Microwave-assisted regioselective [1,3]-dipolar cycloaddition of 3-methyl-2-(substitutedbenzylidene)-5-oxopyrazolidin-2-ium-1-ides to benzothiophene 1,1-dioxide

Article abstract of DOI:10.3906/kim-1502-3

A series of pyrazolidinium ylides was reacted with benzothiophene 1,1-dioxide to afford (3R,5S,5aS,10bS)-3-methyl-5-substitutedphenyl-2,3,5,5a-tetrahydrobenzo[4,5]thieno[3,2-c]pyrazolo[1,2-a]pyrazol-1(10bH )-one 6,6-dioxides under microwave irradiation an

Full text of DOI:10.3906/kim-1502-3

Turk J Chem
Turkish Journal of Chemistry
(2015) 39: 789 – 800
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http://journals.tubitak.gov.tr/chem/
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c
⃝ TUBITAK
doi:10.3906/kim-1502-3
Research Article
Microwave-assisted regioselective [1,3]-dipolar cycloaddition of
3-methyl-2-(substitutedbenzylidene)-5-oxopyrazolidin-2-ium-1-ides to
benzothiophene 1,1-dioxide
∗
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Ya¸sar DURUST , Eda SAGIRLI, Akın SAGIRLI
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Department of Chemistry, Faculty of Arts and Science, Abant Izzet Baysal University, Bolu, Turkey
Received: 01.02.2015
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Accepted/Published Online: 05.05.2015
•
Printed: 28.08.2015
Abstract: A series of pyrazolidinium ylides was reacted with benzothiophene 1,1-dioxide to afford (3R,5S,5aS,10bS)-3-
methyl-5-substitutedphenyl-2,3,5,5a-tetrahydrobenzo[4,5]thieno[3,2-c]pyrazolo[1,2-a]pyrazol-1(10bH )-one 6,6-dioxides un-
der microwave irradiation and their structures were identified by means of spectral/physical characteristics including
X-ray diffraction data and HRMS measurements.
Key words: Microwave-assisted synthesis, pyrazolidinium, ylide, 1,3-dipolar cycloaddition, benzothiophene dioxide
1. Introduction
Heterocyles containing pyrazolone rings have been attracting continuing interest due to their diverse medicinal
chemistry applications, for example as antipyretic and antiparasitic agents. Recently, some sulfanyl pyrazolone
derivatives, which can be used against amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease,
a fatal neurodegenerative disease causing muscle loss and paralysis, were reported (Figure 1).1−12
Figure 1. Some biologically important pyrazolone derivatives.
Pyrazolidium ylides have been studied rarely in terms of 1,3-dipolar cycloaddition. 1,3-Dipolar cycload-
dition of these dipoles to phenyl acetylene, ethyl propiolate, maleimides, and fullerenes is reported.13−17
∗Correspondence: yasardurust@ibu.edu.tr
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The dipolarophilic reagent used in this work, benzothiophene 1,1-dioxide, is also rarely utilized in dipolar
cycloadditions.18−20 Recently, we performed cycloaddition of sydnones to benzothiophene dioxide.21
Taking account of the above considerations and our continuing interest22 in the cycloadditions of various
ylides, we herein focused on the cycloaddition of oxopyrazolidinium ylides to benzothiophene 1,1-dioxide under
microwave irradiation conditions routinely utilized in organic synthesis including cycloaddition and multicom-
ponent reactions.23−28
2. Results and discussion
The major starting 1,3-dipolar compounds, the pyrazolidinum ylides 3a–l, were prepared by reacting ethyl but-
2-enoate with hydrazine hydrate then with substituted benzaldehydes carrying both electron withdrawing and
electron donating groups, according to the procedure previously reported,29 and their structures were confirmed
by spectral/physical characteristics (Scheme 1).
Scheme 1. Synthesis of oxopyrazolidinium ylides 3a–l.
The electron deficient dipolarophile benzothiophene 1,1-dioxide 4 underwent cycloaddition with oxopyra-
zolidinium ylides 3a–l under microwave heating and gave the regioisomers 5a–l in good yields as the only isolable
regioisomeric products (Scheme 2). Even if prolonged reflux conditions were applied, no reaction occurred at
all between the ylides and benzothiophene dioxide.
Typical characteristics of these cycloadducts carrying four stereocenters in their IR spectra are the
carbonyl absorptions of the pyrazolidinone at around 1685–1695 cm−1 and the symmetric and asymmetric
stretching vibrations of SO2 moiety at around 1150 and 1300 cm−1 , respectively. In the proton NMR spectra
of these cycloadducts, the most deshielded aliphatic hydrogen (Ha) originating from benzothiophene 1,1-dioxide
is that attached to the bridge carbon adjacent to the nitrogen with the ring carbonyl group and appeared at
around 5.77 ppm as a doublet. Another bridge proton (Hb) originating from benzothiophene 1,1-dioxide and
spatially trans to the sulfone group and Hc resonated at around 4.35 ppm as a triplet. The Hc proton that
originated from the ylide azomethine group appears as a doublet at around 4.20 ppm with a J value of 8.8
Hz. Hd is split into a septet due to adjacent methyl and methylene protons (He and Hf ) at around 3.24 ppm
(Figure 2a). The most deshielded aromatic protons (Hg) are those attached to the carbon, which are closer to
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Scheme 2. 1,3-Dipolar cycloaddition of pyrazolidinium ylides 3a–l with benzothiophene 1,1-dioxide 4 leading to 5a–l.
the sulfone group spatially and came out at around 8.40 ppm as doublets. As for 13 C NMR data, we observe the
pyrazolone carbonyl carbon resonating at around 170 ppm, while the bridge methine (C1) adjacent to sulfone
resonates at around 73.5 ppm, another bridge carbon (C2) appears at 60.5 ppm and C3 carrying an aromatic
group at 68.2 ppm, while pyrazolone C4 carbon, which is attached to the methyl group, arises at 55.8 ppm
(Figure 2b).
