Synthesis, characterization and antimicrobial studies of 2-(4-methoxy-phenyl)-5-methyl-4-(2-arylsulfanyl-ethyl)-2,4-dihydro-[1,2,4] triazolo-3-ones and their corresponding sulfones

Article abstract of DOI:10.1016/j.ejmech.2010.04.016

In the present investigation,a series of novel 2-(4-methoxy-phenyl)-5- methyl-4-(2-arylsulfanyl-ethyl)-2,4-dihydro-[1,2,4] triazolo-3-ones and their corresponding sulfones were prepared with the objective of developing better antimicrobial agents. The che

Full text of DOI:10.1016/j.ejmech.2010.04.016

European Journal of Medicinal Chemistry 45 (2010) 3329e3334
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, characterization and antimicrobial studies of
2-(4-methoxy-phenyl)-5-methyl-4-(2-arylsulfanyl-ethyl)-2,4-dihydro-[1,2,4]
triazolo-3-ones and their corresponding sulfones
,
b
,
b
c
a
d
Bhimagouda S. Patil a , G. Krishnamurthy , H.S. Bhojya Naik , Prashant R. Latthe , Manjunath Ghate
*
a Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore-560099, Karnataka, India
b Department of Chemistry, Sahyadri Science College, Shimoga-577451, Karnataka, India
c Kuvempu University, Department of Industrial Chemistry, Shimoga-577451, Karnataka, India
d Krupanidhi College of Pharmacy, Chikkabelandur, Bangalore-560035, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present investigation, a series of novel 2-(4-methoxy-phenyl)-5-methyl-4-(2-arylsulfanyl-ethyl)-
2,4-dihydro-[1,2,4] triazolo-3-ones and their corresponding sulfones were prepared with the objective of
developing better antimicrobial agents. The chemical structures of the newly synthesized compounds
were characterized by spectral (IR, 1H NMR, 13C NMR and LCMS) methods. The newly synthesized
compounds (4aei) and (5aee, 5h) were screened for their antimicrobial activity against Bacillus subtilis,
Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa. The
antifungal activity was tested against Rhizopus oryzae, Aspergillus niger, Aspergillus flavus, Candida albi-
cans and Saccharomyces cerevisiae. Among all the compounds synthesized, compounds 4d and 5b
exhibited significant antibacterial activity.
Received 13 November 2009
Received in revised form
10 April 2010
Accepted 14 April 2010
Available online 20 April 2010
Keywords:
1,2,4-Triazolo-3-ones
Sulfones
Ó 2010 Elsevier Masson SAS. All rights reserved.
Thiols
Thioethers
Antimicrobial activity
1. Introduction
HIV, antibacterial and antifungal [2,30], analgesic [31], anti-
malarial [32] and anti-inflammatory [33e35] activities.
The development of drug resistance to clinically used anti-
infective agents has increased the demand for discovery of new
chemical scaffolds with antimicrobial activity. In addition increase
in immuno compromised patients and hospital acquired infections
has necessitated the exploration of new biological targets and
discovery of effective antibacterial and antifungal agents.
Several 1,2,4-triazole containing compounds are used as drugs
(Fig. 1); for instance, fluconazole is used as an antimicrobial drug
[36], while vorozole, letrozole and anastrozole are non steroidal
drugs used for the treatment of cancer [37]. Loreclezole is used as
an anticonvulsant [38] where as itraconazole is used as an anti-
fungal agent.
The 1,2,4-triazoles and their derivatives were found to be
associated with various biological activities such as antibacterial
[1e7], antifungal [4e8], antitubercular [9e11], analgesic [12,13],
anti-inflammatory [13e15], anticancer [16,17], anticonvulsant
[18,19], antiviral [20,21], insecticidal [22], antidepressant [23] and
central nervous system (CNS) [24] activities. Also the 1,2,4-triazole
ring with sulfones and thioethers show a wide range of biological
activities such as antibacterial and antifungal [25], antihypertensive
[26], analgesic, anti-inflammatory [27], and pesticidal [28,29].1,3,4-
oxadiazoles exhibit wide spectrum of biological activities such as
Keeping in mind the above facts, we were interested to
synthesize some more 1,2,4-triazol containing thioethers and their
corresponding sulfones.
