Novel synthesis of highly functionalized pyrazolone systems via rearrangement of 5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-diones

Article abstract of DOI:10.1007/s10593-011-0671-x

Epoxidation of 4-alkylidene(arylidene)-1-phenyl-3,5-pyrazolidinediones using alkaline hydrogen peroxide gave the corresponding 5-phenyl-1-oxa-5,6- diazaspiro[2.4]heptane-4,7-dione derivatives. Their reaction with nucleophilic reagents was investigated. The resulting products depend on the type of the diazaspiro compound and/or the nucleophile used.

Full text of DOI:10.1007/s10593-011-0671-x

Chemistry of Heterocyclic Compounds, Vol. 46, No. 11, February, 2011 (Russian Original Vol. 46, No. 11, November, 2010)
NOVEL SYNTHESIS OF HIGHLY FUNCTIONALIZED
PYRAZOLONE SYSTEMS VIA REARRANGEMENT OF
5-PHENYL-1-OXA-5,6-DIAZASPIRO[2.4]HEPTANE-4,7-DIONES
S. A. M. Metwally1*, T. A. Mohamed1, O. S. Moustafa1, Y. A. El-Ossaily1
Epoxidation of 4-alkylidene(arylidene)-1-phenyl-3,5-pyrazolidinediones using alkaline hydrogen peroxide
gave the corresponding 5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione derivatives. Their
reaction with nucleophilic reagents was investigated. The resulting products depend on the type of the
diazaspiro compound and/or the nucleophile used.
Keywords: 3,5-pyrazolidinediones, epoxidation, 15N NMR, ring transformation.
1-Phenyl-3,5-pyrazolidinedione condenses readily with carbonyl compounds in refluxing dioxane or
glacial acetic acid to yield 4-alkylidene(arylidene)-1-phenyl-3,5-pyrazolidinediones 1a-h [1-4].
The exocyclic olefinic bond at position 4 in derivatives 1a-h is highly reactive towards oxidation using
hydrogen peroxide in alkaline medium to give 5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione derivatives
2a-h. Smooth oxidations with high yield were achieved using acetonitrile as a solvent. The experimental facts
lead to the reaction mechanism proposed in Scheme 1.
Acetonitrile and alkaline hydrogen peroxide forms peroxycarboximidic acid (3) [5-8], which reacts with the
4-exocyclic double bond in 1a-h to give 5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione derivatives 2a-h.
Attempts to use a peroxycarboxylic acid in the oxidation of 1 failed. Peroxycarboxylic acids are electrophilic
oxidizing agents that are unreactive towards the ,-unsaturated carbonyl derivatives 1 [9-14].
Scheme1
R
R
O
O
R1
O
R1
NH
–
OH
+
N
MeCONH2
3
+
H2O2
N
+
MeCN
O
H
H
O
Me
OOH
N
N
3
Ph
Ph
2a–h
1a–h
1,2 a R = R1 = Me, b R+R1 = (CH2)5, c–h R = H, c R1 = Ph, d R1 = 4-MeC6H4,
e R1 = 2-MeOC H , f R1 = 4-ClC H , g R1 = 2-O NC H ,
1
h R = 4-O2NC6H4
6
4
6
4
2
6
4
_______
*To whom correspondence should be addressed, e-mail: Saoudmetwally@hotmail.com.
1 Chemistry Department, Assiut University, Assiut, Egypt
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1659-1669, November, 2010.
Original article received January 10, 2008, revised version submitted October 05, 2010.
1344
0009-3122/11/4611-1344©2011 Springer Science+Business Media, Inc.

The structure of compounds 2a-c was elucidated using elemental analysis, mass spectrometry, IR and,
1
particularly, NMR spectroscopy. The characteristic structural feature in the H NMR analysis of 2c-h is the
oxirane proton found at  values 4.5-5.2 ppm according to the type of the adjacent aromatic substituent [15, 16].
Likewise, 1H NMR spectra of compounds 2c-h indicated the presence of two isomers in equal amounts as shown
by the existence of two oxirane proton signals. This proves the formation of the diazaspiro derivatives 2c-h as
mixtures of diastereomers although according to the literature [17] the epoxidation of ,-unsaturated ketones with
alkaline hydrogen peroxide is diastereoselective.
The pairs of racemic diastereomers 2c-h were separated using the HPLC technique, and further
investigations are in progress.
Derivatives 2a-h are expected to be reactive intermediates due to the highly strained spirooxirane ring.
The present investigation will cover the reactivity of 2a-e with nucleophilic reagents, including nitrogen,
oxygen, and carbon nucleophiles. The reaction products depend on the spirooxirane derivatives used. Spiro
derivatives 2a,b without aromatic substituents on the oxirane ring react with nucleophilic reagents, forming the
corresponding adducts. Thus 2,2-dimethyl-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2a) and
2-phenyl-12-oxa-2,3-diazadispiro[4.0.5.1]dodecane-1,4-dione (2b) can react with different nucleophiles in a
unique fashion via ring transformation to give either 5,5-dialkyl-4-hydroxy-3-oxo-1-phenylpyrazolidine-
4-carboxylic acid derivatives 5a-f or their 3,3-dialkyl isomers 5'. Such ring transformation may occur via the
intermediates 4 or 4' following the proposed reaction mechanism (Scheme 2). Intermediates similar to 4 have been
isolated previously [18].
Scheme 2
R
R
O
O
R1
R1
O
O
R
+ NuH
O
R1
+ NuH
CONu
NuOC
HN
. .
NH
N
N
H
H
O
N
. .
