4-Functionally substituted 3-heterylpyrazoles: XII. 4-Chlorothieno[2,3-c] pyrazole-5-carbonyl chlorides

Article abstract of DOI:10.1023/B:RUJO.0000003171.20020.00

3-(4-Pyrazolyl)acrylic acids reacted with excess thionyl chloride in the presence of benzyltri-ethylammonium chloride affording 4-chlorothieno[2,3-c] pyrazole-5-carbonyl chlorides which were converted into the corresponding acids, esters, and amides.

Full text of DOI:10.1023/B:RUJO.0000003171.20020.00

Russian Journal of Organic Chemistry, Vol. 39, No. 6, 2003, pp. 893 896. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 6, 2003,
pp. 942 945.
Original Russian Text Copyright
2003 by Bratenko, Chornous, Vovk.
4-Functionally Substituted 3-heterylpyrazoles: XII.*
4-Chlorothieno[2,3-c]pyrazole-5-carbonyl Chlorides
M. K. Bratenko1, V. A. Chornous1, and M.V.Vovk2
1
Bukovinskaya State Medical Academy, Chernovtsy, Ukraine
1
Institute of Organic Chemistry, National Academy of Sciences of the Ukraine, Kiev, 02094 Ukraine
Received September 14, 2001
Abstract 3-(4-Pyrazolyl)acrylic acids reacted with excess thionyl chloride in the presence of benzyltri-
ethylammonium chloride affording 4-chlorothieno[2,3-c]pyrazole-5-carbonyl chlorides which were converted
into the corresponding acids, esters, and amides.
1
Reactions of substituted cinnamic acids and their
derivatives with excess thionyl chloride in the
presence of pyridine acquired preparative importance
in the synthesis of 3-chloro[b]thiophene-2-carbonyl
chlorides [2 7]. Among heterocyclic analogs of
cinnamic acids this reaction was investigated only for
benzo[b]thiophen-3-acrylic [8] and (E,E)-2,5-thio-
phenedi(2-ethenyl)carboxylic [7] acids.
products according to H NMR spectra was 80 86%.
Their hydrolysis made possible isolation of analytical-
ly pure acids IIIa e that further by treating with
thionyl chloride almost quantitatively were converted
into pure acyl chlorides IIa e.
We report here on results of investigation of the
reaction between thionyl chloride and 3-(4-pyrazolyl)-
acrylic acids Ia e we have recently synthesized [1].
The reaction is carried out in the presence of pyridine
or benzyltriethylammonium chloride (BTEAC). Our
previous attempts to substitute the position 5 of
4-functionalized pyrazoles by treatment with common
electrophilic reagents were unsuccessful. However
taking into consideration the assumption [4] that the
conversion of cinnamic acids into derivatives of
benzo[b]thiophene probably occurred involving high-
ly electrophilic sulfenyl chlorides we got hope to
carry out similar reaction with the 3-(3-pyrazolyl)-
acrylic acids.
I III, Ar = Ph (a), 4-F-C6H4 (b), 4-ClC6H4 (c),
4-BrC6H4 (d), 4-MeC6H4 (e).
Taking into account that 3-phenylpropanoic acid
treated with thionyl chloride is able to undergo
cyclization into 3-chlorobenzo[b]thiophene-2-carbonyl
chloride [10, 11] we tried to perform similar reaction
It was shown by an example of acid Ia that after
heating for 10 h at 140 C with 5-fold excess of
thionyl chloride in the presence of pyridine (10%
from equimolar amount) 1,3-dipheny-4-chloro-141H-
with
3-(1,3-diphenyl-1H-pyrazol-4-yl)propanoic
acid IV. It was found that under above described
conditions acid IV in 40% yield afforded acyl
chloride IIa.
thieno[2,3-c]pyrazole-5-carbonyl
chloride
(IIa)
actually formed but its yield was only 18%. We
succeeded in raising the yield in the reaction of acids
Ia e with 4-fold excess of thionyl chloride at 160 C
using BTEAC in 50% to equimolar amount instead
of pyridine [9]. As a result acyl chloride IIa was
isolated in the analytically pure state in 43% yield.
The content of acyl chlorides IIb d in the reaction
3-Aryl-1-phenyl-4-chloro-1H-thieno[2,3-c]pyr-
azole-5-carbonyl chlorides (IIa e) and correspond-
ing acids IIIa e (Table 1, 2) are colorless or light-
yellow high-melting crystalline compounds whose
assumed composition is in agreement with elemental
analysis, and the structure is consistent with the
*
1
For communication XI see [1].
measured IR and H NMR spectra. In particular in
1070-4280/03/3906-0893$25.00 2003 MAIK Nauka/Interperiodica

