Received: 17 October 2019 Revised: 4 February 2020 Accepted: 7 February 2020

DOI: 10.1002/aoc.5650

FULL PAPER

Efficient palladium-catalyzed C-S cross-coupling reaction of

benzo-2,1,3-thiadiazole at C-5-position: A potential class of
AChE inhibitors

Beatriz F. dos Santos1 | Caroline F. Pereira2 | Mikaela P. Pinz2 |

1 1 1
Aline R. de Oliveira | George Brand | Ramesh Katla | Ethel A. Wilhelm2 |
Cristiane Luchese2 | Nelson L.C. Domingues1

1
Organic Catalysis and Biocatalysis
Laboratory - LACOB, Federal University Functionalization of 2,1,3-benzothiadiazole (BTD) with thiols at C-5 position
of Grande Dourados - UFGD, remains low explored. Moreover, the arylthiol-substitutions at this position are
Dourados/MS, Brazil
2
also unexplored and can not be found by a SN2 or SN1 reaction. In this sense,
Programa de Pós-Graduaç~ao em
Bioquímica e Bioprospecç~ao, Laboratório
herein we present a new palladium-catalyzed methodology for a wide variety
de Pesquisa em Farmacologia Bioquímica of unpublished 5-arylsulfanyl-benzo-2,1,3-thiadiazole derivatives synthesis
(LaFarBio), Grupo de pesquisa em with moderate to high yields using a low catalytic loading of Pd(L-Pro)2 as
Neurobiotecnologia – GPN, CCQFA,
Universidade Federal de Pelotas, low-coast, and efficient catalyst in low reaction time. Besides, we concluded
Pelotas/RS, Brazil that the pKa of thiol species has an important role in this catalysis, mainly in
the CMD like catalytic cyclo process, which strongly interferes in the reaction
Correspondence
Nelson Luís de Campos Domingues, yields. Furthermore, arylsulfanyl-benzo-2,1,3-thiadiazoles derivatives have
Organic Catalysis and Biocatalysis been assessed (in vitro) as potential acetylcholinesterase inhibitors.
Laboratory, Federal University of Grande
Dourados, Rod. Dourados-Itahum Km KEYWORDS
12 S/N, Cidade Universitaria, Dourados,
acetylcholinesterase inhibitors, Arylsulfanyl-benzo-2,1,3-thiadiazole, cross-coupling, C-S bond
MS 79804-970, Brazil.
Email: nelsondomingues@ufgd.edu.br

Funding information
Ciência e Tecnologia do Estado de Mato
Grosso do Sul (FUNDECT/Brazil -
Chamada FUNDECT/CNPq N
15/2014 –
PRONEM - MS); Conselho Nacional de
Desenvolvimento Científico e Tecnológico
(Chamada CNPq N
12/2017 - Bolsas de
Produtividade em Pesquisa - PQ)

1 | INTRODUCTION or human immunodeficiency virus (HIV) inhibitors.[5]

Organic sulfides and their derivatives constitute an
important class of intermediates in organic chemistry due
to their reactivity and biological and pharmacological
activity.[1–4] Several studies about the activity of aryl sul-
fide compounds indicate that they have anti-
inflammatory properties and are used in the treatment of
various diseases such as Alzheimer's Parkinson, leprosy,
Methodologies for the formation of C-S bonds are highly
inefficient due to, mainly, the reaction conditions.[1] One
of the prime reasons relies on the fact of the sulfur can be
oxidized by many soft oxidizers, like air, leading to dis-
ulfides.[6] To overcome this drawback, many researchers
groups have gain attention, mainly for catalyzed pro-
cesses. In this sense, the demand for new, efficient, and
mild methodologies for the synthesis of these compounds

