Synthesis and antifungal activity of spiro[cyclopropane-1,4′-pyrazol- 3-one] derivatives

Article abstract of DOI:10.1002/jhet.5570450653

(Chemical Equation Presented) A series of new spiro[cyclopropane-1, 4′-pyrazol-3-one] derivatives 3a-h were synthesized by the reaction of 4-arylidene-3H-pyrazol-3-one 1 with secondary and tertiary carbanions derived from a methylene and methine group bearing both a leaving group and electron-withdrawing group, e.g. methyl chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, tert-butyl chloroacetate, chloroacetonitrile, 2-chloro-N,N-diethylacetamide, methyl 2-chloropropionate and 2-chloropropionitrile, in the presence of sodium hydride. All the synthesized compounds 3a-h were active against Candida albicans with MIC ≥ 25 μg/mL in vitro.

Full text of DOI:10.1002/jhet.5570450653

Nov-Dec 2008
1883
Synthesis and Antifungal Activity of Spiro[cyclopropane-1,4'-
pyrazol-3-one] Derivatives
Hiroshi Maruoka,*a Nobuhiro Kashige,a Takafumi Eishima,a Fumi Okabe,a
a
Reiko Tanaka,b Toshihiro Fujioka,a Fumio Miake and Kenji Yamagata a
aFaculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
E-mail: maruoka@fukuoka-u.ac.jp
bMedical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan
Received March 30, 2008
R1
R2
Ph
Ph
Ph
Me
Me
Ph
R1
R2
NaH
+
ClCH
N
N
O
O
DMF
N
N
Ph
Ph
R1 = H, Me R2 = CO2Me, CO2Et, CO2Pri, CO2But, CN, CONEt2
A series of new spiro[cyclopropane-1,4'-pyrazol-3-one] derivatives 3aꢀh were synthesized by the
reaction of 4-arylidene-3H-pyrazol-3-one 1 with secondary and tertiary carbanions derived from a
methylene and methine group bearing both a leaving group and electron-withdrawing group, e.g. methyl
chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, tert-butyl chloroacetate, chloroacetonitrile, 2-
chloro-N,N-diethylacetamide, methyl 2-chloropropionate and 2-chloropropionitrile, in the presence of
sodium hydride. All the synthesized compounds 3aꢀh were active against Candida albicans with MIC ꢁ
25 μg/mL in vitro.
J. Heterocyclic Chem., 45, 1883 (2008).
INTRODUCTION
RESULTS AND DISCUSSION
Pyrazoles are key substructures in a large variety of
compounds of therapeutic importance [1ꢀ3]. Compounds
containing this ring system are known to display diverse
The starting material, 2,4-dihydro-5-methyl-2-
phenyl-4-(diphenylmethylene)-3H-pyrazol-3-one (1),
was prepared by treatment of 2,4-dihydro-5-methyl-2-
phenyl-3H-pyrazol-3-one and benzophenone as
originally reported by Du et al. [39,40]. An initial
pharmacological
activities
such
as
analgesic,
antidepressant, antibacterial, plant growth regulatory,
anti-inflammatory and antihyperglycemic activities [4ꢀ9].
Thus, it seems likely that the biological activities of
pyrazoles depend on the nature of the substituents. In this
context, the synthesis [10ꢀ17] of pyrazole derivatives
continues to attract attention and provides an interesting
challenge. In our previous paper [18], we discussed the
attempt to react compound
1
with methyl
chloroacetate (2a) using the method of Westöö [38]
failed and the expected spiro compound 3a was not
observed at all (Scheme 1). In this reaction, a retro-
Aldol case probably occurs (path a). This reaction
appears to proceed by
a
stepwise mechanism
synthesis
of
1-acyl-1,2-dihydro-3H-pyrazol-3-ones
involving first conjugate addition of the hydroxide ion
to compound 1, giving the intermediate conjugate
addition product A. This addition is then followed by
tautomerization and elimination to afford the intact
2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one and
benzophenone. This result indicates that this type of
straightforward preparation of spiro compounds is not
easy. In order to achieve an efficient synthesis of
spiro compounds, we hypothesized if a carbanion
could be derived from a methylene group of 2a and
Michael adduct B would then be produced readily by
the conjugate addition typical of an ꢂ,ꢃ-unsaturated
carbonyl compound as 1 under appropriate conditions,
the synthesis of the spiro-compound 3a would be
possible (path b).
through Lewis acid-mediated rearrangement of 3-acyl-
oxypyrazoles.