894
BRATENKO et al.
Table 1. Yields, melting points, and elemental analyses of 4-chlorothieno[2,3-c]pyrazole-5-carbonyl chlorides (IIa e)
and 4-chlorothieno[2,3-c]pyrazole-5-carboxylic acids (IIIa e)
Found, %
H
Calculated, %
H
Compd. Yield,
mp,
oC
a
Formula
no.
%
C
N
C
N
IIa
IIb
IIc
IId
43(40)b
49
209 210
240 242
231 232
243-244
215 216
272 273
284 285
324 325
294 295
267 268
58.25
55.61
52.72
48.10
58.51
61.17
58.24
5.57
2.54
2.39
2.04
1.93
3.35
3.24
2.81
2.43
2.09
3.54
7.73
7.01
7.05
6.47
7.45
8.09
7.29
7.41
6.83
7.70
C18H10Cl2N2OS
C18H9Cl2FN2OS
C18H9Cl3N2OS
C18H9BrCl2N2OS
C19H12Cl2N2OS
C18H11ClN2O2S
C18H10ClFN2O2S
C18H10ClN2O2S
C18H10ClBrN2O2S
C19H13ClN2O2S
57.92
55.26
53.03
47.82
58.93
60.93
57.99
55.54
48.85
61.87
2.70
2.32
2.23
2.01
3.12
3.12
2.70
2.59
2.32
3.55
7.50
7.19
6.87
6.20
7.23
7.90
7.51
7.20
6.46
7.59
65
54
61
47
52
67
59
65
IIe
IIIa
IIIb
IIIc
IIId
IIIe
50.10
61.59
a
For compounds IIa e with respect to the corresponding 3-(4-pyrazolyl)acrylic acid.
From acid (IV).
b
1
Table 2. IR and H NMR of 4-chlorothieno[2,3-c]pyrazole-5-carbonyl chlorides (IIa e) and 4-chlorothieno[2,3-c]-
pyrazole-5-carboxylic acids (IIIa e)
1
IR spectrum, cm
Compd.
1H NMR spectrum, , ppm
no.
(C=O)
(OH)
IIa
IIb
IIc
IId
IIe
IIIa
IIIb
1760
1765
1770
1760
1765
1700
1705
7.35 t (1H arom), 7.47 7.82 m (9H arom)
7.33 7.47 m (3H arom), 7.61 7.82 m (6H arom)
7.33 7.60 m (5H arom), 7.81 d, 7.93 d (4H arom)
7.44 t (1H arom), 7.60 7.99 m (8H arom)
2.42 s (3H, CH3), 7.33 t (1H arom), 7.50 7.79 m (8H arom)
7.37 t (1H arom), 7.49 7.79 m (9H arom), 10.82 br.s (1H, COOH)
7.29 7.40 m (3H arom), 7.62 7.78 m (4H arom), 7.90 7.94 m (2H arom),
11.08 br.s (1H, COOH)
2600 3000
2650 3050
IIIc
1710
2650 3100
7.38 t (1H arom), 7.53 7.62 m (4H arom), 7.79 d, 7.90 d (4H arom)
11.20 br.s (1H, COOH)
IIId
IIIe
1710
1700
2600 2950
2650 3050
7.39 t (1H arom), 7.52 7.94 m (8H arom) 10.91 br.s (1H, COOH)
2.42 s (3H, CH3), 7.38 d (2H arom), 7.42 s (1H arom) 7.59 7.62 m (2H
arom), 7.75 7.82 m (4H arom), 11.03 br.s (1H, COOH)
the downfield part of the latter (8.4 9.3 ppm) lacked
the singlet from C5 H proton of the original acids
Ia e indicating that the pyrazole ring fused at this
position.
The approach we developed to the synthesis of
5-functionalized thieno[2,3-c]pyrazole systems sig-
nificantly extends the existing methods of their
preparation [12, 14].
V, Ar = Ph, R1 = Me (a); Ar = 4-ClC6H4, R1 = 2-(MeO)-4-(CH=O)C6H3 (b); VI, Ar = 4-FC6H4, R2 = H, R3 =
2-phurmethyl (a); Ar = 4-ClC6H4, R2 = H, R3 = 3-piridylmethyl (b); Ar = 4-BrC6H4; R2 = H, R3 = Ph (c),
R2R3 = (CH2)5 (d); Ar = 4-MeC6H4; R2 = H, R3 = 4-MeOC6H4 (e); R2R3 = (CH2)2CH(CH3)(CH2)2 (f).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 6 2003

