Synthesis and Antibacterial Screening of 1,3,4-Thiadiazoles, 1,2,4-Triazoles, and 1,3,4-Oxadiazoles Containing Piperazine Nucleus

Article abstract of DOI:10.1002/jhet.2714

A series of novel 1,3,4-thiadiazoles, 1,2,4-triazoles, and 1,3,4-oxadiazoles were synthesized by cyclization of substituted 1-(2-(2-chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-yl)acetyl)thiosemicarbazide. The structures of all newly synthesized compounds were elucidated on the basis of spectral studies. Some of them were screened for their antibacterial activity. The compounds 6b, 6c, 8e, 9a, and 9b have shown moderate activity towards Bacillus Subtilis and Escherichia Coli.

Full text of DOI:10.1002/jhet.2714

Month 2016
Synthesis and Antibacterial Screening of 1,3,4-Thiadiazoles, 1,2,4-
Triazoles, and 1,3,4-Oxadiazoles Containing Piperazine Nucleus
*
Rajendra Deshmukh, Bhausaheb Karale, Hemantkumar Akolkar, and Pratibha Randhavane
P. G. Department of Chemistry, Radhabai Kale Mahila Mahavidyalaya, Ahmednagar 414001, India
*
E-mail: pvrandhavane@gmail.com
Received February 24, 2016
DOI 10.1002/jhet.2714
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 1,3,4-thiadiazoles, 1,2,4-triazoles, and 1,3,4-oxadiazoles were synthesized by cycliza-
tion of substituted 1-(2-(2-chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-yl)acetyl)thiosemicarbazide.
The structures of all newly synthesized compounds were elucidated on the basis of spectral studies. Some
of them were screened for their antibacterial activity. The compounds 6b, 6c, 8e, 9a, and 9b have shown
moderate activity towards Bacillus Subtilis and Escherichia Coli.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
1,3,4-Oxadiazoles are five-membered heterocyclic
compounds containing two nitrogen atoms and one
oxygen atom. The heterocyclic compounds anchored with
1,3,4-oxadiazoles exhibit the pharmacological activities
like antimicrobial [22], anthelmintic [23], anti-
inflammatory [24], analgesic [24], antimitotic [25], and
anti-HIV [26].
Literature survey showed that incorporation of halogen
in heterocyclic compounds increases their activities. Sev-
eral synthetic organic chemists have synthesized haloge-
nated heterocycles and evaluated them for biological
screening. Kumar and coworkers have synthesized series
Piperazines are the saturated analogues of pyrazines
having nitrogen atoms at opposite positions. Piperazines
are an important class of compounds with biological activ-
ities like anthelmintic [1], α1-adrenergic receptor blockers
[2], and antibacterial [3]. Aryl piperazine derivatives show
remarkable activity in neuropathic pain without sedative
side effect [4]. Some important marketed drugs that contain
piperazine nucleus are Cetirizine (antihistamine), Perphe-
nazine (antipsychotic), Trazodone (antidepressant), and
Ranolazine (antianginal).
Thiosemicarbazides are the valuable starting compounds
used for the synthesis of azoles. Thiosemicarbazides are
important compounds having a variety of applications
[5]. They have shown activities like anticancer [6], anti-
HIV [7], antimalarial [8], antifungal [9], and antibacterial
[10].
Thiadiazoles are five-membered heterocyclic com-
pounds containing two nitrogen atoms and one sulfur atom
as part of the aromatic ring. Recently, intense investigation
has been carried out on thiadiazoles having different
substituents. They show various biological activities like
antibacterial [11], antioxidant [12], antimicrobial [13]
cyclooxygenase-2 inhibitors [14], antifungal [15], and anti-
depressant [16].
of
3-[4′(p-chlorophenyl)thiazol-2′-yl]-2-[(substituted
azetidinone/thiazolidinone)-aminomethy]-6-
bromoquinazolin-4-ones and reported their anti-
inflammatory and analgesic activities [27]. Several
commercially available drugs also contain chlorinated
heterocyclic compounds such as clotrimazole, econazole,
miconazole, and ketoconazole (Scheme 1).
Present research article describes the synthesis and
antibacterial screening of thiadiazoles, triazoles, and
oxadiazoles containing piperazine nucleus.
