Combination of bioactive moieties with different heteroatom(s): Application of the Suzuki cross-coupling reaction

Article abstract of DOI:10.1002/hc.21027

Two series of thiophene/benzothiophene-linked quinolinyl oxadiazoles condensed to the substituted N-benzothiazolyl acetamides have been synthesized via the Suzuki cross-coupling reaction. The ester derivative of 6-bromo-substituted quinoline was reacted via the Suzuki cross-coupling reaction with commercially available (benzo)thiophen-2-ylboronic acid at optimized temperature in 1,2-dimethoxy ethane and water in the presence of potassium carbonate and palladium tetrakis. The resulting derivatives were then hydrazinolized using 99% hydrazine hydrate followed by cyclization using carbon disulfide in ethanolic KOH to furnish the corresponding oxadiazoles, which were then condensed with various substituted 2-chloro-N-benzothiazolyl acetamides to produce the final scaffolds involving a unique combination of four heterocycles to be examined for their antimicrobial activity against two Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae), and two fungal species (Aspergillus niger and Candida albicans). The investigation of biological screening data revealed that the majority of the compounds tested have demonstrated excellent activity (minimum inhibitory concentrations; 6.25-50 μg/mL) against most of the microorganisms as compared with the standard and hence they warrant more consideration as prospective antimicrobial agents. New products (9a-10i) were characterized by physicochemical, elemental, and spectral (IR, ¹H NMR, and ¹³C NMR) data.

Full text of DOI:10.1002/hc.21027

Heteroatom Chemistry
Volume 00, Number 0, 2012
Combination of Bioactive Moieties with
Different Heteroatom(s): Application of the
Suzuki Cross-Coupling Reaction
Rahul V. Patel,1 Jigar K. Patel,1 Premlata Kumari,1 and
Kishor H. Chikhalia2
1Department of Applied Chemistry, S. V. National Institute of Technology, Surat 395 007, India
2Department of Chemistry, School of Science, Gujarat University, Ahmedabad 380 009, India
Received 10 February 2012; revised 1 April 2012
compounds tested have demonstrated excellent ac-
ABSTRACT:
Two
series
quinolinyl
of
thiophene/
oxadiazoles
tivity (minimum inhibitory concentrations; 6.25–50
μg/mL) against most of the microorganisms as
compared with the standard and hence they warrant
more consideration as prospective antimicrobial
agents. New products (9a–10i) were characterized
benzothiophene-linked
condensed to the substituted N-benzothiazolyl ac-
etamides have been synthesized via the Suzuki cross-
coupling reaction. The ester derivative of 6-bromo-
substituted quinoline was reacted via the Suzuki
cross-coupling reaction with commercially avail-
able (benzo)thiophen-2-ylboronic acid at optimized
temperature in 1,2-dimethoxy ethane and water in
the presence of potassium carbonate and palladium
tetrakis. The resulting derivatives were then hy-
drazinolized using 99% hydrazine hydrate followed
by cyclization using carbon disulfide in ethanolic
KOH to furnish the corresponding oxadiazoles,
which were then condensed with various substituted
2-chloro-N-benzothiazolyl acetamides to produce the
final scaffolds involving a unique combination of
four heterocycles to be examined for their antimi-
crobial activity against two Gram-positive bacteria
(Staphylococcus aureus and Bacillus cereus), three
Gram-negative bacteria (Escherichia coli, Pseu-
domonas aeruginosa, and Klebsiella pneumoniae),
and two fungal species (Aspergillus niger and
Candida albicans). The investigation of biological
screening data revealed that the majority of the
1
by physicochemical, elemental, and spectral (IR, H
NMR, and 13C NMR) data.
2012 Wiley Periodicals,
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C
Inc. Heteroatom Chem 00:1–12, 2012; View this article
online at wileyonlinelibrary.com. DOI 10.1002/hc.21027
INTRODUCTION
The rapid emergence of several human pathogenic
microorganisms resistant to currently available an-
tibiotics generates severe threats to the future medi-
cal advances [1]. Many effective antimicrobial agents
have been discovered during the past 60 years, but
with the discovery of each new agent several bacte-
ria have found ways to develop resistance. Initially,
discovery and development of new classes of antimi-
crobial agents having different structural features
than the available antimicrobial arsenal overcame
the problem of resistance [2–5], but in the past 20
years that development of new antimicrobial agents
is progressively drying up [6]. To meet this crisis
successfully, many researchers across the globe are
working to unearth new compounds that can selec-
tively attack novel targets in such microorganisms.
To meet this requirement, one of the best ways is
Correspondence to: Rahul V. Patel; e-mail: rahul.svnit11@
gmail.com.
Supporting Information is available in the online issue at
wileyonlinelibrary.com.
c
ꢀ
2012 Wiley Periodicals, Inc.
1

2
Patel et al.
to design new antimicrobial agents and to generate
hybrid molecules by combining different bioactive
heterocyclic moieties in a single molecular scaffold.
During the past few decades, interest has
been rapidly growing in gaining insight into
the biological properties of molecules involving
two or more heterocycles. Recently, we have re-
ported the antimicrobial and antituberculosis ac-
tivity of the s-triazine molecules involving 6-
bromo-4-hydroxyquinolne moiety [7]. In view of
potential bioefficacies of these scaffolds, we have
further structured this moiety to produce novel scaf-
folds with excellent bioactivities. Furthermore, a
quinoline ring is found in many of the approved
antimicrobial drugs as ciprofloxacin, norfloxacin,
ofloxacin, and so on, as a nucleus. Some recent
studies have reported the pharmacological signifi-
cance of substituted thiophene and benzothiophene
derivatives as an intermediate molecule to furnish
newer molecules potentially endowed with multi-
ple biological activities [8–11]. Among pharmaco-
logically important heterocyclic compounds, 1,3,4-
oxadiazole rings have drawn considerable atten-
tion because of their profound biological proper-
ties such as antimicrobial [12–17], antituberculosis
[18–20], and anticancer [21] agents. Some studies re-
vealed that the condensation of aryl/benzothiazolyl
acetamides via a sulfur linkage often resulted in
a class of compounds displaying potential bio-
logical activities [22–25]. We have recently devel-
oped the synthesis of coumarin- and benzimidazole-
based antimicrobial agents bearing a benzothiazole
moiety holding various functional groups such as
halo, nitro, cyano, and alkoxy substituents. The
results demonstrated the potential antimicrobial
efficacy of the above-mentioned scaffolds bear-
ing a benzothiazole nucleus involving substitution
of various electron-withdrawing/donating groups
[26,27]. In the interest of the above, we planned to
synthesize a system that comprises many heterocy-
cles with different heteroatoms in addition to the
presence of various electron-donating/withdrawing
functionalities. Ramaprasad et al. recently reported
the synthesis and antimicrobial properties of such
analogues with aromatic constituents [28]. In this
regard, we have synthesized such analogues with
the heterocyclic scaffolds having different het-
eroatom(s) and the combination was found to en-
hance antimicrobial efficacy significantly.
Scheme 1. The solvents and reagents were used as re-
ceived or were dried prior to use as needed. 6-Bromo-
4-hydroxyquinoline (1) was treated with ethyl bro-
moacetate to yield the corresponding ester deriva-
tive (2). IR spectra of the ester compounds revealed
an absorption band of an ester functional group
at 1729 cm−1, whereas the three methylene pro-
tons were confirmed by the observation of a triplet
peak at 1.24 ppm in addition to a quartet peak at
4.23 ppm for the CH2 proton. The phenoxy linkage
(Qui O CH2 ) was confirmed by its correspond-
ing peak at 5.01 ppm for CH2. Palladium-catalyzed
cross-coupling between a halogenated moiety and an
organometallic species like boron is a versatile syn-
thetic route for making C C bonds [29]. Palladium-
catalyzed cross-coupling with aryl halides in the
presence of a base was an important discovery by
Suzuki et al. [30] to furnish the linked scaffolds.
Hence, the said procedure was adopted to yield the
corresponding products (3i and 3ii) from interme-
diate 2. The correct synthesis of these intermediates
was evidenced by the appearance of multiplet peaks
in the range 7.63–7.38 ppm and 7.56–7.31 ppm due
to the proton atoms corresponding to the thiophene
and benzothiophene moieties, respectively, linked
to the quinoline ring. The esters 3i and3ii on hy-
drazinolysis with 99% hydrazine hydrate yielded the
corresponding hydrazides 4i and 4ii, and its cor-
rect synthesis was confirmed by a broad band at
1686 and 1673 cm−1 due to C O of amide and
disappearance of an ester frequency (1729 cm−1) in
1
the IR spectra. H NMR spectra of compounds 4i
and 4ii displayed a broad singlet at 9.83 and 9.76
ppm due to an NH proton, whereas an NH2 pro-
ton was found to reveal the corresponding signal
at 4.58 and 4.51 ppm in the form of a broad sin-
glet. The resulting carbohydrazide derivatives were
then cyclized using carbon disulfide in ethanolic
potassium hydroxide to furnish the final oxadiazoles
(5i,5ii). The IR spectra of the oxadiazole derivatives
revealed a band at 2587 and 2583 cm−1 due to an
SH group. Correct formation of the cyclized oxa-
1
diazole ring was further confirmed by the H NMR
spectra of the said compound, displaying a peak at
14.75 and 14.83 ppm due to an SH proton, whereas
O CH2was revealed by the corresponding peak
at 4.92 and 4.81 ppm. To produce the substituted
2-chloro-N-(benzo[d]thiazol-2-yl)acetamides (8a–i)
[24,31] from 2-amino-6-substituted benzothiazoles
(7a–i) [32,33], the literature procedures were fol-
lowed. Subsequently, the previously synthesized
oxadiazoles (5i, 5ii) were subjected to react with 2-
chloro-N-(benzo[d]thiazol-2-yl)acetamides (8a–i) to
RESULTS AND DISCUSSION
Chemistry
1
The synthesis of final analogues (9a–10i) was
achieved through the synthetic route outlined in
furnish the final scaffolds (9a–10i). All the IR, H
NMR, 13C NMR spectral data of compounds 9a–10i
Heteroatom Chemistry DOI 10.1002/hc

