A facile four-component sequential protocol in the expedient synthesis of novel 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones in water and their antitubercular evaluation

Article abstract of DOI:10.1016/j.ejmech.2011.07.029

A series of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones has been synthesized by one-pot, four-component sequential reactions of phenylhydrazine, methyl acetoacetate, aromatic aldehydes and β-naphthol in the presence of p-toluenesulphonic acid in water in

Full text of DOI:10.1016/j.ejmech.2011.07.029

European Journal of Medicinal Chemistry 46 (2011) 4530e4536
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
A facile four-component sequential protocol in the expedient synthesis of novel
2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones in water and their antitubercular
evaluation
,
b
b
Pethaiah Gunasekaran a, Subbu Perumal a , Perumal Yogeeswari , Dharmarajan Sriram
*
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai e 625 021, Tamil Nadu, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad e 500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones has been synthesized by one-pot, four-compo-
Received 17 May 2011
Received in revised form
14 July 2011
Accepted 15 July 2011
Available online 23 July 2011
nentsequentialreactions ofphenylhydrazine, methyl acetoacetate, aromaticaldehydesand b-naphtholinthe
presence of p-toluenesulphonic acid in water in good yields. These 2-aryl-5-methyl-2,3-dihydro-1H-3-
pyrazolones were screened for in-vitro antimycobacterial activity against Mycobacterium tuberculosis
H37Rv (MTB) using agar dilution method. Among the 15 compounds screened, 4-[(2,4-dichlorophenyl)(2-
hydroxy-1-naphthyl)methyl]-2-(4-fluorophenyl)-5-methyl-2,3-dihydro-1H-3-pyrazolone displays the
maximum potency with a minimum inhibitory concentration (MIC) of 1.6 mM against MTB, being 2.94 and
4.75 times more active than ciprofloxacin and ethambutol respectively.
Keywords:
Multi-component
Sequential
Ó 2011 Elsevier Masson SAS. All rights reserved.
Methyl acetatoacetate
Phenylhydrazines
b-naphthol
Pyrazolones
Antimycobacterial activity
1. Introduction
public health problem with one-third of the world’s population
infected by the TB bacillus resulting in a death toll of 2 million [24].
According to World Health Organization, within the next 20 years,
approximately 30 million people will be infected with the bacillus
[25]. Further, the emergence of multi-drug-resistant TB (MDR-TB)
that resists two or more of the first-line anti-TB drugs, viz. isoniazid,
rifampicin, pyrizinamide, ethambutol, and streptomycin [26] and
extensively drug-resistant tuberculosis (XDR-TB) further aggra-
vates the problems associated with TB. The root of the drug resis-
tance problem lies in the complexity and length of drug-sensitive
treatment regimens. The pathogenic synergy of tuberculosis with
HIV [27] also enhances the overall incidence of TB in HIV-positive
patients by 50 times relative to the rate for HIV-negative individ-
uals [28]. Furthermore, no new drugs were introduced during last
few decades, except the recently introduced fluoroquinolones,
which discloses the lack of significant research by pharmaceutical
industry in this area. Consequently, the development of new
affordable drugs with novel mechanisms of action and shorter and
simpler regimens capable of effectively treating MDR- and XDR-TB
is of great importance.
Pyrazolones have gained importance as drug substances in
pharmaceutical industry in view of their biological importance. For
instance, the pyrazolones, viz. phenazone, propyphenazone,
ampyrone and metamizole (Fig. 1) are useful antipyretic and
analgesic drugs [1], whilst edaravone (MCI-186) has been used for
treating brain [2,3] and myocardial ischemia [4]. In addition, pyr-
azolones possess antimicrobial, antifungal [5], antimycobacterial
[6,7], antibacterial [8], anti-inflammatory [9], antitumor [10],
gastric secretion stimulatory [11], antidepressant [12] and anti-
filarial activities [13]. They also serve as precursors for dyes,
pigments, pesticides and chelating agents [14], besides finding
applications in the extraction and separation of various metal ions
[15e19]. They are also employed in chromatography, petrochemical
industry, as laser materials and 1H NMR shift reagents [20e23].
Tuberculosis (TB) is a contagious disease caused by respiratory
infection from the Gram positive bacterium, Mycobacterium tuber-
culosis, which in recent years has become an important worldwide
Literature survey reveals that pyrazoline derivatives are active
against many mycobacteria [7,29]. The present work emerges as
* Corresponding author. Tel./fax: þ91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.07.029

P. Gunasekaran et al. / European Journal of Medicinal Chemistry 46 (2011) 4530e4536
4531
O
NH2
OH
ArCHO
+
RNHNH2
+
+
N
N
N
O
O
O
N
N
N
O
OMe
4
1
2
3
Phenazone
Propyphenazone
Ampyrone
H2O
p-TSA
reflux
Na
SO3
Ar
N
N
N
HN
O
O
N
N
N
R
O
O
H
5
Edaravone
Fig. 1. Some pyrazolone drugs.
Metamizole sodium
Scheme 1. Synthesis of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones 5.
Table 2
a part of our research programme recently embarked on the
synthesis of novel heterocycles employing tandem/domino reac-
tions and/or their in-vitro screening for biological activities [30]
and/or unearth new lead molecules with antimycobacterial activi-
ties [31]. Hence we have now synthesized novel 2-aryl-5-methyl-
2,3-dihydro-1H-3-pyrazolones, screened them for preliminary in-
vitro antitubercular activity against M. tuberculosis H37Rv (MTB)
and present the results in this paper.
