4-Functionally substituted 3-heterylpyrazoles: VIII. 3-Aryl(heteryl)-4-hydroxyl(chloro)methylpyrazoles

Article abstract of DOI:10.1023/A:1016346528487

3-Aryl(heteryl)pyrazole-4-carbaldehydes were reduced with sodium tetrahydridoborate under mild conditions to give 3-aryl(heteryl)-4-hydroxymethylpyrazoles which were converted into the corresponding 4-chloromethyl derivatives by treatment with thionyl chloride. The subsequent reaction with triphenylphosphine led to formation of triphenyl(4-pyrazolylmethyl)phosphonium chlorides, and Wittig reaction of the latter with aromatic or heteroaromatic aldehydes yielded 4-[2-aryl(heteryl)ethenyl]pyrazoles.

Full text of DOI:10.1023/A:1016346528487

Russian Journal of Organic Chemistry, Vol. 38, No. 3, 2002, pp. 411 414. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 3, 2002,
pp. 432 435.
Original Russian Text Copyright
2002 by Bratenko, Chornous, Vovk.
4-Functionally Substituted 3-Heterylpyrazoles:
VIII.* 3-Aryl(heteryl)-4-hydroxyl(chloro)methylpyrazoles
M. K. Bratenko, V. A. Chornous, and M. V. Vovk
Bukovina State Medical Academy, Teatral’naya pl. 2, Chernovtsy, 58000 Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received November 15, 2000
Abstract 3-Aryl(heteryl)pyrazole-4-carbaldehydes were reduced with sodium tetrahydridoborate under mild
conditions to give 3-aryl(heteryl)-4-hydroxymethylpyrazoles which were converted into the corresponding
4-chloromethyl derivatives by treatment with thionyl chloride. The subsequent reaction with triphenylphos-
phine led to formation of triphenyl(4-pyrazolylmethyl)phosphonium chlorides, and Wittig reaction of the latter
with aromatic or heteroaromatic aldehydes yielded 4-[2-aryl(heteryl)ethenyl]pyrazoles.
The hydroxy group in hydroxymethylpyrazoles is
a very convenient functional substituent ensuring
purposeful synthetic transformations. In particular,
1-hydroxymethylpyrazole was used as starting com-
pound to prepare the natural amino acid pyrazolyl-
alanine [2] and 1,3,5-substituted 4-hydroxymethyl-
pyrazoles which are intermediate products in the
synthesis of bioactive esters [3]. However, no sys-
matic studies on the chemical properties of 4-hydroxy-
methylpyrazoles have been reported, primarily
because of experimental difficulties in the synthesis
of these compounds. For example, direct hydroxy-
methylation of 1,3,5-trisubstituted pyrazoles is often
accompanied by formation of dipyrazolylmethanes as
by-products [4].
In the present communication we propose a con-
venient procedure for preparation of 3-aryl(heteryl)-
4-hydroxymethyl-1-phenylpyrazoles Ia Ig by mild
reduction of readily accessible [5] 4-pyrazolecarbalde-
hydes IIa IIg (Scheme 1). The procedure is simple
Scheme 1.
I IV, Ar = Ph (a), 4-FC6H4 (b), 4-ClC6H4 (c), 3-BrC6H4 (d), 4-BrC6H4 (e), 4-PhC6H4 (f), 2-thienyl (g); V, Ar = 4-O2NC6H4 (a),
5-nitro-2-furyl (b); VI, Ar = 4-FC6H4, Ar = 4-O2NC6H4 (a), 5-nitro-2-furyl (b); Ar = 4-ClC6H4, Ar = 4-O2NC6H4 (c); Ar =
4-BrC6H4, Ar = 4-O2NC6H4 (d), 5-nitro-2-furyl (e); Ar = 2-thienyl, Ar = 4-O2NC6H4 (f), 5-nitro-2-furyl (g).
