One-pot sequential synthesis and antifungal activity of 2-(benzylsulfonyl)benzothiazole derivatives

Article abstract of DOI:10.1039/c9ra04488d

New antifungal agrochemicals, derived from 2-(benzylsulfonyl)benzothiazole were synthesized by an environmentally friendly method, using water as reaction medium. These compounds were prepared by a one-pot, two-step synthesis, starting from 2-mercaptobenzothiazole and benzyl halides. The potential fungicides were tested against a panel of phytopathogenic fungi, with many of them showing a significant improvement compared to the non-oxidized analogues and the commercial antifungal Captan. The new derivatives 2-((2-chlorobenzyl)sulfonyl)benzo[d]thiazole (4f) and 2-((4-methylbenzyl)sulfonyl)benzo[d]thiazole (4k) presented remarkable properties, being able to inhibit the growth of two resistant moulds (Aspergillus fumigatus and Aspergillus ustus). Both 4f and 4k could be classified as broad-spectrum fungicides, emerging as possible candidates for the control of these moulds, which have negative impact in food production.

Full text of DOI:10.1039/c9ra04488d

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One-pot sequential synthesis and antifungal
activity of 2-(benzylsulfonyl)benzothiazole
Cite this: RSC Adv., 2019, 9, 29405
derivatives†
a
bc
Daniel A. Wunderlin,c
*
Marıa Sol Ballari,
Gabriela E. Feresin
Natividad Herrera Cano,
´
b
and Ana N. Santiagoa
New antifungal agrochemicals, derived from 2-(benzylsulfonyl)benzothiazole were synthesized by an
environmentally friendly method, using water as reaction medium. These compounds were prepared by
a one-pot, two-step synthesis, starting from 2-mercaptobenzothiazole and benzyl halides. The potential
fungicides were tested against
a panel of phytopathogenic fungi, with many of them showing
a significant improvement compared to the non-oxidized analogues and the commercial antifungal
Captan. The new derivatives 2-((2-chlorobenzyl)sulfonyl)benzo[d]thiazole (4f) and 2-((4-methylbenzyl)
sulfonyl)benzo[d]thiazole (4k) presented remarkable properties, being able to inhibit the growth of two
resistant moulds (Aspergillus fumigatus and Aspergillus ustus). Both 4f and 4k could be classified as
broad-spectrum fungicides, emerging as possible candidates for the control of these moulds, which
have negative impact in food production.
Received 14th June 2019
Accepted 9th September 2019
DOI: 10.1039/c9ra04488d
rsc.li/rsc-advances
respiratory infections.9,10 Most of these moulds are capable of
producing mycotoxins, toxic metabolites produced by fungi,
Introduction
particularly by saprophytic moulds growing on agricultural
products.11 These cause not only economic losses but also
health hazards to humans and animals.
Plant and crop protection against plant diseases has been and
still is a recurrent issue to ensure food quality.1 The grain crops,
such as barley, wheat, oat, soybean, corn and sunower are the
most important feeding source worldwide. Crop rotting and
spoilage is mainly caused by fungi, the most important being
yeasts and moulds, including Botrytis,2,3 Fusarium,4 Aspergillus,5
Alternaria6 and Cladosporium.3 Botrytis cinerea is a necrotrophic
plant pathogenic fungus with a broad host range. It causes the
grey mould disease, one of the most important post-harvest
diseases of fruits and vegetables worldwide.7 Fusarium oxy-
sporum is one of the most common soil-borne plant pathogenic
fungi, causing rot and wilt diseases on many economic plants.8
Aspergillus species are abundant and grow saprotrophically on
numerous substrates over a wide range of climatic conditions.
They have long been known to be common contaminants of
human foods and animal feeds, being able to produce
Chemical protection is one of the most important methods
for keeping crops healthy. Recurrent genetic plasticity pre-
sented in most mould species, develop resistance to the most
common fungicides.1 In addition, results have shown that
fungal resistance will accelerate extremely in a few years,
causing the appearance of uncontrollable pathogens, which
leads to a great challenge to handle this new circumstance.12
This possesses a great concern in community and among
professionals, which brings the need for development of safer
and more effective agrochemicals with reduced environmental
toxicity.13
In the past few decades, various companies have introduced
a large number of potent, bioactive fungicides, containing
sulfone units, such as oxycarboxin, tazobactam or dapsone
(Fig. 1A). A key feature for reaching good bioactivity could be a 5
or 6- membered heterocyclic ring attached to the sulfonyl
group.13 Furthermore, benzothiazoles are known for being part
of a wide number of bioactive compounds, being many
commercial antifungals derived from this heterocycle (Fig. 1B).
Benzothiazol-2-thiol and its derivatives are part of an important
class of bioactive compounds, having a broad spectrum of
bioactivities, such as antimycobacterial.14
aINFIQC, CONICET, Universidad Nacional de Cordoba, Facultad de Ciencias
´
´
´
´
Quımicas, Departamento Quımica Organica, Ciudad Universitaria, Haya de la Torre
´
s/n, 5000, Cordoba, Argentina
b
´
Instituto de Biotecnologıa, Universidad Nacional de San Juan, CONICET–CCT San
´
Juan, Av. Libertador General San Martın 1109 (O), 5400, San Juan, Argentina.
E-mail: nhc@fcq.unc.edu.ar; Tel: +54 351 5353867
cICYTAC, CONICET, Universidad Nacional de Cordoba, Facultad de Ciencias
´
´
´
´
Quımicas, Departamento Quımica Organica, Ciudad Universitaria, Bv. Juan Filloy s/
´
n, 5000, Cordoba, Argentina
For example, sulfonylbenzothiazoles with substituents such
as Cl, NO2, F, CH3 on the benzothiazole ring have signicant
antibacterial and antifungal activity.15 In addition, it is known
† Electronic supplementary information (ESI) available: More details about
antifungal susceptibility tests, spectroscopy data for all compounds. See DOI:
10.1039/c9ra04488d
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problematic or hazardous solvents.21–24,26,28–38 Thus, the oxida-
tion of suldes to sulfones using water as reaction medium
should be advantageous. However, to our knowledge the use of
water in such oxidations has not been reported.
We have previously reported the synthesis of 2-(benzylthio)
benzothiazoles, including the verication of its bioactivity
against different phytopathogenic fungi.39 Thus, the main goal
of this work was to obtain several 2-(benzylsulfonyl)benzothia-
zole derivatives by a simple and eco-friendly methodology,
using water as solvent, evaluating their antifungal activity
against phytopathogenic fungi, Botrytis cinerea, Fusarium oxy-
sporum and Aspergillus spp. Additionally, we were interested in
the evaluation of differences in the antifungal activity of
oxidized derivatives prepared in this work versus non-oxidized
compounds previously prepared.
