One-pot synthesis and crystal structure of N-acyl-N′-[1-(2,6- dichloro-4-trifluoromethyl)phenyl-3-cyano-1H-pyrazol-5-yl]thioureas

Article abstract of DOI:10.3184/174751911X13058009785648

Nine novel thiourea derivatives containing pyrazole rings have been prepared in good yields by the reaction of 5-amino-3-cyano-1-(2,6-dichloro-4- trifluoromethylphenyl)pyrazole with acylisothiocyanates, which were generated in situ by potassium thiocyanate and different acyl chlorides in one pot. N-Benzoyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-3-cyano-1H-pyrazol- 5-yl]thiourea was characterised by a single crystal X-ray diffraction study.

Full text of DOI:10.3184/174751911X13058009785648

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 323
JUNE, 323–325
One-pot synthesis and crystal structure of N-acyl-N′-[1-(2,6-dichloro-4-
trifluoromethyl)phenyl-3-cyano-1H-pyrazol-5-yl]thioureas
Xiaohong Zhanga*, Hui Heb, Mei Xua and Ping Zhonga,b
aCollege of Chemistry and Material Engineering, Wenzhou Universtity, Wenzhou 325035, P. R. China
bOujiang College, Wenzhou Universtity, Wenzhou 325035, P. R. China
Nine novel thiourea derivatives containing pyrazole rings have been prepared in good yields by the reaction of
5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole with acylisothiocyanates, which were generated
in situ by potassium thiocyanate and different acyl chlorides in one pot. N-Benzoyl-N′-[1-(2,6-dichloro-4-
trifluoromethyl)phenyl-3-cyano-1H-pyrazol-5-yl]thiourea was characterised by a single crystal X-ray diffraction
study.
Keywords: 5-amino-3-cyano-1-arylpyrazole, acylthiourea, one-pot, crystal structure
Acylthiourea derivatives have attracted much attention due to
their chemical properties1–2 and their biological activities. For
example, some thiourea derivatives have been found to be
useful as insecticides,3 herbicides,4 inhibitors,5 anti-HIV
agents,6 antimicrobial and anticancer agents7 and plant-growth
regulators.8 Furthermore, acylthioureas are important com-
pounds as building blocks in the synthesis of heterocycles with
special biological activities, such as thiadiazolo pyrimidine,5
triazoles9 and benzothiazoles.10
In recent years, close attention has been paid to pyrazole
derivatives owing to their biological activities.11–13 Pyrazole
derivatives possessing fluorine-containing groups, for
example, fipronil (1a) [5-amino-1-[2,6-dichloro-4-(trifluoro-
methyl)-phenyl]-4-trifluoromethylsulfinyl-lH-pyrazole-3-
carbonitrile] is effective against a host of agricultural and
household pests including grass hoppers, boll weevils, rice
insects, termites, houseflies, fruitflies and thrips.14–16 So we
surmised that the acylthiourea derivatives bearing a pyrazole
moiety might have high biological activities.
Results and discussion
The starting material, 5-amino-3-cyano-1-(2,6-dichloro-4-
trifluoromethylphenyl)-1H-pyrazole (1b) was prepared adopt-
ing the reported procedures.17
The experimental procedures were simple. An acyl chloride
(7 mmol) in dry acetonitrile (10 mL) was added to dry potas-
sium thiocyanate (10 mmol) and the mixture refluxed for 2 h
to get the corresponding isothiocyanate. 5-Amino-3-cyano-1-
(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole (5 mmol)
was added, and was reacted until complete consumption of
amine, as monitored by TLC. This gave the compounds 2a–i in
good yields (Scheme 1 and Table 1).