Spiro compounds are well known to possess varied
pharmacological activities [19ꢀ26] and hence their
synthesis has always been a challenge and of attraction to
organic chemists [27ꢀ31]. To the best of our knowledge
there are relatively few methods in the literature
describing the preparation of spiro-cyclopropanepyrazoles
[32ꢀ37], even though they also have biological activity
[38]. For these reasons, we have been interested in the
development of the methods for the synthesis of spiro-
cyclopropanepyrazoles. Thus, we herein wish to report an
efficient method for preparing new spiro[cyclopropane-
1,4'-pyrazol-3-one] derivatives with antifungal activity.

1884
H. Maruoka, N. Kashige, T. Eishima, F. Okabe, R. Tanaka, T. Fujioka, F. Miake and K. Yamagata
Vol 45
yields. The results are listed in Table 1. In the case of the
preparation of 3g,h, the reaction was carried out at room
temperature because the conversion was not completed at
the lower reaction temperature (entries 7 and 8). By
comparison of nmr, mass spectra and elemental analyses
of 3bꢁh it seems that the structural assignments given to
these compounds are correct.
Scheme 1
Ph
Me
Ph
N
+
ClCH2CO2Me
O
N
2a
Ph
1
NaOH/EtOH [38]
Table 1
path b
path a
x
Synthesis of Spiro Compounds 3aꢀh by the Reaction of 1 with 2aꢀh
H
O
R1
CO2Me
Cl
O
R2
1
Ph
Ph
Ph
O
Ph
Ph
Me
Me
Ph
Ph
Me
5
2
Me
4
4
3
Ph
R1
R2
NaH
+
ClCH
N
N
N
N
5
1
O
DMF
O
N
N
3
N
N
7
2
6
2aꢀh
Ph
Ph
Ph
Ph
A
B
1
3aꢀh
R1
R2
Product
Yield (%)
Entry
Reagent
CO2Me
Me
2a
2b
2c
2d
2e
2f
H
H
H
CO2Me
CO2Et
CO2Pri
3a
3b
3c
3d
3e
3f
63 [a]
60 [a]
65 [a]
1
2
3
Ph
Ph
Me
Ph
+
N
N
O
O
Ph
CO2But
81 [a]
33 [a]
59 [a]
N
N
4
5
6
7
8
H
O
H
CN
Ph
Ph
3a
H
CONEt2
CO2Me
CN
3g
3h
2g
2h
Me
Me
57 [b]
88 [b]
After some optimization, the best result was obtained
when 1a was treated with 2a in N,N-dimethylformamide
in the presence of sodium hydride, and the expected spiro
compound 3a was isolated in 63% yield (Table 1).
Although we tested the reactions under a variety of other
[a] 0-5 oC, 2 hours. [b] r.t., 6 hours.
Table 2
In Vitro Antifungal Activity of Compounds 3aꢁh Against C. albicans
and S. cerevisiae
conditions such as
a potassium tert-butoxide/N,N-
MIC (ꢀg/mL)
Compound
dimethylformamide and sodium hydride/tetrahydrofuran
system, those attempts were not successful. It makes us
believe that the conjugate addition reaction of carbanions
and spiro-cyclization of the intermediate Michael adduct
can only be promoted by using sodium hydride/N,N-
dimethylformamide. The ir spectrum of 3a displays two
carbonyl bands at 1751 and 1711 cm-1. The 1H nmr
spectrum of 3a exhibits a three-proton singlet at ꢀ 3.85
attributable to the methyl protons of a methoxy group.
