Polyfunctional pyrazoles. 7. Ethyl 1-aryl-4-formylpyrazole-3-carboxylates in the synthesis of 2-aryl-2,4-dihydro-6H-thieno-[3,4-c]pyrazol-6-ones

Article abstract of DOI:10.1007/s10593-013-1171-y

A convenient method has been developed for the synthesis of 2,4-dihydro-6H-thieno[3,4-c]pyrazol-6-ones by means of an intramolecular cyclization of 4-sulfanylmethylpyrazole-3-carboxylic acids. The latter were prepared from ethyl 4-formylpyrazole-3-carboxylates via the intermediate 4-hydroxy-methyl-, 4-chloromethyl-, and 4-thioureidomethyl derivatives.

Full text of DOI:10.1007/s10593-013-1171-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 10, January, 2013 (Russian Original Vol. 48, No. 10, October, 2012)
POLYFUNCTIONAL PYRAZOLES. 7*. ETHYL 1-ARYL-
4-FORMYLPYRAZOLE-3-CARBOXYLATES IN THE
SYNTHESIS OF 2-ARYL-2,4-DIHYDRO-6H-THIENO-
[3,4-c]PYRAZOL-6-ONES
M. K. Bratenko1**, M. M. Barus1, and M. V. Vovk2
A convenient method has been developed for the synthesis of 2,4-dihydro-6H-thieno[3,4-c]pyrazol-
6-ones by means of an intramolecular cyclization of 4-sulfanylmethylpyrazole-3-carboxylic acids. The
latter were prepared from ethyl 4-formylpyrazole-3-carboxylates via the intermediate 4-hydroxy-
methyl-, 4-chloromethyl-, and 4-thioureidomethyl derivatives.
Keywords: 2,4-dihydro-6H-thieno[3,4-c]pyrazol-6-ones, ethyl 4-formylpyrazole-3-carboxylates, 4-sul-
fanylmethylpyrazole-3-carboxylic acids, cyclization.
Derivatives of the thieno[3,4-c]pyrazole heterocyclic system find use in medicinal chemistry, thanks to
their marked anti-inflammatory, analgesic, and antithrombotic activity [2]. These substances are also promising
for treatment of cardiovascular and hypoglycaemic conditions [3]. In addition, several members of this series
have recently been proposed as novel types of biosynthesis inhibitors for gram-positive bacteria [4].
O
O
O
CH=O
EtO
OH
EtO
Cl
EtO
NaBH4
EtOH
SOCl2
N
N
CH2Cl2
N
N
N
N
Ar
1a–d
Ar
2a–d
Ar
3a–d
O
NH
S
O
O
·HCl
SH
HO
S
EtO
CS(NH2)2
THF
NaOH
H2O
NH2
DCC
THF
N
N
N
N
N
N
Ar
5a–d
Ar
6a–d
Ar
4a–d
_______
*For Communication 6, see [1].
**To whom correspondence should be addressed, e-mail: bratenko@gmail.com.
1Bukovinian State Medical University, 2 Teatralnaya Sq., Chernivtsy 58000, Ukraine.
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02660,
Ukraine; e-mail: mvovk@i.com.ua.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1657-1661, October, 2012.
Original article submitted October 19, 2011.
