Synthesis, Characterization, and Antimicrobial Screening of 4″-methyl-2,2″-diaryl-4,2′:4′,5″-terthiazole Derivatives

Article abstract of DOI:10.1002/jhet.3170

A series of novel 4″-methyl-2,2″-diaryl-4,2′:4′,5″-terthiazole (8a-p) derivatives has been synthesized and screened for antibacterial activity against four pathogenic bacteria, Escherichia coli, Pseudomonas flurescence, Staphylococcus aureus, and Bacillus subtilis. Among them, compounds 8a and 8j exhibited excellent antibacterial activity with minimum inhibitory concentration range of 1.0 to 5.3?μg/mL and compounds 8m and 8p exhibited moderate to good antibacterial activity with minimum inhibitory concentration range of 16.9 to 29.7?μg/mL against all tested strains. All the synthesized compounds were screened for their in vitro antifungal activity against Cocinida candida. Most of the compounds reported moderate antifungal activity. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antimicrobial agent.

Full text of DOI:10.1002/jhet.3170

Month 2018
Synthesis, Characterization, and Antimicrobial Screening of 4″-methyl-
2,2″-diaryl-4,20:40,5″-terthiazole Derivatives
a
b
Jitendra Nalawade, Pravin C. Mhaske,
Abhijit Shinde,b Sachin V. Patil,a Prafulla B. Choudhari,c and
*
a
*
Vivek D. Bobade
aPost-Graduate Department of Chemistry H. P. T. Arts and R. Y. K. Science College, Savitribai Phule Pune University,
Nashik 422005, India
bPost Graduate Department of Chemistry, S. P. Mandali’s Sir Parashurambhau College, Savitribai Phule Pune University,
Tilak Road, Pune 411 030, India
cComputational Chemistry Research Lab, Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of
Pharmacy, Near Chitranageri, Morewadi, Kolhapur 416013, India
*
E-mail: mhaskepc18@gmail.com; v_bobade31@rediffmail.com
Received November 6, 2017
DOI 10.1002/jhet.3170
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 4″-methyl-2,2″-diaryl-4,20:40,5″-terthiazole (8a-p) derivatives has been synthesized and
screened for antibacterial activity against four pathogenic bacteria, Escherichia coli, Pseudomonas
flurescence, Staphylococcus aureus, and Bacillus subtilis. Among them, compounds 8a and 8j exhibited ex-
cellent antibacterial activity with minimum inhibitory concentration range of 1.0 to 5.3 μg/mL and com-
pounds 8m and 8p exhibited moderate to good antibacterial activity with minimum inhibitory
concentration range of 16.9 to 29.7 μg/mL against all tested strains. All the synthesized compounds were
screened for their in vitro antifungal activity against Cocinida candida. Most of the compounds reported
moderate antifungal activity. This study provides valuable directions to our ongoing endeavor of rationally
designing more potent antimicrobial agent.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
antiviral, antibiotic, and antitumor drug isolated from the
bacterium Streptomyces verticillus, Cystothiazole
A
In the 20th century, a large number of antibiotic and
chemotherapeutic agents were developed for medicinal
use. Due to emerging infectious diseases and increase in
antibiotic resistant microbial pathogens, a need for new
classes of antimicrobial agents is obligatory. One of the
biggest challenges is the discovery of novel structures
with high potency for a specific target. These factors have
encouraged the search for new lead compounds that are
active against multidrug resistant pathogens [1–4].
The thiazole ring containing compounds exhibited a
wide spectrum of biological activities such as
antimicrobial [5–10], antitubercular [11–13], antiviral
[14], anti-inflammatory [15–18], anticonvulsant [19–21],
and anticancer [22,23] activities. Polyazoles containing
compounds are the backbone of bioactive natural
products and thiopeptide antibiotics. Recently, many
reports have been published on the biological activity of
bisthiazole derivatives [24–28]. A thiopeptide antibiotic,
antibiotic, inhibits fungi and human tumor cells [31], 20-
Alkyl/aryl-2-aryl-4-methyl-40,5-bithiazolyls showed anti-
inflammatory activity [27], aminoalkyl derivatives of
2,40-bithiazole-4-carboxylic acid were shown to exhibit
antitumor activity [32].
In our previous communication, 4,50-bisthiazole, 2,50-
bisthiazole, thiazole substituted thiosemicarbazideand
thiazolyl-oxazole derivatives were shown as potent
antitubercular and antibacterial agents [33–35].
Encouraged by the observed biological activities of the
various thiazole derivatives and as part of our ongoing
search for compounds as potential antimicrobial agents,
employing molecular simplification, the synthesis and
antimicrobial screening of uncommon 4″-methyl-2,2″-
diphenyl-4,20:40,5″-terthiazole derivatives is reported.
RESULTS AND DISCUSSION
urukthapelstatin A, isolated from
a
culture of
Thermoactinomycetaceae bacterium Mechercharimycesas
porophorigenensis an anticancer drug [29]. Bisthiazole
glycopeptides, commonly known as Bleomycin [30], is
Chemistry.
The synthetic strategy adopted for the
synthesis of title compounds 8a–p is depicted in
Scheme 1. The syntheses of compounds 1a–d to 7a–d
© 2018 Wiley Periodicals, Inc.

J. Nalawade, P. C. Mhaske, A. Shinde, S. V. Patil, P. B. Choudhari, and V. D. Bobade
Vol 000
Scheme 1. Synthetic route of compounds 8a–p.
are reported in our previous papers. [33–36] Ethyl 2-
arylthiazole-4-carboxylate, 1a–d on reduction of
carboethoxy group followed by selective oxidation using
iodoxy benzoic acid furnished 2-arylthiazole-4-
carbaldehyde 2a–d. Aldehyde 2a–d on reaction with
iodine and ammonia in tetrahydrofuran gave 2-
arylthiazole-4-carbonitrile 3a–d. Carbonitrile 3a–d
on reaction with H2S and catalytic amount of
triethylamine in pyridine yielded 2-arylthiazole-4-
carbothioamide 4a–d. 1-(4-Methyl-2-phenylthiazol-5-yl)
ethanone (6a–d) on reaction with bromine in acetic acid
gave 2-bromo-1-(4-methyl-2-phenylthiazol-5-yl)ethanone,
7a–d. Carbothioamide 4a–d on cyclocondensation
with 2-bromo-1-(4-methyl-2-phenylthiazol-5-yl)ethanone,
Table 1
Antibacterial activity, MIC90 in μg/mL of compounds 8a–p.
Comp
R
R1
Escherichia coli
Pseudomonas flurescence
Staphylococcus aureus
Bacillus subtilis
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
4-F
4-F
4-F
4-F
4-CH3
4-CH3
4-CH3
4-CH3
H
4-Cl
4-F
4-CH3
H
4-Cl
4-F
4-CH3
H
4-Cl
4-F
4-CH3
H
4-Cl
4-F
2.2
and
>30
>30
nd
1.4
nd
>30
>30
nd
2.9
nd
>30
>30
nd
>30
>30
>30
>30
2.3
>30
>30
24.2
>30
>30
19.6
1.0
5.3
nd
>30
>30
nd
>30
>30
>30
>30
1.0
>30
>30
20.2
>30
>30
16.9
1.46
1.62
>30
>30
>30
>30
1.5
>30
>30
26.7
>30
>30
25.8
4.36
0.49
>30
>30
>30
>30
3.2
>30
>30
29.7
>30
>30
23.6
10.32
1.35
4-CH3
Ampicillin
Kanamycin
>30
and, Not determined.