The 13C nmr spectrum of 3a shows a signal at ꢀ 52.6 due
to the methyl carbon of a methoxy group, three signals at
ꢀ 42.4, 46.5 and 56.7 due to the spiro-cyclopropane
carbons, and two signals at ꢀ 167.3 and 168.3 due to the
two carbonyl carbons. Elemental analysis and spectral
data of 3a are consistent with the proposed structure (see
experimental section).
C. albicans [a]
S. cerevisiae [b]
3a
25 [c]
25 [c]
25 [c]
25 [c]
25 [c]
25 [c]
25 [c]
25 [c]
2 [e]
50 [d]
50 [d]
50 [d]
50 [d]
50 [d]
50 [d]
50 [d]
50 [d]
0.5 [f]
4 [g]
3b
3c
3d
3e
3f
3g
3h
Miconazole
Itraconazole
DMSO
EtOH
2 [e]
>12.5%
>12.5%
>6.25%
>6.25%
[a] RPMI1640 medium, 37 °C. [b] YM medium, 25 °C. [c] containing 0.2%
DMSO. [d] containing 0.39% DMSO. [e] containing 0.015% DMSO. [f]
containing 0.04% DMSO. [g] containing 0.03% DMSO.
Based on these results, we carried out the reactions of 1
Eight of the newly synthesized spiro-cyclopropane-
pyrazoles 3aꢁh were tested for their in vitro antifungal
activity against Candida albicans and Saccharomyces
cerevisiae. In vitro susceptibility tests were performed to
evaluate MICs and minimal fungicidal concentrations
(MFCs) using the method described in the guidelines of
NCCLS M27-A2 [41]. Miconazole and Itraconazole were
with 2bꢁh by use of
a
sodium hydride/N,N-
dimethylformamide system. Indeed, when a mixture of 1
with 2bꢁh in the presence of sodium hydride in N,N-
dimethylformamide was stirred at 0ꢁ5 °C for 2 hours or at
room temperature for 6 hours, the expected spiro
compounds 3bꢁh were obtained in moderate to good

Nov-Dec 2008
Synthesis and Antifungal Activity of Spiro[cyclopropane-1,4'-pyrazol-3-one] Derivatives
1885
Methyl 5,6-diaza-4-methyl-7-oxo-2,2,6-triphenylspiro[2.4]-
hept-4-ene-1-carboxylate (3a). This compound was obtained as
colorless prisms (1.29 g, 63%), mp 174ꢀ176 ˚C (acetone-
petroleum ether); ir (potassium bromide): ꢂ 1751, 1711 cm-1
(C=O); 1H nmr (deuteriochloroform): ꢁ 1.83 (s, 3H, 4-Me), 3.63
(s, 1H, 1-H), 3.85 (s, 3H, CO2Me), 7.12ꢀ7.30 (m, 7H, Ph-H),
7.34ꢀ7.38 (m, 6H, Ph-H), 7.89ꢀ7.91 ppm (m, 2H, Ph-H); 13C
nmr (deuteriochloroform): ꢁ 18.8 (4-Me), 42.4 (C-1), 46.5 (C-3),
52.6 (CO2Me), 56.7 (C-2), 118.6, 124.9, 127.7, 128.1, 128.2,
128.7, 128.8, 129.3, 136.6, 138.4, 140.1 (Ph-C), 156.5 (C-4),
167.3, 168.3 ppm (C=O); ms: m/z 411 [M+H]+. Anal. Calcd. for
C26H22N2O3: C, 76.08; H, 5.40; N, 6.82. Found: C, 76.10; H,
5.40; N, 6.78.
used as standard drugs for comparison of the antifungal
activity. The results obtained are summarized in Table 2.