Appl Organometal Chem. 2020;e5650. wileyonlinelibrary.com/journal/aoc © 2020 John Wiley & Sons, Ltd. 1 of 9
https://doi.org/10.1002/aoc.5650
2 of 9
has emerged in organic synthesis.[7] Thus, a strong alter-
native sought by researchers is the design of new cata-
lysts, usually composed of transition metals,[8] among
them, the most emblematic is palladium.[9] In the last
few decades, there was an increasing advance of cross-
coupling reactions and palladium catalysts have become
excellent candidates for the construction of carbon–
carbon and carbon-heteroatom bonds.[10] In the context
of heterocyclic compounds, benzothiadiazole (BTD) is an
important structural unit that has received much atten-
tion in recent years due to its several properties as
fungicides,[11] herbicides,[12] antibacterials[13], and photo-
luminescent.[14] Besides, the compounds having the BTD
unit have been widely and successfully employed as
luminescent compounds in light technology, such as
OLEDs, solar cells, liquid crystals, dyes, photovoltaic
cells, and others.[15] Some 2,1,3-benzothiadiazole deriva-
tives also have biological properties of interest, such as,
for example, the muscle relaxant tizanidine which acts as
an adrenergic agonist.[16] Because of the range of applica-
tions presented, various methodologies have been
described in the literature for the preparation of
2,1,3-benzothiadiazole derivatives.[17] Kamboj and co-
workers synthesized sulfanyl-benzo-2,1,3-thiadiazoles
derivatives via palladium-catalyzed reactions and then
they oxidized the compounds to arylsulfonyl-BTDs
(Figure 1a).[18] Recently, Alves and co-workers performed
the synthesis of arylsulfanyl-benzo-2,1,3-thiadiazoles
using copper nanoparticles as catalyst (Figure 1b).[19] All
DOS SANTOS ET AL.
of these reactions mentioned above were performed by
the C-S cross-coupling reaction at the C-4 position of the
BTD ring. To the best of our knowledge, the majority of
functionalization at BTD ring is done at position 4. The
reason for it is that position on BTD unit is activated by
resonance structure and it allows us to perform easily
some reactions, such as SN2, at this position, and that is
why substitution at position 5 remains low explored.[20]
Thus, aiming to perform an arylthiol functionalization at
position 5, using a low-cost, and effective methodology,
herein we present a palladium-catalyzed C-S cross-
coupling methodology (Figure 1c). Our research group
has already described some protocols using hybrid cata-
lysts in some reactions, among them the C-S cross-
coupling reaction using a recyclable Pd(L-Pro)2 as cata-
lyst under mild reaction conditions[21], and as Pd(L-Pro)2
afforded high yields, and recyclability in those proce-
dures, we decided to use it as the catalyst and describe a
new, simple, and efficient methodology for C-5 func-
tionalization of BTD unit.
2 | EXPERIMENTAL
2.1 | General procedures
The catalyst preparation was carried out using dry
starting material under pressure. All other reactions were
carried out using chemical reagents and solvents without
F I G U R E 1 The state of the art of BTD
functionalization at (a and b) C-4 and (c) C-5
position
DOS SANTOS ET AL. 3 of 9

any specific treatment. The respective reactions were
monitored by Thin Layer Chromatography (TLC)
MACHEREY-NAGEL (SIL G/UV254) and were visualized
by fluorescence quenching with UV light at 254 nm. The
purification of the compounds was performed by column
chromatography (only with hexane). 1H and 13C NMR
spectra were recorded in CDCl3 on Bruker (300 MHz and
75 MHz respectively) spectrometer. 1H NMR data are
reported as follows: chemical shift (δ, ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = mul-
tiplet), coupling constants (J) and assignment. The infra-
red spectra were recorded on FT/IR 4100 type A
spectrometer of Jasco.
2.2 | General procedure for the
preparation of catalyst Pd(L-pro)2
The catalyst preparation (see Supporting Informa-
tion) was carried out using dry starting material under
pressure. The palladium catalyst was prepared using L-
proline (2.0 mmol) and Et3N (0.5 mL) in dry methanol
(5 mL) at room temperature. After 1 hour then palladium
acetate (1.0 mmol) which had been dissolved in dry
methanol (5 mL) was added. The mixture was stirred at
room temperature under N2 for 24 h. After completion,
the reaction was centrifuged, washed with methanol and
dried overnight at room temperature and a light-yellow
solid was obtained.
2.3 | General procedure for the C-S cross-
coupling reaction
In a 5 mL round bottle flask was added palladium catalyst
(1.5% mol), 5-bromo-2,1,3-benzothiadiazole (0.4 mmol),
thiol (0.8 mmol) and K2CO3 (0.8 mmol). The mixture was
magnetically stirred in DMF (4 mL) at 100
C in an oil
bath for 6 h. The progress of the reaction was monitored
by TLC (eluent: EtOAc/hexane, 10:90). After this time,
the solution was cooled to room temperature, diluted

