Ultrasonic irradiated synthesis of N-(5-aryl-2-furoyl)thiourea derivatives containing substituted pyrimidine ring under phase transfer catalysis

Article abstract of DOI:10.1002/jccs.200400151

A series of N-(5-aryl-2-furoyl)thiourea derivatives containing substituted pyrimidine ring were synthesized in good yield using PEG-400 as solid-liquid phase transfer catalyst under ultrasonic irradiation. The structures of all newly synthesized compounds

Full text of DOI:10.1002/jccs.200400151

Journal of the Chinese Chemical Society, 2004, 51, 1013-1018
1013
Ultrasonic Irradiated Synthesis of N-(5-aryl-2-furoyl)thiourea Derivatives
Containing Substituted Pyrimidine Ring under Phase Transfer Catalysis
Si-Jia Xuea (
), Shao-Yong Kea* (
), Tai-Bao Weib (
),
Li-Ping Duana (
) and Yan-Ling Guoa (
)
aDepartment of Chemistry, Shanghai Normal University, Shanghai, 200234, P. R. China
bDepartment of Chemistry, Northwest Normal University, Lanzhou, 730070, P. R. China
A series of N-(5-aryl-2-furoyl)thiourea derivatives containing substituted pyrimidine ring were synthe-
sized in good yield using PEG-400 as solid-liquid phase transfer catalyst under ultrasonic irradiation. The
structures of all newly synthesized compounds were elucidated and confirmed by IR, 1H NMR and elemental
analysis. Our method has the advantage of shorter reaction time and higher reaction yield compared to the
conventional heating method. Preliminary biological tests show that some of the target compounds have
better inhibitory activities against roots and stalks of monocotyledon and dicotyledon plants.
Keywords: 5-Aryl-2-furoyl thiourea; 2-Amino pyrimidine; Ultrasonic irradiation; Phase transfer catal-
ysis; Synthesis; Bioactivity.
INTRODUCTION
Various types of biological activities including pestici-
and confirmed by IR, 1H NMR and elemental analysis. Pre-
liminary biological tests show that some of the target com-
pounds have better inhibitory activities against roots and
stalks of monocotyledon and dicotyledon plants.
The title compounds were synthesized by the method in
Scheme I.
dal, herbicidal, fungicidal, and insecticidal activity and the
promoting effect on plant growth have been established for
acylthiourea derivatives1,2,3 and which are also important in-
termediates in organic synthesis. In recent years, the phase
transfer catalysis reaction has been widely recognized as an
efficient synthetic tool and has become one of the most attrac-
tive techniques in organic synthesis.4,5 In addition, we know
that the use of ultrasonic irradiation as a method of agitating a
heterogeneous reaction system is gaining recognition;6,7 ul-
trasonic waves have been utilized in organic synthesis for
their lower reaction temperature and simple operation as
compared with the conventional heating method,8-11 and the
use of ultrasonic irradiation in the presence of PTC for or-
ganic synthesis is well documented.12-15 Moreover, 5-aryl-2-
furoic acid derivatives have been reported as better fungi-
cides and regulators for plant growth.16,17 In view of this, we
report herein the synthesis and biological activity of 5-aryl-
2-furoyl thiourea containing substituted pyrimidine ring us-
ing PEG-400 as solid-liquid phase transfer catalyst under ul-
trasonic irradiation. This is a facile synthesis of acylthiourea
derivatives accelerated by ultrasonic irradiation. The struc-
tures of all newly synthesized compounds were elucidated
RESULTS AND DISCUSSION
In connection with our interest in the synthesis and bio-
logical evaluation of acylthiourea derivatives,18-21 we now re-
port herein a facile and efficient method for the synthesis of
5-aryl-2-furoyl thiourea derivatives under ultrasonic irradia-
tion. In the presence of acetonitrile, 5-aryl-2-furoyl chloride
directly reacted with potassium thiocynate using PEG-400 as
solid-liquid phase transfer catalyst under ultrasonic irradia-
tion to give the intermediate acyl isothiocyanate, then the in-
termediate undergoes a fast reaction with an added amino py-
rimidine to give the corresponding 5-aryl-2-furoyl thiourea
derivatives containing substituted pyrimidine ring in good to
excellent yield. In our experiment, the ultrasonic and phase
transfer catalysis techniques represented a better procedure
in terms of good yield, milder reaction conditions, easier
workup, and it was found that the ultrasonic irradiation was
* Corresponding author. E-mail: keshaoyong@163.com