The activity of active compounds are highlighted in bold.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
4″-Methyl-2,2″-diaryl-4,20:40,5″-terthiazole Derivatives, Synthesis,
Antimicrobial Activity
7a–d
afforded
4″-methyl-2,2″-diphenyl-4,20:40,5″-
dependent effect with serial dilution of compounds in
terthiazole, 8a–p.
DMSO. The result of minimum inhibitory concentration
(MIC) is shown in Table 1.
The in vitro antifungal activity of all the synthesized
compounds was done by the disc diffusion method [40]
against the Candida albicans (NCIM 3100). Fluconazole
serves as positive control for antifungal activity.
The in vitro antibacterial activity results revealed that,
most of the compounds showed moderate to good
activity against E. coli, P. flurescence, S. aureus and
B. subtilis. Among the synthesized compounds 8a–p, the
compounds 8a and 8j exhibited excellent activity with
MIC in the range 1.0 to 5.3 μg/mL. The preliminary
structure activity relationship study revealed that
substitution at 4 or 40 position of phenyl by Chloro,
Fluoro, or methyl group affects the antibacterial activity
(Fig. 1).
From structure activity relationship, it was noted that,
compounds 8a–d, with R═H and R1═H/Cl/F/CH3
substituted phenyl ring B, compound 8a (R1═H),
reported excellent activity (MIC 1.4 to 5.3 μg/mL)
The structure of the synthesized compounds, 8a–p was
confirmed by IR, NMR, and MS. As a representative
analysis of compound 8e, the 1H NMR spectrum of
compound 8e showed a singlet in aliphatic region at δ
2.72, for methyl group of thiazole ring. Two singlets in
aromatic region at δ 7.47 and 8.00 integrated for one
proton each corresponds to thiazole C─H. Five aromatic
protons of one phenyl ring resonated between δ 7.38
and 7.45 as multiplet, while four aromatic protons for
the second phenyl ring appeared at δ 7.90 and 8.00 as a
set of two doublets. The 13C NMR spectrum of
compound 8e revealed a signal at δ 16.93, which
corresponds to thiazole-CH3, whereas, the aromatic and
thiazole carbons appeared between δ 115.87 and 167.29.
The structure of compound 8e was further confirmed by
high-resolution mass spectrometry (HRMS) that showed
molecular ion peak at m/z: 452.0112 (M + H)+, m/z:
+
473.9933 (M + Na) .
Antibacterial activity evaluation.
The antibacterial
activity [37–39] of synthesized compounds was
determined against the standard Gram-positive bacteria,
Staphylococcus aureus (NCIM 2602), Bacillus subtilis
(NCIM 2162) and Gram-negative bacteria, Escherichia
coli (NCIM 2576), Pseudomonas flurescence (NCIM
2059). Ampicillin and Kanamycin served as positive
control for antibacterial activity. The in vitro preliminary
screening values (% inhibition) against microorganisms
tested are summarized in Tables S1. Compounds that
showed more than 90% inhibition (Table S1) at
30 μg/mL were confirmed by carrying out dose-
against
all
Gram-positive
and
Gram-negative
bacterial strains whereas, upon substitution at C-4 by
Cl or F or CH3, the activity decreases. Among the
compounds 8e–h with R = 4-Cl and substituted phenyl
ring B, all the compounds showed moderate activity.
Compounds 8i–l with R = 4-F, and substituted phenyl
ring B, compound 8j (R1 = 4-Cl) reported excellent
activity (MIC 1.0 to 3.2 μg/mL) compared with
standard drug ampicillin, against all tested strains.
Among the compounds 8m–p with R = 4-CH3, and
substituted phenyl ring B, compounds 8m (R1═H) and
8p (R1 = 4-CH3) showed moderate to good activity
against all strains.
From the antifungal activity result (Table 2), it was
noticed that most of the synthesized compounds showed
moderate activity against C. albicans.
It was noteworthy to mention that unsubstituted phenyl
rings A and B or 4-fluoro substituent on phenyl ring A
and 4-chloro on phenyl ring B enhances the antibacterial
activity.
Figure 1. Compounds 8a–p.
Table 2
Antifungal screening of synthesized compounds 8a–p (zone of inhibition in mm).
Comp.
Candida albicans
Comp.
Candida albicans
Comp.
Candida albicans
Comp.
Candida albicans
8a
8b
8c
8d
8
9
10
—
8e
8f
8g
8h
8
9
—
9
8i
8j
8k
8l
7
—
10
10
8m
8n
8o
9
9
12
11
8p
Fluconazole 17
Fluconazole (25 μg/disc) were used as reference; synthesized compounds (100 μg/disc).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Nalawade, P. C. Mhaske, A. Shinde, S. V. Patil, P. B. Choudhari, and V. D. Bobade
Vol 000
CONCLUSIONS
2-(4-Fluorophenyl)thiazole-4-carbonitrile (3c). 1H NMR
(500 MHz, CDCl3): δ 7.17 (t, J = 8.5 Hz, 2H, Ar─H),
7.93–7.97 (m, 2H, Ar─H), 8.63 (s, 1H, Thiazole-H);
LCMS: m/z = 205.1 (M + H)+.
In conclusion, a series of new 4″-methyl-2,2″-diphenyl-
4,20:40,5″-terthiazole (8a–p) derivatives have been
synthesized and screened for antimicrobial activity.
From these results, it is concluded that 4-methyl-2-
phenyl-5-(2-(2-phenylthiazol-4-yl)thiazol-4-yl)thiazole
(8a) 2-(4-chlorophenyl)-5-(2-(2-(4-fluorophenyl)thiazol-4-
yl)thiazol-4-yl)-4-methylthiazole (8j) displayed excellent
antibacterial activity against all tested strains. However,
the antifungal results were not very encouraging. Thus,
these results warrant the need for synthesis of similar
libraries with other substituent’s to ascertain the trend
described in this work.
2-(p-Tolyl)thiazole-4-carbonitrile
(3d).
1H NMR
(500 MHz, CDCl3): δ 2.42 (s, 3H, Ar─CH3), 7.28 (d,
J = 8.0 Hz, 2H, Ar─H), 7.85 (d, J = 8.1 Hz, 2H,
Ar─H), 7.93 (s, 1H, Thiazole-H); LCMS: m/z = 200.9
(M + H)+.
General
procedure
for
synthesis
of
4-methyl-2-phenylthiazole-5-carbothioamide (4a–d).
In a
solution
of
4-methyl-2-phenylthiazole-5-carbonitrile
(7.5 mmol), triethyl amine (2 mL) in pyridine (15 mL),
H2S gas was for 2 h at room temperature. After
completion of the reaction (TLC), the reaction mixture
was quenched in ice cold water and neutralized by dilute
HCl. The product was filtered and washed with water and
dried in air afforded thioamide, (yield 80%).
EXPERIMENTAL
2-Phenylthiazole-4-carbothioamide (4a).