Synthesis of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones 5 along with their MIC
values.
Entry Product
R
Ar
Reaction Yielda (%) MIC (
time (h)
mM)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4eFC6H4
4eFC6H4
4eFC6H4
4eFC6H4
4eFC6H4
4eFC6H4
4eFC6H4
4eO2NC6H4
2eO2NC6H4
4eClC6H4
C6H5
5
4
75
72
74
62
59
63
58
63
65
71
65
66
74
77
69
6.9
13.8
14.1
30.8
14.0
28.6
29.7
3.4
6
8
7
6
10
5
4ePriC6H4
4eMeOC6H4
4eMeC6H4
4eClC6H4
4eO2NC6H4
4eMeC6H4
2,4eCl2C6H3
3eO2NC6H4
4eFC6H4
2. Chemistry
9
5
3.3
10
11
12
13
14
15
8
4
14.2
1.6
The biological importance of pyrazolones mentioned above
prompted us to evolve an efficient, convergent, four-component
sequential protocol for the synthesis of 2-aryl-5-methyl-2,3-
dihydro-1H-3-pyrazolones 5 from the reaction of arylhydrazine 1,
6
6.7
5
7.1
C6H5
12
6
14.7
6.6
4eClC6H4 4eClC6H4
Isoniazid
0.4
Rifampicin
Ciprofloxacin
Ethambutol
0.1
4.7
7.6
Table 1
Screening of catalysts, solvents and reaction conditions.
,b
Entry
Catalyst
Solvent
Conditions
Reaction
time (h)
Yielda
(%)
a
Yield of isolated product.
1
2
3
4
5
6
e
H2O
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
110 ꢀC
20
6
7
9
20
5
ec
74
55
35
ec
40
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
methyl acetoacetate 2, b-naphthol 3 and aromatic aldehydes 4aei
CH3CN
EtOH
CHCl3
Solvent-
free
Solvent-
free
CH3CN
EtOH
CHCl3
H2O
Solvent-
free
CH3CN
EtOH
CHCl3
H2O
in water in the presence of p-toluenesulphonic acid (p-TSA), a mild
Bronsted acid. The choice of water as the medium in the present
work is driven by the fact that it is the most abundant, cheapest,
safest and the least toxic solvent, which enables the trans-
formations green, besides the unique reactivity and selectivity
7
e
110 ꢀC
20
ec
8
9
10
11
12
InCl3
InCl3
InCl3
InCl3
InCl3
Reflux
Reflux
Reflux
Reflux
110 ꢀC
20
20
20
15
18
25
33
15
ec
40
Cl
4''
Cl
6.24, s, 1H
36.0
5''
6'
3''
2''
2
13
14
15
16
17
K10 clay
K10 clay
K10 clay
K10 clay
K10 clay
Reflux
Reflux
Reflux
Reflux
110 ꢀC
7
7
20
20
20
48
39
26
ec
ec
H
1''
11
3
4
1
2.28, s, 3H
12.1
133.8
H2C
H
H
H3C
141.2
11b
11a
129.7
120.7
106.1
10
10a
7a
4a
5
HN
HN
9
148.5
154.5
O
Solvent-
free
6a
N
N
8
O
O
O
6
H
7
7b
H
a
All reactions carried out with phenylhydrazine (1 mmol), methyl acetoacetate
(1 mmol), 4-chlorobenzaldehyde (1 mmol),
(10 mol%).
b-naphthol (1 mmol) and catalyst
b
Yield of isolated product.
c
Reaction failed to occur.
Fig. 2. HMBCs, 1H and 13C NMR chemical shifts of 5c.

4532
P. Gunasekaran et al. / European Journal of Medicinal Chemistry 46 (2011) 4530e4536
consequent minimization of the waste rendering the protocols eco-
friendly [34].
Initially, the reaction was investigated in different solvents and
catalysts (Table 1) as well as under solvent-free conditions with
a view to maximizing the yield of the product. The reaction in the
absence of catalyst either in water or under solvent-free condition
failed to afford the product (entries 1 and 7). In presence of p-TSA,
the reaction afforded a maximum yield of the product in water
(entry 2), while no product could be obtained in chloroform (entry
5). In the presence of Lewis acid, InCl3, the reaction failed to occur in
water (entry 11), while under solvent-free condition a yield of 40%
was obtained (entry 12) disclosing that water, being abundantly
available, in the reaction mixture coordinates to the catalyst and
diminishes its catalytic activity. In other solvents, in presence of
InCl3, the yield varied from 15 to 33% (entries 8e10). The mont-
morillonite K-10 catalyst failed to effect the reaction either in water
or under solvent-free condition (entries 16 and 17), while the yield
was maximum (48%) in acetonitrile. From the above, it is very clear
that the most suitable catalyst-solvent combination, among those
examined, is p-TSA-water for the reaction to afford a maximum
yield of the product. Hence this solvent-catalyst combination was
used for all subsequent experiments taking equimolar amounts of
substituted hydrazine 1, methyl acetoacetate 2, b-naphthol 3 and
Fig. 3. ORTEP diagram of 5a.
