Thiourea: An efficient and inexpensive catalyst for the Knoevenagel condensation of pyrazole derivates

Article abstract of DOI:10.1002/jccs.201190087

Thiourea is an inexpensive, efficient and mild catalyst for the synthesis of Knoevenagel condensation of pyrozoles derivate. In the presence of 10 mol% of thiourea, pyrazole aldehyde react with active methylene compound under microwave-assisted solvent-fr

Full text of DOI:10.1002/jccs.201190087

268
Journal of the Chinese Chemical Society, 2011, 58, 268-271
Note
Thiourea: An Efficient and Inexpensive Catalyst for the Knoevenagel
Condensation of Pyrazole Derivates
Jian-Ping Li,* Ji-Kuan Qiu, Hui-Juan Li and Gui-Sheng Zhang
College of Chemistry and Environmental Science, Key Labaratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Normal University, Xinxiang, 453007, P. R. China
Received July 2, 2010; Accepted December 27, 2010; Published Online January 11, 2011
Thiourea is an inexpensive, efficient and mild catalyst for the synthesis of Knoevenagel condensation
of pyrozoles derivate. In the presence of 10 mol% of thiourea, pyrazole aldehyde react with active methy-
lene compound under microwave-assisted solvent-free conditions at 300 W for 2-5 min to give corre-
sponding products in good yields.
Keywords: Thiourea; Catalyst; Knoevenagel condensation; Pyrazole; Microwave-assisted sol-
vent-free synthesis.
INTRODUCTION
The Knoevenagel condensation of aldehydes with ac-
reported a genuienly green and mild Knoevenagel conden-
sation containing pyrazole ring catalyzed by thiourea under
microwave-assisted solvent-free conditions (Scheme I and
Table 1).
tive methylene compounds is an important and widely em-
ployed method for carbon-carbon bond formation in or-
ganic synthesis with numerous applications in the synthesis
of fine chemicals,1 hetero Diels-Alder reactions2 and in
synthesis of carbocyclic as well as heterocyclic3 com-
pounds of biological significance. The reaction is usually
catalyzed by bases,4 such as sodium hydroxide or sodium
Reactions of pyrazole aldehyde with active
methylene compounds
Scheme I
5
ethoxide in organic solvents. Lewis acids, such as NbCl5
and ZnCl2,6 silica gel7 have also been employed to catalyze
the reaction. Similarly, the use of ionic liquids8 pave a new
path for such organic synthesis. The use of environmen-
tally benign solvents like water9 and microwave-assisted
solvent-free10 reactions represent very powerful green
chemical technology procedures from both the economical
and synthetic point of view. They not only reduce the bur-
den of organic solvent disposal, but also enhance the rate of
many organic reactions. Therefore, efforts have been made
to perform the Knoevenagel condensation in microwave-
assisted solvent-free conditions which is usually catalyzed
by Lewis acids or bases.
RESULTS AND DISCUSSION
An optimization study of the Knoevenagel condensa-
tion under microwave irradiation was tested. We took the
reaction of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde with
malononitrile as a model to examine the effects of catalyst
Recently, the Knoevenagel condesation about the
pyrazole aldehyde as starting materials were reported. But
these reactions are usually catalyzed by sodium acetate or
piperidine in ethanol,11-13 and the yield is low. Herein, we
* Corresponding author. Tel: 86+373-3326781; Fax: 86+373-3325250; E-mail: jplig@163.com

