Reactions of 3-methyl-2-oxopyrazolidinium ylides with phenylsulfonylacrylonitriles

Article abstract of DOI:10.1016/j.tet.2015.10.022

A series of methyl oxopyrazolidinium ylides was reacted with (E)-3-(2-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile and 2-phenylsulfonyl acrylonitrile to give rise to (1R,2S,3S)-5-methyl-7-oxo-1,3-p-substituteddiphenyl-2-(phenylsulfonyl)-hexahydropyrazolo[1,2-a]pyrazole-2-carbonitriles through a sequential reaction accompanying methyl pyrazolone and o-quinone methide releases possibly instead of an anticipated cycloaddition process and 1,3-dipolar cycloaddition route. All the new products were identified by means of spectral/physical characteristics including X-ray diffraction data and HRMS measurements. In addition, a plausible mechanism is proposed for hydroxyphenyl substituted acrylonitrile case.

Full text of DOI:10.1016/j.tet.2015.10.022

Tetrahedron xxx (2015) 1e6
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Reactions of 3-methyl-2-oxopyrazolidinium ylides with
phenylsulfonylacrylonitriles
*
€ €
ꢀ
ꢀ
Yas¸ ar Durust , Eda Sagırlı, Akın Sagırlı
_
Department of Chemistry, Abant Izzet Baysal University, Bolu, TR-14280, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of methyl oxopyrazolidinium ylides was reacted with (E)-3-(2-hydroxyphenyl)-2-(phenyl-
sulfonyl)acrylonitrile and 2-phenylsulfonyl acrylonitrile to give rise to (1R,2S,3S)-5-methyl-7-oxo-1,3-p-
substituteddiphenyl-2-(phenylsulfonyl)-hexahydropyrazolo[1,2-a]pyrazole-2-carbonitriles through a se-
quential reaction accompanying methyl pyrazolone and o-quinone methide releases possibly instead of
an anticipated cycloaddition process and 1,3-dipolar cycloaddition route. All the new products were
identified by means of spectral/physical characteristics including X-ray diffraction data and HRMS
measurements. In addition, a plausible mechanism is proposed for hydroxyphenyl substituted acrylo-
nitrile case.
Received 15 August 2015
Received in revised form 25 September 2015
Accepted 6 October 2015
Available online xxx
Keywords:
Pyrazolidinium
Azomethine ylide
Phenylsulfonyl acrylonitrile
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Pyrazolidinium ylides have been studied rarely in terms of 1,3-
dipolar cycloadditions. 1,3-Dipolar cycloaddition of these azome-
Heterocycles containing a pyrazolone ring have been attracting
continuing interest due to their diverse medicinal chemistry ap-
plications such as antipyretic and antiparasitic agents (Fig. 1). Re-
cently, some sulfanyl pyrazolone derivatives, which can be used
against Lou Gehrig’s disease (ALS), a fatal neurodegenerative dis-
ease causing muscle loss and paralysis, were reported (Fig. 2).1e12
thine imines to acrolein, diphenylsulfonyl alkenes, phenyl acety-
lene, ethyl propiolate, maleimides and fullerenes are reported.13e20
Taking account of the above considerations and our continuing
interest in the cycloadditions of various dipolar species including
azomethine ylides,21e23 we herein focused on the reaction between
3-methyl-2-oxopyrazolidinium ylides 1 and highly electron de-
ficient (E)-3-(2-hydroxyphenyl or 4-substitutedphenyl)-2-(phe-
nylsulfonyl)acrylonitriles 2,3.
2. Results and discussion
The methyl oxopyrazolidinium ylides 1aeg, were prepared by
reacting ethyl but-2-enoate with hydrazine hydrate, then with the
substituted benzaldehydes carrying both electron withdrawing and
electron donating groups, according to the procedure previously
reported24 and their structures were confirmed by spectral/physi-
cal characteristics.
Fig. 1. Some biologically important pyrazolone derivatives.
* Corresponding author. Tel.: þ90 374 254 1243; fax: þ90 374 253 4642; e-mail
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address: yasardurust@ibu.edu.tr (Y. Durust).