2. Chemistry
Synthetic pathway for the preparation of title compounds is
depicted in Scheme 1. The oxadiazolinone (1) was synthesized as
reported in the literature [39]. The key intermediate 4-(2-hydroxy-
ethyl)-2-(4-methoxy-phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-
3-one (2) was prepared from one pot ring conversion of
oxadiazolinone (1). The hydroxyethyl derivative (2) was utilized as
a precursor to introduce various heterocycles. 5-(4-chloro-phenyl)
[1,3,4] oxadiazol-2-thiol (3a) was synthesized according to
a previously reported method [40].
* Corresponding author. Department of Chemistry, Sahyadri Science College,
Shimoga-577451, Karnataka, India. Tel.: þ91 80 2808 3133; fax: þ91 80 2808 3150. .
E-mail address: bhimagouda.patil@syngeneintl.com (B.S. Patil).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.04.016

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B.S. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 3329e3334
antifungal activity was tested against Rhizopus oryzae, Aspergillus
niger, Aspergillus flavus, Candida albicans, and Saccharomyces cer-
evisiae The MIC was determined by using two-fold serial dilution
method with 64-well microtest plates. Streptomycin and Penicillin
were used for antibacterial activity as reference standards and
Ampotericin-B as a reference standard with good antifungal activity.
For determining both antibacterial and antifungal activities, the
synthesized compounds and the control drugs were dissolved in
redistilled DMF. Further dilutions were made at the required
concentrations of 300, 150, 75, 37.5, 18.75, 9.75, 6.25, 3.125 and
1.56 mg/mL respectively. In order to ensure that the solvent had no
effect on bacterial growth, a control test was performed containing
broth supplemented with only DMF at the same dilution as used in
the experiment. The MIC values were obtained from the lowest
concentration of the test compound, where the tubes remain clear,
indicating that the bacterial growth was completely inhibited at
this concentration.
The results of antimicrobial screening revealed that both thio-
ethers (4aei) and their corresponding sulfones (5aee, 5h) dis-
played better antibacterial activity compared with their antifungal
activities. The results of antibacterial activity are given in Table 1.
From the results it was observed that the compound 4d (R ¼ 3-CF3)
showed good inhibition against S. aureus and E. coli. The compound
5b (R ¼ 3-F) had moderate activity against S. aureus and E. coli
(Fig. 2).
Fig. 1. Drugs containing 1,2,4-triazole moiety.
The reaction of hydroxyethyl compound (2) with methane
sulfonyl chloride afforded the mesylate (3). This on further reaction
with different thiols gave thethioethers (4aei) in good yields. These
thioethers on oxidation with m-CPBA afforded the corresponding
sulfones (5aee, 5h) in excellent yields.
3. Biological activity
The compound with fluoro substitution 4a (R ¼ 2-F) exhibited
significant activity against S. aureus, where as the compound with
methoxy group 4f (R ¼ 4-OCH3) showed moderate activity against
B. subtilis and E. coli. Among all the newly synthesized compounds,
4c, 4e, 4g, 4h, 4i, 5a and 5c showed poor activity.
The in vitro antimicrobial activity was carried out by disc diffu-
sion method in dimethylformamide (DMF) as solvent [41,42]. The
newly synthesized compounds were screened for antibacterial
activity against Bacillus subtilis, Staphylococcus aureus, Staphylo-
coccus epidermidis, Escherichia coli and Pseudomonas aeruginosa. The
O
O
OH
ii
O
N
i
O
N
O
N
N
2
N
1
O
O
O
Cl
O
S
O
iii
S
N
N
O
N
O
N
O
N
N
N
N
Cl
O
HS
3
4i
N
N
3a
iv
O
O
O
v
S
N
N
O
N
O
S
N
N
R
N
R
O
4a-h
5a-e, 5h
R = a) 2-F, b) 3-F, c) 4-F, d) 3-CF3,e ) 4-Br, f) 3-OCH3, g) 4-NH2, h) H
i) NH2CH2CH2OH, reflux, 16 h, ii) MsCl, pyridine, 0oC to rt, 4 h, iii) Cs2CO3, CuI, DMF,100oC, 10 h
iv) R-PhSH, Cs2CO3, CuI, DMF,100oC, 6-9 h, v) m-CPBA, DCM, 0-5oC, 30 min
Scheme 1. Synthesis of 1,2,4-triazole thioethers and their corresponding sulfones.

B.S. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 3329e3334
3331
Table 1
Antibacterial activities of the compounds (4aeh) and (5aee).