1H NMR
Chemistry. Melting points of synthesized compounds
were determined in capillary tubes in silicon oil bath
(500 MHz, CDCl3): δ 7.33–7.36 (m, 3H, Ar─H), 7.74 (s,
1H, NH), 7.91 (d, J = 8.4 Hz, 2H, Ar─H), 8.42 (s, 1H,
Thiazole-H), 8.75 (s, 1H, NH); LCMS: m/z = 221.0
(M + H)+.
using
a Veego melting point apparatus and are
uncorrected. All the reactions were monitored by thin
layer chromatography (TLC). TLC was performed on
2-(4-Chlorophenyl)thiazole-4-carbothioamide (4b).
1H
1
Merck 60 F-254 silica gel plates. H NMR and 13C NMR
NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 2H,
Ar─H), 7.76 (s, 1H, NH), 7.88 (d, J = 8.4 Hz, 2H,
Ar─H), 8.45 (s, 1H, Thiazole-H), 8.74 (s, 1H, NH);
LCMS: m/z = 254.8 (M + H)+.
spectra were recorded on Varian mercury XL-300 and
Bruker at either 400/500 MHz (1H NMR) and
100/126 MHz (13C NMR), spectrometer instruments.
2-(4-Fluorophenyl)thiazole-4-carbothioamide (4c).
1H
Chemical
shifts
are
reported
from
internal
tetramethylsilane standard and are given in δ units.
HRMS spectra were recorded on Bruker Compass Data
Analysis 4.2. The chemicals and solvents used were
laboratory grade and were purified as per literature
methods.
NMR (500 MHz, CDCl3) δ 7.16 (t, J = 8.6 Hz, 2H,
Ar─H), 7.71 (s, 1H, NH), 7.94 (dd, J = 8.7, 5.2 Hz, 2H,
Ar─H), 8.44 (s, 1H, Thiazole-H), 8.74 (s, 1H, NH);
LCMS: m/z = 238.8 (M + H)+.
2-(p-Tolyl)thiazole-4-carbothioamide (4d).
1H NMR
(500 MHz, CDCl3) δ 2.41 (s, 3H, Ar─CH3), 7.26 (d, 2H,
J = 8.1 Hz, Ar─H), 7.72 (s, 1H, NH), 7.82 (d,
J = 8.1 Hz, 2H, Ar─H), 8.41 (s, 1H, Thiazole-H), 8.79
(s, 1H, NH); LCMS: m/z = 235.7 (M + H)+.
General
procedure
for
synthesis
of
a
4-methyl-2-phenylthiazole-5-carbonitrile (3a–d).
To
solution of 4-methyl-2-phenylthiazol-5-carbaldehyde
(2.0 gm, 9.8 mmol) in tetrahydofuran (15 mL) and
ammonia (20 mL), iodine (3.73 gm, 29.4 mmol) was
added and reaction mixture was stirred at ambient temp
for 6 h. The progress of reaction was monitored by TLC.
After the completion of the reaction, the reaction mixture
was extracted with ethyl acetate (30 mL × 3), the organic
layer was washed with water, dried (Na2CO3), solvent
removed under vacuum to give 4-methyl-2-
phenylthiazole-5-carbonitrile, (yield 78%). The nitrile
was used further without purification.
General procedure for synthesis of 1-(4-methyl-2-
phenylthiazol-5-yl)ethanone (6a–d).
A
mixture of
benzothioamide (10 mmol) and 3-bromopentane-2,4-
dione (10 mmol) in absolute ethanol was refluxed for 2 h.
After completion of the reaction (TLC), solvent was
distilled under vacuum. The residue was dissolved in
sodium bicarbonate solution (30 mL) and stirred for
10 min. The aqueous layer was extracted with ethyl
acetate (3 × 25 mL) and combined organic layer was
washed with water, dried over sodium sulphate, and
distilled under vacuum. The product was purified by
column chromatography using ethyl acetate:hexane (2:8)
2-Phenylthiazole-4-carbonitrile
(500 MHz, CDCl3): δ 7.32–7.35 (m, 3H, Ar─H), 7.87 (d,
(3a).
1H
NMR
J = 8.4 Hz, 2H, Ar─H), 7.94 (s, 1H, Thiazole-H);
LCMS: m/z = 187.0 (M + H)+.
as elute.
2-(4-Chlorophenyl)thiazole-4-carbonitrile (3b). 1H NMR
(500 MHz, CDCl3): δ 7.46 (d, J = 8.5 Hz, 2H, Ar─H),
1-(4-Methyl-2-phenylthiazol-5-yl)ethanone (6a). 1H NMR
(500 MHz, CDCl3): δ 2.50 (s, 3H, Thiazole-CH3), 2.71 (s,
3H, COCH3), 7.43–7.35 (m, 3H, Ar─H), 7.92–7.88 (m,
2H, Ar─H); 13C NMR (126 MHz, CDCl3): δ 18.49 (CH3,
7.90 (d, J = 8.5 Hz, 2H, Ar─H), 7.99 (s, 1H, Thiazole-
H); LCMS: m/z = 221.0 (M + H)+.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
4″-Methyl-2,2″-diaryl-4,20:40,5″-terthiazole Derivatives, Synthesis,
Antimicrobial Activity
Thiazole-CH3), 30.80 (CH3, CO─CH3), 126.90 (CH,
Ar─C-4), 129.10 (CH, Ar─C-3, C-5), 131.20 (CH,
Ar─C-2, C-6), 131.27 (C, Ar─C-1), 132.79 (C, Thiazole-
C-5), 159.52 (C, Thiazole-C-4), 169.44 (C, Thiazole-C-
2), 190.55 (C, C═O).
Thiazole-C-5), 132.47 (C, Ar─C-1), 162.39 (C, Thiazole-
C-4), 170.47 (C, Thiazole-C-2), 184.11 (C, C═O).
2-Bromo-1-(2-(4-chlorophenyl)-4-methylthiazol-5-yl)
ethanone (7b). 1H NMR (500 MHz, CDCl3): δ 2.73 (s, 3H,
Thiazole-CH3), 4.21 (s, 2H, COCH2─Br), 7.38 (d,
J = 8.6 Hz, 2H, Ar─H), 7.86 (d, J = 8.6 Hz, 2H, Ar─H);
13C NMR (126 MHz, CDCl3): δ 18.64 (CH3, Thiazole-
CH3), 33.74 (CH2, COCH2─Br), 127.34 (C, Ar─C-1),
128.27 (CH, Ar─C-3, C-5), 129.48 (CH, Ar─C-2, C-6),
130.97 (C, Thiazole-C-5), 137.73 (C, Ar─C-4), 162.44 (C,
1-(2-(4-Chlorophenyl)-4-methylthiazol-5-yl)ethanone(6b).
1H NMR (500 MHz, CDCl3): δ 2.57 (s, 3H, Thiazole-
CH3),2.78 (s, 3H, COCH3), 7.43 (d, J = 8.7 Hz, 2H,
Ar─H), 7.91 (d, J = 8.7 Hz, 2H, Ar─H); 13C NMR
(126 MHz, CDCl3): δ 18.45 (CH3, Thiazole-CH3), 30.78
(CH3, CO─CH3), 128.09 (CH, Ar─C-3, C-5), 129.37
(CH, Ar─C-2, C-6), 131.29 (C, Ar─C-1), 131.58 (C,
Thiazole-C-5), 137.28 (C, Ar─C-4), 159.56 (C, Thiazole-
C-4), 168.00 (C, Thiazole-C-2), 190.46 (C, C═O).
