Functionally substituted 3-heterylpyrazoles: IX. 3-Aryl(heteryl)-4-mercapto(thiocyanato, isothiocyanato)-methylpyrazoles

Article abstract of DOI:10.1023/A:1016567727116

By reaction of 3-aryl(heteryl)-4-chloromethylpyrazoles with thiourea and sodium thiocyanate respectively 3-aryl(heteryl)-4-mercaptomethylpyrazoles and 3-aryl(heteryl)-thiocyanatomethylpyrazoles were obtained. The latter were subjected to thermal isomerization into 3-aryl(heteryl)-isothiocyanatomethylpyrazoles.

Full text of DOI:10.1023/A:1016567727116

Russian Journal of Organic Chemistry, Vol. 38, No. 4, 2002, pp. 595 598. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 4, 2002,
pp. 622 626.
Original Russian Text Copyright
2002 by Bratenko, Chornous, Vovk.
Functionally Substituted 3-Heterylpyrazoles: IX.*
3-Aryl(heteryl)-4-mercapto(thiocyanato, isothiocyanato)-
methylpyrazoles
M. K. Bratenko, V. A. Chornous, and M. V. Vovk
Bukovina State Medical Academy, Chernovtsy, 58000 Ukraine
Institute of Organic Chemistry, Ukrainian Academy of Science, Kiev, Ukraine
Received November 15, 2000
Abstract By reaction of 3-aryl(heteryl)-4-chloromethylpyrazoles with thiourea and sodium thiocyanate
respectively 3-aryl(heteryl)-4-mercaptomethylpyrazoles and 3-aryl(heteryl)-thiocyanatomethylpyrazoles were
obtained. The latter were subjected to thermal isomerization into 3-aryl(heteryl)-isothiocyanatomethyl-
pyrazoles.
In the preceding communication [1] we described a
preparation of 3-aryl(heteryl)-4-chloromethylpyr-
azoles and their application to the synthesis of
alkenylpyrazoles. The latter reaction was possible
because 4-chloromethylpyrazoles were capable to
alkylate triphenylphosphines affording 4-pyrazolyl-
methylphosphonium salts.
compounds result either from attack by the sulfur
atom yielding thiocyanates or by the nitrogen atom
affording isocyanates, or both providing mixture of
the products [3]. No published data exist on the reac-
tion between azolylmethyl halides and metal thio-
cyanates, but the kinetics of the reaction of their
carbocyclic analogs, benzyl halides, is investigated
in detail. In particular, it was shown [4] that in SN2
reaction at the benzyl carbon the relative nucleo-
philicity of S and N atoms in the thiocyanate anion
depends mainly on the temperature and the solvent.
Low temperature favors thiocyanate formation, and
at high temperature arise isothiocyanates. Therefore
we carried out the reaction of 4-chloromethylpyr-
azoles Ia g and sodium thiocyanate in boiling acetone.
It was established that the reaction occurred selective-
ly and within 1 h of heating afforded 4-thiocyanato-
methylpyrazoles IVa g (Table 2). Thiocyanates
IVa d, g are colorless crystalline substances, com-
pound IVf is a viscous light-yellow fluid. Their struc-
ture was confirmed by IR spectra (the presence of a
weak band belonging to SCN group in the region
In the present study aiming at the synthesis of new
4-functional sulfur-containing pyrazole derivatives we
carried out alkylation of thiourea and sodium thio-
cyanate with 3-aryl(heteryl)-4-chloromethylpyrasoles
Ia g. The reaction of alkyl halides with thiourea
affording primarily S-alkylthiuronium salts is exten-
sively applied to preparation of alkanethioles [2]. We
demonstrated that 4-chloromethylpyrazoles Ia, b, d, g
reacted with thiourea at heating in tetrahydrofuran
furnishing in high yield S-(4-pyrazolylmethyl)iso-
thiuronium chlorides IIa, b, d, g which were isolated
and characterized, and then subjected to alkaline
hydrolysis with sodium hydroxide. As a result we
obtained in 74 84% yield 4-pyrazolylmethanethiols
IIIa, b, d, g (Table1) as colorless crystalline com-
pounds with no unpleasant odor. Their 1H NMR
spectra are consistent with the assumed structure:
alongside the multiplet signals from the substituents
in positions 1 and 3 of the pyrazole ring in the spectra
are present a singlet from the proton ¢5H (8.51
8.56 ppm) and broadened singlets from protons of
CH2 (3.82 3.87 ppm) and SH groups (2.90
2.94 ppm).
1
1
2160 2170 cm ) and by H NMR spectra where
appeared characteristic singlets from proton C5H of
pyrazole at 8.71 8.84 ppm and from methylene group
at 4.56 4.68 ppm.
We found that 4-thiocyanatomethylpyrazoles
IVa g same as benzylthiocyanates [6] on heating for
2 h in p-xylene were converted into 4-isothiocyanato-
methylpyrazoles Va g. Isothiocyanates Va g are
viscous undistillable oily substances with a strong
Thiocyanate anion is an ambidental nucleophile,
and its kinetically controlled reactions with organic
1
absorption band in the IR spectra at 1970 1990 cm
belonging to antisymmetrical stretching vibrations of
N=C=S group.
*
For communication VIII see [1].
1070-4280/01/3804-595$27.00 2002 MAIK Nauka/Interperiodica

