Ultrasound promoted synthesis of bis(substituted pyrazol-4-ylcarbonyl)- substituted thioureas

Article abstract of DOI:10.3390/molecules14041423

A series of novel bis(substituted pyrazol-4-ylcarbonyl)-substituted thioureas have been synthesized by the reactions of substituted pyrazol-4-ylcarbonyl isothiocyanates with different diamines under ultrasound irradiation and classical heating method at 2

Full text of DOI:10.3390/molecules14041423

Molecules 2009, 14, 1423-1428; doi:10.3390/molecules14041423
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Ultrasound Promoted Synthesis of Bis(substituted pyrazol-4-
ylcarbonyl)-Substituted Thioureas
Li Xiao, Chen-Jiang Liu * and Yan-Ping Li
School of Chemistry and Chemical Engineering, Xinjiang University, Key Laboratory of Oil and Gas
Fine Chemicals, Ministry of Education, 830046 Urumqi, P. R. China; E-mails:
xiaoli56490343@163.com (L.X.), lyp_666@163.com (Y-P.L.)
* Author to whom correspondence should be addressed. E-mail: pxylcj@126.com (C-J.L);
Tel.: +86-9918581211; Fax: +86-9918582809.
Received: 28 February 2009; in revised form: 15 March 2009 / Accepted: 23 March 2009 /
Published: 31 March 2009
Abstract: A series of novel bis(substituted pyrazol-4-ylcarbonyl)-substituted thioureas
have been synthesized by the reactions of substituted pyrazol-4-ylcarbonyl isothiocyanates
with different diamines under ultrasound irradiation and classical heating method at 20-25
°C. In general, substantial improvement in rates and modest yields increases were observed
when reactions were carried out under sonication, compared with the classical heating
method. The structures of these compounds have been elucidated by elemental and spectral
(IR, 1H-NMR) analysis.
Keywords: Thiourea; Pyrazole; Diamine; Ultrasound; Synthesis.
Introduction
Heterocycles bearing a pyrazole moiety represent an interesting class of compounds possessing a
wide spectrum of biological and pharmacological activities, such as herbicidal [1], antitumor [2],
antibacterial [3], antileukemic [4], anti-inflammatory [5] properties. On the other hand, thiourea
compounds have received much attention because of their wide range of biological properties such as
antituberculosis [6], anticancer [7], anti-HIV [8], antimicrobial [9] activity.
The use of ultrasound in chemistry, usually known as sonochemistry, has grown spectacularly in
recent years [10-11]. The success and advantages of sonochemical reactions include higher yields,

