Stereoselective thermal isomerization of bis(spiropyrazolone)cyclopropanes into (4 Z)-4-[(Pyrazol-4-yl)methylene]pyrazolones

Article abstract of DOI:10.1055/s-0032-1318456

Thermal isomerization of bis(spiropyrazolone)cyclopropanes in DMSO at 100 °C results in highly efficient formation of the corresponding 4-[(pyrazol-4-yl)methylene]pyrazolones in 90-98% yields after only five minutes. NMR and single-crystal X-ray diffracti

Full text of DOI:10.1055/s-0032-1318456

LETTER
▌827
lSettteer reoselective Thermal Isomerization of Bis(spiropyrazolone)cyclopropanes
into (4Z)-4-[(Pyrazol-4-yl)methylene]pyrazolones
Thermal Isomerization of Bis(spiropyrazolone)cyclopropanes
Evgeniya O. Dorofeeva,*a Michail N. Elinson,a Anatoly N. Vereshchagin,a Albert G. Nigmatov,a
Ivan S. Bushmarinov,b Gennady I. Nikishina
a
N. D. Zelinsky Institute of Organic Chemistry, Leninsky pr. 47, Moscow, 119991, Russian Federation
Fax +7(499)1355328; E-mail: e.o.dorofeeva@gmail.com
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilova str. 28, Moscow, 119991, Russian Federation
Fax +7(499)1355085; E-mail: ib@ineos.ac.ru
Received: 30.01.2013; Accepted after revision: 22.02.2013
indirect electrochemical oxidation of easily accessible
Abstract: Thermal isomerization of bis(spiropyrazolone)cyclopro-
4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) 1 in methanol
panes in DMSO at 100 °C results in highly efficient formation of
in an undivided cell in the presence of sodium bromide re-
sulted in exclusive formation of the R*,R*-isomer of
the corresponding 4-[(pyrazol-4-yl)methylene]pyrazolones in 90–
98% yields after only five minutes. NMR and single-crystal X-ray
diffraction analysis indicate stereoselective formation of the Z-iso- bis(spiro-2,4-dihydro-3H-pyrazol-3-one)cyclopropanes 2
mers.
in 85–96% yields (Scheme 1).
Key words: isomerization, ring opening, spiro compounds, cyclo-
propane, pyrazolone
R
R
OH
N Ph
O
The cyclopropane subunit plays a prominent role in or-
ganic chemistry. The high degree of reactivity present in
cyclopropane due to its strained structure and unique
bonding characteristics determine a variety of chemical
transformations available for the three-membered ring.1 A
significant synthetic application of cyclopropane deriva-
tives involves ring-opening rearrangements that can lead
to molecular structures inaccessible by other methods.2
The ever-growing importance of thermal cyclopropane re-
arrangements, including selective cyclopropane-to-
propene isomerizations in various synthetic applications,
attests to uniqueness and convenience of methodology es-
pecially when the starting cyclopropane is more readily
available than isomeric propene.3
electrolysis, 2.5 F/mol
MeOH, NaBr
N
N
N Ph
N
N
N
N
OH
O
Ph
Ph
1
2
Scheme 1
Bis(spiropyrazolone)cyclopropanes of type 2 were isolat-
ed by direct filtration of the reaction mixture and did not
require any further purification. Nevertheless, we noted
that recrystallization of pure 2a from boiling ethanol re-
sulted in formation of an impurity readily visible in the 1H
NMR spectrum of the recrystallized product. The above
observation led to the conclusion that bis(spiropyrazo-
lone)cyclopropanes 2 are capable of temperature-promot-
ed rearrangement with formation of an apparently single
isomeric product.