All spiro compounds 3aꢀh were active against Candida
with MIC ꢀ 25 μg/mL and Saccharomyces with MIC ꢀ
50 μg/mL. It is worth noting that none of the test
compounds 3aꢀh showed superior activity to the standard
drugs Miconazole and Itraconazole. Preliminary bioassay
results indicated that all synthesized compounds 3aꢀh
display moderate or week antifungal activity against
Candida and Saccharomyces.
In conclusion, we have developed a convenient
straightforward method for the construction of
spiro[cyclopropane-1,4'-pyrazol-3-one] derivatives 3aꢀh
by the reaction of 2,4-dihydro-5-methyl-2-phenyl-4-
(diphenylmethylene)-3H-pyrazol-3-one with secondary
and tertiary carbanions derived from a methylene and
methine group bearing both a leaving group and electron-
withdrawing group in the presence of sodium hydride.
This methodology offers significant advantages with
regard to the supply of spirocyclopropanepyrazoles,
which may exhibit biological activities such as antifungal
and antimicrobial activities. In this present work, we
showed that spiro compounds 3aꢀh have antifungal
activity in vitro. Our results suggest that 3aꢀh would play
a role in vivo. Additional studies are needed to elucidate
the exact mechanisms for the spiro compounds-mediated
pathogenesis of several diseases. Functionalized pyrazoles
are important building blocks in organic synthesis and for
the preparation of biologically active compounds with
interest in medicinal chemistry.