Fig. 2. Sulfanyl pyrazolones as anti ALS agent.
http://dx.doi.org/10.1016/j.tet.2015.10.022
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2
Pyrazolidinium ylides 1aeg underwent 1,3-dipolar cycloaddi-
4 obtained through Methods A and B were found exactly identical
in terms of spectroscopic and physical data.
Since most of the reaction products are solid except 4e, we were
able to obtain fine crystals of 4c providing its X-ray diffraction data
(Fig. 3), thus, we can establish the exact structure of the compounds
4aeg.
The reaction sequence in Route B is most probably initiated by
the attack of the nucleophilic carbon of the tautomeric form B of 3-
(2-hydroxyphenyl)phenyl sulfonyl acrylonitrile 3 on the azome-
thine imine carbon of the ylide 1 thus affording an intermediate C.
tion (Method A) with acrylonitriles 2 to give only the regioisomers
4. But, however, ylides 1aeg underwent a completely different
reaction sequence (Method B) with (E)-3-(2-hydroxyphenyl)-2-
(phenylsulfonyl)acrylonitrile 3, at which, under reflux condition in
toluene, methyl pyrazolone and ortho-quinone methide losses most
likely occur leading to regioisomers 4aeg also (Scheme 1). In this
way, both phenyl groups are interestingly originated from the
starting pyrazolidinium ylide 1. Yields obtained from Method A are
higher.
Scheme 1. Synthesis of 4aeg.
The only difference is to use p-substituted phenyl sulfonyl ac-
rylonitriles in Method A and all the experimental procedure is the
same including work-up and purification, and overall, end products
Then, negatively charged nitrogen of the pyrazolone may attack
once again on the azomethine imine carbon of the second ylide
molecule producing intermediate D. Cyclization of
D
is
Fig. 3. X-ray ORTEP view of 4c.
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Y. Durust et al. / Tetrahedron xxx (2015) 1e6
3
accompanied by the release of methyl pyrazolone E which might be
oxidized to unsaturated pyrazolone thus having a fully delocalized
tautomeric hydroxy form with exocyclic methylene. Subsequently,
after the cyclization of the intermediate D into F an ortho-quinone
and biphosphate ion buffers.25e27 The thermal formation of o-
quinone methides by heating of 4H-1,2-benzoxazines bearing var-
ious substituents on the benzene ring through a retro-DielseAlder
reaction was also reported.28
Scheme 2. Proposed mechanism leading to the formation of 4aeg by Method B.
methide release may occur to give rise to dipolar intermediate H
which finally undergoes a cyclization route to produce the target
compounds 4 (Scheme 2). Proposed o-quinone methide in this
mechanism as a short-lived transient species was previously re-
ported to have been formed by a flash photolytic transformation of
o-hydroxybenzyl alcohol, o-hydroxybenzyl, p-cyanophenyl ether,
and (o-hydroxybenzyl)trimethylammonium iodide in aqueous
perchloric acid and sodium hydroxide solutions, and in acetic acid
3. Conclusions
In summary, within this report we introduced a synthetic protocol
that allows access to a series of polysubstituted pyrazolopyrazolones,
using both [1,3]-dipolar cycloaddition and sequential nucleophilic
addition-elimination type reactions of 3-methyl-2-oxopyra
zolidinium ylides with phenylsulfonylacrylonitriles. Later may be
consideredfirstexampleintheliteraturetothebestofourknowledge.
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4
4. Experimental section
129.0, 128.8, 126.8, 125.5, 112.9, 80.9, 72.6, 62.0, 53.1, 36.1, 22.4.
HRMS (ESI) calcd for C26H24N3O3S: 458.1538 (MþHþ), found
4.1. General
458.1520.
