α-Keto Acids as Acylating Agents in the Synthesis of 2-Substituted Benzothiazoles and Benzoselenazoles

Article abstract of DOI:10.1002/ejoc.201700648

Herein, we report the first decarboxylative oxidation of α-keto acids that is promoted by sodium metabisulfite (Na₂S₂O₅) to obtain 2-substituted benzothiazoles and benzoselenazoles. Diaryl disulfides and diselenides were used as chalcogen sources, and the desired products were obtained in moderate to excellent yields. This protocol does not require an inert gas, transition metals, or harsh reaction conditions, and CO₂ is released as an environmentally benign coproduct. The presence of Na₂S₂O₅ was essential to guarantee that the reaction reached completion and afforded maximum product yields.

Full text of DOI:10.1002/ejoc.201700648

A Journal of
Accepted Article
Title: α-Keto acids as green acylating agents in the synthesis of 2-
substituted benzothiazoles and benzoselenazoles
Authors: David B Lima, Filipe Penteado, Marcelo M Vieira, Diego
Alves, Gelson Perin, Claudio Santi, and Eder Joao Lenardao
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700648
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10.1002/ejoc.201700648
European Journal of Organic Chemistry
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α-Keto acids as acylating agents in the synthesis of 2-substituted
benzothiazoles and benzoselenazoles
David B. Lima,[a] Filipe Penteado,[a] Marcelo M. Vieira,[a] Diego Alves,[a] Gelson Perin,[a] Claudio Santi[b]
and Eder J. Lenardão*[a]
Abstract: Herein is reported the first decarboxylative oxidation of α-
keto acids promoted by sodium metabisulfite (Na2S2O5) to obtain 2-
substituted benzothiazoles and benzoselenazoles. Diaryl disulfides
and diselenides were used as chalcogen sources and the desired
products were obtained in moderate to excellent yields. This protocol
does not require inert atmosphere, transition metals or drastic
reaction conditions and CO2 is released as an environmental benign
co-product. The presence of Na2S2O5 was essential to guarantee the
reaction completion and maximum yield of products.
compounds involve the cross-coupling reaction between 2-H-
benzothiazoles and aryl halides,14 aryl silanes,15 aromatic
carboxylic acids,16 boronic acids17 and aryl triflates,18 using
transition metal catalysis.
Introduction
Organochalcogen compounds is an important class of
compounds, with a wide range of applications, being used in
organic synthesis as useful building blocks to obtain complex
molecules1 and as catalysts,2 besides presenting a plenty of
pharmacological activities.3 Among them, benzothiazoles and
benzoselenazoles are important scaffolds, that are protagonists
in several fields of science, such as medicinal chemistry4-7 and
materials.8
Considering the pharmacological activity of this class of
compounds, 2-arylbenzothiazole A (GW 610) presented potent
antiproliferative activity, selective for the NCI 60 human cancer
cell line panel,5a while Phortress (B) is an experimental antitumor
agent with potent and selective activity against human-derived
breast carcinomas (Figure 1).5b 2-Substituted benzoselenazole
Fluselenamyl (C) has been studied for the treatment of
Alzheimer’s disease (AD), and may become a commercial drug
in a nearly future.6a 2-Arylbenzothiazole Pittsburgh compound B
(D) was clinically approved for amyloid-imaging positron
emission tomography (PET) tracer in AD diagnosis.6b Riluzole®
(E) is the most famous benzothiazole derivative, which is a
worldwide marketed drug for the treatment of amyotrophic lateral
sclerosis (ALS; motor neuron disease).7
Figure 1. Benzothiazoles and benzoselenazole with pharmacological activities.
Unfortunately, many limitations are found in these
methodologies, such as, the use of 2-aminobenzenethiols as
starting material, which presents an unpleased smell, is hard to
handle and toxic. Besides, it acts as a catalyst poison, being
readily oxidized to the respective stable disulfide.19 Another
drawback of the current methods is the utilization of unstable
acyl transfer groups, such as aldehydes and acyl chlorides.
