Synthesis of 2-arylbenzothiazoles via direct condensation between in situ generated 2-aminothiophenol from disulfide cleavage and carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2017.04.078

In this work we describe a simple and efficient general methodology for 2-arylbenzothiazole preparation employing disulfides and carboxylic acids. The reaction is promoted by tributylphosphine that acts both in disulfide bond cleavage and as activating agent for coupling with carboxylic acids. The reaction scope was studied using bis(2-aminophenyl)disulfide and different carboxylic acids with donor/withdrawing substituents, which resulted in the desired 2-arylbenzothiazole with moderate to good yields. The method was tested with success in preparation of the amyloid probe 2-(4-aminophenyl)-6-methoxybenzothiazole that employed a substituted bis(2-aminophenyl)disulfide.

Full text of DOI:10.1016/j.tetlet.2017.04.078

Accepted Manuscript
Synthesis of 2-arylbenzothiazoles via direct condensation between in situ gen-
erated 2-aminothiophenol from disulfide cleavage and carboxylic acids
Felipe L. Coelho, Leandra F. Campo
PII:
S0040-4039(17)30532-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.078
TETL 48870
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 February 2017
19 April 2017
24 April 2017
Please cite this article as: Coelho, F.L., Campo, L.F., Synthesis of 2-arylbenzothiazoles via direct condensation
between in situ generated 2-aminothiophenol from disulfide cleavage and carboxylic acids, Tetrahedron Letters
(
2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.078
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Synthesis of 2-arylbenzothiazoles via direct
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Felipe L. Coelho, Leandra F. Campo

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Tetrahedron Letters
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Synthesis of 2-arylbenzothiazoles via direct condensation between in situ generated 2-
aminothiophenol from disulfide cleavage and carboxylic acids
Felipe L. Coelho, Leandra F. Campo∗
Institute of Chemistry, Department of Organic Chemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 91501-970, Brazil
ARTICLE INFO
ABSTRACT
Article history:
Received
In this work we describe a simple and efficient general methodology for 2-arylbenzothiazole
preparation employing disulfides and carboxylic acids. The reaction is promoted by
tributylphosphine that acts both in disulfide bond cleavage and as activating agent for coupling
with carboxylic acids. The reaction scope was studied using bis(2-aminophenyl)disulfide and
different carboxylic acids with donor/withdrawing substituents, which resulted in the desired 2-
arylbenzothiazole with moderate to good yields. The method was tested with success in
preparation of the amyloid probe 2-(4-aminophenyl)-6-methoxybenzothiazole that employed a
substituted bis(2-aminophenyl)disulfide.
Received in revised form
Accepted
Available online
Keywords:
Phosphorus nucleophiles
Disulfide bond scission
Arylbenzothiazoles synthesis
o-Aminodisulfides
2
017 Elsevier Ltd. All rights reserved.
Cyclocondensation