0009-3122/13/4810-1545©2013 Springer Science+Business Media New York
1545

TABLE 1. Physicochemical Characteristics of the Synthesized
Compounds 2-6 a-d
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Yield, %
C
H
N
2а
2b
2c
2d
3а
3b
3c
3d
4а
4b
4c
4d
5а
5b
5c
5d
6а
6b
6c
6d
C13H14N2O3
63.08
63.40
55.78
55.62
64.31
64.60
49.65
49.54
58.74
58.99
52.47
52.19
60.60
60.33
46.55
46.81
49.11
49.34
45.07
44.81
50.92
50.77
40.77
41.04
56.45
56.40
49.33
49.17
58.34
58.05
43.81
43.58
5.89
5.73
4.58
4.67
6.04
6.20
3.71
3.84
5.11
4.95
4.18
4.04
5.50
5.42
3.10
3.32
5.08
5.03
4.35
4.30
5.21
5.40
3.60
3.69
4.12
4.30
3.45
3.38
4.60
4.87
2.63
2.66
11.49
11.38
10.09
9.98
134-135
147–148
139–140
151-152
84-85
75
77
71
68
87
84
88
80
94
95
92
96
69
65
72
74
67
74
77
63
C13H13ClN2O3
C14H16N2O3
11.03
10.76
9.06
8.89
10.65
10.58
9.21
9.36
10.27
10.05
8.27
8.40
16.31
16.44
15.12
14.93
15.86
15.79
13.51
13.67
11.72
11.96
10.51
10.42
C13H12Cl2N2O3
C13H13ClN2O2
C13H12Cl2N2O2
C14H15ClN2O2
C13H11Cl3N2O2
C14H17ClN4O2S
C14H16Cl2N4O2S
C15H19ClN4O2S
C14H15Cl3N4O2S
C11H10N2O2S
C11H9ClN2O2S
C12H12N2O2S
C11H8Cl2N2O2S
C11H8N2OS
113-114
96-97
150-151
225-227
220-222
210-211
229-231
146-147
138-140
187-188
206-208
168-169
191-193
173-175
201-203
11.03
11.28
9.05
9.24
60.83
61.09
52.96
52.70
62.71
62.59
46.46
46.33
3.85
3.73
2.87
2.81
4.30
4.38
2.41
2.12
12.71
12.95
11.33
11.17
12.39
12.16
10.04
9.82
C11H7ClN2OS
C12H10N2OS
C11H6Cl2N2OS
The majority of published methods for thieno[3,4-c]pyrazole synthesis are based on pyrazolo-annelation
reactions of hydrogenated thiophene ring, which often occur nonselectively [5-8]. An alternative method for
annelation of a thiophene ring to a pyrazole ring was developed by the authors of [9] for the condensation of
3,4-dibenzoylpyrazoles with P4S10, to give novel 10--electron thieno[3,4-c]pyrazoles with a "tetravalent"
sulfur. However, this variant of forming the indicated bicyclic system has subsequently been seldom used.
We propose a novel variant of such an annelation based on the known [10] transformation of ethyl-
4-chlorobut-2-ene structural fragments to thiolactones. In the present work, we demonstrate the ready
construction of such a fragment based on our recently developed preparative synthesis of 4-formylpyrazole-
3-carboxylic acids [11].
The indicated esters 1a-d were used as the starting material in a chain of subsequent reactions, which
