Synthesis of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1h- pyrazole-4-carbaldehydes

Article abstract of DOI:10.3390/molecules15107472

A series of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl- 1Hpyrazole-4-carbaldehydes 6a-i were synthesized using the Vilsmeier-Haack reagent. The structures of all the title compounds have been confirmed by elemental analysis, ¹H-NMR

Full text of DOI:10.3390/molecules15107472

Molecules 2010, 15, 7472-7481; doi:10.3390/molecules15107472
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Novel 1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-
aryl-1H-pyrazole-4-carbaldehydes
Huanan Hu 1,*, Changhua Ge 1, Lisheng Ding 2 and Anjiang Zhang 3,*
1
College of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai 317000, China;
E-Mail: gechhua@163.com
2
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China;
E-Mail: lsding@cib.ac.cn
3
Ningbo Institute of Material Technology and Engineering, Chinese Academy of Sciences, Ningbo
315211, China
* Author to whom correspondence should be addressed; E-Mails: hhn12192000@yahoo.com.cn
(H.H.); anjiangzhang@gmail.com (A.Z.).
Received: 7 September 2010; in revised form: 29 September 2010 / Accepted: 2 October 2010 /
Published: 25 October 2010
Abstract: A series of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-
pyrazole-4-carbaldehydes 6a-i were synthesized using the Vilsmeier-Haack reagent. The
structures of all the title compounds have been confirmed by elemental analysis, 1H-NMR
13
and C-NMR and in addition, the structure of intermediate 5b was investigated by X-ray
crystallography.
Keywords: Vilsmeier-Haack reagent; phenylhydrazine; phenylhydrazone; 1H-pyrazole-4-
carbaldehyde
1. Introduction
The application of the Vilsmeier-Haack (VH) reagent (POCl3/DMF) for formylation of a variety of
both aromatic and heteroaromatic substrates is well documented [1]. Besides this, the reagent has also
been extensively used for effecting various chemical transformations with other classes of compounds.
Many of these reactions have led to novel and convenient routes for the synthesis of various
heterocyclic compounds [2]. A notable example that finds significant application in heterocyclic

Molecules 2010, 15
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chemistry is the synthesis of 4-formylpyrazoles from the double formylation of hydrazones with the
VH reagent [3,4]. These observations, coupled with the recent developments in the simple synthesis of
pyrazole derivatives [5], especially 4-functionalized 1,3-diphenylpyrazoles as antibacterial [6], anti-
inflammatory [7], antiparasitic [8], and antidiabetic drugs [9], prompted us to undertake the synthesis
of pyrazole-4-carbaldehyde derivatives using the VH reagent.
It has been known for some time that fluorine atoms can lead to unexpected biological activity
results due to the special properties of the fluorine atom, such as the high electronegativity of fluorine
and the high carbon-fluorine bond energy [10]. As a consequence, trifluoromethyl-containing
molecules have been found considerable utilization in the agrochemical and pharmaceutical industries
[10–12], for example, pyrazole derivatives bearing trifluoromethyl groups, such as fipronil and analogs
[13,14] are widely used phenylpyrazole insecticides applied in granular or bait form for residential and
commercial control of turf grass pests, and celecoxib [15], widely prescribed to treat acute or chronic
inflammation by providing symptomatic pain relief, are examples of such compounds. In this paper,
we show a simple and efficient synthetic method using the VH reagent [4,16,17] that affords a series
of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-pyrazole-4-carbaldehydes.
2. Results and Discussion
Phenylhydrazine 3 was synthesized from 2,6-dichloro-4-trifluoromethylphenylamine (1) through
diazotization, reduction and hydration (Scheme 1). The reducing reagent plays an important role in the
reaction. When the intermediate 2 was reduced by SnCl2, an almost quantitative yield of product was
obtained. Use of Na2S2O3 or Zn as reducing reagents led to lower yields.
Scheme 1. Synthesis of phenylhydrazine 3.
NHNH2
Cl
N2Cl
NH2
Cl
Cl
Cl
Cl
Cl
SnCl2
HCl
/HCl
NaNO2
CF3
CF3
CF3
1
2
3
Phenylhydrazones 5 were next synthesized in almost quantitative yields by the reaction between the
phenylhydrazine 3 and 3 or 4-substituted aryl methyl ketones, regardless of whether the ketones
contained electron-withdrawing or electron-donating groups (Scheme 2).