Combination of Bioactive Moieties with Different Heteroatom(s): Application of the Suzuki Cross-Coupling Reaction
3
SCHEME 1 Synthetic protocol for the final thiophene-based analogues (9a–i) and benzothiophene-based analogues (10a–i).
Reagents and conditions: (a) BrCH2COOC2H5, anhydrous K2CO3, Acetone, reflux, 7 h, 76%; (b) Na2CO3, Pd(PPh3)4, DME,
H2O, 85–90◦C, 16–19 h, 71%–76%; (c) 90% NH2NH2.H2O, EtOH, reflux, 3–5 h, 78%–81%; (d) CS2/KOH, EtOH, reflux, 9–11
h, 61%–67%; (e) potassium thiocyanate, Br2, AcOH, room temperature 2–4 h, 61%–80%; (f) ClCH2COCl, anhydrous K2CO3,
benzene, reflux, 6–12 h, 52%–88%; (g) K2CO3, acetone, reflux, 10–21 h, 54%–72%.
are in accordance with assumed structures. The
purity of the synthesized compounds was monitored
by thin layer chromatography (TLC) and ascertained
by elemental analysis.
bial activities. The bioassay results presented in
Table 1 demonstrate that the majority of the fi-
nal analogues succeeded to indicate remarkable
activity against the mentioned microorganisms.
However, it is worth to mention here that by
varying the substituent at C6 position of the ben-
zothiazole nucleus the activity profiles vary. In
addition, the minimum inhibitory concentrations
(MICs) values evidenced that the presence of the
Pharmacology
Several novel heterocyclic scaffolds were synthe-
sized and examined for their in vitro antimicro-
Heteroatom Chemistry DOI 10.1002/hc

4
Patel et al.
TABLE 1 In Vitro Antimicrobial Activity of 9a–10i
MIC (μg/mL)
Staphylococcus Bacillus Escherichia Pseudomonas
Klebsiella
pneumoniae
Aspergillus Candida
Entry
R
aureus
cereus
coli
aeruginosa
niger
albicans
9a
Cl
Br
F
I
12.5
6.25
6.25
50
200
200
62.5
250
250
50
100
50
25
200
50
250
50
200
50
12.5
62.5
50
250
12.5
200
50
200
200
25
200
100
62.5
62.5
200
25
25
62.5
50
200
250
500
25
62.5
250
100
100
25
500
100
250
50
200
100
100
250
100
250
100
62.5
200
200
100
62.5
250
62.5
250
50
9b
9c
62.5
100
200
250
100
500
500
25
25
25
62.5
200
500
50
9d
9e
NO2
CN
OCH3
OC2H5
NHCOCH3
Cl
Br
F
I
NO2
CN
OCH3
OC2H5
NHCOCH3
9f
9g
50
9h
50
25
9i
500
250
50
62.5
100
12.5
200
25
12.5
250
12.5
6.25
100
100
100
62.5
500
250
62.5
50
10a
10b
25
50
25
10c
12.5
62.5
100
250
50
100
200
12.5
6.25
10d
250
12.5
500
62.5
200
250
25
10e
10f
10g
10h
50
100
100
25
25
200
–
–
6.25
–
50
10i
500
6.25
12.5
100
–
–
12.5
–
Ampicillin
Gentamicin
Fluconazole
DMSO
12.5
25
–
–
–
–
–
Note: Values presented in bold letters are lowest MICs.
benzothiophene moiety gave rise to better phar-
macological profiles when compared with those
with thiophene. Final analogues with halogen sub-
stituents (Cl, Br, F) attached to the benzothiazole
moiety involving a thiophene linkage to the quino-
line ring indicated an appreciable activity against
Staphylococcus aureus (9b, 9c, MIC: 6.25 μg/mL),
Pseudomonas aeruginosa (9a, MIC: 12.5 μg/mL),
and Aspergillus niger (9a, MIC: 25 μg/mL), whereas
those bearing the benzothiophene moiety with simi-
lar structural features displayed a considerable activ-
ity against Escherichia coli (10a–c) as well as against
A. niger at 25 μg/mL of MIC. Final analogues with
the strong electron-withdrawing nitrosubstituent-
bearing thiophene ring system showed best activ-
ity against P. aeruginosa (9e, MIC: 12.5 μg/mL),
whereas similar scaffolds with the benzothiophene
ring system (10e) exhibited excellent inhibitory ef-
ficacy against same bacteria at the similar concen-
tration level along with good activity against Bacil-
lus cereus at 12.5 μg/mL of MIC. It can be stated
that scaffolds with a cyano substituent (9f) in addi-
tion to a thiophene ring showed activity (25 μg/mL)
against Klebsiella pneumoniae; however, none of the
similar scaffold with the benzothiophene moiety
showed any noticeable activity. The final thiophene-
based analogues with electron-donating alkoxy sub-
stituents displayed a significant activity against A.
niger (9g) and K. pneumoniae (9h) at 25 μg/mL of
MIC; however, those bearing the thiophene ring with
similar alkoxy functional groups indicated an en-
hanced activity against B. cereus (10h, MIC: 12.5
μg/mL), A. niger (10h, MIC: 25 μg/mL), and Candida
albicans (10g, 10h, MIC: 50 μg/mL). It will suffice
to mention that many of the remaining analogues
displayed good activity against the mentioned mi-
croorganisms at 25–62.5 μg/mL of MIC. Possible
improvements in the antibacterial activity can be
further achieved by slight modifications in the ring
substituents and/or extensive additional structural
activity investigations.
CONCLUSIONS
Eighteen
thiophene-
and
benzothiophene-
based quinolyl oxadiazoles condensed to the
Heteroatom Chemistry DOI 10.1002/hc

