Synthesis of 3-substituted-1-methyl-1H-thieno[2,3-c]pyrazoles

Article abstract of DOI:10.1080/00397910701818578

We report a simple and practical six-step synthesis of new 1-methyl-1H-thieno[2,3-c]pyrazoles from 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701818578

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Synthesis of
3
‐Substituted‐1‐methyl‐1H‐thieno[2,3‐c]pyrazole
a a b
Patrick Toto , Jacques Chenault , Ahmed El Hakmaoui , Mohamed
b
a
Akssira & Gerald Guillaumet
a
Analytic and Organic Chemistry Institute, University of Orleans, UMR CNRS,
Orleans Cedex, France
b
Analytic and Bioorganic Chemistry Laboratory, Faculty of Sciences and
Technology, University Hassan II Mohammedia, Mohammedia, Morocco
Version of record first published: 15 Feb 2008.
To cite this article: Patrick Toto , Jacques Chenault , Ahmed El Hakmaoui , Mohamed Akssira & Gerald
Guillaumet (2008): Synthesis of 3‐Substituted‐1‐methyl‐1H‐thieno[2,3‐c]pyrazoles, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:5, 674-683
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Synthetic Communications , 38: 674–683, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701818578
Synthesis of 3-Substituted-1-methyl-
H-thieno[2,3-c]pyrazoles
1
1
Patrick Toto, Jacques Chenault, Ahmed El Hakmaoui,
1
2
2
Mohamed Akssira, and Gerald Guillaumet
1
1
Analytic and Organic Chemistry Institute, University of Orleans, UMR
CNRS, Orleans Cedex, France
2
Analytic and Bioorganic Chemistry Laboratory, Faculty of Sciences and
Technology, University Hassan II Mohammedia, Mohammedia, Morocco
Abstract: We report a simple and practical six-step synthesis of new 1-methyl-1H-
thieno[2,3-c]pyrazoles from 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester.
Keywords: cyclization, pyrazoles, thienopyrazoles
INTRODUCTION
[
1,2]
[3–5]
Thieno-fused heterocycles as thienopyridines,
[
thienopyrimidines,
and
constitute a group of biologically active structures. Thieno-
6,7]
thienopyrroles
pyrazoles, the diazaanalogs of the corresponding thienopyrroles, are attractive
targets for synthesis and activity studies.
Thienopyrroles are usually synthesized from the corresponding thiophene
[
8,9]
derivatives bearing the appropriate functionality at the ring.
herein the synthesis of the thienopyrazole derivatives 13 and 14 from function-
We report
[10,11]
alized pyrazoles, inspired by Fiesselmann’s procedure,
thienofused heterocycle syntheses. Previously, and related to a study on the
widely used in
[
12,13]
reactivity of pyrazoles,
hetrocyclic ring using Fiesselmann’s procedure.
we obtained the alkylsulfanylpyrazole
Received in Poland June 27, 2007
Address correspondence to Mohamed Akssira, Analytic and Bioorganic Chemistry
Laboratory, Faculty of Sciences and Technology, University Hassan II Mohammedia,
BP 146, 20 800, Mohammedia, Morocco. E-mail: akssira@yahoo.fr
6
74

3-Substituted-1-methyl-1H-thieno[2,3-c]pyrazoles
675
Scheme 1. Reagents and conditions: a) NaNO
2
, AcOH/HCl, 258C, EtOH reflux;
b) AcCl reflux; c) Br , AcONa, EtOH/H O; and d) NaH, THF, MeI.
2
2
RESULTS AND DISCUSSION
The synthesis began by obtaining 5-bromopyrazole-4-carboxylic acid ethyl
esters 4 and 5. Condensation of hydrazine hydrate and ethyl 2-cyano-3-ethoxy-
[
14]
acrylate
gave the corresponding 3-amino-1H-pyrazole-4-carboxylic acid
ethyl ester 1, which was transformed in the derivatives 2 and 3 by reductive dia-
zotation and acylation, respectively. Electrophilic bromination of these deriva-
tives afforded the corresponding bromine derivatives 4 and 5 (Scheme 1).
Scheme 2. Reagents and conditions: a) EtOH/HCl reflux; b) NaNO
2 2 4
, H SO , 258C,
KI; and c) Na S, DMF, 1008C, 2 h, then BrCH CO Et, 1008C, 2 h.