RESULTS AND DISCUSSION
1,2,4-Triazoles are important group of heterocyclic com-
pounds characterized by a five-membered ring having three
nitrogen atoms. The biological activities of 1,2,4-triazoles
have been investigated by various studies. They possess bi-
ological activities like antitubercular [17], antitumor [18],
analgesic [19], diuretic [19], anti-inflammatory [20], anti-
convulsant [20], and antimicrobial [21].
Substituted 1-(2-(2-chlorophenyl)-2-(4-(2,3-dichlorophenyl)
piperazin-1-yl)acetyl)-4-phenyl thiosemicarbazide 6 was syn-
thesized in five steps starting from 2-(2-chlorophenyl)acetic
acid 1. 2-(2-Chlorophenyl)acetic acid 1 was converted into
2-bromo-2-(2-chlorophenyl)acetic acid
2 by using N-
bromosuccinimide [28]. Methyl ester 3 of compound 2 was
treated with 1-(2,3-dichlorophenyl)piperizine hydrochloride in
© 2016 Wiley Periodicals, Inc.

R. Deshmukh, B. Karale, H. Akolkar, and P. Randhavane
Vol 000
Scheme 1
potassium iodide in NaOH (Scheme 2). The spectral analysis
supports these transformations.
The antibacterial activity of some of the newly synthe-
sized compounds was carried out by agar well diffusion
method. Two bacterial species were chosen for the study:
one was Gram Positive Bacillus Subtilis and another was
Gram-negative Escherichia Coli. Ampicillin was used as
a standard drug for this study.
EXPERIMENTAL
Melting points were determined in open capillary tubes
in liquid paraffin bath and are uncorrected. IR spectra were
recorded on Perkin Elmer Spectrophotometer using potas-
sium bromide discs. NMR spectra were recorded on a
Varian NMR 400MHz spectrometer (Varian Inc.,
Switzerland), and chemical shifts are given in δ ppm rela-
tive to TMS using deuterated DMSO and deuterated
chloroform as a solvents. Mass spectra were recorded on
Water’s Acquity Ultra Performance TQ Detector Mass
Spectrometer. Elemental analysis was performed on the
Elemental Instrument Model Vario Micro Cube.
presence of base to afford methyl 2-(2-chlorophenyl)-2-(4-(2,3-
dichlorophenyl)piperazin-1-yl)acetate
4
[29].
2-(2-
Chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-yl)
acetohydrazide 5 was prepared by refluxing compound 4
with hydrazine hydrate. Condensation of compound 5 with
different aryl isothiocyanates in alcohol furnished the cor-
responding thiosemicarbazides 6. Thiosemicarbazides un-
dergo cyclisation to give thiadiazoles in acidic condition,
whereas to triazoles in basic medium. Oxadiazoles were
prepared by treating thiosemicarbazides with iodine and
Preparation of methyl 2-(2-chlorophenyl)-2-(4-(2,3-
dichlorophenyl)piperazin-1-yl)acetate (4) [29].
To the
solution of methyl-2-bromo-2-(2-chlorophenyl)acetate
(0.1 mol) in methanol, 1-(2,3-dichlorophenyl)piperazine
hydrochloride (0.12 mol) and sodium bicarbonate
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antibacterial Screening of 1,3,4-Thiadiazoles, 1,2,4-Triazoles, and
1,3,4-Oxadiazoles Containing Piperazine Nucleus
(0.28mol) were added. The reaction mixture was refluxed
for 6h. After completion of reaction, the product was
extracted with dichloromethane. After the evaporation of
solvent, solid obtained was recrystallized with ethanol to
acquire pure product as a white solid powder.
7.25–7.38 (m, 7H, Ar–H), 7.42–7.49 ( m, 3H, Ar–H), 9.42
(bs, 1H, –NH), 9.60 (bs, 1H, –NH), 10.25 (bs, 1H, –NH);
ms: m/z 548 (M–H) with (M+2), (M+4) & (M+6) peaks;
Anal. Calcd for C25H24Cl3N5OS: C, 54.70; H, 4.41; N,
12.76. Found: C, 54.73; H, 4.45; N, 12.80.
Methyl
2-(2-chlorophenyl)-2-(4-(2,3-dichlorophenyl)
1-(2-(2-Chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-
piperazin-1-yl)acetate (4).
Yield 90.0%; mp 98°C; ir
yl)acetyl)-4-(4-fluorophenyl) thiosemicarbazide (6b).