TABLE 1 Optimization of the reaction conditions

Entrya Thiol (eq.) Catalyst (% mol) Time (h) Solvent Yield (%)b
1 1.0 1.5 6 EtOH 53
2 1.0 5.0 6 EtOH 36
3 1.5 1.5 6 EtOH 60
4 2.0 1.5 6 EtOH 78
5 2.0 0.0 6 EtOH 20
6 2.0 2.0c 6 EtOH 35
7 2.0 1.5d 6 EtOH NR
8 2.0 1.5 6 DMF 85
9 2.0 1.5 6 DMF:EtOH (1:1) 85
10 2.0 1.5 6 EtOH:DMF (1 drop of DMF) 26
11 2.0 0.0 6 DMF 35
e
12 2.0 1.5 6 DMF 76
13 2.0 1.5 6 MeCN 59
14 2.0 0.0 6 DMFe -
a
Reaction conditions: All the reactions were carried out with K2CO3 (2.0 eq.), BTD (1.0 eq.), 4 mL of solvent at 90
C unless indicated in Table;
b
Yields by column chromatography;
c
Pd (OAc)2 as ligandless catalyst;
d
under N2 atmosphere;
e
Reaction carried out at 25
C; NR = no reaction.
4 of 9
with ethyl acetate (20 mL) and washed with water (3x20
mL). The organic phase was separated, dried over Na2SO4
and concentrated under vacuum. The obtained products
were purified by column chromatography using only hex-
ane as the eluent (see Supporting Information).
2.4 | In vitro AChE inhibition assay
Cerebral cortex of male Swiss mice was used to evaluate
in vitro inhibition of AChE activity by the arylsulfanyl-
benzo-2,1,3-thiadiazole derivatives. The activity of AChE
was measured by the method of Ellman et al.[22], using
acetylthiocholine as substrate. The samples of the cere-
bral cortex were homogenized in 0.25 M sucrose buffer
(1:10, weight/volume) and centrifuged at 900 xg at 4
C
for 10 min. An aliquot of 100 μL of supernatant
(2.8 mg/mL protein) was incubated for 2 min at 25
C in
the presence of different concentrations (1–500 μM) of
the compounds, in a medium containing 100 mM
potassium phosphate buffer, pH 7.5. The enzymatic reac-
tion was initiated by the addition of 5,50 -dithio-
bis(2-nitrobenzoic acid) (final concentration of 0.5 mM)
and acetylthiocholine iodide (final concentration of
0.8 mM). The hydrolysis ratio of acetylthiocholine iodide
was measured spectrophotometrically at 412 nm. Results
are expressed as μmol/h/mg protein. All observations
were validated by at least three independent experiments,
in duplicate (see Supporting Information).
3 | R ES U L T S A N D D I S C U S S I O N
Initially, the synthesis of the catalyst Pd(L-Pro)2 was car-
ried out following the reports published by Ding et al.[23]
Later, we selected the reaction between 5-bromo-2,-
1,3-benzothiadiazole (1) and thiophenol (2) as a standard
reaction aiming to get all the reactional parameters
needed for this reaction (optimization) (Table 1). First of
all, the reaction was performed under the same condi-
tions already described by Domingues et al.[21] for the C-
S cross-coupling reaction (Entry 1) affording only moder-
ate yield (53%) in EtOH. We chose to initiate using EtOH
as solvent due to its known property as “green sol-
vent”.[24] To improve the yield, we increased the catalyst
loading up to 5% mol and the yield decreased to 36%
(Entry 2). The influence of the starting material (Entries
3 & 4) was also studied by increasing of the amount of
thiol and a significant increase was observed in yield. In
all these cases, we observed a high formation of disulfide
byproduct. The analysis of these data strongly indicates
that the disulfide reaction, in this case, has a higher rate
reaction constant than the C-S cross-coupling reaction. In
DOS SANTOS ET AL.
other words, we concluded that the increase of catalyst
amount has accelerated the disulfide synthesis instead of
the C-S cross-coupling reaction due to the presence of air
(open flask).[25] Besides, to the best of our knowledge,
thiol can also reduce the NOX of the metal, and the
reduced metal species have an important role in the
cross-coupling reactions (CMD-like process).[21] Thus,
increasing the thiol loading allows us to produce the
product in moderate yields (entry 4). It's worth mention-
ing that the reaction carried out without catalyst
(Entry 5) furnished a low yield of the interest compound
via an SN2 mechanism.[26] Moreover, the reaction was
performed only with palladium acetate (Entry 6) as a
“ligandless” catalyst and the yield dropped to 35%. It
means that the catalyst's type plays a substantial role in
the process. The reaction was carried out under an N2
atmosphere (Entry 7) and did not furnish any interest
compound.
We also performed the screening of several different
solvents and solvent mixtures and this study revealed
that DMF provided the best results (Entries 8, 9, 10 and
13). It is known that DMF act as a palladium reducer and
the use of the DMF accelerates the Pd0 species formation
inside reaction media affording high yields.[27] The reac-
tion in DMF was conducted without any catalyst loading
(Entry 11) and a low yield was obtained via the SN2
mechanism when compared to entry #8. This same reac-
tion was conducted at room temperature (Entry 14) and
the interest compound was not obtained. With all these
data in hand, we established the reaction conditions of
entry #8 as standard procedure. We extended this meth-
odology for several other reactions by changing the
thiophenols which resulted in the compounds 3a-3q
(Table 2). Based on the results for thiols monosubstituted,
we concluded that electron-donating substituents on thiol
increased the reactivity of the substrate compared with
the results of the corresponding substrates bearing
electron-withdrawing substituents at the same position
(3b-3c vs 3d-3e) (3 h and 3 k vs 3i).
In the presence of a thiol bearing a strongly electron-
withdrawing substituent, only traces of the product of
interest were obtained (3 g). To the best of our knowl-
edge, thiol bearing to electron-donating groups at para or
ortho position is less acid. The proposed mechanism
needs the CMD-like transition state to lead to the prod-
uct. In the suggested CMD-like transition state, there is a
mandatory interaction between thiol's hydrogen and car-
bonyl's catalyst group (see proposed mechanism - -
Figure 2). On the other hand, electron-withdrawing
groups make the thiophenol more acid and, the base, in
this specific case, the K2CO3, remove, previously the
hydrogen acid inhibiting the CMD-like transition state.
Further, thiols bearing to electron-donating groups are
DOS SANTOS ET AL. 5 of 9