From Table 1, it can be seen that when the acyl chloride was
an aromatic chloride, the yields were higher than for an ali-
phatic chloride. Moreover, owing to steric hindrance, the yields
Here
a series of new N-Aroyl-N′-[1-(2,6-dichloro-4-
trifluoromethyl)phenyl-3-cyano-1H-pyrazol-5-yl] thioureas
(2a–i) were synthesised based on the reaction of 5-amino-3-
cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole
(1b), the parent of fipronil, with potassium thiocyanate and
different acyl chlorides in one pot. They were characterised by
1
elemental analysis, IR, H NMR and 13C NMR spectroscopy
and compound 3a was also characterised by a single crystal
X-ray diffraction study.
R: 2a = C6H5; 2b = C6H5CH2; 2c = 4-OCH3C6H4; 2d = 2,4-Cl2C6H3; 2e = CH3; 2f = 4-CH3C6H4; 2g = 4-ClC6H4; 2h = 2-CH3C6H4; 2i = 4-FC6H4.
Scheme 1 Synthesis of N-acyl-N′-[1-(2, 6-dichloro-4-trifluoromethyl)phenyl-3-cyano-1H-pyrazol-5-yl] thioureas.
* Correspondent. E-mail:kamenzxh@163.com

324 JOURNAL OF CHEMICAL RESEARCH 2011
Table 1 The yields of compounds 2a–i
bond to their parent atoms, with C—H = 0.93–0.96Å, and Uiso
(H) = 1.2Ueq(C) for aryl H atoms. The CF3 group may be sub-
ject to unresolved disorder, which could account for the weak
diffracting ability of the crystal, leading to a rather high R
value. Selected crystal data and structure refinement details
are presented in Table 2.
CCDC 802496 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre, via www.
ccdc.cam.ac.uk/data_request.cif.
Entry
R
Yield/%
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
85
70
83
73
50
85
86
75
80
C6H5CH2
4-OCH3C6H4
2,4-Cl2C6H3
CH3
4-CH3C6H4
4-ClC6H4
2-CH3C6H4
4-FC6H4
Experimental
All the melting points were determined with a Thomas–Hoover melt-
ing point apparatus; the thermometer was not standardised. 1H and 13
C
NMR spectra were recorded at a 300 MHz and 75 MHz respectively,
using CD3COCD3 as a solvent with TMS as the internal standard. IR
spectra were measured on a FT-IR spectrophotometer as KBr disks.
Silicagel 60 GF254 was used for analytical and preparative TLC. The
elemental analysis values were determined on EA-1112 instrument
from Italy CarloErba; The crystal was mounted on a Bruker APEX
area-detector diffractometer equipped with a graphite-monochromatic
MoKα (λ=0.71073Å) radiation. The structures were solved by
direct methods using the SHELXLS-97 program and refined by using
the SHELXL-97 program.18 All products were characterised using
elemental analysis, IR, 1H, and 13C NMR.
Preparation of N-acyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-
3-cyano-1H-pyrazol-5-yl]thioureas (2a–i)
A solution of an appropriate acyl chloride (7 mmol) in dry acetonitrile
(10 mL) was added to dry potassium thiocyanate (10 mmol) and the
mixture was refluxed for 2h. Then 5-amino-3-cyano-1-(2,6-dichloro-
4-trifluoromethylphenyl)-1H-pyrazole (5 mmol) was added and,
reflux continued for an additional 5–6 h until complete consumption
of the starting material, as monitored by TLC. After the reaction was
finished, the mixture was concentrated under reduced pressure. The
residue was purified by flash column chromatography to give one of
the title compounds. Single crystals suitable for X-ray analysis were
obtained by slow evaporation of the mixed solution in alcohol and
ethyl acetate of 2a.
