Green synthetic investigation and spectral characterization of some spiro pyrazolidine-based heterocycles with potential biological activity

Article abstract of DOI:10.1002/jhet.3898

A green, rapid, and efficient methodology is developed for the synthesis of 1-phenyl-3,5-pyrazolidinedione (3) by the reaction of malonic acid with phenyl hydrazine in the presence of phosphorous oxychloride under solvent-free conditions. The later compou

Full text of DOI:10.1002/jhet.3898

Received: 17 April 2019
DOI: 10.1002/jhet.3898
Revised: 29 November 2019
Accepted: 26 December 2019
A R T I C L E
Green synthetic investigation and spectral characterization
of some spiro pyrazolidine-based heterocycles with
potential biological activity
Yasser A. El-Ossaily1,2
| Saoud A. Metwally2 | Nayef S. Al-Muailkel1
|
Ahmed Fawzy2,3 | Hazim M. Ali1 | Yousra A. Naffea2
1Chemistry Department, College of
Abstract
Science, Jouf University, Sakaka,
Saudi Arabia
2Chemistry Department, Faculty of
A green, rapid, and efficient methodology is developed for the synthesis of
1-phenyl-3,5-pyrazolidinedione (3) by the reaction of malonic acid with phenyl
hydrazine in the presence of phosphorous oxychloride under solvent-free con-
ditions. The later compound 3 was used as a versatile precursor for green syn-
thesis of chalcone derivatives (4a-h) and spiroheterocyclic compounds (5a-h)
with good to excellent isolated yields. The chemical structures of the synthe-
sized compounds were elucidated on the basis of elemental and spectral
analyses.
Science, Assiut University, Assiut, Egypt
3Chemistry Department, Faculty of
Applied Sciences, Umm Al-Qura
University, Makkah, Saudi Arabia
Correspondence
Yasser A. El-Ossaily, Chemistry
Department, College of Science, Jouf
University, P.O. Box: 2014.Sakaka, Saudi
Arabia.
Email: yasserabdelmoez@yahoo.com
1 | INTRODUCTION
effect of solvent on the synthesis of 3 was initially investi-
gated by the reaction of malonic acid, phenyl hydrazine
Pyrazolidinediones have attracted considerable attention
because of their important broad spectrum of biological
applications such as analgesics,[1] antimicrobial,[2–5]
antirheumatics,[6] antiphlogistic agents,[7] and anti-
inflammatory drugs.[8–10] Moreover, pyrazole derivatives
revealed many practical applications in the medicinal
field as antioxidant, antidepressant, anti-influenza, anti-
cancer activities.[11–18] In continuation of our work on
pyrazolidinediones,[19–24] we report herein green syn-
thetic investigation of some spiroheterocycles of potential
biological activity.
and phosphorous oxychloride in different solvents. As
shown in Table 1, the synthesis in halogenated solvents
gave the expected product 3 in different yields (50-60%).
However, solvent-free reaction afforded higher yield
(80%) than their liquid-phase counterparts (Scheme 1).
The structural elucidation of 3 was ascertained through
comparison with the reported data.[20] Intensive spectral
1
analysis as HNMR, 13CNMR, DEPT-135, COSY, HSQC,
and HMBC were proved the dicarbonyl structure
(2 hydrogenated nitrogen) of 3. DEPT-135 showed down-
ward signal characteristic for methylene carbon (─CH2─)
and three upward signals characteristic for methine car-
bons (═CH─). COSY, HSQC, and HMBC were confirmed
the neighbor protons, C─H connectivity and long range
correlation through the bonds.
2 | RESULTS AND DISCUSSION
The main features of green chemistry synthesis are sim-
ple methodology, fast, easy product isolation and purifi-
cation. These advantages prompted us to develop simple
Our approach to the desirable
bioactive
spiroheterocyclic compounds was achieved by the reac-
tion of the versatile precursor 3 with various chemical
reagents. Here a modified method was employed to
improve the isolated yield of the desired compounds
green
method
to
synthesize
1-phenyl-3,5-
Pyrazolidinedione (3) and some of its derivatives. The
J Heterocyclic Chem. 2020;1–8.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

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EL-OSSAILY ET AL.
compared with the previous work.[20,22] Heating of 3 with
different carbonyl compounds under solvent-free condi-
tion gave excellent yield of 4-alkylidene (4a and 4b) or
4-arylidene derivatives (4c-h) (chalcone derivatives)
(Scheme 2) compared with reported literature.[25–39] 4-(20-
Methoxylbenzylidene)-1-phenyl-3,5-pyrazolidinedione
(4e) was ascertained through spectral analysis as 1HNMR,
13CNMR, DEPT-135, COSY, HSQC, and HMBC. The 2D
NMR analysis was in agreement with the proposed struc-
ture. DEPT-135 showed nine upward signals characteris-
tic for methoxy carbon (─OCH3) and methine carbons
(═CH─). COSY, HSQC, and HMBC were showed the
neighbor protons, C─H connectivity and long range cor-
relation through the bonds.
