4-Functionally-substituted 3-heterylpyrazoles: XVII. 3-Aryl-1-phenyl-4- pyrazolmethylsulfanyl(sulfinyl, sulfonyl)acetic acids

Article abstract of DOI:10.1134/S1070428006050101

3-Aryl-1-phenyl-4-mercaptomethylpyrazoles reacted with monochloroacetic acid to give 3-aryl-1-phenyl-4-pyrazolylmethylsulfanylacetic acids whose oxidation with hydrogen peroxide in acetone or acetic acid solution led to 3-aryl-1-phenyl-4-pyrazolylmethylsu

Full text of DOI:10.1134/S1070428006050101

ISSN 1070-4280 Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 5, pp. 703-706. Ó Pleiades Publishing, Inc. 2006.
Original Russian Text Ó M.K. Bratenko, V.A. Chornous, M.V. Vovk, 2006, published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 5,
pp. 721-724.
4-Functionally-Substituted 3-Heterylpyrazoles:
XVII.* 3-Aryl-1-phenyl-4-pyrazolmethylsulfanyl(sulfinyl,
sulfonyl)acetic Acids
M.K. Bratenkoa, V.A. Chornousa, and M.V. Vovkb
aBukovinskaya State Medical Academy, Chernovtsy, Ukraine
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, 02094, Ukraine
e-mail: mvovk@i.com.ua
Received March 5, 2005
Abstract—3-Aryl-1-phenyl-4-mercaptomethylpyrazoles reacted with monochloroacetic acid to give 3-aryl-1-
phenyl-4-pyrazolylmethylsulfanylacetic acids whose oxidation with hydrogen peroxide in acetone or acetic acid
solution led to 3-aryl-1-phenyl-4-pyrazolylmethylsulfinyl- and sulfonylacetic acids, respectively.
DOI: 10.1134/S1070428006050101
Sulfur-containing acetic acids possessing versatile
synthetic possibilities and useful properties are a matter
of rapt attention of chemists. By now a thorough
investigation was carried out on transformations of a series
of benzylsulfanylacetic acids into their sulfinyl and sulfonyl
derivatives [2–8]. The benzylsulfinylacetic acids proper
turned out to be convenient models for studying the optical
properties of sulfoxide systems [6–8], and benzylsulfonyl-
acetic acids found the use as important blocks in the
synthesis of a,b-unsaturated sulfones [9, 10].
We report here on the results of the study on the
synthesis of previously unkhown heterocyclic analogs of
the above mentioned sulfur-containing compounds,
4-pyrazolylmethylthioacetic acids and their oxidation
products. We chose as initial compounds 4-mercapto-
methylpyrazoles Ia–If that we had synthesized previously
[11]. These substances in the presence of alcoholic alkali
were readily alkylated with the monochloroacetic acid to
afford 4-pyrazolylmethylsulfanylacetic acids IIa–IIf in
62–73% yields. The latter were identified based on IR,
2
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* For Communication XVI, see [1].
703

BRATENKO et al.
704
1H NMR spectra, and elemental analysis. In particular,
the H NMR spectra contained characteristic singlets
COOH). Found, %: C 66.42; H 4.81; N 8.56. C18H16N2O2S.
Calculated, %: C 66.67; H 4.94; N 8.64.
1
belonging to the methylene protons of the carboxymethyl
(3.17–3.26) and pyrazolemethyl (3.88–3.92 ppm)
fragments.
1-Phenyl-3-(4-fluorophenyl)-4-pyrazolylmethyl-
sulfanylacetic acid (IIb). Yield 71%, mp 108–111°C.
–1
IR spectrum, cm : 1725 (C=O), 2680–2950 (OH).
1H NMR spectrum, d, ppm: 3.26 s (2H, CH2COOH),
3.91 s (2H, PsrCH2), 7.25–7.87 m (9Harom), 8.45 s (1H,
H5Pyr), 12.47 br.s (1H, COOH). Found, %: C 63.40;
H 4.51; N 7.98. C18H15FN2O2S. Calculated, %: C 63.16;
H 4.39; N 8.19.