aromatic aldehydes 4aei in water at reflux in the presence of
10 mol % p-TSA (Scheme 1). In a typical reaction, a mixture of
substituted hydrazine 1 and methyl acetoacetate 2 was allowed to
realised for reactions in water relative to organic solvents [32]. It is
pertinent to note that multi-component domino/sequential reac-
tions are characterized by elegance and convergence resulting in
rapid building up of molecular complexity and diversity, besides
affording good yields and selectivity [33]. In these reactions, the
intermediates are not isolated and purified as they undergo further
reactions in situ resulting in maximization of the yield and
react for 50e60 min to which aromatic aldehyde and b-naphthol
were added and the reaction allowed to completion (TLC). By this
sequential method, the yield of the final product was found to be
more with a lower impurity profile than when the reaction was
performed by mixing all the reactants in one instance. Hence the
optimized four-component sequential methodology was followed
N
O
O
N
R
R
N
N
R-NH-NH2
+
O
H
O
O
7
1
2
6
H
O
H
O
Ar
4
Ar
H
H
Ar
H
O
O
O
H
9
3
8
7
N
R
N
Ar
Ar
H
H
O
:
Ar
HN
N
N
H
O
N
O
O
O
O
H
R
R
H
5
10
Ar
O
3
5
+
N
N
O
O
H
Ar
N
N
R
R
16
4
Scheme 2. Mechanism for the formation 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones 5.

P. Gunasekaran et al. / European Journal of Medicinal Chemistry 46 (2011) 4530e4536
4533
Ar
Ar
Ar
H
N
N
R
HN
N
N
N
R
O
O
O
O
OH O
H
R
H
H
OH form
CH form
NH form
Fig. 4. Tautomeric forms of pyrazolone 5.
throughout and the product isolated in good yields (58e77%;
Table 2) from the reaction mixture via purification by column
chromatography.
b
-naphthol respectively. Hence information on the relative rates of
formation as well as further reactions of 16 and 9 with -naphthol or
b
pyrazolone respectively could not be obtained and compared.
Consequently, whether the sequential reactions occur through the
intermediate 16 or 9 it could not be ascertained in the present study.
It is seen from a previous report [37] that pyrazolone could exist in
three tautomeric forms, viz. the CH, OH and NH forms (Fig. 4). The
structure of 5, elucidated by NMR spectroscopic and X-ray crystallo-
graphic data, reveals that after the Michael addition, tautomerisation
occurs to afford pyrazolones 5 in the NH form.
The structure of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones
5 is in accord with elemental analysis and NMR spectroscopic data
as illustrated for a representative example, 5c. In the 1H NMR
spectrum, the H-11 gives a singlet at 6.24 ppm, which shows (i)
a C,H-COSY correlation with carbon signal at 36.0 ppm, assigning it
to C-11 and (ii) HMBCs (Fig. 2) with C-10a, C-11a, C-11b, C-100, C-10,
C-6a and C-7a at 106.1, 120.7, 128.7, 133.8,141.2, 148.5 and 154.0 ppm
respectively. The methyl hydrogens of the pyrazole sub-structure
appear as a singlet at 2.28 ppm and its carbon signal occurs at
12.1 ppm. The methyl hydrogens show HMBCs with the signals at
106.1 and 154.0 ppm due to C-10a and C-7a respectively. The
structure of 5c determined from NMR spectroscopic studies was
further confirmed by a single crystal X-ray crystallographic study
[35] of 5a (Fig. 3).
The intermediacy of pyrazolone 6 in this sequential trans-
formation is evident from the fact that 6 prepared in a separate
reaction of phenylhydrazine with methyl acetoacetate, when sub-
jected to reaction with 4-chlorobenzaldehyde 4c and b-naphthol 3
afforded 5c in shorter time duration (by 60 min) than the overall
four-component sequential reaction that affords 5c. It is pertinent
to note that the condensation products of aldehyde with 2 mol of
The sequential reactions presumably proceed through the
mechanism depicted in Scheme 2 via the initial reaction of arylhy-
drazines 1 with methyl acetoacetate 2 to afford the pyrazolones 6
[36], which could be in equilibriumwith their tautomers 7. In another
either pyrazolone affording 12 [38] or b-naphthol 3 leading to 13
[39] or their further annulated products 14 [40] or 15 [41] are not
formed (Fig. 5) in this sequential four-component reaction under
the experimental conditions employed, rendering the trans-
formation product-selective.
reaction, b-naphthol upon nucleophilic addition to aldehydes with
concomitant dehydration presumably results in the formation of
unsaturated ketone 9. Subsequent Michael addition of 7 over
a
,
b
b
-
-
a,
3. Biological results and discussion
unsaturated ketone 9 results in formation of pyrazolone 10. An
alternative reaction pathway via the formation of intermediate 16,
All the newly synthesized compounds were screened for their
in-vitro antimycobacterial activity against MTB in Middlebsook
7H11 agar medium supplemented with OADC by agar dilution
method similar to that recommended by the National Committee
followed by its reaction with
b-naphthol affording 5 remains
a possibility. Our efforts to isolate 16 (Ar ¼ peClC6H4) from (i) the
two-component reaction of 6 and p-chlorobenzaldehyde and (ii) the
three-component reaction of phenylhydrazine with methyl acetoa-
cetate 2 and p-chlorobenzaldehyde in water in presence of p-TSA did
not fructify. These reactions, instead, led to 12 (Ar ¼ peClC6H4).
Similarly, the reaction of equimolar amounts of
b-naphthol and
p-chlorobenzaldehyde was performed with a view to getting 9.