Results and discussion
Chemistry
Fig. 1 Commercial bioactive compounds including the structures of
interest. (A) Sulfonyl derivatives (blue). (B) Benzothiazole derivatives
(red).
Synthesis. In order to synthesize 2-benzylsulfonyl benzo-
thiazole derivatives, we used a two-step synthetic pathway
(Scheme 1). In the rst step, 2-mercaptobenzothiazole (1) and
different benzyl halides (2a–k) react in a nucleophilic substi-
tution reaction to obtain the respective suldes (3a–k).39 Those
suldes were oxidized in the second step to obtain the corre-
sponding sulfones (4a–k).
Compounds 3a–k were prepared according to our previous
work,39 obtaining suldes in very good isolated yields (72–93%),
under mild conditions, and employing water as the reaction
medium. Water is the preferred solvent, as it is low cost,
abundant and safe, so reducing environmental effects. Due to
its unique physicochemical properties, it is possible to perform
a wide range of reactions with high selectivity and usually
reaching good yields and rate increments, compared to organic
solvents.40
In order to perform the oxidation reaction on the suldes
previously synthesized, we used reaction conditions previously
developed by Lai et al.26 Thus, compounds 3a–k were oxidized by
KMnO4, using FeCl3 as catalyst and acetonitrile as solvent. Aer
90 minutes of reaction at room temperature, sulfones 4a–k were
obtained, yielding full substrate conversion, in addition to high
selectivity towards sulde oxidation against other functional
groups present in the compounds (Table 1). Compounds 4a–k
were obtained pure aer solvent extraction, using water and
ethyl acetate to remove the KMnO4 remaining. So, we got very
that small molecules, such as benzothiazoles, bind to tubulin,
interfering in the mitosis process, and, in consequence leading
to apoptosis.16
Organic sulfones are considered useful precursors in organic
synthesis due to their ability to attract electrons, stabilizing
carbanions and radical intermediates during different chemical
reactions.17–19 Additionally, sulfonyl groups can be easily
removed, making them very versatile synthetic intermediates.20
On these bases, there has been great interest in the develop-
ment of methods for the synthesis of sulfonyl derivatives. A
widely used method for their preparation is the oxidation of
different suldes or sulfoxides in the presence of a suitable
oxidizing agent. Hydrogen peroxide is among the most impor-
tant oxidants for transforming sulfur groups to sulfones.21–24
Additionally, permanganate salts,13,25–27 m-chloroperoxybenzoic
acid,28–31 oxone,32–34 periodate salts35 and orthoperiodic acid,36
can be mentioned as efficient oxidants. However, some
synthetic protocols have one or more disadvantages, such as the
use of large excess of oxidant,21,23,36,37 or the need for simulta-
neous application of two oxidants.24,31 Some synthetic pathways
imply the use of sophisticated or toxic catalysts,21–23,33–37 in
addition to previous in situ preparation of reagents.22–24,27,33,35,37
Furthermore, most of these methods involve the use of
Scheme 1 Two-step pathway proposed for sequential synthesis of 2-benzylsulfonyl benzothiazoles.
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Table 1 Oxidation reactions of sulphurs 3a
Table 1 (Contd.)
Entry
1
R
Product
Conversionb Yieldsc
Entry
R
Product
Conversionb Yieldsc
H
Quant.
Quant.
85%
80%
11
4-CH3
Quant.
80%
a
b
3a–k concentration were 0.10 M. Conversions of 3a–k by GC
quantication, Quant. ¼ no substrate 3 was detected. c Isolated yields.
2
3
4
5
4-F
4-CF3
4-CN
4-NO2
Quant.
Quant.
Quant.
83%
86%
85%
good isolated yields (75–86%), being unnecessary further
chromatographic purication.
In an attempt to obtain 2-benzylsulfonyl benzoxazole deriv-
atives (6a–h), we tried to oxidize the respective suldes (5a–h)
using the same conditions as for benzothiazoles (Scheme 2), but
yields were variable (0–86%), aer 24 hours of reaction. This
could be due to complexation of MnO4ꢀ with the oxygen in the
heterocycle, instead of interacting with the sulde, hence the
oxidant is deactivated. However, these sulfonyl derivatives were
very unstable, and within a few hours to one week they
decomposed. More studies are needed to determine the reasons
for the variable reactivity, as well as the lack of stability for these
compounds.
6
2-Cl
Quant.
75%
In addition, looking to simplify the synthetic process, we
designed a one-pot sequential method, starting from 2-mer-
captobenzothiazole (1) and benzyl halides (2a–k), to obtain
compounds 4a–k, without isolating the respective synthetic
intermediate 3a–k. For that reason, it was important to perform
the synthesis in a single solvent, saving both solvent and
workup time. That is why the sequential synthesis was tried
using either water or acetonitrile. Thus, we obtained good
conversions of 2 in both solvents (Table 2). Moreover, we did not
detect remaining substrate in reactions where water was used as
reaction medium, which also facilitated the purication. These
facts, in addition to environmentally friendly solvent, makes
water the solvent of choice.40 To our knowledge, there are no
reports on sulde oxidation carried out using water as the
exclusive reaction medium. There were two cases where 4
derivatives were not fully converted. Thus, 4a and 4k (Table 2,
entries 1 and 11), showed the presence of 3a or 3k, which were
remaining intermediated in the reaction. This partial conver-
sion was observed even aer 24 h reaction to reach the equi-
librium. This may be due to electronic inuences of the benzyl
group on the oxidizable sulfur atom, since they were the only
two cases where the ring was not substituted by electron-
withdrawing groups.
7
4-Br
2-Br
4-I
Quant.
Quant.
Quant.
Quant.
79%
81%
78%
81%
8
9
10
2-I
Comparing the global isolated yields of the nal products,
using the one-pot reaction pathway (75–89%)or the two
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independent steps methodology (60–75%), a greater efficiency analogues such as 4c (IC50(3c) ¼ 57 mM), 4i (IC50(3i) ¼ 73 mM)
for the one-pot method can be observed. Thus, the one-pot and 4k (IC50(3k) ¼ 79 mM) improved their bioactivity compared
pathway allowed improving up to 26% for product recovery to the analogues 3.39 The candidate that stood out against F.
