A novel series of 3,4-disubstituted dihydropyrazoles: Synthesis and evaluation for MAO enzyme inhibition

Article abstract of DOI:10.1002/jhet.1072

In this study, the authors have designed and synthesized a novel series of 3-acyl-4-aryl-4,5-dihydropyrazoles, with the aim to obtain new potential scaffolds for the inhibition of both isoforms of monoamine oxidase.

Full text of DOI:10.1002/jhet.1072

Month 2013
A Novel Series of 3,4-Disubstituted Dihydropyrazoles: Synthesis
and Evaluation for MAO Enzyme Inhibition
a
a
a
*
Maria Cristina Cardia, Maria Luisa Sanna, Rita Meleddu,
Simona Distinto,b Matilde Yañez,c Dolores Viña,c Manuel Lamela,c
and Elias Maccionia
aDipartimento Farmaco Chimico Tecnologico, Università degli Studi di Cagliari
Via Ospedale 72, 09124 Cagliari, Italy
bDipartimento di Scienze Farmaco Biologiche, University “Magna Graecia” of Catanzaro,
Campus “S. Venuta,” 88100 Catanzaro (CZ), Italy
cDepartamento de Farmacología and Instituto de Farmacia Industrial, Universidad de Santiago de Compostela,
Campus Universitario Sur, E-15782 Santiago de Compostela, Spain
*
E-mail: cardiamr@unica.it
Received March 10, 2011
DOI 10.1002/jhet.1072
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
In this study, the authors have designed and synthesized a novel series of 3-acyl-4-aryl-4,5-dihydropyrazoles,
with the aim to obtain new potential scaffolds for the inhibition of both isoforms of monoamine oxidase (MAO)
enzyme. The synthetic pathway to these compounds includes as a key step the 1,3-dipolar cycloaddition reaction
of diazomethane with a chalcone. All the compounds were fully characterized by means of spectroscopic and
analytical data and showed specific inhibition against MAO A.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
In fact, in the 1,3-dipolar cycloadditions of chalcones
and diazomethane, the methylene part of the diazomethane
could theoretically attack both the α and the b carbon atom.
The regioselectivity and the unequivocal structure of the
resulting dihydropyrazole was later fully demonstrated by
L. I. Smith [24,36] and mainly by Lévai et al. [37–41],
who extended the characterization also to other polyunsa-
turated systems, using combined spectroscopic techniques
(UV, IR, 1H NMR, and 13C NMR). The latter, further cor-
roborate the regioselectivity of this reaction by thermal
denitrogenation of the prepared dihydropyrazoles: the
obtained 1,3-diaryl-3-methyl-propenone confirmed the
attack of the methylene group of the diazomethane to the
b-carbon atom of the α,b-enone during the cycloaddition
reaction.
Despite the fact that several dihydropyrazole derivatives
were found to possess important bioactivities, their activity
as monoamine oxidase inhibiting agents (MAOI) has been
reported in recent years only.
The research in this field has been developed after the
discovery by Johnston [42] of two types of MAO, named
MAO A and MAO B, and above all, the determination of
the crystalline structure of human MAO B, registered in
Dihydropyrazoles represent an important class of bioac-
tive nitrogen heterocyclic compounds [1–18]. In particular,
some dihydropyrazoles have played a crucial role in the
development of heterocyclic chemistry and were also
extensively used as key synthones in organic synthesis
[19–22]. As a consequence, a large number of different
substituted 2-pyrazoline derivatives were prepared [23–34].
A classical pathway for the synthesis of 1,3,5-trisubstituted
dihydropyrazole is based on the reaction of compounds having
α,b-unsaturated group in conjugation with carbonyl system
with hydrazines.
Using this method, hydrazones were formed as intermedi-
ates, which can be subsequently cyclized to dihydropyrazole
in the presence of a suitable cyclizing reagent like acetic acid.
The synthetic pathway to dihydropyrazoles by reaction
of diazomethane with α,b-unsaturated ketones was first
published by Azzarello [35], but he could not establish
the exact position of the acyl moiety (either in the position
3 or 5 of the heterocyclic ring).
Later, this reaction was further investigated by a large
number of researchers, whose published results were not
always in agreement.