(a)
(b)
Figure 2. (a) Proton assignments in the 1 H NMR spectrum of 5a–l; (b) assignment of carbons of 5h.
Exact regiochemistry and stereochemistry of the cycloadducts were resolved by means of X-ray diffraction
data obtained from a fine single crystal of 5i (Figure 3). It is clearly seen that aryl and methyl groups are cis;
Hb and Hc protons are trans. Hb and Hd obtain their cis stereochemistry from benzothiophene 1,1-dioxide.
Formation of these single regioisomers coincides with the outcome of a previous observation in which
azomethine ylide generated from isatine in which ylide approach to the dipolarophile occurred through the
less hindered site.18 In the case of benzothiophene-S -oxide–ylide cycloaddition, a contrasting situation was
reported.29 In this regard, in our current case, regioisomers 5a–l were generated by approach of the dipolarophile
benzothiophene 1,1-dioxide, which may be attributed to the possible resonance structure having the higher
electron deficiency on the number 2 carbon and likely less hindrance (Scheme 3).
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Figure 3. X-ray ORTEP diagram of 5i.
Scheme 3. Resonance structures of benzothiophene 1,1-dioxide.
Considering the fact that the electron deficiency is higher in no. 2 carbon of benzothiophene 1,1-dioxide
we may think of drawing an anticipated transition state configuration based on the approaching 1,3-dipolar
azomethine ylide to the electron poor and electron rich ends of the dipolarophile benzothiophene dioxide
(Scheme 4).
Scheme 4. Transition state configuration of the cycloaddition.
3. Conclusions
In summary, we demonstrate a practical method that allows access to a series of substituted benzothiophene
fused pyrazolones carrying substituted aryl groups using [1,3]-dipolar cycloaddition reactions of 3-methyl ox-
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opyrazolidinium ylides to electron deficient dipolarophile benzothiophene 1,1-dioxide. The reactions result in
good yields and are regioselective under microwave irradiation.
4. Experimental
4.1. General
Melting points were determined on a Meltemp apparatus and are uncorrected. Infrared spectra were obtained
from KBr pellets or neat on NaCl plates for liquids and were recorded on a Shimadzu 8000 FTIR spectropho-
tometer. LC-MS spectra were recorded on an Agilent spectrometer and HRMS on a Waters Synapt spectrometer
using the ionization modes specified. NMR spectra were recorded on JEOL and VARIAN spectrometers op-
erating at 400 MHz for 1 H and at 100 MHz for 13 C, respectively, all at 25 ◦ C, as specified for each data
set. All chemical shifts are reported in ppm downfield from TMS. Coupling constants (J) are reported in Hz.
Routine TLC analyses were carried out on pre-coated silica gel plates with fluorescent indicator. Flash column
chromatography was performed on silica gel (230–400 mesh ASTM). A rotary TLC apparatus (Chromatotron)
was utilized for further separation and purifications. Stain solutions of potassium permanganate and iodine
were used for visualization of the TLC spots.
4.2. Preparation of oxopyrazolidinium ylides 3a–l: general procedure30
Ethyl 3-butenoate (5.15 g, 45.0 mmol) was added dropwise to a solution of hydrazine monohydrate (1.4 g,
45.0 mmol) in ethanol (80 mL) and the reaction mixture was refluxed overnight at 78 ◦ C; the intermediate
pyrazolidin-3-one formed. Then substituted benzaldehyde (60.0 mmol) was added to the solution. After stirring
overnight at room temperature, the solvent was removed under reduced pressure. The resultant residue was
purified by column chromatography on silica gel using MeOH/EtOAc (1/10, v/v) to afford 2-arylidene-3-methyl-
5-oxopyrazolidin-2-ium-1-ides (3a–l).
4.2.1. 2-Benzylidene-3-methyl-5-oxopyrazolidin-2-ium-1-ide 3a
Light yellow solid, mp 148–150 ◦ C. Rf : 0.08 (EtOAc) IR (KBr, cm−1): 1654 (C=O), 1585, 1454, 1350, 1319,
1095, 1026, 759. 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (dd, J = 1.7, 7.8 Hz, 2H), 7.70 (s, 1H), 7.52–7.45 (m,
3H), 4.82–4.74 (m, 1H), 2.79 (dd, J = 9.1, 16.3 Hz, 1H), 2.20 (dd, J = 4.1, 16.3 Hz, 1H), 1.52 (d, J = 6.8 Hz,
3H). 13 C NMR (101 MHz, DMSO-d6) δ 183.40 (C=O), 131.94, 131.64, 131.53, 130.62, 129.21, 66.05, 37.59,
22.57.
