Regiocontrolled synthesis of ring-fused thieno[2,3-c]pyrazoles through 1,3-dipolar cycloaddition of nitrile imines with sulfur-based acetylenes

Article abstract of DOI:10.1002/ejoc.201001048

1,3-Dipolar cycloadditions of C-carboxymethyl-N-arylnitrile imines with substituted acetylenes bearing thiol or sulfone groups were studied. The sulfur controls the regiochemistry of the reaction, and this protocol was applied to the synthesis of ring-fus

Full text of DOI:10.1002/ejoc.201001048

FULL PAPER
DOI: 10.1002/ejoc.201001048
Regiocontrolled Synthesis of Ring-Fused Thieno[2,3-c]pyrazoles through
1,3-Dipolar Cycloaddition of Nitrile Imines with Sulfur-Based Acetylenes
Jay Zumbar Chandanshive,[a] Bianca Flavia Bonini,[a] Denis Gentili,[a]
Mariafrancesca Fochi,[a] Luca Bernardi,[a] and Mauro Comes Franchini*[a]
Dedicated to Professor Pelajo Camps on the occasion of his 65th birthday
Keywords: Cycloaddition / Regioselectivity / Sulfur / Alkynes / Heterocycles / Fused-ring systems
1,3-Dipolar cycloadditions of C-carboxymethyl-N-arylnitrile
imines with substituted acetylenes bearing thiol or sulfone
groups were studied. The sulfur controls the regiochemistry
of the reaction, and this protocol was applied to the synthesis
of ring-fused thieno[2,3-c]pyrazoles.
ines have also been tested in terms of inhibition of Abelson
Kinase (Abl) enzymatic activity and antiproliferative prop-
erties towards human leukemic cells.[13] Huang recently re-
ported that a novel class of indazol-4-ones of type B (now
in multiple phase I clinical trials) exhibits low nanomolar
antiproliferative potencies across multiple cancer cell
lines.[14] 2,3-Dihydropyran[2,3-c]pyrazoles of type C have
been recently obtained through multicomponent micro-
wave-assisted organocatalytic domino Knoevenagel/hetero-
Diels–Alder reaction and are potential antitubercular
agents.[15] Pyrazolo[1,5-C]quinazolines[16] of type D are Gly/
NMDA receptor antagonists, whereas pyrazolpiperidines E
and pyrazolpyridines F are acorticotrophin-releasing-factor
(CRF-1) receptor antagonists and are very promising for
the treatment of depression and anxiety.[17]
Introduction
Pyrazole derivatives display a broad spectrum of bio-
logical activities[1] and represent an important structural
class in pharmaceuticals[2] and agrochemicals.[3] They are
present in leading drugs such as Viagra[2a] and Celebrex[2b]
and, therefore, are considered very important for pharma-
ceutical industries.[4,5] Much work has been directed
towards the design and the synthesis of complex pyrazoles
giving particular relevance to the functionalization of the
scaffold in different regions. Two general methods are
known for the synthesis of pyrazoles. The first method in-
volves the standard reaction of hydrazines with 1,3-difunc-
tional substrates such as 1,3-dicarbonyl compounds,[6]
ynones,[7] or β-aminoacrolein.[4] In addition, the 1,3-dipolar
cycloaddition (1,3-DC) between alkynes and nitrile imines
provides direct access to pyrazoles,[8] but regioisomeric mix-
tures of pyrazoles are frequently obtained. Moreover, dur-
ing the last years new paths have emerged, like domino C–
N coupling/hydroamination of enynes,[9] azacyclization of
elaborated structures,[10] and direct N-arylation of a 1H-
pyrazole.[11] However, the scope of these methods is still not
general, in particular for the synthesis of ring-condensed
structures. Indeed, the preparation of pyrazole-fused ring
derivatives seems to be very important and challenging
from a synthetic point of view.
Pyrazolo[3,4-d]pyrimidines of type A (Figure 1) show in-
hibition properties towards Src in a cell-free assay, as well
as antiproliferative activity towards the epidermoid (A431)
and breast cancer (BC-8701) cell line.[12] Pyrazolopyrimid-
Figure 1. Ring-fused pyrazoles A–F.
[a] Dipartimento di Chimica Organica “A. Mangini”,
Università di Bologna,
Thieno[2,3-c]pyrazoles G (Figure 2) are an important
class of potent kinase inhibitors.[18] Their synthesis can start
from functionalized pyrazole derivatives, which through a
Viale Risorgimento 4, 40136 Bologna, Italy
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E-mail: mauro.comesfranchini@unibo.it
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Regiocontrolled Synthesis of Ring-Fused Thieno[2,3-c]pyrazoles
multistep sequence is fused with the thiophene ring.[18a] On readily prepared according to literature procedures (see the
the other hand, in a recent patent,[18b] thieno[2,3-c]- Experimental Section), whereas selected hydrazonoyl chlo-
pyrazoles were prepared starting from a suitable thiophene rides 5a–c were obtained as reported by us.[19]
derivative in which the fusion with the pyrazole ring occurs
in the final step of the synthetic sequence.
Figure 2. Structures G for thienopyrazoles.
Figure 3. Dipolarophiles 1–4 and hydrazonoyl chlorides 5a–c.
We recently developed a method for the regiocontrolled
The cycloadditions of 1 and 2 with the C-carboxymethyl-
N-arylnitrile imines derived from 5a–c were carried out in
dry dioxane at 80 °C for 24 h by using Ag2CO3 (2.5 equiv.),
and 1 or 2 was used in stoichiometric amount with respect
to the dipoles with yields ranging from 35 to 63%
(Scheme 1; Table 1, Entries 1–6).
synthesis of pyrazoles based on the 1,3-DC of nitrile imines
with functionalized acetylenes.[19] As part of our group’s
ongoing effort[20] directed towards the preparation of pyr-
azoles as multikinases inhibitors we decided to investigate
the application of our methodology to the regiocontrolled
synthesis of thieno[2,3-c]-pyrazoles G, through 1,3-DC of
nitrile imines and substituted acetylenes bearing thiol or
sulfone groups.
Heteroatom-substituted acetylenes have been scarcely
studied and reported in the 1,3-DC of nitrile imines as 1,3-
dipoles. Only Zecchi reported the reaction of N-phenyl-C-
phenylnitrile imine with alkynyl phenyl sulfones with yields
of 15–71% and with the cycloadduct having the PhSO2
group in the 4-position as the predominant or exclusive re-
gioisomer,[21] whereas alkynyl phenyl sulfides have never
been investigated in this 1,3-DC. On the other hand, these
kinds of dipolarophiles, and the possible control of the regi-
Scheme 1. 1,3-DC of 1 or 2 with 5a–c.
ochemistry, could play important roles in the installation of
the S atom in the correct position of the pyrazole ring, al-
lowing, after synthetic elaboration, the preparation of ring-
fused thienopyrazoles.