Combination of Bioactive Moieties with Different Heteroatom(s): Application of the Suzuki Cross-Coupling Reaction
5
electron-donating/withdrawing
functionalized
acid was added dropwise at such a rate to keep the
benzothiazoles via an amide linkage have been syn-
thesized with appreciable yield, and the spectral data
were found to be in agreement with the assigned
molecular structures. Most of the tested compounds
exhibited pronounced antimicrobial activities as
compared to standard drugs. The MIC level of
the final scaffolds ranges from 6.25–12.5 μg/mL
against Gram-positive bacteria, 12.5–25 μg/mL
against Gram-negative bacteria, to 25–50 μg/mL
against fungal species that is comparable to the
standard drugs (6.25–25 μg/mL). Hence, these
compounds would represent a fruitful matrix for the
development of a new class of antimicrobial agents.
temperature below 10◦C throughout the addition.
The reaction mixture was stirred at room tempera-
ture for 2–4 h; the hydrobromide (HBr) salt thus sep-
arated was filtered, washed with acetic acid, dried,
dissolved in hot water and basified to pH 11.0 with
ammonia solution (NH4OH), and the resulting pre-
cipitate was filtered, washed with water, and dried
to get the desired product 7a–i. The progress of the
reaction was monitored by TLC using the toluene:
acetone (8:2) solvent system.
Synthesis
of
2-aminobenzo[d]thiazole-6-
carbonitrile (7f). A mixture of 0.1 mol of 4-
aminobenzonitrile and 0.2 mol of potassium
thiocyanate in 100 mL glacial acetic acid was cooled
in an ice bath and stirred for 10–20 min, and then
0.1 mol of bromine in glacial acetic acid was added
dropwise at such a rate to keep the temperature
below 10◦ C throughout the addition. The reaction
mixture was stirred at room temperature for 2–4 h,
and HBr salt was thus separated. In the reaction
mixture, 150 mL of water was added. The solid
4-cyano-2-thiocyanatoaniline thus obtained was
filtered, dried, and recrystallized from ethanol.
Then in 0.05 mol of this intermediate, 10 mL of
concentrated HCl, and 20 mL of water was added,
and the mixture was refluxed for 2 h. After the
completion of the reaction, the solution was cooled
and the product was filtered, washed with water,
and recrystallized from ethanol to give 7f [34]. The
progress of the reaction was monitored by TLC
using the toluene: acetone (9:1) solvent system.
Light yellow solid, yield: 61%, mp 206–207◦C. IR
(KBr, cm−1): 3376 (NH), 1576 (C N). 1H NMR
(400 MHz, DMSO-d6): δH 7.70 (1H, d, J = 1.8 Hz,
H-7), 7.55 (1H, d, J = 7.4 Hz, H-4), 7.26 (1H,
dd, J = 8.4, 2.0 Hz, H-5), 7.18 (2H, s, NH2, D2O
exchangeable).
EXPERIMENTAL
Chemistry
Boronic acid derivatives were purchased from
Sigma–Aldrich (Mumbai, India). HPLC-grade sol-
vents were purchased from Ranker (Surat,
India). The TLC plates (silica gel 60 F254) were ob-
tained from Merck (Darmstadt, Germany). 6-Bromo-
4-hydroxyquinoline was a gift from Silica Hetero
Cyclics (Hyderabad, India).
Melting points were determined in open capillar-
ies on a Veego electronic apparatus VMP-D (Veego
Instrument Corporation, Mumbai, India) and are
uncorrected. IR spectra (4000–400 cm−1) of syn-
thesized compounds were recorded on a Shimadzu
8400-S FT-IR spectrophotometer (Shimadzu India
Pvt. Ltd., Mumbai, India) using KBr pellets. TLC was
performed on object glass slides (2 × 7.5 cm) coated
with silica gel-G, and spots were visualized under
UV irradiation. 1H NMR and 13C NMR spectra were
recorded on a Varian 400 MHz model spectrometer
(Varian India Pvt. Ltd., Mumbai, India) using DMSO
as a solvent and TMS as an internal standard with
1
a H resonant frequency of 400 MHz and 13C reso-
nant frequency of 100 MHz. The H NMR and 13C
1
NMR chemical shifts were reported as parts per mil-
lion (ppm) downfield from TMS (Me4Si) and were
performed at the Centre for Excellence, Vapi, India.
The splitting patterns are designated as follows; s,
singlet; d, doublet; dd, doublet of doublets; q, quar-
tet; and m, multiplet. Elemental analyses (C, H, N)
were performed using a Heraeus Carlo Erba 1180
CHN analyzer (Heraeus, Hanau, Germany).
General synthetic procedure for N-(benzo[d]
thiazol-2-yl)-2-chloroacetamides
(8a–i). Chloro-
acetyl chloride (0.06 mol) was added dropwise to a
mixture of the appropriate 2-amino-6-substituted
benzothiazole,7a–i (0.05 mol) and K2CO3 (0.06
mol) in benzene (50 mL) at room temperature. The
reaction mixture was refluxed for 6–12 h; then, after
cooling to room temperature, it was slowly poured
into 100 mL of ice water. Thereafter, a solid was
formed. The precipitate was separated by filtration
and washed successively with water. The product
was dried under vacuum to obtain 8a–i [27]. The
progress of the reaction was monitored by TLC
using the toluene: acetone (8:2) solvent system.
General synthetic procedure for 2-amino-6-
substituted benzothiazoles (7a–i). A mixture of
0.1 mol of 4-substituted aniline (6a–i) and 0.1 mol of
potassium thiocyanate in 100 mL glacial acetic acid
(AcOH) was cooled in an ice bath and stirred for 10–
20 min, and then 0.1 mol bromine in glacial acetic
Heteroatom Chemistry DOI 10.1002/hc

6
Patel et al.
Synthesis of 1-(6-bromoquinolin-4-yloxy)butan-
1-(6-(benzo[b]thiophen-2-yl)quinolin-4-yloxy)
butan-2-one (3ii). Yellow solid, yield 76%, mp 171–
174◦C; IR (νmax, cm−1): 1731 (ester, C O);1H NMR
(400 MHz, DMSO-d6): δ 8.78 (d, J = 2.1 Hz, 1H, H-5,
quinoline), 8.65 (d, J = 8.2 Hz, 1H, N CH , H-2,
quinoline), 8.37 (s, 1H, H-3, quinoline), 8.19 (d, J =
7.7 Hz, 1H, H-8, quinoline), 8.01 (dd, J = 7.8, 1.8
Hz, 1H, H-7, quinoline), 7.56–7.31 (m, 5H, benzoth-
iophene), 5.19 (2H, s, Qui O CH2), 4.29 (2H, q, J =
6.0 Hz, OCH2CH3), 1.26 (3H, t, J = 6.4 Hz, CH2CH3).
2-one (2). In a mixture of 0.10 mol of 6-bromo-
4-hydroxyquinoline (1) in dry acetone (50 mL)
and anhydrous potassium carbonate (0.10 mol), an
equimolecular amount of ethyl bromoacetate was
added dropwise. Then the reaction mixture was re-
fluxed for 7 h and the progress of the reaction was
monitored by TLC using the toluene: acetone (8:2)
solvent system. After the completion of the reaction,
the solvent was removed under reduced pressure.
The residual mass thus obtained was poured onto
crushed ice and extracted with ether (3×50 mL). The
ether layer was then washed with 10% sodium hy-
droxide solution (3×30 mL) followed by water (3×30
mL), and then dried over anhydrous sodium sulfate
and evaporated to dryness to get a final crude solid
as 2. Recrystallized from acetone, dark yellow solid,
yield 76%, mp 148–150◦C; IR (νmax, cm−1): 1729 (es-
ter, C O);1H NMR (400 MHz, DMSO-d6): δ 8.81 (d,
J = 1.8 Hz, 1H, H-5, quinoline), 8.70 (d, J = 8.6
Hz, 1H, N CH , H-2, quinoline), 8.34 (s, 1H, H-
3, quinoline), 8.23 (d, J = 7.1 Hz, 1H, H-8, quino-
line), 8.13 (dd,J = 8.0, 2.2 Hz, 1H, H-7, quinoline),
5.01 (2H, s, Qui O CH2), 4.23 (2H, q, J = 5.9 Hz,
OCH2CH3), 1.24 (3H, t, J = 6.6 Hz, CH2CH3).
General synthetic procedure for 2 - ( 3 - ( benzo)
thiophen - 2 - yl)quinolin - 4 - yloxy)acetohydrazide (4i,
4ii). Compounds 3i and3ii (0.1 mol) were dissolved
in ethanol (50 mL), 99% hydrazine hydrate (0.1 mol)
was added, and the mixture was refluxed for 3 h (for
4i) and 5 h (for 4ii). The solid thus obtained was
collected by filtration, washed with small quantity
of cold methanol and recrystallized from ethanol to
furnish the final hydrazide derivatives 4i and 4ii. The
progress of the reaction was monitored by TLC using
the toluene: acetone (8:2) solvent system.
2-(3-(Thiophen-2-yl)quinolin-4-yloxy)aceto-
hydrazide (4i). Off white, yield 78%, mp 167–169 ◦C;
IR (νmax, cm−1): 1686 (amide, C O), 3311, 3231
1
(NH NH2). H NMR (400 MHz, DMSO-d6): δ 9.83
General synthetic procedure for 1-6-(benzo)
thiophen-2-yl)quinolin-4-yloxy)butan-2-one (3i, 3ii).
To a mixture of compound 2 (0.5 mol), thiophen-2-
ylboronic acid (for 3i, 0.62 mol) or benzothiophene-
2-ylboronic acid (for 3ii, 0.62 mol), sodium carbon-
ate (1.15 mol), in 1,2-dimethoxy ethane (150 mL) and
water (50 mL), palladium tetrakis (0.005 mol) was
added and resulting mixture was heated to 85–90◦C
for 16 h (for 3i) or 19 h (for 3ii). The solvents were re-
moved under vacuum, and the compound was taken
in ethyl acetate (500 mL). After washing with water
(3×100 mL), saturated sodium bicarbonate solution
(1×100 mL), and saturated sodium chloride solution
(1×100 mL), the compound was dried over sodium
sulfate. The residue was purified by silica gel column
chromatography [ethyl acetate: n-hexane] to afford
compounds 3i and 3ii.
(1H, br s, –CO NH), 8.84 (d, J = 2.3 Hz, 1H, H-5,
quinoline), 8.76 (d, J = 7.8 Hz, 1H, N CH , H-2,
quinoline), 8.42 (s, 1H, H-3, quinoline), 8.24 (d, J =
8.1 Hz, 1H, H-8, quinoline), 7.98 (dd, J = 7.9, 2.0 Hz,
1H, H-7, quinoline), 7.60–7.36 (m, 3H, thiophene),
5.08 (2H, s, Qui O CH2), 4.58 (2H, br s, NH2).
2-(3-(Benzo[b]thiophen-2-yl)quinolin-4-yloxy)
acetohydrazide (4ii). Yellowish white solid, yield
81%, mp 183–184◦C; IR (νmax, cm−1): 1673 (amide,
1
C O), 3325, 3247 (NH NH2). H NMR (400 MHz,
DMSO-d6): δ 9.76 (1H, br s, –CO NH), 8.73 (d, J =
2.1 Hz, 1H, H-5, quinoline), 8.71 (d, J = 7.5 Hz, 1H,
N CH , H-2, quinoline), 8.34 (s, 1H, H-3, quino-
line), 8.16 (d, J = 7.9 Hz, 1H, H-8, quinoline), 8.11
(dd, J = 8.1, 1.5 Hz, 1H, H-7, quinoline), 7.53–7.27
(m, 5H, benzothiophene), 4.87 (2H, s, Qui O CH2),
4.51 (2H, br s, NH2).
1-(6-(Thiophen-2-yl)quinolin-4-yloxy)butan-2-
one (3i). Light yellow solid, yield 71%, mp 162–
164◦C; IR (νmax, cm−1): 1735 (ester, C O);1H NMR
(400 MHz, DMSO-d6): δ 8.73 (d, J = 1.4 Hz, 1H, H-5,
quinoline), 8.68 (d, J = 8.1 Hz, 1H, N CH , H-
2, quinoline), 8.40 (s, 1H, H-3, quinoline), 8.29 (d,
J = 7.7 Hz, 1H, H-8, quinoline), 8.04 (dd, J = 7.7,
2.0 Hz, 1H, H-7, quinoline), 7.63–7.38 (m, 3H, thio-
phene), 4.89 (2H, s, Qui O CH2), 4.14 (2H, q, J =
5.9 Hz, OCH2CH3), 1.33 (3H, t, J = 7.0 Hz, CH2CH3).
General synthetic procedure for 5 - ( 6 - ( benzo )
thiophen-2-yl)quinolin-4-yloxy)methyl)-1,3,4-oxadia-
zole-2-thiol (5i, 5ii). To a solution of 0.05 mol aceto-
hydrazides (4i,4ii) in ethanol (50 mL), carbon disul-
fide (0.05 mol) and potassium hydroxide (0.05 mol)
were added and the reaction mixture was refluxed
for 9–11 h, until the evolution of H2S gas ceased.
Excess solvents were evaporated under reduced
pressure, and the residue was dissolved in water
Heteroatom Chemistry DOI 10.1002/hc