Molecules 2010, 15
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Scheme 2. Synthesis of phenylhydrazones 5.
Ar
Cl
NHNH2
Cl
NHN
Cl
Cl
+
H
ArCOCH3
+
Ethanol
CF3
CF3
3
4
5
5a: Ar=C6H5; 5b: Ar =4-ClC6H4; 5c: Ar =3-ClC6H4; 5d: Ar =4-BrC6H4;
5e: Ar =3-BrC6H4; 5f: Ar =4-MeOC6H4; 5g: Ar =4-CF3C6H4; 5h: Ar =4-NO2C6H4;
5i: Ar =
O CH3
X-ray diffraction
To verify the structural assignment compound 5b was selected as an example for an X-ray
diffraction study (Figure 1 and Table 1). The purified product 5b was dissolved in 50 %
ethanol/acetone (1:1 v/v) and kept at room temperature for 5 days and single crystals of 5b were thus
formed. CCDC 685556 contains the supplementary crystallographic data for this comound [18].
Figure 1. ORTEP drawing of the compound 5b showing the atom numbering scheme.
Table 1. Crystal data and summary of data collection and structure refinement.
Compound
Color
C15 H10 Cl3 F3 N2
Colorless
Formula weight
Crystal system
Temperature,°
Cell constants
a (Å)
381.60
Monoclinic
25(298K)
16.8770(7)
8.0054(8)
24.119(2)
90
b (Å)
c (Å)
α (˚)
β (˚)
99.654(2)
90
γ (˚)
Volume (Å3)
Formula units
Calculated density (g/cm-3)
3212.5(4)
8
1.578

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Table 1. Cont.
F(000)
1536
Absorption coefficient, mμ-3
Limiting indices
0.599
-20<=h<=16, -7<=k<=9, -27<=l<=28
8110 / 2841 [R(int) = 0.0402]
Semi-empirical from equivalents
0.9370 and 0.8314
Reflections collected / unique
Absorption correction
Max. and min. transmission
Refinement method
Full-matrix least-squares on F2
2841 / 0 / 208
Data / restraints / parameters
Goodness-of-fit on F2
1.015
Final R indices
Largest diff. peak and hole (e Å-3)
R1 = 0.1641, wR2 = 0.5152
0.869 and -0.919
The Vilsmeier cyclization of hydrazones could provide an efficient route for the preparation of 1H -
pyrazole-4-carbaldehydes. The reaction was carried out at 80–90 °C for 4 h using 3 equiv. of the VH
reagent, affording a series of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-pyrazole-4-
carbaldehydes in good yields (Scheme 3). The results are shown in Table 2. 1H-Pyrazole-4-
carbaldehydes 6 cannot be obtained if the DMF used is not anhydrous.
Scheme 3. Synthesis of 1H-pyrazole-4-carbaldehydes 6.
OHC
Cl
Ar
Ar
N
NHN
N
POCl3
Cl
Cl
Cl
dry DMF
CF3
CF3
5
6
Table 2. Synthesis of 1H–pyrazole-4-carbaldehydes.
Entry
Ar
Products(6)
Yield(%)a
1
2
3
4
5
6
7
8
C6H5
6a
6b
6c
6d
6e
6f
89
88
83
86
82
83
86
85
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-BrC6H4
4-MeOC6H4
4-CF3C6H4
4-NO2C6H4
6g
6h
OCH
3
9
6i
81
a Isolated yields with regard to the quantity of hydrazones 5

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7476
3. Experimental
3.1. General
All melting points were determined on an XT-4A apparatus and are uncorrected. TLC was
performed using precoated silica gel GF254 (0.25mm), column chromatography was performed using
silica gel (200–300 mesh). The 1H- and 13C-NMR spectra were measured at 25 °C at 300 and 75 MHz,
respectively, on a Bruker Advance 300 spectrometer, using TMS as internal standard. J-values are
given in Hz. The IR spectra were taken on a Bruker Vector 55 spectrometer. Elemental analyses were
carried out with an EA 1112 elemental analyzer. All the reagents used were AR grade.