Cycloadducts 6–6Ј were obtained in 35:65 ratio, 7–7Ј
were obtained in 40:60 ratio, and 8–8Ј were isolated as bal-
anced mixtures in a 54:46 ratio (Table 1, Entries 1–3). These
results of regiochemistry fit with the data obtained for the
N-phenyl-C-phenylnitrile imines[21] and are due to the
strong electron-withdrawing effect of the sulfonyl group,
Results and Discussion
which determines a large LUMO coefficient at the β-carbon
We decided to investigate preliminarily mono- 1 and di- of the acetylene with a consequent HOMO–(dipole)
functional 2 sulfones containing a triple bond to extend LUMO–(dipolarophile) interaction.
Zecchi’s result with the more versatile and unreported C-
The same reactions were repeated in the presence of
carboxymethyl-N-arylnitrile imines. Moreover, we present scandium triflate catalyst for a possible control of the regi-
herein substituted acetylenes 3 and 4 bearing thiol groups ochemistry.[19] As expected, the amount of the 4-isomer was
and their general behavior in 1,3-DCs with nitrile imines higher under Sc(OTf)3 catalysis (Table 1, Entries 1–3), and
derived from 5a–c (Figure 3). Starting acetylenes 1–4 were the 4-isomer increased to 12:88 for 6–6Ј and to 14:86 for 7–
Table 1. 1,3-DC of 1 or 2 with 1,3-dipoles derived from 5a–c.
Entry Dipolarophile
1,3-Dipole
Y
Cycloadducts
Yield [%][a]
Ratio[a]
Yield [%][b]
Ratio[b]
12:88
14:86
14:86
8:92
1
2
3
4
5
6
1
1
1
2
2
2
5a
5b
5c
5a
5b
5c
H
H
H
CO2Et
CO2Et
CO2Et
6–6Ј
7–7Ј
8–8Ј
9–9Ј
10–10Ј
11–11Ј
49
35
58
63
65
60
35:65
40:60
54:46
11:89
20:80
10:90
38
34
39
72
67
64
15:85
9:91
[a] Without Sc(OTf)3. [b] With 10% Sc(OTf)3.
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7Ј and 8–8Ј due to the possibility of a chelated transition the S-substituent having a CH2 in the α-position, and as the
state involving the CO2Me group and the sulfonyl group other substituent of the triple bond, a formyl group pos-
with the scandium catalyst.[19] Disubstituted sulfone 2 gave sessing electronic character similar to that of the ester used
good yields of cycloadducts (60–65%) with an higher quan- in the preliminary investigation and able to undergo intra-
tity of the 4-isomer, ratio 11:89 for 9–9Ј, 20:80 for 10–10Ј, molecular nucleophilic addition with subsequent aromatiza-
and 10:90 for 11–11Ј (Table 1, Entries 4–6), but in this case tion to the thiophene ring.
no significant improvement was observed in the ratio under
Therefore, the starting material was diphenacyl disulfide
scandium catalysis in favor of the 4-isomer. Therefore, we 18, prepared easily and in high yield through a modified
believe that this kind of 1,3-DC is substrate-controlled and literature method[22] from phenacyl mercaptan.[23] After
does not take place under the control of the catalyst. Mov- protection of 18 as dioxolane 19[24] in 81% yield, acetylene
ing to PhS dipolarophiles 3 and 4 a reversal in the regio- 20 was obtained by reaction of 19 with lithium trimethyl-
chemistry in favor of the 5-substituted pyrazoles was ob- silyl acetylene in THF at 0 °C in 80% yield. Compound 21
served. The C-carboxymethyl-N-arylnitrile imines derived was obtained through desilylation with TBAF at 0 °C,
from 5a–c with 3 and 4 gave only regioisomers 12–17 with which occurred in 93% yield (Scheme 3).
the PhS group in the 5-position with or without scandium
catalysis (Scheme 2, Table 2). Satisfactory yields in the
range 45–70% were achieved (Table 2, Entries 1–6). These
results are in line with results obtained by us in 1,3-NED
(normal electron demand) dipolar cycloadditions of nitrile
imines with acetylene derivatives.[19]
Scheme 3. Synthesis of acetylene 21.
Scheme 2. 1,3-DC of 3 or 4 with 5a–c.
In acetylene 21, the formyl group was introduced by re-
The identification of the 5- and 4-pyrazoles in cycload-
ducts 6–8 and 12–14 was based on the H NMR signals by
action with LiHMDS in THF at –78 °C followed by ad-
dition of a mixture of DMF and HMPA (Scheme 4). The
disubstituted acetylene was not isolated but immediately
treated with 5a–c under the usual conditions. The corre-
1
taking advantage of the fact that it is known that the CH
signal of C5 for the 4-substituted derivatives resonates at
about 8.0 ppm. This signal was not found in our cycload-
ducts.[19] Furthermore, NOE experiments confirmed the
formation of 5-pyrazole also for compounds 9–11 and 15–
17.
From these results we understood that different S-based
functionalities control the regiochemistry of the cycload-
dition. The electron-releasing properties of the S atom to-
gether with the electron-withdrawing CO2Et group bring to
a synergistic regiochemical effect that leads exclusively to
one regioisomer, in contrast with the behavior of the SO2-
substituted triple bond. This regiochemistry is correct for
the preparation of ring-fused thienopyrazoles of type G.
To apply this protocol to the synthesis of thieno[2,3-c]-
Scheme 4. General method for the synthesis of ring-fused thieno-
pyrazoles we have “designed” a disubstituted acetylene with [2,3-c]pyrazoles 23a–c.
Table 2. 1,3-DC of 3 or 4 with 1,3-dipoles derived from 5a–c.
Entry
Dipolarophile
1,3-Dipole
Y
Cycloadduct
Yield [%][a]
Regioisomeric ratio
1
2
3
4
5
6
3
3
3
4
4
4
5a
5b
5c
5a
5b
5c
H
H
H
CO2Et
CO2Et
CO2Et
12
13
14
15
16
17
70
57
67
50
45
67
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
[a] Without Sc(OTf)3.
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Regiocontrolled Synthesis of Ring-Fused Thieno[2,3-c]pyrazoles
H) ppm. This oil (0.55 g, 2.3 mmol) was then dissolved in THF
(10 mL) and cooled to –78 °C and then mixed with nBu4NF (1 
in THF, 0.7 mL, 0.7 mmol). The reaction mixture was stirred for
2–3 h at the same temperature. After completion of the reaction,
sat. NH4Cl solution (15 mL) was added, and the mixture was ex-
tracted with diethyl ether (3ϫ10 mL). The combined ether extracts
were washed with water (2ϫ10 mL) and brine and then dried with
anhydrous Na2SO4. The ether layer was carefully evaporated in
vacuo, and crude product 1 (0.33 g, 87% yield) was kept as a stock
solution in diethyl ether (ca. 20% w/v) at –4 °C. The crude product
was used as such for further reactions without purification.
sponding cycloadducts were obtained with good overall
yields, 66% for 22a, 42% for 22b, and 43% for 22c, and
fully characterized after chromatography on silica. Depro-
tection of the dioxolanes in 22a–c and condensation[25] to
thieno[2,3-c]pyrazoles 23a–c took place in one step by reac-
tion with trifluoroacetic acid in acetone in 20–28% overall
yield (see the Experimental Section).