4.2.2. 3-Methyl-2-(4-methylbenzylidene)-5-oxopyrazolidin-2-ium-1-ide 3b
Yellow solid, mp 129–132 ◦ C. Rf : 0.08 (EtOAc). IR (KBr, cm−1): 1654 (C=O), 1585, 1435, 1342, 1315, 1184,
1091, 813. 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.5 Hz, 2H), 7.32–7.22 (m, 2H), 7.07 (d, J = 10.3
Hz, 1H), 4.72–4.62 (m, 1H), 3.45 (d, J = 10.7 Hz, 1H), 2.98 (m, 1H), 2.38 (s, 3H), 1.64 (dd, J = 6.7, 11.8
Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 183.44 (C=O), 143.00 (C=N), 131.80, 129.79, 129.69, 126.75, 65.96,
37.60, 22.59, 21.88.
4.2.3. 3-Methyl-2-(3-methylbenzylidene)-5-oxopyrazolidin-2-ium-1-ide 3c
Light yellow solid, mp 136–138 ◦ C. Rf : 0.10 (EtOAc) IR (KBr, cm−1): 1662 (C=O), 1585, 1342, 1292, 1095,
1026, 1026, 786. 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 9.0 Hz, 2H), 7.00 (s, 1H), 6.65 (d, J = 9.3 Hz,
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2H), 4.61–4.54 (m, 1H), 3.07 (d, J = 8.6 Hz, 1H), 3.05 (s, 2.42 (dd, J = 4.2, 16.4 Hz, 1H), 1.59 (d, J = 6.7
Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 182.76 (C=O), 152.65 (C=N), 134.31, 134.26, 116.91, 111.28, 64.77,
39.86, 22.59, 21.88.
4.2.4. 2-(4-Methoxybenzylidene)-3-methyl-5-oxopyrazolidin-2-ium-1-ide 3d
Yellow solid, mp 114–116 ◦ C. Rf : 0.04 (EtOAc) IR (KBr, cm−1): 1662 (C=O), 1597, 1508, 1346, 1308, 1261,
1172, 1091, 1026, 732. 1 H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.0 Hz, 2H), 7.05 (s, 1H), 6.93 (d, J = 9.1
Hz, 2H), 4.70–4.58 (m, 1H), 3.84 (s, 3H(–OCH3)), 2.98 (dd, J = 9.2, 16.4 Hz, 1H), 2.42 (dd, J = 4.2, 16.4 Hz,
1H), 1.63 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz) δ 183.43, 162.61, 134.00, 132.35, 122.58, 114.43, 65.63,
55.53, 37.74, 22.71.
4.2.5. 2-(3-Methoxybenzylidene)-3-methyl-5-oxopyrazolidin-2-ium-1-ide 3e
Light yellow solid, mp 93–96 ◦ C. Rf : 0.08 (EtOAc) IR (KBr, cm−1): 1662 (C=O), 1589, 1435, 1323, 1099,
1026, 918, 786. 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.38–7.33 (m, 1H), 7.07
(s, 1H), 7.02 (dd, J = 1.7, 8.3 Hz, 1H), 4.78–4.62 (m, 1H), 3.84 (s, 3H), 3.02 (dd, J = 9.1, 16.5 Hz, 1H), 2.46
(dd, J = 4.1, 16.5 Hz, 1H), 1.67 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz) δ 183.58 (C=O), 159.72, 130.54,
130.13, 129.83, 124.51, 118.82, 115.65, 66.45, 55.66, 37.46, 22.63.
4.2.6. 3-Methyl-2-(4-(methylthio)benzylidene)-5-oxopyrazolidin-2-ium-1-ide 3f
Yellow solid, mp 120–122 ◦ C. Rf : 0.04 (EtOAc) IR (KBr, cm−1): 1654 (C=O), 1589, 1427, 1311, 1284, 1091,
1026, 819. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.7 Hz, 2H), 7.64 (s, 1H), 7.36 (d, J = 8.7 Hz,
2H), 4.81–4.67 (m, 1H), 2.77 (dd, J = 9.1, 16.3 Hz, 1H), 2.50 (s, 3H, SCH3)), 2.18 (dd, J = 4.2, 16.3 Hz, 1H),
1.50 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz) δ 182.85 (C=O), 143.54, 131.80, 130.33, 126.80, 125.39, 65.62,
37.72, 22.49, 14.37 (SCH3).
4.2.7. 3-Methyl-5-oxo-2-(4-(trifluoromethyl)benzylidene)pyrazolidin-2-ium-1-ide 3g
White solid, mp 197–199 ◦ C. Rf : 0.14 (EtOAc) IR (KBr, cm−1): 1670 (C=O), 1593, 1562, 1438, 1319, 1111,
1068, 1018, 837. 1 H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.11 (s,
1H), 4.79–4.71 (m, 1H), 3.04 (dd, J = 9.1, 16.6 Hz, 1H), 2.49 (dd, J = 4.1, 16.6 Hz, 1H), 1.71 (d, J = 6.8
Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 183.75 (C=O), 132.84, 132.42, 131.59, 130.00, 129.14, 125.74, 67.07,
37.13, 22.65.