Combination of Bioactive Moieties with Different Heteroatom(s): Application of the Suzuki Cross-Coupling Reaction
7
and then acidified with dilute hydrochloric acid
(10%) to pH 5–6. The precipitate was filtered off,
dried, and crystallized from ethanol to give the
corresponding oxadiazole derivatives (5i,5ii) [35].
The completion of the reaction was monitored by
TLC in the n-hexane: ethyl acetate (8:2) solvent
system.
3308 (NH), 1678 (C O), 1651 (C N, benzothia-
zole), 1642, 1521 (2C N, oxadiazole), 1438, 1246
( C S CH2), 1075 (Qui O CH2), 1049 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ
9.73 (s, 1H, NH), 8.79 (d, J = 1.4 Hz, 1H, H-5,
quinoline), 8.60 (d, J = 8.6 Hz, 1H, N CH , H-2,
quinoline), 8.50 (dd, J = 6.1, 2.2 Hz, 1H), 8.38 (s, 1H,
H-3, quinoline), 8.27 (d, J = 7.3 Hz, 1H, H-8, quino-
line), 8.20 (d, J = 1.3 Hz, 1H, H-7, benzothiazole),
8.12 (dd, J = 8.3, 2.5 Hz, 1H, H-7, quinoline), 7.80
(d, J = 1.3 Hz, 1H, H-4, benzothiazole), 7.51 (dd, J
= 7.7, 3.5 Hz, 1H, H-5, benzothiazole), 7.39–7.31
(m, 2H, Ar-H), 4.88 (s, 2H, O CH2), 4.10 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 173.06
(1C, C-2, oxadiazole), 170.46 (1C, CO), 164.53 (1C,
C-5, oxadiazole), 159.77 (1C, C-2, benzothiazole),
156.54, 153.53 (2C, C2 and C9, quinoline), 151.63
(1C, Qui.C O CH2), 149.26 (1C, C-2, thiophene
ring), 145.65–121.53 (15C, aromatic carbon atoms),
56.73 (1C, OCH2), 38.54 (1C, S CH2). Anal Calcd for
C25H16ClN5O3S3: C, 53.04; H, 2.85; N, 12.37. Found:
C, 53.24;H, 2.76; N, 12.42.
5-((6-(Thiophen-2-yl)quinolin-4-yloxy)methyl)-
1,3,4-oxadiazole-2-thiol (5i). Yellow solid, yield
67%, mp 185–186◦C; IR (νmax, cm−1): 2587 (SH),
1633, 1529 (2C N, oxadiazole), 1078 (Qui O CH2),
1037 (C O C, oxadiazole).1H NMR (400 MHz,
DMSO-d6): δ 14.75 (1H, br s, SH), 8.80 (d, J = 2.0
Hz, 1H, H-5, quinoline), 8.69 (d, J = 7.7 Hz, 1H,
N CH , H-2, quinoline), 8.41 (s, 1H, H-3, quino-
line), 8.23 (d, J = 8.2 Hz, 1H, H-8, quinoline), 8.03
(dd, J = 7.5, 1.7 Hz, 1H, H-7, quinoline), 7.48–7.21
(m, 3H, thiophene), 4.92 (2H, s, Qui O CH2).
5-((6-(Benzo[b]thiophen-2-yl)quinolin-4-yloxy)
methyl)-1,3,4-oxadiazole-2-thiol (5ii). Dark yellow
solid, yield 61%, mp 202–204◦C; IR (νmax, cm−1):
2583 (SH), 1627, 1536 (2C N, oxadiazole), 1081
(Qui O CH2), 1041 (C O C, oxadiazole).1H NMR
(400 MHz, DMSO-d6): δ 14.83 (1H, br s, SH), 8.74
(d, J = 1.8 Hz, 1H, H-5, quinoline), 8.66 (d, J = 8.2
Hz, 1H, N CH , H-2, quinoline), 8.36 (s, 1H, H-
3, quinoline), 8.19 (d, J = 8.3 Hz, 1H, H-8, quino-
line), 7.94 (dd, J = 7.1, 2.2 Hz, 1H, H-7, quino-
line), 7.58–7.34 (m, 5H, benzothiophene), 4.81 (2H,
s, Qui O CH2).
N - ( 6 - Bromobenzo [d] thiazol - 2 - yl ) - 2 - ( 5 - ((6 -
(thiophen-2-yl)quinolin-4-yloxy)methyl) -1, 3, 4-
oxadiazol-2-ylthio)acetamide (9b). Brown solid,
yield 67%, mp 219–221◦C; IR (KBr, cm−1): 3316
(NH), 1674 (C O), 1647 (C N, benzothiazole), 1635,
1528 (2C N, oxadiazole), 1444, 1254 ( C S CH2),
1
1079 (Qui O CH2), 1053 (C O C, oxadiazole). H
NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H, NH),
8.85 (d, J = 1.7 Hz, 1H, H-5, quinoline), 8.66 (d, J
= 8.1 Hz, 1H, N CH , H-2, quinoline), 8.54 (dd,
J = 6.3, 2.5 Hz, 1H), 8.42 (s, 1H, H-3, quinoline),
8.31 (d, J = 7.8 Hz, 1H, H-8, quinoline), 8.18 (d,
J = 1.7 Hz, 1H, H-7, benzothiazole), 8.08 (dd, J =
8.5, 2.1 Hz, 1H, H-7, quinoline), 7.84 (d, J = 1.1 Hz,
1H, H-4, benzothiazole), 7.60 (dd, J = 8.2, 3.2 Hz,
1H, H-5, benzothiazole), 7.43–7.28 (m, 2H, Ar-H),
4.95 (s, 2H, O CH2), 4.17 (s, 2H, S CH2). 13C NMR
(100 MHz, DMSO-d6): δ 174.16 (1C, C-2, oxadiazole),
171.97 (1C, CO), 166.75 (1C, C-5, oxadiazole), 161.32
(1C, C-2, benzothiazole), 154.64, 151.97 (2C, C2 and
C9, quinoline), 150.12 (1C, Qui.C O CH2), 147.90
(1C, C-2, thiophene ring), 143.13-119.73 (15C, aro-
matic carbon atoms), 52.22 (1C, OCH2), 34.27 (1C,
S CH2). Anal Calcd for C25H16BrN5O3S3: C, 49.18; H,
2.64; N, 11.47. Found: C, 49.22; H, 2.75; N, 11.40.
General synthetic procedure for 2-(5-((6-(benzo)
thiophen - 2 - yl ) quinolin - 4 - yloxy ) methyl ) - 1 , 3 , 4 -
oxadiazol - 2 - ylthio ) - N - ( 6 - ( substituted ) benzo [ d ]
thiazol-2-yl)acetamides (9a–10i). To 0.01 mol of 5-
(6-(benzo)thiophen-2-yl)quinolin-4-yloxy) methyl)-
1,3,4-oxadiazole-2-thiol (5i, 5ii) in 25 mL of acetone,
0.01 mol of 2-chloro-N-(substituted)benzothiazolyl
acetamides (8a–i) in acetone and 0.01 mol of K2CO3
was added and the reaction mixture was refluxed
for 10–21 h. Then, after cooling to room tempera-
ture, it was slowly poured into 100 mL of ice water
and the resulting solid was separated by filtration
and washed successively with water. The product
was dried under vacuum to obtain 9a–10i [25]. The
progress of the reaction was monitored by thin layer
chromatography using the n-hexane: ethyl acetate
(8:2) solvent system.
N - (6 - Fluorobenzo [d] thiazol - 2 - yl) - 2 - (5 - ((6 -
(thiophen - 2 - yl)quinolin - 4 - yloxy)methyl) - 1 , 3 , 4 -
oxadiazol-2-ylthio)acetamide (9c). Yellow solid,
yield 56%, mp 246–248◦C; IR (KBr, cm−1): 3322
(NH), 1677 (C O), 1658 (C N, benzothiazole), 1638,
1525 (2C N, oxadiazole), 1436, 1256 ( C S CH2),
N - (6 - Chlorobenzo [d] thiazol - 2 - yl) - 2 - (5 - ((6 -
(thiophen - 2 - yl)quinolin - 4 - yloxy)methyl) - 1 , 3 , 4-
oxadiazol-2-ylthio)acetamide (9a). Light brown
solid, yield 62%, mp 228–230◦C; IR (KBr, cm−1):
Heteroatom Chemistry DOI 10.1002/hc

