Synthesis, multiparametric structure assessment and biological evaluation of some new 1,3,4-oxadiazoles containing piperidine nucleus

Article abstract of DOI:10.14233/ajchem.2017.20564

With an aim to introduce more biologically active compounds, S-substituted derivatives of 5-[1-(4-nitrophenylsulfonyl)piperidin-4-yl]-1,3,4-oxadiazole-2-thiol (3) were synthesized through four steps. In the first step, ethyl 1-(4-nitrophenylsulfonyl)piperidine-4-carboxylate (1)was synthesized by reacting 4-nitrobenzenesulfonyl chloride (a) and ethyl isonipacotate (b) in basic medium. In the second step, compound 1 and hydrazine monohydrate were converted to corresponding hydrazide (2). In third step, hydrazide (2), CS2 and KOH were refluxed in the presence of MeOH to acquire 5-(1-(4-nitrophenylsulfonyl)piperidin-4-yl)-1,3,4-oxadiazole-2-thiol (3). In the last step, alkyl/aralkylhalides (4a-o) and 3 were made to react in an aprotic polar solvent to get the final compounds, 2-(substitutedthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-4-yl]-1,3,4-oxadiazole (5a-o). The synthesized compounds were structurally confirmed by spectroscopic techniques including ¹H NMR, EIMS and IR. Finally the synthesized compounds were screened for antibacterial activity against five bacterial strains.

Full text of DOI:10.14233/ajchem.2017.20564

Asian Journal of Chemistry; Vol. 29, No. 9 (2017), 1901-1906
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20564
Synthesis, Multiparametric Structure Assessment and Biological
Evaluation of Some New 1,3,4-Oxadiazoles Containing Piperidine Nucleus
1
1,*
1
JAVED IQBAL , AZIZ-UR-REHMAN , MUHAMMAD ATHAR ABBASI ,
1
1
1
2
SABAHAT ZAHRA SIDDIQUI , SHAHID RASOOL , MUHAMMAD REHAN and SYED ADNAN ALI SHAH
1
2
Department of Chemistry, Government College University, Lahore-54000, Pakistan
Faculty of Pharmacy and Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA, Puncak Alam
Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
Corresponding author: Tel: +92 42 111000010 Ext. 450; E-mail: azizryk@yahoo.com
Received: 3 February 2017; Accepted: 22 June 2017; Published online: 15 July 2017;
*
AJC-18462
With an aim to introduce more biologically active compounds, S-substituted derivatives of 5-[1-(4-nitrophenylsulfonyl)piperidin-4-yl]-
,3,4-oxadiazole-2-thiol (3) were synthesized through four steps. In the first step, ethyl 1-(4-nitrophenylsulfonyl)piperidine-4-carboxylate
1)was synthesized by reacting 4-nitrobenzenesulfonyl chloride (a) and ethyl isonipacotate (b) in basic medium. In the second step,
compound 1 and hydrazine monohydrate were converted to corresponding hydrazide (2). In third step, hydrazide (2), CS and KOH were
1
(
2
refluxed in the presence of MeOH to acquire 5-(1-(4-nitrophenylsulfonyl)piperidin-4-yl)-1,3,4-oxadiazole-2-thiol (3). In the last step,
alkyl/aralkylhalides (4a-o) and 3 were made to react in an aprotic polar solvent to get the final compounds, 2-(substitutedthio)-5-[1-(4-
nitrophenylsulfonyl)piperidin-4-yl]-1,3,4-oxadiazole (5a-o). The synthesized compounds were structurally confirmed by spectroscopic
1
techniques including H NMR, EIMS and IR. Finally the synthesized compounds were screened for antibacterial activity against five
bacterial strains.
Keywords: Sulfonamide, Ester, 1,3,4-Oxadiazole, Piperidine, Antibacterial activity.
heterocyclic core, piperidine, has been found to possess
potential against acetyl cholinesterase enzyme, in the treatment
of migraine headaches, in the treatment of schizophrenia and
also has great extent of anticonvulsant, anti-inflammatory,
antibacterial and antimalarial acivities [12]. In addition to it,
piperidine heterocyclic ring has some important features like
low toxicity and drugs with water lipid partition coefficient.
That’s why piperidine nucleus has ability to improve the
biological activities of the design drugs system [13,14].
Our research group is already working on derivatives of
INTRODUCTION
The increasing interest of researchers has been observed
to design the oxadiazole system because of its basic application
in the formulation of many drugs with a variety of biological
activities [1,2]. 1,3,4-Oxadiazole, the five membered hetero-
cyclic compound having two nitrogen atoms at position 3 and
4
, exhibits a broad spectrum of biological activities. The pro-
duction of azoles based drugs has reflected a great achievement
in medical field and so serving the humanity against deadly
diseases caused by different microbes [3]. Disubstituted 1,3,4-
oxadiazole has shown a wide variety of biological activities
such as antibacterial, antimycobacterial, antifungal, anti-
inflammatory, analgesic, anticonvulsant and anticancer activi-
ties [4-7]. Recently it has been found that 1,3,4-oxadiazole
has shown the cytotoxity and antiproliferative effect on cancer
cell lines [8,9].