Interestingly, this reaction resulted in the formation of 15
(Ar ¼ peClC6H4) along with 50% of unreacted p-chlorobenzaldehyde,
wherein 9 could not be detected even in traces. These results show
that both intermediates 16 and 9 in the above reactions are very
reactive towards the subsequent reactions with pyrazolone and
Ar
Ar
N
N
N
N
OH
HO
13
HO
12
OH
Ph
Ph
Ar
Ar
N
N
N
N
O
O
15
Ph
Ph
14
Fig. 5. Condensation products of aromatic aldehyde with pyrazolone/2-naphthol.
Fig. 6. Comparison of MIC (mM) values of series 5 and standard drugs.

4534
P. Gunasekaran et al. / European Journal of Medicinal Chemistry 46 (2011) 4530e4536
for Clinical Laboratory Standards for the determination of MIC in
duplicate [42]. The MIC is defined as the minimum concentration of
compounds required to inhibit 99% of bacterial growth. The MIC of
synthesized compounds determined in duplicate measured at 7.4
pH along with that of standard drugs are listed in Table 2. All the
fifteen compounds showed good in-vitro activity with MIC ranging
50e60 min, aromatic aldehyde (1 mmol), b-naphthol (1 mmol) and
p-TSA (0.1 mmol) were added and heated to reflux for the time
given in Table 2. After completion of the reaction (TLC), the reaction
mixture was extracted with ethyl acetate (2 ꢁ 40 ml). After removal
of the solvent, the residue was chromatographed over silica gel
(230e400 mesh) using petroleum ether-ethyl acetate mixture (4:1
v/v), which afforded the pure product 5.
from 1.6 to 30.8
mM.
An examination of the MIC (
mM) values of series 5 and standard
drugs shown in Fig. 6 show that seven compounds, viz. 5a, 5h, 5i,
5k, 5l, 5m and 5o were more active against MTB than the first line
5.1.1. 4-(2-Hydroxy-1-naphthyl)[4-(nitromethyl)phenyl]methyl-5-
methyl-2-phenyl-2,3-dihydro-1H-3-pyrazolone (5a)
anti-TB drug ethambutol (MIC 7.6
mM), whilst three of them, viz. 5k,
(Table 2, entry, 1): Yellow solid; yield: 75%, m.p 207 ꢀC; 1H NMR
(300 MHz, DMSO-d6) dH: 2.22 (s, 3H, CH3), 6.28 (s, 1H, CH),
7.10e7.14 (m, 1H, AreH), 7.20e7.27 (m, 1H, AreH), 7.29e7.34 (m,
3H, AreH), 7.41e7.48 (m, 3H, AreH), 7.68e7.72 (m, 2H, AreH),
7.76e7.79 (m, 1H, AreH), 7.81e7.85 (m, 1H, AreH), 8.10e8.13 (m,
2H, AreH), 8.20e8.22 (m, 1H, AreH), 10.82 (bs, 1H, OH); 13C NMR
(75 MHz DMSO-d6) dC: 12.0, 36.8, 105.3, 119.9, 120.3, 121.0, 123.0,
123.3, 123.4, 125.7, 126.9, 129.0, 129.1, 129.4, 129.5, 133.7, 137.0,
146.0, 148.5, 151.2, 153.9. Anal. Calcd for C27H21N3O4: C, 71.83; H,
4.69; N, 9.31; Found: C, 71.73; H, 4.62; N, 9.23%.
5i and 5h were more potent than ciprofloxacin (MIC 4.7). However,
all the compounds were less potent than rifampicin and isoniazid
against MTB. The compound, 4-[(2,4-dichlorophenyl)(2-hydroxy-
1-naphthyl)methyl]-2-(4-fluorophenyl)-5-methyl-2,3 dihydro-1H-
3-pyrazolone (5k) displayed the maximum potency with
a minimum inhibitory concentration (MIC) of 1.6 mM against MTB,
being 2.94 and 4.75 times more active than ciprofloxacin and
ethambutol respectively.
With respect to structure-MTB activity relationship, the data in
Table 2 show that the substituent on the N-aryl ring of 2-aryl-5-
methyl-2,3-dihydro-1H-3-pyrazolones
5
has
a
profound effect
5.1.2. 4-[(2-Hydroxy-1-naphthyl)(2-nitrophenyl)methyl]-5-methyl-
2-phenyl-2,3-dihydro-1H-3-pyrazolone (5b)
on the antimycobacterial activity, activity order being:
4eFC6H4 > 4eClC6H4 > C6H5. In general, aryl ring at C-11 bearing
electron-withdrawing groups suchas halogens andnitroshowgreater
activity than that with electron-releasing groups, viz. methoxy, methyl
and isopropyl. In particular, among the pyrazolones with nitrogen
bearing 4-flourophenyl ring 5h e 5n, the order of activity with respect
(Table 2, entry, 2): Yellow solid; yield: 72%, m.p 157 ꢀC; 1H NMR
(300 MHz, DMSO-d6) dH: 1.94 (s, 3H, CH3), 6.69 (s, 1H, CH), 7.03 (d,
1H, J ¼ 8.7 Hz, AreH), 7.19e7.29 (m, 3H, AreH), 7.39e7.44 (m, 4H,
AreH & NH), 7.54 (t, 1H J ¼ 7.8 Hz, AreH), 7.67e7.79 (m, 6H, AreH),
8.02 (d, 1H, J ¼ 8.7 Hz AreH), 10.88 (bs, 1H, OH); 13C NMR (75 MHz
DMSO-d6) dC: 11.8, 33.6, 105.1, 118.1, 119.5, 120.0, 122.9, 123.2, 124.5,
125.4, 127.0, 127.5, 128.9, 129.0, 129.4, 130.5, 132.5, 134.0, 136.6,
137.4, 148.7, 149.9, 153.6. Anal. Calcd for C27H21N3O4: C, 71.83; H,
4.69; N, 9.31; Found: C, 71.91; H, 4.76; N, 9.41%.