1014 J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004
Xue et al.
Scheme I
R
N2+Cl-
R
R
SOCl2
COCl
COOH
COOH
O
O
O
CuCl2
1
2
3
X
N
N
H2N
X
O
S
R
N
N
R
KSCN/CH3CN
PEG-400
Y
CNHCNH
CONCS
O
O
Y
4
5
6
spectroscopic data, IR and 1H NMR. The IR (KBr) spectrum
displayed absorptions at about 3225 cm-1, 1650 cm-1 and
1200 cm-1, which are assigned to N-H, C=O and C=S func-
tions, respectively. The medium-strong nC=O band in the IR
spectra of all the compounds appears at about 1650 cm-1, ap-
parently decreasing in wavenumber compared with the ordi-
nary carbonyl absorption (1710 cm-1). The 1H NMR (DMSO-
d6) spectrum revealed signals at about d 12.90 and 12.20 that
were attributed to the protons of N-H, in addition to, the sin-
glet and multiplet signals at about d 6.50 and d 7.20-8.50
were assigned to pyrimidine-CH and aromatic protons, re-
spectively. Based on the foregoing spectral data, the target
compounds were assigned the structure 6. Some compounds
are very soluble in chloroform and dichloromethane; the oth-
ers can be dissolved in DMF, DMSO and other nonprotic sol-
vents.
Table 1. The substituents of target compounds 6a-6j*
Compd.
6a, 6f
6b, 6g
6c, 6h
6d, 6i
6e, 6j
X
Y
OCH3
OCH3
CH3
CH3
CH3
OCH3
CH3
OC2H5
OH
CH3
* 6a-6e, R = 4-NO2; 6f-6j, R = 2-Cl.
very simple and convenient for the synthesis of acylthiourea
derivatives using ultrasonic cleaner with a frequency of 35
KHz.
With our present knowledge, the reactions of acyl iso-
thiocyanates with nucleophiles are complex, since addition to
the -N=C=S system and nucleophilic substitution at the car-
bonyl-carbon atom may compete with one another.22 Acyl
isothiocyanates have been prepared under liquid-liquid phase
transfer catalysis using tetrabutylammonium bromide as the
catalyst, which after isolation reacted with aniline to give the
corresponding thiourea derivatives.23 However, in the pres-
ence of water, hydrolysis of the acyl chloride may occur, and
the yield of the acyl isothiocyanate is decreased. Harrison has
also reported that polymer-supported thiocyanate treated
with benzoyl chloride in benzene yielded benzoyl isothio-
cyanate, but the preparation of the polymer-supported re-
agent required long reaction times and vacuum conditions.24
In search of improving methods to prepare acylthiourea by
reacting acyl isothiocyanates with nucleophiles, we have
found the ultrasonic vibration of a mixture of acyl chloride,
potassium thiocyanate and 3% PEG-400 in acetonitrile can
obtain acyl isothiocyanates in good yield. In this paper, we
have conducted our reaction using ultrasonic irradiation in
the presence of PTC; this modified method shortened the re-
action time from 5-6 h to 1-1.5 h and improved yield com-
pared with the conventional method.
All physical data for the target compounds 6 are given
1
in Table 2, and the H NMR and IR data of the target com-
pounds 6 can be obtained in Table 3.
Biological activity
The biological activities of compounds 6a-6j have been
determined by the flat-utensil method according to the stan-
dard bioactivity test procedures of the Shanghai Branch of
the National Pesticide R&D South Central in China. Com-
pounds 6e, 6j, etc. showed inhibitory activities against roots
and stalks of dicotyledon and monocotyledon plants used.
The inhibition percentage of some compounds is shown in
Table 4. The results revealed that compound 6e has high in-
hibitory activities against roots and stalks of dicotyledon
plants (such as Chenopodium serotinum L.) and active against
roots and stalks of monocotyledon plants (such as Digitaria
sanguinalis (L.) Scop) in higher concentrations (1.0 ´ 10-4),
and the inhibitory rate to the root and stalk attain 100% and
90%, respectively; compound 6j has good inhibitory activi-
All the structures of the newly synthesized compounds
6 were assigned on the basis of their elemental analyses and