(Table 2). This is a consequence of the diminution in handling oxysporum was 4k, which achieved a growth inhibition of 70% at
and workup. Furthermore, in the one-pot method, a chromato- the lowest concentration tested.
graphic method is not required to isolate the nal product,
Against A. fumigatus, derivatives 4a (R ¼ H, IC50 ¼ 15.1 mM,
since a simple extraction with water and ethyl acetate is enough Table 3, entry 1), 4c (R ¼ 4-CF3, IC50 ¼ 18 mM, Table 3, entry 3),
to obtain the product with high purity.
4f (R ¼ 2-Cl, IC50 ¼ 7 mM, Table 3, entry 6) and 4j (R ¼ 2-I, IC50 ¼
23 mM, Table 3, entry 10) showed a similar effect that to Captan
(IC50 ¼ 15 mM, Table 3, entry 12). The derivative 4k stands out (R
¼ 4-CH3, IC50 ¼ 6.3 mM, Table 3, entry 11), since it signicantly
exceeded the inhibition produced by the control. This last
compound becomes a very valuable candidate, since it was the
only compound showing improvements in the potency against
A. fumigatus, respect to the commercial control. Also, oxidized
analogues such as 4a (IC50(3a) ¼ 267 mM), 4c (IC50(3c) >
100 mg Lꢀ1), 4f (IC50(3f) > 100 mg Lꢀ1) and 4k (IC50(3k) ¼ 29 mM)
showed improvement respect the sulfur derivatives 3.39
Antifungal susceptibility test
Fungal growth was evaluated at six concentrations (3.1–
100 mg Lꢀ1), using enriched Czapek broth in the presence of
compounds 4. Each treatment was carried out in triplicate. The
50% Inhibitory Concentration (IC50) was dened as the
minimum concentration required to inhibit the fungal growth
by 50%. IC50 values of the compounds, along with the positive
control Captan, are summarized in a heat map in Table 3.
Signicant differences were determined by calculating the t-
Student hypothesis test P, at 95% condence.
In general, a good bioactivity was observed compared to the
reference compound, nding candidates with equal or signi-
cantly better inhibitory effects than Captan. Also, in many cases,
an increment in the bioactivity was observed for derivatives 4a–
k, when compared to the results obtained for the unoxidized
analogues 3a–k.39 In those cases where IC50 were lower than the
minimum concentration assayed (3.1 mg Lꢀ1), it was specied
the inhibition percentage observed at that concentration as
a footnote in Table 3.
In case of Aspergillus niger, derivatives 4e (R ¼ 4-NO2, IC50
¼
33 mM, Table 3, entry 5) and 4f (R ¼ 2-Cl, IC50 ¼ 14 mM, Table 3,
entry 6) equaled the reference's potency (IC50 ¼ 24 mM, Table 3,
entry 12). On the other hand, 4k (R ¼ 4-CH3, IC50 ¼ 9.7 mM,
Table 3, entry 11) was signicantly more potent, proving to be
the best candidate in the series. Compared to the analogues 3,
4f (IC50(3f) > 100 mg Lꢀ1) and 4k (IC50(3k) ¼ 35 mM) were
signicantly better against A. niger.39
The best candidates selected against Aspergillus terreus were
4a (R ¼ H, IC50 ¼ 0.30 mM, Table 3, entry 1), 4d (R ¼ 4-CN, IC50
¼
43 mM, Table 3, entry 4), 4f (R ¼ 2-Cl, IC50 ¼ 3 mM, Table 3, entry
6) and 4k (R ¼ 4-CH3, IC50 ¼ 39 mM, Table 3, entry 11), which
proved to be signicantly better than Captan (IC50 ¼ 55.8 mM,
Table 3, entry 12). Also, derivatives 4h (R ¼ 2-Br, IC50 ¼ 62 mM,
Table 3, entry 8) and 4j (R ¼ 2-I, IC50 ¼ 82 mM, Table 3, entry 10)
showed inhibition rates comparable to the commercial
compound. On the other hand, oxidized analogues such as 4a
(IC50(3a) ¼ 13.2 mM), 4f (IC50(3f) ¼ 73 mM), 4h (IC50(3h) >
100 mg Lꢀ1), 4j (IC50(3j) > 100 mg Lꢀ1) and 4k (IC50(3k) >
100 mg Lꢀ1) were better than the unoxidized derivatives.39 Of
these compounds, we can highlight 4a and 4f, which have the
lowest IC50 of the series against A. terreus.
Against Aspergillus ustus, it was possible to determine that
derivatives 4d (R ¼ 4-CN, IC50 ¼ 51 mM, Table 3, entry 4), 4f (R ¼
2-Cl, IC50 ¼ 67 mM, Table 3, entry 6), 4g (R ¼ 4-Br, IC50 ¼ 49 mM,
Table 3, entry 7) and 4i (R ¼ 4-I, IC50 ¼ 56 mM, Table 3, entry 9)
did not show signicant differences with respect to the IC50
obtained for Captan (IC50 ¼ 61 mM, Table 3, entry 12). Deriva-
tives 4b (R ¼ 4 F, IC50 ¼ 44 mM, Table 3, entry 2) and 4k (R ¼ 4-
For Botrytis cinerea, compounds 4a (R ¼ H, IC50 ¼ 4 mM,
Table 3, entry 1), 4f (R ¼ 2-Cl, IC50 ¼ 17.2 mM, Table 3, entry 6)
and 4k (R ¼ 4-CH3, IC50 ¼ 24 mM, Table 3, entry 11) showed
inhibitory effects signicantly equal to Captan (IC50 ¼ 17.8
mM, Table 3, entry 12). Derivatives 4c (R ¼ 4-CF3, IC50 ¼ 9.3
mM, Table 3, entry 3) and 4g (R ¼ 4-Br, IC50 ¼ 6 mM, Table 3,
entry 7) achieved signicant improvements respect to the
control. On the other hand, compared to the activity observed
of the suldes derivatives 3 with the oxidized analogues 4, it
could be appreciated that for the analogue 3a (IC50
>
100 mg Lꢀ1
)
antifungal activity was substantially improved
39
for 4a (IC50 ¼ 4 mM).
Regarding Fusarium oxysporum, derivatives 4a (R ¼ H, IC50
¼
23 mM, Table 3, entry 1), 4c (R ¼ 4-CF3, IC50 ¼ 15.2 mM, Table 3,
entry 3) and 4k (R ¼ 4-CH3, IC50 ¼ 2.3 mM, Table 3, entry 11)
proved to have a signicantly better activity than the control
(IC50 ¼ 49 mM, Table 3, entry 12). In addition, the compound 4i
(R ¼ 4-I, IC50 ¼ 37 mM, Table 3, entry 9) achieved an inhibition
rate comparable to that of Captan. On the other hand, oxidized
Scheme 2 Oxidation of benzoxazole derivatives. Products detected by GC-MS. Yields obtained by GC are in brackets.