In this context, α-keto acids have received much attention
recently, both as an efficient acyl transfer in acylation reactions20
and
a
versatile reagent to build many heterocycles.21
Furthermore, it is quite interesting the use of these compounds
in organic synthesis, since pyruvic acid, a simple naturally-
occurring α-keto acid,22 is involved in an important
decarboxylative key path insight cellular respiration in aerobic
organisms.23 Besides the biological importance of this
decarboxylative process, α-keto acids have a great appeal as a
green acyl transfer group, if it is considered the releasing of CO2
as a green by-product of the reaction.
2-Substituted benzothiazoles can be obtained through the
condensation of 2-aminobenzenethiol with aromatic aldehydes,9
carboxylic acids,10 acyl chlorides,10d,11 alcohols,12 or through
radical cyclization of phenylthioformamides promoted by
K3[Fe(CN)6].13 Other successful approaches to obtain these
This peculiar feature of α-keto acids was recently explored
by us in the synthesis of 2-arylbenzothiazoles and 3-
substituted benzoxazin-2-ones
through the
oxidative
decarboxylation of α-keto acids catalyzed by ammonium
niobium oxalate (ANO), in the presence of PEG-400 as the
solvent. This protocol afforded the desired products in
moderate to good yields in short reaction times.24
Recently, Westwell and co-workers have reported an
efficient protocol to synthesize benzothiazoles from aldehydes
using Na2S2O5 as catalyst and DMSO as the solvent.25 In
addition, in 2013, Radatz and co-workers expanded the
Westwell‘s methodology to selenium derivatives, in order to
obtain benzoselenazoles.26 Although the methodology proved
to be effective, high reaction time was necessary to afford
products in good yields. This problem was circumvented by
Radatz and co-workers by employing microwave irradiation to
[a]
D. B. Lima, F. Penteado, M. M. Vieira, Prof. D. Alves, Prof. G. Perin,
Prof. E. J. Lenardão.
Laboratório de Síntese Orgânica Limpa – LASOL
Federal University of Pelotas – UFPel
P.O. Box 354, 96010-900, Pelotas – RS, Brazil.
E-mail: lenardao@ufpel.edu.br
www. http://lattes.cnpq.br/9974684005171829
Prof. C. Santi.
Department of Pharmaceutical Sciences
University of Perugia
[b]
Via del Liceo, 1, Perugia (PG), Italy.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700648
European Journal of Organic Chemistry
FULL PAPER
afford benzoselenazoles in short reaction times.
4
5
3
DMSO
DMSO
DMF
3
5
80
57
77
29
75
61
53
30
In continuation to our efforts in developing new
approaches to obtain important structures, we described herein
none
a
new methodology to prepare benzothiazoles and
6
2
2
2
2
2
2
20
20
3
benzoselenazoles by the reaction of α-keto acids 1 with diaryl
disulfides 2 and diselenides 3, respectively and Na2S2O5 as an
oxidant.
7
PEG-400
glycerol
H2O
8
9
5
10[d]
11[e]
DMSO
DMSO
24
1
[a] Reactions were performed using 1a (0.6 mmol), 2a (0.25 mmol), Na2S2O5
(0.5 mmol), solvent (1.0 mL) at 100 ºC. [b] Yield of isolated product. [c] Used 1
equiv (0.5 mmol) of 1a. [d] The reaction was conducted at 60 ºC. [e] The
reaction was carried out under ultrasound irradiation.
Scheme 1. Synthesis of benzothiazoles 4 and benzoselenazoles 5 from α-
keto acids 1 and diaryl dichalcogenides 2 or 3.
The reaction was performed under milder conditions, but it
was obtained only 53% yield of 4a after 24 h at 60 ºC (Table 1,
entry 10). The use of ultrasound irradiation (US) as an
alternative energy source27 was also checked, but it was not
effective in promoting the reaction, with 4a being isolated in only
30% yield after 1 h (Table 1, entry 11).
