Elemental sulfur mediated synthesis of benzoxazoles, benzothiazoles and quinoxalines: Via decarboxylative coupling of 2-hydroxy/mercapto/amino-anilines with cinnamic acids

Article abstract of DOI:10.1039/c6ra17491d

An easy and practical method has been developed for the synthesis of 2-benzylbenzoxazoles and 2-benzylbenzothiazoles using sulfur mediated decarboxylative coupling of cinnamic acids with 2-hydroxyanilines and 2-mercaptoanilines respectively under metal- and solvent-free conditions. However, the reaction of 2-aminoanilines with cinnamic acids leads to the formation of 2-arylquinoxalines under the same set of reaction conditions. The transformation is versatile and compatible with a number of functional groups.

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Received 00th January 20xx,
Accepted 00th January 20xx
Elemental sulfur mediated synthesis of benzoxazoles,
benzothiazoles and quinoxalines via decarboxylative coupling of
2-hydroxy/mercapto/amino-anilines with cinnamic acids
DOI: 10.1039/x0xx00000x
www.rsc.org/
Tirumaleswararao Guntreddi,a Rajeshwer Vanjari,a Saurabh Kumar,a Rahul Singh,a Neetu Singh,a
Promod Kumara and Krishna Nand Singh*a
An easy and practical method has been developed for the diketones8, alcohols9, nitriles10, amines11, and methylarenes12 under
synthesis of 2-benzylbenzoxazoles and 2-benzylbenzothiazoles high temperature/strong oxidative conditions. Recently, 2-
using sulfur mediated decarboxylative coupling of cinnamic acids benzylbenzoxazoles have been synthesized by the reaction of
with 2-hydroxyanilines and 2-mercaptoanilines respectively under benzoxazoles with benzyl halides13 or benzyl carbonates,14 whereas
metal- and solvent-free conditions. However, the reaction of 2- 2-aryl/aroyl-benzothiazoles have been prepared by the reaction of
aminoanilines with cinnanmic acids leads to the formation of 2- 2-aminothiophenols
with acetophenones, styrenes, and
arylquinoxalines under the same set of reaction conditions. The phenylacetylenes.15,16 Quinoxalines constitute another important
transformation is versatile and compatible with a number of heterocycle frequently present in biologically and pharmaceutically
functional groups.
active compounds.17 The commonly used methods for the synthesis
of quinoxalines involve the direct cyclization reaction of o-
phenylenediamines with 1,2-dicarbonyl derivatives,18 α-hydroxy
ketones,19 α-haloketones,20 vicinal diols,21 diazoketones,22 and
phenylacetylene.23 Recently the synthesis of quinoxalines has been
achieved by the reaction of o-nitroanilines with phenethylamines,24
and oxidative azidation/cyclization of N-arylenamines/N-aryl
ketimines with azides under mild conditions,25 albeit using
transition metal catalysts. However, these methods are now and
then cumbersome and require metal salts, harsh conditions, and
longer reaction time. Therefore, development of an efficient and
direct protocol for the synthesis of 2-benzylbenzazoles and
quinoxalines by using simple and readily available starting materials
under metal-free condition is highly exigent.
Introduction
Past few years have witnessed the emergence of transition metal-
and photo-catalyzed decarboxylative cross-coupling reactions as a
powerful tool to construct carbon-carbon and carbon-heteroatom
bond, with enormous impact on organic synthesis, medicinal
chemistry and material science.1 Carboxylic acids and their
derivatives are widely used coupling partners as they are non-toxic,
inexpensive, stable and readily available in great structurally
diversity.2 The decarboxylative C-N coupling strategy involving the
synthesis of complex molecules is a fascinating and challenging
theme, yet only a few reports do exist involving this approach.3
In light of the above and as a part of our recent interest in sulfur
mediated reactions26 and other protocols,27 we disclose herein a
new strategy involving elemental sulfur mediated decarboxylative
coupling of 2-hydroxy/mercapto/amino-anilines with cinnamic
Benzazoles are privileged heterocyclic scaffolds found in many
natural products with various pharmaceutical applications.