Reagents were purchased from commercial sources and were
used as received. Melting points were recorded in capillary tubes
on a Meltemp apparatus and are uncorrected.1H NMR and 13C NMR
spectra were recorded on JEOL and VARIAN spectrometers oper-
ating at 400 MHz (1H) and 100 MHz (13C) in CDCl3.1H NMR chemical
shifts are reported in parts per million relative to tetramethylsilane
(TMS) with the solvent resonance employed as the internal stan-
dard (CDCl3 at 7.26 ppm). Data are reported as follows: chemical
shift (multiplicity, coupling constant(s) in Hz, integration). Multi-
plicities are abbreviated as follows: s¼singlet, br s¼broad singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet. 13C NMR chemical
shifts are reported in parts per million from tetramethylsilane
(TMS) with the solvent resonance as the internal standard (CDCl3 at
77.20 ppm). IR spectra were recorded in KBr on Shimadzu spec-
trometer; ṽ in cmꢀ1. HRMS measurements were performed on
a Waters Synapt spectrometer using the ionization modes speci-
fied. Routine TLC analyses were carried out on pre-coated silica gel
plates with fluorescent indicator. Flash column chromatography
was performed on silica gel (230e400 Mesh ASTM). A rotary TLC
apparatus (Chromatotron) was utilized for further separation and
purifications. Stain solutions of potassium permanganate and io-
dine were used for visualization of the TLC spots.
4.2.2.2. (1R,2S,3S)-5-Methyl-7-oxo-2-(phenylsulfonyl)-1,3-di-p-
tolylhexahydropyrazolo[1,2-a]pyrazole-2-carbonitrile (4b). Yellow
solid, mp 176e178 ꢁC; Rf 0.50 (EtOAc:n-hexane, 1:1). IR (KBr, cmꢀ1):
3078, 2921, 2368 (CN), 1726 (C]O), 1330, 1155 (SO2). 1H NMR
(400 MHz, CDCl3)
d
8.14e8.13 (m, 2H), 7.84 (t, J¼7.5 Hz, 1H),
7.67e7.65 (m, 2H), 7.39 (d, J¼1.1 Hz, 2H), 7.16 (d, J¼8.2 Hz, 2H), 7.01
(d, J¼7.8 Hz, 2H), 6.73 (d, J¼8.2 Hz, 2H), 5.67 (s, 1H), 4.72 (s, 1H),
3.43 (dd, J¼13.5, 7.0 Hz, 1H), 3.14 (dd, J¼17.8, 8.9 Hz, 1H), 2.37 (dd,
J¼19.2, 16.4 Hz, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 1.36 (d, J¼6.8 Hz, 3H).
13C NMR (101 MHz, CDCl3)
d 175.4, 155.5, 154.9, 147.5, 138.3, 135.3,
134.3, 130.4, 129.5, 129.1, 126.7, 125.5, 117.3, 117.1, 81.0, 72.4, 61.8,
53.0, 36.1, 22.3, 21.4, 21.2. HRMS (ESI) calcd for C28H28N3O3S:
486.1851(MþHþ), found 486.1865.
4.2. General procedure for the preparation of the compounds
4aeg
4.2.1. Method A. A solution of (E)-3-(4-substitutedphenyl)-2-
(phenylsulfonyl)acrylonitrile 2 (0.25 mmol) and substituted pyr-
azolidinium ylide 1 (0.25 mmol) in toluene was refluxed in toluene
for 12 h. 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 chromatog-
raphy to give compound 4.
4.2.2.3. 4,4’-((1R,2S,3S)-2-Cyano-5-methyl-7-oxo-2-(phenyl-
sulfonyl)hexahydropyrazolo[1,2-a]pyrazole-1,3-diyl)dibenzonitrile
(4c). White solid, mp 181e183 ꢁC; Rf 0.20 (EtOAc:n-hexane, 1:1). IR
(KBr, cmꢀ1): 3071, 2928, 2230 (CN), 1723 (C]O), 1347, 1159 (SO2).
4.2.2. Method B. A solution of (E)-3-(2-hydroxyphenyl)-2-(phe-
nylsulfonyl)acrylonitrile 3 (0.25 mmol, 71 mg) and substituted
pyrazolidinium ylides 1aeg (0.25 mmol) in toluene was refluxed in
toluene for 12 h. After the completion of the reaction, as indicated
by TLC (n-hexane/EtOAc, 1:1), the solvent was removed under the
reduced pressure. The crude product was purified by column
chromatography to give compound 4aeg.