O
O
O
S
O
O
N
R
N
N
N
S
R
N
N
O
4a-h
5a-e, 5h
R
Compounds
B. subtilis
S. aureus
S. epidermidis
E. coli
P. aeruginosa
2-F
3-F
4-F
3-CF3
4-Br
3-OCH3
4-NH2
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5h
37.5
150
150
150
75
18.75
75
75
150
150
75
75
37.5
75
9.75
37.5
75
9.75
150
75
75
75
75
37.5
18.75
75
18.75
9.375
37.5
1.56
6.25
150
75
75
150
150
150
75
37.5
150
75
37.5
37.5
75
150
75
75
150
150
9.75
150
18.75
150
37.5
37.5
37.5
75
75
75
75
150
75
150
37.5
150
75
18.75
150
75
150
150
2-F
3-F
4-F
3-CF3
4-Br
H
9.375
37.5
37.5
150
150
3.125
7.81
150
6.25
1.526
Streptomycin
Penicillin
1.562
3.125
3.125
12.5
(MIC, mg/mL) minimum inhibitory concentration.
The results of antifungal activity are depicted in Table 2 and
compared with the standard Amphotericin-B. Almost all the newly
synthesized compounds showed poor activity against all types of
fungal strains. Thus thioethers (4aei) and corresponding sulfones
(5aee, 5h) of 1,2,4-triazole exhibited good antibacterial activity.
Further studies are in progress to develop a novel series of anti-
bacterial agents.
1H NMR spectrum of sulfones showed the downfield shift
of eSO2CH2e protons when compared with thioether derivatives
(4aei). The 1H NMR spectrum (5a) showed a singlet at
d
2.27 ppm
for eCH3 protons of triazolinone ring. The two methylene protons
were merged and observed at 4.01ppm. The signals at 6.94 and
d
7.33e7.79 were assigned to the aromatic protons. The structures
of these compounds were further confirmed by their mass spec-
tral analysis. LCMS of a typical compound (5a) showed [M þ 1]
peak at 392.0 which agrees with the molecular weight of the
compound.
4. Results and discussion
All new compounds were characterized by their spectral data.
The IR spectra of thioethers (4aei) showed bands at 1696 cmꢀ1 (C]
O of triazolinone) 1535 cmꢀ1 (C]N). The 1H NMR spectrum (4a)
5. Conclusion
A series of novel thioethers (4aei) and corresponding sulfones
(5aee, 5h) were synthesized and characterized by NMR, mass
showed a singlet at d 2.25 ppm for the eCH3 protons of triazolinone
ring. The two distorted triplet at 3.85 and 3.33 ppm were assigned
to the methylene protons. The signals at 6.93 and 7.79 were
assigned to the aromatic protons. The structure of these
compounds was further confirmed by its mass spectral analysis.
LCMS of a typical compound (4e) showed the molecular ion peaks
at 420 and 422 (1:1 isotopic peak for bromine) which agrees with
the molecular weight of the compound.
The IR spectrum of sulfones (5aee, 5h) exhibited S]O
stretching bands at 1329 (assym), and 1148 (sym) cmꢀ1 where
as the triazolinone C]O stretching observed at 1710 cmꢀ1. The
Table 2
Antifungal activities of the compounds (4aeh) and (5aee).
R
Compounds
R. oryzae A. niger A. flavus C. albicans S. cerevisiae
2-F
3-F
4-F
3-CF3
4-Br
4a
4b
4c
4d
4e
9.75
37.5
150
18.75
75
37.5
37.5
75
150
150
150
150
75
37.5
37.5
37.5
150
150
150
150
75
75
75
75
150
75
37.5
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
3-OCH3 4f
4-NH2 4g
H
4h
4i
150
150
2-F
3-F
4-F
3-CF3
4-Br
H
5a
5b
5c
5d
5e
5h
18.75
37.5
75
75
37.5
37.5
37.5
37.5
37.5
37.5
F
F
O
F
O
75
75
75
75
O
S
O
O
F
N
N
N
N
S
N
N
O
150
1.562
150
1.56
150
4d
5b
Amphoterin-B
6.25
6.25
6.25
Fig. 2. Most potent compounds among the newly synthesized compounds.
(MIC, mg/mL) minimum inhibitory concentration.

3332
B.S. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 3329e3334
spectrometry and IR studies. The yields were found to be satisfac-
tory. The newly synthesized compounds were screened for their
antibacterial and antifungal activities. Among all the compounds
4d (R ¼ 3-CF3) and 4a (R ¼ 2-F) exhibited good inhibition against S.
aureus and E. coli. Most of the compounds showed better antibac-
terial activity, further optimization and development of this series
is required for drug development.