896
BRATENKO et al.
The acyl chlorides proper can be successfully used
in preparation of various derivatives, e.g., esters
Va, b, amides VIa f (Table 3).
3-Aryl-1-phenyl-4-chloro-1H-thieno[2,3-s]pyr-
azole-5-carboxylic acids esters (Va, b) and amides
(VIa f). To a solution of 0.003 mol of acyl chloride
IIa e in 5 ml of pyridine was added 0.003 mol of an
appropriate alcohol, phenol, or amine, and the mix-
ture was heated at reflux for 2 h. The reaction mix-
ture was then cooled, diluted with 50 ml of water, the
separated precipitate was filtered off and recrystalliz-
ed from acetic acid.
EXPERIMENTAL
IR spectra were recorded on spectrophotometer
1
UR-20 from samples pelletized with KBr. H NMR
spectra were registered on spectrometer Varian-
Gemini (300 MHz) from solutions in DMSO-d6,
internal reference TMS.
REFERENCES
3-Aryl-1-phenyl-4-chloro-1H-thieno[2,3-c]pyr-
azole-5-carbonyl chlorides (IIa e). A mixture of
0.02 mol of acid Ia e or IV, 9.52 g (0.08 mol) of
thionyl chloride, and 2.28 g (0.01 mol) of BTEAC
was heated at 160 C on an oil bath for 4 h. Then the
bath temperature was reduced to 100 110 C, and the
excessive thionyl chloride was distilled off. To the
residue was added 25 ml of chloroform, and the mix-
ture was boiled for 0.5 h (for dissolving resinous
products and BTEAC). The precipitate formed on
cooling was filtered, washed with chloroform (2
15 ml), then heated in toluene till dissolution (com-
pounds IIa) or in a mixture toluene dioxane, 1: 2
(compounds IIb e), and the solution was cooled. The
content of acyl chloride in the formed solid pre-
cipitate amounted to 80 86%. To 0.005 mol (recal-
culated to the content of the main substance) of com-
pound IIa e in 25 ml of dioxane was added 20 ml of
2 N water solution of NaOH, and the mixture was
heated at reflux for 2 h. On cooling the reaction
mixture was diluted with water (100 ml), acidified
with 2 N HCl to pH 5 6, the precipitate was filtered
off, dried, and crystallized from acetic acid (com-
pounds IIIa, e) or from a mixture acetic acid dioxane
(compounds IIIb d). To a suspension of 0.005 mol
of acid IIIb e in 5 ml of thionyl chloride was added
2 drops of DMF and the mixture was heated at reflux
for 2 h. On cooling 10 ml of benzene was added, the
precipitate was filtered off, washed with benzene
(2 10 ml), and dried. Thus were obtained analytical-
ly pure samples of acyl chlorides IIb e.
1. Bratenko, M.K., Chornous, V.A., and Vovk, M.V.,
Zh. Org. Khim., 2002, vol. 38, p. 1223.
2. Nakagawa, S., Okumura, J., Sakai, F., Hoshi, H.,
and Naito, T., Tetrahedron Lett., 1970, no. 42,
p. 3719.
3. Wright, W.B. and Brabander, H., J. Heterocyclic
Chem., 1971, vol. 8, p. 711.
4. Higa, T. and Krubsack, A.J., J. Org. Chem., 1975,
vol. 40, no. 21, p. 3037.
5. Ried, W., Oremek, C., and Ocarcioglu, B., Lieb. Ann.,
1980, no. 9, p. 1424.
6. Garhar, H.K., Kaur, R., and Gupta, S.P., Monatsh.
Chem., 1995, vol. 126, p. 1235.
7. Dogan, J., Karminski-Zamola, G.M., and Boy-
kin, O.W., Heterocycles, 1995, vol. 41, p. 1659.
8. Luo, J.K., Kudo, H., Federspiel, R.F., and
Castle, R.N., J. Heterocyclic Chem., 1995, vol. 32,
p. 317.
9. Sintez sul,fidov tiofenov i tiolov (Synthesis of Sulfides,
Thiophenes, and Thyols), Karaulova N., Ed.,
Moscow: Nauka, 1988, p. 178.
10. Krubsack, A.J. and Higa, T., Tetrahedron Lett.,
1968, no. 49, p. 5149.
11. Krubsack, A.J. and Higa, T., Tetrahedron Lett.,
1973, p. 125.
12. Brown, K.J. and Meth-Cohn, O., Tetrahedron Lett.,
1974, no. 46, p. 4069.
13. Menozzi, G., Mosti, L., Scenone, P., D,Amico M.,
Filippeli, A., and Rossi, F., Farmaco., 1992, vol. 47,
p. 1495.
14. Alluwalia, V.K., Dahiya, A., and Bola, M., Indian
J. Chem. Sect. B, 1996, vol. 35, p. 715.
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