2
2
2

6
76
P. Toto et al.
Scheme 3. Reagents and conditions: a) EtONa/EtOH, toluene 1008C, 1 h, then
AcOH.
Methylation of bromine derivatives 4 and 5 gave the corresponding N-
methylated derivatives 6 and 7 in very good yields.
The other brominated precursors 8 and 9 were easily prepared from 7 by
simple selective N-deprotection and by the sequential deprotection–diazota-
tion–substitution set of reactions shown in Scheme 2.
The alkylsulfanylpyrazoles 10, 11, and 12 were prepared from 6, 8, and 9,
on the
[15]
respectively, following the method reported by Morimoto et al.
synthesis of 3,5-dichloropyrazole-4-carboxylic acids. Sodium sulfide nucleo-
philic substitution and homologation of the resulting thiolate by reaction with
bromoacetic acid ethyl ester installed the required S-containing chain for the
next ring-closing step.
Base-added cyclization of pyrazoles 10 and 12 was accomplished by the
use of sodium ethanolate in toluene, affording the expected thieno[2,3-
c]pyrazoles 13 and 14.
Moreover, cyclization of the amine analog 11, under the same conditions,
yielded the imine derivative 15, which probably comes from the self-conden-
sation of the expected thienofused compound (Scheme 3).
CONCLUSION
We have accomplished the synthesis of novel 3-bromo- and 3-iodo-4-
hydroxy-1-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid ethyl esters
13 and 14. An interesting C-3 N-connected dimer homolog was also
obtained in the cyclization of the amine derivative 11. Different substitution
patterns at positions C-3 and/or C-4 of these heterocyclic structures can be

3-Substituted-1-methyl-1H-thieno[2,3-c]pyrazoles
677
easily accessed by standard palladocatalyzed couplings or regioselective alky-
lations. Studies are in progress in our laboratory.
EXPERIMENTAL
General
1 13
NMR spectra were recorded at 250 and 62.5 for H and C, respectively on a
Bruker DPX250 spectrometer in CDCl or deuterated dimethyl sulfoxide
3
(DMSO). IR spectra were recorded on a Perkin-Elmer FT Paragon 1000
PC. Melting points were recorded on a K o¨ fler apparatus and were uncorrected.
Mass spectra were recorded on Perkin-Elmer Sciex API 3000. The chromato-
graphic purifications were made using silica gel (Merck,, 40–63 mm) under
nitrogen pressure. The reaction’s evolution was monitored by thin-layer
chromatography (TLC, Merck 60 F254).
Procedures and Characterizations
3
-Amino-1H-pyrazole-4-carboxylic Acid Ethyl Ester (1)
Hydrazine hydrate (l0 g, 0.17 mol) in ethanol (400 mL) was stirred with ethyl
-cyano-3-ethoxyacrylate (29 g, 0.17 mol) at room temperature for 18 h. The
ethanol was evaporated under reduced pressure, and the residue was crystal-
2
[
14]
lized at 08C from isopropyl ether. Yield: 93%. Mp: 1028C;
IR (KBr):
2
1 1
1
672 cm ; H NMR (CDCl ): d 1.32 (t, 3H, J ¼ 7 Hz, CH -CH -O), 4.32
3
3
2
1
3
(
q, 2H, J ¼ 7 Hz, CH -CH -O), 6.88 (s, 2H, NH ), 7.78 (s, 1H, C -H);
C
NMR (CDCl ): d 14.8 (CH -CH ), 60.2 (CH -CH ), 98.2 (Cq), 136.3 (CH),
3
2
2
5
3
3
2
3
þ
2
1
54.3 (Cq), 164.9 (C 55 O); MS 156 [M þ H] .
H-Pyrazole-4-carboxylic Acid Ethyl Ester (2)
1
To a cooled solution (08C) of 3-amino-1H-pyrazole-4-carboxylic acid ethyl
ester 1 (5 g, 32.23 mmol, 1 eq) in dry acetic acid (30 mL), HCl 37%
(9.9 mL, 3 eq) and aqueous NaNO (2.34 g, 33.9 mmol, 1.05 eq) (10 ml)
2
were sequentially added, keeping the temperature below 58C. The reaction
mixture was stirred at 08C for 30 min. Ethanol (200) mL was added, and
the mixture was allowed to reflux for 1 h. The ethanol was evaporated
under reduced pressure, and the resulting residue was poured on water
(
150 mL) and extracted with CH Cl (2 ꢀ 150 mL). The combined organic
2
2
phases were dried on MgSO , filtered, and concentrated under reduced
4
[16,17]
pressure to afford 2 as a beige solid (4.47 g, 99%). Mp: 698C;
(
IR
2
1 1
KBr): 1702 cm ; H NMR (CDCl ): d 1.33 (t. 3H, J ¼ 7.5 Hz, CH -CH -
3
3
2
O), 4.28 (q, 2H, J ¼ 7.5 Hz, CH -O), 8.04 (s, 2H, C -H þ C -H), 9.57
2
3
5