Conclusions
Ethyl 3-(Phenylsulfonyl)propiolate (2): To a stirred solution of ethyl
3-(phenylthio)propiolate (4; 0.77 g, 3.7 mmol) in DCM (10 mL)
was added a solution of m-CPBA (77%, 2.1 g, 9.3 mmol) in DCM
(10 mL), and the mixture was left to react at room temperature for
2 h. Afterwards, the solution was washed with 10% aq. Na2S2O4
solution (10 mL) and sat. aq. NaHCO3 solution (2ϫ10 mL). The
organic layer was dried with anhydrous Na2SO4 and evaporated,
and the crude product was purified by chromatography on silica
gel (EtOAc/light petroleum, 1:5) to yield compound 2 (0.59 g, 68%)
as a yellow oil. 1H NMR (300 MHz, CDCl3): δ = 8.03 (d, J =
7.6 Hz, 2 H), 7.76 (t, J = 7.6 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 2 H),
4.28 (q, J = 7.2 Hz, 2 H), 1.31 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 150.8, 139.6, 135.2, 129.6 (2 CH), 127.9 (2
In summary, an efficient multistep synthetic sequence
based on a 1,3-DC of C-carboxymethyl-N-arylnitrile imines
with substituted acetylenes bearing thiol or sulfone groups
has been developed, and this methodology appears suitable
for the regiocontrolled synthesis of thieno[2,3-c]pyrazoles
of type G. Of particular interest is the possible synthetic
elaboration of the ester group that would allow the prepara-
tion of libraries of potentially active thieno[2,3-c]pyrazoles.
Therefore, applications in medicinal chemistry call for other
studies, which will be reported in due course.
CH), 79.7, 78.9, 63.5, 13.7 ppm. IR (CCl ): ν = 3061, 2978, 2532,
˜
4
Experimental Section
1726, 1570, 1472, 1441, 1358, 1238, 1171, 1088 cm–1. MS: m/z =
1
General Comments: H and 13C NMR spectra were recorded using
261 [M + Na]+.
CDCl3, CD3OD, or [D6]DMSO solutions at 300, 400, and
600 MHz for 1H and 75.46, 100.6, and 150.92 MHz for 13C. Chemi-
cal shifts are reported in ppm relative to CHCl3 (δ = 7.26 ppm for
Phenylthioacetylene (3): Trimethylsilylethyne (1 g, 10.2 mmol) was
dissolved in dry THF (15 mL) at 0 °C. A solution of nBuLi (1.6 
in hexane, 6.4 mL, 10.2 mmol) was then added dropwise with stir-
ring under an atmosphere of argon at 0 °C. After 45 min. a solution
of S-phenyl benzenethiosulfonate (2.3 g, 9.2 mmol) in THF
(10 mL) was introduced at 0 °C and stirring was continued for 2 h.
The reaction mixture was then quenched with sat. NH4Cl solution
(20 mL). The reaction mixture was extracted with diethyl ether
(3ϫ15 mL), and the organic layer was washed with water
(2ϫ15 mL) and brine. The ether layer was then dried with anhy-
drous Na2SO4 and the solvents were evaporated in vacuo. The resi-
due was purified by flash column chromatography (n-hexane) to
afford a yellow oil (1.48 g, 70% yield). 1H NMR (300 MHz,
CDCl3): δ = 7.50–7.55 (m, 2 H), 7.42–7.49 (t, J = 7.5 Hz, 2 H),
7.29–7.38 (tt, J = 7.5, 1.5 Hz, 1 H), 0.36–0.38 (s, 9 H) ppm. This
oil, trimethyl(phenylthioethynyl)silane (1 g, 4.8 mmol), was then
dissolved in THF (20 mL), cooled to –78 °C, and then mixed with
nBu4NF (1  in THF, 1.45 mL, 1.4 mmol). The reaction mixture
was stirred for 2–3 h at the same temperature. After completion,
sat. NH4Cl (20 mL) was added, and the reaction mixture was ex-
tracted with diethyl ether (3ϫ15 mL). The combined ether extracts
were washed with water (2ϫ15 mL) and brine and then dried with
anhydrous Na2SO4. The ether layer was carefully evaporated in
vacuo and crude product 3 (0.63 g, 97% yield) was kept as a stock
solution in diethyl ether (ca. 20%w/v) at –4 °C. The crude product
was used as such for further reactions without purification.
1
1H and δ = 77.0 ppm for 13C). H and 13C NMR spectral assign-
ments were made by DEPT, gCOSY, and gHSQC experiments. IR
spectra were recorded with a Perkin Elmer Spectrum RX I FT-
IR System. Mass spectra (MS) were obtained with an electrospray
ionization (ESI) source were recorded by using MeOH as the sol-
vent. High-resolution mass spectra (HRMS) were recorded with a
micromass LCT spectrometer by using electrospray (ESI+) ioniza-
tion techniques. Reactions were conducted in oven-dried (120 °C)
glassware under a positive Ar atmosphere. Transfer of anhydrous
solvents or mixtures was accomplished with oven-dried syringes/
septum techniques. THF was distilled from sodium/benzophenone
just prior to use and stored under an atmosphere of Ar. Toluene
was distilled from sodium. Et2O was distilled from phosphorus
pentoxide. CH2Cl2 was passed through basic alumina and distilled
from CaH2 prior to use. Other solvents were purified by standard
procedures. Light petroleum ether refers to the fraction with b.p.
40–60 °C. The reactions were monitored by TLC performed on sil-
ica gel plates (Baker-flex IB2-F). Column chromatography was per-
formed with Merck silica gel 60 (70–230 mesh). Preparative TLC
was carried out on glass plates using a 1 mm layer of Merck silica
gel 60 Pf 254. All chemicals were used as obtained or purified as
needed.
Ethynylsulfonylbenzene (1): To a stirred solution of trimethyl(phen-
ylthioethynyl)silane (0.5 g, 2.4 mmol) in DCM (5 mL) was added a
solution of m-CPBA (77%, 1.34 g, 6.4 mmol) in DCM (5 mL). The
reaction was vigorously stirred for 1–2 h. After completion, the re-
action was cooled to 0 °C and sat. NaHCO3 solution (15 mL) was
added with caution. Then, the reaction mixture was extracted with
DCM (3ϫ10 mL) and washed with water and brine. The DCM
layer was dried with MgSO4, and the solvents were evaporated. No
purification was necessary as almost pure product was obtained as
Ethyl 3-(Phenylthio)propiolate (4): To a stirred solution of ethyl pro-
piolate (0.4 mL, 4 mmol) in THF (8 mL) at –78 °C was added
slowly a solution of lithium bis(trimethylsilyl)amide (1  in THF,
4 mL, 4 mmol). After 30 min, a solution of S-phenyl benzenethio-
sulfonate (1.0 g, 4 mmol) in THF (6 mL) was added at –78 °C, and
the mixture was left to react at room temperature for 2 h. After
completion of the reaction, a sat. NH4Cl solution (10 mL) was
added, and the reaction mixture was extracted with diethyl ether
(2ϫ10 mL). The combined organic layers were then dried with an-
1
a yellow oil (0.55 g, 96% yield). H NMR (300 MHz, CDCl3): δ =
7.97–8.09 (d, J = 6 Hz, 2 H), 7.55–7.75 (m, 3 H), 0.22–0.25 (s, 9
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M. Comes Franchini et al.