We found conditions for a selective conversion of
acids IIa–IIf into 4-pyrazolylmethylsulfinylacetic acids
IIIa–IIIf and 4-pyrazolylmethyl-sulfonyl-acetic acids
IVa–IVf. It was shown that the treatment of acetone
solutions of compounds IIa–IIf with 30% hydrogen
peroxide at room temperature furnished in 78–92% yields
acids IIIa–IIIf. In their turn, acids IVa–IVf were obtained
in 85-98% yields by oxidation of compounds IIa–IIf with
30% hydrogen peroxide in acetic acid at 60°C.
1-Phenyl-3-(4-chlorophenyl)-4-pyrazolylmethyl-
sulfanylacetic acid (IIc). Yield 68%, mp 119–120°C.
–1
IR spectrum, cm : 1720 (C=O), 2650–2930 (OH).
1H NMR spectrum, d, ppm: 3.17 s (2H, CH2COOH),
3.88 s (2H, PyrCH2), 7.27–7.88 m (9Harom), 8.45 s (1H,
H5Pyr), 12.40 br.s (1H, COOH). Found, %: C 60.03;
H 3.99; N 7.67. C18H15ClN2O2S. Calculated, %: C 60.25;
H 4.18; N 7.81.
The characteristic feature of acids III is the nonequiva-
lence of the protons in both methylene groups caused by
the pyramidal structure of the sulfoxide moiety. In the
1H NMR spectra these protons give rise to quartets of
AB systems in the range 3.63–3.98 and 4.15–4.36 ppm
respectively. At the same time the methylene groups of
3-(4-Bromophenyl)-1-phenyl-4-pyrazolyl-
methylsulfanylacetic acid (IId). Yield 73%, mp 138–
1
acids IVa-IVf appear in the H NMR spectra as two
–1
140°C. IR spectrum, cm : 1725 (C=O), 2700–2980 (OH).
singlets: CH2COOH at 4.30–4.35, PyrCH2 at 4.66–
4.70 ppm. In general the oxidation of sulfides II into
sulfoxides III and sulfones IV tends to increase the acid
character of the methylene groups that is revealed in the
1H NMR spectra by their successive downfield shift by
approximately 0.4–0.6 ppm.
1H NMR spectrum, d, ppm: 3.26 s (2H, CH2COOH),
3.92 s (2H, PyrCH2), 7.30–7.90 m (9Harom), 8.46 s (1H,
H5Pyr), 12.52 br.s (1H, COOH). Found, %: C 53.33;
H 3.60; N 6.81. C18H15BrN2O2S. Calculated, %: C 53.60;
H 3.72; N 6.95.
3-(4-Methoxy)-1-phenyl-4-pyrazolylmethyl-
EXPERIMENTAL
sulfanylacetic acid (IIe). Yield 65%, mp 110–111°C.
–1
IR spectrum, cm : 1720 (C=O), 2670–2920 (OH).
IR spectra of compounds were recorded on a spectro-
photometer UR-20 from KBr pellets. H NMR spectra
were registered from solutions of compounds in (CD3)2SO
on a spectrometer Varian Gemini (300 MHz), internal
reference TMS.
1H NMR spectrum, d, ppm: 3.26 s (2H, CH2COOH),
3.81 s (3H, CH3O), 3.90 s (2H, PyrCH2), 6.99 d (2Harom),
7.26 t (1Harom), 7.46 t (2 Harom), 7.74 d (2Harom), 7.86 d
(2Harom), 8.39 s (1H, H5Pyr), 12.57 br.s (1H, COOH).
Found, %: C 64.16; H 4.91; N 7.78. C19H18N2O3S.
Calculated, %: C 64.41; H 5.08; N 7.91.
1
3-Aryl-1-phenyl-4-pyrazolylmethylsulfanylacetic
acid IIa–IIf. A mixture of 10 mmol of 4-mercapto-
methylpyrazole Ia–If, 1 g (10.6 mmol) of monochloro-
acetic acid, and 10 ml of 20% water solution of NaOH in
10 ml of ethanol was boiled for 2 h, cooled, then 50 ml of
water was added, and the solution was filtered. The
filtrate was acidified with 6 N hydrochloric acid, the
arising oily substance get solid within 24 h and was
recrystallized from 80% aqueous ethanol.