SeCH2), 2.24 (s, 3H, AreCH3); 13C NMR (100 MHz, DMSO-d6):
162.4, 156.4, 151.3, 144.5, 137.8, 130.9, 130.8, 123.6, 119.6, 114.2,
114.1, 112.7, 55.3, 40.5, 29.7, 11.4. MS: m/z 360.0 [M þ 1]; Anal. Calcd
for C18H18FN3O2S: C, 60.15; H, 5.05; N, 11.69; S, 8.9. Found: C, 60.08;
H, 5.04; N, 11.67; S, 8.92.
d
6.4. 4-[2-(4-Fluoro-phenylsulfanyl)-ethyl]-2-(4-methoxy-phenyl)-
5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (4c)
6. Experimental
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 40/60); white solid; yield: 94%; mp 97.8e99.3 ꢁC. 1H NMR
Melting points were determined in Buchi B-545 melting point
apparatus and were presented without corrections. The IR spectra
were recorded on a Nicolet 6700 FT-IR spectrometry using ATR-
technique (ATR ¼ Attenuated Total Reflectance). NMR spectra were
recorded on Bruker (400 MHz) spectrometer instruments. 1H NMR
spectra were recorded in CDCl3 and DMSO-d6 using tetrame-
thylsilane (TMS) as an internal reference. 13C NMR spectra were
recorded for approximately 0.05M solutions in DMSO-d6 at
100 MHz with TMS as internal reference. Mass spectra were
recorded on LC-MS-Agilent 1200 series. C, H, N and S analysis were
carried out on an Elementor (Vario micro cube) instrument. All the
above compounds were purified by flash column chromatography
over silica gel (230e400 mesh).
(400 MHz, DMSO-d6):
d
7.68 (d, 2H, J ¼ 9.14 Hz, AreH), 7.47e7.43
(m, 2H, AreH), 7.16e7.11 (m, 2H, AreH), 6.99 (d, 2H, J ¼ 9.14 Hz,
AreH), 3.82 (t, 2H, J ¼ 6.72 Hz, NeCH2), 3.75 (s, 3H, OeCH3), 3.31 (t,
2H, J ¼ 6.72 Hz, SeCH2), 2.24 (s, 3H, AreCH3); 13C NMR (100 MHz,
DMSO-d6): d 161.0, 156.4, 151.2, 144.5, 131.2, 131.0, 130.1, 119.5, 116.2,
114.1, 55.33, 40.83, 31.29, 11.49. MS: m/z 360.0 [M þ 1]; Anal. Calcd
for C18H18FN3O2S: C, 60.15; H, 5.05; N, 11.69; S, 8.9. Found: C, 60.05;
H, 5.03; N, 11.71; S, 8.91.
6.5. 2-(4-Methoxy-phenyl)-5-methyl-4-[2-(3-trifluoromethyl-
phenylsulfanyl)-ethyl]-2,4-dihydro-[1,2,4] triazol-3-one (4d)
The synthesis of 4-(2-hydroxy-ethyl)-2-(4-methoxy-phenyl)-5-
methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (2) andMethanesulfonic
acid 2-[1-(4-methoxy-phenyl)-3-methyl-5-oxo-1,5-dihydro-[1,2,4]
triazol-4yl]-ethyl ester (3) were carried out by reported methods
[39]. Also 5-(4-chloro-phenyl) [1,3,4] oxadiazol-2-thiol (3a) was
synthesized according to literature method [40].
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 45/55); off white solid; yield: 73%; mp 99.8e101.6 ꢁC; 1H
NMR (400 MHz, DMSO-d6): d 7.77e7.72 (m, 2H, AreH), 7.69 (d, 2H,
J ¼ 9.08 Hz, AreH), 7.53e7.46 (m, 2H, AreH), 6.99 (d, 2H,
J ¼ 9.08 Hz, AreH), 3.88 (t, 2H, J ¼ 6.78 Hz, NeCH2), 3.76 (s, 3H,
OeCH3), 3.46 (t, 2H, J ¼ 6.78 Hz, SeCH2), 2.25 (s, 3H, AreCH3); 13
C
6.1. General procedure to synthesize thioethers (4aei)
NMR (100 MHz, DMSO-d6): d 156.8, 151.6, 144.9, 137.4, 132.1, 131.4,
130.5, 130.2, 125.6, 124.4, 122.9, 119.9, 114.5, 55.72, 41.05, 30.31,
11.81. MS: m/z 409.9 [M þ 1]; Anal. Calcd for C19H18F3N3O2S: C,
55.74; H, 4.43; N, 10.26; S, 7.83. Found: C, 55.69; H, 4.42; N, 10.30; S,
7.81.