2
Several benzothiazole, especially 2-arylbenzothiazoles, have
been disclosed in patent literature as scaffold tau-binding agents
Scheme 1. Synthetic routes for 2-arylbenzothiazoles preparation from stable
disulfides.
1-12
for Alzheimer’s disease (AD) diagnostic agent development.
Currently, definitive confirmation of AD is only possible through
post-mortem histopathologic studies with use of dyes such as
thioflavin T (ThT), congo red, or chrysamine G that stain β-
Apart
from
this,
7
nucleophilic
cleavage of
the S-S bond
in both alkyl
disulfides and
aromatic
amyloid (Aβ) deposits. Among them, the preference for
benzothiazole pattern is based on its structural similarity to ThT,
that represent one of the most brightest agent for imaging of Aβ
plaques. Because ThT is positively charged it is incapable of
penetrating the brain-blood barrier. This has led to the
development of neutral derivatives of ThT dye for potential in
vivo imaging studies.
disulfides by
phosphorus
A literature survey reveals a large number of methods for 2-
arylbenzothiazoles synthesis, in most cases, via o-
aminothiophenol condensation with the substituted aromatic
nucleophiles
is described
at least since
1
3-17
29
aldehydes, carboxylic acids or their derivatives.
recently, a visible-light promoted synthesis of benzothiazoles
More
1
965, and nowadays trialkylphosphines are, for example, highly
effective agents for reducing disulfide bonds in proteins, peptides
and other disulfide bond containing molecules and are relatively
1
8
from 2-aminothiophenols and aldehydes has been developed.
Furthermore, 2-arylbenzothiazole derivatives were obtained
under the action of resin supported under microwave
30
non-reactive toward other functional groups. Although 2-
arylbenzothiazoles synthesis starting from disulfides and
aldehydes have been well described, the use of carboxylic acids
still play attention. Carboxylic acids expand the scope of the
benzothiazoles obtained and improves in chemoselectivity since
reactivity of acids compared with aldehydes and acyl chlorides
are lower and tolerates more functional groups. Through reaction
of stable 2-aminothiophenol disulfides with carboxylic acids
promoted by tributylphosphine, we have been obtained 2-
arylbenzothiazoles with moderate yields, including the 6-OH-
BTA, widely used as Aβ plaques imaging agent.
1
9
irradiation,
triphenylphosphine. The Jacobsen cyclization of substituted
thiobenzamide in presence of aqueous sodium hydroxide and
and in the presence of polymer-supported
20
21
potassium ferricyanide followed by reduction was the method
chosen by Mathis et al. to obtain the neutral analogue of ThT, 2-
4'-aminophenyl)-6-hydroxibenzothiazole (6-OH-BTA). In this
22
(
approach, a previous step of benzamide thionation by use of
Lawesson’s reagent is necessary and results in total five steps to
prepare the 6-OH-BTA.
The 2-arylbenzothiazoles synthesis employing stable o-
aminothiophenol disulfides represent an remarkable approach to
overcome the stability limitations of readily oxidizable o-
Scheme 2 shows synthetic route for 6-OH-BTA. In the first
step, disulfide 2 was obtained by the reported method of
3
1
hydrolysis of benzothiazole 1 with aqueous sodium hydroxide.
Cleavage of 1 in 10 M NaOH at reflux affords the o-
aminothiophenol (not isolated) that is unstable and is oxidized by
1
4
aminothiophenols, mainly for substituted o-aminothiophenols.
Added to this, the use of this methodology avoids the use of toxic
reagents such as potassium ferricyanide and the Lawesson’s
reagent. Scheme 1 highlights some methods that use the disulfide
bond scission to access 2-arylbenzothiazoles. Cyclocondensation
reaction between o-aminodisulfides and aldehydes (Method A) is
a well studied methodology that lead to 2-arylbenzothiazoles
24
3
1
traces of oxygen into the respective disulfide 2. Bis(5-
methoxyanilin-2-yl)disulphide (2) was reduced by PBu and
3
reacted in situ with p-aminobenzoic acid (3b). 2-(4’-
aminophenyl)-6-methoxybenzothiazole (4) was isolated with
32% yield (Table 1, entry 1), proving that PBu can promote the
3
condensation between disulfide 2 and acid 3b. This result let us
2
3
using different systems as Na
2
S.9H
2
O/NaHCO
/p-TsOH and PEG
00/400 assisted by microwave. Reductive cyclization of
3
, MCM-41/O ,
2
1
7
25
20
CuCl
2
/TBHP, copper, supported PPh
3
to investigate this reaction to improve the method.
2
6
2
disulfides (Method B) were reported employing different
reducing agents for the reaction between o-aminodisulfides and
Scheme 2. Synthetic route for 2-(4’-aminophenyl)-6-methoxybenzothiazole
2
acyl chlorides. Also, o-iminedisulfides were isolated and
7
(
6-OH-BTA).
cyclizated employing TiCl
arylbenzothiazoles (Method C).
4
/Sm to afford desired 2-
2
8
The reaction conditions for the synthesis of 4 were optimized
3
by varying the molar concentration of PBu and acid 3b and the
time of reaction. An excess of acid or disulfide did not produce a
significant increase in the yield in comparison with equimolar
quantities (Table 1, entries 1 and 3). Increasing the molar
concentration of PBu
increase of 20% in the yield (Table 1, entry 5). Increasing the
PBu concentration up to 2.5 equivalents or keeping reaction for
3
from 1 to 2 equivalents produced an
3
longer time than 72 hours did not result in better yields (Table 1,
entry 6).
Table 1. Reaction condition optimization for synthesis of 2-(4’-aminophenyl)-6-methoxybenzothiazole 4.
b
Yield (%)
Entry
2 (mmol)
3b (mmol)
PBu
3
(mmol)
Time (h)