Among different types of cyclopropane fragments a spiro-
cyclopropyl moiety jointed with a heterocyclic counter-
part has attracted particular attention due to its synthetic
utility and wide number of pharmacological applications.4
The pyrazolin-5-one ring is one such heterocyclic motif
with pyrazolone derivatives possessing a wide range of bi-
ological effects5 such as analgesic, antipyretic,6 antiviral,7
and antitumor activity.8 Moreover, a bis(spiropyrazo-
lone)cyclopropane was patented recently as an advanced
glycation end product (AGE) formation inhibitor intended
for treatment of human schizophrenia.9
A detailed literature search revealed only two brief men-
tions of thermal rearrangements of analogous cyclopro-
panes.11,12 Westoo suggested that selected representatives
of bis(spiro-3H-pyrazol-3-one)cyclopropanes isomerized
into linear conjugated 4-[(pyrazol-4-yl)methylene]pyr-
azolones after 20–24 hours in refluxing ethanol or boiling
at 95 °C in a dioxane–water mixture, respectively.11 Later,
Hennig and Haessner mentioned the formation of 4-[(pyr-
azol-4-yl)methylene]pyrazolone after recrystallizing un-
In a course of our studies on electrocatalytic synthesis of
cyclopropane derivatives, we recently reported an effi-
cient stereoselective approach to the corresponding
bis(spiropyrazolone)cyclopropanes.10 It was found that
substituted
bis(spiro-3H-pyrazol-3-one)cyclopropane
from ethanol.12 Although both papers suggest the possibil-
ity of a thermal ring-opening cyclopropane-to-propene
isomerization for bis(spiropyrazolone)cyclopropanes,
they variously lack product characterization details, yield
information or describe a very limited number of exam-
ples. Considering the utility of 4-[(pyrazol-4-yl)methy-
lene]pyrazolone derivatives as dyestuffs,13 their potential
SYNLETT 2013, 24, 0827–0830
Advanced online publication: 14.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318456; Art ID: ST-2013-D0099-L
© Georg Thieme Verlag Stuttgart · New York

828
E. O. Dorofeeva et al.
LETTER
biomedical applications, and the ready availability of with high-boiling polar aprotic solvents. Thus, heating 2a
bis(spiropyrazolone)cyclopropanes by our electrocatalyt- at 100 °C in DMF for 15 minutes or in DMSO for five
ic approach (Scheme 1), we were prompted to develop minutes resulted in complete consumption of starting
this thermal isomerization protocol to 4-[(pyrazol-4-yl)- compound and exclusive formation of 4-[(pyrazol-4-
methylene]pyrazolones 3 (Scheme 2).
yl)methylene]pyrazolone 3a (Table 1, entries 8 and 9).
Moreover, these conditions allowed for a 20-fold decrease
of the solvent amount required.
R
R
Under the optimal conditions (0.5 mL of DMSO at 100 °C
for 5 min) the thermal isomerization of bis(spiropyrazo-
lone)cyclopropanes 2a–h afforded the corresponding 4-
[(pyrazol-4-yl)methylene]pyrazolones 3a–h in 90–98%
yields (Scheme 2, Table 2). The developed isomerization
process offers a unique approach to 4-[(pyrazol-4-
yl)methylene]pyrazolone derivatives bearing a wide
range of aryl substituents. Moreover, products 3a–h can
be isolated by simple water-assisted precipitation from the
reaction mixture and do not require any further purifica-
tion.
O
100 °C, 5 min
N
N
N
N
Ph
DMSO
N
N
N
N
O
HO
O
Ph
Ph
Ph
2
3
a R = H
e R = 4-Me
f R = 2-MeO
g R = 4-Et
b R = 2-Cl
c R = 3-Cl
d R = 3-Br
h R = 4-t-Bu
Scheme 2
Table 2 Thermal Isomerization of 2a–h into 3a–ha
First, to validate our initial observations and evaluate the
synthetic potential of this conversion, a thermal isomeri-
zation study of bis(spiropyrazolone)cyclopropane 2a was
undertaken (Table 1). Heating 2a in refluxing water for
two hours did not result in any conversion of the starting
compound probably due to its insolubility (Table 1, entry
1). After two hours under reflux conditions in ethanol or
n-propanol 2a was selectively converted into 4-[(pyrazol-
4-yl)methylene]pyrazolone 3a in 25% and 55% yields, re-
spectively (Table 1, entries 2 and 3). As for aprotic sol-
vents, a solution of 2a in refluxing chloroform was
unreactive; although in refluxing acetone or acetonitrile,
selective conversion into 3a was observed in 10% and
27% yield, respectively (Table 1, entries 4–6). Heating 2a
in toluene to 100 °C similarly resulted in formation of 3a
in 10% yield (Table 1, entries 7); while increased reaction
times and temperatures did not significantly influence on
the yield of 3a but led to considerable amounts of decom-
position products. A dramatic improvement was achieved
Entry
Product
R
Yield (%)b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
H
98
96
98
97
96
98
96
90
2-Cl
3-Cl
3-Br
4-Me
2-MeO
4-Et
3g
3h
4-t-Bu
a Conditions: 2 (1 mmol), DMSO (0.5 mL), 100 °C, 5 min.
b Yield of isolated product.
It should be mentioned that the 4-[(pyrazol-4-yl)methy-
lene]pyrazolones 3a–h could exist as a pair of isomers
with either Z- or E-configuration of the double bond.