1
,3,4-oxadiazole. In continuation to our previous work on
oxadiazole derivatives having azinane core [15] by the cost
effective methods for the synthesis of biologically important
compounds, 1,3,4-oxadiazole derivatives bearing piperidine
nucleus have been synthesized to combat the vastly resistive
pathogens for already available drugs.
Oxadiazole molecule having azinane core is very impor-
tant in the fields of natural products, pharmaceutical industry
and biologically active compounds [10]. A wide variety of
compounds having azinane core have been introduced into
the preclinical practices since a few decades [11]. This azinane
EXPERIMENTAL
Different chemicals utilized to achieve our targeted products
were availed from Sigma Aldrich and Alfa Aesar (Germany).
Purity of synthesized compounds was assured by re-crysta-

1
902 Iqbal et al.
Asian J. Chem.
(KBr, νmax, cm ): 3079 (Ar C-H), 1723 (C=O), 1610 (Ar C=C),
-1
llization and thin layer chromatography technique, generated
on pre-coated silica gel G-25-UV254 aluminum plates, with
n-hexane and ethyl acetate system and visualized using 254
nm UV lamp. The IR spectra were recorded using KBr pellet
method on Jasco-320-A spectrometer. Mass spectra (EI-MS)
1
1519 (N=O), 1455 (S=O), 1176 (C-N); H NMR (CDCl
MHz, δ (ppm)): 8.39 (d, J = 8.8 Hz, 2H, H-3'', H-5''), 7.95 (d,
J = 8.8 Hz, 2H, H-2'', H-6''), 4.11 (q, J = 7.14 Hz, 2H, CH ),
3
, 600
2
3.64 (dt, J = 4.2, 12.1 Hz, 2H, Heq-2', Heq-6'), 2.62 (dt, J = 3.0,
1
were recorded on JMS-HX-110 spectrometer. H NMR spectra
8.9 Hz, 2H, Hax-2', Hax-6'), 2.32-2.28 (m, 1H, H-4'), 2.02-2.00
were recorded in MeOD solvent on Bruker spectrometer
operating at 500 & 600 MHz. Melting points of synthesized
compounds were recorded on Griffin and George meting point
apparatus using open capillary tube and were uncorrected.
Synthesis of ethyl 1-(4-nitrophenylsulfonyl)piperidin-
(m, 2H, Heq-3', Heq-5'), 1.99-1.97 (m, 2H, Hax-3', Hax-5'), 1.22
+
); EI-MS (m/z): 342 [M] , 269, 185,
(t, J = 7.14 Hz, 3H, CH
3
122.
1-(4-Nitrophenylsulfonyl)piperidin-4-carbohydrazide
(2): Light red amorphous solid;Yield: 85 %; m.f.: C12 S;
H
16
N
4
O
5
-1
-1
molecular mass: 328.34 g mol ; IR (KBr, νmax, cm ): 3098
4
-carboxylate (1): 4-Nitrophenyl sulfonyl chloride [0.389
mol; (a)] was reacted with equimolar ethyl isonipecotate (b)
in a 250 mL round bottom flask using 100 mL water as solvent.
The mixture was stirred at room temperature at 140 rpm for
(Ar C-H), 1635 (C=O), 3279 (N-H), 1608 (Ar C=C), 1515
1
(N=O), 1395 (S=O), 1085 (C-N); H NMR (MeOD, 600 MHz,
δ (ppm)): 7.45 (d, J = 8.6 Hz, 2H, H-3'', H-5''), 6.73 (d, J =
8.7 Hz, 2H, H-2'', H-6''), 4.60 (s, 2H, N-H), 3.72-3.68 (m, 2H,
3
h. The aqueous sodium carbonate solution (18 %) was added
to adjust the pH at 9-10. Completion of reaction was confirmed
by TLC and then the solution was neutralized using dil. HCl.
The reaction mixture was poured into 500 mL beaker having
chilled water. The solution was aged until precipitation. The
formed precipitates were filtered, washed and dried.
Heq-2', Heq-6'), 2.29 (dt, J = 3.5, 11.6 Hz, 2H, Hax-2', Hax-6'),
2.12-2.09 (m, 1H, H-4'), 1.82-1.75 (m, 4H, H-3', H-5'); EI-
+
MS (m/z): 328 [M] , 269, 185, 122.
5-[1-(4-Nitrophenylsulfonyl)piperidin-4-yl]-1,3,4-
oxadiazol-2-thiol (3): Light green amorphous solid; Yield:
Synthesis of 1-(4-nitrophenylsulfonyl)piperidine-4-
carbohydrazide (2): Compound 1 (0.015 mol) was dissolved
in methanol (50 mL) in a 250 mL round bottom flask and then
hydrazine monohydrate (5 mL) was added. The mixture was
refluxed for 4 h. The completion of reaction was confirmed
by TLC. The chilled distilled water was added in small amounts
along with shaking until precipitation. The precipitates were
filtered, washed and dried.