Moreover, the green chemistry approach was
employed to investigate the effect of solvent polarity in
the epoxidation of chalcone derivatives 4a-h by using
magnesium monoperoxyphthalate hexahydrate (MMPP)
as a versatile oxidizing agent. The oxidation in presence
of protic solvent (ethanol) was better in yield than aprotic
solvent (THF) (Scheme 2).[40–45] The chemical reactivity
of the oxidizing agent (MMPP) towards chalcone deriva-
tives 4a-h in THF due to their polarity and weak
THF/water hydrogen bond.[46] Compounds 4a-h are
highly reactive towards MMPP reagent. Such chemical
reactivity encouraged us to attempt the green synthesis of
1-phenyl −3,5-dioxo-1,2,3,5-tetrahydrospiropyrazole-4,30-
oxirane derivatives (5a-h). The reaction yield as well as
feasibility were found to be dependent on the structure of
4a-h and solvent used (Scheme 2). The physical and spec-
tral data of compounds 5a-h were identical to the
reported data.[22] 20,20-Dimethyl-1-phenyl-3,5-dioxo-
1,2,3,5-tetrahydrospiropyrazole-4,30-oxirane (5a) was
obtained in good yield and for the first time by epoxida-
tion of 4-isopyropylidene-1-phenyl-3,5-pyrazolidinedione
(4a) using MMPP in ethanol or tetrahydrofuran as sol-
vent in neutral medium. This may be attributed to the
increased activity of the 4-exocyclic double bond due to
the presence of two methyl groups. Such structural
TABLE 1 Solvent effect on the synthesis of 1-phenyl-
3,5-pyrazolidinedione (3)
Entry
Solvent
CHCl3
Time (h)
Yield (%)
1
2
3
4
5
3
3
3
60
55
50
80
CH2Cl2
CCl4
Solvent-free
SCHEME 1 Synthesis of 1-phenyl-3,5-pyrazolidinedione (3)
under solvent-free condition
SCHEME 3 Tautomer's of 20,20-Dimethyl-1-phenyl-3,5-dioxo-
1,2,3,5-tetrahydrospiropyrazole-4,30-oxirane (5a)
SCHEME 2 Synthesis of
chalcone derivatives (4a-h) and
synthesis of 1-phenyl −3,5-dioxo-
1,2,3,5-tetrahydrospiropyrazole-4,30-
oxirane derivatives (5a-h)

EL-OSSAILY ET AL.
3
SCHEME 4 The suggested
reaction mechanism for epoxidation
by magnesium monoperoxyphthalate
hexahydrate (MMPP)
SCHEME 5 General pathway
for the principle fragmentation route
of 5a-h
feature increases the electron density on the exocyclic
double bond, making it feasible to be attacked by the mild
oxidizing agent (MMPP) in neutral medium. 1H-NMR
spectrum of 5a in DMSO-d6 showed two singlets for two
different methyl groups at δ 1.68 and 1.72. This upfield
shift as compared with that of the two methyls of the iso-
propylidene group in derivative (δ 2.6 and δ 2.7 respec-
tively) 4a is attributed to the shielding effect of the
oxirane ring.[25] The nonequivalence of the two-methyl
attached to the oxirane ring is due to the basic structure
(5a) and also its tautomer (5a0) in the polar aprotic
DMSO-d6 solvent (Scheme 3).
stereospecific. Thus, obtaining the pair of diastereomers
mean that the starting 4-ylidene derivative is a mixture of
E/Z. The pair of diastereomer 5c were separated using
the HPLC technique qualitatively. The mechanism of
epoxidation includes a concerted reaction mechanism
characterized by a four-part, cyclic transition state, as a
result, the electropositive, oxygen atom ended up in the
cyclopropane ring, and the COO2H group becomes
COOH.[40–43] MMPP has electropositive oxygen atom on
carboxylic group. The reaction begins with the attack of
electrophilic oxygen atom on the nucleophilic carbon-
carbon double bond (Scheme 4).
Aromatic protons (5H) and the NH or (OH) protons
are indicated by a multiplet at δ values 7.247 (1H; para
aromatic proton), 7.419 (2H; meta aromatic protons),
7.607 (1H; NH) and 7.624 (2H; ortho aromatic protons).
13C-NMR of compound 5a confirmed the suggested struc-
ture 5a, where it showed the presence of two signals at
168.827 and 161.678 characteristic for two carbonyl
groups. The IR of derivative 5a showed appearance of
bands at 3250 cm−1 characteristics for NH group and
The mass spectrometric analysis of 1-phenyl
−3,5-dioxo-1,2,3,5-tetrahydrospiropyrazole-4,30-oxirane
derivatives (5a-h) were investigated. All the samples were
ionized using the electron impact technique at 70 ev. It
was observed that the molecular ion is formed by the rup-
ture of the oxirane ring under electron impact giving the
corresponding carbonyl compound (Scheme 5) as shown
below:[34–37]
1
1760, 1670 cm−1 characteristic for two C═O groups. H-
NMR spectrum of 5b was explained in the experimental
part. The characteristic structural feature in the H NMR
3 | CONCLUSION
1
analysis of 5c-h was the oxirane proton found at δ values
Herein, under solvent free conditions, we have provided a
facile green method for the synthesis of 1-phenyl-3,-
5-pyrazolidinedione (3) in good yield. The latter compound
was first used as a precursor for green spiroheterocycle syn-
thesis by the use of MMPP as versatile oxidizing agent.