596
BRATENKO et al.
I V$(24), Ar = Ph (a), 4-FC6H4 (b), 4-ClC6H4 (c), 4-BrC6H4 (d), 4-MeC6H4 (e), 2-thienyl (f), 2-benzo[b]furyl (g).
Compounds Va g without further purification
were reacted with amines VIa d, hydrazines VIIa c,
hydrazide VIId, and hydrazone VIIe to afford
thioureas VIIIa e and thiosemicarbazides IXa d
(Table 3).
EXPERIMENTAL
IR spectra were recorded on spectrophotometer
UR-20 from samples pelleted with KBr. H NMR
spectra were registered on spectrometer Varian-
Gemini (300 MHz) in (CD3)2SO solution, internal
reference TMS.
1
3-Aryl(heteryl)-1-phenyl-4-chloromethylpyrazoles
I, e, g and their initial 3-aryl(heteryl)-4-hydroxy-
methyl-1-phenylpyrazoles were prepared by proce-
dure [1].
4-Hydroxymethyl-3-(4-tolyl)-1-phenylpyrazole.
Yield 83%. mp 127 128 C (from ethanol). IR spec-
1
1
trum, , cm : 3340 (OH). H NMR spectrum,
,
ppm: 2.28 s (3H, CH3), 4.64 d (2H, CH2), 5.31 t
(1H, OH), 7.16 7.72 m (9H, H arom), 8.50 s (1H,
CH=). Found, %: C 76.91; H 6.02; N 10.34.
C17H16N2O. Calculated, %: C 77.25; H 6.10; N
10.60.
3-(2-Benzo[b]furyl)-4-hydroxymethyl-1-
phenylpyrazole. Yield 80%. mp 128 130 C
1
VI, R = H, R = PhCH2 (a), 2-pyridylmethyl (b),
4-MeOC6H4 (c), 2-pyridyl (d), R = R = (CH2)5 (e);
VII, R = H, R = Ph (a), 2-benzothiazolyl (b),
4-pyridylcarbonyl (d); R = R = (CH2)2N(Me)(CH2)2
(c), 3-(3-pyridyl)-1-phenyl-4-pyrazolylmethylene (e);
VIII, Ar = 4-FC6H4, R = R = (CH2)5 (a); Ar =
4-ClC6H4, R = H, R = 4-MeOC6H4 (b); Ar =
4-BrC6H4, R = R = (CH2)5 (c); Ar = 4-MeC6H4,
R = H, R = 2-pyridyl (d); Ar = 2-thienyl, R= H,
(from ethanol). IR spectrum, , cm : 3360 (OH).
1H NMR spectrum, , ppm: 4.57 d (2H, CH2), 5.28 t
(1H, OH), 7.24 7.80 m (10H, H arom), 8.54 s (1H,
CH=). Found, %: C 74.69; H 4.90; N 9.31.
C18H14N2O2. Calculated, %: C 74.47; H 4.86;
N 9.65.
3-(4-Tolyl)-1-phenyl-4-chloromethylpyrazole
(Ie). Yield 78%. mp 99 101 C (from benzene
1
hexane, 3: 1). H NMR spectrum, , ppm: 2.32s (3H,
R = PhCH2 (e); Ar = 2-benzo[b]furyl, R = H, R
=
CH3), 4.96 s (1H, CH2), 7.34 7.79 m (9H, H arom),
8.82 s (1H, CH=). Found, %: C 72.53; H 5.47; N
10.07. C17H15ClN2. Calculated, %: C 72.21; H 5.35;
N 9.91.
2-pyridylmethyl (f); IŒ, Ar = 4-FC6H4, R = H, R = Ph
(a); Ar = 4-BrC6H4, R = R = (CH2)2N(Me)(CH2)2
(b); Ar = 4-MeC6H4, R = H, R = 2-benzothiazolyl
(c); Ar = 2-thienyl, R = R = 3-(3-pyridyl)-1-
phenyl-4-pyrazolemethylene (d); Ar = 2-benzo[b]-
furyl, R = H, R = 4-pyridylcarbonyl (e).
3-(2-Benzo[b]furyl)-1-phenyl-4-chloromethyl-
pyrazole (Ig). Yield 77%. mp 92 93 C (from benz-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 2 2002