N
O
Ph
Ph
2a–e
4a–i
Ph
4'
R
O
OH
HO
R1
O
CONu
OH
CONu
R
R
N
HN
R1
O
N
Ph
6
N
R1
HN
Ph
O
N
5a–i
Ph
5'
O
N
Ph
;
2a, 5a–d R = R1 = Me, 5 a Nu = HNNH2, b Nu = HNNHPh, c Nu = OMe, d Nu =
N
2b, 5e,f R = R1 = (CH2)5, 5 e Nu = HNNH2, f Nu = HNNHPh; 2c–e, 5g–i R = H,
2c, 5g R1 = Ph, 2d, 5h R1 = 4-MeC6H4, 2e, 5i R1 = 2-MeOC6H4, 5g–i Nu = HNNH2
O
The assigned structures of the products 5ai are inferred from elemental analysis and spectral data using
1
also comparison with similar compounds [16, 19]. The H NMR spectrum of 5b indicates a singlet at 1.16 and
1.27 ppm, a deuterium-exchangeable signal at 5.66 (OH), and broad singlets at 6.69 (NH) and 9.99 ppm (amidic
NH). The 10 aromatic protons are seen as a group of multiplets at 6.7-7.8 ppm.
1345

The 13C NMR spectrum of compound 5b conforms to the proposed structure. The 15N NMR spectrum of
compound 5b shows two signals at 63.09 and at 130.86 ppm, which correspond to one tertiary and three
secondary nitrogens.
The IR absorption spectrum of 5b indicates the presence of the following characteristic absorption
bands: 3310 (NH), 1680 and 1640 cm-1 (C=O).
Mass spectrometric analysis of compound 5b adds additional confirmation for the suggested structure.
The molecular ion represents the most abundant peak, which reflects its high stability under electron impact. The
fragmentation pathway of the molecular ion (m/z 340) indicates the presence of an ion at m/z 133
+
[C6H5N=C(CH3)2] with high relative abundance (51%). The appearance of this stable ion (acetone anil ion) and
the very low abundance (0.1%) of the ion at m/z 57 ((CH3)2C=NH, acetoneimine) can be considered as evidence
for the suggested structure 5b (Scheme 3).
Scheme 3
.
.
+
+
O
O
H
OH
OH
O
H
N
Me
N
Me
Me
N
N
Ph
N
Me
Me
H
Ph
N
NH
H
H
N
Me
Me
H
N
Me
N
O
Ph
Ph
m/z 57 (0.1%)
m/z 133 (51%)
m/z 340 (100%)
5b
m/z 340 (100%)
5'b
CNH(6b)m/e34(10%)
The resolution of 5b to the corresponding diastereomers and optically active isomers is under
investigation.
Scheme 4
R
R
NH
R
NH2
..
NH
O
–
+
OHC Ph
R
NH2
–
N
+
+
O
NH2
O
H
N
H
O
O
Ph
N
O
Ph
NHNH2
N
Ph
+
+
– H
O
H
N
N
+ H
R
O
H
N
Ph
Ph
CH
N
N
H
2c
R
O
8a–d
oxidation
N
N
O
NHN
H
H
N
H
R
O
N
N
H
O
N
Ph
Ph
7a–h
7 a R = H, b R = 4-OMe, c R = 2-Cl, d R = 3-Cl, e R = 4-Cl, f R = 3-Br, g R = 2-NO2,
h R = 3-NO2; 8 a R = H, b R = 2-NO2, c R = 3-NO2, d R = 3-Br
1346

5-Phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione derivatives 2c-e with an aromatic group on the
oxirane ring reacted with hydrazine hydrate with ring transformation to give the 1,5-diarylpyrazolidin-3-one
derivatives 5g-i as expected. With the use of phenylhydrazine or substituted phenylhydrazine with oxiranes 2c-e
having aryl substituent on the oxirane ring, no ring transformation reaction occurred. Starting with 2c as an
example, from its reaction with phenylhydrazine derivatives, 4-arylhydrazono-1-phenyl-3,5-pyrazolidinediones
7a-h were isolated, as well as benzaldehyde phenylhydrazone derivatives 8a-d with the characteristics reported
in the literature [20]. The mechanism for the formation of 7 and 8 is proposed in Scheme 4.
EXPERIMENTAL
Melting points were measured with a Gallenkamp electronic melting point apparatus and are
uncorrected. Elemental analyses were performed on an Elementar Vario EI apparatus. Infrared spectra were
recorded with a Shimadzu 470 infrared spectrophotometer (KBr wafer technique). 1H NMR, 13C NMR, and 15N
NMR spectra were recorded on a Bruker AMX 500 NMR spectrometer (400, 100, and 50.68 MHz, respectively)
in DMSO-d6 (for compounds 2b,c – CDCl3) using TMS as the internal standard for 1H and 13C. Chemical shifts
for 15N are reported with respect to the external standard of saturated 15NH4Cl in D2O. Chemical shifts are
reported in ppm ( scale). Mass spectra were recorded on Jeol JMS 600 spectrometer (FAB for compound 5b,
70 eV EI for all other compounds). HPLC analyses were performed on a Merck Hitachi 655 A-11 liquid
chromatograph using an RP-C18 column, 655A variable wavelength UV monitor, and D-2000 integrator.
Synthesis of 5-Phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione Derivatives 2 (General Method).
The 4-alkylidene(arylidene)-1-phenyl-3,5-pyrazolidinediones 1a-h [1-4] (4 mmol) were suspended in
acetonitrile (25 ml), and aqueous hydrogen peroxide solution (30%, 10 ml) was added to the stirred suspension
followed by aqueous sodium hydroxide solution (10%, -3 ml).
A. As soon as the color of the original 4-alkylidene(arylidene)-1-phenyl-3,5-pyrazolidinedione
disappeared, the reaction mixture was filtered off. The resulting filtrate was diluted with water and neutralized
with oxalic acid (5%) to give a precipitate which was collected, crystallized from the proper solvent, and
identified as the corresponding products 2a-h.