FULL PAPER
hydrous Na2SO4, filtered, and concentrated in vacuo to afford
product 4 as a yellow oil (0.77 g, 93% yield). H NMR (300 MHz,
CDCl3): δ = 7.47 (d, J = 7.9 Hz, 2 H), 7.39 (t, J = 7.9 Hz, 2 H),
7.34–7.43 (t, J = 7.5 Hz, 2 H), 7.12–7.18 (d, J = 9 Hz, 2 H), 6.83–
6.89 (d, J = 9 Hz, 2 H), 3.94–3.97 (s, 3 H), 3.86–3.89 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 161.2, 160.6, 144.0, 142.5, 138.8,
1
7.30 (t, J = 7.3 Hz, 1 H), 4.27 (q, J = 7.2 Hz, 2 H), 1.33 (t, J = 134.0, 130.4, 128.9 (2 C), 128.4 (2 C), 128.0 (2 C), 114.3, 113.6 (2
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.9, 129.6
(2 CH), 129.5, 127.9, 127.4 (2 CH), 91.6, 79.8, 62.0, 14.1 ppm. IR
C), 55.6, 52.5 ppm. IR (CCl ): ν = 2919, 1740, 1550, 1520, 1464,
˜
4
1330, 1251, 1172, 1069 cm–1. MS: m/z = 373 [M + H]+. Data for
1
(CCl ): ν = 3066, 2984, 2153, 1709, 1583, 1479, 1444, 1366, 1232,
8Ј: M.p. 147–148 °C. H NMR (300 MHz, CDCl3): δ = 8.51–8.55
˜
4
1037 cm–1. MS: m/z = 229 [M + Na]+.
(s, 1 H), 8.07–8.14 (d, J = 6 Hz, 2 H), 7.51–7.67 (m, 5 H), 6.97–
7.05 (m, 2 H), 3.89–3.90 (s, 3 H), 3.86–3.89 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.8, 141.0, 140.8, 133.2, 133.1, 131.7,
128.6 (2 C), 128.3, 128.1 (2 C), 126.9, 121.9 (2 C), 114.7 (2 C), 55.7,
General Procedure for the 1,3 Dipolar Cycloaddition: To a stirred
solution of phenylthioacetylene (1 equiv.) and the 1,3-dipole
(1 equiv.) in freshly distilled dioxane (5 mL) was added silver carb-
onate (2.5 equiv.) under an argon atmosphere. The reaction was
heated at reflux overnight. After completion, the reaction mixture
was allowed to cool and filtered through a bed of Celite and
washed with DCM (5 mL). The filtrate was then evaporated in
vacuo to give a dark-red crude oil. The crude product was purified
by column chromatography to give the corresponding title com-
pounds.
52.6 ppm. IR (CCl ): ν = 2919, 1740, 1550, 1520, 1464, 1330, 1251,
˜
4
1172, 1069 cm–1. MS: m/z = 373 [M + H]+.
4-Ethyl 3-Methyl 1-Phenyl-5-(phenylsulfonyl)-1H-pyrazole-3,4-di-
carboxylate and 5-Ethyl 3-Methyl 1-Phenyl-4-(phenylsulfonyl)-1H-
pyrazole-3,5-dicarboxylate (9 and 9Ј): Compounds 9 and 9Ј were
obtained as white solids by following the general procedure for the
1,3-DC and were separated by chromatography on silica gel
(EtOAc/light petroleum, 3:7). The two regioisomers were further
separated by preparative TLC (EtOAc/light petroleum, 2:3) as yel-
Methyl 1-Phenyl-5-(phenylsulfonyl)-1H-pyrazole-3-carboxylate (6)
and Methyl 1-Phenyl-4-(phenylsulfonyl)-1H-pyrazole-3-carboxylate
(6Ј): Compounds 6 and 6Ј were obtained as off-white solids by
following the general procedure for the 1,3-DC and were separated
by chromatography on silica gel (EtOAc/hexane, 2:8). Data for 6:
1
low oils. Data for 9: H NMR (400 MHz, CDCl3): δ = 7.61–7.49
(m, 4 H), 7.43–7.35 (m, 4 H), 7.14 (d, J = 7.8 Hz, 2 H), 4.56 (q, J
= 7.2 Hz, 2 H), 3.94 (s, 3 H), 1.49 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 162.1, 160.4, 141.0, 139.8, 138.8,
137.2, 134.4, 130.6, 129.1 (2 CH), 128.7 (2 CH), 128.4 (2 CH),
1
M.p. 154–155 °C. H NMR (300 MHz, CDCl3): δ = 7.57–7.60 (s,
1 H), 7.44–7.57 (m, 4 H), 7.32–7.42 (q, J = 7.9 Hz, 4 H), 7.22–7.28
(m, 2 H), 3.92–3.98 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 161.2, 144.0, 142.7, 138.7, 137.6, 134.1, 130.2, 129.0 (2 C), 128.6
127.6 (2 CH), 122.7, 62.8, 52.7, 14.0 ppm. IR (CCl ): ν = 2957,
˜
4
2931, 1745, 1504, 1450, 1331, 1222, 1159 cm–1. MS: m/z = 437 [M
1
+ Na]+. Data for 9Ј: H NMR (400 MHz, CDCl3): δ = 8.25 (d, J
(2 C), 128.1 (2 C), 127.1 (2 C), 114.6, 52.6 ppm. IR (CCl ): ν =
˜
4
= 8.6 Hz, 2 H), 7.67–7.44 (m, 8 H), 4.39 (q, J = 7.2 Hz, 2 H), 3.93
(s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 159.8, 158.9, 141.6, 140.7, 139.5, 137.8, 133.5, 130.0,
129.4 (2 CH), 128.7 (2 CH), 128.5 (2 CH), 124.7, 124.4 (2 CH),
2955, 1737, 1509, 1328, 1236, 1151, 1067, 816 cm–1. MS: m/z = 343
[M + H]+. Data for 6Ј: M.p. 147–148 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.64–8.66 (s, 1 H), 8.08–8.14 (d, J = 6 Hz, 2 H), 7.70–
7.77 (d, J = 6 Hz, 2 H), 7.40–7.65 (m, 6 H), 3.88–3.90 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 159.8, 141.1, 140.8, 138.2, 133.3,
133.2, 129.7 (2 C), 128.8, 128.6 (2 C), 128.1 (2 C), 128.3, 120.2 (2
63.7, 52.9, 13.7 ppm. IR (CCl ): ν = 2955, 2928, 1746, 1501, 1447,
˜
4
1336, 1219, 1163 cm–1. MS: m/z = 437 [M + Na]+.
C), 52.6 ppm. IR (CCl ): ν = 2955, 1737, 1509, 1328, 1236, 1151,
˜
4
4-Ethyl 3-Methyl 1-(4-Nitrophenyl)-5-(phenylsulfonyl)-1H-pyrazole-
3,4-dicarboxylate and 5-Ethyl 3-Methyl 1-(4-Nitrophenyl)-4-(phenyl-
sulfonyl)-1H-pyrazole-3,5-dicarboxylate (10 and 10Ј): Compounds
10 and 10Ј were obtained by following the general procedure for
the 1,3-DC and were separated by preparative TLC (EtOAc/light
petroleum, 2:3). Data for 10: M.p. 195–197 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.30 (d, J = 8.9 Hz, 2 H), 7.68–7.61 (m, 3
H), 7.50–7.40 (m, 4 H), 4.54 (q, J = 7.2 Hz, 2 H), 3.95 (s, 3 H),
1.48 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 161.5, 159.8, 148.6, 141.9, 141.2, 140.9, 138.6, 134.9, 129.4 (2
CH), 128.6 (2 CH), 128.1 (2 CH), 124.0 (2 CH), 123.3, 63.0, 53.0,
1067, 816 cm–1. MS: m/z = 343 [M + H]+.