Yield
(KBr, cmÀ1): 1044 (Ar–Cl),1190 (C–O), 1476 & 1579
73%; mp 189°C; ir (KBr, cmÀ1): 1042 (Ar–Cl), 1132
(Ar–F), 1497 & 1598 (C=C), 1657 (C=O), 3207 (N–H),
1
(C=C), 1742 (C=O); H nmr (DMSO-d6): δ 2.68 (m, 4H,
1
–CH2, piperazine), 3.08 (m, 4H, –CH2, piperazine), 3.71
(s, 3H, –OCH3), 4.77 (s, 1H, –CH), 6.94 (dd, 1H, Ar–H),
7.11–7.16 (m, 2H, Ar–H), 7.23–7.31 (m, 3H, Ar–H),
7.41 (d, 1H, Ar–H), 7.67 (m, 1H, Ar–H); ms: m/z 413
(M+H) with (M+2), (M+4) & (M+6) peaks; Anal. Calcd
for C19H19Cl3N2O2: C, 55.16; H, 4.63; N, 6.77. Found:
C, 55.14; H, 4.60; N, 6.74.
3285 (N–H); H nmr (DMSO-d6): δ 2.66 (m, 4H, –CH2,
piperazine), 3.00 (m, 4H, –CH2, piperazine), 4.80 (s, 1H,
–CH), 7.09–7.17 (m, 3H, Ar–H), 7.25–7.49 (m, 7H, Ar–
H), 7.60–7.63 (m, 1H, Ar–H), 9.45 (bs, 1H, –NH), 9.71
(bs, 1H, –NH), 10.35 (bs, 1H, –NH); ms: m/z 566 (M–H)
with (M+2), (M+4) & (M+6) peaks; Anal. Calcd for
C25H23Cl3FN5OS: C, 52.97; H, 4.09; N, 12.35. Found:
C, 53.00; H, 4.13; N, 12.40.
Preparation
of
2-(2-chlorophenyl)-2-(4-(2,3-
dichlorophenyl)piperazin-1-yl)acetohydrazide (5).
Methyl
4-(3-Chlorophenyl)-1-(2-(2-chlorophenyl)-2-(4-(2,3-
2-(2-chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-
yl)acetate (0.01 mol) and hydrazine hydrate (0.31 mol)
were dissolved in 30 mL of ethanol and refluxed for 24h.
After completion of reaction, the contents were cooled,
and the solid obtained was filtered and washed with
ethanol. Then it was recrystallized from ethanol to obtain
2-(2-chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-
yl)acetohydrazide as a white powder.
dichlorophenyl)piperazin-1-yl)acetyl) thiosemicarbazide (6c).
Yield 72%; mp 187°C; ir (KBr, cmÀ1): 1044 (Ar–Cl), 1499
& 1597 (C=C), 1658 (C=O), 3208 (N–H), 3284 (N–H); 1H
nmr (DMSO-d6): δ 2.68 (m, 4H, –CH2, piperazine), 3.10
(m, 4H, –CH2, piperazine), 4.85 (s, 1H, –CH), 7.09–7.12
(m, 3H, Ar–H), 7.26–7.39 (m, 7H, Ar–H), 7.47–7.51 (m,
1H, Ar–H), 9.52 (bs, 1H, –NH), 9.95 (bs, 1H, –NH),
10.26 (bs, 1H, –NH); ms: m/z 582 (M–H) with (M+2),
(M+4) & (M+6) peaks; Anal. Calcd for C25H23Cl4N5OS:
C, 51.47; H, 3.97; N, 12.01. Found: C, 51.50; H, 4.03;
N, 12.06.
2-(2-Chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-yl)
acetohydrazide (5).
Yield 91.0%; mp 148°C; ir (KBr,
cmÀ1): 1043 (Ar–Cl), 1450 & 1577 (C=C), 1678
(C=O), 3175 (N–H); 1H nmr (DMSO-d6): δ 2.54 (m,
4H, –CH2, piperazine), 2.98 (m, 4H, –CH2, piperazine),
4.35 (s, 2H, –NH2), 4.39 (s, 1H, –CH), 7.14 (m, 1H,
Ar–H), 7.29–7.43 (m, 5H, Ar–H), 7.83–7.85 (dd, 1H,
Ar–H), 9.5 (s, 1H, NH). ms: m/z 413 (M+H) with (M
1-(2-(2-Chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-
yl)acetyl)-4-p-tolylthiosemicarbazide (6d).