3
3
4
5
6
1.5
1
1
1
1
1
1
72
72
38
47
59
60
1.5
2
1
72
1
2.5
120
a
Reaction conditions: Disulfide 2, tributylphosphine (1-2.5 equiv.) in dry toluene (20 mL) were agitated at rt for 10 min. Next, p-aminobenzoic acid 3b (1-2
equiv.) was added and the solution was refluxed for the indicated time.
b
Isolated yield based on 1 mmol scale.
Finally, 6-OH-BTA 5 was obtained by demethylation of 6-
was slightly lower than the same procedure on a smaller scale
(79% for 1 mmol scale and 75% for 30 mmol scale).
OMe-BTA 4 with boron tribromide (BBr
3
) in a similar way to
that reported by Mathis afforded the desired product in a
quantitative yield. Before BBr , two other methods were
22
The attempt to use this methodology to obtain 2-
arylbenzothiazoles from disulfides containing the nitro group
was not successful. The hydrolysis of 2-aminobenzo[d]thiazole-
6-nitro do not afforded the desired disulfide resulting in a black
solid very insoluble and difficult to characterize (results not
showed). The second attempt to synthesize a disulfide having an
electron withdrawing substituent was done from the hydrolysis of
3
employed without success in demethylation of 4. In the first one
was used 2 equiv. of bromidric acid (47%) and 1.1 equiv. of NaI
3
2
in acetic acid at reflux for 24 h and the other one applied 10
3
3
4
equiv. of ionic liquid [Bmim][BF ] in bromidric acid (47%), as
the solvent, at 80 ºC for 12 h and did not produce the
demethylated product.
2
-aminobenzo[d]thiazole-6-bromo, obtained in the same way of
Since the condensation between disulfide
2
and p-
2-aminobenzo[d]thiazole-6-methoxy. The hydrolysis of 2-
aminobenzo[d]thiazole-6-bromo provide the bis(5-bromoanilin-
2-yl)disulfide which was condensed with 4-aminobenzoic acid to
afford the 2-(4’-aminophenyl)-6-bromobenzothiazole in 70%
yield (Supplementary Information S5).
aminobenzoic acid 3b was shown to efficiently obtain the
arylbenzothiazole 4 (6-OH-BTA), the scope of this methodology
was investigated (Table 2) using benzoic acid and aromatic
carboxylic acids containing electron-rich and electron-
withdrawing groups (Table 2, entries 1-7). Initially, a simple
bis(2-aminophenyl)disulfide 2a containing no substituent was
prepared by oxidation of 2-aminothiophenol in air. Disulfide 2a
was reacted with benzoic acid and the benzothiazole 4a was
obtained with 90% yield (Table 2, entry 1). Interestingly, the
reaction of disulfide 2a with p-nitrobenzoic acid resulted in the
amino-substituted 4b in detriment of the product with the nitro
group. Arylbenzothiazoles were also obtained from ortho and
meta substituted carboxylic acids (entries 6-7) with good yields.
The highest and lowest yields were obtained from the acid
containing the more electron-rich amino groups 3f and the more
electron-withdrawing nitro group 3c, respectively. We also
performed a scale-up reaction containing 30 mmol of 4-
Based on these results and those previously reported in the
29,30
literature,
a plausible mechanism is proposed for direct
condensation between disulfides and carboxylic acids (Scheme
). Tributylphosphine promotes cleavage of the S-S bond of
disulfide 2a by nucleophilic attack resulting in a thiolate 8 and a
3
29
phosphonium salt 9. Thiolate acts as a base by deprotonating
the carboxylic acid, and the carboxylate reacts with the
phosphonium
acyloxyphosphonium intermediate 10, as reported by Mamdapur
salt
forming
a
pentacoordinate
34
et al. for diselenides. Intramolecular nucleophilic attack of the
amino group to the carbonyl releases amide 11 and
tributylphosphoxide. Finally, an intramolecular cyclization of
amide 11 via a subsequent step of nucleophilic attack of the thiol
group on the carbonyl followed by dehydration leads to
aminosalicylic
Supplementary Information, S5). It is interesting pointed that
when we scaling up this reaction from 1 to 30 mmol, the yield
acid
and
bis(2-aminophenyl)disulfide
(
16
benzothiazole 4.
Table 2. Expansion of the reaction scope in the synthesis of arylbenzothiazoles via condensation between disulfide 2a and
a
carboxylic acids (3a-g).
b
Yield (%)
Entry
1
Carboxylic acid
1,3-Benzothiazole
90
2
3
4
5
6
88
b
47
70
74
92

4
7
79
a
Reaction conditions: Disulfide 2a, tributylphosphine (2 equiv.) in dry toluene (20 mL) were agitated at room temperature for 10 min. Next, acids 3a-g (1 equiv.)
b
were added and the solution was refluxed for 72 h reaction was conducted in anoxic conditions. The 1,3-Benzothiazole with the nitro group was not detected.
b
Isolated yields based on 1 mmol scale.
1
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