Methyl
1-(4-Nitrophenyl)-5-(phenylsulfonyl)-1H-pyrazole-3-carb-
oxylate (7) and Methyl 1-(4-nitrophenyl)-4-(phenylsulfonyl)-1H-pyr-
azole-3-carboxylate (7Ј): Compounds 7 and 7Ј were obtained as off-
white solids by following the general procedure for the 1,3-DC and
were separated by chromatography on silica gel (EtOAc/hexane,
1
2:8). Data for 7: M.p. 192–194 °C. H NMR (300 MHz, CDCl3): δ
= 8.28–8.35 (d, J = 9 Hz, 2 H), 7.59–7.71 (m, 4 H), 7.42–7.53 (m, 3
H), 7.25–7.28 (s, 1 H), 3.96–3.99 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.7, 148.2, 144.4, 143.8, 142.5, 138.6, 134.7, 129.4
(2 C), 128.0 (2 C), 127.8 (2 C), 124.1 (2 C), 115.3, 52.8 ppm. IR
14.1 ppm. IR (CHCl ): ν = 2955, 2930, 1745, 1615, 1600, 1539,
˜
3
1505, 1439, 1347, 1223, 1164 cm–1. MS: m/z = 482 [M + Na]+. Data
(CH Cl ): ν = 3970, 2985, 1737, 1531, 1346, 1236 cm–1. MS: m/z =
˜
2
2
1
388 [M + H]+. Data for 7Ј: M.p. 218–219 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.75–8.79 (s, 1 H), 8.39–8.46 (d, J = 9 Hz, 2 H), 8.09–
8.15 (d, J = 6 Hz, 2 H), 7.96–8.03 (d, J = 9 Hz, 2 H), 7.52–7.69
(m, 3 H), 3.90–3.95 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 159.7, 147.5, 142.6, 140.7, 133.9, 133.8, 129.1, 129.0, 128.6 (2 C),
for 10Ј: M.p. 208–210 °C. H NMR (400 MHz, CDCl3): δ = 8.37
(d, J = 9.1 Hz, 2 H), 8.23 (d, J = 7.7 Hz, 2 H), 7.75 (d, J = 9.1 Hz,
2 H), 7.68–7.56 (m, 3 H), 4.46 (q, J = 7.2 Hz, 2 H), 3.95 (s, 3 H),
1.34 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 159.6, 158.8, 148.1, 142.8, 142.4, 140.4, 139.5, 133.8, 128.9 (2
CH), 128.6 (2 CH), 126.1, 125.0 (2 CH), 124.9 (2 CH), 64.2, 53.0,
125.7 (2 C), 120.5 (2 C), 53.0 ppm. IR (CH Cl ): ν = 3070, 2985,
˜
2
2
1737, 1531, 1346, 1236, 1068 cm–1. MS: m/z
=
388 [M
+
3
13.7 ppm. IR (CHCl ): ν = 2955, 2928, 1747, 1615, 1600, 1537,
˜
1505, 1436, 1345, 1221, 1164 cm–1. MS: m/z = 482 [M + Na]+.
H]+.
Methyl
1-(4-Methoxyphenyl)-5-(phenylsulfonyl)-1H-pyrazole-3-
4-Ethyl 3-Methyl 1-(4-Methoxyphenyl)-5-(phenylsulfonyl)-1H-pyr-
carboxylate (8) and Methyl 1-(4-Methoxyphenyl)-4-(phenylsulfonyl)- azole-3,4-dicarboxylate and 5-Ethyl 3-Methyl 1-(4-Methoxyphenyl)-
1H-pyrazole-3-carboxylate (8Ј): Compounds 8 and 8Ј were ob-
tained as off-white solids by following the general procedure for
the 1,3-DC and were separated by chromatography on silica gel
(EtOAc/hexane, 2:8). Data for 8: M.p. 121–122 °C. 1H NMR
4-(phenylsulfonyl)-1H-pyrazole-3,5-dicarboxylate (11 and 11Ј):
Compounds 11 and 11Ј were obtained as yellow oils by following
the general procedure for the 1,3-DC and were separated by
chromatography on silica gel (EtOAc/light petroleum, 3:7). The two
(300 MHz, CDCl3): δ = 7.54–7.61 (m, 2 H), 7.47–7.53 (m, 2 H), regioisomers were further separated by preparative TLC (EtOAc/
6444
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6440–6447

Regiocontrolled Synthesis of Ring-Fused Thieno[2,3-c]pyrazoles
1
1
light petroleum, 2:8). Data for 11: H NMR (400 MHz, CDCl3): δ by chromatography on silica gel (EtOAc/light petroleum, 1:3). H
= 7.58 (t, J = 8.5 Hz, 3 H), 7.40 (t, J = 8.0 Hz, 2 H), 7.04 (d, J =
8.7 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 4.55 (q, J = 7.2 Hz, 2 H),
3.93 (s, 3 H), 3.88 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 162.2, 161.1, 160.4, 146.1, 134.4, 131.9,
129.9, 129.1 (2 CH), 128.8 (2 CH), 128.6, 128.4 (2 CH), 114.7,
NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 9.1 Hz, 2 H), 7.64 (d,
J = 9.1 Hz, 2 H), 7.20–7.16 (m, 3 H), 7.06–7.03 (m, 2 H), 4.36 (q,
J = 7.2 Hz, 2 H), 3.97 (s, 3 H), 1.31 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 161.8, 161.1, 147.5, 143.6, 142.7,
136.0, 132.3, 129.4 (2 CH), 129.2 (2 CH), 127.7 (2 CH), 126.6 (2
113.7 (2 CH), 62.7, 55.6, 52.7, 14.1 ppm. IR (CCl ): ν = 2955, 1745,
CH), 124.1, 123.5, 61.7, 52.7, 13.9 ppm. IR (CCl ): ν = 3065, 2954,
˜
˜
4
4
1510, 1460, 1441, 1340, 1219, 1163 cm–1. MS: m/z = 467 [M +
1734, 1653, 1533, 1347, 1203, 1127, 1079 cm–1. MS: m/z = 450 [M
1
Na]+. Data for 11Ј: H NMR (400 MHz, CDCl3): δ = 8.24 (d, J =
+ Na]+.
7.8 Hz, 2 H), 7.67–7.54 (m, 3 H), 7.42 (d, J = 8.6 Hz, 2 H), 6.95
(d, J = 8.6 Hz, 2 H), 4.38 (q, J = 7.2 Hz, 2 H), 3.92 (s, 3 H), 3.85
(s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 160.6, 159.8, 159.0, 141.2, 140.7, 139.7, 133.5, 130.7,
128.6 (2 CH), 128.5 (2 CH), 126.0 (2 CH), 124.4, 114.4 (2 CH),
4-Ethyl 3-Methyl 1-(4-Methoxyphenyl)-5-(phenylthio)-1H-pyrazole-
3,4-dicarboxylate (17): Compound 14c was obtained as a white oil
by following the general procedure for the 1,3-DC and was sepa-
rated by chromatography on silica gel (EtOAc/light petroleum, 3:7).