3.2. Synthesis of (2,6-Dichloro-4-trifluoromethyl)phenylhydrazine (3)
2,6-Dichloro-4-trifluoromethylphenylamine (1, 1.73 g, 7.5 mmol) was dissolved in concentrated
HCl (10 mL) and water (10 mL) and cooled to 0 °C, sodium nitrite (0.62 g, 9.0 mmol) was added and
the yellow solution was stirred at 0 °C for 2 h to get a solution of diazotizated compound 2. SnCl2
(2.85 g, 15 mmol) was dissolved in concentrated HCl (10 mL) and cooled to 7 °C, then the
diazotizated solution of 2 was added slowly dropwise. After 1 h of reaction, the precipitate was
filtered, washed with water and air-dried. The precipitate was neutralized by 25% NaOH in water to
pH 8, the light yellow sediment was collected and air-dried to afford a brown solid 3 (1.53 g, 83%),
1
m.p. 65–67 °C. H-NMR (CDCl3) δ: 7.52 (s, 2H, Ar-H), 5.85 (s, 1H, NH), 3.86 (br, 2H, NH2);
13C- NMR (CDCl3) δ: 137.1, 132.5 (q, J = 33.8 Hz), 130.3, 123.8, 122.3 (q, J = 271.8 Hz); IR (KBr) ν:
3517, 3418, 1622, 1583, 1492, 1329, 1281, 1144, 883 cm-1.
3.3. General procedure for synthesis of N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-(1-phenyl-
ethylidene) hydrazines 5a-i
To a solution of compound 3 (12 mmol) in absolute C2H5OH (30 mL) was added substituted
acetophenone 4 (10 mmol). Two drops of concentrated HCl were added to a stirred solution, and the
mixture was refluxed for 1 h. The solid obtained on cooling was filtered, dried and recrystallized from
C2H5OH to give compounds 5a-i .
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-(1-phenylethylidene)hydrazine (5a): White solid, m.p.
1
90–91 °C; H-NMR (CDCl3) δ: 7.82 (d, J = 3.6 Hz, 2H, N’-Ar-H), 7.67 (s, 1H, NH), 7.58 (s, 2H,
13
N-Ar-H), 7.34–7.42 (m, 3H, N’-Ar-H), 2.35 (s, 3H, CH3); C-NMR (CDCl3) δ: 147.2, 140.8, 136.1,
132.5 (q, J = 33.8 Hz), 127.3, 126.8, 126.0, 125.8, 123.8, 122.3 (q, J = 271.8 Hz), 11.7; IR (KBr) ν:
3350, 3072, 2927, 1603, 1538, 1492, 1390, 1351, 1311, 1114, 1009, 887 cm-1.
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-[1-(4-chlorophenyl)ethylidene]hydrazine (5b): White
solid, m.p. 118–120 °C; 1H-NMR (CDCl3) δ: 7.68–7.76 (m, 3H, N’-Ar-H and NH), 7.58 (s, 2H, N-Ar-
13
H), 7.34–7.37 (m, 2H, N’-Ar-H), 2.33 (s, 3H, CH3); C NMR (CDCl3) δ: 146.1, 140.7, 136.3, 134.5
(q, J = 33.5 Hz), 128.3, 126.7, 126.2, 126.0, 123.9, 121.8 (q, J = 271.8 Hz), 11.8; IR (KBr) ν: 3360,
3070, 2924, 1605, 1532, 1490, 1392, 1352, 1303, 1114, 1004, 884 cm-1.

Molecules 2010, 15
7477
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-[1-(3-chlorophenyl)ethylidene]hydrazine (5c): White
1
solid, m.p. 118–120 °C; H-NMR (CDCl3) δ: 7.83 (s, 1H, N’-Ar-H), 7.71–7.76 (m, 2H, N’-Ar-H and
NH), 7.58 (s, 2H, N-Ar-H), 7.36–7.40 (m, 2H, N’-Ar-H), 2.32 (s, 3H, CH3); 13C-NMR (CDCl3) δ:
146.1, 140.7, 136.3, 133.5 (q, J = 33.3 Hz), 129.2, 128.3, 127.5, 126.7, 126.1, 125.6, 123.9, 122.1 (q,
J = 271.8 Hz), 12.1; IR (KBr) ν: 3358, 3073, 2926, 1603, 1536, 1489, 1390, 1352, 1313, 1108, 1011,
886 cm-1.