Molecules 2009, 14
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shorter reaction times and milder reaction conditions when compared with traditional methods.
Recently, we have reported mild and efficient procedures for the synthesis of 4-substituted pyrazolyl-
3,4-dihydropyrimidin-2(1H)-(thi)ones under ultrasonic irradiation [12]. As a part of our interest in the
synthesis of a wide range of heterocyclic systems, and in continuation of our research interest in the
use of ultrasonic irradiation [12], we wish to report herein the synthesis of some novel bis(substituted
pyrazol-4-ylcarbonyl)-substituted thioureas by the reaction of substituted pyrazol-4-ylcarbonyl
isothiocyanates with different diamines under ultrasound irradiation (US) and classical heating
conditions (CH) (Scheme 1).
Scheme 1. Synthesis of bis(substituted pyrazol-4-ylcarbonyl)-substituted thioureas.
O
S
S
O
O
CH3
CNCS
CH3
C NH C NH Ar NH C NH C
CH3
N
CH3CN
+
H2N Ar NH2
2
N
N
Ultrasound or heat
R
R
R
N
N
N
Ph
1
Ph
Ph
3a~3j
2
Results and Discussion
Data in Table 1 clearly show that the reactions of substituted pyrazol-4-ylcarbonyl isothiocyanates
with diamines leading to bis(substituted pyrazol-4-ylcarbonyl)-substituted thioureas was carried out
smoothly under both conventional and ultrasound irradiation conditions. Compared to the conventional
method, the achieved yields under ultrasound irradiation increased two or three percent and the
reaction times under ultrasound irradiation were dramatically shortened to 0.75 h from 7.5 h.
Therefore, ultrasound irradiation exhibited some advantages over the classical condition by improving
the reaction yields and reducing the reaction time. The difference in yields and reaction time (US >
CH) may be a consequence of the specific effects of ultrasound.
We also examined the effect of different ultrasound irradiation frequencies on the reactions. Thus,
in the case of compound 3a, for example, when the frequency was 28 kHz, the reaction required 45
min and resulted in the formation of the desired product in 74% yield, whereas when the frequencies
were 45 kHz or 100 kHz, the reaction was also complete in 45 min affording the product in 75% and
76% yield, respectively. This showed that the irradiation frequency did not significantly influence the
reactions, so all the other reactions were carried out in acetonitrile under 100 kHz ultrasound
irradiation.
The structures of the compounds 3a-j were established on the basis of elemental analysis and
spectral (IR, 1H-NMR) data. In the IR spectra of compounds 3a-j, one sharp absorption band was seen
at 1,650-1,678 cm-1, which belongs to the carbonyl function. The υ(NH) and υ(C=S) stretching
1
frequencies were observed at 3,402-3,044 cm-1 and 1,200-1,127 cm-1, respectively. In the H-NMR
spectra, the proton signals for compounds 3a-j were recorded at 12.60-12.25 ppm (carbonyl band NH)

Molecules 2009, 14
1425
and 9.84-9.40 ppm (benzene ring NH). At the same time, a singlet appearing at 2.26-2.48 ppm could
be assigned to the protons of the methyl group of the pyrazole ring.
Table 1. Comparison between ultrasound irradiation and conventional method.
Yields (%)a
Time (h)b
Entry
3a
R
Ar
Mp (°C)
189-190
205-206
Ac
Bc
Ac
Bc
Cl-
Cl-
73
76
7.5
0.75
3b
66
69
7.5
0.75
3c
3d
3e
Cl-
Cl-
Cl-
91
95
83
92
96
85
7.5
7.5
7.5
0.75
0.75
0.75
220-222
223-224
204-206
CH3
H3C
3f
PhO-
PhO-
80
71
81
73
7.5
7.5
0.75
0.75
210-211
203-205
3g
3h
3i
PhO-
PhO-
PhO-
79
84
76
83
86
78
7.5
7.5
7.5
0.75
0.75
0.75
235-237
218-220
226-228
CH3
H3C
3j
a Isolated yields; b Reactions were stopped on disappearance of starting materials by TLC;
c Method A: without ultrasound irradiation at 20-25 °C. Method B: under ultrasound irradiation at 20-25 °C.
Conclusions
In summary, we have developed an efficient procedure for the synthesis of bis(substituted pyrazol-
4-ylcarbonyl)-substituted thioureas under ultrasonic irradiation. We anticipate that these compounds
will be subjected to biomedical screening. This work is currently in progress and the results will be
reported in due course.
Experimental
General
Melting points were determined using a Büchi B-540 instrument and are uncorrected. The IR
spectra were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, U.S.A).
1
The H-NMR spectra were measured in CDCl3 on a Varian Inova-400 spectrometer using TMS as an
internal standard. Elemental (C, H, N) analysis was performed on a Perkin-Elmer Analyzer 2400.
Sonication was performed in a Kunshan KQ-100VDB ultrasonic cleaner with three frequencies (28