Synthesis of N-(5-aryl-2-furoyl)thiourea Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004 1015
Table 2. Physical constants of compounds 6a-6j
Analytical data.
Calcd. (%) (Found)
Molecular formula
Formula weight
M.P.
(°C)
Compd.
Appearance
Yield (%)
C
H
N
C18H15N5O6S
429
C18H15N5O4S
397
C18H15N5O5S
413
C19H17N5O5S
443
C17H13N5O5S
399
C18H15ClN4O4S
418.5
C18H15ClN4O2S
386.5
C18H15ClN4O3S
402.5
50.35
(50.27)
54.41
(54.56)
52.30
(52.43)
51.47
(51.35)
51.13
(51.04)
51.61
(51.70)
55.89
(55.96)
53.66
(53.74)
52.72
3.50
(3.38)
3.78
(3.65)
3.63
(3.54)
3.84
(3.92)
3.26
(3.39)
3.58
(3.47)
3.88
(3.91)
3.73
(3.64)
3.93
16.32
(16.41)
17.63
(17.52)
16.95
(17.02)
15.80
(15.68)
17.54
(17.42)
13.38
(13.25)
14.49
(14.35)
13.91
(14.02)
12.95
6a
6b
6c
6d
6e
6f
light yellow powder 186-187
78
80
82
74
86
88
84
85
80
77
white powder
yellow powder
196-198
202-204
light yellow powder 208-209
light yellow powder 225-227
white powder
188-189
6g
6h
6i
light yellow powder 193-195
light yellow powder 209-210
C19H17ClN4O3S
432.5
C17H13ClN4O3S
388.5
white powder
white powder
190-191
213-215
(52.85)
52.51
(52.60)
(3.87)
3.35
(3.28)
(13.02)
14.41
(14.49)
6j
Table 3. IR and 1H NMR data of compounds 6a-6j*
IR (nmax/cm-1, KBr)
1H NMR (d, ppm)
Compd.
N-H
C=O
C=S
Ar-H
Py-H
6.08
N-H
N¢-H OCH3/CH2
CH3
7.54-8.38
12.18
12.85 3.83
6a
6b
6c
6d
6e
6f
3190 1615 1260
3205 1650 1252
3217 1645 1215
3215 1630 1230
3245 1660 1226
3195 1648 1235
3210 1640 1218
3213 1632 1212
3185 1652 1235
3200 1647 1245
----
(m, 6H) (s, 1H) (s, 1H) (s, 1H) (s, 6H)
7.05-8.40
(m, 6H) (s, 1H) (s, 1H) (s, 1H)
7.10-8.23 6.44 12.42 12.78
6.80
12.62
12.87
2.40
(s, 6H)
2.25
(s, 3H)
1.18; 2.32
----
3.80
(m, 6H) (s, 1H) (s, 1H) (s, 1H) (s, 3H)
7.14-8.28 6.38 12.35 12.83 4.21
(m, 6H) (s, 1H) (s, 1H) (s, 1H) (q, 2H) (t, 3H; s, 3H)
7.32-8.36
(m, 6H) (s, 1H) (s, 1H) (s, 1H)
7.24-7.86 6.12 12.18 12.52
6.28
12.25
12.74
2.36
(s, 3H)
----
3.86
----
----
(m, 6H) (s, 1H) (s, 1H) (s, 1H) (s, 6H)
7.18-7.81 6.75 12.15 12.64 2.35
(m, 6H) (s, 1H) (s, 1H) (s, 1H) (s, 6H)
7.15-7.84 6.43 12.36 12.75 3.88
(m, 6H) (s, 1H) (s, 1H) (s, 1H) (s, 3H)
7.23-7.94 6.36 12.21 12.84 4.12
6g
6h
6i
2.31
(s, 3H)
1.15; 2.36
(m, 6H) (s, 1H) (s, 1H) (s, 1H) (q, 2H) (t, 3H; s, 3H)
7.10-8.12
6.34
12.30
12.81
2.42
(s, 3H)
6j
----
(m, 6H) (s, 1H) (s, 1H) (s, 1H)
*Abbreviations: s = singlet, t = triplet, q = quarterlet, m = multiplet, Py = pyrimidine.