to aryl ring linked to C-11 is found to be: 2,4eCl2C6H3
>
4eO2NC6H4 > 4eClC6H4 > 3eO2NC6H4 > 4eFC6H4 > 4eMeC6H4 >
C6H5. Similarly, in pyrazolones 5ae5g, with a phenyl ring linked to
nitrogen, the influence of the aryl at C-11 lies in the order:
4eO2NC6H4 > 2eO2NC6H4 > 4ePriC6H4 > 4eClC6H4 > 4eMeOC6H4
> MeC6H4 > C6H5. The compound 5k with one fluorine and two
chlorines in the aryl rings displayed the maximum potency with MIC
5.1.3. 4-[(4-Chlorophenyl)(2-hydroxy-1-naphthyl)methyl]-5-methyl-
2-phenyl-2,3-dihydro-1H-3-pyrazolone (5c)
of 1.6
m
M against MTB.
(Table 2, entry, 3): Yellow solid; yield: 74%, m.p 176 ꢀC; 1H NMR
(300 MHz, DMSO-d6) dH: 2.28 (s, 3H, CH3), 6.24 (s, 1H, CH),
7.12e7.18 (m, 3H, AreH), 7.27e7.34 (m, 4H, AreH), 7.48e7.54 (m,
3H, AreH), 7.75e7.83 (m, 3H, AreH), 7.89 (d, 1H, J ¼ 8.4 Hz, AreH),
8.28 (d, 1H, J ¼ 8.4 Hz, AreH), 10.87 (bs, 1H, OH); 13C NMR (75 MHz
DMSO-d6) dC: 12.1, 36.0, 106.1, 119.9, 120.7, 121.2, 122.9, 123.3, 125.7,
126.8,128.1,129.0,129.1,129.2,129.4,129.7,130.4,133.8,137.0,141.2,
148.5,154.0. Anal. Calcd for C27H21ClN2O2: C, 73.55; H, 4.80; N, 6.35;
Found: C, 73.63; H, 4.89; N, 6.28%.
4. Conclusion
In conclusion, the present work describes a one-pot, convergent,
expedient sequential protocol for the synthesis of 2-aryl-5-methyl-
2,3-dihydro-1H-3-pyrazolones from the reaction of arylhydrazine,
methyl acetoacetate, aromatic aldehydes and
b-naphthol in the
presence of p-TSA in water under mild reaction conditions in good
yields. These compounds displayed significant in-vitro anti-
mycobacterial activity against MTB.
5.1.4. 4-[(2-Hydroxy-1-naphthyl)(phenyl)methyl]-5-methyl-2-phenyl
-2,3-dihydro-1H-3-pyrazolone (5d)
5. Experimental
(Table 2, entry, 4): White solid; yield: 62%, m.p 205 ꢀC; 1H NMR
(300 MHz, DMSO-d6) dH: 2.19 (s, 3H, CH3), 6.18 (s,1H, CH), 7.07e7.10
(m, 4H, AreH), 7.10e7.19 (m, 5H, AreH) 7.25e7.28 (m, 3H, AreH),
7.68e7.80 (m, 4H, AreH & NH), 8.21 (s, 1H, AreH), 10.77 (bs, 1H,
OH); 13C NMR (75 MHz DMSO-d6) dC 16.8, 41.1, 124.5, 125.7, 125.9,
127.5,128.0,130.3,130.6,131.4,132.5,132.9,133.7,133.8,134.1,138.7,
141.7, 146.6, 153.2, 158.8. Anal. Calcd for C27H22N2O2 C, 79.78; H,
5.46; N, 6.89; Found: C, 79.70; H, 5.53; N, 6.79%.
The melting points were measured in open capillary tubes and
are uncorrected. The 1H, 13C and the 2D NMR spectra were recorded
on a Bruker (Avance) 300 MHz NMR instrument using TMS as
internal standard and CDCl3 as solvent. Standard Bruker software
was used throughout. Chemical shifts are given in parts per million
(d-scale) and the coupling constants are given in Hertz. Silica gel-G
plates (Merck) were used for TLC analysis with a mixture of
petroleum ether (60e80 ꢀC) and ethyl acetate as eluent. Elemental
analyses were performed on a Perkin Elmer 2400 Series II
Elemental CHNS analyzer.