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Table 2 One-pot sequential synthesis of 2-(benzylsulfonyl)benzothiazoles 4a
Entry
R
X
Product
Conversion H2Ob
Conversion CH3CNb
Yields one-potc
Two-step global yieldsd
1
2
3
4
5
6
7
8
H
4-F
Cl
Cl
Cl
Br
Br
Cl
Br
Br
Br
Cl
Cl
4a
4b
4c
4d
4e
4f
4g
4h
4i
93%e
85%
90%
91%
94%
89%
88%
95%
93%
92%
91%
86%
75%
83%
85%
82%
87%
81%
88%
86%
82%
89%
78%
72%
60%
71%
68%
70%
65%
62%
63%
69%
75%
73%
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
95%e
4-CF3
4-CN
4-NO2
2-Cl
4-Br
2-Br
4-I
9
10
11
2-I
4-CH3
4j
4k
a
1 and 2a–k concentration were 0.25 M. Reactions performed with 1 equivalent of K2CO3. Before step 2, pH was neutralized and intermediate
b
concentration was reduced to 0.1 M. Conversions to 4a–k by GC quantication, Quant. ¼ no substrate 2 or intermediate 3 were detected.
c
d
Isolated yields for synthesis on water. Global isolated yields for synthesis in two independent steps. Global yields ¼ step 1 yields39 ꢁ step 2
e
yields/100. Reaction time was 24 hours. Substrate 2 was not detected. Remaining intermediate 3 was detected. Product isolated by circular
layer chromatography, using as mobile phase pentane/ethyl acetate (60 : 40).
CH3, IC50 ¼ 14.0 mM, Table 3, entry 11) exceeded the control's (IC50(3i) > 100 mg Lꢀ1) and 4k (IC50(3k) ¼ 17 mg Lꢀ1, 62 mM)
inhibition rate. Thus, oxidized analogues such as 4d (IC50(3d) ¼ improved their effect with respect to the synthetic
92 mM), 4f (IC50(3f) ¼ 229 mM), 4g (IC50(3g) > 100 mg Lꢀ1), 4i intermediate.39
Table 3 Antifungal activity of benzothiazole derivatives 4
a
Heat map scale. Red: most active compounds (low IC50), orange/yellow: compounds with intermediate activity, green: non-active compounds (high
IC50). (–): No inhibitory activity detected (IC50 > 100 mg Lꢀ1). 60% inhibition at 3.1 mg Lꢀ1
. .
70% inhibition at 3.1 mg Lꢀ1
b
c
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When analyzing the potencies of the sulfonyl derivatives 4 Louis, MO) and used as received. Ultrapure water (MilliQ) was
with those of their non-oxidized analogues 3, it is observed that used for reactions on water.
the oxidation of the sulde bridge was benecial in most cases.
This may be due to the increased hydrophilicity of the sulfonyl
derivatives, allowing a more efficient membrane permeation. In
addition, the SO2 group would provide two new hydrogen bond
acceptors, which would increase the interactions in the ligand-
target binding.
Considering results obtained in the antifungal susceptibility
tests, key candidates can be highlighted, according to their
broad action. Among the candidates that showed broad-
antifungal activity, the derivative 4f (R ¼ 2-Cl) can be high-
lighted, since it showed a remarkable inhibitory effect for ve
out of six microorganisms studied. Furthermore, the derivative
4k (R ¼ 4-CH3), achieved an appreciable inhibition growth with
six fungi evaluated, being remarkable the activity observed
against F. oxysporum and Aspergillus spp., especially A. fumigatus
and A. ustus, which are highly resistant species. The derivative
4c (R ¼ 4-CF3) can be also highlighted, because it allowed
Microorganisms
Synthesized compounds were assayed against: (a) Botrytis cin-
erea isolated from Vitis vinifera cv. Chardonnay, cultivated in
Province of San Juan, Argentina; (b) Aspergillus ustus (PN-S4); (c)
Aspergillus terreus (M16C); (d) Fusarium oxysporum (M15-Pa)
(strains b–d were isolated from soil samples from the Prov-
ince of San Juan, Argentina); (e) Aspergillus fumigatus (ATTC
26934); (f) Aspergillus niger (ATCC 9029). The microorganisms
were grown in Czapek medium (Sigma, St. Louis, MO), enriched
ꢂ
with a solution of mineral salts, incubated at 30 C for Asper-
gillus spp. and Fusarium oxysporum, and at 22 ꢂC for Botrytis
cinerea, during 5–10 days.
General procedure for the oxidation of 2-(benzylthio)
benzothiazoles
a selective growth of the different Aspergillus strains, reaching 2-(Benzylthio)benzothiazole (0.2 mmol), KMnO4 (0.6 mmol) and
an adequate inhibition against B. cinerea and F. oxysporum. This FeCl3 (0.06 mmol) were vigorously stirred in 2 mL of acetonitrile
may have positive implications in the design of combined for 90 minutes at room temperature in a sealed vessel. When the
therapies of biological and chemical control. Aspergillus is reaction was nished, 2 mL of water was added to the crude,
a microorganism widely used in biological control treatments,41 and it was extracted with ethyl acetate (three times, 4 mL each),
so that a combined treatment could be designed, using Asper- and washed the organic layer with H2O (three times, 4 mL each).
gillus with one of these antifungals that allow its development The organic layer was dried with anhydrous Na2SO4, and
and, thus, improving the efficiency against a problematic pest. analyzed by Gas Chromatography (GC).