6
78
P. Toto et al.
1
s, 1H, N-H); C NMR (CDCI ): d 14.8 (CH -CH -O), 60.9 (O-CH ), 115.5
3
(
(
3
3
2
2
þ
C ), 135 (C -H þ C -H), 163.9 (C 55 O); MS 141 [M þ H] .
4
3
5
3-Acetamido-1H-pyrazole-4-carboxylic Acid Ethyl Ester (3)
3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester 1 (10 g, 64.5 mmol, 1 eq)
and acetyl chloride (40 mL) were mixed at 08C and heated at reflux for 4 h.
The excess of AcCl was evaporated off under reduced pressure, water
(
time, the white solid precipitate was filtered off and dried to give pure deriva-
100 mL) was added, and the resulting mixture was stirred for 18 h. At this
2
1
21 1
tive 3 (l1.47 g, 90%). Mp: l308C; IR (KBr): 1668 cm , 1697 cm ; H NMR
(
CDCI ): d 1.33 (t, 3H, J ¼ 7.5 Hz, CH -CH -O), 2.25 (s, 3H, CH -C 55 O),
3
3
2
3
4
1
.29 (q, 2H, J ¼ 7.5 Hz, O-CH ), 7.74 (s, 1H, C -H), 9.56 (s, 1H, N-H),
3 3 2 3
2
5
1
1.75 (s, 1H, N-H); C NMR (CDCl ): d 13.0 (CH -CH -O), 22.4 (CH -
3
C 55 O), 59.1 (CH -O), 96.6 (C ), 137.6 (C -H), 141.6 (C ), 163.4 (C 55 O),
3
2
4
5
þ
1
68.0 (C 55 O); MS 198 [M þ H] . Anal. calcd. for C H N O : C, 48.73;
8
11 3 3
H, 5.62; N, 21.31. Found: C, 48.78; H, 5.59; N, 21.34.
3,5-Dibromo-1H-pyrazole-4-carboxylic Acid Ethyl Ester (4)
Aqueous NaOAc (14 g in 120 mL) was added, to a solution of 1H-pyrazole-4-
carboxylic acid ethyl ester 2 (3.5 g, 25 mmol, 1 eq) in ethanol (80 mL). Br2
(
5.25 mL, 100 mmol, 4 eq) was added, and the reaction mixture was stirred
at room temperature 5 h and poured in water (200 mL). The aqueous phase
was extracted with AcOEt (3 ꢀ 500 mL), and the combined organic phases
were sequentially washed with a saturated solution of sodium thiosulfate
(
2 ꢀ 50 mL), dried on MgSO , filtered, and concentrated under reduced
4
pressure to afford 4 as a yellow solid (7.37 g, 99%). Mp: 1328C; IR (KBr):
2
1
1
1
4
1
668 cm ; H NMR (CDCl ): d 1.38 (t, 3H, J ¼ 7.5 Hz, CH -CH -O),
3
3
2
1
3
.34 (q, 2H, J ¼ 7.5 Hz, CH -O), 9.65 (s, 1H, N-H); C NMR (CDCl ): d
2
3
4.5 (CH CH -O), 61.2 (O-CH ), 113.0 (C ), 124.5 (C þ C ), 161.2
3
2
2
4
3
5
þ
(
C 55 O), MS 297, 299, 301 [M þ H] . Anal. calcd. for C H Br N O : C,
6
6
2 2 2
2
4.19; H, 2.03; N, 9.40. Found: C, 24.17; H, 2.01; N, 9.46.