N-Benzoyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-3-cyano-
1H-pyrazol-5-yl]thiourea (2a): White solid. m.p. 157–158 °C; 1H
NMR (CD3COCD3, 300 MHz) δ: 13.37 (s, 1H), 10.84 (s, 1H), 8.20 (s,
2H), 7.93(dd, J = 7.28, 1.26 Hz, 2H), 7.76(s, 1H), 7.67 (dt, J = 7.70,
1.26Hz, 1H), 7.52 (dd, J = 7.28, 7.70 Hz, 2H); 13C NMR (CD3COCD3,
75 MHz) δ: 179.1, 170.0, 141.1, 136.9, 135.9 (q, J = 33.7Hz), 135.2,
134.6, 132.1, 129.6, 129.3, 128.6, 128.0, 123.2 (q, J = 271Hz), 113.9,
104.5; IR (KBr) ν: 3403 (NH), 2245 (CN), 1681 (C=O), 1649 (pyr-
azole ring), 1517 (phenyl), 1311(C=S) cm−1. Anal. Calcd for
C19H10Cl2F3N5OS: C, 47.12; H, 2.08. Found: C, 47.00; H, 2.05%.
N-Phenylacetyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-3-
cyano-1H-pyrazol-5-yl]thiourea (2b): White solid. m.p. 160–162 °C;
1H NMR (CD3COCD3, 300 MHz) δ: 13.0 (s, 1H), 10.95 (s, 1H), 8.10
(s, 2H), 7.60 (s, 1H),7.31(m,5H), 3.81(2H); 13C NMR (CD3COCD3,
75 MHz) δ: 179.3, 175.0, 172.3, 140.9, 136.8, 135.2 (q, J = 33,5Hz),
Fig. 1 Molecular structure of 2a.
from ortho substituted acyl chlorides were lower than from the
para substituted compounds.
The IR spectra of 2a–i revealed, in each case, four charac-
teristic absorptions near 3400, 2245, 1680 and 1311cm−1 due
to NH, nitrile (CN), C=O and C=S groups. The 1H NMR spec-
trum of 2c for example, displayed singlets at δ 13.54 and δ
10.68 due to the NH groups (two protons), a singlet signal at δ
8.21 due to the benzyl ring bearing CF3 (two protons), a singlet
signal at δ 7.76 due to the pyrazolyl ring (one proton), two
double signals at δ 7.96 and δ 7.05 due to the benzyl ring
bearing OCH3 (four protons), and a singlet signal at δ 3.89 due
to OCH3 (three protons).
A
single crystal of N-Benzoyl-N′-[1-(2,6-dichloro-4-
trifluoromethyl)phenyl-3-cyano-1h-pyrazol-5-yl]thiourea (2a)
was grown from a mixed solution of alcohol and ethyl acetate.
The molecular structure is shown in Fig.1. All H atoms were
placed in geometrically idealised positions and constrained to
Table 2 Crystal parameters data collections and structure refinements for 2a
2a
2a
Formula
C19H10Cl2F3N5OS
484.28
Dc/(Mg m−3)
1.528
Molecula weight
Temperature/K
Crystal size/mm3
Crystal system
Space group
a/nm
F(000)
976
298(2)
µ/mm−1
Scan mode
θ range of data collection/(°)
Total reflections collected
Independent reflection
Index ranges
0.455
φ and ω
1.74 to 25.08
10761
3714 (Rint= 0.0338)
–19<=h<=19, –9<=k<=8,
–12<=l<=20
0.9348 and 0.8831
3714/2/286
Full-matrix least-squares on F2
R = 0.0778, wR = 0.1726
R= 0.1057, wR = 0.1883
1.071
0.28 x 0.27 x 0.15
Monoclinic
P 21/n
1.60963(13)
0.77108(6)
b/nm
c/nm
α/(°)
β/(°)
γ/(°)
V/nm3
Z
1.69650(13)
Max. and min. transmission
Data/restraints/parameters
Refine method
Final R indices [I>2σ(1a)]
R indices (all data)
Goodness of fit
90
90.322(2)
90
2.1056(3)
4

JOURNAL OF CHEMICAL RESEARCH 2011 325
130.4, 130.1, 129.3, 129.1, 128.1, 127.6, 123.1 (q, J=272Hz), 113.8,
104.8, 44.2; IR (KBr) ν: 3168 (NH), 2245 (CN), 1695 (C=O), 1576,
1527 (phenyl), 1308 (C=S) cm−1; Anal. Calcd for C20H12Cl2F3N5OS:
C, 48.21; H, 2.43. Found: C, 48.10; H, 2.40%.