1H NMR (400 MHz, CDCl3): δ = 7.26–7.14 (m, 5 H), 7.06–7.02
(m, 2 H), 6.84 (d, J = 9.0 Hz, 2 H), 4.31 (q, J = 7.2 Hz, 2 H), 3.94
(s, 3 H), 3.80 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 162.3, 161.5, 160.0, 142.3, 135.7, 133.2,
130.9, 129.3 (2 CH), 129.0 (2 CH), 127.4 (2 CH), 127.2, 122.1,
63.6, 55.6, 52.8, 13.8 ppm. IR (CCl ): ν = 2953, 1743, 1515, 1463,
˜
4
1444, 1337, 1219, 1163 cm–1. MS: m/z = 467 [M + Na]+.
Methyl 1-Phenyl-5-(phenylthio)-1H-pyrazole-3-carboxylate (12):
Compound 12 was obtained as a light-yellow oil by following the
general procedure for the 1,3-DC and was separated by chromatog-
raphy on silica gel (EtOAc/hexane, 1:9). 1H NMR (300 MHz,
CDCl3): δ = 7.48–7.60 (m, 5 H), 7.30–7.40 (m 4 H), 7.22–7.29 (m,
1 H), 7.12–7.17 (m, 1 H), 4.03–4.08 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 161.4, 143.3, 137.9, 134.9, 132.8, 128.9 (2
C), 128.7 (2 C), 128.2, 128.1 (2 C), 126.9, 124.9 (2 C), 115.2,
113.7 (2 CH), 61.5, 55.4, 52.4, 13.9 ppm. IR (CCl ): ν = 3063, 2955,
˜
4
2839, 1734, 1515, 1478, 1365, 1287, 1253, 1212, 1183 cm–1. MS:
m/z = 435 [M + Na]+.
2-Mercapto-1-phenylethanone: A solution of thiolacetic acid (5.6 g,
73.6 mmol) in dry pyridine (40 mL) was added to a solution of
phenacyl chloride (10 g, 65.0 mmol), and resultant reaction mixture
was maintained at 85 °C for 1.5–2 h. After cooling to room tem-
perature, chloroform (200 mL) was added to the orange reaction
mixture, which was washed with 10% HCl (150 mL) and extracted
with 10% NaOH (150 mL). The organic layer was dried with
MgSO4 and filtered, and the solvent was evaporated in vacuo. The
crude product was purified by flash column chromatography (1–
2% EtOAc/hexane) to afford phenacyl thiolacetate (10.2 g, 80%
yield). 1H NMR (400 MHz, CDCl3): δ = 7.98–8.02 (m, 2 H), 7.58–
7.64 (tt, J = 6, 1.5 Hz, 1 H), 7.47–7.53 (m, 2 H), 4.41 (s, 2 H), 2.42
51.5 ppm. IR (CCl ): ν = 2919, 1726, 1229, 1011 cm–1. MS: m/z =
˜
4
311 [M + H]+.
Methyl 1-(4-Nitrophenyl)-5-(phenylthio)-1H-pyrazole-3-carboxylate
(13): Compound 13 was obtained as a light-yellow solid by follow-
ing the general procedure for the 1,3-DC and was separated by
chromatography on silica gel (EtOAc/hexane, 1:9). M.p. 89–91 °C.
1H NMR (300 MHz, CDCl3): δ = 8.36–8.44 (m, 2 H), 7.85–7.92
(m, 2 H), 7.36–7.42 (m, 3 H), 7.24–7.30 (m, 2 H), 7.19–7.20 (s, 1
H), 4.06–4.09 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.6,
147.0, 145.0, 143.2, 136.0, 132.5, 129.6 (2 C), 129.5 (2 C), 127.9,
(s,
3 H) ppm. A solution of phenacyl thiolacetate (10.2 g,
125.8 (2 C), 124.2 (2 C), 117.0, 52.5 ppm. IR (CCl ): ν = 2919,
˜
4
52.5 mmol) in diethyl ether (60 mL) was stirred vigorously while
aq. 2  NaOH solution (58 mL, 120 mmol) was added. This mix-
ture was stirred for 2 h and then separated. The aqueous layer was
cooled to 0 °C and acidified. This was extracted with DCM
(2ϫ100 mL). The combined organic layers were dried with
MgSO4, and the solvents were evaporated in vacuo. The crude
product 2-mercapto-1-phenylethanone was purified by flash col-
umn chromatography (5% EtOAc/hexane) to afford the pure prod-
uct as a yellow oil (7.3 g, 91% yield). 1H NMR (400 MHz, CDCl3):
δ = 7.93–7.99 (m, 2 H), 7.56–7.63 (m, 1 H), 7.45–7.52 (m, 2 H),
3.94–3.98 (d, J = 8 Hz, 2 H), 2.11–2.15 (t, J = 8 Hz, 1 H) ppm.
1730, 1531, 1345, 1233, 1125, 1009, 854 cm–1. MS: m/z = 356 [M
+ H]+.
Methyl
1-(4-Methoxyphenyl)-5-(phenylthio)-1H-pyrazole-3-carb-
oxylate (14): Compound 14 was obtained as a light-yellow solid by
following the general procedure for the 1,3-DC and was separated
by column chromatography on silica gel (EtOAc/light petroleum,
1
1:9). M.p. 83–85 °C. H NMR (300 MHz, CDCl3): δ = 7.43–7.47
(m, 2 H), 7.32–7.40 (m, 3 H), 7.23–7.27 (m, 2 H), 7.14–7.15 (s, 1
H), 6.98–7.04 (m, 2 H), 4.04–4.06 (s, 3 H), 3.94–3.95 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 162.5, 160.1, 143.9, 136.0, 133.9,
131.9, 129.8 (2 C), 129.6 (2 C), 127.7, 127.3 (2 C), 115.9, 114.1 (2
2,2Ј-Disulfanediylbis(1-phenylethanone) (18): To a stirred solution
of 2-mercapto-1-phenylethanone (5 g, 32.9 mmol) in EtOAc
(30 mL) was added NaI (49.5 mg, 0.33 mmol) and 30% H2O2
(3.38 mL, 32.9 mmol), and the mixture was stirred at room tem-
perature for 1 h. Sat. aq. Na2S2O3 (100 mL) was then added, and
resulting mixture was extracted with EtOAc (3ϫ50 mL). The com-
bined organic extracts were washed with brine and dried with anhy-
drous Na2SO4. The solvent was evaporated in vacuo. The crude
product was purified with flash column chromatography (5%
EtOAc/hexane) to obtain a white solid (4.65 g, 93% yield). 1H
NMR (300 MHz, CDCl3): δ = 7.88–7.99 (d, J = 6 Hz, 4 H), 7.55–
7.63 (tt, J = 7.5, 1.5 Hz, 2 H), 7.42–7.51 (t, J = 7.5 Hz, 4 H), 4.20
(s, 4 H) ppm.