Results and Discussion
We started our investigation evaluating the best reaction
conditions using phenylglyoxylic acid 1a (PGA) and bis(2-
aminophenyl) disulfide 2a as model substrates to prepare 2-
phenylbenzo[d]thiazole 4a. The reaction was carried out in the
presence of Na2S2O5 (2 equiv) and DMSO (1.0 mL) as the
solvent at 100 ºC, affording the desired product 4a in 83% yield
after 3 h (Table 1, entry 1). To our delight, when a 20% excess
of 1a was used, the yield of product 4a increased to 90% (Table
1, entry 2). To extend the investigation, we fixed the amounts of
1a and 2a and examined the effect of the amount of Na2S2O5,
nature of the solvent, temperature, as well as the energy source,
(Table 1). Regarding the amount of Na2S2O5, it was observed
that the best result was obtaining using 2 equivalents (Table 1,
entries 2-5). Interesting, the reaction occurs even in the absence
of the oxidant, however a longer reaction time is necessary and
the yield is not satisfactory (Table 1, entry 5). It seems that the
presence of the oxidant is mandatory to force the
decarboxylative oxidation to the final product (see Scheme 3 for
a plausible mechanism). Different polar solvents were tested as
well and, despite the formation of product was observed in all
cases, DMSO was superior than all of them (Table 1, entries 6-9
vs entry 2). Noteworthy, PEG-400, which was the best solvent
for the ANO-promoted reaction using PGA,24 gave the worst
outcome in the Na2S2O5-promoted reaction, delivering only 29%
of 4a after 20 h of reaction at 100 oC (Table 1, entry 7).
With the best reaction conditions in hands (Table 1, entry
2), we turned our efforts to investigate the scope of the reaction,
starting by using differently substituted α-keto acids 1. The
influence of electron-withdrawing and donating groups, as well
as steric hindrance in the reactivity of the α-keto acids with bis(2-
aminophenyl) disulfide 2a was evaluated (Table 2). It is possible
to observe that better results were obtained when electron-
withdrawing groups are bonded to the aromatic ring of the α-keto
acid, with 4d (R = 4-FC6H4) and 4f (R = 2,4-Cl2C6H3) being
obtained in 87 and 85% yields after 3 and 2 h, respectively,
while 4b (R = 4-CH3C6H4) and 4c (R = 4-CH3OC6H4) were
isolated in 65 and 75% yields after 4 h and 3 h, respectively. The
presence of a bromine atom in the para position of the PGA did
not affects the reaction yield and the respective benzothiazole
4e (R = 4-BrC6H4) was obtained in 77% yield after 2 h of
reaction. When α-keto acids substituted at the ortho position
were used, like in 1g (R = 2-BrC6H4) and 1h (R = 2-CH3OC6H4),
the respective products 4g and 4h were obtained in 48 and 66%
yields, respectively. The reaction works well also with
biologically important pyruvic acid 1i (R = CH3), affording 2-
methyl-benzothiazole 4i in 41% yield after 1 h. The reaction was
followed by TLC and it was observed the total consumption of
starting disulfide 2a after 1 h. However, the respective imines I
and III (see Scheme 3) were not totally converted to the
expected product 4i and no improvement in yields was observed
even after 6 h of reaction. Despite the modest yield, this is an
interesting result, once most of the current methods to prepare
benzothiazoles by the cyclization of 2-aminobenzenethiols are
limited to aryl substituents at the position 2.
Table 1. Screening of the reaction conditions.[a]
Entry
1[c]
2
Na2S2O5 (equiv)
Solvent
DMSO
DMSO
DMSO
Time (h)
Yield (%)[b]
Table 2. Reaction scope of 2-substituted benzothiazoles 4 from 2a.[a]
2
2
1
3
3
6
83
90
75
3
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10.1002/ejoc.201700648
European Journal of Organic Chemistry
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reaction using the disulfide analogue 2a. The low reactivity of
diselenide 3a could be explained, at least in part, by the
formation of intramolecular Se····N interactions,28 which turn the
molecule less susceptible to react with the α-keto acid 1 and in
the following reaction steps (see Table 4 and Scheme 3).
Despite that, benzoselenazoles 5a-d, containing electron-neutral,
electron-withdrawing and electron-donating groups at the α-keto
acid counter parts were obtained in moderate to good yields (50-
70%, Table 4) in short reaction times. Importantly, neither inert
atmosphere nor transition metals were needed, as reported in
previous methodologies to prepare these selenium-containing
heterocycles. Unfortunately, the less reactive pyruvic acid 1i did
not react with diselenide 3a under our conditions, and
benzoselenazole 5e was not observed.