1016 J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004
Xue et al.
Table 4. The inhibition percentage of some active compounds to kinds of plants
Conc.
(ppm)
Echinochloa Sorghum
Digitaria
Chenopodium Amaranthus
Compd.
Inhibition
crusgallis L. bicolot sanguinalis (L.) scop serotinum L. retroflexus L.
The stalk
The root
The stalk
The root
The stalk
The root
The stalk
The root
The stalk
The root
The stalk
The root
0
70
0
80
10
90
0
0
0
20
30
80
30
50
40
90
40
90
0
20
10
20
10
10
70
90
80
90
90
90
0
70
60
80
80
85
85
90
90
90
0
10
50
6e
80
100
100
0
0
20
20
100
100
100
10
0
0
60
70
70
80
20
20
20
20
50
6j
100
ties against roots and stalks of dicotyledon plants (such as
Chenopodium serotinum L.) in higher concentrations (1.0 ´
10-4), and the inhibitory percentage to the root and stalk attain
100%.
chemical or analytical grade purity. Sulfuric chloride was
distilled before use and potassium thiocyanate was baked be-
fore use. 2-Amino-4,6-disubstitute-pyrimidine 5 was pre-
pared by the literature method.25
The melting points were determined on an XT4A micro
digital melting point apparatus and are uncorrected. The iso-
lated compounds 6 were characterized by elemental micro-
analyses. The C, H and N analyses were repeated twice. The
result of elemental analyses are listed in Table 2. IR spectra
were obtained on a Nicolet 5DX FT-IR spectrophotometer in
CONCLUSIONS
In this paper, we have conducted our reaction using
PEG-400 as solid-liquid phase transfer catalyst under ultra-
sonic irradiation; PEG-400 as a phase transfer catalyst is in-
dispensable for these reactions. It can easily react with KSCN
to form complex [PEG-400-K+]SCN-, which makes it possi-
ble for SCN- to readily react with 5-aryl-2-furoyl chloride
and leads to the formation of intermediate 4. In summary, this
is a facile and convenient method for the synthesis of acyl
thiourea derivatives containing substituted pyrimidine ring,
with the advantages of simple operation, short reaction times
and good yields over the typical method, which can make this
procedure a useful and attractive alternative to the currently
available methods. In addition our ultrasonic irradiation
method distinctly improves the efficiency of the synthetic
process and shortens the reaction time. The catalyst PEG-400
is inexpensive, relatively nontoxic, highly stable and easily
available.
1
the region 4000-400 cm-1 KBr discs. H NMR spectra were
recorded on a Varian-300-54 spectrometer with d6-DMSO as
the solvent. Chemical shift values are reported in ppm (d) rel-
ative to TMS as internal standard. Thin layer chromatogra-
phy (TLC) analyses were carried out on 5 ´ 20 cm plates
coated with silica gel GF254 type 60 (50-250 mesh) using a
ethyl acetate-petroleum ether mixture (1:2) as solvent. Ultra-
sonic irradiation was performed within a CQ-250S ultrasonic
cleaner (35 ± 5% KHz, 250 W, made in Shanghai J&L Ultra-
sonic Ltd., Shanghai, P. R. China).
Synthesis of 5-aryl-2-furoic acid (2)
To an ice cold solution of substituted phenylamine
(0.05 mol), water (10 mL) and concentrated hydrochloric
acid (14 mL), a solution containing 3.45 g (0.05 mol) sodium
nitrite in 10 mL water was cooled to 0 °C and slowly added
dropwise over a 20 min period with stirring, and then the re-
action mixture was stirred at 0-5 °C for about 30 min. There-
after, the reaction mixture was filtered to yield a clear solu-
tion. Then furoic acid (0.03 mol), acetone (25 mL), copper
EXPERIMENTAL SECTION
All starting materials are commercial products of

Synthesis of N-(5-aryl-2-furoyl)thiourea Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004 1017
chloride (2.10 g), water (10 mL) and the clear solution were
placed in a round-bottomed flask containing a magnetic stir-
rer and stirred at room temperature for several hours; the pre-
cipitate solid was filtered off, and then dissolved in the solu-
tion of sodium hydrogen carbonate; the mixture was filtered
off, and the filtrate was acidified by hydrochloric acid to
yield precipitate, the resulting precipitate was collected and
recrystallized from DMF-C2H5OH-H2O to obtain pure 5-
aryl-2-furoic acid 2. 5-(4-nitro-phenyl)-2-furoic acid, m.p.
252-253 °C, Yield, 45%; 5-(2-chloro-phenyl)-2-furoic acid,
m.p. 203-205 °C, Yield, 53%.
tivities test was finished by the Shanghai Branch of National
Pesticide R&D South Central, China.
Received December 18, 2003.
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