4.2.8. 2-(4-Cyanobenzylidene)-3-methyl-5-oxopyrazolidin-2-ium-1-ide 3h
Yellow solid, mp 202–204 ◦ C. Rf : 0.09 (EtOAc) IR (KBr, cm−1): 2225(−C≡N), 1666 (C=O), 1581, 1427,
1338, 1311, 1099, 1030, 960, 833. 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6
Hz, 2H), 7.09 (s, 1H), 4.83–4.70 (m, 1H), 3.04 (dd, J = 9.1, 16.7 Hz, 1H), 2.50 (dd, J = 4.1, 16.7 Hz, 1H), 1.71
(d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 183.74 (C=O), 133.09, 132.46, 131.49, 129.98, 118.36,
114.23, 67.07, 37.14, 22.65.
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4.2.9. 2-(4-Fluorobenzylidene)-3-methyl-5-oxopyrazolidin-2-ium-1-ide 3i
Light yellow solid, mp 163–165 ◦ C. Rf : 0.08 (EtOAc) IR (KBr, cm−1): 1662 (C=O), 1597, 1578, 1346, 1307,
1234, 1161, 1091, 840. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 5.7, 9.0 Hz, 2H), 7.72 (s, 1H), 7.36 (t,
J = 9.0 Hz, 2H), 4.84–4.70 (m, 1H), 2.79 (dd, J = 9.1, 16.3 Hz, 1H), 2.20 (dd, J = 4.2, 16.3 Hz, 1H), 1.51
(d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 183.40 (C=O), 162.37, 134.18, 130.85, 127.44, 116.40,
65.97, 37.60, 22.52.
4.2.10. 2-(4-Chlorobenzylidene)-3-methyl-5-oxopyrazolidin-2-ium-1-ide 3j
White solid, mp 128–131 ◦ C. Rf : 0.08 (EtOAc) IR (KBr, cm−1): 1666 (C=O), 1589, 1489, 1427, 1307, 1091,
1026, 821, 732. 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 2H), 7.42 (dd, J = 3.7, 8.8 Hz, 2H), 7.06
(s, 1H), 4.78–4.62 (m, 1H), 3.01 (dd, J = 9.1, 16.5 Hz, 1H), 2.46 (ddd, J = 2.5, 5.5, 16.5 Hz, 1H), 1.67 (d, J
= 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 183.69 (C=O), 137.98, 132.81, 129.56, 129.26, 127.84, 66.56,
37.41, 22.53.
4.2.11. 3-Methyl-2-(4-nitrobenzylidene)-5-oxopyrazolidin-2-ium-1-ide 3k
Bright yellow solid, mp 125–128 ◦ C. Rf : 0.08 (EtOAc) IR (KBr, cm−1): 1705 (C=O), 1600, 1523, 1342, 1195,
1103, 1026, 848, 817. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 9.1 Hz, 2H), 8.34 (d, J = 9.1 Hz, 2H),
7.85 (s, 1H), 4.91–4.81 (m, 1H), 2.84 (dd, J = 9.0, 16.5 Hz, 1H), 2.27 (dd, J = 4.2, 16.5 Hz, 1H), 1.56 (d, J =
6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 192.71 (C=O), 140.56, 132.09, 131.23, 124.95, 124.33, 67.06,
37.43, 22.66.
4.2.12. 2-(4-(Dimethylamino)benzylidene)-3-methyl-5-oxopyrazolidin-2-ium-1-ide 3l
Orange solid, mp 177–180 ◦ C. Rf : 0.07 (EtOAc) IR (KBr, cm−1): 1651 (C=O), 1600, 1531, 1361, 1319, 1188,
1087, 1022, 945, 821. 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 9.0 Hz, 2H), 7.00 (s, 1H), 6.65 (d, J =
9.3 Hz, 2H), 4.61–4.54 (m, 1H), 3.07 (d, J = 8.6 Hz, 1H), 3.05 (s, 6H, N(CH3)2), 2.42 (dd, J = 4.2, 16.4 Hz,
1H), 1.59 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 182.76 (C=O), 152.65, 134.31, 134.26, 116.91,
111.28, 64.77, 39.86, 37.91, 22.45.
4.3. Synthesis of cycloaddition products 5a–l: general procedure
A solution of benzo[b]thiophene 1,1-dioxide 4 (0.25 mmol, 42 mg) and substituted pyrazolidinium ylides 3a–l
(0.25 mmol) in toluene was subjected to microwave irradiation at 125 ◦ C for 45 min. After completion of the
reaction, as indicated by TLC (n-hexane/EtOAc, 1:1), the solvent was removed under reduced pressure. The
crude product was purified by column chromatography to give compounds 5a–l.
4.3.1. (1S,4aR,9bR,10S)-1-Methyl-10-phenyl-1,2,9b,10-tetrahydrobenzo[4,5]thieno[2,3-c]pyrazolo[1,2-
a]pyrazol-3(4aH)-one 5,5-dioxide 5a
White solid, yield: 50 mg, 52%: mp 200–202 ◦ C; Rf 0.33 (EtOAc:n-hexane, 1:1). IR (KBr): 2978, 2928, 1689
(C=O), 1454, 1408, 1315 (SO2 asym), 1192, 1149 (SO2 sym), 1122, 756, 732, 702 cm−1 1 H NMR (400 MHz,
.