1-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)ethanone (6c).
1H NMR (500 MHz, CDCl3): δ 2.49 (s, 3H, Thiazole-
CH3), 2.70 (s, 3H, COCH3), 7.07 (t, J = 8.6 Hz, 2H,
Ar─H), 7.89 (dd, J = 8.9, 5.3 Hz, 2H, Ar─H); 13C NMR
(126 MHz, CDCl3): δ 18.44 (CH3, Thiazole-CH3), 30.75
(CH3, CO─CH3), 116.18 and 116.35 (CH, Ar─C-3, C-5),
128.92 and 128.99 (CH, Ar─C-2, C-6), 129.16 and
129.18 (C, Ar─C-1), 131.41 (C, Thiazole-C-5), 159.48
(C, Thiazole-C-4), 163.54 and 165.55 (C, Ar─C-4),
168.18 (C, Thiazole-C-2), 190.47 (C, C═O).
Thiazole-C-4), 169.00 (C, Thiazole-C-2), 184.09 (C, C═O).
2-Bromo-1-(2-(4-fluorophenyl)-4-methylthiazol-5-yl)
ethanone (7c). 1H NMR (500 MHz, CDCl3) δ 2.72 (s, 3H,
Thiazole-CH3), 4.20 (s, 2H, COCH2─Br), 7.08 (t,
J = 8.6 Hz, 2H, Ar─H), 7.92 (dd, J = 8.9, 5.2 Hz, 2H,
Ar─H); 13C NMR (126 MHz, CDCl3): δ 18.64 (CH3,
Thiazole-CH3), 33.78 (CH2, COCH2─Br), 116.33 and
116.50 (CH, Ar─C-2, C-6), 127.17 (C, Thiazole-C-5),
128.85 and 128.88 (C, Ar─C-1), 129.16 and 129.23 (CH,
Ar─C-2, C-6), 162.40 (C, Thiazole-C-4), 163.77 and
165.78 (C, Ar─C-4), 169.17 (C, Thiazole-C-2),
184.08(C, C═O).
2-Bromo-1-(4-methyl-2-(p-tolyl)thiazol-5-yl)ethanone
(7d).
1H NMR (500 MHz, CDCl3): δ 2.34 (s, 3H,
Ar─CH3), 2.73 (s, 3H, Thiazole-CH3), 4.20 (s, 2H,
COCH2─Br), 7.19 (d, J = 7.9 Hz, 2H, Ar─H), 7.81 (d,
J = 7.9 Hz, 2H, Ar─H); 13C NMR (126 MHz, CDCl3): δ
18.68 (CH3, Thiazole-CH3), 21.61 (CH3, Ar─CH3),
33.95 (CH2, COCH2─Br), 126.86 (C, Ar─C-1), 127.04
(CH, Ar─C-2, C-6), 129.80 (C, Thiazole-C-5), 129.89
(CH, Ar─C-3, C-5), 142.27 (C, Ar─C-4), 162.43(C,
Thiazole-C-4), 170.74 (C, Thiazole-C-2), 184.06(C,
C═O).
1-(4-Methyl-2-(p-tolyl)thiazol-5-yl)ethanone (6d).
1H
NMR (500 MHz, CDCl3): δ 2.33 (s, 3H, Thiazole-CH3),
2.49 (s, 3H, Ar─CH3), 2.70 (s, 3H, COCH3), 7.19–7.16
(m, 2H, Ar─H), 7.79 (d, J = 8.2 Hz, 2H, Ar─H); 13C
NMR (126 MHz, CDCl3): δ 18.49 (CH3, Thiazole-CH3),
21.54 (CH3, Ar─CH3), 30.79 (CH3, CO─CH3), 126.85
(CH, Ar─C-3, C-5), 129.79 (CH, Ar─C-2, C-6), 130.16
(C, Ar─C-1), 130.82 (C, Thiazole-C-5), 141.76 (C,
Ar─C-4), 159.50 (C, Thiazole-C-4), 169.72(C, Thiazole-
C-2), 190.56(C, C═O).
General
procedure
for
synthesis
of
To
4″-methyl-2,2″-diphenyl-4,20:40,5″-terthiazole, (8a–p).
a solution of 4-methyl-2-phenylthiazol-5-carbothiomide
(0.85 mmol) in 8 mL ethanol, 2-bromo-1-(4-methyl-2-(4-
substituted phenyl)thiazol-5yl)ethanone (0.71 mmol)
was added and reaction mixture was reflux for 2 h.
After completion of reaction (TLC), the solid
product was obtained. The product was filtered and
washed with ethanol, dried in air afforded 4″-methyl-
2,2″-diphenyl-4,20:40,5″-terthiazole. Yield 65%, mp: 158–
160°C. Compounds 8a–p were synthesized by the similar
General procedure for synthesis of 2-bromo-1-(4-methyl-2-
(4-substituted phenyl)thiazol-5-yl)ethanone (7a–d).
A
mixture of 1-(4-methyl-2-phenylthiazol-5-yl)ethanone
(10 mmol) and pTSA (5 mmol) in dichloromethane
(DCM) (50 mL) was stirred at 0°C for 10 min. Bromine
(10 mmol) in DCM (20 mL) was then added dropwise to
the reaction mixture and was further stirred for 12 h at
room temperature. After completion of the reaction,
sodium bicarbonate solution was added in reaction
mixture and stirred for 10 min. The aqueous layer was
extracted with DCM, and combined organic layer was
washed with water, dried over sodium sulphate, and
distilled under vacuum.
2-Bromo-1-(4-methyl-2-phenylthiazol-5-yl)ethanone (7a).
1H NMR (500 MHz, CDCl3): δ 2.82 (s, 3H, Thiazole-
CH3), 4.30 (s, 2H, COCH2─Br), 7.50 (m, 3H, Ar─H),
8.00 (dd, J = 8.1, 1.4 Hz, 2H, Ar─H); 13C NMR
(126 MHz, CDCl3): δ 18.67 (CH3, Thiazole-CH3), 33.92
(CH2, COCH2─Br), 126.91 (C, Ar─C-4), 127.08 (CH,
Ar─C-3, C-5), 129.20 (CH, Ar─C-2, C-6), 131.60 (C,
method.
4″-Methyl-2,2″-diphenyl-4,20:40,5″-terthiazole (8a).