General procedure for the one-pot synthesis of 2-
(benzylsulfonyl)benzothiazoles
Conclusions
In conclusion, we present a simple, cheap, one-pot method-
2-Mercaptobenzothiazole (0.5 mmol), K2CO3 (0.5 mmol) and
ology to obtain 2-(benzylsulfonyl)benzothiazole derivatives,
benzyl halide (0.5 mmol) were vigorously stirred in 2 mL of
using a two-step synthetic pathway, affording very good isolated
Ultrapure water for 30 minutes at 50 ꢂC in a sealed vessel. Aer
yields, without using a nal chromatographic step for product
completion, the reaction media was neutralized by adding a few
purication. Those compounds were evaluated against six
drops of acetic acid, with further addition of KMnO4 (1.5 mmol),
phytopathogenic or problematic fungi, nding a series of
FeCl3 (0.15 mmol) and Ultrapure water (2 mL). The reaction
candidates which improved their activity with respect to
vessel was sealed and let to react for 90 minutes at room
a commercial (Captan), and also compared to their sulfur
temperature. When the reaction was completed, 4 mL of water
synthetic intermediates, previously assayed.39 It is worth
were added to the crude yield, followed by extraction with ethyl
remarking that some of these compounds were able to inhibit
acetate (three times, 8 mL each), with further washing of the
the growth of A. fumigatus and A. ustus, which proved to be
organic layer with H2O (three times, 8 mL each). The organic
resistant to a series of benzothiazole and benzoxazole deriva-
layer was dried with anhydrous Na2SO4 and analyzed by GC.
tives. We put a highlight on derivatives 4f (R ¼ 2-Cl) and 4k (R ¼
4-CH3), since they are new compounds that showed the best
inhibition power against these fungi species.
Antifungal susceptibility test
Further studies are ahead, in order to get closer to a mode of Bioactivity was determined by microdilution method, in accor-
action for these compounds. This includes structure–activity dance to Clinical and Laboratory Standard Institute (CLSI
relationships, and computational studies. The present work formerly the National Committee for Clinical Laboratory Stan-
constitutes a contribution to the design, optimization and dards [NCCLS]) (M27-A3 for yeasts and lamentous fungi)
redesign cycle for bioactive compounds, which will lead us to (moulds; the M38-A2 document). Assays were performed in
better and safer agrochemicals in the future.
enriched Czapek broth. The inoculum employed was 1–5 ꢁ 105
conidia per mL. Stock solutions of tested compounds were
prepared in DMSO to give serial two-fold dilutions to nal
concentrations of 3.1–100 mg Lꢀ1 (nal DMSO concentration #
Experimental
Chemicals
2%). Microtiter plates were incubated at 30 ꢂC for Aspergillus
ꢂ
2-Mercaptobenzothiazole, benzyl halides, K2CO3, KMnO4, and Fusarium spp., and at 22 C for B. cinerea in a moist and
FeCl3, acetonitrile were commercially available (Sigma, St. dark chamber. Inhibitory concentrations were recorded aer
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48 h for Aspergillus and Fusarium spp., and aer 72 h for B.
cinerea, according to the control fungal growth. The positive
control of the commercial antifungal Captan and solvent
control, using 2% aqueous DMSO, were included. All tests were
run in triplicate. The 50% Inhibitory Concentration (IC50) was
dened as the minimum concentration of the compound that
resulted in 50% inhibition of the fungal growth. IC50 values
were calculated by linear regression plots of % (inhibition) vs.
ln(concentration), considering 50% inhibition.
2-((4-Nitrobenzyl)sulfonyl)benzo[d]thiazole, 4e. White solid.
mp: 205.5–207.2 ꢂC. 1H-NMR (400 MHz, DMSO-d6), d (ppm):
5.35 (s, 2H), 7.61 (d, J ¼ 8.2 Hz, 2H), 7.68–7.77 (m, 2H), 8.21 (d, J
¼ 8.2 Hz, 1H), 8.29–8.32 (m, 2H). 13C-NMR (100 MHz, DMSO-
d6), d (ppm): 59.48, 123.99 (overlap), 125.45, 128.57, 128.80,
133.17, 135.28, 136.92, 148.26, 152.48, 165.79. MS (EI+) m/z (%):
334.90 (3), 333.90 (16), 270.90 (15), 269.95 (66), 223.95 (15),
222.95 (42), 136.00 (35), 135.00 (14), 133.95 (14), 110.00 (1),
109.05 (4), 107.95 (10), 107.00 (13), 106.05 (72), 91.00 (11), 90.00
(74), 89.00 (69), 79.05 (9), 78.00 (100), 77.00 (13), 69.00 (14),
64.00 (33), 63.00 (43). HRMS (ESI): (M + Na): C14H10N2O4S2Na,
calculated: 356.9974, found: 356.9985.
Spectral information
2-((2-Chlorobenzyl)sulfonyl)benzo[d]thiazole, 4f. White
solid. mp: 123.2–124.3 ꢂC. 1H-NMR (400 MHz, CDCl3), d (ppm):
4.97 (s, 2H), 7.23 (td, J ¼ 7.5 Hz, J ¼ 1.4 Hz, 1H), 7.28 (td, J ¼
7.8 Hz, J ¼ 1.6 Hz, 1H), 7.33 (d, J ¼ 7.8 Hz, 1H), 7.42 (dd, J ¼
7.5 Hz, J ¼ 1.3 Hz, 1H), 7.58 (td, J ¼ 7.1 Hz, J ¼ 0.9 Hz, 1H), 7.64
(td, J ¼ 7.7 Hz, J ¼ 1.2 Hz, 1H), 7.96 (d, J ¼ 8.1 Hz, 1H), 8.24 (d, J
¼ 8.1 Hz, 1H). 13C-NMR (100 MHz, CDCl3), d (ppm): 58.09,
122.29, 125.06, 125.63, 127.26, 127.70, 128.11, 130.01, 130.76,
133.09, 135.75, 137.31, 152.70, 164.93. MS (EI+) m/z (%): 288.15
(33), 261.20 (2), 260.10 (9), 259.10 (5), 258.10 (22), 224.10 (22),
223.05 (12), 127.10 (32), 125.10 (100), 99.05 (7), 90.10 (11), 89.10
(23), 63.05 (11). HRMS (ESI): (M + Na): C14H10NO2S2ClNa,
calculated: 345.9734, found: 345.9742.
2-((4-Bromobenzyl)sulfonyl)benzo[d]thiazole, 4g.28 White
solid. mp: 151.6–153.6 ꢂC. 1H-NMR (400 MHz, CDCl3), d (ppm):
4.71 (s, 2H), 7.15 (d, J ¼ 8.4 Hz, 2H), 7.41 (d, J ¼ 8.4 Hz, 2H), 7.60
(td, J ¼ 7.6 Hz, J ¼ 1.1 Hz, 1H), 7.66 (td, J ¼ 7.7 Hz, J ¼ 1.1 Hz,
1H), 7.97 (d, J ¼ 7.9 Hz, 1H), 8.25 (d, J ¼ 8.2 Hz, 1H). 13C-NMR
(100 MHz, CDCl3), d (ppm): 60.26, 122.39, 123.87, 125.42,
125.50, 127.78, 128.17, 132.16, 132.66, 136.99, 152.53, 164.88.