CDCl3) δ 8.38 (d, J = 7.9 Hz, 1H), 7.75–7.71 (m, 1H), 7.69 (dd, J = 1.3, 7.8 Hz, 1H), 7.64–7.61 (m, 1H),
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7.56 (dd, J = 1.6, 8.0 Hz, 2H), 7.44–7.34 (m, 3H), 5.67 (d, J = 8.4 Hz, 1H), 4.38 (t, J = 8.6 Hz, 1H), 4.14
(d, J = 8.8 Hz, 1H), 3.30–3.20 (m, 1H), 2.73 (dd, J = 7.2, 16.4 Hz, 1H), 2.56 (ddd, J = 1.1, 11.9, 16.4 Hz,
1H), 0.79 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.30 (C=O), 138.62, 135.30, 134.40, 132.48,
131.37, 129.40, 129.16, 128.49, 121.56, 73.33 (C–SO2), 69.07 (N–C–Ar), 60.37 (C–bridge), 55.73 (CH3 –C–N),
44.57 (CH2 –CO), 17.91. HRMS (ESI) calcd for C19 H19 N2 O3 S: 354.1116 (M + H)+ , Found 355.1120.
4.3.2. (1S,4aR,9bR,10S)-1-Methyl-10-(p-tolyl)-1,2,9b,10-tetrahydrobenzo[4,5]thieno[2,3-c]pyra-
zolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5b
Light yellow solid, yield: 65 mg, 71%: mp 151–153 ◦ C; Rf 0.36 (EtOAc:n-hexane, 1:1) IR (KBr, cm−1): 2978,
2928, 2855, 1694 (C=O), 1516, 1454, 1408, 1315 (SO2 asym), 1192, 1153 (SO2 sym), 1122, 829, 763, 736. 1 H
NMR (400 MHz, CDCl3) δ 8.36 (d, J = 7.9 Hz, 1H), 7.72–7.55 (m, 3H), 7.41 (d, J = 8.1 Hz, 2H), 7.17 (d, J
= 8.1 Hz, 2H), 5.63 (d, J = 8.4 Hz, 1H), 4.35 (t, J = 8.6 Hz, 1H), 4.07 (d, J = 8.8 Hz, 1H), 3.28–3.14 (m, 1H),
2.70 (dd, J = 7.2, 16.3 Hz, 1H), 2.52 (ddd, J = 1.1, 11.9, 16.4 Hz, 1H), 2.34 (s, 3H), 0.77 (d, J = 6.2 Hz, 3H).
13 C NMR (101 MHz, CDCl3) δ 165.26 (C=O), 139.17, 138.66, 134.33, 132.65, 132.31, 131.32, 131.26, 129.77,
128.33, 121.50, 73.28 (C–SO2), 68.90 (N–C–Ar), 60.26 (C-bridge), 55.70 (CH3 –C–N), 44.62 (CH2 –CO), 21.31,
18.02. HRMS (ESI) calcd for C20 H21 N2 O3 S: 369.1273 (M + H)+ , Found 369.1273.
4.3.3. (1S,4aR,9bR,10S)-1-methyl-10-(m-tolyl)-1,2,9b,10-tetrahydrobenzo[4,5]thieno[2,3-c]pyra-
zolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5c
White solid, yield: 70 mg, 76%: mp 169–171 ◦ C; Rf : 0.36 (EtOAc:n-hexane, 1:1) IR (KBr, cm−1): 2978,
2928, 1693 (C=O), 1408, 1315 (SO2 asym), 1192, 1153 (SO2 sym), 1064, 914, 763, 732. 1 H NMR (400 MHz,
CDCl3) δ 8.37 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 1.3, 7.7 Hz, 1H), 7.64–7.58
(m, 1H), 7.34 (d, J = 9.1 Hz, 2H), 7.30–7.23 (m, 2H), 5.65 (d, J = 8.4 Hz, 1H), 4.38 (t, J = 8.6 Hz, 1H),
4.10 (dd, J = 3.5, 7.9 Hz, 1H), 3.30–3.16 (m, 1H), 2.73 (dd, J = 7.2, 16.4 Hz, 1H), 2.55 (ddd, J = 1.1, 11.9,
16.4, Hz, 1H), 2.37 (s, 3H), 0.79 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.32 (C=O), 138.84,
138.67, 135.27, 134.35, 132.45, 131.37, 131.31, 130.11, 129.01, 125.54, 121.54, 73.33 (C–SO2), 69.09 (N–C–Ar),
60.30 (C-bridge), 55.79 (CH3 –C–N), 44.59 (CH2 –CO), 21.51, 18.01. HRMS (ESI) calcd for C20 H21 N2 O3 S:
369.1037 (M + H)+ , Found 369.1037.