C), 55.7, 52.3 ppm. IR (CCl ): ν = 2956, 1745, 1726, 1512, 1247,
˜
4
1225, 1126, 1011 cm–1. MS: m/z = 341 [M + H]+.
4-Ethyl 3-Methyl 1-Phenyl-5-(phenylthio)-1H-pyrazole-3,4-dicarb-
oxylate (15): Compound 15 was obtained as a light-yellow oil by
following the general procedure for the 1,3-DC and was separated
1
by chromatography on silica gel (EtOAc/light petroleum, 1:6). H
NMR (400 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 7.15–7.09 (m, 3
H), 7.04–6.99 (m, 2 H), 4.31 (q, J = 7.2 Hz, 2 H), 3.92 (s, 3 H),
1.26 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 162.3, 161.5, 142.5, 138.0, 135.7, 133.0, 129.4 (2 CH), 129.3,
129.0 (2 CH), 128.7 (2 CH), 127.3, 126.0 (2 CH), 122.3, 61.5, 52.4,
13.8 ppm. IR (CCl ): ν = 3065, 2928, 2843, 1731, 1586, 1498, 1472,
˜
4
1363, 1285, 1212, 1186 cm–1. MS: m/z = 405 [M + Na]+.
1,2-Bis[(2-phenyl-1,3-dioxolan-2-yl)methyl]disulfane (19): A solution
of 18 (4.65 g, 15.4 mmol), ethylene glycol (5.9 g, 92.4 mmol), tri-
ethyl orthoformate (11.58 mL, 61.6 mmol), and PTSA (0.3 g,
1.57 mmol) in toluene was heated to 60 °C for 3 h. After comple-
4-Ethyl 3-Methyl 1-(4-Nitrophenyl)-5-(phenylthio)-1H-pyrazole-3,4-
dicarboxylate (16): Compound 16 was obtained as a yellow oil by
following the general procedure for the 1,3-DC and was separated
Eur. J. Org. Chem. 2010, 6440–6447
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6445

M. Comes Franchini et al.
FULL PAPER
tion, the reaction mixture was cooled and diluted with EtOAc
(30 mL) and then washed with aq. K2CO3 and brine. The organic
layer was then dried with anhydrous MgSO4 and the solvents were
evaporated. The crude solid product was purified by column
chromatography (1–5% EtOAc/hexane) to give a light-yellow solid
Methyl 4-Formyl-1-(4-nitrophenyl)-5-[(2-phenyl-1,3-dioxolan-2-yl)-
methylthio]-1H-pyrazole-3-carboxylate (22b): Eluent: 10–20%
EtOAc/hexane. Yield: 60 mg, 42%. 1H NMR (300 MHz, CDCl3):
δ = 10.54 (s, 1 H), 8.35–8.41 (d, J = 9 Hz, 2 H), 7.82–7.87 (d, J =
9 Hz, 2 H), 7.18–7.28 (m, 5 H), 4.02–4.05 (s, 3 H), 3.65–3.75 (m, 4
(4.9 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ = 7.45–7.53 (m, H), 3.46–3.50 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 186.0,
4 H), 7.25–7.38 (m, 6 H), 4.03–4.18 (m, 4 H), 3.77–3.89 (m, 4 H),
3.33 (s, 4 H) ppm.
161.6, 147.9, 145.6, 143.0, 142.8, 140.3, 128.9, 128.5 (2 C), 127.4 (2
C), 125.8 (2 C), 125.6, 124.4 (2 C), 108.8, 65.3 (2 C), 53.1,
45.6 ppm. IR (CCl ): ν = 2956, 1729, 1686, 1598, 1541, 1533, 1347,
˜
4
Trimethyl{[(2-phenyl-1,3-dioxolan-2-yl)methylthio]ethynyl}silane (20):
Trimethylsilylethyne (0.5 g, 5.1 mmol) was dissolved in dry THF
(10 mL) at 0 °C. A solution of nBuLi (1.6  in hexane, 3.8 mL,
6.1 mmol) was then added dropwise with stirring under an atmo-
sphere of argon. After 45 min a solution of 1,2-bis[(2-phenyl-1,3-
dioxolan-2-yl)methyl]disulfane (2 g, 6.6 mmol) in THF (20 mL)
was introduced at 0 °C and stirring was continued for 1–2 h. Then
reaction mixture was quenched with sat. NH4Cl solution (15 mL).
1254, 1141, 1011 cm–1. MS: m/z = 492 [M + Na]+.
Methyl 4-Formyl-1-(4-methoxyphenyl)-5-[(2-phenyl-1,3-dioxolan-2-
yl)methylthio]-1H-pyrazole-3-carboxylate (22c): Eluent: 10–20%
EtOAc/hexane. Yield: 58 mg, 43%.1H NMR (300 MHz, CDCl3): δ
= 10.53 (s, 1 H), 7.44–7.48 (d, J = 6 Hz, 2 H), 7.21–7.25 (m, 5 H),
6.97–7.02 (d, J = 6 Hz, 2 H), 3.99–4.02 (s, 3 H), 3.87–3.89 (s, 3 H),
3.62–3.72 (m, 4 H), 3.36–3.39 (s, 2 H) ppm. 13C NMR (75 MHz,
The mixture was then extracted with diethyl ether (3ϫ15 mL), and CDCl3): δ = 186.4, 162.3, 160.5, 144.7, 142.5, 140.8, 131.4, 128.6,
the organic layer was washed with water (2ϫ15 mL) and brine.
The ether layer was then dried with anhydrous MgSO4 and the
solvents were evaporated in vacuo. The residue was purified by
flash column chromatography (n-hexane) to give a colorless oil
(1.2 g, 80% yield). 1H NMR (300 MHz, CDCl3): δ = 7.45–7.55 (m,
2 H), 7.30–7.44 (m, 3 H), 4.02–4.22 (m, 2 H), 3.78–3.93 (m, 2 H),
3.34 (s, 2 H), 0.14 (s, 9 H) ppm.
128.4 (2 C), 127.9 (2 C), 127.3, 125.8 (2 C), 114.2 (2 C), 108.8, 65.4
(2 C), 55.9, 52.9, 45.1 ppm. IR (CCl ): ν = 3065, 2955, 2892, 1726,
˜
4
1682, 1612, 1515, 1475, 1253, 1172, 1142, 1040 cm–1. MS: m/z =
477 [M + Na]+.
