Structural reassignment of an 'unusual' derivative of 3-methyl-5-phenylpyrazol-5-one (Edaravone)

Article abstract of DOI:10.1016/j.tetlet.2006.04.084

The structure of the major product from the reaction of 4-bromo-3-methyl-1-phenylpyrazol-5-one (1) with ethyl cyanoacetate is shown, by means of an X-ray crystal structure determination, to be the spirocyclic compound 4, rather than the previously propose

Full text of DOI:10.1016/j.tetlet.2006.04.084

Tetrahedron Letters 47 (2006) 4107–4108
Structural reassignment of an ‘unusual’ derivative of
3-methyl-5-phenylpyrazol-5-one (Edaravone)
Jennifer Burgess and Peter J. Steel*
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
Received 7 February 2006; revised 12 April 2006; accepted 19 April 2006
Abstract—The structure of the major product from the reaction of 4-bromo-3-methyl-1-phenylpyrazol-5-one (1) with ethyl cyano-
acetate is shown, by means of an X-ray crystal structure determination, to be the spirocyclic compound 4, rather than the previously
proposed isomer 3.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The chemistry of the derivatives of 3-methyl-1-phen-
ylpyrazol-5-one (Edaravone)1 has been the subject of
much study, as has that of the N-methyl derivative anti-
pyrine, the first truly synthetic pain reliever.2 Recently,3
it was claimed that the 4-bromo derivative 1 reacted with
ethyl cyanoacetate to produce, as the major product, the
‘unusual’ furanopyrazole 3, supposedly via the inter-
mediacy of the symmetrical compound 2 (Scheme 1).
We had reason to question the validity of this claim
and now show unambiguously, using X-ray crystallogra-
phy, that this reaction product is actually the spirocyclic
isomer 4.
We have resynthesized this compound,4 which directly
furnished crystals suitable for single crystal X-ray struc-
ture determination from the crude reaction mixture. The
infrared and 1H NMR spectra matched the reported val-
ues. It crystallizes in the monoclinic space group P21/n,
with a single molecule in the asymmetric unit.5 Figure 1
shows a perspective view of the structure, which reveals
that it is actually a spiro[(pyrano[2,3-c]pyrazole)-4,40-
pyrazoline], rather than the previously proposed struc-
ture. This is a known heterocyclic ring system that has
been previously reported in other derivatives of similar
pyrazolones.6
Br
Me
Me
Me
NC CO2Et
N
N
N
X
O
N
N
N
NCCH2CO2Et
Ph
Ph
OH HO
Ph
1
2
X
EtO2C
Me
Me
N
NH2
O
Ph
N
Me EtO2C
N
N
OH
NH
Ph
N
O
Me
N
O
N
Ph
N
Ph
3
4
Scheme 1.
Keywords: Pyrazolone; Spiro compound; Crystal structure.
*
Corresponding author. Tel.: +64 3 3642432; fax: +64 3 3642110;
e-mail: peter.steel@canterbury.ac.nz
Figure 1. Perspective view of the X-ray structure of 4.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.084

