Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized 2-Pyrazolines

Article abstract of DOI:10.1002/jhet.3055

The styryl ketonic Mannich base 2 has been used as a precursor in the synthesis of 2-pyrazolines having a basic side chain at C-3 and a phenolic Mannich base at C-5. Treatment of the bis(styryl ketonic bases) 6a and 8a with phenylhydrazine affords the bis(3-functionalized 2-pyrazolines) 7 and 9. The transamination between the styryl keto base 10 and 4-aminoantipyrine leads to 12, which reacts with piperazine to give 13. N-Nitrosation of the sec-Mannich bases 15a–d followed by reductive cyclization affords 2-pyrazolines 17a–d. The keto base 14b has been used for the synthesis of 2-pyrazolines having a phenolic Mannich base at C-3 and its reaction with 3,5-dimethyl-1H-pyrazole affords 23. The alkylation of 3-methyl-1-phenyl-2-pyrazolin-5-one with the bis(Mannich base) 25 was investigated.

Full text of DOI:10.1002/jhet.3055

Month 2017
Utility of Ketonic Mannich Bases in Synthesis of Some New
Functionalized 2-Pyrazolines
*
Elsayed M. Afsah,
Eman M. Keshk, Abdel-Rahman H. Abdel-Rahman, and Najla F. Jomah
Chemistry Department, Faculty of Science, Mansoura University, Mansoura ET-35516, Egypt
*
E-mail: emafsah@yahoo.com
Received May 30, 2017
DOI 10.1002/jhet.3055
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
PhN N
MeO
HO
N
Ph
Ph
N
N
N N
N N
N
Ar
Ar
The styryl ketonic Mannich base 2 has been used as a precursor in the synthesis of 2-pyrazolines having a
basic side chain at C-3 and a phenolic Mannich base at C-5. Treatment of the bis(styryl ketonic bases) 6a and
8a with phenylhydrazine affords the bis(3-functionalized 2-pyrazolines) 7 and 9. The transamination be-
tween the styryl keto base 10 and 4-aminoantipyrine leads to 12, which reacts with piperazine to give 13.
N-Nitrosation of the sec-Mannich bases 15a–d followed by reductive cyclization affords 2-pyrazolines
17a–d. The keto base 14b has been used for the synthesis of 2-pyrazolines having a phenolic Mannich base
at C-3 and its reaction with 3,5-dimethyl-1H-pyrazole affords 23. The alkylation of 3-methyl-1-phenyl-2-
pyrazolin-5-one with the bis(Mannich base) 25 was investigated.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
RESULTS AND DISCUSSION
The chemistry and pharmacological activities of
pyrazolines have been the object of considerable
synthetic effort, and a variety of biologically active
pyrazolines have been described [1–4]. Depending
on the substitution pattern and functionalization,
pyrazolines have been found to possess antifungal [5],
antidepressant [6–8], anticonvulsant [6,7], anti-
inflammatory [9], antibacterial [10], antipyretic [11], and
anticancer [12] properties. Ketonic Mannich bases and
their quaternary salts have been used as versatile
In the present study, the styryl keto base 2 was converted
into 1-phenyl-5-vanillyl-3-[β-(piperidino)ethyl]-2-pyrazoline
(3), through its reaction with phenylhydrazine according to
a previous report [29]. The potential of compound 3 as a
precursor to 2-pyrazolines having a phenolic Mannich base
at C-5 and β-(piperidino)-ethyl side chain at C-3 was
realized by treating 3 with dimethylamine or piperidine and
formaldehyde to afford compounds 4 and 5, respectively
(Scheme 1).
The formation of 4 and 5 is of interest, because a variety
of compounds having a phenolic Mannich base as a
structural unit have been synthesized and studied with
interest centered on their potential pharmaceutical activity
[25,36–39].
intermediates in target synthesis of
a variety of
heterocycles [13–20] and bioactive molecules, such as 2-
pyrazolines [14–17,21], piperidinols [22–24], 1,2,4-
triazepines [24,25], and 1,5-benzo- or 1,5-hetero-
diazepines [24–26]. In particular, the reaction of styryl
ketonic Mannich bases with phenylhydrazine is
particularly useful in the synthesis of 2-pyrazolines
having a basic side chain of alkaloidal nature at C-3 [27–
30], which possess local anesthetic activity comparable
with cocaine [28–30].
In connection with our studies in the area of
Mannich bases [24,25,31–35], the present work is
largely concerned with attempts to extend the scope
of the synthesis of 2-pyrazolines from ketonic
Mannich bases to include the synthesis of some
new 3-functionalized 2-pyrazolines of pharmaceutical
interest.
In addition, we have found that bis(styryl ketonic
Mannich bases) could conceivably function as
precursors
to
bis(3-functionalized
2-pyrazolines).
Thus, 5,50-(piperazine-1,4-diyl)bis(1-aryl)pent-1-en-3-one
dihydrochlorides (6a and 6b) were obtained by treating
1b and 1c with piperazine dihydrochloride and
formaldehyde. Reaction of 6a with phenylhydrazine
afforded
the
target
molecule
1,4-bis(2-(5-(4-
methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)ethyl)
piperazine dihydrochloride (7) (Scheme 2). A practical
advantage of the reaction leading to compound 7 is that
it is often unnecessary to isolate the intermediate
di(phenylhydrazone).
© 2017 Wiley Periodicals, Inc.

E. M. Afsah, E. M. Keshk, A.-R. H. Abdel-Rahman, and N. F. Jomah
Vol 000
Scheme 1. Synthesis of Mannich bases 4 and 5.
O
O
1a
R1
R2
piperidine
MeO
HO
Me
.HCl
N
hydrochloride
CH2O
R2
2
R1
1
a
b
c
OMe OH
OMe
1) PhNHNH2
2) NH4OH
H
3,4-(OCH2O)
Ph
Ph
R2NH
CH2O
N
N
N N
MeO
HO
MeO
HO
Hb Ha
N
N
3
NR2
4:
5:
NR2 = NMe2
NR2 = 1-piperidinyl
supported their structures. In the 1H NMR spectra of
compounds 7 and 9, the pyrazoline ring protons 4-Ha, 4-
Hb, and 5-H were observed as doublet of doublet at δ
2.86–2.94 (dd, 2H, 2 × pyrazoline 4-Ha), 3.47–3.52 (dd,
2H, 2 × pyrazoline 4-Hb), and 5.45–5.47 (dd, 2H,
2 × pyrazoline 5-H).
Scheme 2. Synthesis of the bis(styryl keto bases) 6a, b and the bis(2-
pyrazoline) 7.
O
piperazine
N
Ar
dihydrochloride
Ar
N
1b, c
.2 HCl
2 CH2O
O
In the course of this study, it was found that the
transamination reaction between the styryl ketonic
Mannich base 10 [40] and 4-aminoantipyrine led
to the formation of 1,5-di(antipyrin-4-ylamino)-5-(3,4-
methylenedioxyphenyl)pentan-3-one (12), rather than the
styryl ketonic sec-Mannich base 11, which would be the
expected product (Scheme 4).