Molecules 2009, 14
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kHz, 45 kHz, 100 kHz) and a nominal power 100 W. The reaction flask was located in the maximum
energy area in the cleaner, where the surface of reactants is slightly lower than the level of the water.
The reaction temperature was controlled between 20-25 °C by addition or removal of water from
ultrasonic bath. Compounds 1 were synthesized according to literature methods [13].
Synthesis of bis(substituted pyrazol-4-ylcarbonyl) substituted thioureas 3a-3j
Method A (conventional heating): Substituted pyrazol-4-ylcarbonyl isothiocyanates (1 mmol), diamine
(0.5 mmol) and acetonitrile (25 mL) were placed in a Pyrex round bottom flask (50 mL). The mixture
was stirred for a specified period at 20-25 °C. After the reaction was completed (monitored by TLC),
the solids were filtered and dried at 20-25 °C. The crude mixture was recrystallized from a mixture of
DMF/H2O.
Method B (ultrasonic irradiation): Substituted pyrazol-4-ylcarbonyl isothiocyanates (1 mmol),
diamine (0.5 mmol) and acetonitrile (25 mL) were placed in a Pyrex round bottom flask (50 mL). The
mixture was sonicated (100 W) in a ultrasonic cleaning bath at 20-25 °C for a specified period. After
the reaction was complete (as monitored by TLC), the solids were filtered and dried at 20-25 °C. The
crude mixture was recrystallized from a mixture of DMF/H2O. Data of the compounds are shown
below.
1,2-Di[(5-chloro-3-methyl-1-phenylpyrazol-4-yl) acylthiourea]benzene (3a): white powder. IR (νmax.
,
cm–1): 3,402, 3,068, 1,672, 1,161; H-NMR (δ ppm): 12.36 (s, 2H, NH), 9.43 (s, 2H, NH), 8.05-7.26
(m, 14H, ArH), 2.51 (s, 6H, 2xCH3); Anal. calcd. for C30H24Cl2N8O2S2: C, 54.30; H, 3.65; N, 16.89.
Found: C, 54.21; H, 3.59; N, 16.98%.
1
1,3-Di[(5-chloro-3-methyl-1-phenylpyrazol-4-yl)acylthiourea]benzene (3b): flesh powder. IR (νmax.
,
cm–1): 3,395, 3,044, 1,666, 1,189; 1H-NMR (4δ ppm): 12.60 (s, 2H, NH), 9.33 (s, 2H, NH), 8.26-7.26
(m, 14H, ArH), 2.61 (s, 6H, 2xCH3); Anal. calcd. for C30H24Cl2N8O2S2: C, 54.30; H, 3.65; N, 16.89.
Found: C, 54.41; H, 3.72; N, 16.80%.
1,4-Di[(5-chloro-3-methyl-1-phenylpyrazol-4-yl acylthiourea]benzene (3c): grey powder. IR (νmax.
,
cm–1): 3,401, 3,065, 1,664, 1,164; H-NMR (δ ppm): 12.58 (s, 2H, NH), 9.42 (s, 2H, NH), 8.11-7.25
(m, 14H, ArH), 2.54 (s, 6H, 2xCH3); Anal. calcd. for C30H24Cl2N8O2S2: C, 54.30; H, 3.65; N, 16.89.
Found: C, 54.46; H, 3.72; N, 16.77%.
1
4,4'-Di[(5-chloro-3-methyl-1-phenylpyrazol-4-yl)acylthiourea]biphenyl (3d): light yellow powder. IR
(νmax., cm–1): 3,393, 3,054, 1,672, 1,157; 1H-NMR (δ ppm): 12.62 (s, 2H, NH), 9.35 (s, 2H, NH), 7.86-
7.26 (m, 18H, ArH), 2.62 (s, 6H, 2xCH3); Anal. calcd. for C36H28Cl2N8O2S2: C, 58.46; H, 3.82; N,
15.15. Found: C, 58.29; H ,3.76; N, 15.25%.
2,2'-Dimethyl-4,4'-di[(5-chloro-3-methyl-1-phenylpyrazol-4-yl)acylthiourea]biphenyl
(3e):
light
yellow powder. IR (νmax., cm–1): 3,415, 3,084, 1,672, 1,171; 1H-NMR (δ ppm): 12.62 (s, 2H, NH), 9.35