A mixture of mesyl derivative (3) (2 mmol), substituted thiols
(2.1 mmol), Cs2CO3 (4 mmol) and CuI (0.2 mmol) in DMF (4 mL) was
stirred at 100 ꢁC for 6e10 h. The progress of the reaction was
monitored by TLC. After the completion of reaction, the mixture
was cooled and diluted with water. The product was extracted with
ethyl acetate (2 ꢂ 20 mL). The combined organic phase was washed
with water (2 ꢂ 20 mL), brine (20 mL) and dried over sodium
sulfate. The solvent was evaporated to afford the thioethers in
moderate to good yields.
6.6. 4-[2-(4-Bromo-phenylsulfanyl)-ethyl]-2-(4-methoxy-phenyl)-
5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (4e)
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 50/50); pale yellow solid; yield: 93%, mp 108.5e109.8 ꢁC.
1H NMR (400 MHz, CDCl3):
d
7.67 (d, 2H, J ¼ 9.04 Hz, AreH), 7.45 (d,
6.2. 4-[2-(2-Fluoro-phenylsulfanyl)-ethyl]-2-(4-methoxy-phenyl)-
5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (4a)
2H, J ¼ 8.56 Hz, AreH), 7.34 (d, 2H, J ¼ 8.56 Hz, AreH), 6.98 (d, 2H,
J ¼ 9.04 Hz, AreH), 3.84 (t, 2H, J ¼ 6.66 Hz, NeCH2), 3.75 (s, 3H,
OeCH3), 3.34 (t, 2H, J ¼ 6.66 Hz, SeCH2), 2.23 (s, 3H, AreCH3); 13
C
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 40/60); white solid; yield: 96%; mp 90.8e92.2 ꢁC; 1H NMR
NMR (100 MHz, DMSO-d6):
d 156.8, 151.6, 144.9, 134.9, 132.31,
131.3130.4, 120.03, 119.4, 114.5, 55.7, 41.1, 30.5, 11.87. MS: m/z 420
[M þ ] 422 [M þ 2]; Anal. Calcd for C18H18BrN3O2S: C, 51.44; H, 4.32;
N, 10.00; S, 7.63. Found: C, 51.54; H, 4.33; N, 9.98; S, 7.61.
(400 MHz, DMSO-d6):
d
7.67 (d, 2H, J ¼ 9.12 Hz, AreH), 7.57e7.54
(m, 1H, AreH), 7.25e7.13 (m, 3H, AreH), 6.98 (d, 2H, J ¼ 9.12 Hz,
AreH), 3.85 (t, 2H, J ¼ 6.8 Hz, NeCH2), 3.75 (s, 3H, OeCH3), 3.35 (t,
2H, J ¼ 6.8 Hz, SeCH2), 2.24 (s, 3H, AreCH3), 13C NMR (100 MHz,
DMSO-d6):