____________
*
For communication VII, see [1].
1070-4280/02/3803-0411$27.00 2002 MAIK Nauka/Interperiodica

412
BRATENKO et al.
Table 1. Yields, melting points, spectral parameters, and elemental analyses of 3-aryl(heteryl)-4-hydroxymethyl-1-
phenylpyrazoles Ia Ig
Comp.
no.
Yield,
%
IR spectrum,
(OH), cm
mp,
C
1H NMR spectrum, , ppm
1
Ia
Ib
Ic
Id
Ie
If
91
96
84
87
94
81
87
71 73
94 96
3320
3350
3345
3370
3345
3360
3340
4.59 d (2H, CH2), 5.30 t (1H, OH), 7.32 7.64 m (10H, Harom), 8.54 s
(1H, CH)
4.70 d (2H, CH2), 5.26 t (1H, OH), 7.42 7.94 m (9H, Harom), 8.59 s
(1H, CH)
4.56 d (2H, CH2), 5.37 t (1H, OH), 7.34 7.83 m (9H, Harom), 8.62 s
(1H, CH)
4.72 d (2H, CH2), 5.31 t (1H, OH), 7.39 7.87 m (9H, Harom), 8.50 s
(1H, CH)
4.61 d (2H, CH2), 5.30 t (1H, OH), 7.41 7.92 m (9H, Harom), 8.49 s
(1H, CH)
4.53 d (2H, CH2), 5.33 t (1H, OH), 7.29 7.31 m (14H, Harom), 8.60 s
(1H, CH)
4.59 d (2H, CH2), 5.37 t (1H, OH), 7.19 8.01 m (8H, Harom), 8.55 s
(1H, CH)
126 127
103 104
132 133
114 115
93 95
Ig
Found, %
Calculated, %
Formula
Comp.
no.
C
H
N
C
H
N
Ia
Ib
Ic
Id
Ie
If
76.60
71.34
67.21
58.02
58.15
81.30
65.43
5.31
4.61
4.33
3.70
4.12
5.34
4.39
11.04
10.26
9.71
8.32
8.40
C16H14N2O
76.80
71.64
67.48
58.35
58.35
80.90
65.02
5.60
4.85
4.56
3.95
3.95
5.52
4.58
11.20
10.44
9.84
8.51
8.51
C16H13FN2O
C16H13ClN2O
C16H13BrN2O
C16H13BrN2O
C22H18N2O
8.31
11.04
8.58
10.93
Ig
C14H12N2OS
from the preparative viewpoint: the reactions are
carried out in ethanol at room temperature, and the
yields of the reduction products attain 81 96%. The
structure of compounds Ia Ig (Table 1) was proved
by the IR spectra which contained absorption bands in
only compounds which were converted into the corre-
sponding chloromethyl derivatives without side
formation of dipyrazolylmethanes. We have shown
that treatment of 4-hydroxymethylpyrazoles Ia Ig
with thionyl chloride gives 4-chloromethylpyrazoles
IIIa IIIg in 75 78% yield (Table 2). No dipyrazolyl-
methanes were formed, which may be explained in
terms of stabilizing effect of aromatic and hetero-
aromatic substituents in positions 1 and 3.
The chlorine atom in 4-chloromethylpyrazoles III
is fairly labile, and we succeeded in reacting com-
pounds III with triphenylphosphine to obtain hitherto
unknown triphenyl(4-pyrazolylmethyl)phosphonium
salts IVa IVg (Table 3). Using phosphonium salts
IVb, IVc, and IVe as examples, we brought them
into the Wittig reaction with p-nitrobenzaldehyde (Va)
and 5-nitro-2-furaldehyde (Vb). As a result, 4-(2-aryl-
ethenyl)pyrazoles VIa VIg were obtained (Table 4).