8
Patel et al.
1
1H, NH), 8.85 (d, J = 1.9 Hz, 1H, H-5, quinoline),
8.70 (d, J = 7.8 Hz, 1H, N CH , H-2, quinoline),
8.51 (dd, J = 6.6, 2.4 Hz, 1H), 8.36 (s, 1H, H-3,
quinoline), 8.34 (d, J = 7.6 Hz, 1H, H-8, quinoline),
8.19 (d, J = 1.7 Hz, 1H, H-7, benzothiazole), 7.99
(dd, J = 8.4, 2.0 Hz, 1H, H-7, quinoline), 7.89 (d,
J = 1.8 Hz, 1H, H-4, benzothiazole), 7.59 (dd, J =
8.0, 3.2 Hz, 1H, H-5, benzothiazole), 7.39–7.26
(m, 2H, Ar-H), 5.00 (s, 2H, O CH2), 4.15 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 172.98
(1C, C-2, oxadiazole), 169.76 (1C, CO), 165.87 (1C,
C-5, oxadiazole), 161.47 (1C, C-2, benzothiazole),
154.77, 153.48 (2C, C2 and C9, quinoline), 151.27
(1C, Qui.C O CH2), 147.96 (1C, C-2, thiophene
ring), 143.37-118.27 (15C, aromatic carbon atoms),
54.17 (1C, OCH2), 36.27 (1C, S CH2). Anal Calcd for
C25H16N6O5S3: C, 52.07; H, 2.80; N, 14.57. Found: C,
51.96; H, 2.96; N, 14.45.
1083 (Qui O CH2), 1055 (C O C, oxadiazole). H
NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H, NH),
8.87 (d, J = 1.6 Hz, 1H, H-5, quinoline), 8.69 (d,
J = 8.7 Hz, 1H, N CH , H-2, quinoline), 8.58 (dd,
J = 6.7, 2.7 Hz, 1H), 8.40 (s, 1H, H-3, quinoline),
8.33 (d, J = 7.4 Hz, 1H, H-8, quinoline), 8.26 (d,
J = 1.5 Hz, 1H, H-7, benzothiazole), 8.03 (dd, J =
7.9, 2.6 Hz, 1H, H-7, quinoline), 7.90 (d, J = 1.4 Hz,
1H, H-4, benzothiazole), 7.54 (dd, J = 7.8, 4.0 Hz,
1H, H-5, benzothiazole), 7.45–7.30 (m, 2H, Ar-H),
4.90 (s, 2H, O CH2), 4.20 (s, 2H, S CH2). 13C NMR
(100 MHz, DMSO-d6): δ 173.18 (1C, C-2, oxadiazole),
169.24 (1C, CO), 163.22 (1C, C-5, oxadiazole), 160.88
(1C, C-2, benzothiazole), 155.23, 153.64 (2C, C2 and
C9, quinoline), 151.75 (1C, Qui.C O CH2), 148.77
(1C, C-2, thiophene ring), 147.14–120.94 (15C, aro-
matic carbon atoms), 56.94 (1C, OCH2), 37.04 (1C,
S CH2). Anal Calcd for C25H16FN5O3S3: C, 54.63; H,
2.93; N, 12.74. Found: C, 54.60; H, 2.88; N, 12.85.
N - (6 - Cyanobenzo [d] thiazol - 2 - yl ) - 2 - ( 5 - (( 6 -
(thiophen - 2 - yl)quinolin - 4 - yloxy)methyl) - 1 , 3 , 4 -
oxadiazol-2-ylthio)acetamide (9f). Light brown
solid, yield 57%, mp 240–242◦C; IR (KBr, cm−1):
3324 (NH), 1674 (C O), 1651 (C N, benzothia-
zole), 1640, 1520 (2C N, oxadiazole), 1446, 1250
( C S CH2), 1075 (Qui O CH2), 1055 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.70 (s,
1H, NH), 8.88 (d, J = 1.7 Hz, 1H, H-5, quinoline),
8.63 (d, J = 8.1 Hz, 1H, N CH , H-2, quinoline),
8.54 (dd, J = 6.3, 2.0 Hz, 1H), 8.39 (s, 1H, H-3,
quinoline), 8.29 (d, J = 7.1 Hz, 1H, H-8, quinoline),
8.24 (d, J = 1.4 Hz, 1H, H-7, benzothiazole), 8.05
(dd, J = 8.0, 2.4 Hz, 1H, H-7, quinoline), 7.79 (d,
J = 1.5 Hz, 1H, H-4, benzothiazole), 7.53 (dd, J =
7.8, 4.1 Hz, 1H, H-5, benzothiazole), 7.46–7.34
(m, 2H, Ar-H), 4.94 (s, 2H, O CH2), 4.17 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 174.09
(1C, C-2, oxadiazole), 170.23 (1C, CO), 168.12 (1C,
C-5, oxadiazole), 159.95 (1C, C-2, benzothiazole),
155.46, 151.96 (2C, C2 and C9, quinoline), 150.07
(1C, Qui.C O CH2), 147.85 (1C, C-2, thiophene
ring), 143.96–123.46 (14C, aromatic carbon atoms),
105.90 (1C, C≡N), 97.31 (1C, C C N), 51.95
(1C, OCH2), 33.55 (1C, S CH2). Anal Calcd for
C26H16N6O3S3: C, 56.10; H, 2.90; N, 15.10. Found: C,
56.24; H, 2.79; N, 15.24.
N - ( 6 - Iodobenzo [d] thiazol - 2 - yl ) - 2 - ( 5 - (( 6 -
( thiophen - 2 - yl ) quinolin - 4 - yloxy)methyl ) - 1 , 3 , 4 -
oxadiazol-2-ylthio)acetamide (9d). Pale yellow
solid, yield 64%, mp 268–270◦C; IR (KBr, cm−1):
3312 (NH), 1680 (C O), 1649 (C N, benzothia-
zole), 1642, 1523 (2C N, oxadiazole), 1439, 1247
( C S CH2), 1076 (Qui O CH2), 1048 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s,
1H, NH), 8.83 (d, J = 1.3 Hz, 1H, H-5, quinoline),
8.64 (d, J = 8.0 Hz, 1H, N CH , H-2, quinoline),
8.49 (dd, J = 6.4, 2.2 Hz, 1H), 8.46 (s, 1H, H-3,
quinoline), 8.30 (d, J = 7.2 Hz, 1H, H-8, quinoline),
8.21 (d, J = 1.2 Hz, 1H, H-7, benzothiazole), 8.06
(dd, J = 8.2, 2.2 Hz, 1H, H-7, quinoline), 7.86 (d,
J = 1.0 Hz, 1H, H-4, benzothiazole), 7.55 (dd, J =
8.1, 3.5 Hz, 1H, H-5, benzothiazole), 7.40–7.27
(m, 2H, Ar-H), 4.93 (s, 2H, O CH2), 4.12 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 175.03
(1C, C-2, oxadiazole), 172.12 (1C, CO), 167.76 (1C,
C-5, oxadiazole), 157.37 (1C, C-2, benzothiazole),
156.97, 152.39 (2C, C2 and C9, quinoline), 151.14
(1C, Qui.C O CH2), 149.23 (1C, C-2, thiophene
ring), 146.76–122.47 (15C, aromatic carbon atoms),
55.59 (1C, OCH2), 39.47 (1C, S CH2). Anal Calcd for
C25H16IN5O3S3: C, 45.67; H, 2.45; N, 10.65. Found:
C, 45.57; H, 2.54; N, 10.69.
N - ( 6 - Nitrobenzo [d] thiazol - 2 - yl ) - 2 - ( 5 - (( 6 -
(thiophen - 2 - yl)quinolin - 4 - yloxy)methyl) - 1 , 3 , 4 -
oxadiazol-2-ylthio)acetamide (9e). Dark brown
solid, yield 60%, mp 281–282◦C; IR (KBr, cm−1):
3309 (NH), 1676 (C O), 1654 (C N, benzothia-
zole), 1632, 1527 (2C N, oxadiazole), 1442, 1245
( C S CH2), 1080 (Qui O CH2), 1059 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.72 (s,
N-(6-Methoxybenzo[d]thiazol-2-yl)-2-(5-((6-
( thiophen - 2 - yl ) quinolin - 4 - yloxy)methyl) - 1 , 3 , 4 -
oxadiazol-2-ylthio)acetamide (9g). Dark yellow
solid, yield 68%, mp 265–267◦C; IR (KBr, cm−1):
3307 (NH), 1670 (C O), 1656 (C N, benzothia-
zole), 1643, 1522 (2C N, oxadiazole), 1439, 1252
( C S CH2), 1084 (Qui O CH2), 1053 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.74 (s,
Heteroatom Chemistry DOI 10.1002/hc