B. In the case of the soluble 5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione, the reaction product
was isolated by extraction twice with diethyl ether. The ether layer was dried over magnesium sulfate, filtered,
and the solvent was removed under reduced pressure. The residue was purified by crystallization from the
proper solvent.
2,2-Dimethyl-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2a). White amorphous solid
from ether, yield 75%; mp 150-152°C. IR spectrum, , cm-1: 3190 (NH), 3050 (aromatic CH), 2900 and 2850
1
(aliphatic CH), 1730 (C=O), 1700 (C=O), 1110 (st. vib. C–O), 900 (epoxide ring). H NMR spectrum, , ppm:
1.07 (3H, s, CH3); 1.72 (3H, s, CH3); 7.25 (1H, m, p-H Ar); 7.41 (2H, m, m-H Ar); 7.61 (1H, br. s, NH); 7.62 (2H,
13
m, o-H Ar). C NMR spectrum, , ppm: 18.56 (CH3), 18.98 (CH3), 59.88 (C-2), 71.57 (C-3), 135.52, 118.68,
129.40, and 126.33 (C6H5), 161.68 (C=O), 168.83 (C=O). Mass spectrum, m/z (Irel, %): 232 [M]+ (31), 231 (1), 217
(2), 216 (5), 204 (2), 176 (7), 58 (8), 28 (100). Found, %: C 62.22; H 5.21; N 12.12. C12H12N2O3. Calculated, %:
C 62.01; H 5.17; N 12.06.
2-Phenyl-12-oxa-2,3-diazadispiro[4.0.5.1]dodecane-1,4-dione (2b). Pale-yellow amorphous solid
from CHCl3–petroleum ether, 1:1, yield 53.3%; mp 185°C. IR spectrum, , cm-1: 3180 (NH), 3050 (aromatic
1
CH), 2900 and 2850 (aliphatic CH), 1730 (C=O), 1700 (C=O), 1110 (st. vib. C–O ), 890 (epoxide ring). H
NMR spectrum, δ, ppm: 1.39 (4H, m, 8,10-CH2); 1.80 (2H, m, 9-CH2); 2.11 (4H, m, 7,11-CH2); 7.26 (2H, m,
o-H Ar); 7.36 (1H, br. s, NH); 7.47 (1H, m, p-H Ar); 7.63 (2H, m, m-H Ar). 13C NMR spectrum, , ppm: 25.14,
25.58, 28.16, and 28.65 (cyclohexane ring), 59.95 (C-7), 118.71, 126.35, 129.47, 135.73 (C6H5),
1347

161.66 (C=O), 168.96 (C=O). Mass spectrum, m/z (Irel, %): 272 [M]+ (19), 271 (100), 256 (0.4), 244 (10); 176
(1), 108 (46). Found, %: C 66.01; H 5.88; N 10.21. C15H16N2O3. Calculated, %: C 66.11; H 5.88; N 10.28.
2,5-Diphenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2c). Pale-yellow amorphous solid from
benzene, yield 62.9%; mp 160°C. IR spectrum, , cm-1: 3150 (NH), 3050 (aromatic CH), 2850 (aliphatic CH),
1
1740 (C=O), 1700 (C=O), 1105 (st. vib. C–O), 895 (epoxide ring). H NMR spectrum, , ppm: 4.63 and 4.66
(1H, s, oxirane); 7.34 (2H, m, p-H Ar); 7.58 (2H, m, o-H Ar); 7.62 (4H, m, m-H Ar); 7.85 (2H, m, o-H Ar); 8.01
(1H, s, NH). 13C NMR spectrum, , ppm: 58.35 (C-2), 67.93 (C-3), 127.88, 128.84, 129.10, 129.80, 130.11,
136.23 and 144.51 (C6H5), 166.05 (C=O), 166.60 (C=O). Mass spectrum, m/z (Irel, %): 280 [M]+ (99), 279 (2), 265
(1), 252 (2), 251 (7), 247 (3), 195 (141), 106 (19), 56 (100). Found, %: C 68.61; H 4.31; N 9.89. C16H12N2O3.
Calculated, %: C 68.51; H 4.28; N 9.92.
Quantitative HPLC Analysis of 5-Phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione Derivatives
2. A highly pure sample of 2c was dissolved in acetonitrile to give 1×10–3 M solution. Then 20 l of that
solution was injected on an RP-C18 column, the flow rate was adjusted to 1.2 ml/min using a acetonitrile–water,
70:30, as eluent, and the product detection was done using UV-detector at  254 nm. Two isomers were
separated in the ratio 53:47 with retention times 3.02 and 5.82 min, respectively.
2-(4-Methylphenyl)-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2d). Pale-yellow granular
solid from ethanol, yield 80.2%; mp 130°C. IR spectrum, , cm–1: 3150 (NH), 3050 (aromatic CH), 2900 and
1
2850 (aliphatic CH), 1720 (C=O), 1700 (amidic C=O), 1110 (st. vib. CO), 905 (epoxide ring). H NMR
spectrum, , ppm: 2.31 (3H, s, CH3); 4.65 and 4.71 (1H, s, CH oxirane); 7.17 (2H, m, o-H Ar); 7.19 (2H, m,
m-H Ar); 7.49 (2H, m, o-H Ph); 7.51 (2H, m, m-H Ph); 7.55 (1H, s, NH); 7.91 (1H, m, p-H Ph). 13C NMR
spectrum, , ppm: 20.81 (CH3), 56.06 and 64.83 (C-2), 75.07 (C-3), 118.78, 125.16, 128.87 and 136.30 (C6H5),
127.89, 128.35, 128.49, and 129.05 (4-MeC6H4), 164.22 (C=O), 166.65 (C=O). Mass spectrum, m/z (Irel, %):
294 [M]+ (43.9), 293 (4), 278 (6); 279 (3), 266 (2), 265 (4), 209 (56), 120 (9), 91 (100). Found, %: C 69.25;
H 4.70; N 9.55. C17H14N2O3. Calculated, %: C 69.32; H 4.76; N 9.51.