Ethyl 5,6-diaza-4-methyl-7-oxo-2,2,6-triphenylspiro[2.4]-
hept-4-ene-1-carboxylate (3b). This compound was obtained as
colorless prisms (1.27 g, 60%), mp 143ꢀ145 ˚C (acetone-
petroleum ether); ir (potassium bromide): ꢂ 1753, 1711 cm-1
1
(C=O); H nmr (deuteriochloroform): ꢁ 1.37 (t, J = 7.0 Hz, 3H,
CO2CH2CH3), 1.83 (s, 3H, 4-Me), 3.62 (s, 1H, 1-H), 4.30 (q, J =
7.0 Hz, 2H, CO2CH2CH3), 7.14ꢀ7.30 (m, 7H, Ph-H), 7.34ꢀ7.40
(m, 6H, Ph-H), 7.89ꢀ7.91 ppm (m, 2H, Ph-H); 13C nmr
(deuteriochloroform): ꢁ 14.2 (CO2CH2CH3), 18.9 (4-Me), 42.7
(C-1), 46.5 (C-3), 55.7 (C-2), 61.8 (CO2CH2CH3), 118.6, 124.8,
127.6, 128.1, 128.3, 128.7, 128.8, 129.4, 136.7, 138.4, 140.2
(Ph-C), 156.6 (C-4), 166.8, 168.4 ppm (C=O); ms: m/z 425
[M+H]+. Anal. Calcd. for C27H24N2O3: C, 76.39; H, 5.70; N,
6.60. Found: C, 76.40; H, 5.81; N, 6.51.
Isopropyl 5,6-diaza-4-methyl-7-oxo-2,2,6-triphenylspiro-
[2.4]hept-4-ene-1-carboxylate (3c). This compound was
obtained as colorless prisms (1.43 g, 65%), mp 136ꢀ138 ˚C
(acetone-petroleum ether); ir (potassium bromide): ꢂ 1751, 1712
cm-1 (C=O); 1H nmr (deuteriochloroform): ꢁ 1.31 [d, J = 6.1 Hz,
3H, CO2CH(CH3)2], 1.41 [d, J = 6.1 Hz, 3H, CO2CH(CH3)2],
1.84 (s, 3H, 4-Me), 3.60 (s, 1H, 1-H), 5.14 [sep, J = 6.1 Hz, 1H,
CO2CH(CH3)2], 7.14ꢀ7.29 (m, 7H, Ph-H), 7.33ꢀ7.41 (m, 6H,
Ph-H), 7.89ꢀ7.91 ppm (m, 2H, Ph-H); 13C nmr
(deuteriochloroform): ꢁ 19.0 (4-Me), 21.8 [CO2CH(CH3)2], 43.1
(C-1), 46.5 (C-3), 55.7 (C-2), 69.8 [CO2CH(CH3)2], 118.6,
124.8, 127.6, 128.1, 128.2, 128.6, 128.8, 129.5, 136.7, 138.4,
140.2 (Ph-C), 156.6 (C-4), 166.3, 168.5 ppm (C=O); ms: m/z
439 [M+H]+. Anal. Calcd. for C28H26N2O3: C, 76.69; H, 5.98; N,
6.39. Found: C, 76.70; H, 6.05; N, 6.38.
EXPERIMENTAL
All melting points are uncorrected. The ir spectra were
1
recorded on a JASCO FT/IR-230 spectrometer. The H and 13C
nmr spectra were recorded on a JEOL JNM-A500 spectrometer
1
at 500 and 125 MHz, respectively. The H and 13C chemical
shifts (ꢁ) are reported in parts per million (ppm) relative to
tetramethylsilane as internal standard. The positive FAB mass
spectra were obtained on a JEOL JMS-700T spectrometer. The
elemental analyses were performed on a YANACO MT-6 CHN
analyzer.
tert-Butyl 5,6-diaza-4-methyl-7-oxo-2,2,6-triphenylspiro-
[2.4]hept-4-ene-1-carboxylate (3d). This compound was
obtained as colorless needles (1.84 g, 81%), mp 170ꢀ172 ˚C
(acetone-petroleum ether); ir (potassium bromide): ꢂ 1750, 1712
cm-1 (C=O); 1H nmr (deuteriochloroform): ꢁ 1.56 [s, 9H,
CO2C(CH3)3], 1.83 (s, 3H, 4-Me), 3.56 (s, 1H, 1-H), 7.13ꢀ7.38
(m, 7H, Ph-H), 7.33ꢀ7.38 (m, 4H, Ph-H), 7.43ꢀ7.45 (m, 2H, Ph-
H), 7.89ꢀ7.91 ppm (m, 2H, Ph-H); 13C nmr (deuterio-
chloroform): ꢁ 19.0 (4-Me), 28.1 [CO2C(CH3)3], 44.1 (C-1),
46.5 (C-3), 55.7 (C-2), 82.9 [CO2C(CH3)3], 118.6, 124.8, 127.6,
128.1, 128.3, 128.5, 128.6, 128.8, 129.6, 136.9, 138.5, 140.5
(Ph-C), 156.8 (C-4), 165.7, 168.7 ppm (C=O); ms: m/z 453
[M+H]+. Anal. Calcd. for C29H28N2O3: C, 76.97; H, 6.24; N,
6.19. Found: C, 77.07; H, 6.37; N, 6.14.
General Procedure for the Preparation of Spiro
Compounds 3aꢀh from 1 and 2aꢀh. To an ice-cooled and
stirred solution of 1 [39,40] (1.69 g, 5 mmoles) and 2a (2.17 g,
20 mmoles), 2b (2.45 g, 20 mmoles), 2c (2.73 g, 20 mmoles), 2d
(3.01 g, 20 mmoles), 2e (1.52 g, 20 mmoles), 2f (2.99 g, 20
mmoles), 2g (2.45 g, 20 mmoles) or 2h (1.79 g, 20 mmoles) in
N,N-dimethylformamide (20 mL) was added 60% sodium
hydride (0.60 g, 15 mmoles). After the mixture was stirred at 0-5
˚C for 2 hours (in the case of the preparation of 3aꢀf) or room
temperature for 6 hours (in the case of the preparation of 3g,h),
cold water was added to the reaction mixture. The resulting
mixture was extracted with chloroform (60 mL). The extract was
dried over anhydrous sodium sulfate and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel with chloroform as the eluent to afford 3aꢀh.