Yield: 72%, mp: 136–138°C; 1H NMR (500 MHz,
DMSO-d6): δ 2.70 (s, 3H, Thiazole-CH3), 7.46–7.52 (m,
6H, Ar─H), 7.79 (s, 1H, Thiazole-H), 7.93–8.00 (s, 4H,
Ar─H), 8.23 (s, 1H, Thiazole-H); 13C NMR (126 MHz,
DMSO-d6): δ 17.72 (CH3, Thiazole-C-5″-CH3), 116.62
(CH, Thiazole-C-50), 117.78 (CH, Thiazole-C-5), 126.29
(CH, Ar─C-3, C-5), 126.72 (CH, Ar─C-30,C-50), 127.19
(C, Thiazole-C-5″), 129.43 (CH, Ar─C-2, C-6), 129.54
(CH, Ar─C-20, C-60), 130.39 (CH, Ar─C-4), 131.05
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Nalawade, P. C. Mhaske, A. Shinde, S. V. Patil, P. B. Choudhari, and V. D. Bobade
Vol 000
(CH, Ar─C-40), 132.73 (C, Ar─C-1), 133.49 (C, Ar─C-10),
147.79 (C, Thiazole-C-40), 149.24 (C, Thiazole-C-4),
150.13 (C, Thiazole-C-4″), 162.16 (C, Thiazole-C-20),
164.30 (C, Thiazole-C-2), 168.57 (C, Thiazole-C-2″);
Thiazole-C-2), 168.66 (C, Thiazole-C-2″); HRMS m/z:
432.0665 (M + H)+, m/z: 454.0481 (M + Na)+.
2-(4-Chlorophenyl)-4″-methyl-2″-phenyl-4,20:40,5″-
1
terthiazole (8e). Yield: 72%, mp: 212–214°C; H NMR
HRMS m/z: 418.0508 (M + H)+, m/z: 440.0329 (M + Na)+.
(500 MHz, CDCl3): δ 2.72 (s, 3H, Thiazole-CH3), 7.38–
7.45 (m, 5H, Ar─H), 7.47 (s, 1H, Thiazole-H), 7.90 (d,
J = 8.1 Hz, 2H, Ar─H), 7.94 (d, J = 8.7 Hz, 2H, Ar─H),
8.00 (s, 1H, Thiazole-H); 13C NMR (126 MHz, CDCl3):
2″-(4-Chlorophenyl)-4″-methyl-2-phenyl-4,20:40,5″-
1
terthiazole (8b). Yield: 72%, mp: 158–160°C; H NMR
(500 MHz, CDCl3): δ 2.77 (s, 3H, Thiazole-CH3), 7.42
(s, 1H, Thiazole-H), 7.44 (d, J = 8.6 Hz, 2H, Ar─H),
7.50–7.52 (m, 3H, Ar─H), 7.93 (d, J = 8.6 Hz, 2H,
Ar─H), 8.03–8.08 (m, 3H, Thiazole-H and Ar─H); 13C
NMR (126 MHz, CDCl3): δ 17.47 (CH3, Thiazole-C-5″-
CH3), 115.87 (CH, Thiazole-C-50), 116.80 (CH, Thiazole-
C-5), 126.57 (CH, Ar─C-3, C-5), 127.48 (C, Thiazole-C-
5″), 127.55 (CH, Ar─C-20, C-60), 129.07 (CH, Ar─C-30,
C-50), 129.18 (CH, Ar─C-2, C-6), 130.62 (CH, Ar─C-4),
132.18 (C, Ar─C-10), 132.93 (C, Ar─C-1), 135.84
(C, Ar─C-40), 148.17 (C, Thiazole-C-40), 149.69 (C,
Thiazole-C-4), 150.22 (C, Thiazole-C-4″), 162.54 (C,
Thiazole-C-20), 163.77 (C, Thiazole-C-2), 168.76
(C, Thiazole-C-2″); HRMS m/z: 452.0112 (M + H)+, m/z:
δ
16.93 (CH3, Thiazole-C-5″-CH3), 115.87 (CH,
Thiazole-C-50), 116.80 (CH, Thiazole-C-5), 126.57 (CH,
Ar─C-2, C-6), 127.48 (C, Thiazole-C-5″), 127.89 (CH,
Ar─C-30, C-50), 129.16 (CH, Ar─C-3, C-5), 129.27 (CH,
Ar─C-20, C-60), 130.76 (CH, Ar─C-40), 131.30 (C,
Ar─C-1), 132.13 (C, Ar─C-10), 136.44 (C, Ar─C-4),
147.41 (C, Thiazole-C-40), 148.46 (C, Thiazole-C-4),
149.54 (C, Thiazole-C-4″), 162.29 (C, Thiazole-C-20),
165.38 (C, Thiazole-C-2), 167.29 (C, Thiazole-C-2″);
HRMS m/z: 452.0112 (M + H)+, m/z: 473.9933 (M + Na)+.
2,2″-Bis(4-chlorophenyl)-4″-methyl-4,20:40,5″-terthiazole
1
(8f). Yield: 72%, mp: 216–218°C; H NMR (500 MHz,
DMSO-d6): δ 2.70 (s, 3H, Thiazole-CH3), 7.38 (d,
J = 8.6 Hz, 2H, Ar─H), 7.44 (d, J = 8.6 Hz, 2H, Ar─H),
7.47 (s, 1H, Thiazole-H), 7.90 (d, J = 8.6 Hz, 2H,
Ar─H), 7.94 (d, J = 8.6 Hz, 2H, Ar─H), 8.04 (s, 1H,
Thiazole-H); 13C NMR (126 MHz, DMSO-d6): δ 17.30
(CH3, Thiazole-C-5″-CH3), 115.68 (CH, Thiazole-C-50),
116.65 (CH, Thiazole-C-5), 126.60 (CH, Ar─C-2, C-6),
127.52 (C, Thiazole-C-5″), 127.69 (CH, Ar─C-20, C-60),
129.27 (CH, Ar─C-3, C-5), 130.76 (CH, Ar─C-30, C-50),
131.30 (C, Ar─C-1), 132.13 (C, Ar─C-10), 135.85 (C,
Ar─C-4), 136.44 (C, Ar─C-40), 147.45 (C, Thiazole-C-
40), 148.54 (C, Thiazole-C-4), 149.89 (C, Thiazole-C-4″),
162.30 (C, Thiazole-C-20), 165.40 (C, Thiazole-C-2),
168.50 (C, Thiazole-C-2″); HRMS m/z: 485.9721
473.9933 (M + Na)+.
2″-(4-Fluorophenyl)-4″-methyl-2-phenyl-4,20:40,5″-
1
terthiazole (8c). Yield: 72%, mp: 136–138°C; H NMR
(500 MHz, CDCl3): δ 2.78 (s, 3H, Thiazole-CH3), 7.16
(t, J = 8.7 Hz, 2H, Ar─H), 7.41 (s, 1H, Thiazole-H),
7.50–7.52 (m, 3H, Ar─H), 8.00 (dd, J = 7.9, 1.6 Hz, 2H,
Ar─H), 8.04–8.06 (m, 2H, Ar─H), 8.07 (s, 1H, Thiazole-
H); 13C NMR (126 MHz, CDCl3): δ 17.42 (CH3,
Thiazole-C-5″-CH3), 115.08 (CH, Thiazole-C-50), 115.96
and 116.13 (CH, Ar─C-30, C-50), 116.25 (CH, Thiazole-
C-5), 126.72 (CH, Ar─C-3, C-5), 127.19 (C, Thiazole-C-
5″), 128.27 and 128.34 (CH, Ar─C-20, C-60), 129.07
(CH, Ar─C-2, C-6), 132.05 (C, Ar─C-10), 130.62 (CH,
Ar─C-4), 132.94 (C, Ar─C-1), 148.21 (C, Thiazole-C-
40), 149.71 (C, Thiazole-C-4), 149.71 (C, Thiazole-C-4″),
162.53 54 (C, Thiazole-C-20), 164.03 (C, Thiazole-C-2),
162.87 and 164.86 (C, Ar─C-40), 168.76 (C, Thiazole-C-
2″); HRMS m/z: 436.0407 (M + H)+, m/z: 458.0227
(M + H)+, m/z: 507.9545 (M + Na)+.