6a: Ar = C6H4-4-OMe
6b: Ar = C6H3-3,4-(OCH2O)
Hb
Ha
Ha
Hb
N
N
6a
Ar
Ar
Ph
2 PhNHNH2
N
N
N
N
EtOH / H+
.2 HCl
7: Ar = C6H4-4-OMe
Ph
The transamination reaction between 12 and piperazine
was investigated as a route to a bis(Mannich base)
incorporating two antipyrine units. Thus, compound 12
was treated with piperazine to give a sole product,
which was identified on the basis of its analytical
and spectral data as 1,4-bis[5-(antipyrin-4-ylamino)-5-
(3,4-methylenedioxyphenyl)pentan-3-one-1-yl]piperazine
(13) (Scheme 4). Supporting evidence for structure 13
was provided by its mass spectrum, which showed the
molecular ion at m/z = 897 [M]+, and a fragmentation
pattern, which supported its structure. In particular, the
ions at m/z = 336 and 335 are consistent with
the presence of N-(3,4-methylenedioxyphenylmethyl)-
4-aminoantipyrine ion as a structural unit, and the ions
at m/z = 84 and 226 indicated the presence of the
In line with this, Mannich reaction of 1a–c
with 4,40-trimethylenedipiperidine dihydrochloride and
formaldehyde afforded the bis(styryl ketonic Mannich
bases) 8a–c. The synthesis of the bis(3-functionalized 2-
pyrazoline) dihydrochloride 9 has been achieved by
treating 8a with phenylhydrazine (Scheme 3).
The analytical and spectral data of 6a, 6b, 7, 8a–c, and 9
are consistent with their structures. The mass spectra of 7
and 9 revealed molecular ion peaks at m/z = 716 (M++1)
and 871, respectively, and fragmentation patterns, which
Scheme 3. Synthesis of the bis(styryl keto bases) 8a–c and the bis(2-
pyrazoline) 9.
1,4-dialkylated
piperazine
ion.
The
formation
4,4'-trimethylenedipiperidine
dihydrochloride
1a, b, c
of the bis(Mannich base) 13, as a sole product,
indicated the preferential elimination of the terminal
4-aminoantipyrine moiety during the transamination
reaction.
On the other hand, a series of ketonic sec-Mannich bases
15a–d was prepared by transamination reaction between
the ketonic tert-Mannich base hydrochloride 14a and the
appropriate primary aromatic amine, according to an
earlier report [41].
.2HCl
2 CH2O
O
N
N
O
Ar
Ar
8a: Ar = C6H3-3-OMe,4-OH
8b: Ar = C6H4-4-OMe
8c: Ar = C6H3-3,4-(OCH2O)
Ph
Ph
N
N
N
N
N
N
8a
Ar
Ar
2 PhNHNH2
.2HCl
9: Ar = C6H3-3-OMe,4-OH
EtOH / H+
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized
2-Pyrazolines
Scheme 4. Synthesis of 12 and its reaction with piperazine.
O
O
Ph
N
N
O
4-aminoantipyrine
EtOH
Me
Ph
.HCl
N
Ar
N
Ar
H
Me
10
11
Ph
Me
Ph
N
Me
Me
N
N
N
N N
O
Me
O
O
Me
Me
O
O
piperazine
EtOH
NH
NH
O
NH
Ar
Ar
Ar
N
N
NH
N
Me
Me
O
12
13
N
Ph
10, 11, 12, 13: Ar = C6H3-3,4-(OCH2O)
The ketonic sec-Mannich bases 15a–d proved to be a
potentially useful intermediates in the synthesis of 1,3-
diaryl-2-pyrazolines, via a reaction sequence that involves
N-nitrosation of 15a–d followed by reductive cyclization
to give the target compounds 17a–d (Scheme 5). This
reaction is of considerable preparative value, as numerous
aromatic or heterocyclic amines can be used in the
transamination stage. Compound 17c was identical
(m. p., mixed m. p., and spectral data) with an authentic
sample obtained by treating 14a with phenylhydrazine
according to an earlier report [42].
The interest in the pharmacological activity of phenolic
Mannich bases and related compounds, prompted us to
prepare 1-aryl-3-(4-hydroxyphenyl)-2-pyrazolines (18a, b)
by the reaction of 14b with phenylhydrazine and p-
nitrophenylhydrazine, respectively. The Mannich reaction
of the phenolic moiety of 18a is of particular interest,
because it provides access to 2-pyrazolines possessing a
phenolic Mannich base as a structural unit (Scheme 6).
This has been achieved by treating 18a with
2-[(dimetylaminomethyl)-4-(4,5-dihydro-1-phenyl-1H-pyrazol-
3-yl]phenol (19) and the 2,6-bis[(dimetylaminomethyl)
analogue 20, depending on the molar ratio of the reactants
(Scheme 6). The reaction of 14b with hydrazine led to the
formation of 3-(4,5-dihydro-3-(4-hydroxyphenyl)pyrazol-
1-yl)-1-(4-hydroxyphenyl)propan-1-one (22), rather than
the expected product (21). It is believed that 22 was
formed via the intermediacy of (21), resulting from the
cyclocondensation reaction of hydrazine with 14b, which
readily reacts further with a second molecule of 14b via
transamination to afford the new Mannich base 22 as the
end product. Although the formation of the desired
4-(4,5-dihydro-1H-pyrazol-3-yl)phenol (21) was not
achieved, the reaction of 14b with hydrazine furnishes a
convenient route to the new 2-pyrazoline Mannich base
22. In connection with this, the synthesis of the ketonic
Mannich base 23 having a pyrazole moiety as a structural
unit has been achieved by the transamination reaction
between 14b and 3,5-dimethyl-1H-pyrazole (Scheme 6).
In an extension of this study, it has been found that the
reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one (24)
with the bis(ketonic Mannich base) 25 [43] in a molar
ratio of 2: 1 afforded 26. On the other hand, the same
reaction in a molar ratio of 1:1 lead to the formation of
the new spirocyclic system 4-methyl-2,7,9-triphenyl-2,3-
diazaspiro[4,5]dec-3-ene-1,8-dione (27) (Scheme 7). The
mass spectra of 26 and 27 revealed molecular ion peaks
at m/z = 582 and 408, respectively, and fragmentation
dimethylamine
and
formaldehyde
to
give
Scheme 5. Synthesis of 1,3-diaryl-2-pyrazolines 17a–d from ketonic sec-
Mannich bases 15a–d.