Table 1. Yields, melting points and elemental analyses of S-[3-aryl(heteryl)-1-phenyl-4-pyrazolylmethyl]thiuronium chlorides (IIa, b, d, g)
and 3-aryl(heteryl)-1-phenyl-4-pyrazolylmethanethiols (IIIa, b, d, g)
Yield, mp, C
%
1H NMR spectra, , ppm
Found, %
Calculated, %
Compd.
no.
Formula
C
H
N
S
C
H
N
S
IIa
IIb
IId
IIg
IIIa
82
90
87
93
80
176 177
177 178
186 187
184 185
16.55 9.04 C17H17C1N4S
15.11 9.03 C17H16C1FN4S
13.61 7.43 C17H16BrClN4S
14.81 8.48 C19H17C1N4OS
16.25 9.30
15.44 8.84
13.22 7.57
14.56 8.33
43 44 2.92 br.s (1H, SH), 3.86 br.s (2H, CH2), 72.45 5.08 10.68
7.32 7.89 m (10H, H arom), 8.55 s (IH, CH=)
56 57 2.80 br.s (IH, SH), 3.82 br.s (2H, CH2), 67.84 4.47 10.07
7.43 7.87M(9H, H arom), 8.51 s (IH, CH=)
67 68 2.94 br.s (IH, SH), 3.87 br.s (2H, CH2), 55.25 3.95 8.31
7.40 7.79M(9H, H arom), 8.53 s (IH, CH=)
99 100 2.93 br.s (IH, SH), 3.86 br.s (2H, CH2), 70.56 4.61 9.14
7.29 7.91 m (10H, H arom), 8.56 s (IH, CH=)
C16H14N2S
72.15 5.30 10.52
67.58 4.64 9.85
55.66 3.80 8.11
70.56 4.81 9.11
IIIb
IIId
IIIg
84
78
74
C16H13FN2S
C16H13BrN2S
C18H14N2OS
Table 2. Yields, melting points and elemental analyses of 3-aryl(heteryl)-4-thiocyanatomethyl-1-phenylpyrazoles (IVa g)
Compd. Yield, mp, C IRspectrum
Found, %
H
Calculated, %
1H NMR spectra, , ppm
Formula
no.
%
(SCN),
1
cm
C
N
C
H
N
IVa
IVb
IVc
IVd
IVe
IVf
IVg
81
85
56 57
76
2170
2165
2165
2160
2170
2165
2160
4.59 s (2H, CH2), 7.30 7.82 m (10H, H arom), 70.38 4.50
8.74 s (IH, CH=)
4.62 s (2H, CH2), 7.41 7.91 m (9H, H arom), 65.83 3.64
8.80 s (IH, CH=)
4.64 s (2H, CH2), 7.34 7.97 m (9H, H arom), 62.34 3.40
8.81 s (IH, CH=)
4.60 s (2H, CH2), 7.40 7.86 m (9H, H arom), 54.92 3.02
8.83 s (IH, CH=)
2.30 s(3H, CH3), 4.59 s(2H, CH2), 7.18 7.69 m 70.34 4.63
(9H, H arom), 8.77 s (IH, CH=)
4.56 s (2H, CH2), 7.19 7.72 m (8H, H arom), 60.21 3.32
8.71 s (IH, CH=)
4.68 s (2H, CH2), 7.30 7.92 m (10H, H arom), 68.48 3.60
8.81 s (IH, CH=)
14.47 Cl7H13N3S
70.10 4.46
14.43
13.59
12.90
11.35
13.77
14.14
12.68
13.41 C17H12FN3S 66.01 3.88
80 115 117
77 124 125
12.57 C17H12C1N3S 62.67
11.07 C17H12BrN3S 55.13
3.68
3.24
73
64 65
13.49 C18H15N3S
13.83 C15HnN3S2
70.81 4.81
60.60 3.70
83a
86 127 128
12.37 C19H13N3OS 68.88 3.82
a
Viscous light-yellow liquid purified by chromatography on A12O3, eluent chloroform ethyl ether, 3: 1.