3-(3,4-Dimethylphenyl)-1-phenyl-4-pyrazolyl-
methylsulfanylacetic acid (IIf). Yield 62%, mp 99–
–1
101°C. IR spectrum, cm : 1725 (C=O), 2650–2950 (OH).
1H NMR spectrum, d, ppm: 2.28 s (3H, CH3), 2.31 s
(3H, CH3), 3.23 s (2H, CH2COOH), 3.88 s (2H,
PsrCH2), 7.21–7.59 m (6Harom), 7.86 d (2Harom), 8.40 s
(1H, H5Pyr), 12.40 br.s (1H, COOH). Found, %: C 68.44;
H 5.56; N 7.81. C20H20N2O2S. Calculated, %: C 68.18;
H 5.68; N 7.95.
1,3-Diphenyl-4-pyrazolylmethylsulfanylacetic
–1
acid (IIa). Yield 63%, mp 87–88°C. IR spectrum, cm :
1
3-Aryl-1-phenyl-4-pyrazolylmethylsulfinylacetic
acids IIIa–IIIf. To a solution of 5 mmol of acid IIa–IIf
in 20 ml of acetone was added 3 ml of 30% solution of
1720 (C=O), 2650–2940 (OH). H NMR spectrum, d,
ppm: 3.23 s (2H, CH2COOH), 3.91 s (2H, PyrCH2), 7.26–
7.85 m (10Harom), 8.44 s (1H, H5Pyr), 12.51 br.s (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

4-FUNCTIONALLY-SUBSTITUTED 3-HETERYLPYRAZOLES: XVII.
705
hydrogen peroxide, and the mixture was stirred for 3 days
at room temperature. The solution was evaporated, the
residue was recrystallized from 75% acetic acid.
(1H, H5Pyr), 12.93 br.s (1H, COOH). Found, %: C 61.60;
H 3.59; N 7.50. C19H18N2O4S. Calculated, %: C 61.61;
H 4.90; N 7.56.
3-(3,4-Dimethylphenyl)-1-phenyl-4-pyrazol-
ylmethylsulfinylacetic acid (IIIf). Yield 78%, mp 141–
143°C. IR spectrum, cm-1: 1725 (C=O), 2650–2890 (OH).
1H NMR spectrum, d, ppm: 2.28 C (3H, CH3), 2,31
C (3H, CH3), 3.64 d (1H, CH2COOH, 2J14 Hz), 3.96 d
1,3-Diphenyl-4-pyrazolylmethylsulfinylacetic acid
–1
(IIIa). Yield 83%, mp 138–140°C. IR spectrum, cm :
1730 (C=O), 2750–2920 (OH). 1H NMR spectrum, d,
ppm: 3.64 d (1H, CH2COOH, 2J 13 Hz), 3.97 d (1H,
2
CH2COOH, J 13 Hz), 4.17 d (1H, PyrCH2, 2J 14 Hz),
2
2
4.30 d (1H, PyrCH2, 2J 14 Hz), 7.28–7.89 m (10Harom),
8.57 s (1H, H5Pyr), 13.03 br.s (1H, COOH). Found, %:
C 63.80; H 4.68; N 8.42. C18H16N2O3S. Calculated, %:
C 63.53; H 4.71; N 8.23.
(1H, J 14 Hz), 4.20 d (1H, PyrCH2, J 14 Hz), 4.36 d
2
(1H, PyrCH2, J 14 Hz), 7.28–7.64 d (6Harom), 7.87 d
(2Harom), 8.59 C (1H, H5Pyr), 12.94 br.s (1H, COOH).
Found, %: C 65.35; H 5.40; N 7.50. C20H20N2O3S.
Calculated, %: C 65.20; H 5.47; N 7.60.