4.5 to 5.2 ppm according to the type of the adjacent aro-
1
matic substituent.[47,48] Interestingly, H-NMR spectra of
compounds 5c-h indicated the presence of two isomers
in equal amounts as shown by the existence of two
oxirane proton signals. This proved the formation of the
1-phenyl −3,5-dioxo-1,2,3,5-tetrahydrospiropyrazole-4,30-
oxirane derivatives (5c-h) as mixtures of diastereomers.
The assignment of the oxirane as protons as cis or trans
based on correlation with the published data on flavo-
noid and aurone epoxides.[36] Epoxidation reaction is
4 | EXPERIMENTAL
All solvents and reagents used for the synthesis of target
compounds were of commercial grade without further

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EL-OSSAILY ET AL.
purification before use. The time required for completion
of each reaction was monitored by TLC. Melting points
were measured with a Gallenkamp electronic melting
point apparatus and are uncorrected. Elemental analyses
were performed on an Elementar Vario EI apparatus.
(60.9). Anal. Calcd. for: C12H12N2O2 C; 61.66, H;5.55, N;
12.96. Found: C; 61.52, H;5.10, N; 13.10.40%.
4.4 | 4-Cyclohexylidene-1-phenyl-
3,5-pyrazolidinedione (4b)
Infrared spectra were recorded with
a Shimadzu
470 infrared spectrophotometer (KBr wafer technique).
1H and 13C-NMR spectra were measured with a 1H-NMR
LA 400 (Jeol) (400 and 100 MHz, respectively) with TMS
as internal standard. Mass spectrometric analyses were
recorded with JOEL-JMS 600.
Yellow needles from dioxane, yield: 92%; mp 158ꢀC. IR
(ν, cm−1): 3100 (NH),1710 (CO), 1660 (CO), 1H NMR
(CDCl3): δ = 2.55(m,10 H, (CH2)5), 7.35(m,6 H, C6H5;
NH), 13C NMR(CDCl3): 168.68 (CO), 160.71 (C4), 173.12
(CO), 47.13, 59.99, 51.29, 114.20 (cyclohexylidene),
118.92, 126.11, 129.28, 136.16 (C6H5). EI- MS (m/z) (%):
256 [M]+ (100). Anal. Calcd. for: C15H16N2O2 C; 70.31,
H;6.25, N; 10.93. Found: C; 69.81.56, H;6.40, N; 10.78%.
4.1 | 1-Phenyl-3,5-pyrazolidinedione (3)
Phosphorous oxychloride (12 g, 0.078 mol) was added
dropwise at 0ꢀC to 5ꢀC within 5 minutes to a mixture of
malonic acid (5 g, 0.048 mol) and phenyhydrazine (5 g,
0.046 mol). The reaction mixture was stirred at room
temperture for 30 minutes. Then heated on water bath
for 3 hours, cooled, and treated by ice-cold water. The
obtained yellow precipitate had been recrystallized from
ethanol to give yellow plate crystals in 80% yield.; mp
192ꢀC. IR (ν, cm−1): 3250 (NH), 1760 (CO), 1670 (CO),
4.5 | (E/Z) 4-Benzylidene-1-phenyl-
3,5-pyrazolidinedione (4c)
Dark red flakes from dioxane, yield: 90%; mp 275-277ꢀC.
1
IR (ν, cm−1): 3150 (NH),1705 (CO), 1655 (CO), H NMR
(DMSO-d6): δ = 7.9 (m, 12 H, 10 C6H5, NH,═CH). 13C
NMR(DMSO-d6): 160.34(CO), 149.62(C4), 162.96(CO),
118.34, 124.79, 136.54, 129.92 (NC6H5),118.85, 119.88,
132.29, 134.05, 133.40 (═CHC6H5). EI- MS (m/z) (%):
264 [M]+ (100). Anal. Calcd. for: C16H12N2O2 C; 72.72,
H;4.54, N; 10.60. Found: C; 72.18, H;4.75, N; 9.83%.
1
1220(C─N), H NMR (DMSO-d6): δ = 3.57(s, 2H, CH2),
7.4(m,5H, Ph), 13(s,1H, NH), 13C NMR(CDCl3): 37.72
(CH2), 118.48, 124.56, 128.83, 136.86(Ph) 166.06(CO),
167.50(CO). EI- MS (m/z) (%): 176 [M]+ (79). Anal. Calcd.
for: C9H8N2O2 C; 61.36, H;4.54, N; 15.9. Found: C; 61.56,
H;5.21, N; 15.40%.