Yield 70%; mp
185°C; ir (KBr, cmÀ1): 1041 (Ar–Cl), 1497 & 1598
1
(C=C), 1655 (C=O), 3207 (N–H), 3284 (N–H); H nmr
(DMSO-d6): δ 2.25 (s, 3H, –CH3), 2.69 (m, 4H, –CH2,
piperazine), 3.00 (m, 4H, –CH2, piperazine), 4.79 (s, 1H,
–CH), 7.11–7.13 (m, 3H, Ar–H), 7.25–7.37 (m, 6H,
Ar–H), 7.47–7.49 (m, 1H, Ar–H), 7.67–7.69 (m, 1H,
Ar–H) 9.52 (bs, 1H, –NH), 9.63 (bs, 1H, –NH), 10.31
(bs, 1H, –NH); ms: m/z 562 (M–H) with (M+2), (M+4)
& (M+6) peaks; Anal. Calcd for C26H26Cl3N5OS: C,
55.47; H, 4.66; N, 12.44. Found: C, 55.50; H, 4.70; N, 12.47.
1-(2-(2-Chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-
yl)acetyl)-4-(4-methoxyphenyl) thiosemicarbazide (6e). Yield
74%; mp 192°C; ir (KBr, cmÀ1): 1043 (Ar–Cl), 1495 &
+2), (M+4)
&
(M+6) peaks; Anal. Calcd. for
C18H19Cl3N4O: C, 52.25; H, 4.63; N, 13.54. Found: C,
52.23; H, 4.60; N, 13.57.
Preparation
of
1-(2-(2-chlorophenyl)-2-(4-(2,3-
dichlorophenyl)piperazin-1-yl)acetyl)-4- phenylthiosemicarbazide
(6). Equimolar amount (5 mmol) of compound 5 and aryl
isothiocyanate was dissolved in 15 mL of ethanol. The
reaction mixture was heated under reflux for 2h. The progress
of reaction was monitored by TLC (80% Pet ether+ 20%
ethyl acetate). After completion of reaction, contents were
cooled, and the solid obtained was filtered and recrystallized
from ethanol to acquire the pure product 1-(2-(2-
chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-yl)acetyl)-
4- phenylthiosemicarbazide 6.
1
1599 (C=C), 1653 (C=O), 3206 (N–H), 3285 (N–H); H
nmr (DMSO-d6): δ 2.68 (m, 4H, –CH2, piperazine), 3.00
(m, 4H, –CH2, piperazine), 3.72 (s, 3H, –OCH3), 4.79 (s,
1H, –CH), 6.88 (d, 2H, Ar–H), 7.09–7.12 (m, 1H, Ar–
H), 7.25–7.37 (m, 5H, Ar–H), 7.46–7.48 (m, 1H, Ar–H)
7.65–7.68 (m, 2H, Ar–H), 9.42 (bs, 1H, –NH), 9.57 (bs,
1H, –NH), 10.27 (bs, 1H, –NH); ms: m/z 578 (M–H)
with (M+2), (M+4) & (M+6) peaks; Anal. Calcd for
C26H26Cl3N5O2S: C, 53.94; H, 4.53; N, 12.10. Found: C,
53.97; H, 4.58; N, 12.14.
1-(2-(2-Chlorophenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-
yl)acetyl)-4-phenylthiosemicarbazide (6a).
Yield 75%; mp
195°C; ir (KBr, cmÀ1): 1040 (Ar–Cl), 1498 & 1598 (C=C),
1
1655 (C=O), 3206 (N–H), 3280 (N–H); H nmr (DMSO-
d6): δ 2.68 (m, 4H, –CH2, piperazine), 2.99 (m, 4H, –CH2,
piperazine), 4.79 (s, 1H, –CH), 7.10–7.14 (m, 2H, Ar–H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Deshmukh, B. Karale, H. Akolkar, and P. Randhavane
Vol 000
Preparation of 5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
piperazin-1-yl)methyl)-n-phenyl-1,3,4-thiadiazol-2-amine
(7). Thiosemicarbazide 6 (1 mmol) was dissolved in 4 mL
of conc. H2SO4 in a 100mL Round Bottom Flask (RBF).