© 2013 HeteroCorporation

M. C. Cardia, M. L. Sanna, R. Meleddu, S. Distinto, M. Yañez, D. Viña, M. Lamela,
and E. Maccioni
Vol 000
be also noted that the chiral center is now present on C4
instead of C5. Moreover, there is a carbonyl spacer
between the methyl or the aryl group in position 3 and
the heterocyclic core and the N1 of the dihydropyrazole
is unsubstituted.
With respect to the previously reported compounds (I)
the authors have introduced new aromatic substituents as
well as already studied moieties.
Figure 1. I: Structures of the previously published derivatives, active
as MAOI; Ar: p-CH3—C6H4, p-F—C6H4, thiophene; Ar′: p-CH3—
C6H4, p-Cl—C6H4, furan, thiophene. II: Dihydropyrazoles derivatives
4a–s.
The synthetic pathway for the preparation of 4a–s
compounds started from the reaction of an appropriately
substituted enone with diazomethane. The appropriate chal-
cones 3a–s were prepared slightly modifying the published
report methods [46–48] by reacting equimolar amounts of
the appropriate aldehyde and ketone in basic medium.
The diazomethane has been prepared following published
report methods, starting from N-methyl-N-nitroso-p-toluensul-
fonamide (Diazald) or N-nitrosomethylurea [49, 50].
The 1,3-dipolar cycloaddition starts with the attachment
of the diazomethane to the b-carbon of the chalcone, and
the subsequent formation of the 1-pyrazoline. Afterward,
rising to room temperature and during purification steps,
4,5-dihydro-3H-pyrazoles spontaneously rearrange to the
themodynamically more stable 4,5-1H-dihydropyrazoles
(Scheme 1). This synthetic procedure has been selected
because it univocally leads to the desired regioisomer. In
fact, the new dihydropyrazoles (II; Fig. 1) differ from the
previously reported compounds (I; Fig. 1), only for the
reciprocal position of the substituents and for the absence
of the thiocarbamoyl group.
the RCSB Protein Data Bank [43], allowed the rational
design of selective and reversible inhibitors of the
enzyme. Both MAO isoforms are important in the
metabolism of monoamine neurotransmitters and, as a
result, MAO inhibitors (MAOIs) are studied for the treat-
ment of several psychiatric and neurological disorders. In
particular, MAO B inhibitors are adjuvant in the treatment
of Parkinson’s disease (PD) [44], while MAO A inhibitors
are used as antidepressant and anxiolytic drugs. Further-
more, the activity of MAO B is enhanced by aging and
in Alzheimer’s disease (AD) patients [45]. Neurodegen-
erative disorders are associated with an increased MAO
B activity. On the contrary, MAO A does not increase with
age, suggesting that a totally independent mechanism
regulates the expression of the two enzymatic isoforms.
Therefore, new and wider applications for selective
MAOIs are predictable.
In a previous study, we synthesized and studied some
differently substituted 3,5-diaryl-4,5-dihydro-1-thiocarba-
moylpyrazole derivatives [12] (Fig. 1, series I). Most of them
showed very good inhibitory activities against MAO A and
MAO B, some of them showed a very good reversible and
selective activity against the B isoform. The compound of
the series, which showed the best activity was again tested after
the resolution of the racemic sample and its selectivity for
MAO B increased twice and half for the (S)-(−)-enantiomer.
On the basis of their activity and favorable therapeutic index,
the dihydropyrazole derivatives have demonstrated to be good
candidates for the inhibition of this enzyme.
The compounds structures were fully characterized by
means of mass spectrometry, elemental analyses, and
spectroscopic techniques.
In fact, to further confirm the assigned structures, the
1
authors perform H NMR, 13C NMR, and COSY spectra
of compounds 4b and 4i. Protons on position 4 and 5 of
the dihydropyrazole ring give rise to three sets of signals,
as the authors could expect for a ABX system, but the
Scheme 1. Synthetic pathway to dihydropyrazole compounds 4a–s.
RESULTS AND DISCUSSION
To further investigate the dihydropyrazole scaffold, the
authors have now synthesized a new series of 3-acyl-4-
aryl-4,5-dihydropyrazoles 4a–s (Fig. 1, series II; Table 1).