4.6 | (E/Z) 4-(20-Methoxylbenzylidene)-
1-phenyl-3,5-pyrazolidinedione (4e)
4.2 | 4-Alkylidene(arylidene)-1-phenyl-
3,5-pyrazolidinediones (chalcone
derivatives) (4a-h) (general method)
Dark red granular from dioxane, yield: 95%; mp
235-237ꢀC. IR (ν, cm−1): 3200 (NH), 1700 (CO), 1655
1
(CO), H NMR (DMSO-d6): δ = 4.0 (s, 3 H, OCH3), 8.1
Fusion of a mixture of an equimolar amount of 3 and car-
bonyl compounds in oil bath for 45 minutes. After
cooling, the residual solid product was triturated by
diethyl ether, collected and purified by crystallization
from proper solvent. Compounds (4a-h) were obtained in
85% to 95% yields.
(m 11 H, 9 C6H5, NH, ═CH).13C NMR(DMSO-d6): 158.74
(CO), 142.81(C4), 160.71 (CO), 56.08 (OCH3), 118.76,
124.63, 136.74, 128.89 (NC6H5), 111.57, 120.24, 120.25,
120.63, 133.51, 136.08, 59.96 (═CHC6H4). EI- MS (m/z)
(%): 294 [M]+ (100). Anal. Calcd. for: C17H14N2O3 C;
69.38, H;4.76, N; 9.50. Found: C; 69.30, H;4.86, N;10.13%.
4.3 | 4-Isopropylidene-1-phenyl-
3,5-pyrazolidinedione (4a)
4.7 | (E/Z) 4-(40-Methylbenzylidene)-
1-phenyl-3,5-pyrazolidinedione (4d)
Yellow needles from acetonitrile, yield: 90%; mp 149ꢀC.
Dark orange granular from dioxane, yield: 88%; mp
246-248ꢀC. IR (ν, cm−1): 3200 (NH),1700 (CO), 1655
(CO), 1H NMR (DMSO-d6): δ = 2.4(s, 3 H, CH3),7.8
(m 11 H, 9 C6H5, NH,═CH).13C NMR(DMSO-d6): 160.66
(CO), 158.87(C4), 163.88 (CO), 12.52 (CH3), 118.34,
124.76, 136.66, 128.87 (NC6H5), 129.54, 129.88, 134.47,
1
IR (ν, cm−1): 3250 (NH), 1760 (CO), 1670 (CO), H NMR
(DMSO-d6): δ = 2.6(s, 3 H, CH3), 2.7(s, 3 H, CH3),7.35(m,
5 H, C6H5),13CNMR(DMSO-d6):166.86(CO), 160.11(C4),
173.96(CO), 22.42, 23.05, 136.95 (═C[CH3]2), 116.68,
118.96, 124.44, 128.79 (C6H5). EI- MS (m/z) (%): 216 [M]+

EL-OSSAILY ET AL.
5
144.62, 150.07 (═CHC6H4). EI- MS (m/z) (%): 278 [M]+
(100). Anal. Calcd. for: C17H14N2O2 C; 73.38, H;5.03, N;
10.07. Found: C; 72.90, H;5.18, N; 10.30%.
4b) or 4-arylidene (4c-h) (1 eq.) in absolute ethanol or
THF (4 mL/mmol) was stirred for 4 hours at room tem-
perature. The resulting mixture was filtered and concen-
trated. The residue was triturated with water to give a
precipitate which was collected, dried and recrystallized
from the proper solvent.
4.8 | (E/Z) 4-(40-Chlorobenzylidene)-
1-phenyl-3,5-pyrazolidinedione (4f)
Dark red flakes from dioxane, yield: 94%; mp 262-264ꢀC.
4.12 | 20,20-Dimethyl-1-phenyl-3,5-dioxo-
1,2,3,5-tetrahydrospiropyrazole-4,30-
oxirane (5a)
1
IR (ν, cm−1): 3150 (NH),1710 (CO), 1660 (CO), H NMR
(DMSO-d6): δ = 7.85 (m 11 H, 9 C6H5, NH,═CH),13C
NMR(DMSO-d6): 160.136(CO), 147.78(C4), 158.48 (CO),
118.38, 120.23, 129.35, 138.15 (NC6H5),124.87, 131.17,
135.63, 135.72, 136.47 (═CHC6H4).
White plate from diethyl ether; Yield (94%, EtOH, 54%
THF); mp 150ꢀC. IR (ν, cm−1): 3190 (NH), 1730 (C═O),
EI- MS (m/z) (%): 298[M]+(Cl35) (100), 300
[M]+(Cl37) (37.2). Anal. Calcd.for: C16H16N2O2Cl C;
64.42, H;3.69, N; 9.35. Found: C; 64.01, H;3.89, N; 9.25%.