4108
J. Burgess, P. J. Steel / Tetrahedron Letters 47 (2006) 4107–4108
Me
ylpyrazol-5-one (1) with ethyl cyanoacetate is actually
the spirocyclic compound 4, rather than the previously
proposed isomer 3.
O
OH
NC CN
Ph
Ph
N
N
N
X
O
N
N
NH
Ph
5
6
TCNE
EtOH
Acknowledgement
TCNE
MeCN
We thank the Royal Society of New Zealand Marsden
Fund for generous funding.
N
NC
Ph
N
Me
CN
N
5
References and notes
O
N
N
O
EtOH
Ph
N
1. Graul, A.; Castaner, J. Drugs Future 1996, 21, 1014–1016.
2. (a) Madhu, N. T.; Radhakrishnan, P. K.; Grunert, M.;
Weinberger, P.; Linert, W. Rev. Inorg. Chem. 2003, 23, 1–
23; (b) Singh, T. P.; Vijayan, M. Acta Crystallogr. 1973,
B29, 714–720.
O
NH2
CN
Ph
7
8
Scheme 2.
3. El-Rady, E. A.; Abd El Latif, F. M. J. Chin. Chem. Soc.
2004, 51, 785–790.
Thus, the two exchangeable protons in the NMR spec-
trum are associated with the enamino group, rather than
imine and hydroxyl protons. In the solid state, one of
the NH2 hydrogens is involved in an intramolecular
hydrogen bond to the adjacent ester carbonyl oxygen,
while the other participates in an intermolecular hydro-
gen bond to the spiropyrazolidinone oxygen atom of an
adjacent molecule related by a crystallographic centre of
inversion. The molecular packing also involves extensive
p–p stacking interactions between adjacent molecules.
4. Preparation of 4: A solution of 1 (0.253 g, 1.0 mmol), ethyl
cyanoacetate (1 mL, 9 mmol) and four drops of piperidine
in ethanol (15 mL) was refluxed for 5 h. Colourless crystals
of the product were deposited, which were isolated by
filtration and washed with methanol. Yield 84 mg (17%).
Mp 232—233 ꢁC (dec). IR(KBr) 1641, 1686 cmꢀ1 1H
.
NMR (DMSO) d: 0.97 (3H, t, OCH2CH3), 1.97 (3H, s,
CH3), 2.03 (3H, s, CH3), 4.03 (2H, q, OCH2CH3), 7.31 (1H,
t, para-H), 7.47 (1H, t, para-H), 7.56 (2H, t, meta-H), 7.63
(2H, t, meta-H), 7.93 (2H, d, ortho-H), 7.97 (2H, d, ortho-
H), 8.56 (1H, s, NH). It was also obtained in 87% yield
from the reaction of cyanoacetamide with 1 in refluxing
ethanol, in the presence of a trace of piperidine.
Within the structure the pyranopyrazole ring system is
approximately orthogonal (88.7ꢁ) to the other pyrazole
ring, as expected for a spiro centre. The planes of the
N-phenyl rings are inclined to the planes of the attached
pyranopyrazole and pyrazoline rings at angles of 6.8ꢁ
and 25.0ꢁ, respectively. These features and the bond
lengths and angles are similar to those in the only other
reported X-ray crystal structure of this spirocyclic ring
system.7
5. Crystal Data for 4 at 93 K. C25H23N5O4, M 457.48,
monoclinic, space group P21/n,
a
12.9759(16),
113.038(2)ꢁ,
b
V
,
˚
12.2404(15),
c
15.3058(19) A,
b
3
2237.1(5) A , F(000) 960, Dc(Z = 4) 1.358 g cmꢀ1
˚
l(Mo Ka) 0.95 cmꢀ1
0.09 mm, 2hmax 53ꢁ, wR (all 4505 data) 0.0856, conven-
, crystal dimensions 0.55 · 0.44 ·
tional R (3301 data with I > 2r(I)) 0.0364.
Complete crystallographic data, as a CIF file, have been
deposited with the Cambridge Crystallographic Data Cen-
tre (CCDC No. 297340). Copies can be obtained free of
charge from: The Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (e-mail: deposit@ccdc.cam.
ac.uk).
In retrospect, the formation of this product is not totally
unexpected as we have previously demonstrated,7 as part
of a long-standing interest in the chemistry and tauto-
merism of pyrazolones,8 that the product of reaction of
3-methyl-1-phenylpyrazol-5-one (5) with TCNE is the
related compound 8, rather than the previously proposed
isomer 6, formed via the intermediate 7 (Scheme 2). In
the present case, a related mechanism is likely for the
formation of 4.
6. (a) Metwally, S. A. M.; El-Naggar, G. M.; El-Emary, T. I.
Liebigs Ann. Chem. 1991, 961–962; (b) Younes, M. I.; Atta,
A. H.; Metwally, S. A. M.; Elnagdi, M. H. Gazz. Chim. Ital.
1991, 121, 185–195.
7. Guard, J. A. M.; Steel, P. J. Arkivoc 2001, vii, 32–36.
8. (a) Steel, P. J.; Whyte, A. R. Aust. J. Chem. 1984, 37, 459–
464; (b) Ramsay, C. G.; Steel, P. J. Acta Crystallogr. 1985,
C41, 135–136; (c) O’Connell, M. J.; Ramsay, C. G.; Steel,
P. J. Aust. J. Chem. 1985, 38, 401–409; (d) Guard, J. A. M.;
Steel, P. J. Aust. J. Chem. 1994, 47, 1453–1459.
In conclusion, we have shown that the ‘unusual’ major
product from the reaction of 4-bromo-3-methyl-1-phen-