwave-Assisted Solid-State Synthesis and Characterization of Diheterocyclic Thioureas 151
−
1
1
7
2
7
46, 700 cm . H NMR (400 MHz, DMSO-d
.19 (s, 3H, CH ), 3.12 (s, 3H, CH ), 8.54–7.08 (m,
H, ArH), 9.80 (s, 1H, N H), 11.96 (s, 1H, N H).
: C, 52.15; H, 4.38; N,
0.27; Found: C, 52.10; H, 4.42; N, 20.35.
6
) δ:
[2] Villa, C.; Genta, M. T.; Bargagna, A.; Mariani, E.;
Loupy, A. Green Chem 2001, 3, 196.
3
3
[
3] (a) Deshayes, S.; Marion, L.; Loupy, A.; Luche, J. L.;
Petit, A. Tetrahedron 1999, 55, 10851; (b) Tan, N. Y.;
Xiao, X. M.; Li, Z. L. Chin Chem Lett 2004, 15,
687.
Anal. Calcd for C15
H
15
N
5
O
2
S
2
2
[
4] (a) Kaval, N.; Dehaen, W.; Matyus, P.; Eycken, E. V.
Green Chem 2004, 125; (b) Je s˘ elnik, M.; Varma,
R. S.; Polanc, S.; Kocevar, M. Chem Commun 2001,
ꢁ
N-(4-Antipyrinyl)-N -(2-benzothiazole) Thiourea
4
3
1
d [14]. White crystals; IR (KBr) ν: 3225, 3196,
105, 3062, 3003, 1648 (C O), 1603, 1567, 1524,
302 (C S), 764, 752, 697 cm . H NMR (400 MHz,
) δ: 2.21 (s, 3H, CH ), 3.14 (s, 3H, CH ),
.90–7.27 (m, 9H, ArH), 10.09 (s, 1H, N H), 12.37
s, 1H, N H). Anal. Calcd for C19 OS: C, 62.79;
1
716.
[
[
[
[
5] Galabov, A. S.; Galabov, B. S.; Neykova, N. A. J Med
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−1 1
DMSO-d
6
3
3
7
(
H
17
N
5
H, 4.71; N, 19.27; Found: C, 62.75; H, 4.75; N, 19.22.
5
117d.
ꢁ
[9] (a) Li, X. L.; Wang, Y. M.; Do, D. M.; Wen, Z.;
Xiong, G. Q. Sci China (Sr B) 1997, 27, 202;
N,N -Diantipyrinyl Thiourea 4e. Pale yellow
crystals; IR (KBr) ν: 3270 (N H), 3110, 3030, 2981,
662 (C O), 1631 (C=C), 1595, 1532, 1497, 1298
(
b) Huang, Z. S.; Wu, X. L.; Liu, Y.; Jiang, L. S.;
1
(
Wang, Z. C.; Gu, L. Q. Youji Huaxue 1998, 18,
481.
−1 1
C S), 763, 701 cm . H NMR (400 MHz, DMSO-d
δ: 2.18 (s, 3H, CH ), 3.08 (s, 3H, CH ), 7.51–7.29 (m,
H, ArH), 8.79 (s, 2H, 2N H). C NMR (100 MHz,
DMSO-d ) δ: 12.00, 36.75, 120.50, 124.68, 127.22,
30.03, 130.31, 136.30, 163.09 (C O), 184.47 (C S).
Anal. Calcd for C23 S: C, 61.59; H, 5.39; N,
8.74; Found: C, 61.65; H, 5.45; N, 18.63.
6
)
[10] Alaudeen, M.; Abraham, A.; Radhakrishnan, P. K. Pro
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3.
3
3
1
3
9
[
6
1
[
H
24
N
6
O
2
1
[13] Ma, C. M.; Li, J. P.; Zheng, P. Z. Heterocycles 2005,
5, 359.
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6
[
[
4
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