[a] Reactions were performed using 1 (0.6 mmol), 2a (0.25 mmol), Na2S2O5
(0.5 mmol), DMSO (1.0 mL) at 100 ºC. Yields after purification by column
chromatography.
Table 4. Reaction scope of 2-substituted benzoselenazoles 5 from 3a.[a]
Following, bis(2-amino-4-chlorophenyl) disulfide 2b was
reacted with different α-keto acids 1 (see Table 3). In almost all
cases, a clearly decrease in the reaction yields and longer
reaction times were observed compared to 2a, due to the
electron-withdrawing effect of the chlorine at the para position in
the aromatic ring of disulfide 2b, which reduces its reactivity.
Surprisingly, when (2-methoxy-phenyl)-oxo-acetic acid 1h (R =
2-CH3OC6H4) was used, the desired product 4o was obtained in
81% yield after 3 h, while the less hindered 1c (R = 4-
CH3OC6H4)
delivered
the
respective
5-chloro-2-(4-
methoxyphenyl) benzothiazole 4l in 45% yield after 4 h. A
possible explanation for this apparently anomalous behavior
could be the participation of the o-methoxyl group in the
stabilization of the reaction’s intermediate (see intermediate V in
Scheme 3). The aliphatic pyruvic acid 1i could react with 2b,
giving 5-chloro-2-methylbenzothiazole 4p in 41% yield after 1 h
of reaction (Table 3).
[a] Reactions were performed using 1 (0.6 mmol), 3a (0.25 mmol), Na2S2O5
(0.5 mmol), DMSO (1.0 mL) at 100 ºC. Yields after purification by column
chromatography.
To establish a plausible mechanism for the reaction of
bis(2-aminophenyl) disulfide 2a with PGA 1a, some control
experiments were conducted to verify if a radical mechanism
could be involved (Scheme 2). Based on previous mechanisms
described in the literature using Na2S2O5 as catalyst,26 we
initially believed that the main reaction pathway was via radical.
Thus, based on this consideration, our better reaction condition
to prepare benzothiazole 4a was conducted in the presence of 3
equiv of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as a
radical inhibitor (Scheme 2-A). In contrast to the expected by us,
benzothiazole 4a was obtained in the same yield observed for
the reaction in the absence of TEMPO (90%). In order to confirm
this result, the same reaction was carried out in the presence of
hydroquinone (Scheme 2-B) and, again, product 4a was
obtained in 90% yield.
Table 3. Reaction scope of 2-substituted benzothiazoles 4 from 2b.[a]
[a] Reactions were performed using 1 (0.6 mmol), 2b (0.25 mmol), Na2S2O5
(0.5 mmol), DMSO (1.0 mL) at 100 ºC. Yields after purification by column
chromatography.
The methodology was extended to the reaction of α-keto
acids 1 with bis(2-aminophenyl) diselenide 3a, aiming to prepare
the respective benzoselenazoles 5 (Table 4). In a general way,
lower yields were obtained in all examples compared to the
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10.1002/ejoc.201700648
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keto acid acid 129 (0.6 mmol), disulfide 2a or 2b (0.25 mmol),
Na2S2O5 (0.5 mmol; 0.095 g) and DMSO (1.0 mL). The resulting
solution was stirred at 100 ºC (oil bath) for the time indicated on
Tables 2 and 3. After that, the reaction mixture was received in
water (20 mL), extracted with ethyl acetate (3 x 10 mL), dried
over MgSO4 and concentrated under vacuum. The residue was
purified by column chromatography on silica gel utilizing
hexane/ethyl acetate as the eluent.
Scheme 2. Control experiments. A: Using TEMPO as a radical inhibitor. B:
Using hydroquinone as radical inhibitor.