2-(4-Chlorophenyl)-2″-(4-fluorophenyl)-4″-methyl-
4,20:40,5″-terthiazole (8g).
Yield: 72%, mp: 212–214°C;
1H NMR (500 MHz, CDCl3): δ 2.68 (s, 3H, Thiazole-
CH3), 7.19 (m, 2H, Ar─H), 7.49 (d, J = 8.0 Hz, 2H,
Ar─H), 7.70 (s, 1H, Thiazole-H), 7.92–7.98 (m, 4H,
Ar─H), 8.18 (s, 1H, Thiazole-H); 13C NMR (126 MHz,
CDCl3): δ 17.59 (CH3, Thiazole-C-5″-CH3), 116.33 (CH,
Thiazole-C-50), 116.23 and 116.41 (CH, Ar─C-30, C-50),
117.75 (CH, Thiazole-C-5), 127.21 (C, Thiazole-C-5″),
128.18 (CH, Ar─C-2, C-6), 128.35 and 128.42 (CH,
Ar─C-20, C-60), 129.55 (CH, Ar─C-3, C-5), 130.03 and
130.05 (C, Ar─C-10), 131.43 (C, Ar─C-1), 136.01 (C,
Ar─C-4), 147.81 (C, Thiazole-C-40), 149.39 (C,
Thiazole-C-4), 150.06 (C, Thiazole-C-4″), 161.97 (C,
Thiazole-C-20), 163.18 (C, Thiazole-C-2), 162.65 and
(M + Na)+.
4″-Methyl-2-phenyl-2″-(p-tolyl)-4,20:40,5″-terthiazole
(8d). Yield: 72%, mp: 192–194°C; 1H NMR (500 MHz,
DMSO-d6): δ 2.44 (s, 3H, Ar─CH3), 2.92 (s, 3H, Thiazole-
CH3), 7.34 (d, J = 8.6 Hz, 2H, Ar─H), 7.48 (s, 1H,
Thiazole-H), 7.50–7.52 (m, 3H, Ar─H), 8.04–8.07 (m,
4H, Ar─H), 8.09 (s, 1H, Thiazole-H); 13C NMR
(126 MHz, DMSO-d6): δ 16.17 (CH3, Thiazole-C-
5″-CH3), 21.72 (CH3, Ar─CH3), 116.66 (CH, Thiazole-
C-50), 117.21 (CH, Thiazole-C-5), 126.65 (CH, Ar─C-20,
C-60), 126.78 (CH, Ar─C-3, C-5), 127.30 (C, Thiazole-
C-5″), 128.99 (CH, Ar─C-30, C-50), 129.21 (CH, Ar─C-
2, C-6), 129.99 (CH, Ar─C-4), 130.71 (C, Ar─C-10),
132.82 (C, Ar─C-1), 140.10 (C, Ar─C-40), 147.62 (C,
Thiazole-C-40), 149.16 (C, Thiazole-C-4), 150.12
(C, Thiazole-C-4″), 163.01 (C, Thiazole-C-20), 166.65 (C,
164.63 (C, Ar─C-40), 167.21 (C, Thiazole-C-2″); HRMS
m/z: 470.0018 (M + H)+, m/z: 491.9839 (M + Na)+.
2-(4-Chlorophenyl)-4″-methyl-2″-(p-tolyl)-4,20:40,5″-
1
terthiazole (8h). Yield: 72%, mp: 218–220°C; H NMR
(500 MHz, DMSO-d6): δ 2.39 (s, 3H, Ar─CH3), 2.69 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
4″-Methyl-2,2″-diaryl-4,20:40,5″-terthiazole Derivatives, Synthesis,
Antimicrobial Activity
3H, Thiazole-CH3), 7.32 (d, J = 8.0 Hz, 2H, Ar─H), 7.47
(d, J = 7.5 Hz, 2H, Ar─H), 7.78 (s, 1H, Thiazole-H),
7.89 (d, J = 8.0 Hz, 2H, Ar─H), 7.93 (d, J = 7.5 Hz, 2H,
Ar─H), 8.18 (s, 1H, Thiazole-H); 13C NMR (126 MHz,
DMSO-d6): δ 17.64 (CH3, Thiazole-C-5″-CH3), 21.50
(CH3, Ar─CH3), 116.50 (CH, Thiazole-C-50), 117.21
(CH, Thiazole-C-5), 126.30 (CH, Ar─C-20, C-60), 126.66
(CH, Ar─C-2, C-6), 127.28 (C, Thiazole-C-5″), 129.47
(CH, Ar─C-3, C-5), 129.85 (CH, Ar─C-30, C-50), 130.10
(C, Ar─C-1), 130.45 (C, Ar─C-10), 133.42 (C, Ar─C-4),
141.09 (C, Ar─C-40), 147.73 (C, Thiazole-C-40), 149.09
(C, Thiazole-C-4), 150.03 (C, Thiazole-C-4″), 162.23 (C,
Thiazole-C-2), 164.33 (CH, Ar─C-40), 168.50 (C,
Thiazole-C-2″); HRMS m/z: 466.0270 (M + H)+, m/z:
1H, Thiazole-H); 13C NMR (126 MHz, DMSO-d6): δ
17.66 (CH3, Thiazole-C-5″-CH3), 116.26 (CH, Thiazole-
C-50), 116.31 and 116.49 (CH, Ar─C-3, C-5), 116.49 and
116.67 (CH, Ar─C-30, C-50), 117.66 (CH, Thiazole-C-5),
127.25 (C, Thiazole-C-5″), 128.41 and 128.48 (CH,
Ar─C-2, C-6), 128.94 and 129.01 (CH, Ar─C-20, C-60),
129.29 and 129.31 (C, Ar─C-1), 130.04 and 130.07 (C,
Ar─C-10), 147.74 (C, Thiazole-C-40), 149.23 (C,
Thiazole-C-4), 150.09 (C, Thiazole-C-4″), 162.07
(C, Thiazole-C-20), 163.15 (C, Thiazole-C-2), 162.66 and
164.64 (C, Ar─C-40), 163.03 and 165.01 (C, Ar─C-4),
167.39 (C, Thiazole-C-2″); HRMS m/z: 454.0320
(M + H)+, m/z: 476.0142 (M + Na)+.
2-(4-Fluorophenyl)-4″-methyl-2″-(p-tolyl)-4,20:40,5″-
1
terthiazole (8l).