4.3.4. (1S,4aR,9bR,10S)-10-(4-Methoxyphenyl)-1-methyl-1,2,9b,10-tetrahydrobenzo[4,5]thieno
[2,3-c]pyrazolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5d
White solid, yield: 85 mg, 88%: mp 161–163 ◦ C; Rf : 0.26 (EtOAc:n-hexane, 1:1) IR (KBr, cm−1): 2974,
2931, 1689 (C=O), 1612, 1516, 1408, 1311 (SO2 asym), 1253, 1226, 1122 (SO2 sym), 1030, 837, 763. 1 H NMR
(400 MHz, CDCl3) δ 8.38 (d, J = 7.9 Hz, 1H), 7.74–7.65 (m, 2H), 7.61 (d, J = 7.4 Hz, 1H), 7.45 (d, J =
8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.65 (d, J = 8.4 Hz, 1H), 4.34 (t, J = 8.6 Hz, 1H), 4.06 (d, J = 8.9
Hz, 1H), 3.81 (s, 3H), 3.26–3.16 (m, 1H), 2.71 (dd, J = 7.2, 16.4 Hz, 1H), 2.54 (ddd, J = 1.0, 12.0, 16.4 Hz,
1H), 0.78 (d, J = 6.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.19 (C=O), 160.35, 138.60, 134.41, 132.75,
131.27, 129.66, 126.94, 121.52, 114.50, 73.07 (C-SO2), 68.72 (N–C–Ar), 60.27 (C-bridge), 55.65 (OCH3), 55.40
(CH3 –C–N), 44.67 (CH2 –CO), 17.95. HRMS (ESI) calcd for C20 H21 N2 O4 S: 385.1222 (M + H)+ , Found
385.1238.
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4.3.5. (1S,4aR,9bR,10S)-10-(3-Methoxyphenyl)-1-methyl-1,2,9b,10-tetrahydrobenzo[4,5]thieno
[2,3-c]pyrazolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5e
Light yellow oil, yield: 85 mg, 89%: Rf : 0.24 (EtOAc:n-hexane, 1:1) IR (KBr, cm−1): 2974, 2931, 1693
(C=O), 1600, 1492, 1454, 1311 (SO2 asym), 1153 (SO2 sym), 1037, 910, 732. 1 H NMR (400 MHz, CDCl3) δ
8.37 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 1.3, 7.8 Hz, 1H), 7.64–7.59 (m, 1H), 7.33–7.28
(m, 1H), 7.17–7.11 (m, 2H), 6.90 (ddd, J = 1.0, 2.6, 8.3 Hz, 1H), 5.65 (d, J = 8.4 Hz, 1H), 4.37 (t, J = 8.5
Hz, 1H), 4.12 (d, J = 9.3 Hz, 1H), 3.83 (s, 3H), 3.30–3.20 (m, 1H), 2.74 (dd, J = 7.2, 16.4 Hz, 1H), 2.57
(ddd, J = 1.1, 11.8, 16.4 Hz, 1H), 0.84 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.36 (C=O),
160.10, 138.67, 136.93, 134.37, 132.31, 131.38, 131.35, 130.20, 121.55, 120.68, 114.98, 113.65, 73.39 (C–SO2),
68.91 (N–C–Ar), 60.37 (C-bridge), 55.80 (OCH3), 55.45 (CH3 –C–N), 44.54 (CH2 –CO), 18.04. HRMS (ESI)
calcd for C20 H21 N2 O4 S: 385.1222 (M + H)+ , Found 385.1238.
4.3.6. (1S,4aR,9bR,10S)-1-Methyl-10-(4-(methylthio)phenyl)-1,2,9b,10-tetrahydrobenzo[4,5]thi-
eno[2,3-c]pyrazolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5f
Light yellow solid, yield: 75 mg, 75%: mp 156–158 ◦ C; Rf 0.31 (EtOAc:n-hexane, 1:1) IR (KBr, cm−1): 2978,
2924, 1693 (C=O), 1597, 1492, 1408, 1311 (SO2 asym), 1192, 1149 (SO2 sym), 1122, 1033, 829, 736. 1 H NMR
(400 MHz, CDCl3) δ 8.37 (d, J = 7.5 Hz, 1H), 7.75–7.66 (m, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.47 (d, J = 8.4
Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 5.66 (d, J = 8.4 Hz, 1H), 4.34 (t, J = 8.6 Hz, 1H), 4.10 (dd, J = 2.6, 8.0
Hz, 1H), 3.28–3.19 (m, 1H), 2.73 (dd, J = 7.2, 16.4 Hz, 1H), 2.61–2.55 (m, 1H), 2.49 (s, 3H), 0.82 (d, J = 6.2
Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.23 (C=O), 140.25, 138.57, 134.44, 132.55, 131.65, 131.34, 128.85,
126.74, 121.55, 73.17 (C–SO2), 68.71 (N–C–Ar), 60.40 (C-bridge), 55.71 (CH3 –C–N), 44.57 (CH2 –CO), 17.99,