2-(2-Methoxyphenyl)-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione
(2e).
Pale-yellow
granular solid from benzene–ethanol, 8:2, 85.4%; mp 160°C. IR spectrum, , cm–1: 3400 (NH), 3190 (aromatic
CH), 2900 and 2850 (aliphatic CH), 1740 (C=O), 1710 (C=O), 1110, 900 (epoxide ring). 1H NMR spectrum, ,
ppm: 3.51 (3H, s, OCH3); 4.65 and 4.69 (1H, s, CH oxirane); 6.99 (1H, m, m-H Ar); 7.03 (1H; m, o-H Ar); 7.19
(1H, m, m-H Ar); 7.35 (1H, m, p-H Ar); 7.41 (2H, m, o-H Ph); 7.48 (1H, m, p-H Ph); 7.57 (2H, m, m-H Ph); 7.65
13
(1H, s, NH). C NMR spectrum, , ppm: 55.64 (OCH3), 71.14 and 75.26 (C-2), 78.55 (C-3), 121.52, 126.52,
128.76 and 139.44 (C6H5), 111.73, 121.05, 124.23, 126.85, 129.69, and 157.72 (2-CH3OC6H4), 166.98 (C=O),
168.22 (C=O). Mass spectrum, m/z (Irel, %): 310 [M]+ (2), 309 (2), 295 (5.3), 294 (21.3), 282 (11.1), 281 (1.3),
136 (10.8). Found, %: C 65.81; H 4.61; N 9.03. C17H14N2O4. Calculated, %: C 65.74; H 4.51; N 9.02.
2-(4-Chlorophenyl)-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2f). White granular solid
from benzene–ethanol, 7:3, yield 60.1%; mp 187°C. IR spectrum, , cm–1: 3250 (NH), 3050 (aromatic CH),
2950 and 2900 (aliphatic CH), 1670 (C–O), 1180, 900 (epoxide ring). 1H NMR spectrum, , ppm: 4.73 and 4.79
(1H, s, CH oxirane); 7.21 (2H, m, o-H Ar); 7.25 (2H, m, m-H Ar); 7.37 (2H, m, o-H Ph); 7.42 (1H, m, p-H Ar);
7.56 (2H, m, m-H Ph); 7.68 (1H, s, NH). 13C NMR spectrum, , ppm: 58.05 and 58.39 (C-2), 65.41 (C-3),
118.91, 125.41, 129.67 and 136.30 (C6H5), 128.32, 131.18, 133.71 and 160.41 (4-ClC6H4), 161.41 (C=O),
164.90 (C=O). Mass spectrum, m/z (Irel, %): 314 [M]+ (6), 313 (6), 315 (2), 298 (6), 300 (2), 299 (7), 301 (0.4),
286 (1), 288 (1), 285 (2), 287 (5), 229 (11), 231 (2), 140 (3), 142 (0.4), 111 (100). Found, %: C 61.15; H 3.52;
N 8.92. C16H11ClN2O3. Calculated, %: C 61.01; H 3.49; N 8.89.
2-(2-Nitrophenyl)-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2g). Pale-yellow granular
solid from benzene–ethanol, 8:2, yield 63.39%; mp 185-187°C. IR spectrum, , cm–1: 3190 (NH), 3080
1
(aromatic CH), 2900 and 2850 (aliphatic CH), 1740 (C=O), 1705 (C=O), 1150, 915 (epoxide ring). H NMR
spectrum, , ppm: 5.13 and 5.17 (1H, s, CH oxirane); 7.21 (2H, m, o-H Ph); 7.36 (1H, m, p-H Ph); 7.41 (1H, m,
1348

o-H Ar); 7.66 (1H, m, p-H Ar); 7.72 (2H, m, m-H Ph); 8.19 (2H, m, m-H Ar); 8.21 (1H, s, NH). 13C NMR
spectrum, NMR spectrum, , ppm: 58.17 and 63.57 (C-2), 64.05 (C-3), 118.88, 124.41, 125.52, 128.97, 129.14,
130.18, 134.26, 136.28 and 146.58 (Ar), 160.23 (C=O), 161.42 (C=O). Mass spectrum, m/z (Irel, %): 325 [M]+
(42), 324 (1), 309 (10), 310 (4), 297 (2), 296 (2), 240 (3), 151 (18), 46 (100). Found, %: C 59.20; H 3.22;
N 12.23. C16H11N3O5. Calculated, %: C 59.03; H 3.38; N 12.19.
2-(4-Nitrophenyl)-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2h). Yellow granular solid
from benzene–ethanol, 7:3, yield 47.6%; mp 215°C. IR spectrum, , cm–1: 3200 (NH), 3050 (aromatic CH),
1
2900 and 2850 (aliphatic CH), 1110, 895 (epoxide ring). H NMR spectrum, , ppm: 4.86 and 4.91 (1H, s, CH
oxirane); 7.21 (1H, m, p-H Ph); 7.36 (2H, m, m-H Ph); 7.57 (2H, m, o-H Ph); 7.67 (1H, s, NH); 7.87 (2H, m,
o-H Ar); 8.23 (2H, m, m-H Ar). 13C NMR spectrum, , ppm: 58.24 and 64.02 (C-2), 64.58 (C-3), 118.79,
125.21, 129.29, 136.52, and 138.51 (C6H5), 122.63, 128.97, 136.52, 147.66 (4-NO2C6H4), 160.30 (C=O), 164.08
(C=O). Mass spectrum, m/z (Irel, %): 325 [M]+ (70.4), 310 (4.9), 297 (3.9), 296 (0.7), 240 (4.9), 151 (100).