1H NMR (400 MHz, CDCl3)
d
8.11 (dd, J¼8.5, 1.2 Hz, 2H), 7.92 (t,
J¼7.5 Hz, 1H), 7.78e7.73 (m, 2H), 7.68 (d, J¼8.8 Hz, 2H), 7.63 (d,
J¼7.4 Hz, 2H), 7.53 (d, J¼8.6 Hz, 2H), 6.88 (d, J¼8.2 Hz, 2H), 5.74 (s,
1H), 4.80 (s, 1H), 3.50e3.39 (m, 1H), 3.17 (dd, J¼18.1, 8.8 Hz, 1H),
2.42 (dd, J¼18.1, 2.4 Hz, 1H), 1.43 (d, J¼6.8 Hz, 3H). 13C NMR
(101 MHz, CDCl3) d 176.1,140.2,137.7,136.6,133.7,132.8,132.7,131.3,
130.4, 127.5, 118.0, 118.02, 114.2, 113.3, 112.4, 80.4, 71.7, 61.8, 53.3,
35.4, 22.3. HRMS (ESI) calcd for C28H22N5O3S: 508.1443 (MþHþ),
found 508.1461.
4.2.2.1. (1R,2S,3S)-5-Methyl-7-oxo-1,3-diphenyl-2-(phenyl-
sulfonyl)hexahydropyrazolo[1,2-a]pyrazole-2-carbonitrile(4a). Light
yellow solid, mp 163e165 ꢁC; Rf 0.46 (EtOAc:n-hexane, 1:1). IR (KBr,
cmꢀ1): 3071, 2923, 2855, 2238 (CN), 1723 (C]O), 1331, 1154 (SO2).
1H NMR (400 MHz, CDCl3)
d
8.13 (dd, J¼8.4, 1.1 Hz, 2H), 7.85 (t,
J¼7.5 Hz, 1H), 7.70 (t, J¼7.9 Hz, 2H), 7.57e7.49 (m, 2H), 7.40e7.33
(m, 3H), 7.23e7.20 (m, 3H), 6.86 (dd, J¼7.6, 2.0 Hz, 2H), 5.72 (s, 1H),
4.76 (s, 1H), 3.48e3.42 (m, 1H), 3.16 (dd, J¼17.9, 8.9 Hz, 1H), 2.37
(dd, J¼17.9, 2.7 Hz, 1H), 1.38 (d, J¼6.8 Hz, 3H). 13C NMR (101 MHz,
4.2.2.4. (1R,2S,3S)-1,3-Bis(4-chlorophenyl)-5-methyl-7-oxo-2-
(phenylsulfonyl)hexahydropyrazolo[1,2-a]pyrazole-2-carbonitrile
(4d). Light yellow solid, mp 174e176 ꢁC; Rf 0.52 (EtOAc:n-hexane,
1:1). IR (KBr, cmꢀ1): 3071, 2928, 2245 (CN), 1733 (C]O), 1333, 1159
CDCl3)
d
175.7, 136.0, 135.6, 134.5, 132.9, 131.3, 130.0, 129.9, 129.5,
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5
(SO2). 1H NMR (400 MHz, CDCl3)
d
8.12 (t, J¼8.2 Hz, 3H), 7.87 (t,
4.2.2.7. (1R,2S,3S)-5-Methyl-1,3-bis(4-nitrophenyl)-7-oxo-2-
(phenylsulfonyl)hexahydropyrazolo[1,2-a]pyrazole-2-carbonitrile
(4g). Yellow solid, mp 120e122 ꢁC; Rf 0.20 (EtOAc:n-hexane, 1:1).
IR (KBr, cmꢀ1): 3078, 2921, 2361 (CN), 1733 (C]O), 1350, 1159
J¼7.4 Hz, 1H), 7.71 (t, J¼7.7 Hz, 3H), 7.55 (t,J¼7.7 Hz, 2H), 7.19 (d,
J¼8.4 Hz, 2H), 6.75 (d, J¼8.5 Hz, 2H), 5.68 (s, 1H), 4.71 (s, 1H),
3.48e3.36 (m, 1H), 3.14 (dd, J¼18.0, 8.8 Hz, 1H), 2.37 (dd, J¼17.9,
2.5 Hz,1H),1.38 (d, J¼6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d
175.7,
(SO2). 1H NMR (400 MHz, CDCl3)
d
8.23 (d, J¼8.7 Hz, 2H), 8.11 (t,
147.5, 136.2, 135.3,134.3,134.0,131.2, 130.1, 129.5,129.1, 128.1, 125.5,
117.1, 112.7, 80.7, 71.9, 61.5, 53.1, 35.7, 22.3. HRMS (ESI) calcd for
J¼9.0 Hz, 4H), 7.94 (t, J¼7.5 Hz, 1H), 7.77 (t, J¼7.8 Hz, 2H), 7.71
(d, J¼7.8 Hz, 2H), 6.96 (d, J¼8.6 Hz, 2H), 5.80 (d, J¼7.8 Hz, 1H),
4.88 (s, 1H), 3.52e3.41 (m, 1H), 3.20 (dd, J¼18.2, 8.8 Hz, 1H), 2.44
(d, J¼18.1 Hz, 1H), 1.45 (d, J¼6.8 Hz, 3H). 13C NMR (101 MHz,
C
26H22Cl2N3O3S: 526.0741(MþHþ), found 526.0735.