The reaction mixture was stirred at room temperature for
3 h. After completion of reaction, 20 g of crushed ice was
added in it. The solid obtained was separated by filtration
and recrystallized from ethanol to afford thiadiazoles 7.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-n-phenyl-1,3,4-thiadiazol-2-amine (7a). Yield 72%;
mp 167°C; ir (KBr, cmÀ1): 1041 (Ar–Cl), 1478 & 1597
methyl)-n-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine (7e).
Yield 67%; mp 162°C; ir (KBr, cmÀ1): 1051 (Ar–Cl),
1
1478 &1599 (C=C), 3223 (N–H); H nmr (DMSO-d6): δ
3.27 (m, 4H, –CH2, piperazine), 3.72 (s, 3H, –OCH3),
4.26 (m, 4H, –CH2, piperazine), 5.57 (s, 1H, –CH), 6.74
(d, 8 Hz, 2H, Ar–H), 6.91–7.17 (m, 2H, Ar–H), 7.30–
7.35 (m, 4H, Ar–H) 7.46–7.59 (m, 2H, Ar–H), 7.65–7.67
(m, 1H, Ar–H), 9.66 (s, 1H, –NH); ms: m/z 560 (M–H)
with (M+2), (M+4) & (M+6) peaks; Anal. Calcd For
C26H24Cl3N5OS: C, 55.67; H, 4.31; N, 12.49. Found: C,
55.71; H, 4.35; N, 12.52.
1
(C=C), 3211(N–H); H nmr (DMSO-d6): δ 3.20 (m, 4H,
Preparation of 5-((2-chlorophenyl)(4-(2,3-dichlorophenyl)
piperazin-1-yl)methyl)-4-phenyl-4h-1,2,4-triazole-3-thiol
–CH2, piperazine), 4.09 (m, 4H, –CH2, piperazine), 5.26
(s, 1H, –CH), 7.17–7.19 (m, 2H, Ar–H), 7.32–7.42 ( m,
6H, Ar–H), 7.44–7.46 (m, 2H, Ar–H) 7.51–7.53 (m, 1H,
Ar–H), 7.62–7.65 (m, 1H, Ar–H), 9.79 (s, 1H, –NH); ms:
m/z 530 (M–H) with (M+2), (M+4) & (M+6) peaks;
Anal. Calcd for C25H22Cl3N5S: C, 56.56; H, 4.18; N,
13.19. Found: C, 56.59; H, 4.18; N, 13.22.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-n-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (7b).
Yield 78%; mp 157°C; ir (KBr, cmÀ1): 1052 (Ar–Cl), 1134
(Ar–F), 1478 & 1597 (C=C), 3225 (N–H); 1H nmr
(DMSO-d6): δ 3.19 (m, 4H, –CH2, piperazine), 4.10
(m, 4H, –CH2, piperazine), 5.26 (s, 1H, –CH), 7.15–7.20
(m, 2H, Ar–H), 7.30-7.39 (m, 5H, Ar–H), 7.48–7.50
(m, 2H, Ar–H) 7.62–7.63 (m, 1H, Ar–H), 7.68–7.70
(m, 1H, Ar–H), 9.90 (s, 1H, –NH); ms: m/z 548 (M–H)
with (M+2), (M+4) & (M+6) peaks; Anal. Calcd. for
C25H21Cl3FN5S: C, 54.70; H, 3.86; N, 12.76. Found: C,
54.75; H, 3.90; N, 12.80.
(8).
Thiosemicarbazide 6 (1 mmol) was dissolved in
10mL of 2N NaOH. The reaction mixture was heated
under mild reflux. The progress of reaction was
monitored by TLC (80% Pet ether +20% Ethyl acetate).
After completion of reaction, contents were cooled and
poured into crushed ice. Then it was acidified with
glacial acetic acid. The product was separated by
filtration and recrystallized from ethanol to acquire
corresponding triazoles 8.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-4-phenyl-4h-1,2,4-triazole-3-thiol (8a). Yield 65%;
mp 233°C; ir (KBr, cmÀ1): 1044 (Ar–Cl), 1498 & 1592,
(C=C), 3065 (NH); 1H nmr (CDCl3): δ 2.77 (m, 4H,
–CH2, piperazine), 3.00 (m, 4H, –CH2, piperazine), 5.13
(s, 1H, –CH), 6.89–7.00 (m, 2H, Ar–H), 7.15–7.19 ( m,
3H, Ar–H), 7.23–7.28 (m, 2H, Ar–H) 7.49–7.56 (m, 5H,
Ar–H), 11.16 (s, 1H, –SH); ms: m/z 530 (M–H) with (M
+2), (M+4)
&
(M+6) peaks; Anal. Calcd for
N-(3-Chlorophenyl)-5-((2-chlorophenyl)(4-(2,3-
C25H22Cl3N5S: C, 56.56; H 4.18; N, 13.19. Found: C,
56.60; H, 4.22; N, 13.23.