MS (EI+) m/z (%): 369.05 (5), 367.05 (5), 305.10 (14), 304.10 (32),
303.10 (13), 302.10 (29), 223.15 (14), 171.05 (76), 169.05 (100),
See spectroscopy data of compounds 5a–h.39
2-(Benzylsulfonyl)benzo[d]thiazole, 4a.42 Yellow solid. mp:
103.8–106.0 ꢂC. 1H-NMR (400 MHz, CDCl3), d (ppm): 4.76 (s,
2H), 7.26–7.32 (m, 5H), 7.58 (t, J ¼ 7.3 Hz, 1H), 7.65 (t, J ¼ 7.3 Hz,
1H), 7.94 (d, J ¼ 8.0 Hz, 1H), 8.26 (d, J ¼ 8.2 Hz, 1H). 13C-NMR
(100 MHz, CDCl3), d (ppm): 61.03, 122.30, 125.50, 126.36,
127.66, 128.01, 128.92, 129.24, 131.13, 137.08, 152.59, 165.21.
MS (EI+) m/z (%): 289.00 (3), 225.15 (20), 224.05 (52), 91.05 (100),
65.05 (17). HRMS (ESI): (M + Na): C14H11NO2S2Na, calculated:
312.0123, found: 312.0138.
2-((4-Fluorobenzyl)sulfonyl)benzo[d]thiazole, 4b. White
solid. mp: 141.8–143.4 ꢂC. 1H-NMR (400 MHz, CDCl3), d (ppm):
4.72 (s, 2H), 6.96 (t, J ¼ 8.6 Hz, 2H), 7.25 (dd, J ¼ 8.5 Hz, J ¼
5.2 Hz, 2H), 7.58 (t, J ¼ 7.5 Hz, 1H), 7.64 (t, J ¼ 7.2 Hz, 1H), 7.95
(d, J ¼ 8.1 Hz, 1H), 8.24 (d, J ¼ 8.1 Hz, 1H). 13C-NMR (100 MHz,
CDCl3), d (ppm): 60.13, 116.05 (d, J2 ¼ 21.8 Hz), 122.26 (d, J4
F–C
F–
¼ 3.4 Hz), 122.34, 125.48, 127.73, 128.11, 132.96 (d, J3 ¼ 8.5
C
F–C
Hz), 137.01, 152.56, 163.30 (d, J1 ¼ 249.4 Hz), 165.02. MS (EI+)
F–C
m/z (%): 306.90 (4), 242.95 (9), 241.95 (26), 110.00 (7), 109.00
(100), 108.05 (2), 107.00 (3), 90.00 (4), 89.00 (2), 83.00 (17), 68.95
(2), 63.00 (6). HRMS (ESI): (M + Na): C14H10NO2S2FNa, calcu-
lated: 330.0029, found: 330.0039.
90.15 (56), 89.10 (35), 63.05 (17). HRMS (ESI): (M + Na): C14
H10NO2S2BrNa, calculated: 389.9229, found: 389.9241.
-
2-((4-(Triuoromethyl)benzyl)sulfonyl)benzo[d]thiazole,
4c.29 White solid. mp: 180.1–181.5 ꢂC. 1H-NMR (400 MHz,
CDCl3), d (ppm): 4.81 (s, 2H), 7.43 (d, J ¼ 8.0, 2H), 7.55 (d, J ¼
8.1, 2H), 7.59 (t, J ¼ 8.0, 1H), 7.66 (t, J ¼ 7.3, 1H), 7.96 (d, J ¼ 7.9,
1H), 8.25 (d, J ¼ 8.2, 1H). 13C-NMR (100 MHz, CDCl3), d (ppm):
60.35, 122.37, 123.84 (q, J1 ¼ 272.7 Hz), 125.50, 125.83 (q, J3
2-((2-Bromobencyl)sulfonil)benzo[d]tiazol, 4h. White solid.
mp: 147.2–148.7 ꢂC. 1H-NMR (400 MHz, CDCl3), d (ppm): 4.99 (s,
2H), 7.21 (t, J ¼ 7.1 Hz, 1H), 7.29 (t, J ¼ 7.3 Hz, 1H), 7.44 (d, J ¼
7.3 Hz, 1H), 7.52 (d, J ¼ 7.8 Hz, 1H), 7.59 (t, J ¼ 7.3 Hz, 1H), 7.65
(t, J ¼ 7.4 Hz, 1H), 7.97 (d, J ¼ 8.0 Hz, 1H), 8.24 (d, J ¼ 8.1 Hz,
1H). 13C-NMR (100 MHz, CDCl3), d (ppm): 60.51, 122.29, 125.66,
126.18, 126.91, 127.71, 127.90, 128.11, 130.90, 133.12, 133.39,
137.38, 152.71, 164.86. MS (EI+) m/z (%): 304.85 (5), 303.85 (20),
302.90 (5), 301.90 (19), 288.90 (12), 287.95 (65), 223.95 (35),
222.95 (22), 170.90 (66), 168.90 (67), 91.05 (9), 90.00 (100), 89.00
(64), 64.00 (14), 63.00 (35). HRMS (ESI): (M + Na): C14H10NO2-
S2BrNa, calculated: 389.9229, found: 389.9226.
F–C
F–
¼ 3.7 Hz), 127.83, 128.24, 131.29 (d, J2
¼ 32.7 Hz), 131.55,
C
F–C
136.96, 152.51, 164.82. MS (EI+) m/z (%): 356.95 (4), 293.10 (34),
292.15 (63), 222.95 (7), 159.10 (100), 133.85 (5), 118.90 (9),
109.15 (30), 107.90 (6), 88.95 (5), 69.00 (4), 63.00 (10). HRMS
(ESI): (M + Na): C15H10NO2S2F3Na, calculated: 379.9997, found:
379.9989.
4-((Benzo[d]thiazol-2-ylsulfonyl)methyl)benzonitrile,
4d.
White solid. mp: 185.5–186.8 ꢂC. 1H-NMR (400 MHz, CDCl3),
d (ppm): 4.81 (s, 2H), 7.41 (d, J ¼ 8.1 Hz, 2H), 7.57 (d, J ¼ 8.0 Hz,
2H), 7.61 (d, J ¼ 7.7 Hz, 1H), 7.66 (t, J ¼ 7.6 Hz, 1H), 7.96 (d, J ¼
8.0 Hz, 1H), 8.24 (d, J ¼ 8.1 Hz, 1H). 13C-NMR (100 MHz, CDCl3),
d (ppm): 60.46, 113.35, 118.01, 122.41, 125.52, 127.93, 128.38,
131.73, 131.88, 132.53, 136.90, 152.44, 164.55. MS (EI+) m/z (%):
314.20 (4), 250.25 (31), 249.15 (65), 116.15 (100), 90.15 (13),
89.15 (30), 63.10 (12). HRMS (ESI): (M + Na): C15H10N2O2S2Na,
calculated: 337.0076, found: 337.0091.