O
O
14a
Ph
1) ArNH2
Ar
R
NMe2
.HCl
N
R
1
2)
NaNO2
patterns, which supported their structures. The H NMR
AcOH
14a: R = H
15a-d: R = H
16a-d: R = NO
spectrum of 27 – as an example – displays a singlet at
δ = 2.31 (3H, CH3), a doublet at 2.35 (4H, 6-H2, 10-H2),
a triplet at 2.60 (2H, 7-H, 9-H) in addition to signals of
aromatic moieties, and the 13C NMR spectrum gave
further support to its structure.
14b: R = OH
Ph
Zn / AcOH
Ar
N
N
15, 16, 17
a
b
c
d
p-tolyl
Ar
p-anisyl
phenyl
The formation of 26 and 27 may be rationalized on the
basis of a mechanism, which involves two successive
17a-d
antipyrin-4-yl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. Afsah, E. M. Keshk, A.-R. H. Abdel-Rahman, and N. F. Jomah
Vol 000
Scheme 6. Synthesis of phenolic 2-pyrazolines and their Mannich bases 19 and 20.
Ar
Me2NH
CH2O
2 Me2NH
2 CH2O
18a
N
N
HO
Ph
Ph
Me2N
HO
18a: Ar = ph
18b: Ar = C6H4-4-NO2
N
N
N
N
HO
Me2N
Me2N
19
20
Ar-NHNH2
AcOH
O
NH2NH2
14b
N
NH
N
Ar
N
Ar
EtOH-H2O
Ar
21
22: Ar = C6H4-4-OH
O
Ar
N
N
3,5-dimethyl-1H-pyrazole
Me
Me
EtOH-H2O
23: Ar = C6H4-4-OH
Scheme 7. Alkylation of the 2-pyrazolin-5-one (24) with the bis(Mannich
base) 25.
compounds were monitored by thin-layer chromatography
using EM science silica gel coated plates, 0.25 nm, 60 GF
254 (Merck, Darmstadt, Germany) with visualization by ir-
radiation with an ultraviolet lamp. Compounds 8b, 12, and
18a are of limited solubility in common 1H NMR solvents.
Compounds 3 [29], 15a–d [41], 17c [42], and 25 [43] were
prepared as previously described.
2-((Dimethylamino)methyl)-4-(4,5-dihydro-H-pyrazol-5-yl)-
6-methoxyphenol (4). A solution of 3 (1.5 g, 4 mmol),
O
Ph
Ph
(2:1)
Me
Me
N
N
Ph
N
N
Ph
Me
O
O
O
Ph
Ph
26
+
N
O
N
R2N
NR2
Ph
24
25: NR2 = 4-morpholinyl
Me
Ph
7
4
6
formalin (37%, 0.4 mL, 5 mmol), and dimethylamine
(40%, 0.6 mL, 5 mmol) in ethanol (30 mL) was heated
under reflux for 4 h. The product obtained on cooling was
filtered and crystallized from ethanol to give 4 as white
powder. Yield 72%, mp 129–130°C; IR (KBr):ν = 3452
3
(1:1)
5
N
N
O
2
Ph
8
10
9
1
Ph
O
27
1
(OH), 1600 (C = N), 1321, 1122, 841 cmꢀ1; H NMR
deamination reactions of the bis(Mannich base) 25,
followed by nucleophilic addition of 24 to give either 26
or 27 depending on the molar ratio of the reactants.
([D6]DMSO): δ = 1.48–1.51 (m, 2H, 4-H2 of piperidine),
1.68–1.71 (m, 4H, 3-H2, 5-H2 of piperidine), 2.25 (t, 2H,
CH2CH2N), 2.59 (s, 6H, NMe2), 2.70–2.72 (m, 4-H,
2-H2, 6-H2 of piperidine), 2.78 [dd, 1H, (pyrazoline 4-
Ha)], 2.81 (t, 2H, CH2CH2N), 3.46 [dd, 1H, (pyrazoline 4-
Hb)], 3.60 (s, 2H, ArCH2N), 3.82 (s, 3H, OCH3), 4.79
(dd, 1H, 5-H of pyrazoline), 5.01 (br s, 1H, OH), 6.51–
7.27 ppm (m, 7H, aromatic); 13C NMR ([D6]DMSO):
δ = 23.84, 25.21, 27.37, 30.01, 45.45, 49.06, 54.28,
55.59, 62.63, 65.033, 113.37, 117.64, 118.83, 122.33,
126.04, 133.25, 146.47, 148.27, 150.09, 163.02 ppm
(C = N); MS (EI, 70 eV): m/z (%) = 436 (2) [M]+, 437 (1)
[M + 1]+, 338 (1), 256 (1), 98 (100), 84 (1), 77 (4). Anal.
Calcd for C26H36N4O2 (436.59): C 71.53, H 8.31, N
12.83. Found C 71.49, H 8.28, N 12.77.
4-(4,5-Dihydro-1-phenyl-3-(2-(piperidin-1-yl)ethyl)-1H-
pyrazol-5-yl)-2-methoxy-6-((piperidin-1-yl)methyl)phenol (5).
This compound was obtained from 3 (1.5 g, 4 mmol) in the
manner described for the synthesis of 4, except for the use
of piperidine (0.42 g, 5 mmol) instead of dimethylamine.
The product was obtained as pale-yellow crystals
(ethanol). Yield 60%, mp 120–122°C; IR (KBr):ν = 3507
EXPERIMENTAL
All melting points (uncorrected) were determined on
a
Gallenkamp electric melting point apparatus
(Sanyo Gallenkamp, Southborough, UK). Elemental
microanalyses were carried out on a Carlo Erba 1108
Elemental Analyzer (Heraeus, Hanau, Germany) at the Mi-
croanalytical Unit, Faculty of Science, Cairo University.
Infrared spectra were measured on a Mattson 5000 FTIR
spectrometer (Mattson Instruments, Inc., Madison, WI,
1
USA). H and 13C NMR data were obtained in CDCl3 or
[D6]DMSO solution on a Varian XL 300 MHz instrument
(Varian, Inc., CA, USA) using TMS as internal standard.
Chemical shifts are reported in ppm (δ) downfield from in-
ternal TMS. Mass spectra were recorded on a GC-MS QP–
1000 EX Shimadzu instrument (Shimadzu, Tokyo, Japan).
The course of the reaction and the purity of the synthesized
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized
2-Pyrazolines
(OH), 1600 (CN), 1500, 1385, 1110, 840 cmꢀ1; H NMR
(CDCl3): δ = 1.48–1.49 (m, 4H, 2 × 4-H2 of piperidine),
1.62–1.66 (m, 8H, 2 × (3-H2, 5-H2 of piperidine), 2.65 (t,
2H, CH2CH2N), 2.69–2.71 (m, 8H, 2 × (2-H2, 6-H2 of
piperidine)), 2.89 [dd, 1H, (pyrazoline 4-Ha)], 3.34 (t,
2H, CH2CH2N), 3.41 (s, 2H, ArCH2N), 3.66 [dd, 1H,
(pyrazoline 4-Hb)], 3.82 (s, 3H, OCH3), 4.79 (dd, 1H, 5-
H of pyrazoline), 4.85 (s, 1H, OH), 6.51–7.26 ppm (m,
7H, aromatic); MS (EI, 70 eV): m/z (%) = 476 (3) [M]+,
477 (1) [M + 1]+, 378 (1), 98 (100), 84 (4), 77 (3). Anal.