1-Phenyl-3-(4-fluorophenyl)-4-pyrazolyl-
3-Aryl-1-phenyl-4-pyrazolylmethylsulfanylacetic
acids IVa–IVf. To a solution of 5 mmol of acid IIa–IIf
in 20 ml of acetic acid was added 6 ml of 30% solution of
hydrogen peroxide, and the mixture was stirred for 2 h at
room temperature, then 2 h more at 60°C. The reaction
mixture was cooled, diluted with 50 ml of water, the
separated precipitate was filtered off and recrystallized
from 20% acetic acid.
methylsulfinylacetic acid (IIIb). Yield 90%, mp 183–
185°C. IR spectrum, cm : 1735 (C=O), 2720–2950 (OH).
–1
1H NMR spectrum, d, ppm: 3.63 d (1H, CH2COOH,
2J14 Hz), 3.93 d (1H, CH2COOH, 2J14 Hz), 4.16 d (1H,
PyrCH2, 2J14 Hz), 4.28 d (1H, PyrCH2, 2J14 Hz), 7.24–
7.87 m (9Harom), 8.53 s (1H, H5Pyr), 12.87 br.s (1H,
COOH). Found, %: C 60.07; H 4.32; N 8.03.
C18H15FN2O3S. Calculated, %: C 60.34; H 4.19; N 7.82.
1,3-Diphenyl-4-pyrazolylmethylsulfonylacetic
1-Phenyl-3-(4-chlorophenyl)-4-pyrazolylmethyl-
acid (IVa). Yield 93%, mp 156–157°C. IR spectrum,
sulfinylacetic acid (IIIs). Yield 92%, mp 178–180°C.
–1
cm : 1730 (C=O), 2560–2850 (OH). 1H NMR spectrum,
–1
IR spectrum, cm : 1735 (C=O), 2700–2930 (OH).
d, ppm: 4.31 s (2H, CH2COOH), 4.69 d (2H, PyrCH2),
7.29–7.83 m (10Harom), 8.53 s (1H, H5Pyr), 13.03 br.s (1H,
COOH). Found, %: C 60.91; H 4.63; N 7.99.
C18H16N2O4S. Calculated, %: C 60.67; H 4.49; N 7.86.
1H NMR spectrum, d, ppm: 3.68 d (1H, CH2COOH,
2J13 Hz), 3.95 d (1H, CH2COOH, 2J13 Hz), 4.18 d (1H,
PyrCH2, 2J14 Hz), 4.33 d (1H, PyrCH2, 2J14 Hz), 7.32–
7.53 m (5Harom), 7.79 d (2Harom), 7.88 d (2Harom), 8.56 s
(1H, H5Pyr), 13.09 br.s (1H, COOH). Found, %: C 57.94;
H 4.17; N 7.68. C18H15ClN2O3S. Calculated, %: C 57.68;
H 4.01; N 7.48.
1-Phenyl-3-(4-fluorophenyl)-4-pyrazolylmethyl-
sulfonylacetic acid (IVb). Yield 97%, mp 178–179°C.
–1
IR spectrum, cm : 1730 (C=O), 2590–2820 (OH).
1H NMR spectrum, d, ppm: 4.33 s (2H, CH2COOH),
4.68 s (2H, PyrCH2), 7.26–7.89 m (9Harom), 8.55 s (1H),
13.03 br.s (1H, COOH). Found, %: C 57.43; H 4.20;
N 7.26. C18H15FN2O4S. Calculated, %: C 57.75; H 4.01;
N 7.49.
3-(4-Bromophenyl)-1-phenyl-4-pyrazolyl-
methylsulfinylacetic acid (IIId). Yield 89%, mp 189–
–1
191°C. IR spectrum, cm : 1730 (C=O), 2700–2900 (OH).
1H NMR spectrum, d, ppm: 3.64 d (1H, CH2COOH,
2J12 Hz), 3.94 d (1H, CH2COOH, 2J12 Hz), 4.15 d (1H,
PyrCH2, 2J13 Hz), 4.31 d (1H, PyrCH2, 2J13 Hz), 7.32–
7.93 m (9Harom), 8.55 s (1H, H5Pyr), 13.01 br.s (1H, COOH).