77 %; m.p.: 176-177 °C; m.f.: C13
H
14
N
4
O
5
S
2
; molecular mass:
370.40 g mol ; IR (KBr, νmax, cm ): 3075 (Ar C-H), 2567
-1
-1
(S-H), 1678 (C=N), 1596 (Ar C=C), 1523 (N=O), 1435 (S=O),
1
1222, 1039 (C-O-C), 1076 (C-N), 605 (C-S); H NMR (MeOD,
600 MHz, δ (ppm)): 7.43 (d, J = 8.7 Hz, 2H, H-3'', H-5''),
6.75 (d, J = 8.7 Hz, 2H, H-2'', H-6''), 3.68-3.64 (m, 2H, Heq-2',
Heq-6'), 2.51 (dt, J = 11.6,11.3 Hz, 2H, Hax-2',Hax-6'), 2.15-
2.11 (m, 1H, H-4'), 1.85-1.79 (m, 4H, H-3', H-5'); EI-MS (m/z):
+
370 [M] , 311, 297, 295, 269, 185, 122.
Synthesis of 5-[1-(4-nitrophenylsulfonyl)piperidin-4-
yl]-1,3,4-oxadiazol-2-thiol (3): Compound 2 (0.0304 mol)
was dissolved in 100 mL ethanol in a 250 mL round bottom
flask along with KOH (0.0304 mol) and set to reflux till comp-
2-(Ethylthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-4-
yl]-1,3,4-oxadiazole(5a): Sticky greenish solid;Yield: 82 %;
-1
m.f.: C15
H
18
N
4
O
5
S
2
; molecular mass: 398.46 g mol ; IR (KBr,
-
1
lete dissolution of KOH. After this, CS
2
(0.0608 mol) was
νmax, cm ): 3132 (Ar C-H), 1678 (C=N), 1584 (Ar C=C), 1518
added at room temperature and then again refluxed for 5 h.
TLC was used to confirm the completion of reaction. Excess
distilled water was added and the pH was adjusted to 5-6. The
mixture was aged for 5 h to acquire maximum yield and formed
precipitates were filtered, washed and dried.
(N=O), 1426 (S=O), 1226, 1028 (C-O-C), 1148 (C-N), 628
1
(C-S); H NMR (MeOD, 600 MHz, δ (ppm)): 7.73 (d, J = 8.2
Hz, 2H, H-3'', H-5''), 7.05 (d, J = 8.1 Hz, 2H, H-2'', H-6''),
3.74-3.72 (m, 2H, Heq-2', Heq-6'), 3.24 (q, J = 7.3 Hz, 2H, H-
1'''), 2.66 (dt, J = 11.6 Hz, 2H, Hax-2',Hax-6'), 1.44 (t, J = 7.2
+
General procedure for the synthesis of target compounds
5a-o): Compound 3 (0.5 mmol) was taken in 50 mL round
Hz, 3H, H-2'''); EI-MS (m/z): 398 [M] , 311, 297, 295, 269,
185, 122.
(
bottom flask along with 10 mL of N,N-dimethyl formamide.
Then LiH was added as an activator and mixture was set to
stirrer for 30 min. Equimolar amount of aralkyl/aralkyl halides
2-(n-Propylthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-
4-yl]-1,3,4-oxadiazole (5b): Light green amorphous solid;
20 4 5 2
Yield: 82 %; m.p.: 111-112 °C; m.f.: C16H N O S ; molecular
-1
-1
mass: 412 g mol ; IR (KBr, νmax, cm ): 3098 (Ar C-H), 1654
(
4a-o) were added and the reaction mixture was stirred for 3-
h at room temperature. TLC was performed to confirm the
4
(C=N), 1594 (Ar C=C), 1523 (N=O), 1446 (S=O), 1238, 1042
1
(C-O-C), 1168 (C-N), 642 (C-S); H NMR (MeOD, 600MHz,
completion of reaction. The excess chilled water was added
on vigorous shaking and the mixture was aged for 1 h for
precipitation. The precipitates were filtered, washed and dried.
Some compounds were extracted by chloroform.
Antibacterial activity assay: The synthesized com-
pounds were screened for the antibacterial activity by the
reported method [16].
δ (ppm)): 7.48 (d, J = 8.8 Hz, 2H, H-3'', H-5''), 6.75 (d, J =
6.7 Hz, 2H, H-2'',H-6''), 3.67-3.65 (m, 2H, Heq-2', Heq-6'), 3.22
(t, J = 7.2 Hz, 2H, H-1'''), 2.52 (dt, J = 2.7, 12.2 Hz, 2H, Hax-
2', Hax-6'), 2.16-2.14 (m, 1H, H-4'), 1.89-1.86 (m, 4H, H-3',
H-5'), 1.80 (sex, J = 7.4 Hz, 2H, H-2'''), 1.05 (t, J = 7.3 Hz,
+
3H, H-3'''); EI-MS (m/z): 412 [M] , 311, 297, 295,269, 185,
1
22.