Combination of Bioactive Moieties with Different Heteroatom(s): Application of the Suzuki Cross-Coupling Reaction
9
1
1H, NH), 8.79 (d, J = 1.4 Hz, 1H, H-5, quinoline),
1080 (Qui O CH2), 1058 (C O C, oxadiazole). H
NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H, NH),
9.24 (s, 1H, NH), 8.86 (d, J = 2.2 Hz, 1H, H-5,
quinoline), 8.62 (d, J = 8.6 Hz, 1H, N CH , H-2,
quinoline), 8.48 (dd, J = 6.6, 2.3 Hz, 1H), 8.37 (s,
1H, H-3, quinoline), 8.27 (d, J = 7.9 Hz, 1H, H-8,
quinoline), 8.25 (d, J = 1.5 Hz, 1H, H-7, benzothia-
zole), 8.11 (dd, J = 8.4, 2.8 Hz, 1H, H-7, quinoline),
7.90 (d, J = 1.8 Hz, 1H, H-4, benzothiazole), 7.57
(dd, J = 8.5, 3.9 Hz, 1H, H-5, benzothiazole), 7.41–
7.29 (m, 2H, Ar-H), 5.01 (s, 2H, O CH2), 4.11 (s, 2H,
S CH2), 1.91 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6): δ 172.97 (1C, C-2, oxadiazole), 169.44
(1C, CO), 167.76 (1C, CO, acetamide), 164.08 (1C,
C-5, oxadiazole), 161.16 (1C, C-2, benzothiazole),
154.44, 152.07 (2C, C2 and C9, quinoline), 150.47 (1C,
Qui.C O CH2), 147.99 (1C, C-2, thiophene ring),
143.36–121.45 (15C, aromatic carbon atoms), 50.05
(1C, OCH2), 32.16 (1C, S CH2), 19.92 (1C, CH3). Anal
Calcd for C27H20N6O4S3: C, 55.09; H, 3.42; N, 14.28.
Found: C, 55.22; H, 3.33; N, 14.39.
8.67 (d, J = 8.5 Hz, 1H, N CH , H-2, quinoline),
8.50 (dd, J = 6.5, 2.6 Hz, 1H), 8.47 (s, 1H, H-3,
quinoline), 8.33 (d, J = 7.8 Hz, 1H, H-8, quinoline),
8.17 (d, J = 1.3 Hz, 1H, H-7, benzothiazole), 8.00
(dd, J = 8.5, 2.1 Hz, 1H, H-7, quinoline), 7.83 (d,
J = 1.6 Hz, 1H, H-4, benzothiazole), 7.61 (dd, J =
8.0, 3.4 Hz, 1H, H-5, benzothiazole), 7.45–7.33
(m, 2H, Ar-H), 4.87 (s, 2H, O CH2), 3.83 (s, 3H,
OCH3), 4.14 (s, 2H, S CH2). 13C NMR (100 MHz,
DMSO-d6): δ 175.15 (1C, C-2, oxadiazole), 172.19
(1C, CO), 166.64 (1C, C-5, oxadiazole), 157.44 (1C,
C-2, benzothiazole), 154.04, 152.16 (2C, C2 and C9,
quinoline), 150.96 (1C, Qui.C O CH2), 148.15 (1C,
C-2, thiophene ring), 144.44–117.04 (15C, aromatic
carbon atoms), 57.23 (1C, OCH3), 53.73 (1C, OCH2),
38.94 (1C, S CH2). Anal Calcd for C26H19N5O4S3: C,
55.60; H, 3.41; N, 12.47. Found: C, 55.65; H, 3.35; N,
12.58.
N-(6-Ethoxybenzo[d]thiazol-2-yl) -2-(5-((6-
(thiophen-2-yl) quinolin- 4- yloxy) methyl )-1, 3, 4-
oxadiazol-2-ylthio)acetamide (9h). Light brown
solid, yield 71%, mp 273–275◦C; IR (KBr, cm−1):
3318 (NH), 1683 (C O), 1652 (C N, benzothia-
zole), 1636, 1529 (2C N, oxadiazole), 1441, 1256
( C S CH2), 1086 (Qui O CH2), 1051 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.71 (s,
1H, NH), 8.84 (d, J = 2.0 Hz, 1H, H-5, quinoline),
8.59 (d, J = 8.2 Hz, 1H, N CH , H-2, quinoline),
8.55 (dd, J = 6.9, 2.5 Hz, 1H), 8.43 (s, 1H, H-3,
quinoline), 8.30 (d, J = 7.6 Hz, 1H, H-8, quinoline),
8.20 (d, J = 1.9 Hz, 1H, H-7, benzothiazole), 8.13
(dd, J = 8.8, 2.3 Hz, 1H, H-7, quinoline), 7.81 (d,
J = 1.2 Hz, 1H, H-4, benzothiazole), 7.64 (dd, J =
8.3, 3.3 Hz, 1H, H-5, benzothiazole), 7.42–7.28 (m,
2H, Ar-H), 4.89 (s, 2H, O CH2), 4.19 (s, 2H, S CH2),
3.92 (q, J = 6.8 Hz, 2H, O CH2 CH3), 1.23 (t, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6): δ 173.16
(1C, C-2, oxadiazole), 171.96 (1C, CO), 167.83 (1C,
C-5, oxadiazole), 158.94 (1C, C-2, benzothiazole),
156.36, 153.11 (2C, C2 and C9, quinoline), 151.23
(1C, Qui.C O CH2), 149.46 (1C, C-2, thiophene
ring), 145.97–119.16 (15C, aromatic carbon atoms),
64.99 (1C, OCH2CH3), 56.27 (1C, OCH2), 39.26
(1C, S CH2), 23.91 (1C, OCH2CH3). Anal Calcd for
C27H21N5O4S3: C, 56.33; H, 3.68; N, 12.17. Found: C,
56.30; H, 3.47; N, 12.37.
2 - ( 5 - (( 6 - ( Benzo [b] thiophen - 2 - yl ) quinolin -
4-yloxy)methyl) -1,3,4-oxadiazol-2-ylthio)-N-(6-
chlorobenzo[d]thiazol-2-yl)acetamide (10a). Dark
yellow solid, yield 72%, mp 245–246◦C; IR (KBr,
cm−1): 3312 (NH), 1671 (C O), 1653 (C N, benzoth-
iazole), 1632, 1526 (2C N, oxadiazole), 1440, 1248
( C S CH2), 1082 (Qui O CH2), 1047 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s,
1H, NH), 8.90 (d, J = 1.5 Hz, 1H, H-5, quinoline),
8.60 (d, J = 8.1 Hz, 1H, N CH , H-2, quinoline),
8.53 (dd, J = 6.4, 2.4 Hz, 1H), 8.41 (s, 1H, H-3,
quinoline), 8.29 (d, J = 7.5 Hz, 1H, H-8, quinoline),
8.23 (d, J = 1.8 Hz, 1H, H-7, benzothiazole), 8.13
(dd, J = 8.2, 2.0 Hz, 1H, H-7, quinoline), 7.87 (d,
J = 1.0 Hz, 1H, H-4, benzothiazole), 7.53 (dd, J =
7.7, 3.8 Hz, 1H, H-5, benzothiazole), 7.43–7.34
(m, 4H, Ar-H), 4.90 (s, 2H, O CH2), 4.16 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 174.00
(1C, C-2, oxadiazole), 170.43 (1C, CO), 166.23 (1C,
C-5, oxadiazole), 160.84 (1C, C-2, benzothiazole),
155.69, 151.04 (2C, C2 and C9, quinoline), 150.02
(1C, Qui.C O CH2), 147.94 (1C, C-2, thiophene
ring), 143.44–122.37 (19C, aromatic carbon atoms),
52.47 (1C, OCH2), 33.06 (1C, S CH2). Anal Calcd for
C29H18ClN5O3S3: C, 56.53; H, 2.94; N, 11.37. Found:
C, 56.66; H, 2.84; N, 11.25.
N-(6-Acetamidobenzo[d]thiazol-2-yl) -2-(5-((6-
(thiophen - 2 - yl)quinolin - 4 - yloxy)methyl) - 1 , 3 , 4 -
oxadiazol-2-ylthio)acetamide (9i). Yellowish white
solid, yield 65%, mp 222–224◦C; IR (KBr, cm−1): 3321
(NH), 1678 (C O), 1659 (C N, benzothiazole), 1639,
1531 (2C N, oxadiazole), 1435, 1244 ( C S CH2),
2-(5-((6-(Benzo[b]thiophen-2-yl)quinolin-4-
yloxy) methyl) - 1 , 3 , 4 - oxadiazol - 2 - ylthio) - N - (6 -
bromobenzo[d]thiazol-2-yl)acetamide (10b). Light
brown solid, yield 68%, mp 237–238◦C; IR (KBr,
cm−1): 3320 (NH), 1679 (C O), 1649 (C N, benzoth-
iazole), 1638, 1519 (2C N, oxadiazole), 1442, 1250
Heteroatom Chemistry DOI 10.1002/hc