Found, %: C 59.05, H 3.41; N 12.95. C16H11N3O5. Calculated, %: C 59.04, H 3.38; N 12.91.
4-Hydroxy-5,5-dimethyl-3-oxo-1-phenylpyrazolidine-4-carbohydrazide (5a). White flakes from
ethanol, yield 70.4%; mp 225°C. IR spectrum, , cm–1: 3400 and 3300 (NH2), 3200 (NH), 3050 (aromatic CH),
2950 (aliphatic CH), 1680 (C=O), 1620 (C=O) 1590 (bending vib. NH). 1H NMR spectrum, , ppm: 1.08 (3H, s,
CH3); 1.15 (3H, s, CH3); 4.39 (2H, s, NHNH2); 5.63 (1H, s, OH); 6.65 (1H, m, NHNH2); 7.12 (1H, m, p-H Ph);
13
7.37 (2H, m, m-H Ph); 7.80 (2H, m, o-H Ph); 9.24 (1H, s, NHC=O). C NMR spectrum, , ppm: 21.70 (CH3),
24.95 (CH3), 62.21 (C-5), 83.73 (C-4), 118.01, 124.18, 128.60, and 139.21 (C6H5), 167.75 (C=O). Mass
spectrum, m/z (Irel, %): 264 [M]+ (100), 263 (94), 262 (21), 250 (3), 249 (11), 247 (12), 236 (2), 234 (12), 233
(2), 207 (20), 205 (85), 187 (4), 178 (9), 176 (74), 175 (7), 130 (17). Found, %: C 54.51; H 6.12; N 21.22.
C12H16N4O3. Calculated, %: C 54.49; H 6.05; N 21.19.
4-Hydroxy-5,5-dimethyl-3-oxo-N',1-diphenylpyrazolidine-4-carbohydrazide (5b). Pale-yellow flakes
from ethanol, yield 68.3%; mp 185°C. IR spectrum, , cm–1: 3310 (amidic st. vib. NH), 3050 (aromatic CH),
2900 and 2950 (aliphatic CH), 1680 (C=O), 1640 (C=O), 1590 (amidic bending vib. NH). 1H NMR spectrum, ,
ppm: 1.16 (3H, s, CH3); 1.27 (3H, s, CH3); 5.66 (1H, s, OH); 6.69 (2H, s, NHNH); 6.71 (1H, m, p-H Ar); 6.80
(4H, m, o-H Ar); 7.14 (1H, m, p-H Ar); 7.37 (2H, m, m-H Ar); 7.81 (2H, m, m-H Ar); 9.99 (1H, s, NH).
13C NMR spectrum, , ppm: 19.74 (CH3), 21.96 (CH3), 62.45 (C-5), 83.96 (C-4), 112.52, 118.00, 128.68, and
139.20 (C6H5), 118.66, 124.16, 128.60, 149.22 (C6H5), 169.64 (C=O), 170.29 (C=O). Mass spectrum, m/z
(Irel, %): 340 [M]+ (100), 339 (43), 338 (8), 326 (0.2), 249 (2), 233 (2), 206 (68), 205 (3) 176 (5), 175 (4), 148
(66), 134 (12), 133 (51). Found, %: C 63.48; H 5.91; N 16.42. C18H20N4O3. Calculated, %: C 63.46; H 5.88;
N 16.45.
4-Hydroxy-3-oxo-1-phenyl-1,2-diazaspiro[4.5]decane-4-carbohydrazide (5e). White flakes from
ethanol, yield 71.7%; mp 215°C. IR spectrum, , cm–1: 4300 and 3300 (NH2), 3200 (amidic st. vib. NH), 3050
1
(aromatic CH), 2900 and 2850 (aliphatic CH), 1680 (C=O), 1660 (C=O), 1630 (amidic bending vib. NH). H
NMR spectrum, , ppm: 1.37, 1.42 and 1.67 (10H, m, (CH2)5); 4.35 (2H, s, NHNH2); 5.47 (1H, s, OH); 7.11,
7.64 and 7.37 (6H, m, Ar and NHNH2); 9.17 (1H, s, NHC=O). 13C NMR spectrum, , ppm: 21.32, 25.31, 27.89
(cyclohexane ring), 63.80 (C-5), 84.22 (C-4), 117.83, 123.92, 128.62, and 139.46 (C6H5), 167.53 (C=O), 170.71
(C=O). Mass spectrum, m/z (Irel, %): 303 [M−H]+ (15.1), 188 (7), 179 (17), 170 (12), 145 (11), 117 (16), 103
(20), 75 (21), 46 (100). Found, %: C 59.22; H 6.67; N 18.41. C15H20N4O3. Calculated, %: C 59.14; H 6.57;
N 18.39.