Spectral characterization of the synthesized compounds
2
-(Isopropylthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-
4-yl]-1,3,4-oxadiazole (5c): Dark brown sticky solid; Yield:
Ethyl 1-(4-nitrophenylsulfonyl)piperidin-4-carboxylate
-1
(
1): Off white amorphous solid; Yield: 90 %; m.p.: 142-145
78 %; m.f.: C16
H
20
4 5 2
N O S ; molecular mass: 412.38 g mol ; IR
-1
-1
(KBr, νmax, cm ): 3062 (Ar C-H), 1668 (C=N), 1615 (Ar C=C),
°
18 2 6
C; m.f.: C14H N O S; molecular mass: 342.37 g mol ; IR

Vol. 29, No. 9 (2017)
Synthesis and Biological Evaluation of Some New 1,3,4-Oxadiazoles Containing Piperidine Nucleus 1903
1
6
8
3
2
1
3
549 (N=O), 1398 (S=O), 1215, 1021 (C-O-C), 1096 (C-N),
1
43 (C-S); H NMR (MeOD, 600 MHz, δ (ppm)): 7.40 (d, J =
(m, 6H, H-4''' to H-6'''), 0.89 (t, J = 7.0 Hz, 3H, H-7'''); EI-MS
+
(m/z): 468 [M] , 311, 297, 295,269, 185, 122, 99.
.6 Hz, 2H, H-3'', H-5''), 6.72 (d, J = 8.5 Hz, 2H, H-2'', H-6''),
.68-3.62 (m, 2H, Heq-2', Heq-6'), 2.75-2.65 (m, 1H, H-1'''),
.59-2.49 (m, 2H, Hax-2', Hax-6'), 2.12-2.07 (m, 1H, H-4'), 1.95-
.94 (m, 4H, H-3', H-5'), 1.87 (d, J = 7.2 Hz, 6H, H-2''', H-
2-(Benzylthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-
4-yl]-1,3,4-oxadiazole (5h): Yellow sticky solid;Yield: 86 %;
-
1
m.f.: C20
H
20
N
4
O
5
S
2
; molecular mass: 460.53 g mol ; IR (KBr,
-
1
ν
max, cm ): 3132 (Ar C-H), 1678 (C=N), 1584 (Ar C=C), 1518
(N=O), 1426 (S=O), 1226, 1028 (C-O-C), 1148 (C-N), 628
1
(C-S); H NMR (MeOD, 500 MHz, δ (ppm)): 7.43 (d, J = 8.5
+
'''); EI-MS (m/z): 412 [M] , 311, 297, 295,269, 185, 122.
2
-(n-Butylthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-
-yl]-1,3,4-oxadiazole (5d): Light brown amorphous solid;
; molecular
mass: 426.51 g mol ; IR (KBr, νmax, cm ): 3068 (Ar C-H),
4
Hz, 2H, H-3'', H-5''), 7.38 (d, J = 7.0 Hz, 2H, H-2''', H-6'''),
7.33-7.26 (m, 3H, H-3'''to H-5'''), 6.70 (d, J = 8.5 Hz, 2H, H-
Yield: 83 %; m.p.: 85-86 °C; m.f.: C17
H
22
N
O S
4 5 2
-1
-1
2'', H-6''), 4.42 (s, 2H, H-7'''), 3.67-3.58 (m, 2H, Heq-2', Heq
-
1
662 (C=N), 1610 (Ar C=C), 1543 (N=O), 1368 (S=O), 1218,
1
024 (C-O-C), 1096 (C-N), 646 (C-S); H NMR (MeOD, 600
6'), 2.98 (br.s, 1H, H-4'), 2.54-2.49 (m, 2H, Hax-2',Hax-6'), 2.16-
2.13 (m, 2H, Heq-3', Heq-5'), 1.83-1.80 (m, 2H, Hax-3', Hax-5');
1
+
EI-MS (m/z): 460 [M] , 311, 297, 295,269, 185, 122, 91,65.
MHz, δ (ppm)): 7.47 (d, J = 9.8 Hz, 2H, H-3'', H-5''), 6.75 (d,
J = 8.8 Hz, 2H, H-2'', H-6''), 3.68-3.65 (m, 2H, Heq-2', Heq-6'),
2-(2-Methylbenzylthio)-5-[1-(4-nitrophenylsulfonyl)-
3
.23 (t, J = 7.3 Hz, 2H, H-1'''), 2.54 (dt, J = 2.7, 8.9 Hz, 2H,
ax-2', Hax-6'), 2.16-2.14 (m, 1H, H-4'), 1.91-1.84 (m, 4H, H-
', H-5'), 1.75 (qui, J = 7.3 Hz, 2H, H-2'''), 1.50 (sex, J = 7.5
Hz, 2H, H-3'''), 0.97 (t, J = 6.3 Hz, 3H, H-4'''); EI-MS (m/z):
piperidin-4-yl]-1,3,4-oxadiazole (5i): Sticky brown solid;
H
Yield: 85 % m.f.: C21
H
22
N
4
O
5
S
2
; molecular mass: 474.55 g
-1
-1
mol ; IR (KBr, νmax, cm ): 3090 (Ar C-H), 1658 (C=N), 1598
3
(Ar C=C), 1545 (N=O), 1397 (S=O), 1242, 1023 (C-O-C),
1
1127 (C-N), 625 (C-S); H NMR (MeOD, 600 MHz, δ (ppm)):
+
4
26 [M] , 311, 297, 295,269, 185, 122, 57.