5,6-Diaza-4-methyl-7-oxo-2,2,6-triphenylspiro[2.4]hept-4-
ene-1-carbonitrile (3e). This compound was obtained as
colorless needles (0.63 g, 33%), mp 174ꢀ176 ˚C (acetone-
petroleum ether); ir (potassium bromide): ꢂ 2246 (CꢀN), 1714
1
cm-1 (C=O); H nmr (deuteriochloroform): ꢁ 1.78 (s, 3H, 4-Me),
3.35 (s, 1H, 1-H), 7.17ꢀ7.40 (m, 11H, Ph-H), 7.53ꢀ7.55 (m, 2H,

1886
H. Maruoka, N. Kashige, T. Eishima, F. Okabe, R. Tanaka, T. Fujioka, F. Miake and K. Yamagata
Vol 45
Ph-H), 7.86ꢀ7.88 ppm (m, 2H, Ph-H); 13C nmr (deuterio-
chloroform): ꢁ 16.9 (4-Me), 24.2 (C-1), 45.3 (C-3), 53.9 (C-2),
115.1 (CꢀN), 118.6, 125.3, 128.1, 128.3, 128.9, 129.1, 129.4,
135.5, 137.4, 138.1 (Ph-C), 154.8 (C-4), 166.8 ppm (C=O); ms:
m/z 378 [M+H]+. Anal. Calcd. for C25H19N3O: C, 79.55; H, 5.07;
N, 11.13. Found: C, 79.78; H, 5.21; N, 11.10.
[4] Hiremath, S. P.; Rudresh, K.; Saundane, A. R. Indian J.
Chem. 2002, 41B, 394.
[5] Bailey, D. M.; Hansen, P. E.; Hlavac, A. G.; Baizman, E. R.;
Pearl, J.; DeFelice A. F. J. Med. Chem. 1985, 28, 256.
[6] Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Iwai,
N.; Hiyama, Y.;Suzuki, K.; Ito, H.; Kawasaki, M.; Nagai, K.; Wachi,
M.; Yamagishi, J. J. Med. Chem. 2004, 47, 3693.
[7] Vassile, G. N.; Terebenina, A. V.; Dimcheva, Z. P.; Kostova,
K. V.; Jordanov, M.; Jordanov, I.; Kouzmanova, R. B.; Borissov, G.
Dokl. Bolg. Akad. Nauk. 1981, 34, 591.
[8] Sugiura, S.; Ohno, S.; Ohtani, O.; Izumi, K.; Kitamikado,
T.; Asai, H.; Kato, K.; Hori, M.; Fujimura, H. J. Med. Chem. 1997,
20, 80.
[9] Kees, K. L.; Fitzgerald, J. J.; Steiner, K. E.; Mattes, J. F.;
Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. J. Med. Chem. 1996,
39, 3920.
5,6-Diaza-N,N-diethyl-4-methyl-7-oxo-2,2,6-triphenyl-
spiro[2.4]hept-4-ene-1-carboxamide (3f). This compound was
obtained as colorless needles (1.33 g, 59%), mp 134ꢀ136 ˚C
(acetone-petroleum ether); ir (potassium bromide): ꢂ 1703, 1656
1
cm-1 (C=O); H nmr (deuteriochloroform): ꢁ 1.17 [t, J = 7.0 Hz,
3H, N(CH2CH3)2], 1.24 [t, J = 7.0 Hz, 3H, N(CH2CH3)2], 1.78 (s,
3H, 4-Me), 3.39ꢀ3.47 and 3.57ꢀ3.63 [m, 4H, N(CH2CH3)2],
3.57 (s, 1H, 1-H), 7.14ꢀ7.36 (m, 9H, Ph-H), 7.37ꢀ7.39 (m, 2H,
Ph-H), 7.44ꢀ7.46 (m, 2H, Ph-H), 7.91ꢀ7.94 ppm (m, 2H, Ph-H);
13C nmr (deuteriochloroform): ꢁ 12.8 and 14.1 (2xNCH2CH3),
18.3 (4-Me), 40.4 and 42.4 (2xNCH2CH3), 42.3 (C-1), 47.1 (C-
3), 56.7 (C-2), 118.6, 124.8, 127.4, 127.7, 128.0, 128.4, 128.6,
128.8, 130.3, 136.5, 138.5, 140.9 (Ph-C), 157.5 (C-4), 164.6,
169.0 ppm (C=O); ms: m/z 452 [M+H]+. Anal. Calcd. for
C29H29N3O2: C, 77.14; H, 6.47; N, 9.31. Found: C, 77.17; H,
6.53; N, 9.24.