TABLE 2 Study of the C-S cross-coupling reaction using Pd(L-Pro)2 as a catalyst

All the reactions were performed with 1 (0.4 mmol), 2 (0.8 mmol), catalyst (1.5% mol), K2CO3 (0.8 mmol) in DMF (4 mL) at 110
C. The isolated yield of 3 in
6 hours, determined by 1H and 13C NMR.

known to be better nucleophiles than electron-
withdrawing ones, which affects directly to the trans-
metallation step. Further, it can be concluded that little
effect is observed on reactivity when the same electron-
donating substituent is present in the para, meta or ortho
positions of thiol (3b, 3f, and 3 h). A substrate substituted
by a benzyl group provided the product 3j in good yield.
Products 3 l and 3o bearing disubstituted-phenyl groups
were obtained in excellent yields. Substrates bearing
strongly electron-donating substituents gave their
corresponding product with excellent results (3 m and
3n). These specific results (3 m and 3n) address the
regioselectivity effect afforded by the Pd(L-Pro)2 catalyst.
In other words, there was no observation of any C-N
cross-coupling reaction involving the amine group for
these respective reactions (3 m and 3n). Further, there
is no deactivating on the catalyst due to nitrogen
attaching on the metal, which reinforces that CMD-
like transition state has a preference for the nitrogen
attack. To reinforce this conclusion, we have per-
formed a reaction using aniline and any interest com-
pound was obtained even in 12 hours. The reaction
using aniline gave us a strong indication that hydrogen
donating from nucleophile at CMD-like transition
state, plays an important role in the catalytic cycle and
as aniline is not suitable to donate the hydrogen in
the catalytic step, the interesting compound, C-N
cross-coupling reaction, was not obtained. Another
thiol used was bearing group pyridine and good yield
was obtained to the compound 3p. The product 3q
6 of 9
was obtained in small quantities due to the low reac-
tivity of the thiol used.
Based on the results obtained we proposed a plau-
sible mechanism for the coupling of thiols and
5-bromo-2,1,3-benzothiadiazole using Pd(L-Pro)2 cata-
lyst (Figure 2). In the proposed mechanism, the sulfur
species are added to the catalyst getting to intermedi-
ate #2. At this point, we observed that pKa of the
thiol plays an important role in the catalysis. For
thiols that have pKa between 6–9[28] the reaction
afforded hight yields. To the best of our knowledge,
this fact strong indicates that the CMD-like process is
very plausible to generate Pd0 species. The reverse
example was presented by 4-nitrothiophenol which has
pKa = 4.4.[29] In the presence of a base, the neutrali-
zation produces a thiolate. This thiolate is a poison to
the catalyst and the reaction does not occur. Besides,
the presence of thiolate and air oxygen produces a rad-
ical RS that reacts to producing disulfide. In this
sense, Domingues et al.[21] have proved that disulfide
is not suitable to perform this type of reaction. After
the elimination of disulfide (byproduct) occurs the
reducing of Pd+2 to Pd0 species (intermediate #3). This
is a crucial step of the mechanism because the species
of Pd0 are suitable to be attacked by the 5-bromo-2,-
1,3-benzothiadiazole via oxidative addition affording