dichlorophenyl)piperazin-1-yl)methyl)-1,3,4-thiadiazol-2-amine
(7c). Yield 70%; mp 159°C; ir (KBr, cmÀ1): 1052 (Ar–Cl),
1
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-4-(4-fluorophenyl)-4h-1,2,4-triazole-3-thiol (8b).
Yield 68%; mp 228°C; ir (KBr, cmÀ1): 1048 (Ar–Cl),
1477 & 1598 (C=C), 3222 (N–H); H nmr (DMSO-d6): δ
3.17 (m, 4H, –CH2, piperazine), 4.08 (m, 4H, –CH2,
piperazine), 5.25 (s, 1H, –CH), 7.14–7.20 (m, 2H, Ar–H),
7.31–7.39 (m, 5H, Ar–H), 7.47–7.50 (m, 2H, Ar–H),
7.60–7.63 (m, 1H, Ar–H), 7.65–7.68 (m, 1H, Ar–H), 9.95
(s, 1H, –NH); ms: m/z 564 (M–H) with (M+2), (M+4) &
(M+6) peaks; Anal. Calcd for C25H21Cl4N5S: C, 53.11;
H, 3.74; N, 12.39. Found: C, 53.15; H, 3.78; N, 12.43.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-n-p-tolyl-1,3,4-thiadiazol-2-amine (7d). Yield 69%;
mp 158°C; ir (KBr, cmÀ1): 1050 (Ar–Cl), 1477 & 1595
1
1140 (Ar–F), 1497 & 1599 (C=C), 3071 (NH); H nmr
(CDCl3): δ 2.74 (m, 4H, –CH2, piperazine), 3.02 (m, 4H,
–CH2, piperazine), 5.14 (s, 1H, –CH), 6.90–6.92 (m, 2H,
Ar–H), 7.10–7.16 (m, 3H, Ar–H), 7.26–7.31 (m, 2H, Ar–
H) 7.48-7.56 (m, 4H, Ar–H), 11.05 (s, 1H, –SH); ms:
m/z 548 (M–H) with (M+2), (M+4) & (M+6) peaks;
Anal. Calcd for C25H21Cl3FN5S: C, 54.70; H 3.86; N,
12.76. Found: C, 54.74; H, 3.91; N, 12.80.
1
4-(3-Chlorophenyl)-5-((2-chlorophenyl)(4-(2,3-
(C=C), 3220 (N–H); H nmr (DMSO-d6): δ 2.25 (s, 3H,
dichlorophenyl)piperazin-1-yl)methyl)-4h-1,2,4-triazole-3-thiol
–CH3), 3.24 (m, 4H, –CH2, piperazine), 3.59 (m, 4H,
–CH2, piperazine), 5.48 (s, 1H, –CH), 7.11–7.17 (m, 3H,
Ar–H), 7.25–7.29 ( m, 2H, Ar–H), 7.30–7.34 (m, 4H,
Ar–H) 7.63–7.66 (m, 1H, Ar–H), 7.72–7.75 (m, 1H,
Ar–H), 9.71 (s, 1H, –NH); ms: m/z 544 (M–H) with
(8c). Yield 65%; mp 226°C; ir (KBr, cmÀ1): 1050 (Ar–
1
Cl), 1495 & 1598 (C=C), 3075(NH); H nmr (CDCl3): δ
2.74 (m, 4H, –CH2, piperazine), 3.02 (m, 4H, –CH2,
piperazine), 5.14(s, 1H, –CH), 6.90–6.93 (m, 2H, Ar–H),
7.10–7.17(m, 2H, Ar–H), 7.26–7.33 (m, 4H, Ar–H)
7.48–7.50 (m, 3H, Ar–H), 11.08 (s, 1H, –SH); ms: m/z
564 (M–H) with (M+2), (M+4) & (M+6) peaks; Anal.