1700 (C═O), 1110 (C─O), H NMR (CDCl3): δ = 1.07
1
(3H, s, CH3), 1.72 (3H, s, CH3), 7.25 (1H, m, p-H
C6H5),7.41 (2H, m, m-H C6H5), 7.61 (1H, s, NH), 7.62
(2H, m, o-H C6H5). 13C NMR(CDCl3): 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). EI- MS
(m/z) (%): 232 [M]+ (31). Anal. Calcd. for: C12H12N2O3 C;
62.01, H;5.17, N; 12.06. Found: C; 62.22, H;5.21,
N; 12.12%.
4.9 | (E/Z) 4-(20-Nitrobenzylidene)-
1-phenyl-3,5-pyrazolidinedione (4g)
Brown granular from dioxane, yield: 85%; mp 230-232ꢀC.
1
IR (ν, cm−1): 3100 (NH),1710 (CO), 1670 (CO), H NMR
(DMSO-d6) δ = 11.6(s,1 H, NH), 7.75 (m 10 H, 9 C6H5,
═CH), 13C NMR(DMSO-d6): 160.57(CO), 147.69(C4),
4.13 | 2-Phenyl-12-oxa-2,3-diazadispiro
[4.0.5.1] dodecane-1,4-dione (5b)
159.41
(CO),
118.56,
127.95,
129.82,
136.72
(─NC6H5),124.85, 127.75128.87, 132.62, 134.22, 145.31,
157.84 (═CHC6H4). EI- MS (m/z) (%): 309 [M]+ (42.6).
Anal. Calcd. for: C16H11N3O4 C; 62.14, H;3.56, N; 13.59.
Found: C; 62.02, H;3.84, N; 13.40.40%.
Yellow fine powder from CHCl3-petroleum ether, 1:1;
Yield (92% EtOH, 50% THF); mp 185ꢀC. IR (ν, cm−1):
1
3180 (NH), 1730 (C═O), 1700 (C═O), 1110 (C─O). H
NMR (DMSO-d6): δ = 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
C6H5),7.36 (1H, s, NH); 7.47 (1H, m, p-H C6H5), 7.63 (2H,
m, m-H C6H5). 13C NMR (DMSO-d6): 25.14, 25.58, 28.16,
and 28.65 (CH2)5, 59.95 (C-7), 118.71, 126.35, 129.47,
135.73 (C6H5), 161.66 (C═O), 168.96 (C═O). MS(m/z)
(%): 272 [M]+ (19). Anal. Calcd. for C15H16N2O3 C; 66.11,
H; 5.88; N, 10.28. Found: C; 66.01, H; 5.88, N; 10.21%.
4.10 | (E/Z) 4-(40-Nitrobenzylidene)-
1-phenyl-3,5-pyrazolidinedione (4h)
Dark brown amorphous from dioxane, yield: 87%; mp
280-282ꢀC. IR (ν, cm−1): 3100 (NH),1700 (CO), 1660
1
(CO), H NMR (DMSO-d6): δ = 7.90 (m 11 H, 9 C6H5,
NH,═CH), 13C NMR(DMSO-d6): 161.04(CO), 150.62(C4),
159.59 (CO), 118.88, 125.02, 129.0, 136.54 (NC6H5),
123.42, 130.62, 134.51, 137.93, 136.93 (═CHC6H4).
EI- MS (m/z) (%): 309 [M]+ (100). Anal. Calcd. for:
C16H11N3O4 C; 62.14, H;3.56, N; 13.59. Found: C; 62.40,
H;4.0, N; 13.59%.
4.14 | 1,20-Diphenyl-3,5-dioxo-
1,2,3,5-tetrahydrospiropyrazole-4,30-
oxirane (5c)
Yellow fine powder from benzene, yield (89% EtOH, 52%
THF), mp 160ꢀC. IR (ν, cm−1): 3150 (NH), 1740 (C═O),
1
4.11 | Synthesis of 1-phenyl −3,5-dioxo-
1,2,3,5-tetrahydrospiropyrazole-4,30-oxirane
derivatives (5a-h) (general method)
1700 (C═O), 1105 (C─O), H NMR (DMSO-d6): δ = 4.63
(cis)and 4.66(trans) (1H, s, epoxide); 7.34 (2H, m, p-H
C6H5); 7.58 (2H, m, o-H C6H5); 7.62 (4H, m, m-H C6H5);
7.85 (2H, m, o-H C6H5); 8.01 (1H, s, NH). 13C NMR
(DMSO-d6): 58.35 (C-2), 67.93 (C-3), 127.88, 128.84,
129.10, 129.80, 130.11, 136.23 and 144.51 (2 C6H5), 166.05
A solution of magnesium monoperoxyphthalic acid hexa-
hydrate (4 eq.) and the appropriate 4-alkylidene (4a and

6
EL-OSSAILY ET AL.
(C═O), 166.60 (C═O). EI- MS (m/z) (%): 280 [M]+ (99).
Anal. Calcd. for C16H12N2O3 C; 68.51, H; 4.28, N; 9.92.
Found: C; 68.61, H; 4.31, N; 9.89%.