Thiourea Catalyst for the Knoevenagel Condensation
J. Chin. Chem. Soc., Vol. 58, No. 2, 2011 269
Besides, the reaction rate and yield were not significantly
affected by the position and the properties of substituted
groups on the pyrazole aldehyde. Furthermore, we also try
some other methylene compounds such as difluorometh-
ane, dichloromethane, dibromomethane and dimethoxy-
methane. However, no desired product was obtained. Per-
haps because these methylene compounds are not very ac-
tive.
Table 1. Knoevenagel condensation catalyzed by thiourea under
microwave-assisted solvent-free conditions
Time/
Entry
R1
R2
R3
Product
Yield/%
min
1
C6H5
CN COOEt
CN COOEt
CN COOEt
CN COOEt
3a
3b
3c
3d
3e
3f
4
3
3
4
2
2
2
4
4
5
4
75
78
79
75
80
82
80
76
74
73
76
2
p-CH3OC6H4
p-ClC6H4
p-CH3C6H4
C6H5
3
4
5
CN
CN
CN
CN
CN
CN
The possible mechanism of thiourea catalyzed
Knoevenagel reaction has been proposed in Scheme II. At
first, thiourea reacts with active methylene compound 2 to
form a six-membered cyclic intermediate 4. Because the
active hydrogen of 2 is pulled by the more electronegative
nitrogen atom in intermediate, it is easier for active methy-
lene compound to add nucleophilically to the pyrazole al-
dehydes 1. Then the intermediate 5 and 6 are obtained.
There is an equilibrium between 6 and 7. At last, the target
product 3 is afforded along with removeing one mole of
H2O, and regenerate the thiourea.
6
p-CH3OC6H4
p-ClC6H4
p-CH3OC6H4
p-ClC6H4
p-CH3C6H4
C6H5
7
3g
3h
3i
O
8
O
9
10
11
3j
O
3k
O
ranging from 0-20 mol% and microwave power at 100,
200, 300, 400, 500 W. The results were evaluated qualita-
tively through TLC. It was found that the quantitative yield
was achieved when the reaction was carried out in the pres-
ence of 10 mol% thiourea at 300W under solvent-free con-
ditions (Scheme I).
In conclusion, thiourea has been used efficiently to
catalyze the Knoevenagel condensation reaction between
active methylene compounds and pyrazole aldehydes. A
microwave-assisted solvent-free reaction conditions with a
shorter time and inexpensive and easily available catalyst
are the key features involved in the present protocol. These
features will enable this protocol to find widespread appli-
cations in the field of organic synthesis.
In this paper, several substituted pyrazole aldehyde
with three active methylene compounds reacted under the
microwave-assisted solvent-free conditions catalyzed by
thiourea. The results are summarized in Table 1, which in-
dicated that the reactions gave yields of 73-82%. 2,2-Di-
methyl-1,3-dioxane-4,6-dione (Entry 8-11) showed much
faster reaction rate than literature.14 Comparatively, mal-
ononitrile proved to be of higher reactivity than ethyl
cyanoacetate and 2,2-dimethyl-1,3-dioxane-4,6-dione.
The presence of electronwithdrawing groups on active
methylene compounds resulted in the corresponding prod-
ucts in high yield and in short reaction times (Entry 5-7).
EXPERIMENTAL SECTION
Melting points were determined with a XRC-1 micro-
melting point apparatus and were uncorrected. NMR spec-
tra were measured on a Bruker DPX 400 M, respectively,
using TMS at internal standard and CDCl3 as solvent.
Scheme II Possible mechanism of thiourea catalyzed Knoevenagel reaction