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B.; Svete, J. Heterocycles 2006, 68, 897.
Methyl 5,6-diaza-1,4-dimethyl-7-oxo-2,2,6-triphenylspiro-
[2.4]hept-4-ene-1-carboxylate (3g). This compound was
obtained as pale orange prisms (1.21 g, 57%), mp 166ꢀ168 ˚C
(acetone-petroleum ether); ir (potassium bromide): ꢂ 1737, 1710
1
cm-1 (C=O); H nmr (deuteriochloroform): ꢁ 1.45 (s, 3H, 4-Me),
1.86 (s, 3H, 1-Me), 3.75 (s, 3H, CO2Me), 7.13ꢀ7.27 (m, 10H,
Ph-H), 7.38ꢀ7.56 (m, 3H, Ph-H), 7.99ꢀ8.02 ppm (m, 2H, Ph-H);
13C nmr (deuteriochloroform): ꢁ 16.8 (1-Me), 18.2 (4-Me), 46.3
(C-3), 48.0 (C-1), 52.4 (CO2Me), 57.6 (C-2), 118.8, 124.8,
127.1, 127.5, 128.3, 128.4, 128.8, 129.3, 129.9, 137.1, 138.6,
139.1 (Ph-C), 156.6 (C-4), 167.9, 169.8 ppm (C=O); ms: m/z
425 [M+H]+. Anal. Calcd. for C27H24N2O3: C, 76.39; H, 5.70; N,
6.60. Found: C, 76.42; H, 5.74; N, 6.60.
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5,6-Diaza-1,4-dimethyl-7-oxo-2,2,6-triphenylspiro[2.4]-
hept-4-ene-1-carbonitrile (3h). This compound was obtained as
colorless needles (1.72 g, 88%), mp 196ꢀ198 ˚C dec.
(chloroform-petroleum ether); ir (potassium bromide): ꢂ 2238
1
(CꢀN), 1708 cm-1 (C=O); H nmr (deuteriochloroform): ꢁ 1.77
(s, 3H, 4-Me), 1.96 (s, 3H, 1-Me), 7.15ꢀ7.29 (m, 8H, Ph-H),
7.30ꢀ7.39 (m, 2H, Ph-H), 7.40ꢀ7.50 (m, 3H, Ph-H), 7.94ꢀ7.97
ppm (m, 2H, Ph-H); 13C nmr (deuteriochloroform): ꢁ 15.5 (1-
Me), 17.7 (4-Me), 31.3 (C-1), 46.1 (C-3), 56.2 (C-2), 118.9 (Ph-
C), 119.0 (CꢀN), 125.3, 127.9, 128.5, 128.7, 128.9, 129.1,
129.2, 134.7, 138.0, 138.2 (Ph-C), 155.3 (C-4), 166.2 ppm
(C=O); ms: m/z 392 [M+H]+. Anal. Calcd. for C26H21N3O: C,
79.77; H, 5.41; N, 10.73. Found: C, 79.77; H, 5.58; N, 10.66.
A. H. Tetrahedron 2007, 63, 1191.
Acknowledgment. We are grateful to Mr. Hiroshi Hanazono
and Ms. Yukiko Iwase for obtaining mass and nmr spectra and
to Ms. Junko Honda for her valuable help with elemental
analyses.
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Nov-Dec 2008
Synthesis and Antifungal Activity of Spiro[cyclopropane-1,4'-pyrazol-3-one] Derivatives
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