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-[1-(4-bromophenyl)-ethylidene]hydrazine (5d): White
solid, m.p. 114–115 °C; 1H-NMR (CDCl3) δ: 7.65–7.69 (m, 3H, N’-Ar-H and NH), 7.58 (s, 2H, N-Ar-
13
H), 7.48–7.52 (m, 2H, N’-Ar-H), 2.33 (s, 3H, CH3); C-NMR (CDCl3) δ: 146.5, 141.7, 134.3, 132.5
(q, J = 33.5 Hz), 127.6, 127.1, 126.7, 125.6, 123.9, 121.9 (q, J = 271.8 Hz), 11.7; IR (KBr) ν: 3362,
3074, 2928, 1606, 1540, 1495, 1393, 1354, 1308, 1106, 1012, 887 cm-1.
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-[1-(3-bromophenyl)ethylidene]hydrazine (5e): White
solid, m.p. 114–115 °C; 1H-NMR (CDCl3) δ: 7.94 (s, 1H, N’-Ar-H), 7.70–7.75 (m, 2H, N’-Ar-H and
NH), 7.58 (s, 2H, N-Ar-H), 7.46–7.49 (m, 2H, N’-Ar-H), 2.32 (s, 3H, CH3); 13C-NMR (CDCl3) δ:
147.1, 141.9, 139.3, 132.3 (q, J = 33.5 Hz), 128.3, 127.6, 127.1, 126.7, 126.0, 124.6, 123.9, 121.9 (q,
J = 271.8 Hz), 11.9; IR (KBr) ν: 3360, 3072, 2924, 1600, 1538, 1492, 1390, 1356, 1307, 1115, 1019,
889 cm-1.
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-[1-(4-methoxyphenyl)ethylidene]-hydrazine (5f): White
solid, m.p. 89–90 °C; 1H-NMR (CDCl3) δ: 7.81 (s, 1H, N’-Ar-H), 7.79 (s, 1H, N’-Ar-H), 7.67 (s, 1H,
NH), 7.58 (m, 2H, N-Ar-H), 6.73–6.89 (m, 2H, N’-Ar-H), 3.83 (s, 3H, OCH3), 2.32 (s, 3H, CH3). 13C-
NMR (CDCl3) δ: 158.1, 147.5, 136.2, 133.6 (q, J = 33.6 Hz), 127.8, 126.2, 125.6, 124.7, 121.9 (q,
J = 270.2 Hz), 114.2, 55.1, 11.7; IR (KBr) ν: 3355, 3072, 2925, 1603, 1530, 1489, 1391, 1351, 1307,
1112, 1016, 887 cm-1.
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-[1-(4-trifluoromethylphenyl)-ethylidene]hydrazine (5g):
1
White solid, m.p. 165–166 °C; H-NMR (CDCl3) δ: 7.91 (d, J = 8.4 Hz, 2H, N’-Ar-H), 7.78 (s, 1H,
13
NH), 7.59–7.65 (s, 4H, N’ and N-Ar-H), 2.36 (s, 3H, CH3); C-NMR (CDCl3) δ: 145.5, 144.7, 133.5
(q, J = 32.6 Hz), 130.4 (q, J = 32.1 Hz), 126.3, 125.8, 125.2, 124.6, 124.4, 123.2 (q, J = 270.2 Hz),
121.8 (q, J = 272.6 Hz), 11.9; IR (KBr) ν: 3351, 3070, 2926, 1601, 1535, 1490, 1389, 1350, 1313,
1116, 1021, 889 cm-1.