Particularly, 2-substituted benzazoles are widely present in drugs to
combat various diseases.4 Traditional methods for the synthesis of
2-substituted benzazoles involve the reaction of o-
hydroxy/mercapto anilines with acylhalides5, acids6, aldehydes7, β-
acids/phenylpropiolic
acid
for
the
synthesis
of
2-
benzylbenzoxazoles, 2-benzylbenzothiazoles and 2-arylquinoxalines
respectively under metal- and solvent-free conditions (Scheme 1).
To the best of our knowledge, this is the first report in which
aromatic amines undergo the Willgerodt-Kindler rearrangement.
aDepartment of Chemistry (Centre of Advanced Study), Institute of Science,
Banaras Hindu University, Varanasi 221005, India. E-mail: knsingh@bhu.ac.in,
knsinghbhu@yahoo.co.in.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Results and discussion
The study was envisioned to achieve the synthesis of 2-substituted
benzoxazole by the reaction of cinnamic acid with 2-aminophenol.
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Table 1: Optimization of the reaction conditionsa
To start with, a model reaction involving 2-aminophenol (1a) and
cinnamic acid (3a) was undertaken in the presence of elemental
sulfur and N-methylmorpholine in DMSO at 120 °C for 15 h. To our
utmost delight, the desired product 2-benzylbenzoxazole (4a) was
formed in 35% (Table 1, entry 1).
entry
base (x equiv)
solvent
temp
(°C)
yield
(%)b
1
2
N-methylmorpholine (2)
N-methylmorpholine (2)
N-methylmorpholine (2)
N-methylmorpholine (2)
N-methylmorpholine (2)
DABCO (2)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
-
120
130
140
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
35
51
48
50c
43d
25
27
15
0
3
4
5
6
7
DMAP (2)
8
Pyridine (2)
9
-
10
11
12
13
14
15
16
17
18
19
20
K2CO3 (2)
0
Na2CO3 (2)
0
K3PO4 (2)
0
t-BuOK (2)
0
NaHCO3 (2)
0
CH3COONa (2)
0
N-methylmorpholine (2)
N-methylmorpholine (3)
N-methylmorpholine (4)
N-methylmorpholine (4)
N-methylmorpholine (3)
67
72
71
70e
65f
-
-
-
-
aConditions: 2-Aminophenol 1a (1 mmol), cinnamic acid 3a (1 mmol), elemental
sulfur (3 mmol, 96 mg), 15 h. bIsolated yield. C20 h. d10 h. esulfur (4 mmol). fsulfur
(2 mmol).
Scheme 1: Previous reports and present strategy.
amino-4-chlorophenol under the established set of reaction
conditions to afford the desired products 4a-j in reasonably good
yields. 3-(Thiophen-2-yl)acrylic acid also underwent the reaction
smoothly to give the product 4e in 59% yield. Nevertheless, 4-
nitrocinnamic acid failed to provide the product 4k under the
stipulated conditions. After ascertaining the viability of sulfur
mediated decarboxylative coupling of cinnamic acids with 2-
aminophenols, we next turned our attention to the synthesis of 2-
substituted benzothiazoles by using 2-aminothiophenols. As
anticipated, when the reaction was conducted using cinnamic acid
and 2-aminothiophenol under the same conditions, the product 2-
benzylbenzothiazole (5a) was formed in 71% yield. The versatility of
the reaction was further explored by using different cinnamic acids
with 2-aminothiophenol and 2-amino-4-chlorobenzenethiol under
the identical conditions to afford the desired products 2-
Increasing the reaction temperature to 130 °C increased the
product yield to 51% (entry 2). However, a further increase in the
reaction temperature (140 °C) and time (20 h) did not improve the
product yield again (entries 3 & 4), but a decrease in the reaction
time (10 h) diminished the product yield to 43% (entry 5). To further
advance the product yield, different organic bases such as DABCO,
DMAP and pyridine were screened (entries 6-8), but none of them
could match the efficacy of N-methylmorpholine. Notably, the
formation of the product was not observed in the absence of the
base (entry 9). Moreover, the use of inorganic bases like K2CO3,
Na2CO3, K3PO4, t-BuOK, NaHCO3 and CH3COONa in the solvent
DMSO remained futile (entries 10-15). Interestingly, when the
reaction was conducted under solvent-free conditions, the yield of
the product was improved to 67% (entry16). Increasing the molar
ratio of the base (3 equiv.) brought about some improvement in the
yield (entry17). Further increase in the molar equivalence of base
and elemental sulfur did not make any positive change (entries 18
& 19), but decreasing the molar ratio of sulfur (2.0 equiv.) lowered
down the product yield slightly (entry 20).
benzylbenzothiazole
5 in high yields (cf. Scheme 2). The
heteroaromatic 3-(thiophen-2-yl)acrylic acid also offered the
product 5e in 51% yield. It is worth noting that the disubstituted 3-
(2,4-dichlorophenyl)acrylic acid also reacted nicely giving 5f in 55%
yield.
Having established the optimum reaction conditions (entry 17), the
scope and limitations of the reaction were investigated in detail by
using different cinnamic acids and 2-aminophenols. The outcome is
summarized in Scheme 2. Cinnamic acids having substituent such as
chloro, bromo, methyl, and methoxy at different positions were
made to react with 2-aminophenol, 2-amino-4-methylphenol and 2-
2 | J. Name., 2012, 00, 1-3
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After concluding the above results, the reaction was also carried out
under the same set of reaction conditions by replacing cinnamic
acid with phenylpropiolic acid. Notably, the representative reaction
between 2-hydroxy/mercapto/amino-anilines and phenylpropiolic
acid under the established conditions led to the formation of 2-
benzylbenzoxazole (4a), 2-benzylbenzothiazole (5a) and 2-
arylquinoxaline (7a) in 75%, 73% and 70% yields respectively.
O
XH
X
N
S8
OH
R1
N-methylmorpholine
NH2
1 (X = O)
R
R
R1
130 °C
4 (X = O)
5 (X = S)
3
2 (X = S)
In order to gain an insight into the mechanistic pathway, a typical
reaction was undertaken in the presence of a radical scavenger
TEMPO (Scheme 4). As a result, the reaction proceeded well
without any effect, thereby excluding the possibility of involvement
of any radical intermediate.
O
OH
TEMPO
O
N
OH
NH2
Standard conditions
1a
3a
4a, 72%
Scheme 4: Radical trapping experiment
Based on the radical trapping experiment and existing literature,28
plausible mechanism is outlined in figure 1.
a
HX
N
HX
S
COO
COO
H2N
COOH
base
base
COO
S8
HX
HN
HX
N
HX
Scheme 2: The scope of the reaction between cinnamic acids and 2-
(1 mmol),
HX
N
X = O/S
S8
hydroxy/mercapto anilines. Conditions:
1
/2
(1 mmol), cinnamic acid
3
HN
N-methylmorpholine (3 mmol), sulfur (3 mmol, 96 mg) for 15 h. aWith
phenylpropiolic acid
H
COO
COO
COO
SH
SH
H
SH
X = NH
H
N
Finally, the process was extended to the reaction of cinnamic acids
and o-phenylenediamines with an aim to achieve the synthesis of 2-
benzylbenzimidazoles. Surprisingly, the formation of 2-
H
N
N
N
HS
HX
Oxdation
N
H
HS
7
phenylquinoxalines
7a-g
instead
of
expected
2-
HS
X
X
benzylbenzimidazoles was observed in good yields by the reaction
of different cinnamic acids with 2-aminoanilines under the
established conditions (Scheme 3).
N
HN
4 (X = O)
5 (X = S)
Figure 1: Plausible mechanism
Conclusion
In summary,
a practical approach has been developed to
accomplish 2-benzylbenzoxazoles, 2-benzylbenzothiazoles and 2-
arylquinoxalines by the reaction of cinnamic acids and 2-
hydroxy/mercapto/amino-anilines via decarboxylative C-N coupling
followed by cyclization. Aromatic amines have been successfully
employed for the first time in Willgerodt-Kindler type
rearrangement. The methodology is operationally simple, uses
readily available starting materials, and is free from the use of
metals, solvents and external oxidants.
Acknowledgements
We are thankful to the Department of Science and Technology,
Government of India, for providing financial assistance. T. G.,
R. V. and K. S are thankful to the CSIR, New Delhi for providing
research fellowships.
Scheme 3: The scope of the reaction between cinnamic acids and 1,2-
phenylenediamines. Conditions: 2-Aminoaniline
6 (1 mmol), cinnamic acid 3 (1
mmol), N-methylmorpholine (3 mmol), sulfur (3 mmol, 96 mg) for 15 h. aWith
phenylpropiolic acid
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