-(sec-Butylthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-
-yl]-1,3,4-oxadiazole (5e): Light brown amorphous solid;
2
7.45 (d, J = 8.8 Hz, 2H, H-3'', H-5''), 7.23-7.11 (m, 4H, H-
3'''to H-6'''), 6.68 (d, J = 7.8 Hz, 2H, H-2'', H-6''), 4.74 (s, 2H,
4
Yield: 81 %; m.p.: 122-123 °C; m.f.: C17
H
22
N
4
O
5
S
2
; molecular
H-7'''), 3.70 (br.s, 2H, Heq-2', Heq-6'), 2.43 (br.s, 2H, Hax-2',Hax
-
-1
-1
mass: 426.51 g mol ; IR (KBr, νmax, cm ): 3038 (Ar C-H),
6'), 2.37 (s, 3H, CH -2'''), 2.28-2.26 (m, 1H, H-4'), 1.68-1.81
3
+
1
1
6
642 (C=N), 1590 (Ar C=C), 1513 (N=O), 1395 (S=O), 1168,
1
044 (C-O-C), 1066 (C-N), 626 (C-S); H NMR (MeOD,
(m, 4H, H-3', H-5'); EI-MS (m/z): 474 [M] , 311, 297, 295,269,
185, 122, 105.
00MHz, δ (ppm)): 7.48 (d, J = 8.7 Hz, 2H, H-3'', H-5''), 6.74
2-(4-Fluorobenzylthio)-5-[1-(4-nitrophenylsulfonyl)-
piperidin-4-yl]-1,3,4-oxadiazole (5j): Brown sticky solid;
(
d, J = 6.7 Hz, 2H, H-2'', H-6''), 3.74-3.72 (m, 1H, H-1'''),
.72-3.65 (m, 2H, Heq-2', Heq-6'), 2.55 (dt, J = 2.6, 8.9 Hz, 2H,
ax-2', Hax-6'), 2.17-2.14 (m, 1H, H-4'), 1.91-1.85 (m, 4H, H-
3
Yield: 78 %; m.f.: C20
H
19
N
4
O
5
S
2
F; molecular mass: 478.52 g
-1
-1
mol ; IR (KBr, νmax, cm ): 3120 (Ar C-H), 1678 (C=N), 1610
H
3
3
', H-5'), 1.68 (qui, J = 7.3 Hz, 2H, H-2'''), 1.47 (d, J = 7.9 Hz,
H, H-4'''), 0.97 (t, J = 7.3 Hz, 3H, H-3'''); EI-MS (m/z): 426
(Ar C=C), 1543 (N=O), 1437 (S=O), 1192, 1043 (C-O-C),
1
1157 (C-N), 629 (C-S); H NMR (MeOD, 600 MHz, δ (ppm)):
+
M] , 311, 297, 295,269, 185, 122, 57.
[
7.47 (d, J = 8.8 Hz, 2H, H-3'', H-5''), 7.29 (d, J = 8.7 Hz, 2H,
H-3''', H-5'''), 7.06 (d, J = 8.8 Hz, 2H, H-2''', H-6'''), 6.74 (d, J
= 8.8 Hz, 2H, H-2'', H-6''), 4.45 (s, 2H, H-7'''), 7.67 (br.s, 2H,
2-(n-Pentylthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-
-yl]-1,3,4-oxadiazole (5f): Orange sticky solid;Yield: 76 %;
4
-
1
m.f.: C18
H
24
N
4
O
5
S
2
; molecular mass: 440.54 g mol ; IR (KBr,
Heq-2', Heq-6'), 2.53-2.51 (m, 2H, Hax-2', Hax-6'), 2.15-2.12 (m,
-
1
ν
max, cm ): 3084 (Ar C-H), 1672 (C=N), 1606 (Ar C=C), 1518
N=O), 1386 (S=O), 1234, 1027 (C-O-C), 1064 (C-N), 628
1H, H-4'), 1.84-1.80 (m, 4H, H-3', H-5'); EI-MS (m/z): 478
+
[M] , 311, 297, 295, 269, 185, 122, 109, 65.
(
(
1
C-S); H NMR (MeOD, 600MHz, δ (ppm)): 7.40 (d, J = 8.9
2-(2-Chlorobenzylthio)-5-[1-(4-nitrophenylsulfonyl)-
piperidin-4-yl]-1,3,4-oxadiazole (5k): Light brown sticky
Hz, 2H, H-3'', H-5''), 6.74 (d, J = 8.6 Hz, 2H, H-2'', H-6''),
3
1
1
.68-3.65 (m, 2H, Heq-2', Heq-6'), 3.23 (t, J = 7.3 Hz, 2H, H-
'''), 2.54 (dt, J = 2.8, 9.0 Hz, 2H, Hax-2',Hax-6'), 2.16-2.14 (m,
H, H-4'), 1.91-1.87 (m, 4H, H-3', H-5'), 1.78 (qui, J = 7.4
4 5 2
liquid; Yield: 80 %; m.f.: C20H19ClN O S ; molecular mass:
-
1
-1
494.97 g mol ; IR (KBr, νmax, cm ): 3115 (Ar C-H), 1639
(C=N), 1605 (Ar C=C), 1527 (N=O), 1447 (S=O), 1225, 1027
1
(C-O-C), 1155 (C-N), 637 (C-S); H NMR (MeOD, 600 MHz,
Hz, 2H, H-2'''), 1.47-1.43 (m, 2H, H-3'''), 1.37 (sex, J = 7.6
Hz, 2H, H-4'''), 0.95 (t, J = 7.1 Hz, 3H, H-5'''); EI-MS (m/z):
δ (ppm)): 7.49 (d, J = 8.8 Hz, 1H, H-6'''), 7.4 (d, J = 6.8 Hz,
2H, H-3'', H-5''), 7.31 (d, J = 9.0 Hz, 2H, H-2'', H-6''), 7.29-
7.24 (m, 3H, H-3''' to H-5'''), 4.49 (s, 2H, H-7'''), 3.85-3.83
(m, 2H,Heq-2', Heq-6'), 3.01 (br.s, 2H,Hax-2', Hax-6'), 2.27-2.10
(m, 1H, H-4'), 1.85-1.75 (m, 4H, H-3', H-5'); EIMS (m/z): 496
+
40 [M] , 311, 297, 295,269, 185, 122, 71.