2-((4-Iodobenzyl)sulfonyl)benzo[d]thiazole, 4i. White solid.
mp: 177.5–179.2 ꢂC. 1H-NMR (400 MHz, CDCl3), d (ppm): 4.70 (s,
2H), 7.01 (d, J ¼ 8.2 Hz, 2H), 7.79–7.48 (m, 4H), 7.97 (d, J ¼
8.1 Hz, 1H), 8.25 (d, J ¼ 8.1 Hz, 1H). 13C-NMR (100 MHz, CDCl3),
d (ppm): 60.39, 95.68, 122.39, 125.50, 126.04, 127.77, 128.16,
132.79, 136.99, 138.12, 152.54, 164.90. MS (EI+) m/z (%): 414.85
(8), 351.00 (24), 349.95 (29), 224.15 (18), 223.25 (14), 217.05
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(100), 90.15 (66), 89.10 (37), 63.00 (22). HRMS (ESI): (M + Na):
Notes and references
C
14H10NO2S2INa, calculated: 437.9090, found: 437.9088.
2-((2-Iodobenzyl)sulfonil)benzo[d]tiazol, 4j. White solid. mp:
1 P. E. Russell, J. Agric. Sci., 2005, 143, 11–25.
2 Y. Elad, Biol. Rev., 1997, 72, 381–422.
3 Y. Elad, Biocontrol Sci. Technol., 2000, 10, 499–507.
4 A. D. Omer, J. Granett and R. J. Wakeman, J. Phytopathol.,
1999, 147, 433–436.
5 C. S. Carranza, C. L. Barberis, S. M. Chiacchiera and
C. E. Magnoli, Rev. Argent. Microbiol., 2017, 49, 384–393.
6 Y. Wang, Y. Bao, D. Shen, W. Feng, T. Yu, J. Zhang and
X. D. Zheng, Int. J. Food Microbiol., 2008, 123, 234–239.
7 J. P. Munafo and T. J. Gianfagna, J. Agric. Food Chem., 2011,
59, 5945–5954.
8 M. S. M. Mohamed, A. M. Saleh, I. B. Abdel-Farid and S. A. El-
Naggar, Pestic. Biochem. Physiol., 2017, 141, 57–64.
9 P.-K. Chang, B. W. Horn, K. Abe and K. Gomi, in Encyclopedia
of Food Microbiology, 2014, vol. 1, pp. 77–82.
162.1–163.4 ꢂC. 1H-NMR (400 MHz, CDCl3), d (ppm): 5.00 (s,
2H), 7.02 (t, J ¼ 7.6 Hz, 1H), 7.32 (t, J ¼ 7.5 Hz, 1H), 7.45 (d, J ¼
7.7 Hz, 1H), 7.59 (dd, J ¼ 11.6, 4.5 Hz, 1H), 7.64 (dd, J ¼ 11.2,
4.1 Hz, 1H), 7.81 (d, J ¼ 7.9 Hz, 1H), 7.97 (d, J ¼ 8.2 Hz, 1H), 8.25
(d, J ¼ 8.0 Hz, 1H). 13C-NMR (100 MHz, CDCl3), d (ppm): 64.96,
102.18, 122.28, 125.69, 127.69, 128.10, 128.71, 130.51, 130.82,
132.35, 137.44, 140.22, 152.74, 164.96. MS (EI+) m/z (%): 350.80
(4), 349.80 (18), 287.90 (52), 223.95 (25), 222.95 (16), 216.85 (58),
91.05 (10), 90.00 (100), 89.05 (48), 64.00 (12), 63.05 (24). HRMS
(ESI): (M + Na): C14H10NO2S2INa, calculated: 437.9090, found:
437.9076.
2-((4-Methylbenzyl)sulfonyl)benzo[d]thiazole, 4k. White
solid. mp: 113.3–115.1 ꢂC. 1H-NMR (400 MHz, CDCl3), d (ppm):
2.30 (s, 3H), 4.72 (s, 2H), 7.08 (d, J ¼ 7.9 Hz, 2H), 7.15 (d, J ¼
8.0 Hz, 2H), 7.59 (dd, J ¼ 11.2 Hz, J ¼ 4.0 Hz, 1H), 7.65 (dd, J ¼
11.3 Hz, J ¼ 4.1 Hz, 1H), 7.95 (d, J ¼ 8.1 Hz, 1H), 8.26 (d, J ¼
8.2 Hz, 1H). 13C-NMR (100 MHz, CDCl3), d (ppm): 21.22, 60.74,
122.30, 123.17, 125.49, 127.61, 127.95, 129.65, 130.98, 137.07,
139.27, 152.63, 165.41. MS (EI+) m/z (%): 303.15 (4), 239.25 (7),
238.15 (22), 223.10 (2), 105.15 (100), 90.10 (3), 77.05 (10), 63.00
´
10 F. Alvarez Lerma, P. Olaechea Astigarraga, M. Palomar
´
´
Martınez, M. Rodrıguez Carvajal, J. F. Machado Casas,
´
M. M. Jimenez Quintana, F. Esteve Urbano,
´
J. C. Ballesteros Herraez and E. Zavala Zegarra, Med.
Intensiva, 2015, 39, 149–159.
11 P. Bhatnagar-Mathur, S. Sunkara, M. Bhatnagar-Panwar,
F. Waliyar and K. K. Sharma, Plant Sci., 2015, 234, 119–132.
12 X. Pan, S. Xu, J. Wu, J. Luo, Y. Duan, J. Wang, F. Zhang and
M. Zhou, Pestic. Biochem. Physiol., 2018, 145, 8–14.
13 W. Xu, J. He, M. He, F. Han, X. Chen, Z. Pan, J. Wang and
M. Tong, Molecules, 2011, 16, 9129–9141.
(3). HRMS (ESI): (M
+ Na): C15H13NO2S2Na, calculated:
326.0280, found: 326.0284.