4-Hydroxy-3-oxo-N',1-diphenyl-1,2-diazaspiro[4.5]decane-4-carbohydrazide (5f). Dark-yellow flakes
from ethanol, yield 71.6%; mp 139°C. IR spectrum, , cm–1: 3320 (amidic st. vib. NH), 3050 (aromatic CH), 2950
1
and 2850 (aliphatic CH), 1680 (C=O), 1640 (C=O), 1590 (amidic bending vib. NH). H NMR spectrum, , ppm:
1.38, 1.49, and 1.66 (10H, m, (CH2)5); 5.48 (1H, s, OH); 6.69, 6.81, 7.12, 7.37, 7.67, 7.77, and 7.84 (12H, m,
1349

10 H Ar and 2 NH); 9.95 (1H, s, NHC=O). 13C NMR spectrum, , ppm: 21.38, 25.31, 27.87 (cyclohexane ring),
64.02 (C-5), 84.56 (C-4), 117.91, 118.59, 123.98, 125.44, 128.50, 128.98, 139.39, 149.22 (C6H5), 169.33
(C=O), 170.44 (C=O). Mass spectrum, m/z (Irel, %): 379 [M−H]+ (17), 231 (6), 203 (8), 189 (14), 188 (27),
161 (5), 28 (100). Found, %: C 66.31; H 6.26; N 14.33. C22H24N4O3. Calculated, %: C 67.27; H 6.12; N 14.27.
Reaction of 2,2-Dimethyl-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2a) with Sodium
Methoxide in Absolute Methanol (Oxygen Nucleophile). A mixture of equimolar amounts (0.1 mmol) of
compound 2a and sodium methoxide in the presence of absolute methanol as a solvent was refluxed for 4 h.
After filtration, the resulting filtrate was evaporated under reduced pressure till dryness. The resulting residue
was neutralized by dilute HCl to give a precipitate that was collected and crystallized from chloroform–
petroleum ether, 3:7, and identified as methyl 4-hydroxy-5,5-dimethyl-3-oxo-1-phenyl-pyrazolidine-4-carboxylate
(5c) in the form of pale-yellow flakes, yield 70.4%; mp 118-120°C. IR spectrum, , cm1: 3190 (amidic st. vib.
NH), 3050 (aromatic CH), 2900 and 2850 (aliphatic CH), 1730 (C=O), 1700 (C=O), 1580 (amidic bending vib.
NH). 1H NMR spectrum, , ppm: 1.61, 1.60 (6H; s, C(CH3)2); 3.72 (3H, s, COOCH3); 7.22, 7.40, 7.66, 7.79 and
7.81 (7H, m, H Ar, NH, and OH). 13C NMR spectrum, , ppm: 18.05 (CH3), 18.54 (CH3), 52.39 (COOCH3), 69.87
(C-5), 84.07 (C-4), 118.88, 123.37, 128.59, 136.28 (C6H5), 169.21 (C=O), 170.05 (C=O). Mass spectrum, m/z
(Irel, %): 264 [M]+ (2), 263 (9), 262 (2), 250 (10), 249 (1), 247 (1), 234 (1), 233 (1), 207 (2), 205 (34), 187 (7),
175 (4), 148 (14), 130 (3), 46 (100). Found, %: C 57.09; H 5.99; N 10.68. C13H16N2O4. Calculated, %: C 59.03;
H 6.05; N 10.59.
Reaction of 2,2-Dimethyl-5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2a) with the Sodium
Salt of 1-Phenyl-3,5-pyrazolidinedione (Carbon Nucleophile). A mixture of equimolar amounts (0.1 mmol) of
compound 2a (0.467 g, 2.00 mmol), 1-phenyl-3,5-pyrazolidinedione (0.352 g, 2.00 mol), and metallic sodium
(0.046 g, 2.0 mmol) in absolute ethanol as a solvent was refluxed for 6 h. After cooling, the reaction mixture
was diluted and acidified by dilute HC1 to give a precipitate that was collected and crystallized from ethanol,
and identified as 1-[(4-hydroxy-5,5-dimethyl-3-oxo-1-phenylpyrazolidin-4-yl)carbonyl]-2-phenylpyrazolidine-
3,5-dione (5d) in the form of a pale-yellow granular solid from ethanol, yield 56.9%; mp 210°C. IR spectrum, ,
cm1: 3210 (amidic st. vib. NH), 3050 (aromatic CH), 2900 (aliphatic CH), 1740 (C=O), 1700 (C=O), 1589
(bending vib. NH). 1H NMR spectrum, δ, ppm : 2.67 (6H, s, 2CH3); 5.96 (1H, s, OH); 7.51 (13H, m, H Ar, 2 NH
13
and OH). C NMR spectrum, δ, ppm: 16.47 (CH3), 53.23 (C-5), 111.82 (C-4), 118.21, 122.97, 129.03, 144.30
(C6H5), 119.56, 121.58, 128.85, 146.99 (C6H5), 160.55 (C=O), 170.34 (C=O), 174.42 (C=O), 194.46 (C=O).
FAB mass spectrum, m/z (Irel, %): 408 [M]+ (2). Found, %: C 61.67; H 4.85; N 13.66. C21H20N4O5. Calculated, %:
C 61.71; H 4.89; N 13.71.
Reaction of 5-Phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione Derivatives 2c-e with Hydrazine
Hydrate (Nitrogen Nucleophiles) (General Method). A mixture of equimolar amounts (0.1 mmol) of
compounds 2ce and hydrazine hydrate in absolute ethanol was refluxed for 4 h. After cooling, the precipitate
was collected, crystallized from the proper solvent, and identified as 5-aryl-4-hydroxy-3-oxo-1-phenyl-
pyrazolidine-4-carboxylic acid hydrazides 5g-i. The results are summarized as follows.