Based on these results and on literature,26 a plausible
mechanism, which goes through an anionic pathway, was
proposed (Scheme 3). Initially, imine I and iminium II are formed
by the condensation between 2a with 2 equiv of 1. Then,
species II is cyclized by a nucleophilic attack of one sulfur-
electron pair to the iminium site, leading to the zwitterion
intermediate III. Then, intermediate III suffers a decarboxylation
process by the delocalization of an electron pair, cleaving the S-
S bond to form the protonated benzothiazole IV (path ‘a’) and
2-Phenylbenzo[d]thiazole (4a): Yield: 0.095 g (90%); White
1
solid; mp 107-109 ºC (Lit.30: 107-110 °C). H NMR (CDCl3, 400
the imine V (path ‘b’). After that, sulfonium ion IV is deprotonated, MHz) δ 8.11-8.07 (m, 3H), 7.91-7.89 (m, 1H), 7.51-7.47 (m, 4H),
7.38 (m, 1H). 13C NMR (CDCl3, 100 MHz) δ 168.1, 154.1, 135.1,
leading to the aromatic stable 2-organyllbenzothiazole 4. On the
other hand, following path ‘b’, imine V is cyclized to VI, which in
the presence of Na2S2O5 is oxidized, releasing H+ and CO2 in the
reaction media and forming the desired product 4.
133.6, 130.9, 129.0, 127.6, 126.3, 125.2, 123.2, 121.6.
2-(4-Methylphenyl)benzo[d]thiazole (4b): Yield: 0.073
g
(65%); White solid; mp 72-74 ºC (Lit.31: 70.5-72 °C). 1H NMR
(CDCl3, 400 MHz) δ 8.05 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.0 Hz,
2H), 7.86 (d, J = 8.0 Hz, 1H), 7.48-7.44 (m, 1H), 7.36-7.32 (m,
1H), 7.27 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H). 13C NMR (CDCl3, 100
MHz) δ 168.2, 154.1, 141.3, 134.9, 130.9, 129.6, 127.4, 126.2,
124.9, 123.0, 121.5, 21.4.
2-(4-Methoxyphenyl)benzo[d]thiazole (4c): Yield: 0.085 g
(71%); Beige solid; mp 114-116 ºC (Lit.15: 115-116 °C). 1H NMR
(CDCl3, 400 MHz) δ 8.04-8.02 (m, 3H), 7.87 (d, J = 8.4 Hz, 1H),
7.49-7.45 (m, 1H), 7.37-7.33 (m, 1H), 7.01-6.97 (m, 2H), 3.87 (s,
3H). 13C NMR (CDCl3, 100 MHz) δ 167.8, 161.9, 154.2, 134.8,
129.1, 126.4, 126.2, 124.7, 122.8, 121.5, 114.3, 55.4.
2-(4-Fluorophenyl)benzo[d]thiazole (4d): Yield: 0.099
g
(87%); White solid: mp 96-98 ºC. (Lit.32: 96-98 °C). 1H NMR
(CDCl3, 400 MHz) δ 8.10-8.05 (m, 3H), 7.89 (d, J = 8.0 Hz, 1H),
7.51-7.47 (m, 1H), 7.40-7.36 (m, 1H), 7.21-7.15 (m, 2H). 13C
NMR (CDCl3, 100 MHz) δ 166.7, 164.4 (d, J = 251.7 Hz), 154.1,
135.0, 129.9 (d, J = 3.1 Hz), 129.5 (d, J = 8.7 Hz), 126.4, 125.2,
123.2, 121.6, 116.1 (d, J = 22.5 Hz).
Scheme 3. Plausible mechanism for the formation of 2-substituted
benzothiazole 4a.
Thus, based on the control experiments using radical
inhibitors (Scheme 2), we can confirm that the reaction does not
go through a radical mechanism. Besides that, the hypothesis
that there are two reaction pathways and that one of them does
not depend of the Na2S2O5 is confirmed, once 4a was obtained
from 1a and 2a in 57% yield in its absence (Table 1, entry 5)
considering that only path ‘a’ was working. On the other hand, in
the presence of Na2S2O5 (Table 1, entry 2) the yield increased to
90%, showing that the oxidant is essential to promote the
reaction through the path ‘b’, which in addition to the path ‘a’,
provides the maximum efficiency of the reaction.
2-(4-Bromophenyl)benzo[d]thiazole (4e): Yield: 0.111
g
(77%); White solid: mp 128-129 ºC (Lit.33: 127-129 °C). 1H NMR
(CDCl3, 400 MHz) δ 8.07-8.04 (m, 1H), 7.93-7.89 (m, 2H), 7.87-
7.84 (m, 1H), 7.60-7.56 (m, 2H), 7.50-7.46 (m, 1H), 7.39-7.35
(m, 1H). 13C NMR (CDCl3, 100 MHz) δ 166.5, 154.0, 134.9,
132.4, 132.1, 128.8, 126.4, 125.3, 123.2, 121.6.