All the newly synthesized compounds are characterized
by a dihydropyrazole ring bearing either two aromatic
substituents or a methyl aryl di-substitution (4a), which
are differently bonded to the heterocyclic moiety, if
compared with the previously synthesized compounds:
compounds 4a–s are substituted in the position 3 and 4
of the heterocyclic ring instead of position 3 and 5. It can
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A Novel Series of 3,4-Disubstituted Dihydropyrazoles:
Synthesis and Evaluation for MAO Enzyme Inhibition
Month 2013
The chemical shifts (δ) were recorded in ppm units, and J are
given in Hertz. The H NMR splitting patterns are as follows: s,
multiplicity of the signal ranging around 4 ppm, a triplet, is
apparently not in agreement with the assigned structure,
because the expected multiplicity was a doublet of doublets.
The partial decoupled 13C NMR revealed one doublet at
47 ppm and one triplet at 58 ppm, which are due to the
coupling of the C4H and C5H carbons with the bonded
protons of the dihydropyrazole ring, respectively. The
COSY spectra revealed two spin systems, one in the
aromatic region and the other one in the region ranging
between 3.5 and 4.8 ppm, which was composed by three
sets of strictly coupled system, due to the ABX system,
thus confirming the assigned structure. The authors were
also able to confirm that the triplet ranging around 4 ppm
effectively corresponds to the HB proton of the ABX
system and this unusual multiplicity is probably due to
1
singlet; d, doublet; t, triplet; dd, doublet of doublets; “t,” false
triplet; m, multiplet; br s, broad singlet. Microanalysis for CHN
were carried out on a Carlo Erba 1106 analyzer.
The reactions were followed by tlc, using DC Alufolien
Kieselgel 60 F 254 Merck plates.
All reagents and solvents were purchased from Sigma Aldrich,
and used directly without further purifications.
General method for the synthesis of 3-acyl-4-aryl-4,5-
dihydropyrazoles (4a–s). In a 500 mL flask under nitrogen flux
were introduced 50 mL of an ethereal solution of diazomethane
(16 mmol) and 100 mL of dry ethyl ether, maintained in an
ethanol bath at −10°C by a cryostat. To this solution, a 150 mL
ethereal solution of the appropriate chalcone (8 mmol) was
added. The reaction mixture was stirred vigorously at −10°C for
1 h, then it was allowed to reach room temperature and further
stirred for 24 h. The reaction was followed by tlc. At the end
the solvent was removed under vacuo and a product was
obtained, which was crystallized from isopropyl ether/methanol,
ethanol.
3-Acetyl-4-(3,4-methylendioxyphenyl)-4,5-dihydropyrazole
(4a). Bright yellow-colored product; m/z 232. 1H NMR
(CDCl3): δ 2.38 (s, 3H, CH3), 3.62 (dd, 1H, CH2, J = 10.3,
4.8), 3.94 (“t,” 1H, CH2, J = 11.5, 10.3), 4.27 (dd, 1H, CH,
J = 11.5, 4.8), 5.91 (s, 2H, O-CH2-O), 6.30 (br s, 1H, NH,
deuterium oxide exchangeable), 6.67 (d, 1H, phenyl proton,
J = 8.8), 6.69 (s, 1H, phenyl proton), 6.71 (d, 1H, phenyl
proton, J = 8.8). Anal. Calcd. for C12H12N2O3: C, 62.06; H,
5.21; N, 12.06. Found: C, 61.81; H, 5.19; N, 12.01.
the similarity of the geminal (JAB) with the cis (JBX
)
coupling constants.
All compounds were tested to evaluate their capability to
inhibit the two MAO isoforms. Compound 4k showed the
highest activity toward the A isoform of the enzyme (IC50
MAO A = 49.04 2.53 μM). All the other compounds did
not exhibit inhibitory activity at concentration lower than
100 μM. In general, it has been observed that both the
introduction of the carbonyl spacer and the change in the
position of the aryl moiety from C5 to C4, leads to a
decrease of the enzymatic activity, with respect to the
previously reported compounds.