led to a novel 2,4-dihydro-6H-thieno[3,4-c]pyrazole derivatives. Our proposed scheme includes a selective
reduction of the aldehyde group in compounds 1a-d by sodium borohydride, to form the 4-hydroxymethyl
derivatives 2a-d. The latter were treated with thionyl chloride and readily formed the 4-chloromethyl derivatives
3a-d. Their reaction with thiourea gave a virtually quantitative yield of the thiouronium salts 4a-d, which underwent
1546

TABLE 2. Spectroscopic Characteristics of Compounds 2-6 a-d
Com- IR spectrum, , cm-1*
1Н NMR spectrum, , ppm (J, Hz)
С=О ОН (NH)*2
pound
1
2
3
4
2а
1720
3470
1.34 (3Н, t, J = 7.0, CH2СН3); 4.30 (2Н, q, J = 7.0, CH2СН3);
4.67 (2Н, d, J = 4.6, СН2ОH); 5.18 (1Н, t, J = 4.6, ОН);
7.40 (1Н, t, J = 7.4, Н Ph); 7.58 (2Н, t, J = 7.6, Н Ph);
7.85 (2Н, d, J = 8.2, Н Ph); 8.44 (1Н, s, Н-5)
2b
2с
2d
3а
1720
1725
1715
1725
3475
3480
3460
—
1.33 (3Н, t, J = 7.0, CH2СН3); 4.32 (2Н, q, J = 7.0, CH2СН3);
4.68 (2Н, d, J = 5.0, СН2ОH); 5.20 (1Н, t, J = 5.0, ОН);
7.58 (2Н, d, J = 8.0, Н Ar); 7.94 (2Н, d, J = 8.0, Н Ar);
8.51 (1Н, s, Н-5)
1.34 (3Н, t, J = 7.0, CH2СН3); 2.26 (3Н, s, СН3);
4.30 (2Н, q, J = 7.0, CH2СН3); 4.68 (2Н, d, J = 4.0, СН2ОH);
5.14 (1Н, t, J = 4.0, ОН); 7.32 (2Н, d, J = 7.8, Н Ar);
7.76 (2Н, d, J = 7.8, Н Ar); 8.41 (1Н, s, Н-5)
1.33 (3Н, t, J = 7.2, CH2СН3); 4.30 (2Н, q, J = 7.2, CH2СН3);
4.66 (2Н, d, J = 4.8, СН2ОH); 5.11 (1Н, t, J = 4.8, ОН);
7.76-7.83 (2Н, m, Н Ar); 8.21 (1Н, d, J = 2.4, Н Ar);
8.59 (1Н, s, Н-5)
1.35 (3Н, t, J = 6.8, CH2СН3); 4.36 (2Н, q, J = 6.8, CH2СН3);
4.92 (2Н, s, СН2Cl); 7.42 (1Н, t, J = 7.2, Н Ph);
7.56 (2Н, t, J = 7.6, Н Ph); 7.87 (2Н, d, J = 8.4, Н Ph);
8.78 (1Н, s, Н-5)
3b
3c
1725
1720
—
—
1.35 (3Н, t, J = 7.0, CH2СН3); 4.36 (2Н, q, J = 7.0, CH2СН3);
4.91 (2Н, s, СН2Cl); 7.61 (2Н, d, J = 8.5, Н Ar);
7.91 (2Н, d, J = 8.5, Н Ar); 8.81 (1Н, s, Н-5)
1.36 (3Н, t, J = 6.0, CH2СН3); 2.36 (3Н, s, СН3);
4.36 (2Н, q, J = 6.0, CH2СН3); 4.91 (2Н, s, СН2Cl);
7.35 (2Н, d, J = 8.1, Н Ar);
7.75 (2Н, d, J = 8.1, Н Ar); 8.73 (1Н, s, Н-5)
3d
1725
—
1.35 (3Н, t, J = 6.5, CH2СН3); 4.36 (2Н, q, J = 6.5, CH2СН3);
4.90 (2Н, s, СН2Cl); 7.81-7.94 (2Н, m, Н Ar);
8.24 (1Н, d, J = 1.5, Н Ar); 8.88 (1Н, s, Н-5)
4а
1730 3340-3385 1.35 (3Н, t, J = 7.0, CH2СН3); 4.36 (2Н, q, J = 7.0, CH2СН3);
4.64 (2Н, s, СН2S); 7.44 (1Н, t, J = 7.0, Н Ph);
7.57 (2Н, t, J = 7.4, Н Ph); 7.91 (2Н, d, J = 7.8, Н Ph);