2-(2,4-Dichlorophenyl)benzo[d]thiazole (4f): Yield: 0.119 g
(85%); White solid: mp 135-137 ºC (Lit.34: 136 °C). 1H NMR
(CDCl3, 400 MHz) δ 8.22 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.2 Hz,
1H), 7.93 (d, J = 8.0 Hz, 1H), 7.53-7.50 (m, 2H), 7.42 (t, J = 7.6
Hz, 1H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H). 13C NMR (CDCl3, 100
MHz) δ. 162.9, 152.3, 136.6, 136.0, 133.3, 132.5, 130.8, 130.5,
127.5, 126.4, 125.6, 123.4, 121.4.
Conclusions
In summary, we report herein the first synthesis of
benzothiazoles and benzoselenazoles from α-keto acids using
diaryl dichalcogenides in short reaction time and using open air
atmosphere. This transition metal-free protocol is promoted by
Na2S2O5 in good yields. The biologically important pyruvic acid
was successfully used as a α-keto acid in the synthesis of 2-
methylbenzothiazoles.
2-(2-Methoxyphenyl)benzo[d]thiazole (4g): Yield: 0.079 g
(66%); Light green solid: mp 98-101 ºC (Lit.35: 95-98 °C). 1H
NMR (CDCl3, 400 MHz) δ 8.57-8.55 (m, 1H), 8.12 (d, J = 8.2 Hz,
1H), 7.93 (d, J = 7.9 Hz, 1H), 7.52-7.43 (m, 2H), 7.40-7.36 (m,
1H), 7.16-7.12 (m, 1H), 7.05 (d, J = 8.2 Hz, 1H), 4.03 (s, 3H).
Experimental Section
General procedure for the synthesis of 2-(aryl)-
benzothiazoles 4a-p: In a round-bottomed flask were added α-
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10.1002/ejoc.201700648
European Journal of Organic Chemistry
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13C NMR (CDCl3, 100 MHz) δ 163.0, 157.1, 152.1, 136.0, 131.7,
129.4, 125.8, 124.5, 122.7, 122.2, 121.1, 121.0, 111.6, 55.5.
5-Chloro-2-methylbenzo[d]thiazole (4p): Yield: 0.075 g (41%);
1
White solid: mp 68-70ºC (Lit.41: 68-69 °C). H NMR (CDCl3, 400
MHz) δ 7.93 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.5, 0.5 Hz, 1H),
7.32 (dd, J = 8.5, 2.0 Hz, 1H), 2.83 (s, 3H). 13C NMR (CDCl3,
100 MHz) δ 168.9, 154.2, 133.9, 131.9, 125.2, 122.3, 122.0,
20.2.
2-(2-Bromophenyl)benzo[d]thiazole (4h): Yield: 0.139
g
(48%); White solid: mp 61-63 ºC (Lit.32: 61-63 °C). 1H NMR
(CDCl3, 400 MHz) δ 8.16 (d, J = 8.0 Hz, 1H), 8.02 (dd, J = 7.8,
1.7 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.0, 1.1 Hz,
1H), 7.56-7.52 (m, 1H), 7.49-7.42 (m, 2H), 7.37-7.32 (m, 1H).
13C NMR (CDCl3, 100 MHz) δ 165.7, 152.7, 136.1, 134.5, 134.1,
132.2, 131.3, 127.6, 126.3, 125.5, 123.6, 122.1, 121.4.
General procedure for the synthesis of 2-(aryl)-
benzoselenazoles 5a-e: In a 10 mL round-bottomed flask were
added α-keto acid acid 1 (0.6 mmol), bis(2-aminophenyl)
diselenide 3a (0.25 mmol; 0.086 g), Na2S2O5 (0.5 mmol, 0.095
g) and DMSO (1.0 mL), respectively. The resulting solution was
stirred at 100 ºC (oil bath) for the time indicated on the Table 4.
After that, the reaction mixture was received in water (20 mL),
extracted with ethyl acetate (3 x 10 mL), dried over MgSO4 and
concentrated under vacuum. The residue was purified by
column chromatography on silica gel utilizing hexane/ethyl
acetate as the eluent.