2-((4-Fluorobenzyl)sulfonyl)benzo[d]oxazole, 6b. MS (EI+) m/
z (%): 291.20 (1), 226.15 (23), 227.15 (7), 110.20 (8), 109.00 (100),
108.05 (2), 107.00 (5), 93.95 (1), 90.95 (1), 90.00 (3), 89.00 (2),
83.00 (11), 68.95 (2), 64.00 (6), 63.00 (7).
ˇ´
ˇ
´
´
14 J. Kocı, V. Klimesova, K. Waisser, J. Kaustova, H.-M. Dahse
2-((4-(Triuoromethyl)benzyl)sulfonyl)benzo[d]oxazole, 6c.
MS (EI+) m/z (%): 341.05 (2), 278.20 (2), 277.15 (20), 276.10 (58),
249.15 (2), 248.10 (7), 208.10 (4), 160.10 (9), 159.05 (100), 120.15
(1), 119.10 (7), 110.10 (2), 109.10 (25), 107.10 (1), 91.10 (2), 90.10
(8), 89.00 (4), 65.05 (1), 64.00 (7), 63.05 (9). HRMS (ESI): (M + Na):
¨
and U. Mollmann, Bioorg. Med. Chem. Lett., 2002, 12, 3275–
3278.
15 R. S. Keri, M. R. Patil, S. a. Patil and S. Budagumpi, Eur. J.
Med. Chem., 2015, 89, 207–251.
16 D. E. McNamara, S. Senese, T. O. Yeates and J. Z. Torres,
Protein Sci., 2015, 24, 1164–1172.
17 F. Chemla, J. Chem. Soc., Perkin Trans. 1, 2002, 275–299.
18 T. G. Back, Tetrahedron, 2001, 57, 5263–5301.
19 L. A. Paquette, Synlett, 2001, 2001, 1–12.
20 C. Najera and M. Yus, Tetrahedron, 1999, 55, 10547–10658.
21 C. Zhao, Y. Zhao, H. Chai and P. Gong, Bioorg. Med. Chem.,
2006, 14, 2552–2558.
22 M. Rahimizadeh, G. Rajabzadeh, S. M. Khatami, H. Eshghi
and A. Shiri, J. Mol. Catal. A: Chem., 2010, 323, 59–64.
23 R. Afrasiabi, M. R. Farsani and B. Yadollahi, Tetrahedron
Lett., 2014, 55, 3923–3925.
24 B. Maleki, S. Hemmati, A. Sedrpoushan, S. S. Ashra and
H. Veisi, RSC Adv., 2014, 4, 40505–40510.
C
15H10NO3SF3Na, calculated: 364.0226, found: 364.0234.
2-((4-Bromobenzyl)sulfonyl)benzo[d]oxazole, 6g. MS (EI+) m/
z (%): 353.95 (1), 353.00 (3), 351.00 (3), 289.95 (1), 289.15 (7),
288.15 (24), 287.15 (7), 286.15 (24), 209.15 (1), 208.15 (6), 207.15
(3), 172.10 (7), 171.05 (77), 170.10 (6), 169.05 (100), 91.10 (6),
90.15 (53), 89.10 (32), 65.05 (1), 64.05 (12), 63.05 (17).
´
2-((2-Bromobenzyl)sulfonyl)benzo[d]oxazole, 6h. MS (EI+) m/
z (%): 289.10 (3), 288.10 (16), 287.10 (3), 286.05 (17), 273.20
(119), 272.15 (75), 209.15 (6), 208.15 (37), 207.05 (10), 172.05 (7),
170.95 (83), 169.00 (100), 91.10 (8), 90.10 (66), 89.05 (45), 87.10
(1), 65.05 (2), 64.05 (14), 63.05 (23), 62.05 (5). HRMS (ESI): (M +
Na): C14H10NO3SBrNa, calculated: 373.9457, found: 373.9470.
25 N. Xie, R. A. Binstead, E. Block, W. D. Chandler, D. G. Lee,
T. J. Meyer and M. Thiruvazhi, J. Org. Chem., 2000, 65,
1008–1015.
26 S. Lai and D. G. Lee, Tetrahedron, 2002, 58, 9879–9887.
27 A. Shaabani, P. Mirzaei, S. Naderi and D. G. Lee, Tetrahedron,
2004, 60, 11415–11420.
Conflicts of interest
There are no conicts of interest to declare.
Acknowledgements
28 M. T. Makhija, R. T. Kasliwal, V. M. Kulkarni and
N. Neamati, Bioorg. Med. Chem., 2004, 12, 2317–2333.
This work was supported in part by CONICET, CICITCA UNSJ,
SECYT and ANPCyT. M. S. B. and N. H. C. gratefully acknowl-
edge receipt of a fellowship from CONICET.
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¨
¨
29 N. Allendorfer, M. Es-Sayed, M. Nieger and S. Brase, 36 L. Xu, J. Cheng and M. L. Trudell, J. Org. Chem., 2003, 68,
Synthesis, Stuttg, 2010, pp. 3439–3448. 5388–5391.
30 N. K. Konduru, S. Dey, M. Sajid, M. Owais and N. Ahmed, 37 R. Afrasiabi, F. Jalilian, B. Yadollahi and M. R. Farsani, Inorg.
Eur. J. Med. Chem., 2013, 59, 23–30. Chem. Commun., 2014, 50, 113–116.
31 A. Dishington, S. Fillery and M. R. V. Finlay, Tetrahedron 38 D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy,
Lett., 2010, 51, 4211–4213.
32 J. S. Yadav, P. V. Reddy and L. Chandraiah, Tetrahedron Lett.,
2007, 48, 145–148.
S. Abou-Shehada and P. J. Dunn, Green Chem., 2016, 18,
288–296.
39 M. S. Ballari, N. Herrera Cano, A. G. Lopez, D. A. Wunderlin,
´
33 M. Bagherzadeh, J. Chem. Res., 2003, 765–767.
34 A. Ghaemi, S. Rayati, S. Zakavi and N. Safari, Appl. Catal., A,
2009, 353, 154–159.
G. E. Feresın and A. N. Santiago, J. Agric. Food Chem., 2017,
65, 10325–10331.
40 A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725–748.
35 V. Mirkhani, S. Tangestaninejad, M. Moghadam, 41 H. A. Alwathnani and K. Perveen, Afr. J. Biotechnol., 2012, 11,
I. Mohammadpoor-Baltork and Z. Saedi, J. Iran. Chem.
Soc., 2010, 7, 673–677.
1100–1105.
42 A. K. Ghosh and B. Zajc, Org. Lett., 2006, 8, 1553–1556.
This journal is © The Royal Society of Chemistry 2019
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