1
the region 3320 3370 cm , characteristic of hydroxy
1
groups, and by the H NMR spectra. The latter con-
tained multiplet signals from aromatic protons of the
substituents in positions 1 and 3 of the pyrazole ring,
a singlet at 8.49 8.62 ppm from the 5-H proton,
a triplet at 5.26 5.37 ppm from the hydroxy proton,
and a doublet at 4.56 4.72 ppm from protons of the
CH2 group in position 4.
Grandberg et al. [4] previously found that 1,3,5-tri-
substituted 4-hydroxymethylpyrazoles react with
thionyl chloride in a nonselective fashion. 5-Chloro-
4-hydroxymethyl-3-methyl-1-phenylpyrazole and
4-hydroxymethyl-1,3,5-triphenylpyrazole were the
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4-FUNCTIONALLY SUBSTITUTED 3-HETERYLPYRAZOLES: VIII.
413
1
Table 2. Yields, melting points, H NMR spectra, and elemental analyses of 3-aryl(heteryl)-4-chloromethyl-1-phenyl-
pyrazoles IIIa IIIg
Found, %
H
Calculated, %
Comp. Yield,
1H NMR spectrum,
, ppm
mp,
C
Formula
no.
%
C
N
C
H
N
IIIa
87
84 85 4.92 s (2H, CH2), 7.34 71.21 5.06 10.23 C16H13ClN2
7.88 m (10H, Harom),
71.50 4.84 10.42
8.77 s (1H, CH)
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
81
79
85
83
75
76
92 93 4.90 s (2H, CH2), 7.40 66.88 3.96
7.92 m (9H, Harom),
8.83 s (1H, CH)
74 75 4.98 s (2H, CH2), 7.30 63.03 3.71
7.64 m (9H, Harom),
8.72 s (1H, CH)
84 85 4.93 s (2H, CH2), 7.36 55.42 3.18
7.82 m (9H, Harom),
8.76 s (1H, CH)
103 104 4.93 s (2H, CH2), 7.24 55.03 3.27
7.63 m (9H, Harom),
8.80 s (1H, CH)
140 141 4.91 s (2H, CH2), 7.30 76.97 4.71
7.87 m (14H, Harom),
8.74 s (1H, CH)
79 81 4.97 s (2H, CH2), 7.04 60.90 3.83 10.43 C14H11ClN2S
7.79 m (8H, Harom),
9.69 C16H12ClFN2
9.54 C16H12Cl2N2
67.01 4.18
63.36 3.96
9.47
9.24
8.05
7.91
8.12
7.83 C16H12BrClN2 55.25 3.45
7.91 C16H12BrClN2 55.25 3.45
7.98 C22H17ClN2
76.63 4.93
61.20 4.00 10.20
8.77 s (1H, CH)
Compounds VI are mono- and dihetero analogs of
stilbene, and they can be regarded as promising syn-
thons for prepatration of dyes, complexing agents,
and medicinals [6].
4-hydroxymethylpyrazole Ia IIg in 10 ml of benzene.
The mixture was refluxed for 2 h and evaporated to
1/4 of the initial volume. After cooling, the precipitate
was filtered off, washed with hexane, and recrystal-
lized from benzene hexane (3:1).
EXPERIMENTAL
3-Aryl(heteryl)-1-phenyl-4-pyrazolylmethyl(tri-
phenyl)phosphonium chlorides IVa IVg. A solution
of 0.01 mol of 4-chloromethylpyrazole IIIa IIIg and
2.62 g (0.01 mol) of triphenylphosphine in 20 ml of
dry benzene was heated for 3 h under reflux. After
cooling, the precipitate was filtered off and washed
with 5 ml of benzene, and the filtrate was heated
again for 3 h. The precipitate was separated and com-
bined with the first portion, and the product was
recrystallized from chloroform ethyl acetate (4:1).