Calcd for C29H40N4O2 (476.65): C 73.07, H 8.46, N
11.75. Found C 72.98, H 8.40, N 11.71.
3.75 (s, 6H, 2 × OCH3), 5.45 [dd, 2H, 2 × (pyrazoline 5-
H)], 6.71–7.74 ppm (m, 18H, aromatic); MS (EI, 70 eV):
m/z (%) = 716 (15) [M + 1]+, 717 (14) [M + 2]+, 274
(19), 276 (35), 250 (31), 174 (41), 97 (59), 84 (14), 85
(63), 69 (60), 63 (100). Anal. Calcd for C40H48Cl2N6O2
(715.75): C 67.12, H 6.76, N 11.74. Found C 67.00, H
1
6.71, N 11.69.
5,50-(4,40-(Propane-1,3-diyl)bis(piperidine-4,1-diyl))bis(1-
(aryl)pent-1-en-3-one) dihydrochlorides (8a–c). A mixture
of (1a) or (1b) or (1c) (20 mmol), paraformaldehyde
(0.9 g, 30 mmol), 4,40-trimethylenedipiperidine
dihydrochloride (2.83 g, 10 mmol) in ethanol (40 mL)
was heated under reflux for 2 h. The product obtained on
cooling was filtered and crystallized from DMSO to give
5,50-(Piperazine-1,4-diyl)bis(1-aryl)pent-1-en-3-one
dihydrochlorides (6a, 6b).
A mixture of 1b or 1c
(20 mmol), paraformaldehyde (0.9 g, 30 mmol),
piperazine dihydrochloride (1.59 g, 10 mmol) in ethanol
(40 mL) was refluxed for 2 h. The product obtained on
cooling was filtered and crystallized from DMSO to give
8a–c.
5,50-(4,40-(Ppropane-1,3-diyl)bis(piperidine-4,1-diyl))bis(1-
(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one) dihydrochloride
(8a).
Yellow powder, yield 65%, mp 238–240°C; IR
(KBr): ν = 3422 (OH), 1678 (CO), 1625, 1590, 1236,
6a, b.
1192, 849 cmꢀ1. ꢀ H NMR ([D6]DMSO): δ = 1.06–
1
5,50-(Piperazine-1,4-diyl)bis(1-(4-methoxyphenyl)pent-1-en-
1.16 (m, 2H, 2 × 4-H of piperidine), 1.36–1.45 (m, 2H,
CH2CH2CH2), 1.69–1.72 [m, 4H, (CH2CH2CH2)], 2.26–
2.29 [m, 8H, 2 × (3-H2, 5-H2 of piperidine)], 2.76 (t, 4H,
2 × CH2CH2CO), 3.15 (t, 4H, 2 × NCH2 of side chain),
3.29–3.34 [m, 8H, 2 × (2-H2, 6-H2 of piperidine)], 3.80
(s, 6H, 2 × OCH3), 6.34 (d, 2H, 2 × COCH = CH), 6.62
(d, 2H, 2 × CH = CHAr), 6.72–7.66 (m, 6H, aromatic),
3-one) dihydrochloride (6a).
Pale-yellow powder, yield
80%, mp 228–230°C; IR (KBr): ν = 1660 (CO), 1623,
1508, 1440, 1303, 1255, 1022 cmꢀ1 1H NMR ([D6]
;
DMSO): δ = 3.82 (s, 6H, 2 × OCH3), 2.28 (t, 4H,
2 × NCH2CH2CO), 2.57 (t, 4H, 2 × NCH2CH2CO), 2.68
(br s, 8H, [N(CH2CH2)2N], 6.56 (d, 2H, 2 × Ar-
CH = CHCO), 6.88 (d, 2H, 2 × Ar-CH = CHCO), 7.10–
7.68 ppm (m, 8H, aromatic); MS (EI, 70 eV): m/z
(%) = 534 [M-1]+ (2), 355 (7), 301 (20), 249 (12), 189
(21), 113 (25), 107 (30), 99 (14), 100 (10), 84 (25). Anal.
Calcd for C28H36Cl2N2O4 (535.50): C 62.80, H 6.78, N
9.80 ppm (s, 2H,
2 ×
OH); 13C NMR ([D6]
DMSO):δ = 22.57, 25.09, 32.77, 34.02, 38, 50.98, 51.84,
55.70, 111.48, 115.65, 120.89, 121.35, 122.77, 124.20,
125.52, 135.64, 143.87, 144.05, 147.94, 149.90,
196.11 ppm (CO); MS (EI, 70 eV): m/z (%) = 690 (1)
[M-1]+, 210 (42), 209 (17), 205 (13), 204 (100), 177
(34), 149 (10), 133 (18), 126 (57), 112 (45), 97 (3), 98
(45). Anal. Calcd for C37H52Cl2N2O6 (691.72): C 64.24,
5.23. Found C 62.78, H 6.71, N 5.17.
5,50-(Piperazine-1,4-diyl)bis(1-(benzo[d][1,3]dioxol-5-yl)
pent-1-en-3-one) dihydrochloride (6b).
Pale-yellow
powder, yield 62%, mp 244–245°C dec.; IR (KBr):
ν = 1656 (CO), 1619, 1525, 1422, 1300, 1235,
H 7.58, N 4.05. Found C 64.20, H 7.51, N 3.98.
5,50-(4,40-(Propane-1,3-diyl)bis(piperidine-4,1-diyl))bis(1-(4-
methoxyphenyl)pent-1-en-3-one) dihydrochloride (8b).
1037 cmꢀ1 1H NMR ([D6]DMSO): δ = 2.24 (t, 4H,
;
2 × NCH2CH2CO), 2.59 (t, 4H, 2 × NCH2CH2CO), 2.69
(br s, 8H, [N(CH2CH2)2N], 5.88 (s, 4H, 2 × OCH2O),
6.58 (d, 2H, 2 × Ar-CH = CHCO), 6.86 (d, 2H, 2 × Ar-
CH = CHCO), 7.15–7.69 ppm (m, 6H, aromatic). Anal.
Calcd for C28H32Cl2N2O6 (563.47): C 59.68, H 5.72, N
4.97. Found C 59.61, H 5.69, N 4.90.
Yellow powder, yield 70%, mp 198–200°C; IR (KBr):
ν = 1658 (CO), 1598, 1508, 1423, 1307, 1253, 1099,
827 cmꢀ1; MS (EI, 70 eV): m/z (%) = 658 (1)
[M-1]+, 425 (2), 410 (3), 265 (12), 237 (14), 208 (5), 189
(13), 121 (100), 107 (3). Anal. Calcd for C37H52Cl2N2O4
(659.73): C 67.36, H 7.94, N 4.25. Found C 67.30, H
7.91, N 4.27.