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-[1-(4-nitrophenyl)ethylidene]hydrazine (5h): Yellowish
solid, m.p. 146–147 °C; 1H-NMR (CDCl3) δ: 8.24 (d, J = 6.0 Hz, 2H, N’-Ar-H), 7.88–7.97 (m, 3H, N’-
13
Ar-H and NH), 7.60 (s, 2H, N-Ar-H), 2.38 (s, 3H, CH3); C-NMR (CDCl3) δ: 147.5, 144.3, 143.9,
140.4, 132.8 (q, J = 33.6 Hz), 126.5, 125.1, 124.7, 123.6, 120.9 (q, J = 272.6 Hz), 11.8; IR (KBr) ν:
3320, 3073, 2926, 1583, 1513, 1393, 1339, 1307, 1117, 890 cm-1.
N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N’-[1-(6-methoxy-naphthalen-2-yl)-ethylidene]hydrazine
1
(5i): White solid, m.p. 191–193 °C; H-NMR (CDCl3) δ: 8.11 (d, J = 6.2 Hz, 1H, N’-Ar-H), 8.00 (s,
1H, N’-Ar-H), 7.71–7.78 (m, 3H, N’-Ar-H and NH), 7.58 (s, 2H, N-Ar-H), 7.14-7.17 (m, 2H, N’-Ar-

Molecules 2010, 15
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H), 3.84 (s, 3H, OCH3), 2.43 (s, 3H, CH3); 13C-NMR (CDCl3) δ: 157.9, 147.5, 134.6, 133.2 (q,
J = 32.5 Hz), 129.6, 128.2, 126.7, 126.2, 126.1, 125.3, 124.8, 123.8, 123.7, 121.7
(q, J = 271.6 Hz), 118.7, 105.5, 55.0, 11.7; IR (KBr) ν: 3353, 3069, 2938, 1602, 1528, 1487, 1390,
1346, 1305, 1127, 1026, 889 cm-1.
3.4. General procedure for synthesis of 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-
pyrazole-4- carbaldehydes 6a-i
POCl3 (0.5 g, 3.0 mmol) was added dropwise to an ice-cold stirred solution of hydrazone 5
(1.0 mmol) in dry DMF (4 mL), the reaction mixture was allowed to attain room temperature and then
heated at 80 °C for 4 h. The resulting mixture was poured onto crushed ice, neutralized with dilute
sodium hydroxide and left standing overnight. The pale yellow precipitate obtained was purified by
flash column chromatography with ethyl acetate–petroleum ether mixture to yield the products 6a-i.
1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-phenyl-1H-pyrazole-4-carbaldehyde (6a): White solid,
1
m.p. 147–149 °C; H-NMR (CDCl3) δ: 10.11 (s, 1H, CHO), 8.22 (s, 1H, pyrazole H), 7.79–7.83 (m,
4H, 1 and 3-Ar-H), 7.27–7.54 (m, 3H, 3-Ar-H); 13C-NMR (CDCl3) δ: 182.4, 153.8, 137.8, 135.0,
133.9 (q, J = 33.8 Hz), 129.0, 126.1, 125.8, 125.3, 124.6, 123.7, 122.6, 121.9 (q, J = 271.8 Hz); IR
(KBr) ν: 3107, 3062, 2843, 1695, 1602, 1531, 1403, 1310, 1131, 850, 719 cm-1; Anal. Calcd. for
C17H9Cl2F3N2O: C, 53.01; H, 2.36; N, 7.27. Found: C, 53.30; H, 2.45; N, 7.33%.
1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde
(6b):
1
White solid, m.p. 108–110 °C; H-NMR (CDCl3) δ: 10.08 (s, 1H, CHO), 8.22 (s, 1H, pyrazole H),
7.79–7.83 (m, 4H, 1 and 3-Ar-H), 7.45–7.48 (m, 2H, 3-Ar-H); 13C-NMR (CDCl3) δ: 183.6, 152.8,
138.8, 136.0, 133.8 (q, J = 33.8 Hz), 129.1, 128.5, 126.1, 125.8, 125.3, 123.7, 122.6, 121.9 (q,
J = 271.8 Hz); IR (KBr) ν: 3107, 3060, 2845, 1695, 1600, 1529, 1401, 1314, 1130, 858, 719 cm-1;
Anal. Calcd. for C17H8Cl3F3N2O: C, 48.66; H, 1.92; N, 6.68. Found: C, 48.77; H, 2.03; N, 6.60%.