10 Patel et al.
( C S CH2), 1075 (Qui O CH2), 1052 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.71 (s,
1H, NH), 8.82 (d, J = 1.7 Hz, 1H, H-5, quinoline),
8.64 (d, J = 8.3 Hz, 1H, N CH , H-2, quinoline),
8.55 (dd, J = 6.7, 2.1 Hz, 1H), 8.45 (s, 1H, H-3, quino-
line), 8.32 (d, J = 7.7 Hz, 1H, H-8, quinoline), 8.18
(d, J = 1.3 Hz, 1H, H-7, benzothiazole), 8.09 (dd, J =
8.6, 2.4 Hz, 1H, H-7, quinoline), 7.84 (d, J = 1.9 Hz,
1H, H-4, benzothiazole), 7.58 (dd, J = 8.1, 4.3 Hz,
1H, H-5, benzothiazole), 7.40–7.29 (m, 4H, Ar-H),
4.88 (s, 2H, O CH2), 4.12 (s, 2H, S CH2). 13C NMR
(100 MHz, DMSO-d6): δ 175.19 (1C, C-2, oxadiazole),
172.08 (1C, CO), 168.86 (1C, C-5, oxadiazole), 159.18
(1C, C-2, benzothiazole), 156.84, 153.96 (2C, C2 and
C9, quinoline), 151.63 (1C, Qui.C O CH2), 149.15
(1C, C-2, thiophene ring), 146.73–118.75 (19C, aro-
matic carbon atoms), 57.33 (1C, OCH2), 38.14 (1C,
S CH2). Anal Calcd for C29H18BrN5O3S3: C, 52.73; H,
2.75; N, 10.60. Found: C, 52.78; H, 2.56; N, 10.69.
1H, NH), 8.80 (d, J = 1.6 Hz, 1H, H-5, quinoline),
8.69 (d, J = 8.2 Hz, 1H, N CH , H-2, quinoline),
8.50 (dd, J = 6.3, 2.6 Hz, 1H), 8.36 (s, 1H, H-3,
quinoline), 8.35 (d, J = 7.8 Hz, 1H, H-8, quinoline),
8.19 (d, J = 1.3 Hz, 1H, H-7, benzothiazole), 8.10
(dd, J = 8.1, 2.5 Hz, 1H, H-7, quinoline), 7.83 (d,
J = 1.3 Hz, 1H, H-4, benzothiazole), 7.55 (dd, J =
7.7, 3.9 Hz, 1H, H-5, benzothiazole), 7.46–7.33
(m, 4H, Ar-H), 4.96 (s, 2H, O CH2), 4.19 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 174.05
(1C, C-2, oxadiazole), 170.12 (1C, CO), 167.74 (1C,
C-5, oxadiazole), 161.23 (1C, C-2, benzothiazole),
154.11, 153.42 (2C, C2 and C9, quinoline), 151.32
(1C, Qui.C O CH2), 148.12 (1C, C-2, thiophene
ring), 146.26–124.94 (19C, aromatic carbon atoms),
54.97 (1C, OCH2), 37.88 (1C, S CH2). Anal Calcd
for C29H18IN5O3S3: C, 49.23; H, 2.56; N, 9.90. Found:
C, 49.17; H, 2.64; N, 9.89.
2-(5-((6-(Benzo[b]thiophen-2-yl)quinolin-4-
yloxy ) methyl ) - 1 , 3 , 4 - oxadiazol - 2 - ylthio ) - N - ( 6 -
nitrobenzo[d]thiazol-2-yl)acetamide (10e). Khaki
solid, yield 71%, mp 293–295◦C; IR (KBr, cm−1):
3316 (NH), 1682 (C O), 1655 (C N, benzothia-
zole), 1642, 1530 (2C N, oxadiazole), 1438, 1247
( C S CH2), 1085 (Qui O CH2), 1053 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.73 (s,
1H, NH), 8.89 (d, J = 1.5 Hz, 1H, H-5, quinoline),
8.65 (d, J = 8.3 Hz, 1H, N CH , H-2, quinoline),
8.48 (dd, J = 6.7, 2.3 Hz, 1H), 8.41 (s, 1H, H-3,
quinoline), 8.28 (d, J = 7.5 Hz, 1H, H-8, quinoline),
8.17 (d, J = 1.1 Hz, 1H, H-7, benzothiazole), 8.04
(dd, J = 8.0, 2.6 Hz, 1H, H-7, quinoline), 7.89 (d,
J = 1.6 Hz, 1H, H-4, benzothiazole), 7.56 (dd, J =
8.2, 4.1 Hz, 1H, H-5, benzothiazole), 7.39–7.31
(m, 4H, Ar-H), 4.99 (s, 2H, O CH2), 4.09 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 173.20
(1C, C-2, oxadiazole), 170.86 (1C, CO), 165.85 (1C,
C-5, oxadiazole), 160.86 (1C, C-2, benzothiazole),
155.36, 151.33 (2C, C2 and C9, quinoline), 150.05
(1C, Qui.C O CH2), 147.89 (1C, C-2, thiophene
ring), 144.89–120.28 (19C, aromatic carbon atoms),
53.25 (1C, OCH2), 34.39 (1C, S CH2). Anal Calcd for
C29H18N6O5S3: C, 55.58; H, 2.90; N, 13.41. Found: C,
55.62; H, 2.99; N, 13.37.
2 - (5 - ((6 - (Benzo[b]thiophen - 2 - yl)quinolin - 4 -
yloxy)methyl) - 1 , 3 , 4 - oxadiazol - 2 - ylthio) - N - (6 -
fluorobenzo[d]thiazol-2-yl)acetamide
(10c). Pale
yellow solid, yield 60%, mp 255–256◦C; IR (KBr,
cm−1): 3318 (NH), 1675 (C O), 1657 (C N, benzoth-
iazole), 1639, 1522 (2C N, oxadiazole), 1437, 1254
( C S CH2), 1079 (Qui O CH2), 1058 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.74 (s,
1H, NH), 8.81 (d, J = 1.9 Hz, 1H, H-5, quinoline),
8.67 (d, J = 8.4 Hz, 1H, N CH , H-2, quinoline),
8.52 (dd, J = 6.5, 2.0 Hz, 1H), 8.40 (s, 1H, H-3,
quinoline), 8.30 (d, J = 7.3 Hz, 1H, H-8, quinoline),
8.22 (d, J = 1.7 Hz, 1H, H-7, benzothiazole), 8.07
(dd, J = 8.3, 2.2 Hz, 1H, H-7, quinoline), 7.88 (d,
J = 1.1 Hz, 1H, H-4, benzothiazole), 7.52 (dd, J =
8.0, 4.6 Hz, 1H, H-5, benzothiazole), 7.41–7.31
(m, 4H, Ar-H), 4.93 (s, 2H, O CH2), 4.15 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 172.95
(1C, C-2, oxadiazole), 169.34 (1C, CO), 163.12 (1C,
C-5, oxadiazole), 157.17 (1C, C-2, benzothiazole),
155.17, 152.65 (2C, C2 and C9, quinoline), 150.45
(1C, Qui.C O CH2), 147.90 (1C, C-2, thiophene
ring), 144.79–123.85 (19C, aromatic carbon atoms),
55.38 (1C, OCH2), 36.37 (1C, S CH2). Anal Calcd for
C29H18FN5O3S3: C, 58.08; H, 3.03; N, 11.68. Found:
C, 58.16; H, 3.14; N, 11.54.
2 - ( 5 - (( 6 - ( Benzo [b] thiophen - 2 - yl ) quinolin -
4-yloxy)methyl)-1,3,4-oxadiazol-2-ylthio)-N-(6-
2 - ( 5 - (( 6 - ( Benzo [b] thiophen - 2 - yl ) quinolin -
4-yloxy)methyl) -1,3,4-oxadiazol-2-ylthio)-N-(6-
iodobenzo[d]thiazol-2-yl)acetamide (10d). Yellow
solid, yield 64%, mp 281–282◦C; IR (KBr, cm−1):
3324 (NH), 1673 (C O), 1650 (C N, benzothia-
zole), 1640, 1529 (2C N, oxadiazole), 1446, 1255
( C S CH2), 1074 (Qui O CH2), 1060 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.72 (s,
cyanobenzo[d]thiazol-2-yl)acetamide
(10f). Dark
yellow solid, yield 57%, mp 261–263◦C; IR (KBr,
cm−1): 3310 (NH), 1675 (C O), 1653 (C N, benzoth-
iazole), 1635, 1524 (2C N, oxadiazole), 1440, 1256
( C S CH2), 1080 (Qui O CH2), 1056 (C O C,
oxadiazole). 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s,
1H, NH), 8.86 (d, J = 1.9 Hz, 1H, H-5, quinoline),
Heteroatom Chemistry DOI 10.1002/hc