121.05, 124.23, 126.85, 129.69, and 157.72 (o-anisyl),
166.98 (C═O), 168.22 (C═O). EI- MS (m/z) (%): 310 [M]+
(2). Anal. Calcd. for C17H14N2O4 C; 65.74, H;4.51, N;
9.02. Found: C; 65.81, H; 4.61, N; 9.03%.
4.15 | Qualitative HPLC analysis of
1-phenyl −3,5-dioxo-
4.18 | 1-Phenyl-20(4-chlorophenyl)-
3,5-dioxo-1,2,3,5-tetrahydrospiropyrazole-
4,30-oxirane (5f)
1,2,3,5-tetrahydrospiropyrazole-4,30-oxirane
derivatives (5c-h)
Pure sample of 5c was dissolved in acetonitrile to give
1 × 10−3 M solution. Then 20 μL of that solution was
injected on an RP-C18 column, the flow rate was adjusted
to 1.2 mL/minute by using an acetonitrile-water, 70:30,
as eluent, and the product detection was performed using
UV-detector at λ 254 nm. Two isomers were separated in
the ratio 53:47 with retention times 3.02 and
5.82 minutes, respectively.
White grains from benzene-ethanol, 7:3, yield (82%
EtOH, 46% THF); mp 187ꢀC. IR (ν, cm−1): 3250
(NH),1720 (C═O), 1670 (C═O), 1H NMR (DMSO-d6):
δ = 4.73(cis) and 4.79(trans) (1H, s, CH epoxide), 7.21
(2H, m, o-H o-ClC6H4); 7.25 (2H, m, m-H o-ClC6H4); 7.37
(2H, m, o-H C6H5); 7.42 (1H, m, p-H C6H5); 7.56 (2H, m,
m-H C6H5); 7.68 (1H, s, NH). 13C NMR (DMSO-d6): 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). EI- MS (m/z)
(%): 314 [M]+ (6). Anal. Calcd. for C16H11ClN2O3 C;
61.01, H; 3.49, N; 8.89. Found: C; 61.15, H; 3.52,
N; 8.92%.
4.16 | 1-Phenyl-20(4-methylphenyl)-
3,5-dioxo-1,2,3,5-tetrahydrospiropyrazole-
4,30-oxirane (5d)
Yellow grains from ethanol, yield (88% EtOH, 48% THF),
mp 130ꢀC. IR (ν, cm−1): 3150 (NH), 1720 (C═O), 1700
4.19 | 1-Phenyl-20(2-nitrophenyl)-
3,5-dioxo-1,2,3,5-tetrahydrospiropyrazole-
4,30-oxirane (5g)
1
(C═O), 1110 (C─O). H NMR (DMSO-d6): δ = 2.31 (3H,
s, CH3), 4.65(cis) and 4.71(trans) (1H, s, CH epoxide),
7.17 (2H, m, o-H p-tolyl), 7.19 (2H, m, m-H p-tolyl), 7.49
(2H, m, o-H C6H5); 7.51 (2H, m, m-H C6H5); 7.55 (1H, s,
NH); 7.91 (1H, m, p-H C6H5). 13C NMR (DMSO-d6):
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). EI-
MS (m/z) (%): 294 [M]+ (43.9). Anal. Calcd. for
C17H14N2O3 C; 69.32, H; 4.76, N; 9.51. Found: C; 69.25, H
4.70, N; 9.55%.
Yellow grains from benzene-ethanol, 8:2, yield (85%
EtOH, 54% THF), mp 185ꢀC. IR (ν, cm−1): 3190
(NH),1740 (C═O), 1705 (C═O). 1H NMR (DMSO-d6):
δ = 5.13(cis) and 5.17(trans) (1H, s, CH epoxide); 7.21
(2H, m, o-H C6H5); 7.36 (1H, m, p-H C6H5); 7.41 (1H, m,
o-H 2- NO2C6H4); 7.66 (1H, m, p-H 2- NO2C6H4); 7.72
(2H, m, m-H C6H5); 8.19 (2H, m, m-H 2- NO2C6H4); 8.21
(1H, s, NH). 13C NMR (DMSO-d6): 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 (2- NO2C6H4 and C6H5), 160.23
(C═O), 161.42 (C═O). EI- MS (m/z) (%): 325 [M]+ (42).
Anal. Calcd. for C16H11N3O5 C; 59.03, H; 3.38, N 12.19.
Found: C; 59.20, H; 3.22, N; 12.23%.