However, in the NMR spectra of 3a–h only a single set of
signals was identified indicating stereoselective formation
Table 1 Thermal Isomerization of 2a into 3a in Different Solventsa
Entry
Solvent
Temp (°C) Time (min) Conv. of 2a (%)b
1
1
2
3
4
5
6
7
8
9
H2O
100
79
120
120
120
120
120
120
120
15
0
25
of a single isomer in the thermal isomerization. The H
NMR and 13C NMR spectra revealed that the methyl
groups of the pyrazole rings are spatially similar suggest-
ing a Z-configuration of the molecules.
EtOH
n-PrOH
CHCl3
acetone
MeCN
toluene
DMFc
97
55
The structure of 4-[(pyrazol-4-yl)methylene]pyrazolone
3a was further confirmed by a single-crystal X-ray dif-
fraction study (Figure 1). The X-ray diffraction data un-
ambiguously support the Z-configuration of 3a which can
profit from stabilization by intramolecular hydrogen
bonding between the carbonyl and hydroxyl moieties of
the adjacent pyrazole rings (Figure 1). The lengths of the
C5–C6 and C6–C7 bonds [1.4414(3) and 1.3951(3) Å, re-
spectively] indicate a strong delocalization between the
sp2 atoms in 3a. The PBE/L113 energy scan in the PRIRO-
DA program14 along the C1–C5–C6–C7 torsion angle (36
61
0
56
10
82
27
100
100
100
25
100
100
DMSOc
5
a Conditions: 2a (1 mmol), solvent (10 mL), heating.
b Selective conversion into 3a, 1H NMR data.
c Conditions: 0.5 mL of solvent.
Synlett 2013, 24, 827–830
© Georg Thieme Verlag Stuttgart · New York

LETTER
Thermal Isomerization of Bis(spiropyrazolone)cyclopropanes
829
56.56), 5386 unique (Rint = 0.1403) which were used in all calcula-
tions. The final R1 was 0.0638 [ >2σ(I)] and wR2 was 0.1324 (all da-
ta). CCDC 921007 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
points, 10° step size) shows that the Z-configuration of 3a
is by 12 kcal/mol more favorable than the E, and the rota-
tional barrier from E- to Z-configuration is around 11
kcal/mol. Thus, the E-isomer should not be present in
measurable quantities among the reaction products. Con-
sidering the facts given above, compounds 3b–h should
also possess the Z-configuration.
the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Selected Analytical Data
(4Z)-4-[(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(phe-
nyl)methylene]-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-
one (3a)
Orange solid; mp 246–247 °C (lit.11 240–241.5 °C). 1H NMR (300
MHz, CDCl3): δ = 1.44 (s, 6 H, CH3), 7.25–7.63 (m, 11 H, Ph), 7.98
(d, J = 7.6 Hz, 4 H, Ph). 13C NMR (75 MHz, CDCl3): δ = 16.2 (2 C),
113.0, 121.2 (4 C), 126.5 (2 C), 128.6 (2 C), 128.9 (4 C), 130.5 (2
C), 130.6, 137.7 (2 C), 139.9, 151.6 (2 C), 158.3 (2 C), 161.4 (2 C).
MS (EI, 70 eV): m/z (%) = 435 (3) [M+ + 1], 434 (15) [M+], 417 (6),
227 (11), 226 (100), 106 (24). IR (KBr): 3437, 3064, 1604, 1499,
1488, 1377, 1319, 1011, 757 cm-1. Anal. Calcd for C27H22N4O2: C,
74.64; H, 5.10; N, 12.89. Found: C, 74.58; H, 5.24; N, 12.81.
(4Z)-4-[(2-Chlorophenyl)(5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-4-yl)methylene]-5-methyl-2-phenyl-2,4-dihydro-3H-
pyrazol-3-one (3b)
Orange solid; mp 151–152 °C. 1H NMR (300 MHz, CDCl3):
δ = 1.50 (s, 6 H, CH3), 7.25–7.63 (m, 10 H, Ph), 7.97 (d, J = 7.6 Hz,
4 H, Ph). 13C NMR (75 MHz, CDCl3): δ = 15.7 (2 C), 112.5, 121.1
(4 C), 126.5 (2 C), 127.1, 128.8 (4 C), 129.9, 131.5, 131.7, 133.8,
137.6 (2 C), 138.1, 150.9 (2 C), 153.7 (2 C), 161.5 (2 C). MS (EI,
70 eV): m/z (%) 469 (37) [M+ + 1], 468 (100) [M+], 453 (68), 451
(21), 434 (50), 433 (76), 118 (39), 91 (23), 77 (44). IR (KBr): 3441,
3064, 1600, 1518, 1495, 1378, 1317, 1012, 757 cm–1. Anal. Calcd
for C27H21ClN4O2: C, 69.15; H, 4.51; Cl, 7.56; N, 11.95. Found: C,
69.02; H, 4.63; Cl, 7.42; N, 12.08.