(M+2), (M+4)
& (M+6) peaks; Anal. Calcd for
C26H24Cl3N5S: C, 57.31; H, 4.44; N, 12.85. Found: C,
57.34; H, 4.48; N, 12.88.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antibacterial Screening of 1,3,4-Thiadiazoles, 1,2,4-Triazoles, and
1,3,4-Oxadiazoles Containing Piperazine Nucleus
Calcd for C25H21Cl4N5S: C, 53.11; H 3.74; N, 12.39.
Found: C, 53.15; H, 3.78; N, 12.41.
Ar–H), 7.25–7.39 ( m, 6H, Ar–H), 7.48–7.50 (m, 1H,
Ar–H) 7.66–7.70 (m, 2H, Ar–H) 9.90 (s, 1H, –NH); ms:
m/z 532 (M–H) with (M+2), (M+4) & (M+6) peaks;
Anal. Calcd for C25H21Cl3FN5O: C, 56.35; H 3.97; N,
13.14. Found: C, 56.38; H, 4.00; N, 13.19.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-4-p-tolyl-4h-1,2,4-triazole-3-thiol (8d). Yield 66%;
mp 228°C; ir (KBr, cmÀ1): 1045 (Ar–Cl), 1495 & 1596
(C=C), 3072 (NH); 1H nmr (CDCl3): δ 2.43 (s, 3H,
–CH3), 2.67 (m, 4H, –CH2, piperazine), 3.01 (m, 4H,
–CH2, piperazine), 5.08 (s, 1H, –CH), 7.06–7.14 (m, 3H,
Ar–H), 7.25–7.52 (m, 5H, Ar–H), 7.53–7.55 (m, 2H, Ar–
H), 7.78–7.80 (m, 1H, Ar–H) 11.50 (s, 1H, –SH); ms:
m/z 544 (M–H) with (M+2), (M+4) & (M+6) peaks;
Anal .Calcd. for C26H24Cl3N5S: C, 57.31; H 4.44; N,
12.85. Found: C, 57.35; H, 4.48; N, 12.88.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-4-(4-methoxyphenyl)-4h-1,2,4-triazole-3-thiol (8e).
Yield 60%; mp 226°C; ir (KBr, cmÀ1): 1047 (Ar–Cl),
1497 &1598, (C=C), 3074 (NH); 1H nmr (CDCl3): δ
2.63 (m, 4H, –CH2, piperazine), 3.00 (m, 4H, –CH2,
piperazine), 3.89 (s, 3H, –OCH3), 5.28 (s, 1H, –CH),
7.05–7.13 (m, 3H, Ar–H), 7.28–7.55 (m, 5H, Ar–H),
7.58–7.50 (m, 2H, Ar–H), 7.69–7.72 (m, 1H, Ar–H)
11.32 (s, 1H, –SH); ms: m/z 560 (M–H) with (M+2), (M
+4) & (M+6) peaks; Anal. Calcd for C26H24Cl3N5OS: C,
55.67; H 4.31; N, 12.49. Found: C, 55.70; H, 4.35; N,
12.52.
N-(3-Chlorophenyl)-5-((2-chlorophenyl)(4-(2,3-
dichlorophenyl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-amine
(9c).
Yield 63%; mp 210°C; ir (KBr, cmÀ1): 1042
(Ar–Cl), 1496 & 1599 (C=C), 3250 (NH); 1H nmr
(CDCl3): δ 2.68 (m, 4H, –CH2, piperazine), 3.15 (m, 4H,
–CH2, piperazine), 4.80 (s, 1H, –CH), 7.10–7.18 (m, 2H,
Ar–H), 7.24–7.37 ( m, 6H, Ar–H), 7.48–7.51 (m, 1H,
Ar–H) 7.64–7.68 (m, 2H, Ar–H) 9.88 (s, 1H, –NH); ms:
m/z 548 (M–H) with (M+2), (M+4) & (M+6) peaks;
Anal. Calcd for C25H21Cl4N5O: C, 54.67; H 3.85; N,
12.75. Found: C, 54.71; H, 3.89; N, 12.80.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-n-p-tolyl-1,3,4-oxadiazol-2-amine (9d). Yield 59%;
mp 195°C; ir (KBr, cmÀ1): 1045 (Ar–Cl), 1498 & 1598
(C=C), 3252 (NH); 1H nmr (CDCl3): δ 2.43 (s, 3H,
–CH3), 2.67 (m, 4H, –CH2, piperazine), 3.01 (m, 4H,
–CH2, piperazine), 5.12 (s, 1H, –CH), 6.90–6.93 (m, 2H,
Ar–H), 7.13–7.16 ( m, 3H, Ar–H), 7.28–7.32 (m, 4H,
Ar–H) 7.58–7.63 (m, 2H, Ar–H) 9.90 (s, 1H, –NH);
ms: m/z 528 (M–H) with (M+2), (M+4) & (M+6)
peaks; Anal. Calcd for C26H24Cl3N5O: C, 59.05; H
4.57; N, 13.24. Found: C, 59.10; H, 4.60; N, 13.27.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-n-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine (9e).