4.17 | 1-Phenyl-20(2-methoxyphenyl)-
3,5-dioxo-1,2,3,5-tetrahydrospiropyrazole-
4,30-oxirane (5e)
Yellow grains from benzene-ethanol, 8:2, yield (85. %
EtOH, 45% THF); mp 160ꢀC. IR (ν, cm−1): 3400 (NH),
4.20 | 1-Phenyl-20(4-nitrophenyl)-
3,5-dioxo-1,2,3,5-tetrahydrospiropyrazole-
4,30-oxirane (5h)
1
1740 (C═O), 1710 (C═O). H NMR (DMSO-d6): δ = 3.51
(3H, s, OCH3); 4.65(cis) and 4.69(trans) (1H, s, CH epox-
ide); 6.99 (1H, m, m-H o- anisyl); 7.03 (1H; m, o-H o-
anisyl); 7.19 (1H, m, m-H o- anisyl); 7.35 (1H, m, p-H o-
anisyl); 7.41 (2H, m, o-H C6H5); 7.48 (1H, m, p-H C6H5);
7.57 (2H, m, m-H C6H5); 7.65 (1H, s, NH). 13C NMR
(DMSO-d6):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,
Yellow grains from benzene-ethanol, 7:3, yield (87%
EtOH, 52% THF), mp 215ꢀC. IR (ν, cm−1): 3200 (NH),
1
1720 (C═O), 1705 (C═O). H NMR (DMSO-d6): 4.86(cis)
and 4.91(trans) (1H, s, CH epoxide), 7.21 (1H, m, p-H
C6H5); 7.36 (2H, m, m-H C6H5); 7.57 (2H, m, o-H C6H5);

EL-OSSAILY ET AL.
7
[19] R. M. Zaki, S. A. Metweally, Y. A. Elossaily, T. A. Gaber,
J. Heterocyclic Chem. 2018, 55, 2417.
[20] Y. A. El-Ossaily, O. S. Moustafa, S. A. Ibrahim, G. M. Elnager,
S. A. M. Metwally, Trends in Heterocyclic Chemistry 2013,
16, 23.
[21] S. A. M. Metwally, T. A. Mohamed, O. S. Moustafa, Y. A.
El-Ossaily, Chemistry of Heterocyclic Compounds 2007, 9, 1335.
[22] S. A. M. Metwally, T. A. Mohamed, O. S. Moustafa, Y. A. El-
Ossaily, Chemistry of Heterocyclic Compounds 2011, 46, 426.
[23] Y. A. El-Ossaily, R. M. Zaki, S. A. Metwally, J. Sci. Res. 2014, 6
(2), 293.
7.67 (1H, s, NH); 7.87 (2H, m, o-H 4- NO2C6H4); 8.23
(2H, m, m-H 4- NO2C6H4). 13C NMR (DMSO-d6): 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). EI- MS (m/z)
(%): 325 [M]+ (70.4). Anal. Calcd. for C16H11N3O5 C;
59.04, H; 3.38, N; 12.91. Found: C; 59.05, H; 3.41,
N; 12.95%.
ACKNOWLEDGMENTS
[24] S. A. Abdel Mohsen, Y. A. El-Ossaily, R. M. Zaki, S. A.
Metwally, Trends in Heterocyclic Chemistry 2013, 16, 77.
[25] S. N. Ege, A. D. Adams, E. J. Gess, K. S. Ragone, B. J. Kober,
M. B. Lampert, J. Chem. Soc. Perkin Trans. 1983, I, 325.
[26] E. M. Hussein, S. A. Ahmed, E. Nizar, K. S. Khairou, Journal
of Chemical Research 2017, 41(6), 346.
The authors are very grateful to Prof Dr. Etafy Bekhit,
chairman of Chemistry Department for all the facilities pro-
vided to us, and very grateful too to staff members of Chem-
istry Department, Faculty of Science in Jouf University and
Assuit University for their support during this work.
[27] R. Kamal, R. Kumar, V. Kumar, V. Bhardwaj, Che-
mistrySelect. 2019, 4(39), 11578.
[28] H. Cheng-Ying, K. Pi-Wen, C. Yu-Jui, K. Mohit, L. Yu-Chuan,
C. Hsueh-Liang, L. Hui-Hsien, H. Jia-Cherng, H. Ming-Hua,
Molecules 2019, 24(18), 3259.
ORCID
Yasser A. El-Ossaily https://orcid.org/0000-0003-4605-
340X
[29] L. Saadi, S. Adnan, Journal of Global Pharmatechnology 2018,
10(7), 89.
REFERENCES
[1] J. Mayer, O. Nemeck, Czch. 1963, 106, 252.
[2] S. Tawab, A. Moustafa, M. Kira, Nature 1960, 186, 165.
[3] U. B. Chougale, P. R. Kharade, S. R. Dhongade, Research Jour-
nal of Life sciences, Bioinformatics, Pharmaceutical and Chemi-
cal Science 2019, 5, 343.
[4] H. Kumar, S. Jain, International Journal of Pharmaceutical Sci-
ences and Research 2013, 4(1), 453.
[5] B. V. Subrahmanya Lokesh, Y. R. Prasad, A. B. Shaik, Infec-
tious Disorders: Drug Targets 2019, 19(3), 310.
[30] H. E. Zimmerman, L. Singer, B. S. Thyagarajan, J. Am. Chem.
Soc. 1959, 81, 108.
[31] D. A. Singleton, S. R. Merrigan, J. Liu, K. N. Houk, Journal of
the American Chemical Society 1997, 119 (14) 3385.