3-(4-Methylbenzoyl)-4-(3,4-methylendioxyphenyl)-4,5-
dihydropyrazole (4b). Yellow powder; m/z 308. 1H NMR (CDCl3):
δ 2.38 (s, 3H, CH3), 3.64 (dd, 1H, CH2, J = 10.3, 5.2), 4.01 (“t,” 1H,
CH2, J = 12.0, 10.3), 4.53 (dd, 1H, CH, J = 12.2, 5.2), 5.88 (s, 2H,
O-CH2-O), 6.35 (br s, 1H, NH, deuterium oxide exchangeable),
6.70 (d, 1H, phenyl proton, J = 8.0), 6.76 (dd, 1H, phenyl
proton, J =8.0, 1.7), 6.77 (d, 1H, phenyl proton, J = 1.7), 7.23 (d,
2H, phenyl protons, J = 8.0), 7.99 (d, 2H, phenyl protons,
J = 8.0). 13C NMR (CDCl3): δ 186.8 (C¼O), 153.0 (—C¼N—),
148.0 (—C—O), 146.6 (—C—O), 140.3 (—C¼), 135.0 (—C¼),
134.7 (—C¼), 130.3 (—C¼), 128.7 (—C¼), 120.4 (—C¼), 108.5
(—C¼), 107.6 (—C¼), 101.0 (CH2), 57.4 (—C—N), 48.6 (—C—),
21.6 (—CH3). Anal. Calcd. for C18H16N2O3: C, 70.12; H, 5.23; N,
9.08. Found: C, 69.86; H, 5.26; N, 9.13.
Significantly all compounds are exclusively active, even
though at relatively high concentration, on the MAO A
isoform, suggesting that this structural modification could
lead to a valid scaffold for the selective inhibition of the
A isoform. These results are very encouraging. In fact,
MAOAIs are capable to raise multiple monoamine levels
with respect to other antidepressant agents such as selective
serotonin reuptake inhibitors (SSRIs). In spite of this evident
advantage, there is less development of MAOIs when com-
pared with SSRIs. Therefore, the development of new, more
selective and reversible MAOAIs is an attractive target.
Prompted by these results, the authors will further investigate
these derivatives, with the aim to obtain new and useful
information for the design of more efficient molecules for
the selective inhibition of the A isoform of MAO.
3-(4-Fluorobenzoyl)-4-(3,4-dimethoxyphenyl)-4,5-dihydro-
1
pyrazole (4c). Yellow crystals; m/z 328. H NMR (CDCl3): δ
3.70 (dd, 1H, CH2, J = 10.3, 5.0), 3.90 (s, 6H, OCH3), 4.03
(“t,” 1H, CH2, J = 12.0, 10.3), 4.60 (dd, 1H, CH, J = 12.0,
5.0), 6.43 (br s, 1H, NH, deuterium oxide exchangeable), 6.80
(d, 1H, phenyl proton, J = 8.4), 6.83 (d, 1H, phenyl proton,
J = 8.4), 6.86 (s, 1H, phenyl proton), 7.12 (t, 2H, phenyl
protons, J = 8.4), 8.18 (dd, 2H, phenyl protons, J = 8.4, 5.5).
Anal. Calcd. for C18H17FN2O3: C, 65.84; H, 5.22; N, 8.53.
Found: C, 66.05; H, 5.20; N, 8.49.
3-Benzoyl-4-(3,4-methylendioxyphenyl)-4,5-dihydropyrazole
(4d). Yellow crystals; m/z 294. 1H NMR (CDCl3): δ 3.70 (dd, 1H,
CH2, J = 10.5, 5.0), 4.03 (“t,” 1H, CH2, J = 11.6, 10.5), 4.58
(dd, 1H, CH, J = 11.6, 5.0), 5.94 (s, 2H, O—CH2—O), 6.44 (br s,
1H, NH, deuterium oxide exchangeable), 6.75 (d, 1H, phenyl
proton, J = 8.4), 6.78 (d, 1H, phenyl proton, J = 8.4), 6.82 (d, 1H,
phenyl proton, J = 1.7), 7.45 (t, 2H, phenyl protons, J = 7.8), 7.55
EXPERIMENTAL
Chemistry. Melting points are uncorrected and recorded on
Electrothermal 9100 apparatus. Electron ionization mass spectra
were obtained by a Fisons QMD 1000 mass spectrometer
(70 eV, 200 μA, ion source temperature 200°C). Samples
were directly introduced into the ion source. Found mass
values are in agreement with theoretical ones. 1H NMR
spectra were performed on a Varian Unity 300 MHz, using
deuterochloroform or dimethylsulfoxyde-d6 as solvents and
tetramethylsilane as internal standard. 13C NMR and COSY
spectra were performed on a Varian 400 MHz spectrometer.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. C. Cardia, M. L. Sanna, R. Meleddu, S. Distinto, M. Yañez, D. Viña, M. Lamela,
and E. Maccioni
Vol 000
(t, 1H, phenyl proton, J = 7.8), 8.11 (d, 2H, phenyl protons, J = 7.9).