15.54. HRMS (ESI) calcd for C20 H21 N2 O3 S2 : 401.0994 (M + H)+ , Found 401.0978.
4.3.7. (1S,4aR,9bR,10S)-1-Methyl-10-(4-(trifluoromethyl)phenyl)-1,2,9b,10-tetrahydrobenzo[4,5]
thieno[2,3-c]pyrazolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5g
White solid, yield: 76 mg, 71%: mp 165–167 ◦ C; Rf 0.36 (EtOAc:Hex, 1:1) IR (KBr, cm−1): 2978, 2935,
1697 (C=O), 1620, 1423, 1323 (SO2 asym), 1165, 1122 (SO2 sym), 1064, 1018, 848, 736. 1 H NMR (400 MHz,
CDCl3) δ 8.36 (d, J = 7.9 Hz, 1H), 7.74–7.69 (m, 4H), 7.68–7.64 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H), 5.65 (d,
J = 8.3 Hz, 1H), 4.32 (t, J = 8.5 Hz, 1H), 4.20 (d, J = 8.7 Hz, 1H), 3.30–3.19 (m, 1H), 2.73 (dd, J = 7.1,
16.4 Hz, 1H), 2.56 (ddd, J = 1.0, 11.8, 16.5 Hz, 1H), 0.79 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3)
δ 165.24 (C=O), 145.13–145.15 (quarternary C in Ph ring, Jpara = 3.8 Hz), 139.85, 138.39, 134.52, 132.35,
131.66, 131.44, 131.36, 128.86, 127.9–119.8 (CF3 carbon, J = 271.0 Hz) 126.13, 121.57, 119.8–119.9 (β -C to
CF3 , Jmeta = 10.8 Hz), 116.3–116.5 (α-C to CF3 , Jortho = 32.5 Hz), 73.46 (C–SO2), 68.26 (N–C–Ar), 60.50
(C-bridge), 55.68 (CH3 –C–N), 44.48 (CH2 –CO), 18.08 (CH3). HRMS (ESI) calcd for C20 H18 F3 N2 O3 S:
423.0990 (M + H)+ , Found 423.0992.
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4.3.8. 4-((1S,4aR,9bR,10S)-1-methyl-5,5-dioxido-3-oxo-1,2,3,4a,9b,10-hexahydrobenzo[4,5]thieno
[2,3-c]pyrazolo[1,2-a]pyrazol-10-yl)benzonitrile 5h
White solid, yield: 65 mg, 67%: mp 230–232 ◦ C; Rf 0.21 (EtOAc:n-hexane, 1:1) IR (KBr, cm−1): 2974, 2928,
2229 (C=N), 1689 (C=O), 1408, 1315 (SO2 asym), 1192, 1149 (SO2 sym), 1122, 1064, 848, 736. 1 H NMR (400
MHz, CDCl3) δ 8.36 (d, J = 7.8 Hz, 1H), 7.79–7.73 (m, 2H), 7.72 (d, J = 2.1 Hz, 3H), 7.69 (dd, J = 5.7,
1.7 Hz, 1H), 7.66–7.61 (m, 1H), 5.66 (d, J = 8.3 Hz, 1H), 4.30 (t, J = 8.5 Hz, 1H), 4.20 (d, J = 8.7 Hz, 1H),
3.32–3.18 (m, 1H), 2.75 (dd, J = 7.1, 16.4 Hz, 1H), 2.58 (ddd, J = 1.0, 11.8, 16.4 Hz, 1H), 0.81 (d, J = 6.2
Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.21 (C=O), 141.12, 138.27, 134.62, 132.94, 132.24, 131.53, 131.37,
129.24, 121.62, 118.27, 113.38 (C≡N), 73.40 (C–SO2), 68.10 (C-bridge), 60.59 (N–C–Ar), 55.67 (CH3 –C–N),
44.42 (CH2 –CO), 18.07 (CH3). HRMS (ESI) calcd for C20 H18 N3 O3 S: 380.1069 (M + H)+ , Found 380.1065.
4.3.9. (1S,4aR,9bR,10S)-10-(4-Fluorophenyl)-1-methyl-1,2,9b,10-tetrahydrobenzo[4,5]thieno[2,3-
c]pyrazolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5i
White solid, yield: 65 mg, 70%: mp 174–176 ◦ C; Rf : 0.29 (EtOAc:n-hexane, 1:1) IR (KBr, cm−1): 2982,
2935, 1685 (C=O), 1508, 1454, 1408, 1315 (SO2 asym), 1226, 1122 (SO2 sym), 844, 763. 1 H NMR (400 MHz,
CDCl3) δ 8.38 (d, J = 7.9 Hz, 1H), 7.75–7.71 (m, 1H), 7.69 (dd, J = 7.7, 1.4 Hz, 1H), 7.64–7.59 (m, 1H),
7.57–7.53 (m, 2H), 7.10 (t, J = 8.6 Hz, 2H), 5.65 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 8.7 Hz, 1H), 4.11 (d, J =
8.9 Hz, 1H), 3.27–3.17 (m, 1H), 2.73 (dd, J = 7.2, 16.4 Hz, 1H), 2.56 (ddd, J = 1.1, 11.9, 16.4 Hz, 1H), 0.79
(d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.17 (C=O), 138.51, 134.51, 132.56, 131.37, 131.19,
130.25, 130.17, 121.56, 116.30, 116.08, 73.29 (C–SO2), 68.34 (C-bridge), 60.39 (N–C–Ar), 55.64 (CH3 –C–N),
44.61 (CH2 –CO), 17.98 (CH3). HRMS (ESI) calcd for C19 H18 FN2 O3 S: 373.1023 (M + H)+ , Found 373.1022.