1,4-Bis(2-(5-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)ethyl)-piperazine dihydrochloride (7).
A
5,50-(4,40-(Propane-1,3-diyl)bis(piperidine-4,1-diyl))bis(1-
mixture of 6a (1.07 g, 2 mmol), phenylhydrazine (0.43 g,
4 mmol), and glacial acetic acid (0.5 mL) in ethanol
(20 mL) was heated on a water bath for 5 min. The
product obtained on cooling was filtered and crystallized
from ethanol to give 7. Pale-yellow crystals, yield 69%,
mp 260–262°C; IR (KBr): ν = 1629 (C = N), 1557, 1439,
(benzo[d][1,3]dioxol-5-yl)pent-1-en-3-one)
(8c).
dihydrochloride
Yellow powder, yield 73%, mp 188–190°C; IR
(KBr): ν = 1681 (CO), 1645, 1501, 1402, 1374, 1190,
816 cmꢀ1 1H NMR ([D6]DMSO): δ = 1.01–1.19
;
(m, 2H, 2 × 4-H of piperidine), 1.33–1.35 (m, 2H,
CH2CH2CH2), 1.71–1.74 [m, 4H, (CH2CH2CH2)], 2.24–
2.26 [m, 8H, 2 × (3-H2, 5-H2 of piperidine)], 2.86 (t, 4H,
2 × CH2CH2CO), 3.16 (t, 4H, 2 × NCH2 of side chain),
3.28–3.31 [m, 8H, 2 × (2-H2, 6-H2 of piperidine)], 6.08 (s,
1
1378, 740 cmꢀ1; H NMR ([D6]DMSO): δ = 2.20–2.23
[m, 4H, 2 × (CH2CH2N)], 2.86 [dd, 2H, 2 × (pyrazoline
4-Ha)], 3.12 [br s, 8H, N(CH2CH2)2N], 3.25 [m, 4H,
2 × (CH2CH2N)], 3.47 [dd, 2H, 2 × (pyrazoline 4-Hb)],
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. Afsah, E. M. Keshk, A.-R. H. Abdel-Rahman, and N. F. Jomah
Vol 000
4H, 2 × OCH2O), 6.80 (d, 2H, 2 × COCH = CH), 7,19 (d,
2H, 2 × CH = CHAr), 7.21–7.71 ppm (m, 6H, aromatic);
13C NMR ([D6]DMSO):δ = 22.05, 25.83, 32.77, 34.07,
38.66, 50.02, 51.89, 101.64, 106.59, 108.57, 124.01,
125.39, 128.54, 143.23, 148.07, 149.58, 196.04 ppm
(CO); MS (EI, 70 eV): m/z (%) = 688 (2) [M + 1]+, 210
(2), 209 (4), 202 (84), 189 (17), 175 (59), 147 (14), 122
(23), 89 (100), 69 (6), 55 (47). Anal. Calcd for
C37H48Cl2N2O6 (687.69): C 64.62, H 7.04, N 4.07. Found
The product obtained on cooling was filtered and
crystallized from ethanol to give 13. Colorless crystals,
yield 66%, mp 248–250°C; IR (KBr): ν = 3416 (NH),
1710 (CO of side chain), 1643 (CO of antipyrine),
1623, 1260 cmꢀ1 1H NMR ([D6]DMSO): δ = 2.19
;
[s, 6H, 2 × CH3], 2.21 (t, 4H, 2 × CH2COCH2), 2.38
(d, 4H, 2 × CH2COCH2), 2.45 (s, 6H, 2 × N-CH3),
2.65 (t, 4H, 2 × NCH2CH2CO), 3.14 [br. s, 8H,
N(CH2CH2)2N], 3.42 (m, 2H, 2 × Ar-CH), 6.00 (s, 4H,
C 64.60, H 6.91, N 3.89.
2
×
OCH2O), 6.83–7.56 (m, 16H, aromatic),
4,40-(3,30-(2,20-(4,40-(Propane-1,3-diyl)bis(piperidine-4,1-
diyl))bis(ethane-2,1-diyl))-bis(1-phenyl-4,5-dihydro-1H-
pyrazole-5,3-diyl))bis(2-methoxyphenol) dihydrochloride (9).
9.64 ppm (s, 2H,
2
×
NH); 13C NMR ([D6]
DMSO):δ = 10.22, 35.87, 41.21, 42.55, 48.12, 48.65,
54.11, 101.34, 106.01, 108.17, 116.53, 124.33, 126.12,
134.80, 148.20, 151.49, 160.73 (CO of antipyrine),
209.85 ppm (CO); MS (EI, 70 eV): m/z (%) = 897
[M]+, 898 [M + 1]+, 335 (25), 226 (5), 168 (2), 84
(12), 77 (15), 56 (100). Anal. Calcd for C50H56N8O8
(897.03): C 66.95, H 6.29, N 12.49. Found C 66.90, H
6.23, N 12.51.
A mixture of 8a (1.38 g, 2 mmol), phenylhydrazine
(0.43 g, 4 mmol), and glacial acetic acid (0.4 mL) in
ethanol (20 mL) was heated on a water bath for 5 min.
The product obtained on cooling was filtered and
crystallized from ethanol to give 9. Pale-yellow crystals,
yield 62%, mp 208–210°C; IR (KBr): ν = 3405 (OH),
1600 (C = N), 1514, 1497, 1378, 1212, 960, 753 cmꢀ1
;
3-(N-Nitroso-N-arylamino)-1-phenylpropan-1-ones
1H NMR ([D6]DMSO):δ = 1.14–1.17 (m, 2H, 2 × 4-H of
piperidine), 1.32–1.35 (m, 2H, CH2CH2CH2), 1.66–1.69
(m, 4H, CH2CH2CH2), 2.20–2.22 (m, 8H, 2 × (3-H2, 5-
H2 of piperidine)], 2.25–2.27 [m, 4H, 2 × (CH2CH2N)],
2.94 [dd, 2H, 2 × (pyrazoline 4-Ha)], 3.10–3.17 [m, 8H,
(16a–d).