d
160.0, 156.4, 151.2, 144.5, 130.9, 130.2, 128.4, 125.1,
6.7. 2-(4-Methoxy-phenyl)-4-[2-(3-Methoxy-phenylsulfanyl)-
121.7, 119.6, 115.6, 114.11, 55.31, 40.7, 29.57, 11.38. MS: m/z 360.0
[M þ 1]; Anal. Calcd for C18H18FN3O2S: C, 60.15; H, 5.05; N, 11.69; S,
8.9. Found: C, 59.98; H, 5.03; N, 11.70; S, 8.88.
ethyl]-5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (4f)
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 45/55); off white solid; yield: 90%; mp 74.6e75.9 ꢁC. 1H
6.3. 4-[2-(3-Fluoro-phenylsulfanyl)-ethyl]-2-(4-methoxy-phenyl)-
5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (4b)
NMR (400 MHz, DMSO-d6):
d
7.69 (d, 2H, J ¼ 8.98 Hz, AreH), 7.19
(m, 2H, AreH), 6.98 (d, 2H, J ¼ 8.98 Hz, AreH), 6.95e6.93 (m, 2H,
AreH), 6.72e6.70 (m, 1H, AreH), 3.84 (t, 2H, J ¼ 6.70 Hz, NeCH2),
3.75 (s, 3H, OeCH3), 3.71 (s, 3H, OeCH3), 3.33 (t, 2H, J ¼ 6.70 Hz,
SeCH2), 2.23 (s, 3H, AreCH3); 13C NMR (100 MHz DMSO-d6):
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 40/60); off white solid; yield: 94%; mp 94.9e96 ꢁC. 1H NMR
(400 MHz, DMSO-d6):
d
7.70 (d, 2H, J ¼ 9.08 Hz, AreH), 7.35e7.28
d 160.1, 156.8, 151.6, 145.0, 136.5, 131.4, 130.4, 120.4, 120.0, 114.5,
(m, 2H, AreH), 7.21 (d, 1H, J ¼ 8.00 Hz, AreH), 6.99 (d, 2H,
J ¼ 9.08 Hz, AreH), 6.98e6.95 (m, 2H, AreH), 3.86 (t, 2H,
J ¼ 6.78 Hz, NeCH2), 3.76 (s, 3H, OeCH3), 3.38 (t, 2H, J ¼ 6.78 Hz,
113.3, 112.3, 55.7, 55.5, 41.2, 30.2, 11.8. MS: m/z 372 [M þ 1]; Anal.
Calcd for C19H21N3O3S: C, 61.44; H, 5.70; N, 11.31; S, 8.63. Found: C,
61.37; H, 5.72; N, 11.34; S, 8.62.

B.S. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 3329e3334
3333
6.8. 4-[2-(4-Amino-phenylsulfanyl)-ethyl]-2-(4-methoxy-phenyl)-
5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (4g)
AreH), 7.37e7.33 (m, 1H, AreH), 6.96 (d, 1H, J ¼ 8.96 Hz, AreH),
4.01 (s, 4H, eCH2eCH2), 3.74 (s, 3H, OeCH3), 2.27 (s, 3H, AreCH3);
13C NMR (100 MHz, DMSO-d6):
d 159.2, 156.8, 151.2, 144.6, 137.5,
Purified by column chromatography (Petroleum ether/Ethyl
131.0, 129.8, 126.8, 125.7, 119.9, 117.7, 114.4, 55.7, 51.9, 36.3, 11.7. MS:
m/z 392 [M þ 1]; Anal. Calcd for C18H18FN3O4S: C, 55.23; H, 4.64; N,
10.74; S, 8.19. Found: C, 55.18; H, 4.65; N, 10.76; S, 8.21.
acetate, 30/70), Dark brown thick liquid; yield: 73%; 1H NMR
(400 MHz, DMSO-d6):
d
7.72 (d, 2H, J ¼ 8.92 Hz, AreH), 7.15 (d, 2H,
J ¼ 8.34 Hz, AreH), 6.99 (d, 2H, J ¼ 8.92 Hz, AreH), 6.52 (d, 2H,
J ¼ 8.34 Hz, AreH), 5.28 (s, 2H, AreNH2), 3.76 (s, 3H, OeCH3), 3.74
(t, 2H, J ¼ 6.28 Hz, NeCH2), 3.04 (t, 2H, J ¼ 6.28 Hz, SeCH2), 2.21 (s,
6.13. 4-[2-(3-Fluoro-benzenesulfonyl)-ethyl]-2-(4-methoxy-
phenyl)-5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (5b)
3H, AreCH3); 13C NMR (100 MHz, DMSO-d6):
d 156.4, 151.26, 148.6,
144.6, 133.3, 131.0, 119.6, 117.5114.5, 114.1 55.3, 40.8, 33.4, 11.4. MS:
m/z 357 [M þ 1]; Anal. Calcd for C18H20N4O2S: C, 60.65; H, 5.66; N,
15.72; S, 9.00. Found: C, 60.73; H, 5.65; N, 15.70; S, 8.99.
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 10/90); off white solid; yield: 97%; mp 193.2e195.5 ꢁC; 1H
NMR (400 MHz, DMSO-d6):
d 7.79e7.76 (m, 2H, AreH), 7.69e7.65
(m, 1H, AreH), 7.63 (d, 2H, J ¼ 9.08 Hz, AreH), 7.55e7.50 (m, 1H,
AreH), 6.98 (d, 2H, J ¼ 9.08 Hz, AreH), 3.99e3.96 (m, 4H, eCH2),
3.75 (s, 3H, OeCH3), 2.29 (s, 3H, AreCH3). 13C NMR (100 MHz,
6.9. 4-(2-Phenylsulfanyl-ethyl)-2-(4-methoxy-phenyl)-5-methyl-
2,4-dihydro-[1,2,4] triazol-3-one (4h)
DMSO-d6): d 162.1, 156.8, 151.2, 144.2, 141.2, 132.2, 131.2, 124.1, 121.7,
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 30/70), pale yellow solid; yield: 91%; mp 86.3e86.5 ꢁC.