4.3.10. (1S,4aR,9bR,10S)-10-(4-Chlorophenyl)-1-methyl-1,2,9b,10-tetrahydrobenzo[4,5]thieno[2,3-
c]pyrazolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5j
White solid, yield: 67 mg, 69%: mp 180–182 ◦ C; Rf : 0.29 (EtOAc:n-hexane, 1:1) IR (KBr, cm−1): 2978,
2931, 1685 (C=O), 1492, 1408, 1315 (SO2 asym), 1192, 1149 (SO2 sym), 910, 732. 1 H NMR (400 MHz,
CDCl3) δ 8.38 (d, J = 7.9 Hz, 1H), 7.76–7.72 (m, 1H), 7.70 (dd, J = 7.7, 1.4 Hz, 1H), 7.65–7.59 (m, 1H),
7.52 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 5.65 (d, J = 8.4 Hz, 1H), 4.31 (t, J = 8.7 Hz, 1H), 4.11
(dd, J = 2.7, 8.0 Hz, 1H), 3.29–3.18 (m, 1H), 2.74 (dd, J = 7.2, 16.4 Hz, 1H), 2.57 (ddd, J = 16.4, 11.9,
1.1, Hz, 1H), 0.81 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.19 (C=O), 138.44, 135.31, 134.52,
133.98, 132.48, 131.41, 131.35, 129.78, 129.42, 121.58, 73.29 (C–SO2), 68.30 (C-bridge), 60.49 (N–C–Ar), 55.65
(CH3 –C–N), 44.57 (CH2 –CO), 18.03 (CH3). HRMS (ESI) calcd for C19 H18 ClN2 O3 S: 389.0727 (M + H)+ ,
Found 389.0724.
4.3.11. (1S,4aR,9bR,10S)-1-Methyl-10-(4-nitrophenyl)-1,2,9b,10-tetrahydrobenzo[4,5]thieno[2,3-c]
pyrazolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5k
Orange oil, yield: 70 mg, 71%: Rf : 0.24 (EtOAc:n-hexane, 1:1). IR (KBr, cm−1): 2978, 2928, 1697 (C=O),
1523, 1454, 1408, 1350, 1315 (SO2 asym), 1192, 1153 (SO2 sym), 860, 736. 1 H NMR (400 MHz, CDCl3) δ 8.37
(d, J = 7.8 Hz, 1H), 8.27 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H), 7.77–7.69 (m, 2H), 7.64 (t, J = 7.5
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Hz, 1H), 5.67 (d, J = 8.1 Hz, 1H), 4.32 (dd, J = 8.1, 8.6 Hz, 1H), 4.26 (d, J = 8.7 Hz, 1H), 3.34–3.20 (m, 1H),
2.76 (dd, J = 7.1, 16.4 Hz, 1H), 2.59 (dd, J = 11.8, 16.4 Hz, 1H), 0.82 (d, J = 6.2 Hz, 3H). 13 C NMR (101
MHz, CDCl3) δ 165.23 (C=O), 148.56, 143.06, 138.26, 134.64, 132.23, 131.55, 131.37, 129.45, 124.34, 121.63,
73.46 (C–SO2), 67.91 (C-bridge), 60.64 (N–C–Ar), 55.69 (CH3 –C–N), 44.41 (CH2 –CO), 18.11 (CH3). HRMS
(ESI) calcd for C19 H18 N3 O5 S: 400.0967 (M + H)+ , Found 400.0949.
4.3.12. (1S,4aR,9bR,10S)-10-(4-(Dimethylamino)phenyl)-1-methyl-1,2,9b,10-tetrahydrobenzo
[4,5]thieno[2,3-c]pyrazolo[1,2-a]pyrazol-3(4aH)-one 5,5-dioxide 5l
White solid, yield: 70 mg, 71%: mp 205–207 ◦ C; Rf : 0.20 (EtOAc:n-hexane, 1:1). IR (KBr, cm−1): 2978,
2928, 1685 (C=O), 1612, 1523, 1408, 1311 (SO2 asym), 1192 (SO2 sym), 910, 825, 732. 1 H NMR (400 MHz,
CDCl3) δ 8.39 (d, J = 7.9 Hz, 1H), 7.76–7.65 (m, 3H), 7.60 (t, J = 7.7 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H),
5.65 (d, J = 8.4 Hz, 1H), 4.35 (t, J = 8.6 Hz, 1H), 4.02 (d, J = 9.0 Hz, 1H), 3.24–3.16 (m, 1H), 2.98 (s, 6H),
2.71 (dd, J = 7.2, 16.3 Hz, 1H), 2.54 (dd, J = 12.0, 16.3 Hz, 1H), 0.80 (d, J = 6.1 Hz, 3H). 13 C NMR (101
MHz, CDCl3) δ 165.28 (C=O), 145.49, 138.66, 136.64, 136.26, 134.37, 132.93, 131.29, 131.21, 129.36, 121.52,
72.87 (C–SO2), 68.97 (C-bridge), 60.17 (N–C–Ar), 55.64 (CH3 –C–N), 44.71 (CH2 –CO), 18.00 (CH3). HRMS
(ESI) calcd for C21 H24 N3 O3 S: 398.1538 (M + H)+ , Found 398.1537.
Acknowledgments
¨
˙
The Scientific and Technological Research Council of Turkey (TUBITAK) (grant no. 113Z866) is gratefully
acknowledged for financial support. We thank Dr Benson M Kariuki (School of Chemistry, Cardiff University,
Cardiff, UK) for X-ray diffraction data of 5i.
Supporting information
Crystallographic data of 5i have been deposited at the CCDC, with reference number 1024964, and can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data request/cif.
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