A cold solution of 15a, 15b, 15c, or 15d
(5 mmol) in a mixture of glacial acetic acid and conc.
hydrochloric acid (3:1) (20 mL) was added with stirring to
a solution of sodium nitrite (0.62 g, 9 mmol) in cold water
(20 mL) at 0–5°C. The cold reaction mixture was stirred
for 1 h and diluted with water (20 mL). The precipitated
product was filtered and crystallized from ethyl acetate to
give 16a–c, except for 16d, which was obtained as
2
× (2-H2, 6-H2 of piperidine)], 3.22 [m, 4H,
2 × (CH2CH2N)], 3.52 [dd, 2H, 2 × (pyrazoline 4-Hb)],
3.78 (s, 6H, 2 × OCH3), 5.47 [dd, 2H, 2 × (pyrazoline
5-H)], 6.71–7.74 (m, 16H, aromatic), 9.84 ppm (s, 2H,
2 × OH); 13C NMR ([D6]DMSO): δ = 22.52, 25.02,
31.77, 32.66, 35.80, 38.01, 50.19, 52.02, 55.48, 118.47,
124.20, 126.70, 129.03, 132.74, 134.77, 148.09, 149.50,
151.57, 160.82 ppm (C = N); MS (EI, 70 eV): m/z
(%) = 870 (3) [M-1]+, 872 (2) [M + 1]+, 721 (2), 521
(9), 294 (8), 281 (3), 267 (17), 238 (8), 208 (9), 191
(20), 162 (20), 150 (15), 145 (26), 123 (12), 106 (11),
73 (100), 75 (38). Anal. Calcd for C49H64Cl2N6O4
(871.98): C 67.49, H 7.40, N 9.64. Found C 67.41, H
viscous oil, sufficiently pure for direct use in the next step.
3-(N-Nitroso-N-p-tolylamino)-1-phenylpropane-1-one
(16a).
Yellow powder, yield 77%, mp 65–66°C; IR
(KBr): ν = 1681 (CO), 1595, 1228, 1109, 884 cmꢀ1
.
Anal. Calcd for C16H16N2O2 (268.31): C 71.62, H 6.01,
N 10.44. Found C 71.60, H 5.99, N 10.40.
3-(N-(4-Methoxyphenyl)-N-nitrosoamino)-1-phenylpropane-
1-one (16b). Yellow powder, yield 72%, mp 78–79°C; IR
(KBr):ν = 1684 (CO), 1594, 1222, 1111, 889 cmꢀ1. Anal.
Calcd for C16H16N2O3 (284.31): C 67.59, H 5.67, N
9.85. Found C 67.61, H 5.61, N 9.80.
7.38, N 9.60.
3-(N-Nitroso-N-phenylamino)-1-phenylpropane-1-one
1,5-di(antipyrin-4-ylamino)-5-(3,4-methylenedioxyphenyl)
pentan-3-one (12). A mixture of 10 (0.58 g, 1.8 mmol)
(16c).
Yellow powder, yield 82%, mp 90–92°C; IR
(KBr): ν = 1681 (CO), 1598, 1224, 1136, 887 cmꢀ1
.
and 4-aminoantipyrine (0.73 g, 3.6 mmol) in ethanol
(50%, 20 mL) was refluxed for 2 h. The product obtained
on cooling was filtered and crystallized from ethanol to
give 12. Yellow powder, yield 72%, mp 238–240°C; IR
(KBr): ν = 3440 (NH), 1691 (CO of side chain), 1642
(CO of antipyrine), 1628, 1260 cmꢀ1; MS (EI, 70 eV):
m/z (%) = 608 (1) [M]+, 607 (0.5) [M-1]+, 335 (20), 215
(2), 201 (2), 188 (4), 167 (17), 121 (20), 85 (3), 57 (6),
56 (100). Anal. Calcd for C34H36N6O5 (608.69): C 67.09,
Anal. Calcd for C15H14N2O2 (254.28): C 70.85, H 5.55,
N 11.02. Found C 70.87, H 5.50, N 10.92.
1,3-Diaryl-2-pyrazolines (17a–d).
A solution of 16a,
16b, 16c, or 16d (2 mmol) in ethanol (25 mL) and acetic
acid (50%, 15 mL) was added with stirring to a
suspension of zinc dust (0.8 g) in ethanol (10 mL) at
10°C. The cold reaction mixture was allowed to stand for
1 h. Then the mixture was heated on water bath for
30 min and filtered to remove zinc dust. The product
obtained on cooling was filtered and crystallized from
ethanol to give 17a–d.
H 5.96, N 13.81. Found C 67.12, H 5.92, N 13.77.
1,4-Bis[5-(antipyrin-4-ylamino)-5-(3,4-
methylenedioxyphenyl)pentan-3-one-1-yl]-piperazine (13).
A
4,5-Dihydro-3-phenyl-1-p-tolyl-1H-pyrazole (17a).
yellow crystals, yield 78%, mp 135–137°C; IR (KBr):
Pale-
mixture of 12 (1.22 g, 2 mmol) and piperazine (0.12 g,
1 mmol) in ethanol (50%, 20 mL) was refluxed for 1 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized
2-Pyrazolines
ν = 1606 (C = N), 1549, 1443, 1346, 1222, 835 cmꢀ1
;
6.88–7.90 ppm (m, 8H, aromatic); MS (EI, 70 eV): m/z
(%) = 283 (20) [M]+, 284 (8) [M + 1]+, 237 (8), 133
(8), 72 (100). Anal. Calcd for C15H13N3O3 (283.28): C
63.60, H 4.63, N 14.83. Found C 63.62, H 4.60, N
1H NMR ([D6]DMSO): δ = 2.40 (s, 3H, CH3), 3.26
(t, 2H, 4-H2), 3.94 (t, 2H, 5-H2), 6.76–7.94 ppm (m,
9H, aromatic); MS (EI, 70 eV): m/z (%) = 236 (94)
[M]+, 237 (19) [M + 1]+,159 (61) [M-Ph]+, 145 (6)
[M-(p-tolyl)]+, 117 (100), 119 (76), 91 (47) [p-tolyl
ion]+, 77 (56) [Ph]+. Anal. Calcd for C16H16N2
(236.31): C 81.32, H 6.82, N 11.85. Found C 81.29, H
14.79.
2-((Dimethylamino)methyl)-4-(4,5-dihydro-1-phenyl-1H-
pyrazol-3-yl)phenol (19). A solution of 18a (1 g, 4 mmol),
formalin (37%, 0.5 mL, 6 mmol), and dimethylamine
(40%, 0.67 mL, 6 mmol) in ethanol (30 mL) was heated
under reflux for 4 h. After cooling in a refrigerator for
24 h, the product was filtered and crystallized from
ethanol-chloroform (1:1) to give 19. Pale-yellow powder,
yield 64%, mp 143–145°C; IR (KBr): ν = 3440 (OH),
6.80, N 11.79.