2-Methylbenzo[d]thiazole (4i):10 Yield: 0.061 g (41%); red oil.
1H NMR (CDCl3, 400 MHz) δ 7.87 (d, J = 8.0 Hz, 1H), 7.74 (d, J
= 8.0 Hz, 1H), 7.39-7.35 (m, 1H), 7.28-7.24 (m, 1H), 2.76 (s, 2H).
13C NMR (CDCl3, 100 MHz) δ 166.9, 153.3, 135.6, 125.9, 124.6,
122.3, 121.3, 20.1.
5-Chloro-2-phenylbenzo[d]thiazole (4j): Yield: 0.189 g (77%);
White solid: mp 132-134 ºC (Lit.36: 139 °C). 1H NMR (CDCl3, 400
MHz) δ 8.07-8.05 (m, 3H), 7.78 (d, J = 8.5 Hz, 1H), 7.51-7.47 (m,
3H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ
169.9, 154.9, 133.3, 133.2, 132.3, 131.3, 129.0, 127.6, 125.6,
123.0, 122.2.
2-Phenylbenzo[d][1,3]selenazole (5a): Yield: 0.160 g (62%);
White solid: mp 112-114 ºC (Lit.42: 115-116 °C). 1H NMR (CDCl3,
400 MHz) δ 8.14-8.12 (m, 1H), 8.04-8.01 (m, 2H), 7.95-7.93 (m,
1H), 7.51-7.47 (m, 4H), 7.34-7.29 (m, 1H). 13C NMR (CDCl3, 100
MHz) δ 172.4, 155.8, 138.3, 136.1, 131.0, 129.0, 127.9, 126.3,
125.2, 124.8.
5-Chloro-2-4fluorophenyl)benzo[d]thiazole (4k): Yield: 0.184
g (70%); White solid: mp 113-114 ºC (Lit.37: 112-113 °C). 1H
NMR (CDCl3, 400 MHz) δ 8.07-8.02 (m, 3H), 7.78 (d, J = 8.5 Hz,
1H), 7.35 (m, 1H), 7.21-7.15 (m, 2H). 13C NMR (CDCl3, 100
MHz) δ 168.5, 164.6 (d, J = 252.6 Hz), 154.9, 133.3, 132.4,
129.6 (d, J = 8.7 Hz), 125.7, 123.0, 122.3, 116.2 (d, J = 22.1 Hz).
2-(4-Methoxyphenyl)benzo[d][1,3]selenazole (5b):
Yield:
0.201 g (70%); White solid: mp 125-127 ºC (Lit.43: 122-124 °C).
1H NMR (CDCl3, 400 MHz) δ 8.08-8.06 (m, 1H), 7.98-7.94 (m,
2H), 7.92-7.90 (m, 1H), 7.49-7.45 (m, 1H), 7.30-7.26 (m, 1H),
7.00-6.96 (m, 2H), 3.87 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ
172.0, 161.9, 155.9, 136.0, 129.5, 129.0, 126.2, 124.8, 124.7,
124.3, 114.3, 55.4.
5-Chloro-2-(4-methoxyphenyl)benzo[d]thiazole (4l): Yield:
0.124 g (45%); White solid: mp 135-137 ºC (Lit.38: 138-140 °C).
1H NMR (CDCl3, 400 MHz) δ 8.00-7.96 (m, 3H), 7.73 (d, J = 8.5
Hz, 1H), 7.30 (dd, J = 8.5, 2.0 Hz, 1H), 6.99-6.96 (m, 2H), 3.86
(s, 3H). 13C NMR (CDCl3, 100 MHz) δ 169.6, 162.2, 155.0, 133.1,
132.1, 129.1, 126.0, 125.1, 122.6, 122.1, 114.4, 55.4.