Found, %: C 51.79; H 3.51; N 6.60. C18H15BrN2O3S.
Calculated, %: C 51.55; H 3.58; N 6.68.
1-Phenyl-3-(4-chlorophenyl)-4-pyrazolylmethyl-
sulfonylacetic acid (IVc). Yield 95%, mp 183–185°C.
–1
IR spectrum, cm : 1725 (C=O), 2550–2860 (OH).
1H NMR spectrum, d, ppm: 4.34 s (2H, CH2COOH),
4.69 s (2H, PyrCH2), 7.34–7.69 m (5Harom), 7.69 d
(2Harom), 7.86 d (2Harom), 8.59 s (1H, H5Pyr), 12.99 br.s
(1H, COOH). Found,%: C 55.06; H 3.97; N 7.34.
C18H15ClN2O4S. Calculated,%: C 55.31; H 3.84; N 7.17.
3-(4-Methoxyphenyl)-1-phenyl-4-pyrazol-
ylmethylsulfinylacetic acid (IIIe). Yield 81%, mp 156–
–1
157°C. IR spectrum, cm : 1725 (C=O), 2680–2900 (OH).
1H NMR spectrum, d, ppm: 3.65 d (1H, CH2COOH ,
2J 14 Hz), 3,82 s (3H, CH3O), 3.98 d (1H, CH2COOH,
3-(4-Bromophenyl)-1-phenyl-4-pyrazolylmethyl-
2
2J 14 Hz), 4.19 d (1H, PyrCH2, J 15 Hz), 4.33 d (1H,
sulfonylacetic acid (IVd). Yield 98%, mp 195–197°C.
2
–1
PyrCH2, J 15 Hz), 7.03 d (3Harom.), 7.30 t (1Harom),
IR spectrum, cm : 1730 (C=O), 2580–2900 (OH).
1H NMR spectrum, d, ppm: 4.35 s (2H, CH2COOH),
7.51 t (2Harom), 7.65 d (2Harom), 7.83 d (2Harom), 8.52 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

BRATENKO et al.
706
REFERENCES
4.70 s (2H, PyrCH2), 7.33–7.64 m (5Harom), 7.74 d
(2Harom), 7.89 d (2Harom), 8.57 s (1H, H5Pyr), 13.07 br.s
(1H, COOH). Found,%: C 49.95; H 3.28; N 6.61.
C18H15BrN2O4S. Calculated,%: C 49.66; H 3.45; N 6.44.
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3-(4-Methoxyphenyl)-1-phenyl-4-pyrazolyl-
methylsulfonylacetic acid (IVe). Yield 89%, mp 164–
165°C. IR spectrum, cm-1: 1730 (C=O), 2580–2910 (OH).
1H NMR spectrum, d, ppm: 3.81 s (3H, CH3O), 4.30 s
(2H, CH2COOH), 4.68 s (2H, PyrCH2), 6.99 d (2Harom),
7.31 t (1Harom), 7.50 t (2Harom), 7.70 d (2Harom), 7.90 d
(2Harom), 8.57 s (1H, H5Pyr), 13.07 br.s (1H, COOH).
Found,%: C 49.95; H 3.28; N 6.61. C18H15BrN2O4S.
Calculated,%: C 49.66; H 3.45; N 6.44.
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methylsulfonylacetic acid (IVf). Yield 85%, mp 148–
–1
150°C. IR spectrum, cm : 1730 (C=O), 2610–2890 (OH).
1H NMR spectrum, d, ppm: 2.25 s (3H, CH3), 2.28 s
(3H, CH3), 4.32 s (2H, CH2COOH), 4.67 s (2H, PyrCH2),
7.21–7.59 m (6Harom), 7.90 d (2Harom), 8.52 s (1H, H5Pyr),
12.93 br.s (1H, COOH). Found,%: C 62.75; H 5.04;
N 7.47. C20H20N2O4S. Calculated,%: C 62.50; H 5.21;
N 7.29.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006