128.9, 128.0, 127.8, 126.6, 123.2(q, J = 271.3Hz), 114.0, 104.2, 19.8;
IR (KBr) ν: 3365(NH), 2241 (CN), 1699 (C=O), 1580 (phenyl), 1308
(C=S), 1177 cm−1; Anal. Calcd for C20H12Cl2F3N5OS: C, 48.21; H,
2.43. Found: C, 48.19; H, 2.40%.
N-4-Methoxylacyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-3-
cyano-1H-pyrazol-5-yl]thiourea (2c): White solid. m.p. 185–187 °C;
1H NMR (CD3COCD3, 300 MHz) δ: 13.54 (s, 1H), 10.68 (s, 1H), 8.21
(s, 2H), 7.96 (d, J = 8.91 Hz, 2H), 7.76 (s, 1H), 7.05 (d, J = 8.91 Hz,
2H)，3.89 (s, 3H); 13C NMR (CD3COCD3, 75 MHz) δ: 179.3, 169.2,
162.3, 141.2, 137.0, 135.7, 135.4(q, J = 34.3 Hz), 131.6, 127.9, 127.7,
123.7, 123.2(q, J = 272Hz), 114.9, 113.9, 104.4, 56.1; IR (KBr) ν:
3332 (NH), 2243 (CN), 1671 (C=O), 1575(phenyl), 1311(C=S), 1173
cm−1; Anal. Calcd for C20H12Cl2F3N5O2 S: C, 46.71; H, 2.35. Found:
C, 46.65; H, 2.30%.
N-4-fluoroacyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-3-
cyano-1H-pyrazol-5-yl]thiourea (2i): White solid. m.p. 201–203°C;
1H NMR (CD3COCD3, 300 MHz) δ: 13.20 (s, 1H), 10.82 (s, 1H), 8.08
(s, 2H), 7.90(d, J=9.45Hz 2H), 7.63(s, 1H), 7.16(d, J=9.45Hz 2H);
13C NMR (CD3COCD3, 125 MHz) δ: 179.0, 169.0, 166.8(d, 1C,
J=252.5Hz), 141.0, 136.9, 135.7, 135.4(q, J = 34.1 Hz), 132.4, 128.6,
127.9, 127.7, 123.2 (q, J = 272.3Hz), 116.6, 113.9, 104.2; IR (KBr)
ν: 3362(NH), 2241 (CN), 1698 (C=O), 1580 (phenyl), 1309 (C=S),
1178 cm−1;Anal. Calcd for C19H9Cl2F4N5OS: C, 45.44; H, 1.81. Found:
C, 45.43; H, 1.80%.
N-2,4-Dichloroacyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-
3-cyano-1H-pyrazol-5-yl]thiourea (2d): White solid. m.p. 150–
152 °C; 1H NMR (CD3COCD3, 300 MHz) δ: 12.85 (s, 1H), 11.26 (s,
1H), 8.21 (s, 2H), 7.75 (s,1H), 7.67 (s,1H), 7.64 (d, J = 7.98Hz 1H),
7.50 (d, J = 7.98Hz 1H); 13C NMR (CD3COCD3, 75 MHz) δ: 178.6,
168.6, 140.7, 138.4, 136.9, 135.2 (q, J = 33.3 Hz), 135.0, 132.8,
132.7, 131.6, 130.5, 128.4, 128.0, 127.8, 123.3(q, J = 272Hz), 113.8,
104.9; IR (KBr) ν: 3369 (NH), 2246 (CN), 1675 (C=O), 1574 (phenyl),
1315 (C=S), 1173 cm−1; Anal. Calcd for C19H8Cl4F3N5OS: C, 41.25;
H, 1.46. Found: C, 41.20; H, 1.43%.
The authors thank the National Natural Science Foundation of
China (No. 20972114), Zhejiang Provincial Natural Science
Foundation of China (Y4100578).