4-Hydroxy-3-oxo-1,5-diphenylpyrazolidine-4-carbohydrazide (5g). White granular solid from
ethanol, yield 71.8 %; mp 300°C. IR spectrum, , cm1: 3350 and 3250 (NH2), 3050 (aromatic CH), 2900 and
2850 (aliphatic CH), 1740 (C=O), 1640 (amidic C=O), 1590 (amidic bending vib. NH). 1H NMR spectrum, ,
ppm : 4.65 (1H, s, H-5 pyrazolone); 4.59 (1H, s, OH); 5.36 (2H, s, NH2); 6.06, 6.55, 6.86, and 7.39 (10H, m, H
13
Ar); 9.44 (1H, s, NH); 9.93 (1H, s, NHC=O). C NMR spectrum, δ, ppm: 70.44 (C-5), 80.69 (C-4), 112.01,
118.08, 124.60, 126.31, 128.30, 134.76, and 148.59 (C6H5), 168.21 (C=O), 173.65 (C=O). Mass spectrum, m/z
(Irel, %): 312 [M]+ (38), 311 (0.4), 310 (0.3), 298 (1), 297 (2), 295 (1), 253 (6), 235 (2), 134 (6), 28 (100).
Found, %: C 61.59; H 5.15; N 17.85. C16H16N4O3. Calculated, %: C 61.48; H 5.12; N 17.93.
4-Hydroxy-3-(4-methylphenyl)-5-oxo-1-phenylpyrazolidine-4-carbohydrazide (5h). White granular
solid from ethanol, yield 72.7%; mp 230°C. IR spectrum, , cm1: 3390 and 3220 (NH2), 3050 (aromatic CH),
2900 and 2850 (aliphatic CH), 1700 (C=O), 1650 (C=O) 1590 (amidic bending vib. NH). 1H NMR spectrum, δ,
1350

ppm: 2.33 (3H, s, CH3); 5.18 (1H, s, H-5 pyrazolone); 5.21 (1H, s, OH); 5.06 (2H, s, NH2); 6.60 (1H, s, NH);
7.56, 7.93, 7.43, 7.17 and 7.20 (9H, m, H Ar); 11.35 (1H, s, NHC=O). 13C NMR spectrum, δ, ppm: 20.73 (CH3),
65.12 (C-5), 82.27 (C-4), 112.22, 118.28, 129.47, 149.18 (C6H5), 127.17, 128.76, 137.18, 139.71 (4-CH3C6H4),
165.69 (C=O), 168.29 (C=O). Mass spectrum, m/z (Irel, %): 326 [M]+ (15), 325 (76), 324 (1), 312 (0.4), 309 (3),
295 (3), 267 (4), 235 (2), 234 (2), 209 (17), 134 (34), 28 (100). Found, %: C 62.51; H 5.61; N 17.40.
C12H18N4O3. Calculated, %: C 62.60; H 5.61; N 17.21.
4-Hydroxy-3-(2-methoxylphenyl)-5-oxo-1-phenylpyrazolidine-4-carbohydrazide (5i). Orange granular solid
from ethanol, yield 80.9%; mp 175°C. IR spectrum, , cm1: 3400 and 3300 (NH2), 3040 (aromatic CH), 2900
and 2850 (aliphatic CH), 1680 (C=O), 1590 (amidic bending vib. NH). 1H NMR spectrum, δ, ppm: 3.70 (3H, s,
OCH3); 5.22 (1H, s, 5-H pyrazolone); 5.24 (1H, s, OH); 6.29 (2H, s, NHNH2); 6.58 (1H, s, NHNH2); 6.88, 6.90,
13
6.96, 7.26, 7.42, 7.63, and 7.70 (9H, m, H Ar); 8.93 (1H, s, NHC=O). C NMR spectrum, δ, ppm: 55.54
(OCH3), 81.35 (C-4), 110.72, 118.30, 128.79, 138.52 (C6H5), 117.87, 128.14, 128.79, 128.90, 133.33, 155.82
(2-MeOC6H4), 128.79 (C-5), 157.25 (C=O), 168.31 (C=O). Mass spectrum, m/z (Irel, %): 342 [M]+ (1), 341 (3),
340 (1), 327 (0.4), 325 (2), 311 (1), 283 (4), 235 (1), 234 (3), 225 (64), 134 (29), 46 (100). Found, %: C 59.49;
H 5.22; N 16.46. C17H18N4O4. Calculated, %: C 59.58; H 5.26; N 16.36.
Reactions of 2,5-Diphenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-dione (2c) with Phenylhydrazine
and Substituted Phenylhydrazines (General Method). A mixture of equimolar amounts (0.1 mmol) of 2c and
phenylhydrazine or substituted phenylhydrazine in absolute ethanol was refluxed for 4 h. After cooling, a
precipitate was formed, which was collected, crystallized from the proper solvent, and identified as 4-aryl-
hydrazono-1-phenyl-3,5-pyrazolidinediones 7a-c [17]. The filtrate was evaporated under reduced pressure, and the
remaining residue was crystallized from the proper solvent. The product was identified as the corresponding
benzaldehyde arylhydrazones 8a-d.
1-Phenyl-4-(2-phenylhydrazinylidene)pyrazolidine-3,5-dione (7a). Orange flakes from ethanol, yield
62%; mp 232233 °C (232°C lit. [17]). IR spectrum, , cm1: 3200 (NH), 3040 (aromatic CH), 2900 and 2850
(aliphatic CH), 1710 (C=O), 1640 (C=O), 1590 (N=N), 1550 (C=N). Mass spectrum, m/z (Irel, %): 280 [M]+ (16),
279 (100), 119 (2), 106 (10), 92 (49). Found, %: C 64.31; H 4.30; N 19.68. C15H12N4O2. Calculated, %: C 64.22;
H 4.28; N 19.98.
Benzaldehyde Phenylhydrazone (8a). Pale-yellow needles from cyclohexane, yield 57.1%; mp
158160 °C, mp of a mixture with authentic sample 158-160°C. IR spectrum, , cm1: 3285 (NH), 3020
(aromatic CH), 1585 (C=N). Found, %: C 79.52; H 5.98, N 14.35. C13H12N2. Calculated, %: C 79.59; H 6.12;
N 14.28.