4
2-(n-Heptylthio)-5-[1-(4-nitrophenylsulfonyl)piperidin-
-yl]-1,3,4-oxadiazole (5g): Dark brown sticky solid; Yield:
4
-1
8
28 4 5 2
6 %; m.f.: C20H N O S ; molecular mass: 468.59 g mol ; IR
-1
+
+
(KBr, νmax, cm ): 3124 (Ar C-H), 1664 (C=N), 1596 (Ar C=C),
[M+2] , 494 [M] , 311, 297, 295, 269, 185, 125, 122.
2-(4-Chlorobenzylthio)-5-[1-(4-nitrophenylsulfonyl)-
piperidin-4-yl]-1,3,4-oxadiazole (5l): Greenish sticky
1
6
9
3
1
512 (N=O), 1446 (S=O), 1185, 1047 (C-O-C), 1164 (C-N),
1
18 (C-S); H NMR (MeOD, 500 MHz, δ (ppm)): 7.44 (d, J =
.0 Hz, 2H, H-3'', H-5''), 6.71 (d, J = 9.0 Hz, 2H, H-2'', H-6''),
.65-3.62 (m, 2H, Heq-2', Heq-6'), 3.19 (t, J = 7.0 Hz, 2H, H-
'''), 2.96-2.91 (m, 1H, H-4'), 2.50 (dt, J = 2.5, 12.0 Hz, 2H,
4 5 2
product;Yield: 81 %; m.f.: C20H19ClN O S ; molecular mass:
-1
-1
494.97 g mol ; IR (KBr, νmax, cm ): 3116 (Ar C-H), 1634
(C=N), 1606 (Ar C=C), 1530 (N=O), 1442 (S=O), 1228, 1027
1
(C-O-C), 1135 (C-N), 638 (C-S); H NMR (MeOD, 600 MHz,
H
ax-2',Hax-6'), 2.12 (dd, J = 3.5,13.5 Hz, 2H, Heq-3',Heq-5'),
.86 (dq, J = 4.0, 9.5 Hz, 2H, Hax-3',Hax-5'), 1.75 (qui, J = 7.5
Hz, 2H, H-2'''), 1.42 (qui, J = 8.0 Hz, 2H, H-3'''), 1.38-1.27
1
δ (ppm)):7.42 (d, J = 8.5 Hz, 2H, H-3'', H-5''), 7.34 (d, J = 8.7
Hz, 2H, H-2''', H-6'''), 7.33 (d, J = 8.4 Hz, 2H, H-3''', H-5'''),

1
904 Iqbal et al.
Asian J. Chem.
6
.74 (d, J = 8.8 Hz, 2H, H-2'', H-6''), 4.44 (s, 2H, H-7'''), 3.67
(Ar C-H), 1675 (C=N), 1610 (Ar C=C), 1533 (N=O), 1445
1
(S=O), 1168, 1024 (C-O-C), 1128 (C-N), 634 (C-S); H NMR
(br.s, 2H,Heq-2', Heq-6'), 2.58-2.51 (m, 2H,Hax-2', Hax-6'), 2.15-
2
.11 (m, 1H, H-4'), 1.89-1.81 (m, 4H, H-3', H-5'); EI-MS (m/z):
(MeOD, 600 MHz, δ (ppm)); 7.51 (d, J = 8.7 Hz, 2H, H-3'',
H-5''), 6.83 (d, J = 8.6 Hz, 2H, H-2'', H-6''), 3.69-3.67 (m, 2H,
Heq-2', Heq-6'), 3.16 (t, J = 5.8 Hz, 2H, H-1'''), 2.32 (dt, J = 6.6
+
+
4
96 [M+2] , 494 [M] , 311, 297, 295,269, 185, 125, 122.