270 J. Chin. Chem. Soc., Vol. 58, No. 2, 2011
Li et al.
Chemical shift (d) were expressed in ppm downfield from
internal standand TMS and coupling constants J were
given in Hz. Mass spectra were performed on a Bruker-Es-
quire 3000 Mass spectrometer. Elemental analysis was per-
formed on PE-2400 Analyzer. The experiment was carried
out with Galanz microwave oven (750 W). Common re-
agents and materials were purchased from commercial
sources and purified by recrystallization or distillation. The
starting material, 1-phenyl-3-aryl-1H-pyrazole-4-carbal-
dehyde (1) was prepared according to Ref. 15.
Ethyl 2-cyano-3-[3-(4-chlorophenyl)-1-phenyl-1H-
pyrazol-4-yl]acrylate 3c
Light yellow crystal; mp. 117 ~ 119 °C; 1H NMR (400
MHz, CDCl3) d 1.387 (t, J = 7.2 Hz, 3 H, CH3), 4.335 ~
4.388 (m, 2 H, CH2), 7.421 (t, J = 6.8 Hz, 1 H, ArH), 7.499
~ 7.577 (m, 7 H, ArH), 7.819 (d, J = 8.0 Hz, 2 H, ArH),
8.242 (s, 1 H, N-CH), 9.130 (s, 1 H, C=CH); 13C NMR (100
MHz, CDCl3) d 14.20, 62.50, 100.22, 114.87, 116.56,
119.95, 128.30, 129.28, 129.37, 129.72, 130.36, 135.65,
138.75, 145.66, 155.13, 162.56; MS (m/z): 377.8 (M+).
Anal. Calcd. for C21H16ClN3O2: C, 66.76; H, 4.27; N,
11.12. Found: C, 66.67; H, 4.38; N, 11.01.
General procedure for the Knoevenagel condensation
To a mixture of pyrazole aldehyde (1 mmol), active
methylene compound (1.1 mmol), and the thiourea (10
mol%), was mixed in an agate mortar and exposed to mi-
crowave irradiation for appropriate time (see Table 1) un-
der solvent-free conditions. The power of the microwave
oven is 300 W. The end of the reaction was tested by TLC.
After the reaction was complete, the crude products were
purified by column chromatography (petroleum ether:
ethyl acetate = 10:1).
Ethyl 2-cyano-3-(1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)-
acrylate 3d
White crystal; mp. 136 ~ 138 °C; 1H NMR (400 MHz,
CDCl3) d 1.377 (t, J = 7.2 Hz, 3 H, CH3), 2.437 (s, 3 H,
ArCH3), 4.321 ~ 4.374 (m, 2 H, CH2), 7.331 (d, J = 7.6 Hz,
2 H, ArH), 7.400 (t, J = 7.4 Hz, 1 H, ArH), 7.516 (t, J = 7.4
Hz, 4 H, ArH), 7.827 (d, J = 8.0 Hz, 2 H, ArH), 8.306 (s, 1
H, N-CH), 9.122 (s, 1 H, C=CH); 13C NMR (100 MHz,
CDCl3) d 14.21, 21.37, 62.35, 99.56, 114.92, 116.76,
119.93, 127.91, 128.08, 129.02, 129.22, 129.65, 129.70,
138.88, 139.43, 146.45, 156.49, 162.73; MS (m/z): 357.8
(M+). Anal. Calcd. for C22H19N3O2: C, 73.93; H, 5.36; N,
11.76. Found: C, 74.09; H, 5.45; N, 11.69.
Physical properties and spectral data
Ethyl 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acry-
late 3a
White crystal; mp. 134 ~ 136 °C; 1H NMR (400 MHz,
CDCl3) d 1.382 (t, J = 7.2 Hz, 3 H, CH3), 4.327 ~ 4.380 (m,
2 H, CH2), 7.412 (t, J = 7.2 Hz, 1 H, ArH), 7.501 ~ 7.558
(m, 5 H, ArH), 7.621 (d, J = 6.4 Hz, 2 H, ArH), 7.837 (d, J =
8.0 Hz, 2 H, ArH), 8.313 (s, 1 H, N-CH), 9.145 (s, 1 H,
C=CH); 13C NMR (100 MHz, CDCl3) d 14.20, 62.40,
99.80, 114.94, 116.71, 119.93, 128.51, 129.01, 129.15,
129.26, 129.37, 129.68, 130.82, 138.84, 146.27, 156.38,
162.68; MS (m/z): 343.9 (M+). Anal. Calcd. for C21H17N3O2:
C, 73.45; H, 4.99; N, 12.24. Found: C, 73.49; H, 4.82; N,
12.28.
2-[(1,3-Diphenyl-1H-pyrazol-4-yl)methylene]malono-
nitrile 3e
Light yellow solid; mp. 158 ~ 160 °C; 1H NMR (400
MHz, CDCl3) d 7.455 (d, J = 7.6 Hz, 1 H, ArH), 7.524 ~
7.564 (m, 7 H, ArH), 7.803 (s, 1 H, N-CH), 7.811 ~ 7.834
(m, 2 H, ArH), 9.064 (s, 1 H, C=CH); 13C NMR (100 MHz,
CDCl3) d 78.50, 113.85, 113.89, 114.99, 120.07, 128.65,
129.17, 129.20, 129.26, 129.81, 129.84, 130.09, 138.54,
151.11, 156.36; MS (m/z): 296.9 (M+). Anal. Calcd. for
C19H12N4: C, 77.01; H, 4.08; N, 18.91. Found: C, 77.23; H,
4.01; N, 18.82.
Ethyl 2-cyano-3-[3-(4-methoxyphenyl)-1-p-henyl-1H-
pyrazol-4-yl]acrylate 3b
White crystal; mp. 155 ~ 157 °C; 1H NMR (400 MHz,
CDCl3) d 1.383 (t, J = 7.0 Hz, 3 H, CH3), 3.884 (s, 3 H,
OCH3), 4.327 ~ 4.381 (m, 2 H, CH2), 7.051 (d, J = 8.4 Hz, 2
H, ArH), 7.383 ~ 7.422 (t, J = 7.8 Hz, 1 H, ArH), 7.498 ~
7.566 (m, 4 H, ArH), 7.827 (d, J = 8.0 Hz, 2 H, ArH), 8.300
(s, 1 H, N-CH), 9.116 (s, 1 H, C=CH); 13C NMR (100 MHz,
CDCl3) d 14.21, 55.40, 62.36, 99.43, 114.48, 114.83,
119.91, 123.22, 128.07, 129.20, 129.61, 130.43, 130.81,
138.88, 146.49, 156.25, 160.57, 162.79; MS (m/z): 373.9
(M+). Anal. Calcd. for C22H19N3O3: C, 70.76; H, 5.13; N,
11.25. Found: C, 70.89; H, 5.22; N, 11.11.
2-{[3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]-
methylene}malononitrile 3f
Kelly crystal; mp. 176 ~ 177 °C; 1H NMR (400 MHz,
CDCl3) d 3.898 (s, 3 H, OCH3), 7.069 (d, J = 8.8 Hz, 2 H,
ArH), 7.436 (t, J = 7.4 Hz, 1 H, ArH), 7.494 ~ 7.556 (m, 4
H, ArH), 7.788 (s, 1 H, N-CH), 7.810 (d, J = 8.0 Hz, 2 H,
ArH), 9.036 (s, 1 H, C=CH); 13C NMR (100 MHz, CDCl3)
d 55.46, 78.07, 113.92, 114.01, 114.67, 114.93, 120.04,
122.40, 128.57, 129.19, 129.79, 130.48, 138.56, 151.29,
156.23, 160.91; MS (m/z): 326.9 (M+). Anal. Calcd. for
C20H14N4O: C, 73.61; H, 4.32; N, 17.17. Found: C, 73.42;