5.1.5. 4-[(2-Hydroxy-1-naphthyl)(4-isopropylphenyl)methyl]-5-met-
hyl-2-phenyl-2,3-dihydro-1H-3-pyrazolone (5e)
(Table 2, entry, 5): Viscous liquid; yield: 59%. 1H NMR (300 MHz,
CDCl3) dH: 1.08 (d, 6H, J ¼ 6.9 Hz, 2CH3), 2.09 (s, 3H, CH3), 2.69e2.73
(m, 1H, CH), 5.97 (s, 1H, CH), 6.79e6.90 (m, 3H, AreH), 6.97e7.14
(m, 7H, AreH & NH), 7.25e7.35 (m, 2H, AreH), 7.46 (t,1H, J ¼ 8.4 Hz,
AreH), 7.64 (d, 1H, J ¼ 8.9 Hz, AreH), 7.80 (d, 1H, J ¼ 8.4 Hz, AreH),
8.02 (d, 1H J ¼ 8.9 Hz, AreH), 10.67 (bs, 1H, OH); 13C NMR (75 MHz
CDCl3) dC: 11.2, 23.8, 33.4, 35.7, 106.3, 120.3, 121.5, 121.7, 122.4, 126.1,
5.1. General procedure for the synthesis of 2-aryl-5-methyl-2,3-
dihydro-1H-3-pyrazolones (5)
To a mixture of phenylhydrazine (1 mmol) and methyl acetoa-
cetate (1 mmol) in water (4 ml) stirred at room temperature for

P. Gunasekaran et al. / European Journal of Medicinal Chemistry 46 (2011) 4530e4536
4535
126.4, 126.9, 128.7, 129.0, 129.1, 129.5, 133.7, 134.9, 137.7, 146.3,
146.5, 153.7, 162.1. Anal. Calcd for C30H28N2O2: C, 80.33; H, 6.29; N,
6.25. Found: C, 80.43; H, 6.22; N, 6.16%.
128.1, 128.4, 132.1, 132.8, 134.2, 137.2, 146.2, 157.7, 160.9. Anal. Calcd
for C28H23FN2O2: C, 76.69; H, 5.29; N, 6.39; Found: C, 76.80; H, 5.20;
N, 6.45%.
5.1.6. 4-[(2-Hydroxy-1-naphthyl)(4-methoxyphenyl)methyl]-5-me-
thyl-2-phenyl-2,3-dihydro-1H-3-pyrazolone (5f)
5.1.11. 4-[(2,4-Dichlorophenyl)(2-hydroxy-1-naphthyl)methyl]-2-
(4-fluorophenyl)-5-methyl-2,3-dihydro-1H-3-pyrazolone (5k)
(Table 2, entry 11): White solid; yield: 65%, m.p. 198 ꢀC; 1H NMR
(300 MHz, CDCl3) dH : 2.30 (s, 3H, CH3), 6.12 (s,1H, CH), 7.07e7.17 (m,
2H, AreH), 7.26e7.33 (m, 2H, AreH), 7.48e7.50 (m, 2H, AreH & NH),
7.57e7.59 (m, 2H, AreH), 7.64e7.72 (m, 4H, AreH), 7.78 (d, 1H,
J ¼ 8.1 Hz, AreH), 8.06 (d,1H, J ¼ 8.1 Hz, AreH),10.78 (bs,1H, OH); 13C
NMR (75 MHz CDCl3) dC: 12.0, 36.4, 106.2, 116.0, 116.4, 120.0, 121.0,
121.1, 122.1, 122.4, 123.0, 123.4, 127.0, 129.0, 129.1, 129.5, 129.7, 133.7,
135.0,144.9,148.0,149.0,153.9,161.4. Anal. Calcd for C27H19Cl2FN2O2:
C, 65.73; H, 3.88; N, 5.68; Found: C, 65.65; H, 3.80; N, 5.78%.
(Table 2, entry, 6): White solid; yield: 63%, m.p 184 ꢀC; 1H NMR
(300 MHz, DMSO-d6) dH: 2.16 (s, 3H, CH3), 3.67 (s, 3H, OCH3), 6.09 (s,
1H, CH), 6.74e6.80 (m, 2H, AreH), 6.92e6.95 (m, 2H, AreH), 7.04e7.07
(m, 1H, AreH), 7.22e7.27 (m, 2H, AreH), 7.41e7.44 (m, 3H, AreH),
7.64e7.71 (m, 3H, AreH), 7.77e7.80 (m, 1H, AreH), 8.18 (s,1H, AreH),
10.89 (bs, 1H, OH); 13C NMR (75 MHz DMSO-d6) dC: 11.4, 34.9, 54.6,
106.4, 112.9, 119.0, 120.3, 122.0, 122.5, 124.8, 125.9, 128.1, 128.2, 128.3,
128.6, 132.8, 133.2, 136.3, 147.8, 148.7, 153.3, 156.8. Anal. Calcd for
C28H24N2O3: C, 77.04;H, 5.54; N, 6.42; Found: C, 77.13;H, 5.62; N, 6.35%.