-(4-Bromobenzylthio)-5-[1-(4-nitrophenylsulfonyl)-
piperidin-4-yl]-1,3,4-oxadiazole (5m): Yellow amorphous
solid; Yield: 77 %; m.p.: 99-101 °C; m.f.: C20 Br;
molecular mass: 538.42 g mol ; IR (KBr, νmax, cm ): 3064
2
Hz, 2H, Hax-2', Hax-6'), 2.22 (qui, J = 6.5 Hz, 2H, H-2'''), 2.13-
2.11 (m, 1H, H-4'), 1.91-1.83 (m, 4H, H-3', H-5'), 0.92 (t, J =
+
6.9 Hz, 2H, H-3'''); EI-MS (m/z): 491 [M] , 311, 297, 295,
19 4 5 2
H N O S
-1
-1
(
(
(
Ar C-H), 1658 (C=N), 1612 (Ar C=C), 1542 (N=O), 1398
1
S=O), 1245, 1036 (C-O-C), 1155 (C-N), 607 (C-S); H NMR
269, 185, 122, 121.
RESULTS AND DISCUSSION
MeOD, 600 MHz, δ (ppm)): 7.48 (d, J = 7.02 Hz, 2H, H-3'',
H-5''), 7.36 (d, J = 8.4 Hz, 2H, H-2''', H-6'''), 7.30 (d, J = 8.5
Hz, 2H, H-3''', H-5'''), 6.70 (d, J = 8.2 Hz, 2H, H-2'', H-6''),
Resistivity of microbes against existing drugs prompted
us to synthesize some new S-substituted-5-[1-(4-nitrophenyl-
sulfonyl)piperidin-4-yl]-1,3,4-oxadiazole.All the compounds
4
2
4
2
.58 (s, 2H, H-7'''), 3.66-3.59 (m, 2H, Heq-2', Heq-6'), 2.58-
1
.54 (m, 2H,Hax-2', Hax-6'), 2.20-2.10 (m, 1H, H-4'), 1.30 (br.s,
were characterized by IR, H NMR and EIMS. The protocol
for synthesis is given in Scheme-I and the varying groups are
given in Table-1.
+
+
H, H-3', H-5'); EI-MS (m/z): 540 [M+2] , 538 [M] , 311,
97, 295, 269, 185, 169, 122, 65.
2
-(2-Bromoethylthio)-5-[1-(4-nitrophenylsulfonyl)-
piperidin-4-yl]-1,3,4-oxadiazole (5n): Yellow amorphous
solid; Yield: 83 %; m.p.: 186-187 °C; m.f.: C15 Br;
molecular mass: 476.35 g mol ; IR (KBr, νmax, cm ): 3132
Compound 5b has been considered for single compound
discussion. It was obtained in the form of light green amor-
phous solid having melting point of 111-112 °C. Its molecular
17 4 5 2
H N O S
-1
-1
20 4 5 2
formula was found to be C16H N O S with molecular mass of
-1
(
(
(
Ar C-H), 1678 (C=N), 1584 (Ar C=C), 1518 (N=O), 1426
1
S=O), 1226, 1028 (C-O-C), 1148 (C-N), 628 (C-S); H NMR
412 g mol erected from mass spectrum data and the integra-
1
tion curves of protons in H NMR spectrum. In IR spectrum,
-1
MeOD, 500 MHz, δ (ppm)): 7.45 (d, J = 8.2 Hz, 2H, H-3'',
the stretching absorption peaks appeared at 3098 cm for
aromatic C-H of benzene ring chloride, at 1654 for C=N of
oxadiazole ring, at 1594 for aromatic C=C of benzene ring, at
1523 for N=O of nitro group, at 1446 for S=O of sulfonyl
group, at 1238, 1042 for C-O-C of oxadiazole ring, at 1168
H-5''), 6.71 (d, J = 8.5 Hz, 2H, H-2'', H-6''), 5.70 (t, J = 9.5
Hz, 2H, H-2'''), 3.65-3.62 (m, 2H, Heq-2', Heq-6'), 3.45 (t, J =
6.5 Hz, 2H, H-1'''), 2.85 (br.s, 1H, H-4'), 2.51 (dt, J = 2.5, 12
Hz, 2H, Hax-2',Hax-6'), 2.13 (dd, J = 3.5, 13.5 Hz, 2H, H-2'''),
+
.89-1.81 (m, 4H, H-3', H-5'); EI-MS (m/z): 478 [M+2] , 476
1
1
for C-N bond and at 642 for C-S bond. In H NMR spectrum,
+
[
M] , 311, 297, 295, 269, 185, 122, 107.