Thiourea Catalyst for the Knoevenagel Condensation
J. Chin. Chem. Soc., Vol. 58, No. 2, 2011 271
H, 4.15; N, 17.26.
MHz, CDCl3) d 1.787 (s, 6 H, 2 CH3), 7.418 (t, J = 7.0 Hz, 1
H, ArH), 7.517 ~ 7.569 (m, 5 H, ArH), 7.626 (t, J = 3.8 Hz,
2 H, ArH), 7.875 (d, J = 7.6 Hz, 2 H, ArH), 8.518 (s, 1 H,
N-CH), 9.746 (s, 1 H, C=CH).
2-{[3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-
methylene}malononitrile 3g
Light yellow solid; mp. 217 ~ 218 °C; 1H NMR (400
MHz, CDCl3), d 7.453 (t, J = 7.2 Hz, 1 H, ArH), 7.504 ~
7.566 (m, 6 H, ArH), 7.744 (s, 1 H, N-CH), 7.794 ~ 7.817
(t, J = 4.6 Hz, 2 H, ArH), 9.055 (s, 1 H, C=CH); 13C NMR
(100 MHz, CDCl3) d 78.99, 113.72, 114.88, 120.07,
128.58, 128.78, 129.38, 129.50, 129.85, 130.37, 136.21,
138.44, 150.50, 155.09; MS (m/z): 330.8 (M+). Anal.
Calcd. for C19H11ClN4: C, 68.99; H, 3.35; N, 16.94. Found:
C, 68.95; H, 3.23; N, 3.52.
ACKNOWLEDGMENTS
This work was supported by the National Natural Sci-
ences Foundation of China (2087 2029).
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Mp. 206 ~ 208 °C; Lit14: 205 ~ 207 °C; 1H NMR (400