5.1.7. 4-[(2-Hydroxy-1-naphthyl)(4-methylphenyl)methyl]-5-meth-
yl-2-phenyl-2,3-dihydro-1H-3-pyrazolone (5g)
5.1.12. 2-(4-Fluorophenyl)-4-[(2-hydroxy-1-naphthyl)(3-
nitrophenyl)methyl]-5-methyl-2,3-dihydro-1H-3-pyrazolone (5l)
(Table 2, entry 12): White solid; yield: 66%, m.p. 148 ꢀC; 1H NMR
(300 MHz, DMSO-d6) dH: 2.21 (s, 3H, CH3), 6.31 (s,1H, CH), 7.11e7.20
(m, 1H, AreH), 7.30e7.34 (m, 3H, AreH), 7.42e7.47 (m, 1H, AreH),
7.53e7.55 (m, 2H, AreH), 7.70e7.91 (m, 5H, AreH), 8.04e8.10 (m,
1H, AreH), 8.22e8.31 (m, 1H, AreH), 10.71 (bs, 1H, OH); 13C NMR
(75 MHz DMSO-d6) dC: 16.8, 41.1, 120.8, 121.1, 124.8, 125.8, 126.9,
127.1, 127.8, 128.1, 131.7, 133.8, 133.9, 134.3, 134.7, 138.4, 139.7, 149.7,
152.8, 153.4, 158.6, 162.9, 166.1. Anal. Calcd for C27H20FN3O4: C,
69.08; H, 4.29; N, 8.95; Found: C, 69.02; H, 4.20; N, 8.85%.
(Table 2, entry 7): White solid; yield: 58%, m.p. 179 ꢀC; 1H NMR
(300 MHz, DMSO-d6) dH : 2.27 (s, 3H, CH3), 2.46 (s, 3H, CH3), 6.09 (s,
1H, CH), 7.01e7.08 (m, 4H, AreH), 7.15e7.21 (m, 2H, AreH),
7.30e7.41 (m, 4H, AreH & NH), 7.50 (t, 1H, J ¼ 7.5 Hz, AreH),
7.69e7.71 (m, 3H, AreH), 7.81 (d, 1H, J ¼ 7.5 Hz, AreH), 8.15 (d, 1H,
J ¼ 9.0 Hz, AreH), 10.81 (bs, 1H, OH); 13C NMR (75 MHz DMSO-d6)
dC 11.9, 21.0, 35.9, 106.5, 120.1, 121.2, 121.6, 122.5, 125.6, 126.5, 127.4,
128.7, 128.8, 128.9, 129.0, 129.1, 129.8, 133.8, 134.7, 136.6, 138.3,
147.7, 154.0, 162.4. Anal. Calcd for C28H24N2O2: C, 79.98; H, 5.75; N,
6.66; Found: C, 79.88; H, 5.83; N, 6.73%.
5.1.13. 2-(4-Fluorophenyl)-4-[(4-fluorophenyl)(2-hydroxy-1-
5.1.8. 4-[(4-Chlorophenyl)(2-hydroxy-1-naphthyl)methyl]-2-(4-
fluorophenyl)-5-methyl-2,3-dihydro-1H-3-pyrazolone (5h)
(Table 2, entry 8): White solid; yield: 63%, m.p. 159 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 2.31 (s, 3H, CH3), 6.02 (s, 1H, CH), 6.80e6.86
(m, 2H, AreH), 7.02e7.07 (m, 3H, AreH), 7.10e7.12 (m, 3H, AreH),
7.26e7.30 (m, 2H, AreH & NH), 7.37 (t, 1H, J ¼ 7.5 Hz, AreH), 7.53
(t, 1H, J ¼ 7.5 Hz, AreH), 7.69 (d, 1H, J ¼ 8.7 Hz, AreH), 7.83 (d, 1H,
J ¼ 8.7 Hz, AreH), 8.05 (d, 1H, J ¼ 8.7 Hz, AreH), 10.90 (bs, 1H, OH);
13C NMR (75 MHz CDCl3) dC: 11.8, 35.6, 106.3, 114.4, 114.7, 115.2,
115.7, 121.4, 121.8, 122.2, 122.4, 122.5, 122.8, 126.5, 128.5, 128.8,
129.2, 132.6, 133.8, 136.5, 146.9, 153.6, 161.9. Anal. Calcd for
C27H20ClFN2O2: C, 70.66; H, 4.39; N, 6.10; Found: C, 70.59; H, 4.49;
N, 6.18%.
naphthyl)methyl]-5-methyl-2,3-dihydro-1H-3-pyrazolone (5m)
(Table 2, entry 13): White solid; yield: 74%, m.p. 183 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 2.26 (s, 3H, CH3), 6.01 (s, 1H, CH), 6.72e6.80
(m, 2H, AreH), 6.81e6.87 (m, 2H, AreH), 7.01e7.07 (m, 3H, AreH),
7.15e7.20 (m, 2H, AreH),), 7.36 (t, 1H, J ¼ 10.2 Hz, AreH), 7.51 (t, 1H,
J ¼ 7.2 Hz, AreH)), 7.68 (d, 1H, J ¼ 9.0 Hz, AreH)), 7.82 (d, 1H,
J ¼ 7.2 Hz, AreH), 8.04 (d, 1H, J ¼ 9.0 Hz, AreH), 10.91 (bs, 1H, OH);
13C NMR (75 MHz CDCl3) dC: 11.8, 35.6, 105.9, 114.4, 114.8, 115.5,
115.7, 121.4, 121.5, 122.4, 122.5, 122.6, 126.5, 128.5, 128.6, 129.0,
129.2, 133.5, 136.6, 147.9, 162.3. Anal. Calcd for C27H20F2N2O2: C,
73.29; H, 4.56; N, 6.33; Found: C, 73.39; H, 4.62; N, 6.22%.