4-[2-(4-Methoxyphenyl)hydrazinylidene]-1-phenylpyrazolidine-3,5-dione (7b). Orange flakes from
ethanol, yield 54.3%; mp 238-240°C. IR spectrum, , cm1: 3150 (NH), 3030 (aromatic CH), 2850 (aliphatic
CH), 1680 (C=O), 1650 (C=O). Mass spectrum, m/z (Irel, %): 310 [M]+ (21), 309 (100), 279 (2), 135 (2), 122
(38). Found, %: C 62.01; H 4.45; N 17.99. C16H14N4O3. Calculated, %: C 61.88; H 4.52; N 18.11.
4-[2-(2-Chlorophenyl)hydrazinylidene]-1-phenylpyrazolidine-3,5-dione (7c). Brown granular solid
from ethanol, yield 50.9%; mp 238°C. IR spectrum, , cm1: 3200 (NH), 3050 (aromatic CH), 2950 (aliphatic
CH), 1690 (C=O), 1660 (C=O), 1580 (N=N). Mass spectrum, m/z (Irel, %): 316 (4), 314 (14), 313 (46), 128 (15),
28 (100). Found, %: C 57.45, H 3.52 N 17.85. C15H11N4O2. Calculated, %: C 57.32, H 3.50, N 17.83.
4-[2-(3-Chlorophenyl)hydrazinylidene]-1-phenylpyrazolidine-3,5-dione (7d). Orange granular solid
from ethanol, yield 43.2%; mp 143-145°C. IR spectrum, , cm1: 3150 (NH), 3050 (aromatic CH), 2900 and
2850 (aliphatic CH), 1690 (C=O), 1660 (C=O), 1560 (N=N). Mass spectrum, m/z (Irel, %): 315 (14), 313 (55),
175 (8), 128 (7), 126 (45), 106 (7), 103 (15), 91 (13), 77 (7), 56 (100). Found, %: C 57.28; H 3.49; N 17.85.
C15H11ClN4O2. Calculated, %: C 57.32; H 3.50; N 17.83.
4-[2-(4-Chlorophenyl)hydrazinylidene]-1-phenylpyrazolidine-3,5-dione (7e). Orange granular solid
from ethanol, yield 40.7%; mp 263-265°C. IR spectrum, , cm1: 3190 (NH), 3050 (aromatic CH), 2950
(aliphatic CH), 1710 (C=O), 1640 (C=O), 1580 (N=N). Mass spectrum, m/z (Irel, %): 316 (7), 315 (12), 314
1351

(19), 313 (48), 279 (5), 175 (1), 133 (12), 128 (18), 28 (100). Found, %: C 57.38; H 3.48; N 17.78.
C12H16ClN4O2. Calculated, %: C 57.32; H 3.50; N 17.83.
4-[2-(3-Bromophenyl)hydrazinylidene]-1-phenylpyrazolidine-3,5-dione (7f). Orange flakes from
ethanol, yield 46.9%; mp 262°C. IR spectrum, , cm1: 3150 (NH), 3050 (aromatic CH), 2850 (aliphatic CH),
1690 (C=O), 1660 (C=O), 1580 (N=N). Mass spectrum, m/z (Irel, %): 360 (15), 359 (90), 358 (19), 357 (100),
172 (5), 170 (7), 134 (5). Found, %: C 50.22; H 3.11; N 15.61. C15H11BrN4O2. Calculated, %: C 50.2; H 3.12;
N 15.63.
Benzaldhyde 3-bromophenylhydrazone (8d). Pale-yellow granular solid from ethanol, yield 40.8%;
mp 125°C. IR spectrum, , cm1: 3300 (NH), 3050 (aromatic CH), 1590 (C=N). Found, %: C 57.71; H 4.10;
N 10.02. C13H11BrN2. Calculated, %: C 56.69; H 3.99; N 10.18.
4-[2-(2-Nitrophenyl)hydrazinylidene]-1-phenylpyrazolidine-3,5-dione (7g). Brown granular solid
from ethanol, yield 51.7%; mp 280°C. IR spectrum, , cm1: 3290 (NH), 3050 (aromatic CH), 2900 and 2850
(aliphatic CH), 1690 (C=O), 1660 (C=O), 1580 (N=N), 1530 (C=N), 1490 (CNO2). Mass spectrum, m/z,
(Irel, %): 325 [M+] (25), 324 (100), 137 (27), 135 (11). Found, %: C 55.41; H 3.32; N 21.42. C15H11N5O4.
Calculated, %: C 55.34; H 3.38; N 21.52.
Benzaldehyde 2-Nitrophenylhydrazone (8b). Dark-red flakes from ethanol, yield 41.9%; mp 130-133°C.
IR spectrum, , cm1: 3295 (NH), 3050 (aromatic CH), 1610 (C=N), 1500 (C–NO2). Found, %: C 64.73; H 4.62;
N 17.51. C13H11N3O2. Calculated, %: C 64.67; H 4.56; N 17.41.
4-[2-(3-Nitrophenyl)hydrazinylidene]-1-phenylpyrazolidine-3,5-dione (7h). Orange flakes from ethanol,
yield 43.1%; mp 158-187°C. IR spectrum, , cm1: 3200 (NH), 3030 (aromatic CH), 2900 (aliphatic CH), 1710
(C=O), 1680 (C=O), 1610 (C=N), 1580 (N=N). Mass spectrum, m/z (Irel, %): 325 [M+] (16), 324 (56), 137 (45),
134 (6), 133 (38), 106 (20), 77 (100).
Benzaldehyde 3-Nitrophenylhydrazone (8c). Orange flakes from ethanol, yield 39.5%; mp 198°C. IR
spectrum, , cm1: 3300 (NH), 3050 (aromatic CH), 1610 (C=N), 1540 (CNO2).
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