598
BRATENKO et al.
Table 3. Yields, melting points and elemental analyses of N-[3-aryl(heteryl)-1-phenyl-4-pyrazolylmethyl]thioureas
VIIIa f and 1-[3-aryl(heteryl)-1-phenyl-4-pyrazolylmethyl]thiosemicarbazides IŒa e
Found, %
H
Calculated, %
H
Compd.
no.
Yield, %
mp,
C
Formula
C
N
C
N
VIIIa
VIIIb
VIIIc
VIIId
VIIIe
VIIIf
IŒa
IŒb
IŒc
IŒd
IŒe
58
54
63
67
71
31
58
61
47
56
28
169 170
190 191
170 171
184 185
129 130
215 216
190 192
204 205
183 184
221 222
189 191
66.78
69.31
57.81
68.80
65.13
68.11
65.97
55.81
64.07
64.04
63.88
5.01
5.13
4.90
5.02
4.70
4.51
4.56
5.11
4.40
4.07
4.08
19.03
13.26
12.04
17.34
13.68
15.67
16.61
14.57
17.10
19.81
17.71
C22H23FN4S
C24H22N4OS
C22H23BrN4S
C23H21N5S
C22H20N4S2
C25H21N5OS
C23H20FN5S
C22H25BrN5S
C25H22N6S2
C30H24N8S2
C25H20N6O2S
67.00
69.56
58.02
69.17
65.34
68.33
66.18
56.05
63.82
64.28
64.10
5.83
5.31
5.05
5.26
4.95
4.78
4.79
5.30
4.68
4.28
4.27
14.24
13.52
12.30
17.54
13.86
15.94
16.78
14.86
17.87
20.00
17.95
1
ene hexane, 5: 1). H NMR spectrum, , ppm: 4.95 s
(2H, CH2), 7.29 7.91 m (10H, H arom), 8.87 s (1H,
CH=). Found, %: C 69.69; H 4.32; N 9.23.
C18H13ClN2O. Calculated, %: C 70.02; H 4.24; N
9.07.
was cooled to 10 C, the separated precipitate was
filtered off and crystallized from ethanol.
N-[Aryl(heteryl)-1-phenyl-4-pyrazolylmethyl]-
thioureas VIIIa f and 1-[aryl(heteryl)-1-phenyl-4-
pyrazolylmethyl]thiosemicarbazides IXa d(Table3).
A solution of 0.002 mol of thiocyanate Vb g in 10 ml
of p-xylene was heated to boiling for 2 h. In the IR
spectrum of the reaction mixture disappeared the ab-
S-[Aryl(heteryl)-1-phenyl-4-pyrazolylmethyl]-
thiuronium chlorides IIa, b, d, g (Table 1). To a
solution of 0.015 mol of 4-chloromethylpyrazole
Ia, b, d, g in 20 ml of THF was added 1.3 g
(0.017 mol of thiourea, the reaction mixture was
heated to boiling for 0.5 h, and then was left standing
at room temperature for 12 h. The precipitate formed
was filtered off and crystallized from ethanol.
1
sorption band of thiocyano group at 2160 2170 cm
and was present the band of isothiocyano group at
1
1970 1990 cm . To the reaction mixture was added
0.02 mol of amino compound VIa d, VIIa d, and
the heating was continued for 1 h more at the same
temperature. The solvent was evaporated, the residue
was crystallized from ethanol.
3-Aryl(heteryl)-1-phenyl-4-pyrazolylmethane-
thiols IIIa, b, d, g (Table 1). To a heated to boiling
solution of 0.01 g of thiuronium salt IIa, b, d, g in
40 ml of ethanol was added 15 ml of 10% water solu-
tion of sodium hydroxide, and the mixture was stirred
for 3 h at 75 80 C. The reaction mixture was cooled,
the undissolved precipitate was filtered off,, the
filtrate was neutralized with20% sulfuric acid till
pH 7, the reaction product was extracted into chloro-
form (3 50 ml), the extract was dried with
magnesium sulfate. On removing the solvent the
residue was crystallized from a mixture benzene
hexane, 1: 1.
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vol. 60, 2825g.
Aryl(heteryl)-4-thiocyanatomethyl-1-phenylpyr-
azoles IVa g (Table 2). To a dispersion of 1 g
(0.0123 mol) of anhydrous sodium thiocyanate in
10 ml of anhydrous acetone was added 0.01 mol of
4-chloromethylpyrazole Ia g, and the mixture was
heated to boiling for 1 h. Then the reaction mixture
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 2 2002