5.1.14. 2-(4-Fluorophenyl)-4-[(2-hydroxy-1-naphthyl)(phenyl)
methyl]-5-methyl-2,3-dihydro-1H-3-pyrazolone (5n)
5.1.9. 2-(4-Fluorophenyl)-4-(2-hydroxy-1-naphthyl)[4-(nitromethyl)
phenyl]methyl-5-methyl-2,3-dihydro-1H-3-pyrazolone (5i)
(Table 2, entry 14): White solid; yield: 77%, m.p. 192 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 2.31 (s, 3H, CH3), 6.10 (s,1H, CH), 6.84e6.91 (m,
2H, AreH), 7.08e7.13 (m, 6H, AreH), 7.31e7.38 (m, 3H, AreH), 7.50 (t,
1H, J ¼ 7.5 Hz, AreH), 7.75 (d, 1H, J ¼ 8.7 Hz, AreH), 7.83 (d, 1H,
J ¼ 7.5 Hz, AreH), 8.06 (d, 1H, J ¼ 8.7 Hz, AreH), 10.78 (bs, 1H, OH);
13C NMR (75 MHz CDCl3) dC: 12.1, 36.4,105.8,115.9,116.2,121.0,121.2,
122.0, 122.1, 122.7, 123.2, 125.8, 126.6, 127.8, 128.2, 129.0, 133.5, 134.0,
142.1, 148.5, 154.1, 158.2, 161.4. Anal. Calcd for C27H21FN2O2: C, 76.40;
H, 4.99; N, 6.60; Found: C, 76.33; H, 4.91; N, 6.70%.
(Table 2, entry 9): White solid; yield: 65%, m.p. 172 ꢀC; 1H NMR
(300 MHz, DMSO-d6) dH: 2.13 (s, 3H, CH3), 6.25 (s, 1H, CH), 7.09 (d,
1H, J ¼ 9.0 Hz, AreH), 7.25e7.30 (m, 5H, AreH), 7.41 (t, 1H,
J ¼ 7.2 Hz, AreH), 7.66e7.70 (m, 2H, AreH), 7.73 (d, 1H, J ¼ 8.7 Hz,
AreH), 7.81 (d, 1H, J ¼ 8.4 Hz, AreH,), 8.07e8.16 (m, 2H, AreH), 8.26
(s, 1H, AreH), 10.93 (bs, 1H, OH); 13C NMR (75 MHz DMSO-d6) dC
:
16.7, 41.5, 109.8, 120.7, 121.0, 124.9, 125.5, 126.9, 127.0, 127.7, 128.1,
131.6,133.8, 134.2, 138.3, 150.6, 153.3, 155.9, 158.5, 162.9, 166.1. Anal.
Calcd for C27H20FN3O4: C, 69.08; H, 4.29; N, 8.95; Found: C, 69.15; H,
4.39; N, 8.89%.
5.1.15. 2-(4-Chlorophenyl)-4-[(4-chlorophenyl)(2-hydroxy-1-
naphthyl)methyl]-5-methyl-2,3dihydro-1H-3-pyrazolone (5o)
(Table 2, entry,15): Yellow solid; yield: 69%, m.p.153 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 2.26 (s, 3H, CH3), 6.09 (s, 1H, CH), 7.01e7.10
(m, 6H, AreH & NH), 7.19e7.22 (m, 2H, AreH), 7.26e7.30 (m, 2H,
AreH), 7.36 (t, 1H, J ¼ 7.2 Hz, AreH), 7.55 (t, 1H, J ¼ 7.2 Hz, AreH),
7.68 (d, 1H, J ¼ 8.7 Hz, AreH), 7.82 (d, 1H, J ¼ 8.7 Hz, AreH), 8.06 (d,
1H, J ¼ 8.7 Hz, AreH), 10.73 (bs, 1H, OH); 13C NMR (75 MHz DMSO-
d6) dC: 13.2, 35.7, 106.1, 120.0, 121.3, 122.3, 123.1, 126.8, 127.0, 127.7,
128.3, 128.8, 128.9, 129.0, 129.2, 129.5, 131.1, 131.8, 133.4, 134.8,
139.0, 145.6, 153.4. Anal. Calcd for C27H20Cl2N2O2: C, 68.22; H, 4.24;
N, 5.89; Found: C, 68.29; H, 4.34; N, 5.80%.
5.1.10. 2-(4-Fluorophenyl)-4-[(2-hydroxy-1-naphthyl)(4-methy-
lphenyl)methyl]-5-methyl-2,3-dihydro-1H-3-pyrazolone (5j)
(Table 2, entry 10): Yellow solid; yield: 71%, m.p. 183 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 2.26 (s, 3H, CH3), 2.42 (s, 3H, CH3), 6.09 (s, 1H,
CH), 7.03e7.16 (m, 6H, AreH & NH), 7.15 (d, 1H, J ¼ 8.7 Hz, AreH),
7.32e7.35 (m, 1H, AreH), 7.44e7.52 (m, 2H, AreH), 7.67e7.70 (m,
3H, AreH), 7.79 (d, 1H, J ¼ 5.4 Hz, AreH), 8.15 (d, 1H, J ¼ 5.4 Hz,
AreH), 10.81 (bs, 1H, OH); 13C NMR (75 MHz CDCl3) dC: 11.0, 20.0,
35.0, 106.5, 114.6, 114.9, 120.7, 120.9, 121.6, 125.5, 126.1, 127.8, 127.9,

4536
P. Gunasekaran et al. / European Journal of Medicinal Chemistry 46 (2011) 4530e4536
[27] www.who.int/mediacentre/factsheets/fs104/en/
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S.P. thanks the Council of Scientific and Industrial Research, New
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