Received 28 December 2011; accepted 30 April 2011
Paper 1000497 doi: 10.3184/174751911X13058009785648
Published online: 11 July 2011
N-Acetyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-3-cyano-
1H-pyrazol-5-yl]thiourea (2e): White solid. 199–200 °C. H NMR
1
References
(CD3COCD3, 300 MHz)：δ: 13.19 (s,1H), 10.87 (s, 1H), 8.21 (S, 2H),
7.74 (s, 1H), 2.16 (s, 3H); 13C NMR (CD3COCD3, 75 MHz) δ: 178.0,
173.9,140.2, 136.1, 135.9 (q, 1 C, J= 33.7 Hz), 134.8, 127.0, 126.9,
123.2 (q, 1 C, J= 271 Hz), 113.0, 103.2, 23.0. IR (KBr) ν: 3253, 2244,
1698 (C=O), 1610 (phenyl), 1530, 1310 (C=S) cm−1; Anal. Calcd for
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N-4-Methylacyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-
1
3-cyano-1H-pyrazol-5-yl]thiourea (2f): White solid. 169–171 °C. H
NMR (CD3COCD3, 300 MHz)：δ: 13.21(s,1H), 10.8(s, 1H), 8.31(S,
2H), 7.94(d, J = 7.97 Hz 2H), 7.86(s, 1H), 7.44(d, J = 7.97 Hz 2H),
2.50(s, 3H); 13C NMR (CD3COCD3, 125 MHz) δ: 179.2, 169.9, 145.8,
141.2, 136.9, 135.7, 135.6(q, 1 C, J=34.8 Hz), 130.2, 129.4, 129.2,
127.9, 127.8, 123.2 (q, 1 C, J= 270.8 Hz), 113.9, 104.4, 21.5;
IR (KBr) ν: 3250, 2240, 1699(C=O), 1578 (phenyl), 1492, 1305 (C=S)
cm−1; Anal. Calcd for C20 H12 Cl2F3N5OS: C, 48.21; H, 2.43. Found:
C, 48.19; H, 2.40%.
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N-4-Chloroacyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-3-
cyano-1H-pyrazol-5-yl]thiourea (2g): White solid. m.p. 209–210 °C;
1H NMR (CD3COCD3, 300 MHz) δ: 13.30 (s, 1H), 11.00 (s, 1H), 8.22
(s, 2H), 7.96 (d, J = 8.22 Hz 2H), 7.77 (s,1H), 7.57 (d, J = 8.22 Hz
2H); 13C NMR (CD3COCD3, 125 MHz) δ: 179.1, 169.2, 141.0, 140.4,
137.0, 135.8, 135.5 (q, J = 35 Hz), 131.2, 131.0, 129.8, 127.9, 127.8,
123.2 (q, J = 271.2Hz), 113.9, 104.7; IR (KBr) ν: 3370 (NH), 2241
(CN), 1699 (C=O), 1583 (phenyl), 1310 (C=S), 1181cm−1;Anal. Calcd
for C19 H9 Cl3F3N5OS: C, 43.99; H, 1.75. Found: C, 43.95; H, 1.72%.
N-2-Methylacyl-N′-[1-(2,6-dichloro-4-trifluoromethyl)phenyl-3-
cyano-1H-pyrazol-5-yl]thiourea (2h): White solid. m.p. 151–152 °C;
1H NMR (CD3COCD3, 300 MHz) δ: 13.18 (s, 1H), 10.94 (s, 1H), 8.11
(s, 2H), 7.66 (s, 1H), 7.42 (d, J=7.7 Hz 1H), 7.32 (d, J=7.5 Hz 1H),
7.18–7.73 (m, 2H); 13C NMR (CD3COCD3, 125 MHz) δ: 179.0, 172.5,
141.1, 138.2, 137.0, 135.7, 135.5(q, J = 33.8 Hz), 133.4, 132.7, 132.1,

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