-(3-Bromopropylthio)-5-[1-(4-nitrophenylsulfonyl)-
piperidin-4-yl]-1,3,4-oxadiazole (5o): Light brown amorphous
solid; Yield: 84 %; m.p.: 142-143 °C; m.f.: C16 Br;
molecular mass: 491.38 g mol ; IR (KBr, νmax, cm ): 3125
the aromatic protons of 4-nitrobenzenesulfonyl appeared at d
7.48 (d, J = 8.8 Hz, 2H, H-3'', H-5'') and 6.75 (d, J = 6.7 Hz,
2H, H-2'', H-6''). The piperidine ring presented signals at 3.67-
3.65 (m, 2H, Heq-2', Heq-6'), 2.52 (dt, J = 2.7 Hz, 2H, Hax-2',
2
19 4 5 2
H N O S
-1
-1
Hax-6'), 2.16-2.14 (m, 1H, H-4') and 1.89-1.86 (m, 4H, H-3',
O
O
O
O
O
S
O
S
18% Na CO (aq)
2
pH = 9-10
3
HN
N
Cl
+
OC H Stir at RT
OC H
2 5
2
5
O N
2
O N
2
1
a
b
NH .NH /MeOH Reflux
2
2
O
O
O
O
O
S
S
N
N
N
CS /KOH/EtOH
2
N
NH
2
Reflux
NH
SH
O N
2
O
O N
2
3
2
O
O
DMF, LiH
R-X
Stir at RT
1'
S
3'
N
N
3
N
4
a-o
5'' 1''
''
4
5
'
R
3
1
O
S
O N
2
5
a-o
Scheme-I: Synthesis of 2-(substituted thio)-5-[1-(4-nitrophenylsulfonyl)piperidin-4-yl]-1,3,4-oxadiazole (5a-o)

Vol. 29, No. 9 (2017)
Synthesis and Biological Evaluation of Some New 1,3,4-Oxadiazoles Containing Piperidine Nucleus 1905
TABLE-1
DIFFERENT ALKYL/ARALKYL GROUPS
compounds against all the bacterial strains. The compound 5e
remained inactive at all against the bacterial strains. Against
B. subtilis, the compounds, 5c and 5l, were active with %
inhibition of 35.04 and 30.49 with respect to that of ofloxacin
with % inhibition of 95.60. Against S. aureus, 5m was the
most active with % inhibition of 19.49. The compound 5g
was the best inhibitor of E. coli bacterial strain. Against S.
typhi, 5g was the most active inhibitor. The best activity of 5c,
5l, 5m and 5g might be attributed to the presence of isopropyl,
Compound
R
CH2 CH3
5a
1'''
2'''
CH2 CH2 CH3
5b
1
'''
2'''
''' CH3
3'''
3
5c
CH CH3
2'''
1'''
4
-chlorobenzyl, 4-bromobenzyl and n-heptyl groups respec-
CH2 CH2 CH2 CH3
4'''
5d
tively.
1'''
2'''
''' CH3
3'''
4
TABLE-2
% INHIBITION OF ANTIBACTERIAL ACTIVITY
5e
CH CH2 CH3
'''
2''' 3'''
1
Inhibition (%)
CH2 CH2 CH2 CH2 CH3
4'''
5
f
B.
subtilis
(+)
S.
aureus
(+)
P.
aeruginosa
(–)
1'''
2'''
3'''
5'''
Compd.
E. coli
(–)
S. typhi
(–)
CH2 CH2 CH2 CH2 CH2 CH2 CH3
7'''
5g
4'''
5'''
6'''
1'''
2'''
3'''
5
a
–
–
–
9.39
5.20
15.21
17.52
–
–
–
7
CH2
'''
3'''
5b
–
–
–
1
'''
5h
5'''
5c
35.04
–
–
12.78
5d
–
3.6
–
–
–
H3C
5
e
–
–
–
7
CH2
'''
3'''
5
i
5f
–
14.09
7.36
–
3.50
22.04
9.41
7.49
6.56
11.67
–
–
–
1
'''
5g
–
4.68
15.29
5'''
5h
–
–
3.42
7
'''
CH2
3'''
5i
–
3.38
6.92
4.85
–
–
–
1
'''
5j
F
5j
–
–
–
5
'''
5k
–
30.49
–
–
14.62
Cl
5l
–
–
7'''
3'''
5m
19.49
9.19
–
6.31
6.59
8.17
93.98
–
–
–
–
5k
1'''
CH2
5n
–
5'''
5o
–
–
–
7
'''
CH2
3'''
Ofloxacin
95.60
95.43
94.28
92.75
1
'''
5l
Cl
Br
5
'''
Conclusion
7''
3'''
1'''
5m
CH2
All the compounds were obtained in notable yields and
were well corroborated by spectral data. The antibacterial
activity evaluation demonstrated lowantibacterial potential of
these compounds except a few ones.
5
'''
CH2 CH2 Br
5n
1
'''
2'''
CH2 CH2 CH2 Br
5o
1'''
2'''
3'''
ACKNOWLEDGEMENTS
H-5'). The signals due to substitution at heteroatom ‘S’ were
The authors are thankful to Higher Education Commission
of Pakistan for the financial support regarding this research
work and also for the spectroscopic analysis.
3
2
.22 (t, J = 7.2 Hz, 2H, H-1'''), 1.80 (sex, J = 7.4 Hz, 2H, H-
''') and 1.05 (t, J = 7.3 Hz, 3H, H-3''') for n-propyl group. In
the EI-MS spectral data, the fragment at 311 confirmed the
formation of 1,3,4-oxadiazole ring. This fragment was further
converted into small fragments of 297, 295, 269, 185 and 122.
The above mentioned spectroscopic evidences corroborated
the structure of 2-(n-propylthio)-5-[1-(4-nitrophenylsulfonyl)-
piperidin-4-yl]-1,3,4-oxadiazole. The structures of other syn-
thesized derivatives were also confirmed by the spectroscopic
data given in the experimental section.
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5