8.78 (1Н, s, Н-5); 9.22-9.26 (4Н, m, N+H2)
4b
1715 3320-3365 1.35 (3Н, t, J = 7.0, CH2СН3); 4.36 (2Н, q, J = 7.0, CH2СН3);
4.64 (2Н, s, СН2S); 7.63 (2Н, d, J = 8.8, Н Ar);
7.89 (2Н, d, J = 8.8, Н Ar); 8.80 (1Н, s, Н-5);
9.36 (4Н, br. s, N+H2)
4с
1720 3310-3350 1.34 (3Н, t, J = 6.9, CH2СН3); 2.36 (3Н, s, СН3);
4.30 (2Н, q, J = 6.9, CH2СН3); 4.60 (2Н, s, СН2S);
7.36 (2Н, d, J = 8.4, Н Ar); 7.72 (2Н, d, J = 8.4, Н Ar);
8.70 (1Н, s, Н-5); 9.31 (4Н, br. s, N+H2)
4d
1725 3330-3380 1.36 (3Н, t, J = 6.9, CH2СН3); 4.35 (2Н, q, J = 6.9, CH2СН3);
4.61 (2Н, s, СН2S); 7.84-7.91 (2Н, m, Н Ar);
8.17 (1Н, d, J = 1.6, Н Ar); 8.86 (1Н, s, Н-5); 9.36 (4Н, br. s, N+H2)
5а
1705 2430-2850 2.86 (1Н, t, J = 6.0, SН); 3.87 (2Н, d, J = 6.0, СН2SH);
7.38 (1Н, t, J = 7.2, Н Ph); 7.57 (2Н, t, J = 7.8, Н Ph);
7.92 (2Н, d, J = 7.8, Н Ph); 8.62 (1Н, s, Н-5);
13.08 (1Н, br. s, СООН)
5b
5c
1700 2460-2890 2.87 (1Н, t, J = 4.2, SН); 3.85 (2Н, d, J = 4.2, СН2SH);
7.61 (2Н, d, J = 8.6, Н Ar); 7.90 (2Н, d, J = 8.6, Н Ar);
8.58 (1Н, s, Н-5); 13.12 (1Н, br. s, СООН)
1700 2450-2840 2.36 (3Н, s, СН3); 2.85 (1Н, t, J = 5.0, SН);
3.86 (2Н, d, J = 5.0, СН2SH); 7.34 (2Н, d, J = 8.0, Н Ar);
7.73 (2Н, d, J = 8.0, Н Ar); 8.60 (1Н, s, Н-5);
13.06 (1Н, br. s, СООН)
5d
1705 2440-2830 2.87 (1Н, t, J = 4.8, SН); 3.85 (2Н, d, J = 4.8, СН2SH);
7.78-7.90 (2Н, m, Н Ar); 8.17 (1Н, d, J = 2.1, Н Ar);
8.66 (1Н, s, Н-5); 13.06 (1Н, br. s, СООН)
1547

TABLE 2 (continued)
1
2
3
4
1705 2440-2830 2.87 (1Н, t, J = 4.8, SН); 3.85 (2Н, d, J = 4.8, СН2SH);
7.78-7.90 (2Н, m, Н Ar); 8.17 (1Н, d, J = 2.1, Н Ar);
8.66 (1Н, s, Н-5);
5d
13.06 (1Н, br. s, СООН)
6а*3
1700
—
4.52 (2Н, s, СН2S); 7.34 (1Н, t, J = 7.2, Н Ph);
7.57 (2Н, t, J = 7.2, Н Ph); 7.90 (2Н, d, J = 7.8, Н Ph);
8.68 (1Н, s, Н-3)
1705
1700
1700
—
—
—
4.51 (2Н, s, СН2S); 7.63 (2Н, d, J = 8.4, Н Ar);
7.91 (2Н, d, J = 8.4, Н Ar); 8.70 (1Н, s, Н-3)
2.36 (3Н, s, СН3); 4.50 (2Н, s, СН2S); 7.35 (2Н, d, J = 8.0, Н Ar);
7.77 (2Н, d, J = 8.0, Н Ar); 8.66 (1Н, s, Н-3)
4.54 (2Н, s, СН2S); 7.85-7.96 (2Н, m, Н Ar);
8.24 (1Н, d, J = 2.4, Н Ar); 8.78 (1Н, s, Н-3)
6b
6с
6d*4
_______
*Absorption bands for the SH groups of compound 5a-d overlapped with those for the OH
groups.
*2 For compounds 4a-d.
3
*
13C NMR spectrum, , ppm: 27.2 (С-4); 119.7 (С-2',6'); 125.4 (С-3а); 128.1 (С-4');
129.7 (С-3',5'); 132.2 (С-3); 139.5 (С-1'); 152.9 (С-6а); 188.6 (С-6).