[32] T. Tsumaki, Bull. Chem. Soc. Japan 1931, 6, 1; CA: 1931, 25,
2145.
[33] J. Van Alphen, Rec. Trav. Chim. 1924, 43, 823.
[34] J. M. Quntilla, Span. Pat. 1955, 211, 285.
[35] C. Bosso, A. Chraibi, C. Luu-duc, J. Ulrich, European Journal
of Mass Spectrometry in Biochemical, Medicine and Environ-
mental Research 1982, 2(314), 89.
[6] J. R. Geigy, A.-G. Brit, Pat. 1963, 921, 467.
[7] J. Mayer, J. Ctvrtnik, O. Nemeck, Czeh. 1962, 103, 65.
[8] G. D'Alo, G. Conti, S. Gadel, R. Dalla Vedova, Farmaco, Ed.
Sci. 1978, 33, 106.
[36] A. Mustafa, A. Summour, M. Kira, M. K. Hilmy, M. Anwar,
S. N. Nakhla, Arch. Pharm. 1965, 298, 516.
[9] C. Abdelmajid, F. Houda, L. D. Cuong, Ann. Pharm. Fr. 1980,
38, 429.
[37] G. Gardillo, L. Merlini, R. Mondelli. Gazz. Chim. Ital. 1965,
95, 320.
[10] S. Kumar, R. Kalra, Pharmacia Lettre 2018, 10(10), 19.
[11] F. K. Keter, J. Darkwa, Biometals 2012, 25, 9.
[12] V. Kumar, K. Kaur, G. K. Gupta, A. K. Sharma, Eur. J. Med.
Chem. 2013, 69, 735.
[13] B. Caliskan, A. Yilmaz, I. Evren, S. Menevse, O. Uludag,
E. M. Banoglu, Med. Chem. Res. 2013, 22, 782.
[14] N. Gokhan-Kelekci, S. Koyunoglu, S. Yabanoglu, K. Yelekci,
O. Ozgen, G. Ucar, K. Erol, E. Kendi, A. Yesilada, Bioorg. Med.
Chem. 2009, 17, 675.
[38] C. Cardani, B. Cavalleri, A. Mantogani, Gazz. Chim. Ital. 1962,
92, 200.
[39] K. Kiran, M. Sarasiia, R. B. Ananda, V. Namratha, D. Ashok,
R. A. Srinivasa, Russian Journal of General Chemistry 2019, 89
(9), 1859.
[40] K. Martina, S. Tagliapietra, V. V. Veselov, G. Cravotto, frontiers
in chemistry 2019, 7, 1.
[41] M. Dekhici, S. Plihon, N. Bar, D. Villemin, H. Elsiblani,
N. Cheikh, Chemistryselect 2019, 4, 705.
[15] S. R. Shih, T. Y. Chu, G. R. Reddy, S. N. Tseng, H. L. Chen,
W. F. Tang, M. S. Wu, J. Y. Yeh, Y. S. Chao, J. Hsu,
H. P. Hsieh, J. T. Horng, J. Biomed. Sci. 2010, 17, 13.
[16] W. E. Krikpatrick, T. Okabe, I. W. Hillyard, R. K. Robins,
A. T. Dren, T. Novinson, J. Med. Chem. 1977, 20, 386.
[17] A. A. Elagamey, F. A. El-Taweel, F. A. Amer, H. H. Zoorob,
Arch Pharm. 1987, 320, 246.
[42] A. I. Almansour, N. Arumugam, R. S. Kumar, G. A.
Periyasami, H. Ghabbour, H. K. Fun, Molecules 2015, 20, 780.
[43] R. N. Bulter, A. G. Coyne, Org. Biomol. Chem. 2016, 14,
9945.
[44] J. F. S. Caryalho, M. M. C. Silva, M. L. Sae Melo, Tetrahedron
2009, 65(14), 2773.
[45] A. Temperini, M. Curini, O. Rosati, L. Minuti, Beilstein Journal
of Organic Chemistry 2014, 10, 1267.
[46] M. J. Shultz, T. H. Vu, J. Phys. Chem. B. 2015, 1 19(29), 9167.
[18] K. Ajay Kumar, P. Jayaroapa, International Journal of pharm
Tech Research 2013, 5(4), 1473.

8
EL-OSSAILY ET AL.
[47] D. D. Keane, W. I. O'Sullivan, E. M. Philgbin, R. M. Simons,
P. C. Teague. Tetrahedron 1970, 26, 2533.
[48] L. J. Jakman, Application of Nuclear Magnetic Resonance spec-
troscopy in Organic Chemistry, Pergamon Press, Chap. 7, 1959.
How to cite this article: El-Ossaily YA,
Metwally SA, Al-Muailkel NS, Fawzy A, Ali HM,
Naffea YA. Green synthetic investigation and
spectral characterization of some spiro
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pyrazolidine-based heterocycles with potential
biological activity. J Heterocyclic Chem. 2020;1–8.
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