CDCl3)
d 176.1, 148.9, 148.1, 142.0, 139.5, 136.8, 133.7, 131.3, 130.4,
127.8, 124.2, 124.1, 117.1, 112.4, 80.4, 71.5, 61.7, 53.4, 35.4, 22.3.
HRMS (ESI) calcd for C26H21N5O7S: 548.1240 (MþHþ), found
548.1234.
Supporting information
X-Ray diffraction data of the compound 4c have been deposited
at the Cambridge Crystallographic Data Centre and assigned CCDC
1045939 deposition number. It can be obtained free of charge from
http://www.ccdc.cam.ac.uk/data_request/cif.
4.2.2.5. (1R,2S,3S)-1,3-Bis(4-methoxyphenyl)-5-methyl-7-oxo-2-
(phenylsulfonyl)hexahydropyrazolo[1,2-a]pyrazole-2-carbonitrile
(4e). Light yellow oil. Rf 0.30 (EtOAc:n-hexane, 1:1). IR (KBr, cmꢀ1):
2921, 2853, 2361 (CN), 1743 (C]O), 1381, 1162 (SO2). 1H NMR
Acknowledgements
€ _
TUBITAK (Turkish Scientific and Technological Research Council,
(400 MHz, CDCl3)
d
8.11 (dd, J¼8.5, 1.2 Hz, 2H), 7.83 (t, J¼7.5 Hz, 1H),
grant no. 113Z866) is gratefully acknowledged for financial support.
Authors thank Dr. Yunus Zorlu (Gebze Technical University, Kocaeli,
Turkey) for obtaining X-ray data.
7.68 (t, J¼7.9 Hz, 2H), 7.42 (d, J¼5.0 Hz, 2H), 6.87 (d, J¼9.0 Hz, 2H),
6.79 (d, J¼8.8 Hz, 2H), 6.72 (d, J¼9.0 Hz, 2H), 5.66 (s, 1H), 4.70 (s,
1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.46e3.37 (m, 1H), 3.13 (dd, J¼17.8,
8.9 Hz, 1H), 2.35 (dd, J¼17.8, 2.8 Hz, 1H), 1.35 (d, J¼6.8 Hz, 3H). 13
C
References and notes
NMR (101 MHz, CDCl3)
d 175.3, 160.6, 159.8, 135.9, 134.6, 131.2,
130.0,128.1, 127.8, 124.5,114.1,113.2, 81.0, 72.3, 61.5, 55.3, 55.2, 52.9,
36.1, 22.3. HRMS (ESI) calcd for C28H28N3O5S: 518.1750 (MþHþ),
found 518.1747.
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2H), 7.91 (t, J¼7.5 Hz, 1H), 7.75 (t, J¼7.9 Hz, 2H), 7.71e7.61 (m, 4H),
7.50 (d, J¼8.1 Hz, 2H), 6.92 (d, J¼8.4 Hz, 2H), 5.76 (s,1H), 4.83 (s,1H),
3.52e3.39 (m, 1H), 3.18 (dd, J¼18.0, 8.8 Hz, 1H), 2.41 (dd, J¼18.0,
2.5 Hz,1H),1.42 (d, J¼6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 176.0,
147.5,139.2,136.7,136.4,134.3,133.9,131.3,130.3,129.5,129.1,127.2,
125.9, 125.5, 117.1, 112.5, 80.5, 71.8, 61.7, 53.2, 35.6, 22.3. HRMS (ESI)
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