119.8, 115.1, 114.5, 55.7, 51.4, 35.8, 11.75. MS: m/z 392 [M þ 1]; Anal.
Calcd for C18H18FN3O4S: C, 55.23; H, 4.64; N, 10.74; S, 8.19. Found: C,
55.31; H, 4.63; N, 10.74; S, 8.16.
1H NMR (400 MHz, DMSO-d6):
d
7.69 (d, 2H, J ¼ 9.14 Hz, AreH),
7.41e7.37 (m, 2H, AreH), 7.31e7.27 (m, 2H, AreH), 7.18e7.14 (m,
1H, AreH), 6.98 (d, 2H, 9.14 Hz, AreH), 3.83 (t, 2H,
J ¼ 6.72 Hz, NeCH2), 3.75 (s, 3H, OeCH3), 3.32 (t, 2H, J ¼ 6.72 Hz,
SeCH2), 2.21 (s, 3H, AreCH3); 13C NMR (100 MHz, CDCl3):
157.1,
151.7, 143.5, 134.4, 131.0, 129.2, 129.1, 126.6, 120.4, 114.0, 55.4,
41.6, 31.5, 11.8. MS: m/z 342.2 [M 1]; Anal. Calcd for
J
¼
6.14. 4-[2-(4-Fluoro-benzenesulfonyl)-ethyl]-2-(4-methoxy-
phenyl)-5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (5c)
d
þ
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 10/90); off white solid; yield: 95%; mp 168.3e169.5 ꢁC. 1H
NMR (400 MHz, DMSO-d6): d 7.99e7.96 (m, 2H, AreH), 7.63 (d, 2H,
C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31; S, 9.39. Found: C, 63.53;
H, 5.60; N, 12.30; S, 9.36.
J ¼ 9.00 Hz, AreH), 7.43 (m, 2H, AreH), 6.98 (d, 2H, J ¼ 9.00 Hz,
AreH), 3.99e3.96 (m, 2H, eCH2), 3.92e3.89 (m, 2H, eCH2), 3.76 (s,
3H, OeCH3), 2.29 (s, 3H, AreCH3). 13C NMR (100 MHz, DMSO-d6):
6.10. 4-{2-[5-(4-Chloro-phenyl)-[1,3,4] oxadiazol-2-yl-sulfanyl]-
ethyl}-2-(4-methoxy-phenyl)-5-methyl-2,4-dihydro-[1,2,4] triazol-
3-one (4i)
d
165.5, 156.8, 151.2, 144.7, 135.6, 131.2, 119.9, 117.2, 116.9, 114.5, 55.7,
52.1, 35.9, 11.7. MS: m/z 392 [M þ 1]; Anal. Calcd for C18H18FN3O4S:
C, 55.23; H, 4.64; N, 10.74; S, 8.19. Found: C, 55.29; H, 4.64; N, 10.71;
S, 8.20.
Purified by recrystallisation (DCM/Methanol); light brown solid;
yield: 68%; mp 181.9e183.2 ꢁC. 1H NMR (400 MHz, DMSO-d6):
d
7.91 (d, 2H, J ¼ 9.00 Hz, AreH), 7.63e7.58 (m, 4H, AreH), 6.90 (d,
2H, J ¼ 9.00 Hz, AreH), 4.09 (t, 2H, J ¼ 6.20 Hz, NeCH2), 3.73 (s, 3H,
OeCH3), 3.64 (t, 2H, J ¼ 6.20 Hz, SeCH2), 2.31 (s, 3H, AreCH3); 13
C
6.15. 2-(4-Methoxy-phenyl)-5-methyl-4-[2-(3-
trifluoromethylbenzenesulfonyl)-ethyl]-2,4-dihydro-[1,2,4]
triazol-3-one (5d)
NMR (100 MHz, DMSO-d6):
d 164.8, 163.8, 156.7, 151.6, 145.0, 137.1,
131.3, 129.9, 128.6, 122.1, 119.8, 114.4, 55.6, 40.5, 31.1, 11.96. MS: m/z
443 [M þ 1]; Anal. Calcd for C20H18ClN5O3S: C, 54.15; H, 4.09; N,
15.7; S, 7.22. Found: C, 54.06; H, 4.10; N, 15.73; S, 7.24.