#4. Subsequently, the thiol attack occurs (intermediate
#5) and the product of the C-S cross-coupling reaction
DOS SANTOS ET AL.
F I G U R E 2 The proposed reaction mechanism
for the C-S cross-coupling reaction
is provided by reductive elimination, affording again
the Pd0 species in a new catalytic cycle.
Aiming to test some of this new class of compounds
as a probe for acetylcholinesterase (AChE) inhibitors, we
have performed an in vitro study. The results
arylsulfanyl-benzo-2,1,3-thiadiazoles are valuable com-
pounds with great potential for inhibition of acetylcholin-
esterase, which is a feature of the compounds that are
used in the treatment of Alzheimer's disease. The results
of the assays showed that all the arylsulfanyl-benzo-2,-
1,3-thiadiazoles derivatives have the ability to, in vitro,
inhibit the AChE enzyme activity in the cerebral cortex
of mice (Figure 3). Compounds 3b, 3c, 3d, 3e, 3 h, and 3i
inhibited AChE activity from the concentration of
100 μM (Figures 3B-E, 3G, 3H, respectively). Compounds
3a, 3f, 3j, and 3 l caused inhibition of AChE activity from
the concentration of 200 μM (3A, 3F, 3I, 3 L). Com-
pounds 3 k, 3 m, 3n, and 3o inhibited enzyme activity
only at the concentration of 500 μM (3 J, 3 M-O). The
results shown in Table 3 indicate that the compounds
followed the order of maximal inhibition (Imax):
3b>3j>3h=3m>3l>3a>3i>3c>3k>3o>3d=3n>3f>3e.
In this context, the compound 3b had a higher Imax,
upper than 90%, indicating the higher the effectiveness of
this compound when compared to the others. We can
suggest that the presence of the electron-donating group
(mainly methoxy group) at the para position of
thiophenol contributes to the anticholinesterase effect of
DOS SANTOS ET AL. 7 of 9

F I G U R E 3 Effect of the arylsulfanyl-benzo-2,1,3-thiadiazoles derivatives (compounds 3a-3o), in different concentrations (1–500 μM), in
the in vitro inhibition of AChE activity in the cerebral cortex of mice. Data are reported as the mean ± standard error of the mean of three
independent experiments performed on different days. The activity of AChE is expressed as μmol/h/mg protein. (*) denotes p < 0.05 when
compared to the control group (one-way analysis of variance followed by the Newman–Keuls test)
8 of 9 DOS SANTOS ET AL.

TABLE 3 Maximum inhibition values (Imax) of the Chamada FUNDECT/CNPq N
15/2014 – PRONEM -
arylsulfanyl-benzo-2,1,3-thiadiazoles derivatives MS) and the Conselho Nacional de Desenvolvimento
Compound Imax (%)
Científico e Tecnológico (Chamada CNPq N
12/2017 -
Bolsas de Produtividade em Pesquisa - PQ) for financial
3a 81,6
support and fellowship. Furthermore, the author (B.F.S)
3b 94,7 thanks to Coordenaç~ao de Aperfeiçoamento de Pessoal
3c 78,9 de Nivel Superior (CAPES/Brazil) for her scholarship.
3d 75,0
3e 48,7
ORCID
3f 72,5
Nelson L.C. Domingues https://orcid.org/0000-0003-
3h 85,0 3954-047X
3i 79,5
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SU PP O R TI N G I N F O RMA TI O N
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: dos Santos BF,
Pereira CF, Pinz MP, et al. Efficient palladium-
catalyzed C-S cross-coupling reaction of benzo-
2,1,3-thiadiazole at C-5-position: A potential class
of AChE inhibitors. Appl Organometal Chem. 2020;
e5650. https://doi.org/10.1002/aoc.5650