Yield 66%; mp 197°C; ir (KBr, cmÀ1): 1043 (Ar–Cl),
1497 & 1599 (C=C), 3255 (NH); 1H nmr (CDCl3): δ
2.68 (m, 4H, –CH2, piperazine), 3.02 (m, 4H, –CH2,
piperazine), 3.80 (s, 3H, –OCH3), 5.13 (s, 1H, –CH),
6.89–6.97 (m, 3H, Ar–H), 7.09–7.15( m, 2H, Ar–H),
7.25–7.29 (m, 5H, Ar–H) 7.57–7.60 (m, 1H, Ar–H) 9.91
(s, 1H, –NH); ms: m/z 544 (M–H) with (M+2), (M+4) &
(M+6) peaks; Anal. Calcd for C26H24Cl3N5O2: C, 57.31;
H 4.44; N, 12.85. Found: C, 57.35; H, 4.47; N, 12.89.
Preparation of 5-((2-chlorophenyl)(4-(2,3-dichlorophenyl)
piperazin-1-yl)methyl)-n-phenyl-1,3,4-oxadiazol-2-amine
(9).
The mixture thiosemicarbazide
6
(1mmol),
potassium iodide (2mmol), iodine (2 mmol) was
dissolved in 4N sodium hydroxide (10 mL). The reaction
mixture was heated under mild reflux for 5 h. The
progress of reaction was monitored by TLC (80% Pet
ether + 20% Ethyl acetate). After completion of reaction,
contents were poured over crushed ice and were extracted
with ethyl acetate. The crude product isolated after
evaporation of ethyl acetate was recrystallized from
ethanol to acquire pure product 9.
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-n-phenyl-1,3,4-oxadiazol-2-amine (9a). Yield 62%;
mp 199°C; ir (KBr, cmÀ1): 1046 (Ar-Cl), 1498 & 1599
(C=C), 3249 (NH); 1H nmr (CDCl3): δ 2.78 (m, 4H,
–CH2, piperazine), 3.09 (m, 4H, –CH2, piperazine), 5.43
(s, 1H, –CH), 6.95 (m,1H, Ar–H), 7.07–7.15 (m, 5H, Ar–
H), 7.26–7.43 (m, 5H, Ar–H) 7.89–7.91 (m, 1H, Ar–H)
9.85 (s, 1H, –NH); ms: m/z 514 (M–H) with (M+2),
(M+4) & (M+6) peaks; Anal. Calcd for C25H22Cl3N5O: C,
58.32; H 4.31; N, 13.60. Found: C, 58.36; H, 4.35; N,
13.63.
Table 1
Antibacterial screening of synthesized compounds.
E.
B.
E.
B.
Compound
Coli
Subtilis
Compound
Coli
Subtilis
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
11
15
14
13
12
9
8
9
9
11
12
16
17
12
16
14
14
15
13
15
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
13
14
15
13
13
15
14
15
13
15
16
13
12
11
14
15
15
16
12
16
13
17
5-((2-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)
methyl)-n-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (9b).
Yield 64%; mp 202°C; ir (KBr,cmÀ1): 1043 (Ar–Cl),
1
1138 (Ar–F), 1497 & 1596 (C=C), 3251 (NH); H nmr
(CDCl3): δ 2.70 (m, 4H, –CH2, piperazine), 3.18 (m, 4H,
–CH2, piperazine), 4.83 (s, 1H, –CH), 7.10–7.18 (m, 2H,
Standard drug: Ampicillin
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Deshmukh, B. Karale, H. Akolkar, and P. Randhavane
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet