Synthesis and antibacterial activity of hydroxylated 2-arylbenzothiazole derivatives

Article abstract of DOI:10.1080/00397911.2020.1791342

N-acyliminium reagents formed in situ from benzothiazole and alkyl chloroformates react with hydroxyarenes in a Friedel-Crafts manner, providing access to 2-(hydroxyaryl)-benzothiazolines with antibacterial properties.

Full text of DOI:10.1080/00397911.2020.1791342

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis and antibacterial activity of
hydroxylated 2-arylbenzothiazole derivatives
Yordan Stremski , Desislava Kirkova , Stela Statkova-Abeghe , Plamen
Angelov , Iliyan Ivanov & Danail Georgiev
To cite this article: Yordan Stremski , Desislava Kirkova , Stela Statkova-Abeghe ,
Plamen Angelov , Iliyan Ivanov & Danail Georgiev (2020): Synthesis and antibacterial
activity of hydroxylated 2-arylbenzothiazole derivatives, Synthetic Communications, DOI:
10.1080/00397911.2020.1791342
To link to this article: https://doi.org/10.1080/00397911.2020.1791342
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https://doi.org/10.1080/00397911.2020.1791342
Synthesis and antibacterial activity of hydroxylated
2-arylbenzothiazole derivatives
Yordan Stremskia , Desislava Kirkovaa,b , Stela Statkova-Abeghea
Plamen Angelova , Iliyan Ivanova , and Danail Georgievc
,
b
aDepartment of Organic Chemistry, University of Plovdiv “Paisii Hilendarski”, Plovdiv, Bulgaria; Tobacco
and Tobacco Products Institute, Chemistry of Tobacco and Tobacco Smoke, Markovo, Plovdiv, Bulgaria;
cDepartment of Biochemistry and Microbiology, University of Plovdiv “Paisii Hilendarski”,
Plovdiv, Bulgaria
ABSTRACT
ARTICLE HISTORY
Received 7 April 2020
N-acyliminium reagents formed in situ from benzothiazole and alkyl
chloroformates react with hydroxyarenes in a Friedel-Crafts manner,
providing access to 2-(hydroxyaryl)-benzothiazolines with antibacter-
ial properties.
KEYWORDS
2-arylbenzothiazoles;
phenols; naphthols;
amidoalkylation;
GRAPHICAL ABSTRACT
antibacterial activity
Introduction
The 2-arylbenzothiazole moiety is present in many biologically active compounds and
medicines.[1] Hydroxylated 2-phenylbenzothiazoles in particular are interesting as cyto-
toxic agents[2] and calcium antagonists.[3] In recent years their successful application as
CN-sensors,[4] photosensitizers,[5] immunomodulators,[6] b-glucuronidase inhibitors[7]
and DNA binders[8] has also been reported. The most common use of 2-hydroxyphenyl
(or naphthyl) benzothiazoles is as fluorescent probes[9–19] due to their excited-state
intramolecular proton transfer (ESIPT) based emission possibility and large Stokes
shifts. Because of this wide spectrum of possible applications, 2-substituted benzothia-
zoles have attracted considerable attention from the synthetic community.[20] The
mainly employed method for the preparation of 2-arylbenzothiazoles is based on the
cyclocondensation of o-aminothiophenol with aromatic aldehydes[21–23] or carboxylic
acids.[24] Other approaches involve cyclization reactions of bis-(2-benzalaminophenyl)di-
sulfides,[25,26] thiophenolic schiff bases[27] or thiobenzanilides.[28] This heterocyclic
CONTACT Yordan Stremski
stremski@uni-plovdiv.net, stab@uni-plovdiv.bg
Department of Organic Chemistry,
University of Plovdiv “Paisii Hilendarski”, 24 Tsar Asen Str, 4000 Plovdiv, Bulgaria.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
Y. STREMSKI ET AL.
system has also been accessed via reactions of o-chloronitrobenzenes or o-iodoanilines
with various cyclization agents[29–31] and arylmethyl thiols with o-substituted amines.[32]
Less popular synthetic routes include annulation of anilines with ethers,[33] azolylation
of heteroarenes[34] and hydroxylation of heteroaryl halides.[35] Methods of direct aryla-
tion of benzothiazole[36,37] and cross-coupling of heteroaryl thiols with arylzinc
reagents[38] have also been investigated.
Although the variety of known reactions leading to 2-substituted benzothiazoles is sig-
nificant, many of them are limited with regard to functional group tolerance and/or avail-
ability of reagents and catalysts. Such limitations are particularly relevant to the synthesis
of hydroxylated 2-arylbenzothiazoles, and for this reason we chose to investigate an
approach for alkylative coupling of the benzothiazole ring to the aromatic rings of various
phenols and naphthols. This approach relies on the initial conversion of the thiazole ring
to a N-acyliminium species, which is sufficiently electrophilic to further react in a
Friedel-Crafts manner with activated aromatic nucleophiles. Combined with a subsequent
oxidative rearomatization, this approach has previously been very useful to us in the syn-
thesis 2-heteroaryl substituted thiazoles, such as the natural product Camalexin and
related analogues.[39,40] Additional interest in the hydroxyarene-coupled benzothiazoles is
based on analogy with some antibacterial and cytotoxic compounds.[41,42]
Results and discussion
The N-acyliminim reagents 2 were prepared simply by adding methyl or ethyl chloro-
formate to a solution of benzothiazole in acetonitrile and were used immediately in
reactions with activated aromatic substrates. We studied the reactivity of 2 toward five
different phenols – phenol, pyrocatechol, pyrogallol, resorcinol and hydroquinone
(Scheme 1, Table 1). In the initial experiments all hydroxyarenes were successfully ami-
doalkylated in the aromatic ring for 1 to 6 h at reflux temperature, but in nearly all
cases except for phenol these conditions led to formation of positional isomers and
overalkylation. The best yields of mono amidoalkylated products 3 were obtained when
the N-acyliminium agent was taken in twofold excess and the reaction mixtures were
allowed to stand at 20 ꢀC for two to three days (3a–d, 3i–j) or at 0 ꢀC for 3 to 5 h
(3e–h). Under these conditions only pyrogallol gave minor amount (10%) of dialky-
lated products.
The amidoalkylation was also tried with a set of three naphthols (Table 2). Here the
reactions proceeded better with no excess of the N-acyliminium reagent. The
Scheme 1. Amidoalkylative coupling of benzothiazole and hydroxyarenes. Reagents and conditions:
(i) 1–1.5 equiv. R1OCOCl in CH3CN; (ii) Hydroxyarene. See Table 1 for temperature and duration.

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SYNTHETIC COMMUNICATIONSV
3
Table 1. Products obtained from the corresponding phenols according to Scheme 1.
3
R1
R2
R3
R4
R5
T (j‘)
Time (h)
Yield (%)
a
b
c
d
e
f
g
h
i
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
H
H
H
H
ŽH
ŽH
ŽH
ŽH
ŽH
ŽH
H
H
ŽH
ŽH
ŽH
ŽH
H
H
H
H
OH
OH
OH
OH
ŽH
ŽH
ŽH
ŽH
H
H
H
H
H
H
H
H
H
ŽH
ŽH
20
20
20
20
0
0
0
0
20
20
80
80
80
80
5
5
3
3
50
50
83
75
94
91
60
68
52
65
75
55
j
H
Table 2. Products obtained from the corresponding naphthols and acyliminium reagents 2 in
acetonitrile at 20 ꢀC.
Product
R1
Time (h)
Yield (%)
4a
4b
Me
Et
50
50
60
40
5a
5b
Me
Et
80
80
97
80
6a
6b
Me
Et
24
24
72
53
amidoalkylated products 4a, b–6a, b were obtained in 40ꢁ97% yield at 20 ꢀC, with reac-
tion durations indicated in Table 2.
After the successful amidoalkylative coupling of benzothiazole with hydroxyaryl sub-
strates, we experimented with oxidative rearomatization of the benzothiazoline ring in
the obtained products 326. In the 2-(hydroxyphenyl) series 3 these experiments led to
complex mixtures of oxidized products and failed to provide access to the desired ben-
zothiazole derivatives. An exception was the pair 3a, b – both compounds were cleanly
converted to the known[23,35] product 7 upon oxidation with o-chloranil at 20 ꢀC in
acetonitrile (Scheme 2).
In the 2-(hydroxynaphthyl) series 426, under the same conditions, only the oxidation
of beta-naphthol derivatives 5a, b proceeded cleanly and with good yields. However, the
spectral characteristics of the obtained products 8 indicated that their structure is of
quinone methide type rather than aromatic (Scheme 3).
The newly synthesized benzothiazoline derivatives 327 were screened for antibacter-
ial activity against two Gram-positive strains (Staphylococcus aureus ATCC 6538 P and
Bacillus licheniformis ATCC 14580) and one Gram-negative strain (Escherichia coli
ATCC 8739), using the hole plate method in Mueller-Hinton agar with 100 mL loading
of 1 mg/mL solutions in DMSO-Water (1:1 vol.). Inhibition of bacterial growth was

4
Y. STREMSKI ET AL.
Scheme 2. Oxidative rearomatization of 3a, b to 7. Reagents and conditions: (i) o-chloranil,
acetonitrile, 20 ꢀC, 2 h.
Scheme 3. Oxidation of beta-naphthol derivatives 5a, b. Reagents and conditions: (i) o-chloranil,
acetonitrile, 20 ꢀC, 2 h.
Table 3. Antibacterial activity of the obtained benzothiazole derivatives 3–7.
S. aureus ATCC 6538P
B. licheniformis ATCC 14580
Inhibition zone (mm)a MIC (mg/mL)b
Compound
Inhibition zone (mm)a
MIC (mg/mL)b
3a
3b
3c
3d
3e
3f
3g
3h
3i
19
13
19
20
17
16
19
16
16
14
15
14
13
13
15
0.0063
0.0125
0.0063
0.0063
0.0063
0.0032
0.0063
0.0016
0.0016
0.0063
0.0063
0.0125
0.0032
0.0016
0.0063
–
–
–
–
17
19
15
14
15
15
16
15
12
–
0.0125
0.0032
0.0063
0.0500
0.0016
0.0250
0.0008
0.0016
0.0125
–
3j
4b
5a
5b
6b
7
–
–
–
–
–
–
aAssessed by the hole-plate method with 100 mL loading of 1 mg/mL solutions in 1:1 DMSO-Water.
bAmpicillin was used as a positive control with MIC ¼ 0.0004 mg/mL against both strains.
observed only for the Gram-positive strains. Minimal inhibitory concentrations (MIC)
were determined for all active compounds with Ampicillin as positive control (Table 3).
The selectivity of the tested compounds toward Gram-positive bacteria along with the
low MICs observed for some of them (notably the hydroquinone derivative 3i) provide
a good lead for further structure optimization.
A screening was also done against Candida albicans and Saccharomyces serevisiae, but
only three compounds (3a, 3b and 4b) showed weak activity against these yeasts.

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SYNTHETIC COMMUNICATIONSV
5
Experimental
General information
All solvents and reagents, such as benzothiazole, phenols, naphthols and alkyl chlorofor-
mates were purchased from Sigma-Aldrich or Merck and were used without further
purification. Melting points were measured on a Boetius PHMKO5 hot stage apparatus
and are uncorrected. IR spectra were measured on VERTEX 70 FT-IR spectrometer
1
(Bruker Optics, Germany). H-, 13C-NMR spectra were measured on Bruker Avance
AV600 or DRX250 spectrometers and chemical shifts (d, ppm) are downfield from TMS.
The NMR spectra of the amidoalkylated hydroxyaryl derivatives, both phenyl and naph-
thyl, indicated slow rotameric interconversions with broad coalescent signals at 20 ꢀC,
which is most likely due to the presence of tertiary carbamate group. Adequate assign-
ment of peaks and structure determination in most cases became possible only when the
spectra were measured at 80 ꢀC in DMSO-d6, as indicated in the text below. TLC was
done on precoated 0.2 mm Merck silica gel 60 plates. Silica gel or neutral alumina were
used for column chromatography. Mass spectral measurements were performed on a
Thermo Scientific Q Exactive hybrid quadrupole-orbitrap mass spectrometer.
Synthesis of amidoalkylated phenols (3), general procedure
The corresponding alkyl chloroformate (2 mmol) was added dropwise to a magnetically
stirred solution of benzothiazole (0.270 g, 2 mmol, 0.22 mL) in acetonitrile (10 mL), fol-
lowed immediately by the corresponding phenol (1 mmol). The stirring was then con-
tinued under the conditions indicated in Table 1. After that, the solvent was evaporated
under reduced pressure, the residue was dissolved in dichloromethane (40 mL) and
washed twice with water. The organic layer was dried (Na2SO4) and the crude mixture
was dry-loaded onto silica gel. The products were isolated by column chromatography
on silica gel with mixtures of petrol/diethyl ether as the eluent.
Synthesis of amidoalkylated naphthols (4, 5 and 6), general procedure
The corresponding alkyl chloroformate (1.2 mmol) was added dropwise to a magnetic-
ally stirred solution of benzothiazole (0.135 g, 1 mmol, 0.11 mL) in acetonitrile (7 mL),
followed immediately by the corresponding naphthol (1 mmol). The stirring was then
continued at 20 ꢀC for the time indicated in Table 2. The solvent was evaporated under
reduced pressure and the crude mixture was dry-loaded onto silica gel. The products
were isolated by column chromatography on silica gel with mixtures of petrol/diethyl
ether as the eluent.
Oxidation of the amidoalkylated phenols. Synthesis of compounds 7 and 8, gen-
eral procedure
To the corresponding compound 3 or 5 (0.5 mmol) in acetonitrile (7 mL) was added
j-chloranil (0.5 mmol, 0.123 g). The reaction mixture was stirred for 2 h at 20 ꢀC and
the solvent was then removed under reduced pressure dry loading the crude mixture
onto silica gel. The products were isolated by silica gel column chromatography with
petrol – diethyl ether as the eluent.

6
Y. STREMSKI ET AL.
4-(benzo[d]thiazol-2-yl)phenol 7: The spectral and melting point data for this
compound coincided with the literature.[23,35]
Conclusions
We have demonstrated that the N-acyliminium reagents formed in situ from benzothia-
zole and alkyl chloroformates react with hydroxyarenes in a Friedel-Crafts manner,
providing access to 2-(hydroxyaryl)-benzothiazoline derivatives. Although the attempts
for oxidative rearomatization of the obtained benzothiazolines have been only partly
successful, these compounds have shown encouraging antibacterial properties.
1
Full experimental details, characterization data and copies of H, 13C-NMR spectra
for synthesized compounds can be found via the “Supplementary content” section.
Acknowledgement
The authors are grateful to the Faculty of Biology, Department of Plant Physiology and
Molecular Biology and Dr. Mladen Naydenov for carrying out high resolution mass spectral
measurements on equipment provided under the EC FP7/REGPOT-2009-1/BioSupport project.
Funding
This research was funded by the Bulgarian National Science Fund [Grant DN09/15-2016] and
the University of Plovdiv [Grant MU19-HF-012]. Yordan Stremski and Desislava Kirkova thank
the Ministry of Education and Science for financial support under National Program “Young
Scientists and Postdoctoral Researchers” [PMC 577/2018].
ORCID
Yordan Stremski
Desislava Kirkova
http://orcid.org/0000-0001-8665-3130
http://orcid.org/0000-0001-5394-0109
Stela Statkova-Abeghe
http://orcid.org/0000-0002-3833-6779
Plamen Angelov
Iliyan Ivanov
Danail Georgiev
http://orcid.org/0000-0002-3625-9933
http://orcid.org/0000-0002-4662-3735
http://orcid.org/0000-0002-8518-611X
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