-Acetylamino-5-bromo-lH-pyrazole-4-carboxylic Acid Ethyl Ester (5)
-Acetylamino-1-H-pyrazole-4-carboxylic acid ethyl ester 3 was brominated
3
3
using the same procedure as in the case of compound 4. Yield: 72%; mp:
2
1
21
1
1
998C; IR (KBr): 1690 cm , 1661 cm
;
H NMR (CDCl ): d 1.41
3
(
t, 3H, J ¼ 7.5 Hz, CH -CH -O), 2.28 (s, 3H, CH -C 55 O), 4.31 (q, 2H,
3
2
3
1
3
J ¼ 7.5 Hz, O-CH ), 9.77 (s, lH, N-H), 11.83 (s, 1H, N-H); C NMR
2
(
CDCl ): d 14.0 (CH -CH O), 23.6 (CH -C 55 O), 60.8 (CH -O), 97.2 (C ),
3 3 2 3 2 4
þ
1
27.1 (C ), 144.2 (C ), 163.6, 169.7 (C 55 O); MS 276, 278. [M þ H] .
5
3
Anal. calcd. for C H BrN O : C, 34.80; H, 3.65; N, 15.22. Found: C,
8 10 3 3
34.85; H, 3.62; N, 15.28.

3-Substituted-1-methyl-1H-thieno[2,3-c]pyrazoles
679
3
,5-Dibromo-l-methyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester (6)
NaH (0.296 g, 7.38 mmol, 1.1 eq) was carefully added to a cooled (08C)
solution of 3-5-dibromo-1H-pyrazo1e-4-carboxylic acid ethyl ester 4 (2 g,
6
.7 mmol, 1 eq) in dry THF (30 ml). The resulting mixture was stirred at
room temperature for 30 min, and MeI (1.2 mL, 19.2 mmo1, 2.9 eq) was
added. The new mixture was allowed to stir overnight at room temperature.
Addition of water (150 mL) followed by organic extraction (CH Cl ,
2
2
3
ꢀ 200 mL), drying on MgSO , filtration, and concentration under reduced
4
pressure afforded 6 as a beige solid (1.99 g, 95%). Mp: 698C; IR (KBr):
2
1
1
1
710 cm ; H NMR (CDCl ): d 1.35 (t, 3H, J ¼ 7.5 Hz, CH -CH -O),
3
3
2
1
3
3
d 14.5 (CH -CH -O), 38.9 (N-CH ), 61.2 (CH -CH -O), 113.5 (C ), 119.8
.86 (s, 3H, N-CH ), 4.31 (q, 2H, J ¼ 7.5 Hz, CH -O); C NMR (CDCl ):
3 2 3
3
2
3
3
2
4
þ
(
C -Br), 128.6 (C -Br), 160.9 (C 55 O); MS 311, 313, 315 [M þ H] . Anal.
5
3
calcd. for C H Br N O : C, 26.95; H, 2.58; N, 8.98. Found: C, 26.83; H,
7
8
2 2 2
2
.59; N, 9.02.
3-Acetylamino-5-bromo-l-methyl-1H-pyrazole-4-carboxylic Acid
Ethyl Ester (7)
3-Acetylamino-5-bromo-1H-pyrazole-4-carboxylic acid ethyl ester 5 was
methylated using the same procedure as in the case of compound 6. Yield:
2
1
21 1
8
1
2%; Mp: 1508C; IR (KBr): 1703 cm , 1678 cm ; H NMR (CDCl ): d
3
.39 (t, 3H, J ¼ 7.5 Hz, CH -CH -O), 2.25 (s, 3H, CH -C 55 O), 3.89 (s, 3H,
3
2
3
1
3
N-CH ), 4.33 (q, 2H, J ¼ 7.5 Hz, O-CH ), 9.29 (s, 1H, N-H); C NMR
3
2
(
CDCl ): d 13.9 (CH -CH -O), 24.3 (CH -C 55 O), 38.0 (N-CH ), 60.7
3 3 2 3 3
(
CH -O), 100.6 (C ), 117.2 (C ), 148.9 (C ), 163.2, 167.0 (C 55 O); MS 290,
2 4 5 3
þ
92 [M-H] . Anal. calcd. for C H BrN O : C, 37.26: H, 4.17; N, 14.48.
9 12 3 3
2
Found: C, 37.30; H, 4.15; N, 14.47.
3-Amino-5-bromo-1-methyl-1H-pyrazole-4-carboxylic Acid Ethyl
Ester (8)
Acetylaminopyrazole 7 (2.5 g, 8.62 mmol, 1 eq) was dissolved in a cooled
(08C) solution of HCl (1 ml) in ethanol (50 mL), and the solution was
refluxed for 30 min. The ethanol was evaporated off under reduced pressure,
and a solution of aqueous NaHCO (5%, 150 ml) was added, to neutralize
3
the residue. The aqueous phase was extracted with AcOEt (3 ꢀ 100 mL),
and the combined organic phases were dried on MgSO , filtered, and concen-
4
trated under reduced pressure to afford 8 as a crystalline solid (1.6 g, 75%). Mp:
2l l
6
88C; IR (KBr): 1725 cm ; H NMR (CDCl ): d 1.30 (t, 3H, J ¼ 7 Hz, CH -
3
3
CH -O), 3.65 (s, 3H, N-CH ), 4.25 (q, 2H, J ¼ 7.5 Hz, CH -O), 4.76 (s, 2H,
2 3 2
1
NH ); C NMR (CDCl ): d 14.4 (CH -CH -O), 37.5 (N-CH ), 60.2 (CH -
3
2
3
3
2
3
2
O), 98.7 (C ), 116.8 (C ), 156.7 (C ), 170.9 (C 55 O). MS 248, 250
5
4
3

6
80
P. Toto et al.
þ
[
C, 34.01; H, 4.08; N, 16.89.
M þ H] . Anal. calcd. for C H BrN O : C, 33.89; H, 4.06; N, 16.94. Found:
7
10
3 2
5-Bromo-3-iodo-1-methyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester (9)
An aqueous solution of NaNO (1.58 g, 22.84 mmol, 1.1 eq) (10 mL) was
2
dropwise added to a cooled (2108C) solution of aminopyrazole 8 (5.15 g,
2
0.77 mmol, 1 eq) in H SO (50%, 100 mL), keeping the temperature
2 4
below 08C. The reaction mixture was stirred for 30 min, at 08C, and then an
aqueous solution of KI (10.35 g, 62.3 mmol, 3 eq) (10 mL) was added. The
aqueous mixture was allowed to stir for 10 min, and water (200 mL) was
added. The aqueous phase was extracted with CH Cl (3 ꢀ 200 mL), and
2
2
the combined organic layers were sequentially washed with NaHCO (5%,
3
2
dried on MgSO , filtered, and concentrated under reduced pressure to give a
ꢀ 50 mL) and a saturated solution of sodium thiosulfate (2 ꢀ 100 mL),
4
solid residue. Column chromatography (7/3, petroleum ether/AcOEt)
afforded pure compound 9 (4 g, 53%) of a white solid. Mp: 1348C, IR
2
1 1
(
KBr): 1712 cm . H NMR (CDCl ): d 1.40 (t, 3H, J ¼ 7.5 Hz, CH -CH -
3
3
2
1
3
O), 3.93 (s, 3H, N-CH ), 4.32 (q, 2H, J ¼ 7.5 Hz, CH -O); C NMR
3
2
(
CDCl ): d 14.5 (CH -CH -O), 39.0 (N-CH ), 61.2 (O-CH ), 98.8 (C ),
3 3 2 3 2 4
þ
1
16.9 (Cq), 118.9 (Cq), 161.0 (C 55 O); MS 359, 361 [M þ H] . Anal.
calcd. for C H BrIN O : C, 23.42; H, 2.25; N, 7.80. Found: C, 23.47; H,
2 2
7
8
2
.30; N, 7.82.
3-Bromo-5-ethoxycarbonylmethylsulfanyl-1-methyl-1H-pyrazole-4-
carboxylic Acid Ethyl Ester (10)
A mixture of dibromopyrazole 6 (l.83 g, 5.8 mmol, 1 eq) and Na S (60%,
2
920 mg, 7.08 mmol, 1.2 eq) in dry DMF (20 mL) was heated at l008C for
2
h. The mixture was allowed to cool at room temperature, and bromoacetic
acid ethyl ester (0.72 mL, 6.38 mmol, 1.1 eq) was added. After 2 h, the
DMF was removed under reduced pressure, and the residue was poured on
water (50 mL). The aqueous phase was extracted with AcOEt (3 ꢀ 100 mL),
and the combined organic phases were washed with brine (2 ꢀ 50 mL), dried
on MgSO , filtered, and concentrated. Yield: 76%; Mp: 678C; IR (KBr):
4
1
2
21 1
1
744 cm ; 1694 cm ; H NMR (CDCl ): d 1.17 (t, 3H, J ¼ 7.5 Hz, CH -
3
3
CH -O), 1.37 (t, 3H, J ¼ 7.5 Hz, CH -CH -O), 3.74 (s, 2H, S-CH ), 3.98
2 3 2 2
(
s, 3H, N-CH ), 4.08 (q, 2H, J ¼ 7.5 Hz, CH -CH -O), 4.33 (q, 2H,
3 2 3
3
3
2
1
3
J ¼ 7.5 Hz, CH -CH -O); C NMR (CDCl ): d 15.1 (CHrCH2-O), 15.2
(CH -CH -O), 38.3 (S-CH ), 38.9 (N-CH ), 61.9 (CH -CH -O), 62.9 (CH -
CH -O), 117.7 (C ), 128.9 (C ), 139.4 (C ), 162.5 (C 55 O), 169.9 (C 55 O);
3 2 2 3 3 2 3
2
4
5
3
þ
MS 351, 353 [M þ H] . Anal. calcd. for C H BrN O S: C, 37.62; H, 4.30;
ll 15
2 4
N, 7.98. Found: C, 37.60; H, 4.32; N, 7.99.