Molecules 2009, 14
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(s, 2H, NH), 7.86-7.26 (m, 16H, ArH), 2.62 (s, 6H, 2xCH3), 2.42 (s, 6H, 2xCH3); Anal. calcd. for
C38H32Cl2N8O2S2: C, 59.45; H, 4.20; N, 14.60. Found: C, 59.61; H, 4.24; N, 14.71%.
1,2-Di[(3-methyl-5-phenoxyl-1-phenylpyrazol-4-yl)acylthiourea]benzene (3f): light yellow powder. IR
(νmax., cm–1): 3,413, 3,075, 1,678, 1,145; 1H-NMR (δ ppm): 12.49 (s, 2H, NH), 9.36 (s, 2H, NH), 7.88-
7.32 (m, 24H, ArH), 2.55 (s, 6H, 2xCH3); Anal. calcd. for C42H34N8O4S2: C, 64.77; H, 4.40; N, 14.39.
Found: C, 64.65; H, 4.45; N, 14.35%.
1,3-Di[(3-methyl-5-phenoxyl-1-phenylpyrazol-4-yl)acylthiourea]benzene (3g): grey powder. IR (νmax.
,
cm–1): 3,392, 3,052, 1,671, 1,176; H-NMR ( δ ppm): 12.48 (s, 2H, NH), 9.33 (s, 2H, NH), 8.07-6.92
(m, 24H, ArH), 2.62 (s, 6H, 2xCH3); Anal. calcd. for C42H34N8O4S2: C, 64.77; H, 4.40; N, 14.39.
Found: C, 64.68; H, 4.43; N, 14.29%.
1
1,4-Di[(3-methyl-5-phenoxyl-1-phenylpyrazol-4-yl)acylthiourea]benzene (3h): brown powder. IR
(νmax., cm–1): 3,412, 3,064, 1,668, 1,127; 1H-NMR (δ ppm): 12.58 (s, 2H, NH), 9.29 (s, 2H, NH), 7.89-
7.56 (m, 24H, ArH), 2.58 (s, 6H, 2xCH3); Anal. calcd. for C42H34N8O4S2: C, 64.77; H, 4.40; N, 14.39.
Found: C, 64.64; H, 4.36; N, 14.30%.
4,4'-Di[(3-methyl-5-phenoxyl-1-phenylpyrazol-4-yl)acylthiourea]biphenyl (3i): yellow powder. IR
(νmax., cm–1): 3,338, 3,065, 1,650, 1,182; 1H-NMR (δ ppm): 12.53 (s, 2H, NH), 9.37 (s, 2H, NH), 7.77-
6.94 (m, 28H, ArH), 2.64 (s, 6H, 2xCH3); Anal. calcd. for C48H38N8O4S2: C, 67.43; H, 4.48; N, 13.11.
Found: C, 67.32; H, 4.52; N, 13.26%.
2,2'-Dimethyl-4,4'-di[(3-methyl-5-phenoxyl-1-phenylpyrazol-4-yl)acylthiourea]biphenyl (3j): yellow
powder. IR (νmax., cm–1): 3,403, 3,072, 1,678, 1,153; 1H-NMR (δ ppm): 12.48 (s, 2H, NH), 9.45 (s, 2H,
NH), 7.93-7.02 (m, 26H, ArH), 2.60 (s, 6H, 2xCH3), 2.43 (s, 6H, 2xCH3); Anal. calcd. for
C50H42N8O4S2: C, 68.01; H, 4.79; N, 12.69. Found: C, 68.19; H, 4.85; N, 12.59%.
Acknowledgements
We gratefully ackonwledge support from the National Natural Science Foundation of China (No.
20662009).
References
1. Liu, H.; Wang, H.Q.; Liu, Z.J. Synthesis and herbicidal activity of novel pyrazolo[3,4-
d]pyrimidin-4-one derivatives containing aryloxyphenoxypropionate moieties. Bioorg. Med. Chem.
Lett. 2007, 17, 2203-2209.
2. Park, H.J; Lee, K.; Park, S.J; Ahn, B.; Lee, J.C; Cho, H.Y.; Lee, K.I. Identification of antitumor
activity of pyrazole oxime ethers. Bioorg. Med. Chem. Lett. 2005, 15, 3307-3312.
3. Akbas, E.; Berber, I.; Sener, A.; Hasanov, B. Synthesis and antibacterial activity of 4-benzoyl-1-
methyl-5-phenyl-1H-pyrazole-3-carboxylic acid and derivatives. Il Farmaco. 2005, 60, 23-26.

Molecules 2009, 14
1428
4. Daidone, G.; Maggio, B.; Raffa, D.; Plescia, S.; Schillaci, D.; Raimondi, M.V. Synthesis and in
vitro antileukemic activity of new 4-triazenopyrazole derivatives. Il Farmaco. 2004, 59, 413-417.
5. Bekhit, A.A.; Ashour, H.M.A.; Ghany, Y.S.A.; Bekhit, A.E.A.; Baraka, A. Synthesis and
biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-
inflammatory antimicrobial agents. Eur. J. Med. Chem. 2008, 43, 456-463.
6. Dixit, P.P.; Patil, V.J.; Nair, P.S.; Jain, S.; Sinha, N.; Arora, S.K. Synthesis of 1-[3-(4-
benzotriazol-1/2-yl-3-fluorophenyl)-2-oxo-oxazolidin-5-ylmethyl]-3-substituted-thiourea
derivatives as antituberculosis agents. Eur. J. Med. Chem. 2006, 41, 423-428.
7. Mahajan, A.; Yeh, S.; Nell, M.; Rensburg, C.E.J.V.; Chibale, K. Synthesis of new 7-
chloroquinolinyl thioureas and their biological investigation as potential antimalarial and
anticancer agents. Bioorg. Med. Chem. Lett. 2007, 17, 5683-5685.
8. Küçükgüzel, I.; Tatar, E.; Küçükgüzel, S.G.; Rollas, S.; Clercq, E.D. Synthesis of some novel
thiourea derivatives obtained from 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-
1,2,4-triazole-3-thiones and evaluation as antiviral/anti-HIV and anti-tuberculosis agents. Eur. J.
Med. Chem. 2008, 43, 381-392.
9. Arslan, H.; Duran, N.; Borekci, G.; Ozer, C.K.; Akbay, C. Antimicrobial activity of some thiourea
derivatives and their nickel and copper complexes. Molecules 2009, 14, 519-527.
10. Ding, L.Q.; Wang, W.; Zhang, A.Q. Synthesis of 1,5-dinitroaryl-1,4-pentadien-3-ones under
ultrasound irradiation. Ultrason. Sonochem. 2007, 14, 563-567.
11. Lin, H.X.; Yang, M.F.; Huang, P.G.; Cao, W.G. A facile procedure for the generation of
dichlorocarbene from the reaction of carbon tetrachloride and magnesium using ultrasonic
Irradiation. Molecules 2003, 8, 608-613.
12. Zhang, X.L.; Li, Y.P.; Liu, C.J.; Wang, J.D. An efficient synthesis of 4-substituted pyrazolyl-3,4-
dihydropyrimidin-2(1H)-(thio)ones catalyzed by Mg(ClO4)2 under ultrasound irradiation. J. Mol.
Catal. A: Chem. 2006, 253, 207-211.
13. Jia, Z.X.; Li, Y.P.; Liu, C.J. Synthesis of N-Substituted Benzothiazol-2-yl-amino-N'-substituted
pyrazol-4-yl-carbonylthiourea under ultrasound. Chin. J. Org. Chem. 2005, 25, 1450-1453.
Sample Availability: Available from the authors
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