2-(4-Fluorophenyl)benzo[d][1,3]selenazole (5c): Yield: 0.140
g (51%); White solid: mp 97-100 ºC (Lit.44: 101-103 °C). 1H NMR
(CDCl3, 400 MHz) δ 8.10-8.07 (m, 1H), 8.02-7.97 (m, 2H), 7.93-
7.91 (m, 1H), 7.50-7.46 (m, 1H), 7.32-7.28 (m, 1H), 7.19-7.13 (m,
2H). 13C NMR (CDCl3, 100 MHz) δ 170.9, 164.4 (d, J = 251.9
Hz), 155.7, 138.3, 132.5 (d, J = 3.1 Hz), 129.9 (d, J = 8.5 Hz),
126.5, 125.3, 124.8, 116.1 (d, J = 22.0 Hz).
5-Chloro-2-(p-tolyl)benzo[d]thiazole (4m): Yield: 0.124
g
(63%); White solid: mp 141-144 ºC (Lit.39: not observed). 1H
NMR (CDCl3, 400 MHz) δ 8.01 (d, J = 2.0 Hz, 1H), 7.94 (d, J =
8.1 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.5, 2.0 Hz,
1H), 7.28 (d, J = 8.1 Hz, 2H), 2.41 (s, 3H). 13C NMR (CDCl3, 100
MHz) δ 170.0, 155.0, 141.8, 133.2, 132.2, 130.6, 129.7, 127.5,
125.4, 122.8, 122.2, 21.5.
2-(2-Methoxyphenyl)benzo[d][1,3]selenazole (5d):
Yield:
0.144 g (50%); White solid: mp 104-106 ºC. 1H NMR (CDCl3,
400 MHz) δ 8.59 (dd, J = 7.9, 1.5 Hz, 1H), 8.18 (d, J = 8.1 Hz,
1H), 7.99 (d, J = 7.8 Hz, 1H), 7.52-7.44 (m, 2H), 7.33-7.29 (m,
1H), 7.17-7.13 (m, 1H), 7.05 (d, J = 8.3 Hz, 1H). 13C NMR
(CDCl3, 100 MHz) δ 165.1, 156.9, 153.7, 139.1, 131.6, 128.5,
125.9, 124.5, 124.4, 124.2, 124.2, 121.0, 111.5, 55.5.
2-(4-Bromophenyl)-5-chlorobenzo[d]thiazole (4n): Yield:
0.210 g (65%); White solid: mp 145-148 ºC (Lit.24: 140-143 °C).
1H NMR (CDCl3, 400 MHz) δ 8.03 (d, J = 2.0 Hz, 1H), 7.93-7.90
(m, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.63-7.60 (m, 2H), 7.36 (dd, J
= 8.5, 2.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ 168.5, 154.9,
133.2, 132.5, 132.3, 132.1, 128.9, 125.9, 125.8, 123.1, 122.3.
Acknowledgements
5-Chloro-2-(2-methoxyphenyl)benzo[d]thiazole (4o): Yield:
0.223 g (81%); White solid: mp 121-124ºC (Lit.40: not observed).
1H NMR (CDCl3, 400 MHz) δ 8.50 (dd, J = 7.9, 1.7 Hz, 1H), 8.05
(d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.48-7.44 (m, 1H),
7.32 (dd, J = 8.5, 2.0 Hz, 1H), 7.14-7.10 (m, 1H), 7.05 (d, J = 8.4
Hz, 1H), 4.04 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 164.9, 157.3,
153.0, 134.4, 132.1, 131.8, 129.5, 125.0, 122.5, 121.9, 121.2,
111.6, 55.7.
Authors thank CNPq, FAPERGS and CAPES for financial
support. This research was undertaken as part of the scientific
activity of the international multidisciplinary “SeS Redox and
Catalysis” network.
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Keywords: benzothiazoles, benzoselenazoles, α-keto acids,
organochalcogen, selenium.
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FULL PAPER
benzothiazole and benzoselenazole
David B. Lima, Filipe Penteado, Marcelo
M. Vieira, Diego Alves, Gelson Perin,
Claudio Santi and Eder J. Lenardão*
Page No. – Page No.
Benzothiazoles and benzoselenazoles were efficiently prepared by the
decarboxylative oxidation of α-keto acids in the presence of sodium metabisulfite.
Diaryl disulfides and diselenides were used as chalcogen source no inert
atmosphere or transition metals were required. By this straightforward procedure
were prepared 20 differently substituted heterocycles in good yields.
α-Keto acids as acylating agents in
the synthesis of 2-substituted
benzothiazoles and benzoselenazoles
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