Methyl 5-Benzoyl-1-phenyl-1H-thieno[2,3-c]pyrazole-3-carboxylate
(23a): To a stirred solution of 22a (100 mg, 0.23 mmol) in acetone
(10 mL) was added 50% TFA in water (10 mL). The resulting mix-
ture was then heated at 65 °C overnight. After completion, the re-
action was cooled to room temperature and then acetone was re-
moved carefully under reduced pressure. The aqueous layer was
then extracted with EtOAc (3ϫ5 mL). The combined organic lay-
ers were washed with water till neutral and then with brine. The
organic layer was dried with anhydrous MgSO4, and the solvents
were evaporated in vacuo to give the crude product. This crude
product was then purified by preparative TLC (DCM) to give 23a
as a white solid. Yield: 17 mg, 20%. M.p. 212–213 °C. 1H NMR
2-(Ethynylthiomethyl)-2-phenyl-1,3-dioxolane (21): To a stirred solu-
tion of 20 (0.5 g, 1.71 mmol) in THF (10 mL) at 0 °C was added
dropwise a solution of TBAF-hydrate (0.5 g, 1.91 mmol) dissolved
in THF (5 mL). The reaction mixture was then vigorously stirred
at 0 °C for 1–2 h. After completion, sat. NH4Cl (15 mL) was added,
and the mixture was extracted with diethyl ether (3ϫ10 mL). The
combined ether extracts were washed with water (2ϫ15 mL) and
brine. The ether layer was then dried with anhydrous MgSO4, and
the solvents were evaporated in vacuo to give 21 as a brown solid
1
(351 mg, 93% yield). H NMR (300 MHz, CDCl3): δ = 7.49–7.57 (400 MHz, CDCl3): δ = 7.88–7.97 (m, 4 H), 7.87 (s, 1 H), 7.62–
(m, 2 H), 7.32–7.44 (m, 3 H), 4.17–4.25 (m, 2 H), 3.88–3.94 (m, 2
H), 3.34 (s, 2 H), 2.70 (s, 1 H) ppm.
7.69 (t, J = 16 Hz, 1 H), 7.51–7.62 (q, J = 12 Hz, 4 H), 7.37–7.46 (t,
J = 16 Hz, 1 H), 4.03 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 189.7, 162.0, 145.6, 144.8, 138.9, 138.0, 137.4, 132.9, 132.1, 130.0,
General Procedure for the Preparation of Compounds 22: To a solu-
tion of 21 (0.1 g, 0.43 mmol) in dry THF (5 mL) at –78 °C was
added dropwise a solution of LiHMDS (1  in THF, 0.47 mL,
0.47 mmol), and the resulting mixture was stirred for 20 min at the
same temperature. After 20 min freshly distilled HMPA (0.37 mL,
129.3, 128.9, 127.9, 125.5, 119.3, 52.8 ppm. IR (CCl ): ν = 3005,
˜
4
2950, 1750, 1725 cm–1. MS: m/z = 385 [M + Na]+.
Methyl
5-Benzoyl-1-(4-nitrophenyl)-1H-thieno[2,3-c]pyrazole-3-
carboxylate (23b): To a stirred solution of 22b (80 mg, 0.16 mmol)
2.15 mmol) was added to the reaction, and the mixture was in acetone (6 mL) was added 50% TFA in water (6 mL). Isolation
warmed slowly to –35 °C over 2 h. The reaction was again cooled
to –78 °C and dry DMF (0.06 mL, 0.86 mmol) was added. The
reaction was warmed to –35 °C over 2 h and kept at the same tem-
perature for a further 1.5 h, then quenched at –35 °C with sat.
NH4Cl (5 mL) and extracted with diethyl ether (3ϫ10 mL). The
combined ether extracts were washed with water (2ϫ10 mL) and
brine. The organic layer was then dried with anhydrous MgSO4,
and the solvents were evaporated in vacuo. The crude product was
used as such for further reactions without purification. Com-
pounds 22a–c were then obtained as a light-yellow oils by following
the general procedure for the 1,3-DC and were separated by
chromatography on silica gel.
of 23b as a yellow solid was carried out as for 23a. Eluent: 25%
EtOAc/hexane. Yellow solid. Yield: 18 mg, 28%. M.p. 223–224 °C.
1H NMR (300 MHz, CDCl3): δ = 8.45–8.49 (d, J = 9 Hz, 2 H),
8.09–8.13 (d, J = 9 Hz, 2 H), 7.90–7.96 (dt, J = 9, 1.5 Hz, 2 H),
7.88–7.90 (s, 1 H), 7.64–7.72 (tt, J = 7.5, 1.5 Hz, 1 H), 7.53–7.62 (tt,
J = 7.5, 1.5 Hz, 2 H), 4.05–4.07 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 189.3, 161.5, 146.3, 145.9, 145.7, 143.2, 139.5, 137.0,
133.2, 132.8, 129.3 (2 C), 129.0 (2 C), 125.9 (2 C), 125.1, 119.3 (2
C), 53.1 ppm. IR (CCl ): ν = 2927, 1752, 1727, 1640, 1532, 1508,
˜
4
1341, 1285 cm–1. MS: m/z = 430 [M + Na]+.
Methyl 5-Benzoyl-1-(4-methoxyphenyl)-1H-thieno[2,3-c]pyrazole-3-
carboxylate (23c): To a stirred solution of 22c (100 mg, 0.22 mmol)
Methyl
4-Formyl-1-phenyl-5-[(2-phenyl-1,3-dioxolan-2-yl)methyl- in acetone (6 mL) was added 50% TFA in water (6 mL). Isolation
thio]-1H-pyrazole-3-carboxylate (22a): Eluent: 10–20% EtOAc/hex- of 23c as an off-white solid was carried out as for 23a. Eluent: 25%
1
ane. Yield: 126 mg (66% overall). H NMR (400 MHz, CDCl3): δ EtOAc/hexane. Yield: 20 mg, 23%. M.p. 191–192 °C. 1H NMR
= 10.54 (s, 1H), 7.41–7.66 (m, 5 H), 7.16–7.33 (m, 5 H), 4.00 (s, 3 (400 MHz, CDCl3): δ = 7.88–7.93 (d, J = 6 Hz, 2 H), 7.84–7.86 (s,
H), 3.58–3.68 (m, 4 H), 3.38 (s, 2 H) ppm. 13C NMR (100 MHz, 1 H), 7.80–7.84 (d, J = 6 Hz, 2 H), 7.62–7.68 (tt, J = 6, 1.5 Hz, 1
CDCl3): δ = 186.3, 162.1, 144.9, 142.5, 140.8, 138.4, 129.7, 129.1,
H), 7.52–7.58 (t, J = 6 Hz, 2 H), 7.05–7.09 (d, J = 9 Hz, 2 H), 4.00–
4.03 (s, 3 H), 3.87–3.90 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 189.7, 162.1, 159.3, 145.4, 144.7, 137.5, 132.8, 132.4, 132.0,
128.6, 128.4, 126.7, 125.8, 124.8,108.9, 65.4, 52.9, 45.3 ppm. IR
(CCl ): ν = 3003, 2960, 1728, 1690 cm–1. MS: m/z = 447 [M + Na]+.
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4
6446
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6440–6447

Regiocontrolled Synthesis of Ring-Fused Thieno[2,3-c]pyrazoles
G. Maga, F. Carraro, C. Martini, F. Bondavalli, M. Botta, J.
Med. Chem. 2008, 51, 1252–1259.
129.3 (2 C), 128.9 (2 C), 125.6, 123.0, 121.0 (2 C), 115.1 (2 C), 55.9,
52.7 ppm. IR (CCl ): ν = 3005, 2954, 1748, 1723, 1543, 1518, 1287,
˜
4
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Acknowledgments
This work was funded by the University of Bologna. We thank
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α to sulfur, where several undesired side reactions took place.
Received: July 23, 2010
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Published Online: September 28, 2010
Eur. J. Org. Chem. 2010, 6440–6447
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6447