1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-(3-chlorophenyl)-1H-pyrazole-4-carbaldehyde
(6c):
1
White solid, m.p. 105–106 °C; H-NMR (CDCl3) δ: 10.09 (s, 1H, CHO), 8.21 (s, 1H, pyrazole H),
7.83–7.91 (m, 3H, 1 and 3-Ar-H), 7.31–7.62 (m, 3H, 3-Ar-H); 13C-NMR (CDCl3) δ: 183.6, 152.8,
137.8, 136.0, 159.6, 133.8 (q, J = 33.8 Hz), 129.1, 128.5, 128.1, 126.1, 125.8, 125.2, 123.6, 122.7,
121.8 (q, J = 271.8 Hz); IR (KBr) ν: 3106, 3062, 2840, 1696, 1602, 1530, 1403, 1310, 1134, 856, 719
cm-1; Anal. Calcd. for C17H8Cl3F3N2O: C, 48.66; H, 1.92; N, 6.68. Found: C, 48.81; H, 1.90; N,
6.80%.
1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-(4-bromophenyl)-1H-pyrazole-4-carbaldehyde
(6d):
1
White solid, m.p. 116–118 °C; H-NMR (CDCl3) δ: 10.08 (s, 1H, CHO), 8.22 (s, 1H, pyrazole H),
7.74–7.79 (m, 4H, 1 and 3-Ar-H), 7.61–7.64 (m, 2H, 3-Ar-H); 13C-NMR (CDCl3) δ: 183.6, 152.8,
138.8, 136.0, 134.6, 133.8 (q, J = 33.8 Hz), 129.1, 128.5, 125.8, 125.3, 123.5, 122.6, 121.9 (q,
J = 271.8 Hz); IR (KBr) ν: 3108, 3063, 2841, 1697, 1604, 1532, 1407, 1315, 1131, 858, 719 cm-1;
Anal. Calcd. for C17H8BrCl2F3N2O: C, 44.00; H, 1.74; N, 6.04. Found: C, 43.87; H, 1.79; N, 5.96%.

Molecules 2010, 15
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1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-(3-bromophenyl)-1H-pyrazole-4-carbaldehyde
(6e):
1
White solid, m.p. 110–112 °C; H-NMR (CDCl3) δ: 10.09 (s, 1H, CHO), 8.22 (s, 1H, pyrazole H),
13
7.79–7.83 (m, 4H, 1 and 3-Ar-H), 7.59–7.62 (m, 1H, 3-Ar-H), 7.35–7.38 (m, 1H, 3-Ar-H); C-NMR
(CDCl3) δ: 182.9, 153.8, 139.0, 136.7, 134.2, 133.8 (q, J = 33.8 Hz), 129.1, 128.5, 126.1, 125.9, 125.3,
123.7, 123.3, 122.6, 121.8 (q, J = 271.8 Hz); IR (KBr) ν: 3106, 3062, 2840, 1695, 1602, 1530, 1401,
1313, 1132, 856, 719 cm-1; Anal. Calcd. for C17H8BrCl2F3N2O: C, 44.00; H, 1.74; N, 6.04. Found: C,
43.70; H, 1.83; N, 6.36%.
1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde
(6f):
1
White solid, m.p. 75–77 °C; H-NMR (CDCl3) δ: 10.08 (s, 1H, CHO), 8.20 (s, 1H, pyrazole H),
7.76–7.79 (m, 4H, 1 and 3-Ar-H), 7.00–7.03 (m, 2H, 3-Ar-H), 3.87 (s, 3H, OCH3); 13C-NMR (CDCl3)
δ: 183.2, 160.4, 154.5, 136.1, 134.9, 133.8 (q, J = 33.8 Hz), 130.0, 128.2, 125.8, 125.7, 122.8, 121.9
(q, J = 271.6 Hz), 113.9, 55.0; IR (KBr) ν: 3110, 3060, 2963, 2850, 1695, 1600, 1530, 1403, 1312,
1130, 858, 719 cm-1; Anal. Calcd. for C18H11Cl2F3N2O2: C, 52.07; H, 2.67; N, 6.75. Found: C, 52.10;
H, 2.65; N, 6.78%.
1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-(4-trifluoromethylphenyl)-1H-pyrazole-4-carbaldehyde
1
(6g): White solid, m.p. 88–90 °C; H-NMR (CDCl3) δ: 10.11(s, 1H, CHO), 8.25 (s, 1H, pyrazole H),
8.01–8.03 (m, 2H, 3-Ar-H), 7.74–7.83 (m, 4H, 1 and 3-Ar-H); 13C-NMR (CDCl3) δ: 183.2, 151.8,
148.3, 139.1, 137.8, 136.9, 135.0, 133.9 (q, J = 33.8 Hz), 129.8 (q, J = 32.6 Hz), 129.0, 126.1, 123.7
(q, J = 270.1 Hz), 122.6, 121.9 (q, J = 271.8 Hz); IR (KBr) ν: 3110, 3060, 2842, 1695, 1600, 1528,
1400, 1313, 1130, 858, 719 cm-1; Anal. Calcd. for C18H8Cl2F6N2O: C, 47.71; H, 1.78; N, 6.18. Found:
C, 47.84; H, 1.85; N, 6.23%.
1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-(4-nitrophenyl)-1H-pyrazole-4-carbaldehyde
(6h):
1
Yellowish solid, m.p. 206–208 °C; H-NMR (CDCl3) δ: 10.12 (s, 1H, CHO), 8.33–8.36 (m, 2H, 3-Ar-
13
H), 8.27(s, 1H, pyrazole H), 8.13–8.15 (m, 2H, 3-Ar-H), 7.82 (s, 2H, 1-Ar-H); C-NMR (CDCl3) δ:
183.2, 151.8, 148.3, 139.1, 137.8, 136.9, 135.0, 133.8 (q, J = 33.8 Hz), 129.6, 126.1, 123.7, 122.6, 121.9
(q, J = 271.6 Hz); IR (KBr) ν: 3106, 3062, 2843, 1695, 1602, 1530, 1403, 1310, 1132, 858, 719 cm-1;
Anal. Calcd. for C17H8Cl2F3N3O3: C, 47.47; H, 1.87; N, 9.77. Found: C, 47.56; H, 1.93; N, 9.62%.
1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-(6-methoxy-naphthalen-2-yl)-1H-pyrazole-4-carb-
1
aldehyde (6i): White solid, m.p. 144–146 °C; H-NMR (CDCl3) δ: 10.19(s, 1H, CHO), 8.25 (s, 1H,
pyrazole H), 7.80–7.92 (m, 5H, 1 and 3-Ar-H), 7.19–7.23 (m, 3H, 3-Ar-H), 3.94 (s, 3H, OCH3);
13C- NMR (CDCl3) δ: 183.2, 158.2, 155.0, 136.4, 134.9, 134.7, 133.8 (q, J = 33.8 Hz), 129.7, 128.3,
128.2, 127.0, 126.4, 125.8, 125.4, 123.5, 122.1, 121.9 (q, J = 271.6 Hz), 119.2, 105.4, 55.0; IR (KBr)
ν: 3108, 3062, 2963, 2840, 1695, 1600, 1528, 1400, 1313, 1130, 858, 719 cm-1; Anal. Calcd. for
C22H13Cl2F3N2O2: C, 56.79; H, 2.82; N, 6.02. Found: C, 56.65; H, 2.93; N, 6.15%.
4. Conclusions
In conclusion, The Vilsmeier cyclization of hydrazones provided an efficient route for the
preparation of 1H-pyrazole-4-carbaldehydes, and we have successfully developed a general method

Molecules 2010, 15
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for the synthesis in good yields of a series of 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-
pyrazole-4-carbaldehydes 6a-i using the Vilsmeier-Haack reagent. The structures of all the title
1
13
compounds have been confirmed by elemental analysis, H-NMR and C-NMR and in addition, the
structure of intermediate 5b was confirmed by X-ray crystallography.
Acknowledgements
We are grateful for financial support from Taizhou University (Project No. 2010PY21) and the
Nature Science Foundation of China (Project No. 20905057).
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18. CCDC 685556 contains the supplementary crystallographic data for this paper. These data can be
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Sample Availability: Samples of the compounds 6a-i are available from the authors.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).