4,5-Dihydro-1-(4-methoxyphenyl)-3-phenyl-1H-pyrazole
(17b). Pale-yellow crystals, yield 66%, mp 163–165°C;
IR (KBr): ν = 1600 (C = N), 1489, 1329, 1220, 1113,
806 cmꢀ1 1H NMR ([D6]DMSO): δ = 3.86 (s, 3H,
;
1598 (C
=
N), 1473, 1355, 1260, 1072, 1014,
OCH3), 3.35 (t, 2H, 4-H2), 3.80 (t, 2H, 5-H2),
6.76–7.94 ppm (m, 9H, aromatic); MS (EI, 70 eV): m/
z (%) = 252 (52) [M]+, 253 (10) [M + 1]+, 250 (19)
[M-2]+, 237 (47), 107 (3) [p-anisyl ion]+, 80 (100), 77
(22) [Ph]+. Anal. Calcd for C16H16N2O (252.31): C
76.16, H 6.39, N 11.10. Found C 76.18, H 6.31, N
854 cmꢀ1
;
1H NMR ([D6]DMSO):δ = 2.38 [s, 6H,
N(CH3)2], 3.21 (t, 2H, 4-H2), 3.73 (s, 2H, CH2NMe2),
3.87 (t, 2H, 5-H2), 7.98 (s,1H, OH), 6.83–7.51 ppm (m,
8H, aromatic); 13C NMR ([D6]DMSO): δ = 32.19,
44.33, 48.22, 62.38, 112.81, 116.15, 118.69, 121.76,
126.77, 128.98, 138.33, 141.14, 146.27, 149.32,
158.86 ppm (C = N); MS (EI, 70 eV): m/z (%) = 295
(36) [M]+, 296 (9) [M + 1]+, 251 (24) [M-(NMe2)]+,
250 (100), 237 (21) [M-(CH2NMe2)]+, 221 (8), 219 (2),
77 (40), 58 (11). Anal. Calcd for C18H21N3O (295.38):
C 73.19, H 7.17, N 14.23. Found C 73.12, H 7.14, N
10.95.
4,5-Dihydro-1,3-diphenyl-1H-pyrazole (17c). Pale-yellow
crystals, yield 74%, mp 150–151°C (151°C [38]); IR
(KBr): ν = 1612 (C = N), 1480, 1329, 1228, 806 cmꢀ1
.
1,2-Dihydro-4-(4,5-dihydro-3-phenylpyrazol-1-yl)-2,3-
dimethyl-1-phenylpyrazol-5-one (17d).
White powder,
yield 71%, mp 239–240°C; IR (KBr):ν = 1645 (CO),
14.18.
1
1610 (C = N), 1598, 1241, 1182 cmꢀ1; H NMR ([D6]
2,6-Bis[(dimetylaminomethyl)-4-(4,5-dihydro-1-phenyl-1H-
pyrazol-3-yl]phenol (20).
This compound was obtained
DMSO): δ = 1.74 (s, 3H, CH3), 2.48 (s, 3H, N-CH3),
3.83 (t, 2H, 4-H2), 4.21 (t, 2H, 5-H2), 7.15–7.88 ppm
(m, 10H, aromatic); MS (EI, 70 eV): m/z (%) = 332
(20) [M]+, 331 (22) [M-1]+, 306 (23), 199 (14), 197
(17), 178 (17), 160 (26), 145 (14) [M-antipyrine]+, 187
(15) [antipyrine ion]+, 84 (19), 67 (30), 60 (100), 77
(14) [Ph]+. Anal. Calcd for C20H20N4O (332.16): C
72.27, H 6.06, N 16.86. Found C 72.20, H 6.00, N
16.81.
from 18a (1 g, 4 mmol), formalin (37%, 1 ml, 12 mmol),
and dimethylamine (40%, 1.4 ml, 12 mmol), following
the procedure described for the synthesis of 19. The
product was crystallized from ethanol-chloroform (1:1) to
give 20. Pale-yellow powder, yield 58%, mp 140–142°C;
IR (KBr): ν = 3443 (OH), 1600 (C = N), 1471, 1356,
1258, 1072, 1014, 855 cmꢀ1 1H NMR ([D6]DMSO):
;
δ = 2.36 (s, 12H, 4 × CH3), 3.25 (t, 2H, 4-H2), 3.60 (s,
4H, 2 × CH2NMe2), 3.84 (t, 2H, 5-H2), 7.50 (s, 1H, OH),
6.83–7.45 ppm (m, 7H, aromatic); 13C NMR ([D6]
DMSO): δ = 32.19, 44.46, 48.21, 62.75, 112.82, 115.99,
118.66, 122.11, 125.77, 126.62, 129.33, 136.81, 146.31,
149.38, 159.03 ppm (C = N); MS (EI, 70 eV): m/z
(%) = 352 (2) [M]+, 295 (23), 250 (100), 221 (13), 105
(16), 77 (83), 58 (55). Anal. Calcd for C21H28N4O
(352.47): C 71.56, H 8.01, N 15.90. Found C71.50, H
1-Aryl-3-(4-hydroxyphenyl)-2-pyrazolines (18a, 18b).
A
solution of 14b (1 g, 4.6 mmol) and (4.6 mmol)
phenylhydrazine or p-nitrophenylhydrazine in acetic
acid (50%, 10 mL) and ethanol (10 mL) was heated
under reflux for 2 h. The product obtained on cooling
was filtered and crystallized from ethanol to give 18a–b.
4-(4,5-Dihydro-1-phenyl-1H-pyrazol-3-yl)phenol (18a).
Pale-brown crystals, yield 77%, mp 171–172°C; IR
(KBr):ν = 3482 (OH), 1598 (C = N), 1482, 1324, 1222,
1111, 806 cmꢀ1; MS (EI, 70 eV): m/z (%) = 238 (100)
[M]+, 237 (38) [M-1]+, 236 (16) [M-2]+, 161 (3), 133
(17), 119 (18), 105 (13), 91 (39), 77 (77). Anal. Calcd for
C15H14N2O (238.28): C 75.60, H 5.92, N 11.76. Found
75.58, H 5.89, N 11.70.
4-(4,5-Dihydro-1-(4-nitrophenyl)-1H-pyrazol-3-yl)phenol
(18b). Yellow crystals, yield 66%, mp 204–206°C; IR
7.98, N 15.84.
3-(4,5-Dihydro-3-(4-hydroxyphenyl)pyrazol-1-yl)-1-(4-
hydroxyphenyl)propan-1-one (22).
A solution of 14b
(2.29 g, 10 mmol) and hydrazine hydrate (80%, 0.4 mL,
5.5 mmol) in ethanol (30 mL) was heated under reflux
for 2 h. The product obtained on cooling was filtered
and crystallized from ethanol to give 22. Pale-yellow
crystals, yield 59%, mp 174–176°C; IR (KBr): ν = 3441
(KBr):ν = 3430 (OH), 1620 (C = N), 1439, 1329,
(OH), 1652 (CO), 1600 (C
1125 cmꢀ1 1H NMR ([D6]DMSO): δ = 2.86 (t, 2H,
COCH2), 2.92 (t, 2H, 4-H2), 3.06 (t, 2H, COCH2CH2),
= N), 1510, 1457,
1132, 870 cmꢀ1
;
1H NMR ([D6]DMSO): δ = 3.39 (t,
;
2H, 4-H2), 3.84 (t, 2H, 5-H2), 10.55 (s, 1H, OH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. Afsah, E. M. Keshk, A.-R. H. Abdel-Rahman, and N. F. Jomah
Vol 000
3.13 (t, 2H, 5-H2), 9.23 (s, 2H, 2 × OH), 6.72–7.51 ppm
(m, 8H, aromatic); MS (EI, 70 eV): m/z (%) = 308 (6) [M-
2]+, 307 (25), 293 (3), 217 (3), 162 (3), 149 (20), 135 (3),
125 (6), 93 (12), 69 (100). Anal. Calcd for C18H18N2O3
(310.35): C 69.66, H 5.85, N 9.03. Found C 69.60, H
(17), 104 (36), 77 (92). Anal. Calcd for C27H24N2O2
(408.49): C 79.39, H 5.92, N 6.86. Found C 79.33, H
5.89, N 6.80.
5.81, N 8.96.
REFERENCES AND NOTES
1-(4-Hydroxyphenyl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)
propan-1-one (23). A mixture of 14b (0.68 g, 3 mmol)
[1] Kumar, S.; Bawa, S.; Drabu, S.; Kumar, R.; Gupta, H. Recent
Pat Antiinfect Drug Discov 2009, 4, 154.
[2] Azizur Rahman, M.; Siddiqui, A. A. Int J Pharm Sci Drug Res
2010, 2, 165.
[3] Marella, A.; Rahmat Ali, M.; Tauquir Alam, M.; Saha, R.;
Tanwar, O.; Akhter, M.; Shaquiquzzaman, M.; Mumtaz Alam, M. Mini-
Rev Med Chem 2013, 13, 921.
[4] Sharma, S.; Kaur, S.; Bansal, T. J Chem Sci Trans 2014, 3,
861.
and 3,5-dimethyl-1H-pyrazole (0.28 g, 3 mmol) in
ethanol (50%, 20 mL) was refluxed for 4 h. The product
obtained on cooling was filtered and crystallized from
ethanol to give 23. White powder, yield 41%, mp 170–
171°C; IR (KBr):ν = 3451 (OH), 1667 (CO), 1601 (CN),
1578 (C = C), 1515, 1484, 1109, 829 cmꢀ1; H NMR
1
[5] Shailesh, H. S.; Pankaj, S. P. Chem Sci Trans 2012, 1, 632.
[6] Palaska, E.; Aytemir, M.; Uzbay, T.; Erol, D. Eur J Med Chem
2001, 36, 539.
[7] Rajendra Prasad, Y.; Lakshmana Rao, A.; Prasoona,
L.; Murali, K.; Ravi Kumar, P. Bioorg Med Chem Lett 2005, 15,
5030.
[8] Palaska, E.; Erol, D.; Demirdamar, R. Eur J Med Chem 1996,
31, 43.
[9] Ozdemir, Z.; Kandilici, H. B.; Gumusel, B.; Calis, U.; Bilgin,
A. A. Eur J Med Chem 2007, 42, 373.
(CDCl3):δ = 2.25 (s, 3H, 5-CH3), 2.43 (s, 3H, 3-CH3),
3.45 (t, 2H, COCH2), 4.40 (t, 2H, CH2N), 5.85 (s, 1H,
4-H), 6.76 (d, 2H, 3-H, 5-H, of phenol), 7.56 (d, 2H, 2-
H, 6-H, of phenol), 7.27 ppm (s, 1H, OH); MS (EI,
70 eV): m/z (%) = 244 (4) [M]+, 245 (1) [M + 1]+, 246
(0.5) [M + 2]+, 136 (1), 123 (100), 124 (9), 121 (24),
109 (14), 95 (6), 93 (10). Anal. Calcd for C14H16N2O2
(244.29): C 68.83, H 6.60, N 11.47. Found C 68.80, H
[10] Seham, Y. H. Molecules 2013, 18, 2683.
[11] Souza, F. R.; Souaza, V. T.; Ratzlaff, V.; Borges, L. P.; Olivera,
M. R.; Bonacorso, H. G.; Zanatta, N.; Martina, M. A.; Mello, C. F. Eur J
Pharmacol 2002, 451, 141.
6.40, N 11.40.
4,40-(3-Oxo-2,4-diphenylpentane-1,5-diyl)bis(3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one) (26).
A solution of 25
(1.6 g, 4 mmol) and 3-methyl-1-phenyl-2-pyrazolin-5-one
(1.4 g, 8 mmol) in ethanol (40 mL) was refluxed for 6 h.
The product obtained on cooling was filtered and
crystallized from ethanol to give 26. White powder, yield
55%, mp 189–190°C; IR (KBr): ν = 1702 (CO), 1654
(CO of pyrazolone), 1627 (C = N), 1594, 1491, 1328,
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18, 5620.
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873.
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H.; Z Naturforsch 2008, 63b, 577.
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1255 cmꢀ1 1H NMR ([D6]DMSO): δ = 2.48 (s, 6H,
;
2 × CH3), 2.77 (m, 4H, 2 × CH2), 2.81 (m, 2H,
2 × CH2CHPh), 3.57 (t, 2H, 2 × 4-H of pyrazolone),
6.95–7.91 ppm (m, 20H, aromatic); MS (EI, 70 eV): m/z
(%) = 582 (1) [M]+, 395 (1), 307 (2), 306 (1), 277 (2),
186 (8), 173 (4) [pyrazolone ion]+, 174 (28), 98 (24), 97
(46), 81 (36), 55 (75), 57 (100). Anal. Calcd for
C37H34N4O3 (582.69): C 76.27, H 5.88, N 9.62. Found C
76.20, H 5.81, N 9.59.
4-Methyl-2,7,9-triphenyl-2,3-diazaspiro[4,5]dec-3-ene-1,8-
dione (27).
A solution of 25 (1.6 g, 4 mmol) and 3-
methyl-1-phenyl-2-pyrazolin-5-one (0.7 g, 4 mmol) in
ethanol (40 ml) was refluxed for 6 h. The product
obtained on cooling was filtered and crystallized from
ethanol to give 27. White crystals, yield 68%, mp 180–
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49, 575.
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M. Z Naturforsch 2007, 62b, 540.
182°C; IR (KBr):ν
=
1724 (CO), 1654 (CO of
N), 1595, 1491, 1327,
[28] Nisbet, H. B. J Chem Soc 1938, 1237.
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Pharm Res 1993, 16, 68.
pyrazolone), 1627 (C
=
1
1256 cmꢀ1; H NMR (CDCl3):δ = 2.31 (s, 3H, CH3),
2.35 (d, 4H, 6-H2, 10-H2), 2.60 (t, 2H, 7-H, 9-H), 7.27–
8.06 ppm (m, 15H, aromatic); 13C NMR
(CDCl3):δ = 12.93, 38.39, 49.21, 49.78, 118.90, 125.29,
126.03, 127.19, 128.25, 136.85, 137.68, 161.49, 174.76,
206.29 ppm; MS (EI, 70 eV): m/z (%) = 408 (12) [M]+,
276 (100), 277 (17), 278 (2), 186 (73), 174 (10), 118
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized
2-Pyrazolines
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet