Niobium-promoted reaction of α-phenylglyoxylic acid with ortho-functionalized anilines: Synthesis of 2-arylbenzothiazoles and 3-aryl-2H-benzo[b][1,4]benzoxazin-2-ones

Article abstract of DOI:10.1039/c6gc02495e

A new and general method to prepare 2-arylbenzothiazoles and 3-aryl-2H-benzo[b][1,4]benzoxazin-2-ones by the reaction of α-arylglyoxylic acid with o-aminothiophenol and o-aminophenol respectively is described. The use of ammonium niobium oxalate (ANO) as the catalyst and PEG-400 as the solvent were crucial to afford the title compounds in good yields and selectivity. The reaction time can be reduced from hours to few minutes when ultrasound is used as an alternative energy source.

Full text of DOI:10.1039/c6gc02495e

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Niobium-promoted reaction of α-phenylglyoxylic acid with ortho-
functionalized anilines: synthesis of 2-arylbenzothiazoles and 3-
aryl-2H-benzo[b][1,4]benzoxazin-2-ones
Received 00th January 20xx,
Accepted 00th January 20xx
Filipe Penteado,a Marcelo M. Vieira,a Gelson Perin,a Diego Alves, Raquel G. Jacob,a Claudio Santi,b
DOI: 10.1039/x0xx00000x
Eder J. Lenardão*,a
A new and general method to prepare 2-arylbenzothiazoles and 3-aryl-2H-benzo[b][1,4]benzoxazin-2-ones by the reaction
of α-arylglyoxylic acid with o-aminothiophenol and o-aminophenol respectively is described. The use of ammonium
niobium oxalate (ANO) as the catalyst and PEG-400 as the solvent were crucial to afford the title compounds in good yields
and selctively. The reaction time can be reduced from hours to few minutes when ultrasound was used as an alternative
energy source.
www.rsc.org/
compounds.11 For instance, Ofloxacin
®, which has on its structure a
Introduction
benzoxazine center, is a commercially available drug used in the
treatment of acute bacterial exacerbations of chronic bronchitis and
against several bacterial infections.12
Heterocyclic compounds are widely found in natural products and
are important in the pharmaceutical industry, being present on the
structure of different drugs consumed worldwide.1 Among them, 2-
substituted benzothiazoles have attracted great interest, since they
are the core motif of many bioactive molecules. For instance, 2-
arylbenzoxazole A has anti-cancer activity,2a benzo[d]thiazole-2-
An interesting and still scarcely studied class of benzoxazine
derivatives are the 2H-benzo[b][1,4]benzoxazin-2-ones, which are
known to have photoactive properties, as the aldehyde E,13a or
antibacterial activity, as the aryl ketone F (Figure 1).13b Besides that,
the actinomycin D analogue G presented antitumor activity.13c The
current methods to prepare benzoxazin-2-ones involve the use of
Pd or Cu catalysts,14b volatile solvents,14b strong oxidizing agents14d
and usually large reaction times.14 Due the potential application of
this class of compounds in material and medicinal chemistry, the
development of efficient and green methodologies to obtain 3-
substituted 2H-benzo[b][1,4]benzoxazin-2-ones is very attractive.
Since it was firstly described by Fontana and co-workers in
1991,15a α-phenylglyoxylic acid (PGA) has aroused the interest of
organic chemists as a versatile acyl transfer reagent in the synthesis
of a diversity of compounds (Scheme 1).15,16 Among the green
features in using PGA as acylating are the high atom economy and
the formation of CO2 as the only waste in the reaction. Despite the
high potential of PGA as a green acyl transfer in organic synthesis, it
is still far from being a popular reagent. This is due probably to the
peculiar or nontrivial reaction conditions required for the metal-
catalyzed decarboxylative coupling, which include the use of
expensive palladium and ruthenium catalysts, equivalent amounts
of strong oxidizing agents, volatile solvents and large reaction times
(Scheme 1).16-18
thiol
B
is an anti-oxidant,2b and the amide-functionalized
benzothiazole C presents antibacterial activity (Figure 1).2c This
important structural unity is present in commercially available
drugs, such as the Riluzole® D, used in the treatment of the
amyotrophic lateral sclerosis2d and a sort of materials, such as dyes
and agrochemicals.3 These compounds are usually prepared
through the condensation of 2-aminothiols with aldehydes or acyl
chlorides.4 They also can be obtained by the direct C-H activation
promoted by the transition metal-catalyzed cross-coupling of
benzothiazoles with aryl halides,5 aromatic carboxylic acids,6 aryl
boronic acids,7 aryl silanes,8 aldehydes9 or by the double C-H
activation of arenes.10
2-Substituted Benzothiazoles:
3-Substituted Benzoxazin-2-ones:
S
S
N
N
O
O
SH
H
N
N
O
N
O
H
N
A
B
O
E
O
O
P
O
P
O
F
C
G
3
S
O
O
O
S
N
NH
2
NH
P= Thr-D-Val-Pro-Sar-MeVal
N
N
H
O

C
F
D
Riluzole
Cl
Figure 1: Bioactive 2-substituted benzothiazoles (A-D) and 3-substituted benzoxazin-2-
ones (E-G).
Recently,
a visible-light-mediated decarboxylative/oxidative
Another important class of the heterocyclic compounds are the
1,4-benzoxazines, which has been receiving attention due to the
pharmacological and biological activities associated to these
amidation of PGAs catalyzed by Ru-complex to prepare aromatic
amides from anilines was described.17 The strategy was extended to
the construction of heterocyclic compounds, including
benzimidazoles, benzoxazoles and benzothiazoles, when the ortho
position of the starting aniline was substituted with NH2, OH and SH
groups respectively. However, the use of expensive reagents,
oxidizing solvent and long reaction times together with the restrict
number of studied examples (only one benzothiazole was prepared)
are some disadvantages of this protocol. More recently, Wang and
Huang described an electrochemical method for the
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decarboxylative coupling of PGA with ortho-phenylenediamines and NH4ClO4 for up 22 h to afford good yields of the respective 2-
2-aminothiophenols to afford 2-substituted benzimidazoles and substituted benzimidazoles (Scheme 1). Thus, the development of
benzothiazoles, respectivey.18 Besides a special apparatus, this mild and green methodologies to apply PGA and its derivatives in
protocol requires the use of 3 equiv of 2-aminothiophenol, over organic synthesis remains an endeavour for synthetic organic
equiv amounts of TFA, DIPEA and the highly reactive oxidant chemists.
Scheme 1: PGA as an acylating agent.
Ammonium
niobium
oxalate
(ANO),
Table 1: Optimization study to obtain 2-phenylbenzothiazole 3a a
.
NH4[NbO(C2O4)2(H2O)x]•nH2O, is used as precursor in the
preparation of important materials, such as ceramic, optical lenses,
highly pure niobium oxides, tin films and catalysts.18 Besides that,
ANO is not air- or moisture-sensitive, it is easy to handle, cheap and
has a low toxicity.19,20 Recently, we described the first use of ANO
as a catalyst in the reaction between aldehydes and indoles,
leading to bis-indolylmethanes under ultrasound irradiation only in
few minutes of reaction, showing the possibility of using these Nb
species as a cheap and available catalyst.21
Entry
Catalyst (mol%)
Solvent
Yield of 3a (%)b
1
2
3
4
5
6
7
8
9
ANO (10)
Nb2O5 (10)
Nb2O5·H2O (10)
ANO (5)
ANO (15)
-
ANO (10)
ANO (10)
ANO (10)
ANO (10)
ANO (10)
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
Glycerol
H2O
DMSO
DMF
PEG-400
PEG-400
85
84
46
62
70
30
50
44
45
NR
73
NR
In continuation to our studies in the development of greener
approaches to efficiently synthesize bioactive compounds, we
describe herein
benzothiazoles
a
new methodology to obtain 2-substituted
and 3-substituted 1,4-benzoxazin-2-ones
3
5
starting from α-arylglyoxylic acid 1. The method involves the use of
ANO as a catalyst and PEG-400 as a green solvent under both,
conventional heating and ultrasound (US) irradiation as an
alternative energy source (Scheme 2).
10
11c
12d
ANO (10)
a
Reactions were performed using α-phenylglyoxylic acid 1a (0.6 mmol), 2-
aminothiophenol 2a (0.5 mmol), the catalyst (mol%), solvent (1.0 mL) at 100 °C for 2 h.
The product 3a was isolated by chromatography column. Stoichiometry of the
b
c
reagents = 1:1. d The reaction was proceeded at 60 oC.
The performance of the reaction was studied using three
different niobium catalysts at 100 °C in PEG-400, for 2 h (Table 1,
entries 1-3). This time and temperature were chosen based on our
previous works on the use of Nb oxide as catalyst. Among the
tested catalysts, ANO and anhydrous Nb2O5 (10 mol%) provided the
expected benzothiazole 3aa in 85 and 84% yields, respectively.
Because ANO is cheaper, bench stable and easier to manipulate
compared to Nb2O5,19 it was chosen as the catalyst for the
following optimization studies. In order to evaluate the ideal
catalyst amount, the reaction was performed using 5 and 15 mol%
of ANO, leading to the formation of 62 and 70% yields respectively,
showing that 10 mol% is enough (Table 1, entries 4-5 vs. entry 1).
When the reaction was performed in the absence of ANO, only 30%
yield of 3aa was obtained, confirming the importance of the ANO
as the catalyst of the reaction (Table 1, entry 6).
Scheme 2: General scheme of the reactions.
Results and discussion
Initially, our study was focused on determining the optimum
condition to obtain 2-arylbenzothiazoles 3aa using a niobium-based
catalyst under conventional heating (Table 1).
Thus, firstly we chose α-phenylglyoxylic acid 1a (0.6 mmol) and
2-aminothiophenol 2a (0.5 mmol) as standard substrates for the
optimization study (Table 1).
After the best catalyst and catalyst amount were determined, it
was performed a study in order to evaluate the effect of the
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solvent in the reaction medium. Changing the solvent for glycerol,
H2O and DMSO gave 3aa in modest yields of 50, 44 and 45%,
respectively (Table 1, entries 7-9), while with DMF no reaction was
observed and the starting materials were recovered (Table 1, entry
10). Thus, PEG-400 showed to be the best solvent for this reaction.
Changing the reagents’ stoichiometry to 1:1 led to a decrease in the
yield (73%), showing that a little excess of 1a is mandatory in order
to obtain better results (Table 1, entry 11). Finally, the reaction was
performed at 60 °C for 2 h, but no reaction occurred at this
temperature (Table 1, entry 12). Thus, our best reaction condition
to prepare 2-phenylbenzothiazole 3aa was using α-phenylglyoxylic
acid 1a (0.6 mmol), 2-aminothiophenol 2a (0.5 mmol), ANO (10
mol%) as the catalyst and PEG-400 (1.0 mL) as the solvent under
conventional heating (oil bath) at 100 °C for 2 h, affording the
product in 85% yield (Table1, entry 1).
are formed, with predominance of bis(4-chloro-2-aminophenyl)
disulfide, the oxidation product of the starting thiol 2b. Similarly,
the reaction time to prepare 3ba and 3bb could be reduced to 1 h
under sonication, while the yields were essentially the same that
those under conventional heating (Table 2).
Based on the successful results using 2-aminobenzenethiols 2,
we investigated the applicability of the protocol in the reaction
between α-phenylglyoxylic acid 1a and 2-aminophenol 4a instead
2-aminothiophenol 2a, in order to obtain the correspondent 2-
phenylbenzo[d]oxazole. However, instead the benzoxazole, 2H-
benzo[b][1,4]benzoxazin-2-one 5aa was the only observed product,
obtained in 80% yield (Scheme 2).
O
X
N
O
OH
not observed
OH
With the optimal reaction condition in hands, it was performed
a study in order to examine the scope of the reaction, evaluating
the behaviour of substituted 2-aminothiophenols and α-
arylglyoxylic acids and confirm the efficiency and generality of the
methodology.
ANO (10 mol%)
O
O
PEG-400 (1.0 mL)
100 ºC, 2 h
O
NH2
1a (0.6 mmol)
4a (0.5 mmol)
N
5aa 80%
Scheme 3: Synthesis of 2H-benzo[b][1,4]benzoxazin-2-one 5aa.
A study on the scope of the reaction showed that this is a
general protocol which can be extended to several α-arylglyoxylic
acids 1a-c and 2-aminophenols 4a-c, affording the respective 3-
substituted 2H-benzo[b][1,4]benzoxazin-2-ones 5aa-cc in moderate
to good yields after 1-2.5 h of reaction (Table 3).
Table 2: Reaction scope of the niobium-catalyzed synthesis of 2-substituted
benzothiazoles 3.a
Similarly to the observed for 2-aminothiophenol 2a (Table 2),
the reaction of 2-aminophenol 4a with 4-methoxyphenylglyoxylic
acid 1b (R= CH3O) afforded lower yield of the respective product
5ba (65% after
2
h). On the other hand, when 4-
bromophenylglyoxylic acid 1c (R= Br) was used, the reaction time
decreased from 2 to 1 h, affording the respective product 5ca in
70% yield. The effect of the presence of EWG and electron
releasing group (ERG) bonded to the aromatic ring of the 2-
aminophenol
4 was also evaluated. Products 5ab and 5bb,
prepared by the reaction of 2-amino-4-methylphenol 4b (R1= CH3)
with arylglyoxylic acids 1a (R= H) and 1b (R= CH3O) were obtained
in 87 and 86% yields respectively, in 2 h of reaction.
When 2-(4-bromophenyl)-2-glyoxylic acid 1c (R= Br) was used,
the respective benzoxazin-2-one 5cb was formed in 93% yield after
1 h. In this case, electronic effects in both, the acid 1c and the
aminophenol counterpart 4b were evidenced, promoting the
acceleration of the reaction.
a
Reactions were performed using α-arylglyoxylic acids 1a-d (0.6 mmol), 2-
aminothiophenols 2a-b (0.5 mmol), ANO as the catalyst (10 mol%), PEG-400 as the
b
solvent (1.0 mL) at 100 °C under stirring in air atmosphere. The mixture was
submitted to ultrasound irradiation (60% of amplitude) instead using an oil bath. c The
final reaction temperature was 110 °C. The yields were determined after isolation by
chromatography column.
The reaction of 2-amino-4-chlorophenol 4c (R1= Cl) with acids
1a-c afforded the respective products 5ac, 5bc and 5cc in 70, 70
and 66% yields, respectively in 2-2.5 h. The electron-withdrawing
effect exercised by the chloro in the ring of the 2-aminophenol 4c is
considerable, causing a significant decreasing in the yield.
In order to improve the efficiency on the synthesis of 3-
substituted 2H-benzo[b][1,4]benzoxazin-2-ones 5, since this class of
compounds is underexploited in materials and medicinal chemistry,
it was performed a study on the use of ultrasound irradiation,
similarly to that for the synthesis of benzothiazoles 3.
Fortunately, excellent results were obtained, leading to the
formation of the products between 83 and 96% yields in only a few
minutes of reaction (Table 3, values between parentheses). This is a
very promising result, once the energy efficiency in using US
irradiation contributes to improve the greenness of the reaction.23
Besides that, the reaction was performed using 2-amino-4-
chlorobenzenethiol 2b and α-arylglyoxylic acids 1a-c, in order to
evaluate the behaviour of an electron withdrawing group (EWG) in
the aromatic ring of the 2-aminothiophenol. As expected, it was
observed an increase in the reaction time (up to 6 h) and the
respective products 3ab, 3bb and 3cb were obtained in 77, 30 and
60% yields, respectively. This is due to the deactivation of the
aromatic ring, decreasing the nucleophilicity of the NH2 and SH
groups in both important reaction steps, the formation of the imine
by the NH2 attack and the cyclization from the SH.22 Aiming to
reduce the reaction time while increasing the yields of
benzothiazoles 3ab, 3ba, 3bb and 3cb, the reaction was performed
under sonication with an ultrasound probe.
Thus, when
a
solution of PGA 1a and 2-amino-4-
chlorobenzenethiol 2b in PEG-400 was sonicated (60% of
amplitude) for 1 h in the presence of ANO, the respective product
3ab was obtained in 55% yield (Table 2, values between
parentheses). If the US irradiation is continued, several co-products
Table 3: Reaction scope of the niobium-catalyzed synthesis of 3-substituted
2H-benzo[b][1,4]benzoxazin-2-ones 5.a
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Conclusions
Ammonium
niobium
oxalate
(ANO),
NH4[NbO(C2O4)2(H2O)x]•nH2O, proved to be an excellent catalyst in
promoting the reaction of 2-aminothiophenols and 2-aminophenols
with α-arylglyoxylic acids, leading to the formation of 2-aryl
benzothiazoles and 3-aryl 2H-benzo[b][1,4]benzoxazin-2-ones in
good to excellent yields. The protocol is selective, producing CO2 as
the only co-product and it can be accelerated by ultrasound
irradiation, reducing the reaction time from hours to few minutes,
while increasing the product yields. The use of PEG-400 as a green,
cheap and available solvent allowed a good solubility of reagents
and catalyst and enabled the sonication of the reaction mixture.
Taken together, the features of this alternative protocol make it a
green and robust alternative to prepare 2-substituted
benzothiazoles and 3-substituted 2H-benzo[b][1,4]benzoxazin-2-
ones.
a
Reactions were performed using α-arylglyoxylic acids 1a-c (0.6 mmol), 2-
aminophenols 4a-c (0.5 mmol), ANO as the catalyst (10 mol%), PEG-400 as the solvent Acknowledgements
b
(1.0 mL) at 100 °C (oil bath) under stirring in air atmosphere. The mixture was
submitted to ultrasound irradiation (60% of amplitude) instead using an oil bath. c The
final reaction temperature was 110 °C. The yields were determined after purification
by column chromatography.
CNPq, CAPES and FAPERGS are thanked for financial
support. EJL, GP, DA and RGJ are recipients of CNPq fellows.
CBMM (Brazil) is thanked for providing the ANO. This research
was undertaken as part of the scientific activity of the
international multidisciplinary “SeS Redox and Catalysis”
network.
Based on our results and in previously described works,14d,22
plausible mechanisms for the synthesis of 2-substituted
benzothiazoles
3 and 3-substituted benzoxazin-2-ones 5 are
depicted in Scheme 4, for 3aa and 5aa. The first step in the
synthesis of benzothiazole 3aa (Scheme 4, mechanism I) is the
condensation between 2-aminothiophenol 2a and PGA 1a, which is
catalysed by ANO, leading to the formation of the intermediate
zwitterion 6. In the sequence, elimination of water occurs to give
the iminium 7, which after the intramolecular attack of SH group
affords 8, that in a step of decarboxylation and after a N-Csp3 bond
oxidation, deliver the product 3aa.
On the other hand, in the synthesis of the 3-phenyl benzoxazin-
2-one 5aa (Scheme 4, mechanism II), the first step involves an ANO-
catalysed esterification reaction between the 2-aminophenol 4a
and PGA 1a, following by water elimination, leading to the
intermediate 10. After that, an ANO-catalysed cyclization by attack
of the remaining NH2 group leads to the cyclic intermediate 11,
which after water elimination is converted to the product 5aa.
Notes and references
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Green Chemistry
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DOI: 10.1039/C6GC02495E
Ammonium niobium oxalate promotes the reaction of α-phenylglyoxylic acid with o-
functionalized anilines for the synthesis of benzothiazoles and benzoxazin-2-ones.