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 10/90); off white solid; yield: 98%; mp 138.2e140.4 ꢁC; 1H
NMR (400 MHz, DMSO-d6): d 8.22e8.21 (m, 2H, AreH), 8.01 (d, 1H,
J ¼ 7.8 Hz, AreH), 7.81 (t, 1H, J ¼ 8.00 Hz, AreH), 7.60 (d, 2H,
J ¼ 9.16 Hz, AreH), 6.95 (d, 2H, J ¼ 9.16 Hz, AreH), 4.05e3.99 (m,
4H, eCH2), 3.75 (s, 3H, OeCH3), 2.28 (s, 3H, AreCH3). 13C NMR
6.11. General procedure to synthesize 4-[substituted-
(benzenesulfonyl)-ethyl]-2-(4-methoxy-phenyl)-5-methyl-2,4-
dihydro-[1,2,4] triazole-3-one (5aee)
To a solution of thioethers (4aee, 4h) (2 mmol) in CH2Cl2 (5 mL)
was added m-CPBA (m-chloroperbenzoic acid) (75% purity,
6.8 mmol) at 0e5 ꢁC. The mixture was stirred for 30 min, and the
reaction completion was monitored through TLC. After completion
of the reaction, reaction mixture was quenched with 20% aqueous
Na2S2O3 solution. The organic phase was separated and aqueous
phase extracted thrice with ethyl acetate. The combined organic
phase was washed with 1M NaOH solution and brine, dried over
anhydrous Na2SO4, filtered, and concentrated to afford the
compounds (5aee, 5h) in excellent yields.
(100 MHz, DMSO-d6): d 156.4, 150.8, 144.3, 140.1, 131.5, 131.2, 130.9,
130.7, 124.4, 124.2, 119.4, 114.1, 55.3, 51.5, 35.3, 11.3. MS: m/z 442
[M þ 1]; Anal. Calcd for C19H18F3N3O4S: C, 51.70; H, 4.11; N, 9.52; S,
7.26. Found: C, 51.79; H, 4.10; N, 9.42; S, 7.23.
6.16. 4-[2-(4-Bromo-benzenesulfonyl)-ethyl]-2-(4-methoxy-
phenyl)-5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (5e)
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 20/80); pale yellow solid; yield: 90%; mp 177.2e179.4 ꢁC;
6.12. 4-[2-(2-Fluoro-benzenesulfonyl)-ethyl]-2-(4-methoxy-
phenyl)-5-methyl-2,4-dihydro-[1,2,4] triazol-3-one (5a)
1H NMR (400 MHz, CDCl3):
d
7.68e7.62 (m, 6H, AreH), 6.93e6.91
(m, 2H, AreH), 4.12 (m, 2H, eCH2), 3.82 (s, 3H, OeCH3), 3.76 (m, 2H,
eCH2), 2.41 (s, 3H, AreCH3). 13C NMR (100 MHz, DMSO-d6):
156.8,
d
Purified by column chromatography (Petroleum ether/Ethyl
acetate, 10/90); off white solid; yield: 98%, mp 191.2e193.4 ꢁC. 1H
151.2, 144.7, 138.5, 132.9, 131.1, 129.8, 128.7, 119.9, 114.5, 55.7, 51.9,
35.9, 11.7. MS: m/z 452.0 [M þ ] and 454.0 [M þ 2]; Anal. Calcd for
C18H18BrN3O4S: C. 47.8; H. 4.01; N. 9.29; S. 7.09. Found: C, 47.88; H,
4.02; N, 9.30; S; 7.06.
NMR (400 MHz, DMSO-d6)
d 7.77e7.73 (m, 1H, AreH), 7.67e7.61
(m, 1H, AreH), 7.56 (d, 2H, J ¼ 8.96 Hz, AreH), 7.45e7.41 (m, 1H,

3334
B.S. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 3329e3334
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Acknowledgements
The authors gratefully acknowledge Dr. Goutam Das, COO, and
Dr. Sathyashanker P., CSM, Syngene International Ltd for their
invaluable support. We thank Dr. Bharati V. Badami, retired
Professor of Organic Chemistry, Department of chemistry, Karna-
taka University, Dharwad, for encouragement and suggestions.
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