3-Substituted-1-methyl-1H-thieno[2,3-c]pyrazoles
681
3-Amino-5-ethoxycarbonylmethylsulfanyl-1-methyl-1H-pyrazole-4-
carboxylic Acid Ethyl Ester (11)
Aminopyrazole 8 was alkylated using the same procedure as in the case of
21
2
1
compound 10. Yield: 60%; Mp: 568C; IR (KBr): 1750 cm ; 1696 cm
;
1
H NMR (CDCl ): d 1.21 (t, 3H, J ¼ 7.5 Hz, CH -CH -O), 1.38 (t, 3H,
3
3
2
J ¼ 7.5 Hz, CH -CH -O), 3.7 (s, 2H, S-CH ), 3.84 (s, 3H, N-CH ), 4.11
3
2
2
3
(
q, 2H, J ¼ 7.5 Hz, O-CH ), 4.34 (q, 2H, J ¼ 7.5 Hz, O-CH ), 4.75 (s, 2H,
2
2
1
3
NH ); C NMR (COCl ): d 13.2 (CH -CH -O), 13.6 (CH -CH -O), 35.9
(N-CH ), 36.3 (S-CH ), 59.2 (CH -CH -O), 60.8 (CH -CH -O), 100.0 (C ),
2 3 3 2 3 2
3 2 3 2 3 2 4
þ
134.5 (C ), 155.6 (C ), 162.7 (C 55 O), 168.2 (C 55 O); MS 288 [M þ H] .
Anal. calcd. for C H N O S: C, 45.98; H, 5.96; N, 14.62. Found: C,
11 17 3 4
5
3
4
5.89; H, 5.97; N, 14.68.
5-Ethoxycarbonylmethylsulfanyl-3-iodo-1-methyl-1H-pyrazole-4-
carboxyl Carboxylic Acid Ethyl Ester (12)
Iodopyrazole 9 was alkylated using the same procedure as in the case of
2
l
21 1
compound 10. Yield: 80%; Mp: 768C, IR (KBr): 1740 cm , 1692 cm , H
NMR (CDCl ): d 1.18 (t, 3H, J ¼ 7.5 Hz, CH -CH -O), 1.40 (t, 3H,
3
3
2
J ¼ 7.5 Hz, CH -CH -O), 3.74 (s, 2H, S-CH ), 4.02 (s, 3H, N-CH ), 4.05
3
2
2
3
1
3
(
(
q, 2H, J ¼ 7.5 Hz, CH -O), 4.35 (q, 2H, J ¼ 7.5 Hz, CH -O); C NMR
2
2
CDCl ): d 14.1 (CH -CH -O), 14.3 (CH -CH -O), 37.4 (S-CH ), 38.0 (N-
3 3 2 3 2 2
CH ), 61.0 (CH -O), 61.9 (CH -O), 98.5 (C ), 120.7 (C ), 137.5 (C ),
3
3
2
2
4
5
þ
1
C H IN O S: C, 33.18; H, 3.80; N, 7.03. Found: C, 33.09; H, 3.81; N, 7.06.