Yield: 72%, mp: 192–194°C; H NMR
488.0086 (M + Na).+
2-(4-Fluorophenyl)-4″-methyl-2″-phenyl-4,20:40,5″-
(500 MHz, CDCl3): δ 2.37 (s, 3H, Ar─CH3), 2.69 (s, 3H,
Thiazole-CH3), 7.28 (d, J = 8.0 Hz, 2H, Ar─H), 7.32
(t, J = 8.8 Hz, 2H, Ar─H), 7.83 (d, J = 8.0 Hz, 2H, Ar─H),
7.84 (s, 1H, Thiazole-H), 8.05 (dd, J = 8.8, 5.3 Hz, 2H,
Ar─H), 8.25 (s, 1H, Thiazole-H); 13C NMR
(126 MHz, CDCl3): δ 17.68 (CH3, Thiazole-C-5″-CH3),
21.46 (CH3, Ar─CH3), 116.56 (CH, Thiazole-C-50), 116.60
and 116.78 (CH, Ar─C-3, C-5), 117.98 (CH, Thiazole-C-
5), 126.27 (CH, Ar─C-20, C-60), 126.64 (C, Thiazole-C-5″),
129.02 and 129.09 (CH, Ar─C-2, C-6), 129.33 (C, Ar─C-
1), 130.05 (CH, Ar─C-30, C-50), 130.83 (C, Ar─C-10),
140.39 (C, Ar─C-40), 147.83 (C, Thiazole-C-40), 149.16
(C, Thiazole-C-4), 150.38 (C, Thiazole-C-4″), 162.03 (C,
Thiazole-C-20), 163.02 and 165.01 (C, Ar─C-4), 164.49 (C,
Thiazole-C-2), 167.42 (C, Thiazole-C-2″); HRMS m/z:
1
terthiazole (8i). Yield: 72%, mp: 250°C (dec.); H NMR
(500 MHz, CDCl3): δ 2.78 (s, 3H, Thiazole-CH3), 7.16
(t, J = 8.7 Hz, 2H, Ar─H), 7.41 (s, 1H, Thiazole-H),
7.52–7.49 (m, 3H, Ar─H), 7.99 (dd, J = 8.7, 5.1 Hz, 2H,
Ar─H), 8.06 (m, 3H, Thiazole-H and Ar─H); 13C NMR
(126 MHz, CDCl3): δ 17.67 (CH3, Thiazole-C-5″-CH3),
116.57 and 116.75 (CH, Ar─C-3, C-5), 116.75 (CH,
Thiazole-C-50), 117.94 (CH, Thiazole-C-5), 126.33 (CH,
Ar─C-30, C-50), 127.22 (C, Thiazole-C-5″), 129.00 and
129.07 (CH, Ar─C-2, C-6), 129.30 and 129.33 (C,
Ar─C-1), 129.46 (CH, Ar─C-20, C-60), 130.50 (CH,
Ar─C-40), 133.35 (C, Ar─C-10), 147.70 (C, Thiazole-C-
40), 149.15 (C, Thiazole-C-4), 150.01 (C, Thiazole-C-4″),
162.08 (C, Thiazole-C-20), 163.02 and 165.01 (C, Ar─C-
4), 164.34 (C, Thiazole-C-2), 167.42 (C, Thiazole-C-2″);
450.0571 (M + H)+, m/z: 472.0393 (M + Na)+.
4″-Methyl-2″-phenyl-2-(p-tolyl)-4,20:40,5″-terthiazole
HRMS m/z: 436.0411 (M + H)+, m/z: 458.0227 (M + Na)+.
2″-(4-Chlorophenyl)-2-(4-fluorophenyl)-4″-methyl-
(8m). Yield: 72%, mp: 190–192°C; 1H NMR (500 MHz,
CDCl3): δ 2.39 (s, 3H, Ar─CH3), 2.69 (s, 3H, Thiazole-
CH3), 7.30 (d, J = 7.9 Hz, 2H, Ar─H), 7.45–7.49 (m,
3H, Ar─H), 7.77 (s, 1H, Thiazole-H), 7.88 (d,
J = 8.1 Hz, 2H, Ar─H), 7.90–7.95 (m, 2H, Ar─H), 8.16
(s, 1H, Thiazole-H); 13C NMR (126 MHz, CDCl3): δ
17.67 (CH3, Thiazole-C-5″-CH3), 21.53 (CH3, Ar─C-4-
CH3), 116.58 (CH, Thiazole-C-50), 117.20 (CH, Thiazole-
C-5), 126.64 (CH, Ar─C-2,C-6), 127.68 (C, Thiazole-C-
5″), 127.78 (CH, Ar─C-30, C-50), 129.45 (CH, Ar─C-3,
C-5), 130.07 (CH, Ar─C-20, C-60), 130.15 (CH, Ar─C-
40), 131.49 (C, Ar─C-1), 135.02 (C, Ar─C-10), 140.07
(C, Ar─C-4), 147.64 (C, Thiazole-C-40), 149.11 (C,
Thiazole-C-4), 150.23 (C, Thiazole-C-4″), 162.92
(C, Thiazole-C-20), 164.28 (C, Thiazole-C-2), 168.66 (C,
Thiazole-C-2″); HRMS m/z: 432.0665 (M + H)+, m/z:
4,20:40,5″-terthiazole (8j). Yield: 72%, mp: 204–204°C; 1H
NMR (500 MHz, DMSO-d6): δ 2.78 (s, 3H, Thiazole-
CH3), 7.20 (t, J = 8.6 Hz, 2H, Ar─H), 7.42 (s, 1H,
Thiazole-H), 7.44 (d, J = 8.0 Hz, 2H, Ar─H), 7.92–7.96
(m, 2H, Ar─H), 8.02–8.07 (m, 3H, Thiazole-H and
Ar─H); 13C NMR (126 MHz, DMSO-d6): δ 17.39 (CH3,
Thiazole-C-5″-CH3), 115.24 (CH, Thiazole-C-50), 116.11
and 116.29 (CH, Ar─C-3, C-5), 116.23 (CH, Thiazole-C-
5), 127.53 (C, Thiazole-C-5″), 127.61 (CH, Ar─C-20, C-
60), 128.67 and 128.73 (CH, Ar─C-2, C-6), 129.22 (CH,
Ar─C-30, C-50), 129.88 (C, Ar─C-10), 131.92 (C, Ar─C-
1), 136.01 (C, Ar─C-40), 148.10 (C, Thiazole-C-40),
149.68 (C, Thiazole-C-4), 149.99 (C, Thiazole-C-4″),
162.41 (C, Thiazole-C-20), 163.21 and 163.20 (C, Ar─C-
4), 163.88 (C, Thiazole-C-2), 167.54 (C, Thiazole-C-2″);
HRMS m/z: 470.0018 (M + H)+, m/z: 491.9839 (M + Na)+.
454.0481 (M + Na)+.