Figure 1 The general view of 3a in crystal. Atoms are represented
by thermal displacement ellipsoids (p = 50%).
In conclusion, we have developed an efficient approach to
4-[(pyrazol-4-yl)methylene]pyrazolone derivatives by
thermal isomerization of readily accessible bis(spiro-
pyrazolone)cyclopropanes. The isomerization rapidly
proceeds simply on heating in DMSO, does not require
(4Z)-4-[(3-Bromophenyl)(5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-4-yl)methylene]-5-methyl-2-phenyl-2,4-dihydro-3H-
pyrazol-3-one (3d)
Orange solid; mp 135–136 °C. 1H NMR (300 MHz, CDCl3):
δ = 1.50 (s, 6 H, CH3), 7.25–7.49 (m, 9 H, Ph), 7.56 (s, 1 H, Ph),
7.96 (d, J = 8.1 Hz, 4 H, Ph). 13C NMR (75 MHz, CDCl3): δ = 16.5
any additional reagents or catalysts, and stereoselectively (2 C), 112.8, 121.1 (4 C), 122.7, 126.6 (2 C), 128.8 (4 C), 129.1,
130.1, 133.2, 133.5, 137.5 (2 C), 141.6, 151.1 (2 C), 155.7 (2 C),
affords the (4Z)-4-[(pyrazol-4-yl)methylene]pyrazolones
in excellent yields. The isomerization products are isolat-
ed by water-assisted precipitation directly from the reac-
tion mixture and do not require any further purification.
161.3 (2 C). MS (EI, 70 eV): m/z (%) = 514 (78) [M+ + 2], 512 (78)
[M+], 497 (27), 495 (26), 340 (28), 185 (40), 128 (35), 118 (21), 91
(45), 77 (100). IR (KBr): 3436, 3062, 1680, 1597, 1516, 1378,
1316, 1215, 1013, 757, 690 cm–1. Anal. Calcd for C27H21BrN4O2: C,
63.17; H, 4.12; Br, 15.56; N, 10.91. Found: C, 63.10; H, 4.21; Br,
15.49; N, 10.98.
General Procedure
(4Z)-4-[(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(4-me-
thylphenyl)methylene]-5-methyl-2-phenyl-2,4-dihydro-3H-py-
razol-3-one (3e)
A suspension of bis(spiropyrazolone)cyclopropane 2 (1 mmol) in
DMSO (0.5 mL) in a 25 mL round-bottom flask was rapidly heated
to 100 °C and stirred for 5 min. Then, the reaction mixture was al-
lowed to cool down to r.t. and H2O (10 mL) was added. The orange
precipitate was filtered off, washed with H2O (2 × 5 mL), and dried
under reduced pressure.
Orange solid; mp 221–222 °C; 1H NMR (300 MHz, CDCl3):
δ = 1.47 (s, 6 H, CH3), 2.50 (s, 3 H, CH3), 7.23–7.34 (m, 5 H, Ph),
7.46 (t, J = 7.8 Hz, 5 H, Ph), 7.97 (d, J = 7.8 Hz, 4 H, Ph) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 16.2 (2 C), 21.4, 113.0, 121.1 (4 C),
126.4 (2 C), 128.8 (4 C), 129.3 (2 C), 130.5 (2 C), 136.9, 137.7 (2
C), 141.1, 151.7 (2 C), 158.6 (2 C), 161.3 (2 C). MS (EI, 70 eV):
m/z (%) = 449 (14) [M+], 448 (26) [M+], 432 (35), 431 (50), 357
(10), 118 (29), 91 (39), 77 (100). IR (KBr): 3034, 1600, 1489, 1375,
1317, 1214, 1014, 810, 757, 689 cm–1. Anal. Calcd for C28H24N4O2:
C, 74.98; H, 5.39; N, 12.49. Found: C, 74.90; H, 5.45; N, 12.41.
X-ray Experiment
Product 3a was crystallized from an acetone–hexane (1:1) mixture.
Data were obtained on a Bruker SMART APEX II diffractometer.
The crystal was kept at 100 K during data collection. Using Olex2,15
the structure was solved with the XS16 structure solution program
using direct methods and refined with the XL refinement package16
using least-squares minimization.