Anal. Calcd. for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C,
69.17; H, 4.74; N, 9.47.
NH, deuterium oxide exchangeable), 7.20 (d, 2H, phenyl protons,
J = 7.5), 7.23-7.35 (m, 4H, phenyl protons), 7.44 (d, 2H, phenyl
protons, J = 8.7). Anal. Calcd. for C17H15ClN2O: C, 68.34; H,
5.06; N, 9.38. Found: C, 68.59; H, 5.08; N, 9.43.
3-(3-Methylbenzoyl)-4-(4-chlorophenyl)-4,5-dihydropyrazole
(4k). Pale yellow crystals; m/z 298–300. 1H NMR (CDCl3):
δ 2.39 (s, 3H, CH3), 3.71 (dd, 1H, CH2, J = 10.5, 5.4), 4.07
(dd, 1H, CH2, J = 11.4, 10.5), 4.61 (dd, 1H, CH, J = 11.7, 5.4),
6.45 (br s, 1H, NH, deuterium oxide exchangeable), 7.10–7.32
(m, 6H, phenyl protons), 7.87 (d, 2H, phenyl protons, J = 8.7).
Anal. Calcd. for C17H15ClN2O: C, 68.34; H, 5.06; N, 9.38.
Found: C, 68.55; H, 5.04; N, 9.41.
3-(4-Methylbenzoyl)-4-(4-chlorophenyl)-4,5-dihydropyrazole
(4l). Pale yellow crystals; m/z 298–300. 1H NMR (CDCl3): δ 2.39
(s, 3H, CH3), 3.70 (dd, 1H, CH2, J = 10.2, 5.1), 4.06 (dd, 1H,
CH2, J = 12.0, 10.2), 4.61 (dd, 1H, CH, J = 12.0, 5.1), 6.42 (br
s, 1H, NH, deuterium oxide exchangeable), 7.21-7.29 (m, 7H,
phenyl protons), 8.00 (d, 2H, phenyl protons, J = 8.4). Anal.
Calcd. for C17H15ClN2O: C, 68.34; H, 5.06; N, 9.38. C, 68.58;
H, 5.03; N, 9.42.
3-(2,4-Dichlorobenzoyl)-4-(4-chlorophenyl)-4,5-dihydropyrazole
(4m). Pale yellow crystals; m/z 351–353. 1H NMR (CDCl3): δ 3.78
(dd, 1H, CH2, J = 10.6, 5.5), 4.17 (dd, 1H, CH2, J = 12.1, 10.6), 4.57
(dd, 1H, CH, J = 12.1, 5.5), 6.62 (br s, 1H, NH, deuterium oxide
exchangeable), 7.24–7.33 (m, 6H, phenyl protons), 7.42 (s, 1H,
phenyl proton). Anal. Calcd. for C16H11Cl3N2O: C, 54.34; H, 3.14;
N, 7.92. Found: C, 54.49; H, 3.15; N, 7.89.
3-(3-Methoxybenzoyl)-4-(4-chlorophenyl)-4,5-dihydropyrazole
(4n). Pale yellow crystals; m/z 314–316. 1H NMR (CDCl3): δ 3.70
(dd, 1H, CH2, J = 10.5, 5.4), 3.82 (s, 3H, OCH3), 4.07 (dd, 1H,
CH2, J = 11.7, 10.5), 4.60 (dd, 1H, CH, J = 12.0, 5.1), 6.44 (br s,
1H, NH, deuterium oxide exchangeable), 7.05–7.35 (m, 6H,
phenyl protons), 7.60 (dd, 1H, phenyl proton, J = 1.5, 2.7), 7.74
(dt, 1H, phenyl proton, J = 7.8, 1.5). Anal. Calcd. for
C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90. Found: C, 64.99; H,
4.78; N, 8.87.