*
4 13C NMR spectrum, , ppm: 27.4 (С-4); 121.1 (С-6'); 122.1 (С-2'); 125.8 (С-3а); 132.5
(С-3); 133.8 (С-4'); 134.0 (С-3'); 134.1 (С-5'); 138.9 (С-1'); 153.1 (С-6а); 188.3 (С-6).
alkaline hydrolysis to give the 4-sulfanylmethylpyrazole-3-carboxylic acids 5a-d. The latter represent a model
of bifunctional, electrophile-nucleophile type system and react with the condensing reagent dicyclohexyl-
carbodiimide (DCC) in THF via an intramolecular cyclization, to give the 2,4-dihydrothieno[3,4-c]pyrazol-
6-ones 6a-d in 63-77% yields (Table 1).
The composition of the synthesized intermediate compounds 2-5 a-d and the target compounds 6a-d
was confirmed from the results of elemental analysis (Table 1), and their structures are in agreement with IR, 1H
NMR and 13C NMR spectra (Table 2).
Hence the developed method is characterized by the use of readily available reagents and high yields in
all of the synthetic steps, and can be recommended as an efficient method for the preparation of novel
2,4-dihydro-6H-thieno[3,4-c]pyrazol-6-ones.
EXPERIMENTAL
1
IR spectra were recorded on a UR-20 instrument for KBr pellets. H and 13C NMR spectra were
recorded on a Bruker Avance DRX-500 spectrometer (500 and 125 MHz, respectively) using DMSO-d6 with
TMS as internal standard. Elemental analysis was carried out on a Perkin Elmer CHN analyzer. Melting points
for the compounds prepared were determined on a Koffler hot stage apparatus, and are not corrected.
Compounds 1a-d were prepared as reported in [11].
Ethyl 1-Aryl-4-hydroxymethyl-1H-pyrazole-3-carboxylates 2a-d (General Method). NaBH4 (5 g)
was added with stirring to a suspension of the ester 1a-d (0.1 mol) in EtOH (50 ml) and stirred for 2 h at room
temperature. The reaction mixture was poured into ice water (300 ml) and left for 10 h at 0-5ºC. The precipitate
formed was filtered off, washed with water (250 ml), dried, and crystallized from EtOH.
Ethyl 1-Aryl-4-chloromethyl-1H-pyrazole-3-carboxylates 3a-d (General Method). SOCl2 (3.6 g,
0.03 mol) was added with stirring to a solution of ester 2a-d (0.02 mol) in CH2Cl2 (40 ml), stirred at room
1548

temperature for 2 h, and then for 1 h at 40ºC. The mixture was cooled, solvent and excess SOCl2 were distilled
off, and the residue was washed with hexane (230 ml) and crystallized from EtOH.
Ethyl 1-Aryl-4-[(carbamidoylsulfanyl)methyl]-1H-pyrazole-3-carboxylate Hydrochlorides 4a-d
(General Method). A mixture of ester 3a-d (0.015 mol) and thiourea (1.2 g, 0.016 mol) in THF (30 ml) was
refluxed for 1 h, cooled, and the solid product was filtered off, washed with Et2O (220 ml), dried, and
crystallized from EtOH.
Ethyl 1-Aryl-4-sulfanylmethyl-1H-pyrazole-3-carboxylates 5a-d (General Method). The
thiouronium salt 4a-d (0.01 mol) was added to 20% NaOH solution (20 ml) and heated for 2-3 h to full
dissolution. The solution was cooled, poured into water (100 ml) and filtered. The filtrate was acidified with
20% HCl solution (40 ml), cooled to 10ºC, and the precipitate formed was filtered off, washed with water (230
ml), dried, and crystallized from 60% aqueous AcOH.
2-Aryl-2,4-dihydro-6H-thieno[3,4-c]pyrazol-6-ones 6a-d (General Method). A solution of DCC
(1.05 g, 5 mmol) in THF (5 ml) was added with stirring to a solution of the thiol 5a-d (5 mmol) in THF (10 ml).
The reaction mixture was stirred at room temperature for 10 h, and the precipitated dicyclohexylurea was
filtered off and washed with cold THF (3 ml). The filtrate was evaporated and the residue was crystallized from
a mixture of EtOAc and hexane (2:1).
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