Combination of Bioactive Moieties with Different Heteroatom(s): Application of the Suzuki Cross-Coupling Reaction 11
8.70 (d, J = 8.0 Hz, 1H, N CH , H-2, quinoline),
line), 8.64 (d, J = 8.5 Hz, 1H, N CH , H-2, quino-
line), 8.51 (dd, J = 6.5, 2.2 Hz, 1H), 8.39 (s, 1H, H-3,
quinoline), 8.33 (d, J = 7.4 Hz, 1H, H-8, quinoline),
8.20 (d, J = 2.0 Hz, 1H, H-7, benzothiazole), 8.06
(dd, J = 8.5, 2.2 Hz, 1H, H-7, quinoline), 7.82 (d,
J = 2.2 Hz, 1H, H-4, benzothiazole), 7.59 (dd, J =
8.4, 3.9 Hz, 1H, H-5, benzothiazole), 7.47–7.35 (m,
4H, Ar-H), 4.90 (s, 2H, O CH2), 4.17 (s, 2H, S CH2),
3.82 (q, J = 7.3 Hz, 2H, O CH2 CH3), 1.21 (t, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6): δ 173.16
(1C, C-2, oxadiazole), 170.78 (1C, CO), 164.24 (1C,
C-5, oxadiazole), 161.75 (1C, C-2, benzothiazole),
156.32, 152.76 (2C, C2 and C9, quinoline), 150.63 (1C,
Qui.C O CH2), 148.53 (1C, C-2, thiophene ring),
146.64–124.47 (19C, aromatic carbon atoms), 57.74,
56.27 (2C, 2OCH2), 37.96 (1C, S CH2), 22.78 (1C,
OCH2CH3). Anal Calcd for C31H23N5O4S3: C, 59.50;
H, 3.70; N, 11.19. Found: C, 59.38; H, 3.77; N, 11.09.
8.54 (dd, J = 6.5, 2.5 Hz, 1H), 8.43 (s, 1H, H-3,
quinoline), 8.30 (d, J = 7.2 Hz, 1H, H-8, quinoline),
8.19 (d, J = 1.6 Hz, 1H, H-7, benzothiazole), 8.01
(dd, J = 7.8, 2.2 Hz, 1H, H-7, quinoline), 7.91 (d,
J = 1.2 Hz, 1H, H-4, benzothiazole), 7.60 (dd, J =
8.5, 4.5 Hz, 1H, H-5, benzothiazole), 7.44–7.32
(m, 4H, Ar-H), 5.01 (s, 2H, O CH2), 4.14 (s, 2H,
S CH2). 13C NMR (100 MHz, DMSO-d6): δ 175.14
(1C, C-2, oxadiazole), 172.04 (1C, CO), 166.35 (1C,
C-5, oxadiazole), 157.23 (1C, C-2, benzothiazole),
156.74, 152.93 (2C, C2 and C9, quinoline), 150.53
(1C, Qui.C O CH2), 147.92 (1C, C-2, thiophene
ring), 143.25–117.47 (18C, aromatic carbon atoms),
106.52 (1C, C≡N), 96.28 (1C, C C N), 50.70
(1C, OCH2), 32.86 (1C, S CH2). Anal Calcd for
C30H18N6O3S3: C, 59.39; H, 2.99; N, 13.85. Found: C,
59.27; H, 2.91; N, 13.96.
2-(5-((6-(Benzo[b]thiophen-2-yl) quinolin-4-yloxy)
methyl)-1,3,4-oxadiazol-2-ylthio)-N-(6-methoxybenzo
[d]thiazol-2-yl)acetamide (10g). Brown solid, yield
66%, mp 277–279◦C; IR (KBr, cm−1): 3315 (NH),
1680 (C O), 1649 (C N, benzothiazole), 1637, 1520
(2C N, oxadiazole), 1442, 1246 ( C S CH2), 1082
(Qui O CH2), 1059 (C O C, oxadiazole). 1H NMR
(400 MHz, DMSO-d6): δ 9.72 (s, 1H, NH), 8.90 (d,
J = 2.2 Hz, 1H, H-5, quinoline), 8.66 (d, J = 8.1
Hz, 1H, N CH , H-2, quinoline), 8.56 (dd, J =
6.6, 2.5 Hz, 1H), 8.46 (s, 1H, H-3, quinoline), 8.32
(d, J = 7.7 Hz, 1H, H-8, quinoline), 8.22 (d, J = 1.8
Hz, 1H, H-7, benzothiazole), 7.99 (dd, J = 8.2, 2.7
Hz, 1H, H-7, quinoline), 7.85 (d, J = 1.5 Hz, 1H,
H-4, benzothiazole), 7.63 (dd, J = 8.1, 3.6 Hz, 1H,
H-5, benzothiazole), 7.46–7.33 (m, 4H, Ar-H), 4.93
(s, 2H, O CH2), 4.10 (s, 2H, S CH2), 3.76 (s, 3H,
OCH3). 13C NMR (100 MHz, DMSO-d6): δ 172.92
(1C, C-2, oxadiazole), 169.34 (1C, CO), 168.85 (1C,
C-5, oxadiazole), 159.56 (1C, C-2, benzothiazole),
154.66, 153.64 (2C, C2 and C9, quinoline), 151.15
(1C, Qui.C O CH2), 149.98 (1C, C-2, thiophene
ring), 145.94-121.29 (19C, aromatic carbon atoms),
58.52 (1C, OCH3), 52.16 (1C, OCH2), 35.52 (1C,
S CH2). Anal Calcd for C30H21N5O4S3: C, 58.90; H,
3.46; N, 11.45. Found: C, 58.95; H, 3.36; N, 11.39.
N-(6-Acetamidobenzo[d]thiazol-2-yl)-2-(5-((6-
(benzo[b]thiophen-2-yl)quinolin-4-yloxy)methyl)-1,
3,4-oxadiazol-2-ylthio)acetamide (10i). Off white
solid, yield 68%, mp 244–246◦C; IR (KBr, cm−1): 3325
(NH), 1676 (C O), 1656 (C N, benzothiazole), 1647,
1526 (2C N, oxadiazole), 1442, 1258 ( C S CH2),
1
1084 (Qui O CH2), 1058 (C O C, oxadiazole). H
NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H, NH), 9.08
(s, 1H, NH), 8.88 (d, J = 1.5 Hz, 1H, H-5, quinoline),
8.67 (d, J = 8.3 Hz, 1H, N CH , H-2, quinoline),
8.57 (dd, J = 6.6, 2.3 Hz, 1H), 8.37 (s, 1H, H-3, quino-
line), 8.35 (d, J = 7.6 Hz, 1H, H-8, quinoline), 8.21
(d, J = 2.4 Hz, 1H, H-7, benzothiazole), 8.03 (dd,
J = 8.8, 2.5 Hz, 1H, H-7, quinoline), 7.84 (d, J = 2.1
Hz, 1H, H-4, benzothiazole), 7.58 (dd, J = 8.5, 3.7
Hz, 1H, H-5, benzothiazole), 7.48–7.39 (m, 4H, Ar-
H), 4.93 (s, 2H, O CH2), 4.13 (s, 2H, S CH2), 1.77 (s,
3H, CH3). 13C NMR (100 MHz, DMSO-d6): δ 174.18
(1C, C-2, oxadiazole), 172.79 (1C, CO), 167.09 (1C,
CO), 165.22 (1C, C-5, oxadiazole), 160.79 (1C, C-2,
benzothiazole), 154.30, 153.70 (2C, C2 and C9, quino-
line), 151.67 (1C, Qui.C O CH2), 146.58 (1C, C-2,
thiophene ring), 145.60–122.46 (19C, aromatic car-
bon atoms), 55.72 (1C, OCH2), 39.94 (1C, S CH2),
21.97 (1C, CH3). Anal Calcd for C31H22N6O4S3: C,
58.29; H, 3.47; N, 13.16. Found: C, 58.36; H, 3.39;
N, 13.28.
2 - ( 5 - (( 6 - ( Benzo [b] thiophen - 2 - yl ) quinolin -
4-yloxy)methyl)-1,3,4-oxadiazol-2-ylthio)-N-(6-
ethoxybenzo[d]thiazol-2-yl)acetamide (10h). Dark
yellow solid, yield 54%, mp 291–293◦C; IR (KBr,
cm−1): 3322 (NH), 1673 (C O), 1653 (C N, benzoth-
iazole), 1643, 1528 (2C N, oxadiazole), 1445, 1250
( C S CH2), 1086 (Qui O CH2), 1050 (C O C,
Microbiology
Antimicrobial activity for the final analogues
was carried out as described by Clause [36]
with minor modifications against two Gram-
positive bacteria (S. aureus, Microbial Type Cul-
ture Collection (MTCC) 96; B. cereus, MTCC 430),
1
oxadiazole). H NMR (400 MHz, DMSO-d6): δ 9.74
(s, 1H, NH), 8.87 (d, J = 1.5 Hz, 1H, H-5, quino-
Heteroatom Chemistry DOI 10.1002/hc

12 Patel et al.
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SUPPORTING INFORMATION
Supporting Information related to the synthesis
and analytical characterization of intermediate com-
pounds and biological methods is available in the
online issue at wileyonlinelibrary.com.
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ACKNOWLEDGMENTS
The authors are thankful to Applied Chemistry De-
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Surat, India, for the scholarship, encouragement,
and facilities. The authors wish to offer their deep
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