3-(4-Methoxybenzoyl)-4-(4-chlorophenyl)-4,5-dihydropyrazole
(4o). Yellow crystals; m/z 314–316. 1H NMR (CDCl3): δ 3.67 (dd,
1H, CH2, J = 10.5, 5.1), 3.85 (s, 3H, OCH3), 4.03 (dd, 1H, CH2,
J = 11.7, 10.2), 4.61 (dd, 1H, CH, J = 11.7, 5.4), 6.37 (br s, 1H,
NH, deuterium oxide exchangeable), 6.90 (d, 2H, phenyl protons,
J = 9.0), 7.24 (s, 4H, phenyl protons), 8.16 (d, 2H, phenyl
protons, J = 8.5), 8.07 (d, 2H, phenyl protons, J = 8.7). Anal.
Calcd. for C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90. Found: C,
64.62; H, 4.81; N, 8.93.
3-(4-Chlorobenzoyl)-4-(4-chlorophenyl)-4,5-dihydropyrazole
(4p). Pale yellow crystals; m/z 318–320. 1H NMR (CDCl3): δ 3.72
(dd, 1H, CH2, J = 10.7, 5.2), 4.08 (“t,” 1H, CH2, J = 11.6, 10.7), 4.60
(dd, 1H, CH, J = 11.9, 5.2), 6.46 (br s, 1H, NH, deuterium oxide
exchangeable), 7.23 (d, 2H, phenyl protons, J = 8.5), 7.27 (d, 2H,
phenyl protons, J = 8.2), 7.38 (d, 2H, phenyl protons, J = 8.5),
8.07 (d, 2H, phenyl protons, J = 8.5). Anal. Calcd. for
C16H12Cl2N2O: C, 60.21; H, 3.80; N, 8.77. Found: C, 59.98;
H, 3.83; N, 8.80.
3-(3-Methylbenzoyl)-4-phenyl-4,5-dihydropyrazole (4q). Yellow
powder, m/z 264. 1H NMR (CDCl3): δ 2.38 (s, 3H, CH3); 3.73
(dd, 1H, CH2, J = 10.5, 5.4); 4.06 (“t,” 1H, CH2, J = 11.4,
10.5); 4.65 (dd, 1H, CH, J = 11.4, 5.1); 6.39 (br s, 1H, NH,
deuterium oxide exchangeable); 7.20–7.31 (m, 7H, phenyl
protons); 7.86–7.90 (m, 2H, phenyl protons). Anal. Calcd. for
C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.02; H,
6.08; N, 10.55.
3-Benzoyl-4-(3,4-dichlorophenyl)-4,5-dihydropyrazole (4e).
White product; m/z 318–320. 1H NMR (CDCl3): δ 3.71 (dd, 1H,
CH2, J = 10.5, 5.0), 4.05 (“t,” 1H, CH2, J = 11.9, 10.5), 4.58 (dd,
1H, CH, J = 11.9, 5.0), 6.58 (br s, 1H, NH, deuterium oxide
exchangeable), 7.17 (dd, 1H, phenyl proton, J = 8.4, 2.1), 7.38
(d, 1H, phenyl proton, J = 8.4), 7.43 (t, 2H, phenyl protons,
J = 7.6, 7.1), 7.48 (s, 1H, phenyl proton), 7.53 (t, 1H, phenyl
proton, J = 7.1), 8.12 (d, 2H, phenyl protons, J = 7.6). Anal.
Calcd. for C16H12Cl2N2O: C, 60.20; H, 3.79; N, 8.78. Found:
C, 59.95; H, 3.81; N, 8.82.
3-(2-Thiophenoyl)-4-(3,4-methylendioxyphenyl)-4,5-dihydro-
1
pyrazole (4f). Pale yellow crystals; m/z 300. H NMR (CDCl3):
δ 3.70 (dd, 1H, CH2, J = 10.1, 5.0), 4.02 (“t,” 1H, CH2, J = 11.8,
10.1), 4.52 (dd, 1H, CH, J = 11.8, 5.0), 5.93 (s, 2H, O—CH2—O),
6.47 (br s, 1H, NH, deuterium oxide exchangeable), 6.75 (d, 1H,
phenyl proton, J = 8.4), 6.78 (d, 1H, phenyl proton, J = 8.4), 6.79
(s, 1H, phenyl proton), 7.13 (t, 1H, thiophenyl proton, J = 3.8, 5.0),
7.63 (d, 1H, thiophenyl proton, J = 5.0), 8.21 (d, 1H, thiophenyl
proton, J = 3.8). Anal. Calcd. for C15H12N2O3S: C, 59.99; H, 4.03;
N, 9.33. Found: C, 60.23; H, 4.01; N, 9.29.
3-(4-Methylbenzoyl)-4-(3,4-dimethoxyphenyl)-4,5-dihydro-
pyrazole (4g). White crystals; m/z 324. 1H NMR (CDCl3):
δ 2.44 (s, 3H, CH3), 3.50 (dd, 1H, CH2, J = 10.3, 5.0), 3.77
(s, 6H, OCH3), 4.29 (“t,” 1H, CH2, J = 12.0, 10.3), 5.05 (dd,
1H, CH, J = 12.0, 5.0), 6.68 (br s, 1H, NH, deuterium oxide
exchangeable), 6.71 (d, 1H, phenyl proton, J = 8.0), 6.73 (d,
1H, phenyl proton, J = 8.0), 6.75 (s, 1H, phenyl proton), 6.93
(d, 2H, phenyl protons, Jo = 8.0), 7.80 (d, 2H, phenyl protons,
Jo = 8.0). Anal. Calcd. for C19H20N2O3: C, 70.35; H, 6.21; N,
8.64. Found: C, 70.61; H, 6.18; N, 8.60.
3-(4-Fluorobenzoyl)-4-(3,4-methylendioxyphenyl)-4,5-dihydro-
1
pyrazole (4h). White crystals; m/z 312. H NMR (CDCl3): δ 3.70
(dd, 1H, CH2, J = 10.3, 5.0), 4.03 (“t,” 1H, CH2, J = 12.0, 10.3),
4.56 (dd, 1H, CH, J = 12.0, 5.0), 5.94 (s, 2H, O—CH2—O), 6.45
(br s, 1H, NH, deuterium oxide exchangeable), 6.75 (d, 1H,
phenyl proton, J = 8.4), 6.77 (d, 1H, phenyl proton, J = 8.4), 6.79
(s, 1H, phenyl proton), 7.12 (t, 2H, phenyl protons, J = 8.8), 8.18
(dd, 2H, phenyl protons, J = 8.8, 5.7). Anal. Calcd. for
C17H13FN2O3: C, 65.40; H, 4.20; N, 8.97. Found: C, 65.66; H,
4.08; N, 9.01.
3-(4-Trifluoromethylbenzoyl)-4-(3,4-methylendioxyphenyl)-
4,5-dihydropyrazole (4i). Pale yellow crystals; m/z 362. 1H
NMR (CDCl3): δ 3.70 (dd, 1H, CH2, J = 10.5, 5.3), 4.03 (“t,”
1H, CH2, J = 12.1, 10.5), 4.52 (dd, 1H, CH, J = 12.1, 5.3),
5.90 (s, 2H, O—CH2—O), 6.54 (s, 1H, NH, deuterium oxide
exchangeable), 6.72 (d, 1H, phenyl proton, J = 8.4), 6.74 (d,
1H, phenyl proton, J = 8.4), 6.75 (d, 1H, phenyl proton,
J =1.26), 7.65 (t, 2H, phenyl protons, J = 8.4), 8.15 (d, 2H,
phenyl protons, J = 8.4). 13C NMR (CDCl3): δ 185.9 (C¼O),
152.1 (—C¼N—), 148.0 (—C—O), 146.7 (—C—O), 140.3
(—C¼), 134.8 (—C¼), 130.3 (—C¼), 129.8 (—C¼), 124.9
(—C¼), 124.8 (CF3), 120.3 (—C¼), 108.5 (—C¼), 107.5 (—C¼),
101.0 (CH2), 57.7 (—C—N), 48.0 (—C—). Anal. Calcd. for
C18H13F3N2O3: C, 59.67; H, 3.62; N, 7.73. Found: C, 59.93; H,
3.60; N, 7.69.
3-(2-Methylbenzoyl)-4-(4-chlorophenyl)-4,5-dihydropyrazole
(4j). Yellow crystals; m/z 298–300. 1H NMR (DMSO): δ 2.26 (s,
3H, CH3), 3.74 (dd, 1H, CH2, J = 10.4, 5.4), 4.10 (dd, 1H, CH2,
J = 12.0, 10.8), 4.58 (dd, 1H, CH, J = 12.0, 5.4), 6.42 (br s, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A Novel Series of 3,4-Disubstituted Dihydropyrazoles:
Synthesis and Evaluation for MAO Enzyme Inhibition
Month 2013
Table 1
Synthesized compounds 4a–s.
Compound
R
R′
Yield (%)
M.P. (°C; cryst. solv.)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
CH3
4─CH3─C6H4
4─F─C6H4
C6H5
C6H5
c─C4H3S
4─CH3─C6H4
4─F─C6H4
4─CF3─C6H4
2─CH3─C6H4
3─CH3─C6H4
4─CH3─C6H4
2,4─di─Cl─C6H3
3─CH3O─C6H4
4─CH3O─C6H4
4─Cl─C6H4
3─CH3─C6H4
4─CH3─C6H4
4─CH3O─C6H4
3,4─O─CH2─O─
3,4─O─CH2─O─
3,4─di─CH3O
3,4─O─CH2─O─
3,4─di─Cl
3,4─O─CH2─O─
3,4─di─CH3O
3,4─O─CH2─O─
3,4─O─CH2─O─
4─Cl−
62
75
71
77
81
78
60
75
66
65
70
72
68
74
80
67
83
75
73
114–115 (Isoprop. ether/CH3OH)
139–140 (EtOH)
121–122 (EtOH)
164–167 (EtOH)
160–163 (EtOH)
150–151 (EtOH)
163–165 (EtOH)
170–172 (EtOH)
150–151 (EtOH)
129–131 (EtOH)
132–134 (EtOH)
174–175 (EtOH)
162–165 (EtOH)
131–133 (EtOH)
149–150 (EtOH)
157–159 (EtOH)
131–132 (EtOH)
140–141 (EtOH)
145–146 (EtOH)
4─Cl−
4─Cl−
4─Cl−
4─Cl−
4─Cl−
4─Cl−
H
H
H
3-(4-Methylbenzoyl)-4-phenyl-4,5-dihydropyrazole (4r). Yellow
powder; m/z 264. H NMR (DMSO): δ 2.38 (s, 3H, CH3), 3.72
BMG Labtech GmbH, Offenburg, Germany) based on the
fluorescence generated (excitation 545 nm, emission 590 nm) over
a 15-min period, in which, the fluorescence increased linearly.
Control experiments were carried out simultaneously by replacing
the test drugs (new compounds and reference inhibitors) with
appropriate dilutions of the vehicles.
1
(dd, 1H, CH2, J = 10.3, 5.3), 4.06 (dd, 1H, CH2, J = 11.5,
10.3), 4.65 (dd, 1H, CH, J = 11.7, 5.5), 6.36 (br s, 1H, NH,
deuterium oxide exchangeable), 7.20–7.31 (m, 7H, phenyl
protons), 8.02 (t, 2H, phenyl protons, J = 8.2). Anal. Calcd. for
C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.47; H,
6.07; N, 10.63.
3-(4-Methoxybenzoyl)-4-phenyl-4,5-dihydropyrazole (4s). White
crystals; m/z 280. 1H NMR (CDCl3): δ 3.71 (dd, 1H,
CH2, J = 10.1, 5.5), 3.84 (s, 3H, OCH3), 4.04 (dd, 1H, CH2,
J = 11.6, 10.3), 4.65 (dd, 1H, CH, J = 11.7, 5.5), 6.33 (br s, 1H,
NH, deuterium oxide exchangeable), 6.90 (d, 2H, phenyl
protons, J = 8.8), 7.24–7.30 (m, 5H, phenyl protons), 8.16 (d,
2H, phenyl protons, J = 8.6). Anal. Calcd. for C17H16N2O2: C,
72.84; H, 5.75; N, 9.99. Found: C, 72.63; H, 5.77; N, 10.04.
Acknowledgments. The authors wish to thank Mr. Roberto Mascia
for his technical support. This work has been supported by a grant of
the Fondazione Banco di Sardegna.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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