3-Aryl-4-[2-aryl(heteryl)ethenyl]-1-phenylpyra-
zoles VIa VIg. A solution of 0.33 g (0.006 mol) of
sodium methoxide in 10 ml of methanol was added
under stirring to a solution of 0.005 mol of phospho-
nium salt IIIa IIIg and 0.005 mol of aldehyde Va
or Vb in 20 ml of methanol. The mixture was stirred
for 3 h, and the precipitate was filtered off, washed
with methanol, and recrystallized from toluene.
The IR spectra were recorded on a UR-20 spec-
1
trometer in KBr. The H NMR spectra were measured
on a Varian Gemini instrument (300 MHz) using
DMSO-d6 as solvent and TMS as internal reference.
3-Aryl(heteryl)-4-hydroxymethyl-1-phenylpyra-
zoles Ia Ig (Table 1). A solution of 0.76 g (0.02 mol)
of sodium tetrahydridoborate in 100 ml of ethanol
was added with stirring to a solution of 0.02 mol of
4-pyrazolecarbaldehyde IIa IIg in 60 ml of ethanol.
The mixture was stirred for 1 h, 200 ml of water was
added, and the mixture was left to stand for 12 h
at 0 C. The precipitate was filtered off, washed with
water, dried, and recrystallized from ethanol.
3-Aryl(heteryl)-4-chloromethyl-1-phenylpyra-
zoles IIIa IIIg (Table 2). Thionyl chloride, 2.4 g
(0.02 mol), was added to a suspension of 0.01 mol of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 3 2002

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BRATENKO et al.
Table 3. Yields, melting points, and elemental analyses of 3-aryl(heteryl)-1-phenyl-4-pyrazolylmethyl(triphenyl)phos-
phonium chlorides IVa IVg
Found, %
Calculated, %
Comp.
no.
Yield,
%
mp,
C
Formula
C
H
Cl
N
C
H
Cl
N
IVa
IVb
IVc
IVd
IVe
IVf
IVg
87
82
81
79
89
71
91
273 275 76.49
244 246 74.03
261 263 71.84
259 260 67.25
263 264 66.71
272 274 78.84
255 256 71.32
5.03
4.63
4.51
4.18
4.26
5.44
4.51
6.31
6.20
6.09
5.61
5.50
5.53
6.32
6.05
5.31
5.15
4.81
5.34
4.95
5.60
C34H28ClN2P
C34H27ClFN2P
C34H27Cl2N2P
C34H27BrClN2P 66.94
C34H27BrClN2P 66.94
76.90
74.38
72.21
5.27
4.92
4.77
4.43
4.43
5.27
4.84
6.69
6.47
6.28
5.82
5.82
5.85
6.61
5.84
5.65
5.48
5.08
5.08
5.11
5.77
C40H32ClN2P
C32H26ClN2PS
79.14
71.57
Table 4. Yields, melting points, IR spectra, and elemental analyses of 3-aryl-4-[2-aryl(heteryl)ethenyl]-1-phenyl-
pyrazoles VIa VIg
Found, %
H
Calculated, %
H
Comp.
no.
Yield,
%
IR spectrum,
(C C), cm
mp,
C
Formula
1
C
N
C
N
VIa
VIb
VIc
VId
VIe
VIf
VIg
63
57
56
64
51
50
43
161 163
159 160
183 184
158 159
201 202
165 166
104 105
1635
1630
1640
1630
1630
1635
1640
71.40
67.43
68.99
61.81
57.61
67.33
63.11
3.86
3.61
3.69
3.44
3.09
3.88
3.43
10.63
11.02
10.28
9.18
9.41
11.05
11.34
C23H16FN3O2
C21H14FN3O3
C23H16ClN3O2
C23H16BrN3O2
C23H16BrN3O3
C21H15N3O2S
C19H13N3O3S
71.68
67.20
68.74
61.88
57.79
67.56
62.80
4.15
3.73
3.98
3.58
3.21
4.02
3.58
10.90
11.20
10.46
9.41
9.63
11.26
11.57
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