61.5 (C 55 O), 169.0 (C 55 O); MS 399 [M þ H] . Anal. calcd. for
ll 15
2 4
3-Bromo-4-hydroxy-1-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylic
Acid Ethyl Ester (13)
To a solution of sodium (23.5 mg, 1.03 mmol, 1.2 eq) in dry ethanol (0.5 mL),
a solution of 10 (300 mg, 0,86 mmol, 1 eq) in dry toluene (10 mL) was added,
and the reaction mixture was heated under reflux for 1 h. Acetic acid (0.2 ml)
was then added to destroy the excess of base, and the resulting mixture was
diluted with AcOEt (200 ml), washed with water (30 mL), dried on MgSO4,
filtered, and concentrated under reduced pressure to afford 13 (251 mg,
2
1 1
9
6%); Mp: 1338C; IR (KBr): 1640 cm ; H NMR (CDCl ): d 1.38 (t, 3H,
3
J ¼ 7.5 Hz, CH -CH -O), 3.88 (s, 3H, N-CH ), 4.36 (q, 2H, J ¼ 7.5 Hz,
3
2
3
1
CH -O), 10.39 (s, 1H, O-H); C NMR (CDCl ): d 14.7 (CH -CH -O), 38.6
3
2
3
3
2
(
N-CH ), 61.7 (0-CH ), 117.7 (C ), 120.9 (C ), 155.0 (C-OH), 168.3
3 2 4 5
þ
(C 55 O); MS 305, 307 [M þ H] . Anal. calcd. for C H BrN O S: C, 35.43;
9
9
2 3
H, 2.97; N, 9.18. Found: C, 35.48; H, 2.98; N, 9.19.

6
82
P. Toto et al.
4-Hydroxy-3-iodo-1-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxylic
Acid Ethyl Ester (14)
Thieno[2,3-c]pyrazole 14 was obtained from 12 using the same procedure as
2
1 l
in the case of compound 13. Yield: 92%; Mp: 1408C; IR (KBr): 1651 cm ; H
NMR (DMSO-d ): d 1.28 (t, 3H, J ¼ 7.5 Hz, CH -CH -O), 3.90 (s, 3H,
6
3
2
1
3
N-CH ), 4.28 (q, 2H, J ¼ 7.5 Hz, CH -O), 10.45 (s, 1H, O-H); C NMR
3
2
(
DMSO-d ): d 15.1 (CH CH -O), 38.7 (N-CH ), 61.5 (O-CH ), 87.9 (Cq),
6 3 2 3 2
þ
1
01.9 (Cq), 145.0 (Cq), 153.2 (Cq), 165.2 (C 55 O); MS 353 [M þ H] .
Anal. calcd. for C H IN O S: C, 30.70; H, 2.58; N, 7.95. Found: C,
11 15 2 4
3
0.76; H, 2.60; N, 7.89.
Imine of the 3-Amino-4-hydroxy-1-methyl-1H-thieno[2,3-c]-pyrazole-
-carboxylic Acid Ethyl Ester (15)
5
Compound 15 was obtained from aminopyrazole 11 using the same procedure
2
1
as in the case of compound 13. Yield: 90%; mp: 2058C; IR (KBr): 1698 cm
,
2
l
21 1
1
732 cm , 1741 cm ; H NMR (DMSO-d ): d 1.25 (t, 3H, J ¼ 6.9 Hz, CH -
6
3
CH -O), 1.26 (t, 3H, J ¼ 6.9 Hz, CH -CH -O), 3.66 (s, 3H, N-CH ), 3.80
2 3 2 3
(
s, 3H, N-CH ), 3.86 (s, 2H, N-H þ O-H), 4.18 (q, 2H, J ¼ 6.9 Hz, CH -
2 2
3
2
1
3
O), 4.20 (q, 2H, J ¼ 6.9 Hz, CH -O), 5.50 (s, 2H, NH ). C NMR
(
DMSO-d ): d 12.9 (CH -CH -O), 13.2 (CH -CH -O), 35.1 (N-CH ), 36.1
6 3 2 3 2 3
(
N-CH ), 58.2 (O-CH ), 58.7 (O-CH ), 98.6 (Cq), 109.5 (Cq), 124.2 (Cq),
3 2 2
1
35.0 (Cq), 142.9 (Cq), 149.2 (Cq), 155.5 (Cq), 161.1 (C 55 O), 161.9
þ
(C 55 O), 167.0 (C 55 N); MS 465 [M þ H] . Anal. calcd. for C H N O S :
1
8 20 6 5 2
C, 46.54; H, 4.34; N, 18.09. Found: C, 46.62; H, 4.38; N, 17.98.
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1