Acknowledgment
Crystal Data for 3a
C27H22N4O2 (M = 434.49): monoclinic, space group P21/c (no. 14),
a = 17.189(4) Å, b = 13.459(3) Å, c = 9.432(2) Å, β = 90.637(6)°,
V = 2182.0(9) Å3, Z = 4, T = 100 K, μ(MoKα) = 0.086 mm–1,
This work was supported by the Presidential Scholarship Program
for the State Support of young Russian scientists – PhD (project no.
MK-387.2012.3).
D
calcd = 1.323 g/mm3, 12678 reflections measured (2.36 ≤ 2Θ ≤
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 827–830

830
E. O. Dorofeeva et al.
LETTER
(5) (a) Wiley, R. H.; Wiley, P. Pyrazolones, Pyrazolidones, and
Derivatives, In The Chemistry of Heterocyclic Compounds;
Vol. 20; Weissberger, A., Ed.; Chap. VIII; Interscience:
New York, 1964. (b) 100 Years of Pyrazolone Drugs:
Agents and Actions Supplements – An Update; Vol. 19;
Brune, K., Ed.; Birkhäuser: Basil, 1986, 355.
(6) Brogden, R. N. Drugs 1986, 32, Suppl. 4: 60.
(7) (a) Ramajayam, R.; Tan, K.-P.; Liu, H.-G.; Liang, P.-H.
Bioorg. Med. Chem. 2010, 18, 7849. (b) Sujatha, K.;
Shanthi, G.; Selvam, N. P.; Manoharan, S.; Perumal, P. T.;
Rajendran, M. Bioorg. Med. Chem. Lett. 2009, 19, 4501.
(8) (a) Zuliani, V.; Carmi, C.; Rivara, M.; Fantini, M.; Lodola,
A.; Vacondio, F.; Bordi, F.; Plazzi, P. V.; Cavazzoni, A.;
Galetti, M.; Alfieri, R. R.; Petronini, P. G.; Mor, M. Eur. J.
Med. Chem. 2009, 3471. (b) Ramajayam, R.; Tan, K.-P.;
Liu, H.-G.; Liang, P.-H. Bioorg. Med. Chem. Lett. 2006, 16,
2158.
(9) Itokawa, M.; Miyata, T.; Arai, M. EP 2189537 A1, 2010.
(10) Elinson, M. N.; Vereshchagin, A. N.; Tretyakova, E. O.;
Bushmarinov, I. S.; Nikishin, G. I. Synthesis 2011, 3015.
(11) Westoo, G. Acta Chem. Scand. 1957, 11, 1359.
(12) Hennig, L.; Haessner, R.; Rissanen, K. J. Prakt. Chem. 1989,
331, 681.
(13) Laikov, D. N. Chem. Phys. Lett. 2005, 416, 116.
(14) Laikov, D. N. Chem. Phys. Lett. 1997, 281, 151.
(15) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J.
A. K.; Puschmann, H. J. Appl. Cryst. 2009, 42, 339.
(16) Sheldrick, G. Acta Crystallogr., Sect. A: Found. Crystallogr.
2008, 64, 112.
References
(1) For reviews, see: (a) Patai, S.; Rappoport, Z. The Chemistry
of the Cyclopropyl Group; Wiley: New York, 1987. (b) Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321.
(c) Paquette, L. A. Chem. Rev. 1986, 86, 733. (d) Dolbier,
W. R.; Battiste, M. A. Chem. Rev. 2003, 103, 1071.
(e) Fedorynski, M. Chem. Rev. 2003, 103, 1099.
(2) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(b) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007,
107, 3117. (c) Chagarovskiy, A. O.; Ivanova, O. A.;
Rakhmankulov, E. R.; Budynina, E. M.; Trushkov, I. V.;
Melnikova, M. Y. Adv. Synth. Catal. 2010, 352, 3179.
(d) Hudlicky, T.; Reed, J. W. Angew. Chem. Int. Ed. 2010,
49, 4864.
(3) (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.;
Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
(b) Baldwin, J. E. Chem. Rev. 2003, 103, 1197.
(4) (a) Laroche, C.; Behr, J.-B.; Szymoniak, J.; Bertus, P.;
Schutz, C.; Vogel, P.; Plantier-Royon, R. Bioorg. Med.
Chem. 2006, 14, 4047. (b) Sandanayaka, V. P.; Prashad, A.
S.; Yang, Y.; Williamson, R. T.; Lin, Y. I.; Mansour, T. S. J.
Med. Chem. 2003, 46, 2569. (c) Jiang, T.; Kuhen, K. L.;
Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.;
Wub, T. Y.-H.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
2105. (d) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza,
K.; Caldwell, J.; Bursulaya, B.; Tuntland, T.; Zhang, K.;
Karanewsky, D.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
2109.
Synlett 2013, 24, 827–830
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.