2,2″-Bis(4-fluorophenyl)-4″-methyl-4,20:40,5″-terthiazole
2″-(4-Chlorophenyl)-4″-methyl-2-(p-tolyl)-4,20:40,5″-
(8k). Yield: 72%, mp: 138–140°C; 1H NMR (500 MHz,
DMSO-d6): δ 2.68 (s, 3H, Thiazole-CH3), 7.22 (t,
J = 8.6 Hz, 2H, Ar─H), 7.28 (t, J = 8.6 Hz, 2H, Ar─H),
7.77 (s, 1H, Thiazole-H), 7.96 (dd, J = 8.2, 5.6 Hz, 2H,
Ar─H), 8.03 (dd, J = 8.3, 5.4 Hz, 2H, Ar─H), 8.20 (s,
terthiazole (8n). Yield: 72%, mp >240°C (dec.); 1H NMR
(500 MHz, DMSO-d6): δ 2.38 (s, 3H, Ar─CH3), 2.70 (s,
3H, Thiazole-CH3), 7.31 (d, J = 8.0 Hz, 2H, Ar─H), 7.46
(d, J = 7.5 Hz, 2H, Ar─H), 7.80 (s, 1H, Thiazole-H),
7.88 (d, J = 8.0 Hz, 2H, Ar─H), 7.93 (d, J = 7.5 Hz, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Nalawade, P. C. Mhaske, A. Shinde, S. V. Patil, P. B. Choudhari, and V. D. Bobade
Vol 000
Ar─H), 8.19 (s, 1H, Thiazole-H); 13C NMR (126 MHz,
DMSO-d6): δ 17.68 (CH3, Thiazole-C-5″-CH3), 21.52
(CH3, Ar─C-4─CH3), 116.55 (CH, Thiazole-C-50), 117.24
(CH, Thiazole-C-5), 126.31 (CH, Ar─C-2, C-6), 126.65
(CH, Ar─C-30, C-50), 127.24 (C, Thiazole-C-5″), 129.41
(CH, Ar─C-20, C-60), 130.11 (CH, Ar─C-3, C-5), 130.13
(C, Ar─C-10), 130.43 (C, Ar─C-1), 133.42 (C, Ar─C-40),
141.09 (C, Ar─C-4), 147.73 (C, Thiazole-C-40), 149.09
(C, Thiazole-C-4), 150.03 (C, Thiazole-C-4″), 162.23 (C,
Thiazole-C-20), 164.32 (C, Thiazole-C-2), 168.71 (C,
Thiazole-C-2″); HRMS m/z: 466.0270 (M + H)+, m/z:
488.0086 (M + Na+)+.
bacterial strains E. coli (NCIM 2576), P. flurescence
(NCIM 2059) and Gram-positive bacterial strains
S. aureus (NCIM 2602) and B. subtilis (NCIM 2162)
were obtained from NCIM (NCL, Pune) and were grown
in Luria-Bertani medium from Hi Media, India. The assay
was performed in 96-well plates after 8 and 12 h for Gram-
negative and Gram-positive bacteria, respectively [38–40].
A total of 0.1% of 1 O.D. culture at 620 nm was used for
screening inoculated culture was added into each well of
96-well plates containing the compounds to be tested. Op-
tical density for each plate was measured at 620 nm after
8 h for Gram-negative bacteria and after 12 h for Gram-
positive bacteria.
2″-(4-Fluorophenyl)-4″-methyl-2-(p-tolyl)
ꢀ
+4,20:40,5″-
1
terthiazole (8o). Yield: 72%, mp: 174–176°C; H NMR
(500 MHz, DMSO-d6) δ 2.45 (s, 3H, Ar─CH3), 2.77 (s,
3H, Thiazole-CH3), 7.16 (t, J = 8.6 Hz, 2H, Ar─H), 7.31
(d, J = 7.9 Hz, 2H, Ar─H), 7.40 (s, 1H, Thiazole-H), 7.95
(d, J = 7.9 Hz, 2H, Ar─H), 7.97–8.00 (m, 2H, Ar─H),
8.03 (s, 1H, Thiazole-H); 13C NMR (126 MHz,
DMSO-d6) δ: 17.44 (CH3, Thiazole-C-5″-CH3), 21.51
(CH3, Ar─C-4-CH3), 114.99 (CH, Thiazole-C-50), 115.81
(CH, Thiazole-C-5), 115.94 and 116.11 (CH, Ar─C-30, C-
50), 126.64 (CH, Ar─C-2, C-6), 127.21 (C, Thiazole-C-
5″), 128.24 and 128.30 (CH, Ar─C-20, C-60), 129.73 (CH,
Ar─C-3, C-5), 130.07 (C, Ar─C-10), 130.33 (C, Ar─C-1),
140.97 (C, Ar─C-4), 148.21 (C, Thiazole-C-40), 149.55
(C, Thiazole-C-4), 150.07 (C, Thiazole-C-4″), 162.61 (C,
Thiazole-C-20), 162.84 and 164.83 (C, Ar─C-40), 163.97
(C, Thiazole-C-2), 168.93 (C, Thiazole-C-2″); HRMS m/z:
450.0572 (M + H)+, m/z: 472.0394 (M + Na)+.
ANTIFUNGAL ACTIVITY
The in vitro antifungal activity of all the synthesized
compounds was done by the disc diffusion method [40]
against the C. albicans (NCIM 3100) obtained from
National Chemical Laboratory Pune, India. A standard disc
containing Fluconazole (25 μg/disc) was used as positive
control. The plates were left for 30 min at room tempera-
ture to allow the diffusion of synthesized compounds and
then incubated at 37°C for 24 h. The antifungal activity
was evaluated by measuring the zone of inhibition against
the test microorganism. All experiments were carried in
triplicates.
4″-Methyl-2,2″-di-p-tolyl-4,20:40,5″-terthiazole (8p).
Acknowledgments. P. C. M. would like to thank University
Grant Commission (UGC No. 42-355(SR)/2013), New Delhi,
India for the financial assistance and CSIR-NCL, Pune for
supporting biological activity. Central Analysis facility, Savitribai
Phule Pune University, Pune is also acknowledged for spectral
analysis.
Yield: 72%, mp: 194–196°C; 1H NMR (500 MHz,
DMSO-d6): δ 2.38 (s, 3H, Ar─CH3), 2.68 (s, 3H,
Ar─CH3), 2.70 (s, 3H, Thiazole-CH3), 7.30–7.45 (m, 4H,
Ar─H), 7.78 (s, 1H, Thiazole-H), 7.86–7.94 (m, 4H,
Ar─H), 8.19 (s, 1H, Thiazole-H); 13C NMR (126 MHz,
DMSO-d6): δ 17.62 (CH3, Thiazole-C-5″-CH3), 21.42
(CH3, Ar─CH3), 21.52 (CH3, Ar─CH3), 116.54 (CH,
Thiazole-C-50), 117.22 (CH, Thiazole-C-5), 126.35 (CH,
Ar─C-2, C-6), 126.70 (CH, Ar─C-20, C-60), 127.28 (C,
Thiazole-C-5″), 129.50 (CH, Ar─C-3, C-5), 130.20 (CH,
Ar─C-30, C-50), 130.40 (C, Ar─C-1), 133.46 (C, Ar─C-
10), 140.08 (C, Ar─C-4), 141.1 (C, Ar─C-40), 147.72 (C,
Thiazole-C-40), 149.10 (C, Thiazole-C-4), 150.06 (C,
Thiazole-C-4″), 162.22 (C, Thiazole-C-20), 164.34
(C, Thiazole-C-2), 168.68 (C, Thiazole-C-2″); HRMS m/
z: 446.0815 (M + H)+, m/z: 468.0630 (M + Na)+.
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SUPPORTING INFORMATION
Additional Supporting Information may be found online
in the supporting information tab for this article.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet