Utilization of carbon disulfide as a powerful building block for the synthesis of 2-aminobenzoxazoles

Article abstract of DOI:10.1039/c3ra41189c

This protocol describes a novel, mild and convenient route to afford 2-aminobenzoxazoles in high yields, and represents a significant advance towards an environmentally friendly strategy. Aliphatic amines are made to react with carbon disulfide to provide intermediate dithiocarbamates (DTC), which in the presence of 2-aminophenol, subsequently undergo successive intermolecular nucleophilic attack and desulfurization to produce 2-aminobenzoxazoles within 3 h.

Full text of DOI:10.1039/c3ra41189c

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Utilization of carbon disulfide as a powerful building
block for the synthesis of 2-aminobenzoxazoles3
Cite this: DOI: 10.1039/c3ra41189c
Tirumaleswararao Guntreddi, Bharat Kumar Allam and Krishna Nand Singh*
This protocol describes a novel, mild and convenient route to afford 2-aminobenzoxazoles in high yields,
and represents a significant advance towards an environmentally friendly strategy. Aliphatic amines are
made to react with carbon disulfide to provide intermediate dithiocarbamates (DTC), which in the
presence of 2-aminophenol, subsequently undergo successive intermolecular nucleophilic attack and
desulfurization to produce 2-aminobenzoxazoles within 3 h.
Received 11th March 2013,
Accepted 10th April 2013
DOI: 10.1039/c3ra41189c
www.rsc.org/advances
2-aminophenols.8,9 While these protocols have advantages,
they also possess limitations such as availability and toxicity of
1. Introduction
Eco-friendly straightforward processes and innovative pro-
ducts, which have lower the environmental impact, are now a
top priority. Integrating green chemistry principles into the
development of new processes and re-evaluation of existing
processes are the key elements of sustainable development. In
order to replace processes which have negative environmental
impacts, new developments must use nontoxic materials, save
energy, and generate less waste.1
Nitrogen-rich heterocyclic compounds have a profound
effect on human health because these chemical motifs are
present in a number of drugs used to combat a broad range of
diseases and pathophysiological conditions.2 Functionalized
azoles are especially important structural designs present in a
variety of natural products.3 Amongst them, 2-aminobenzox-
azoles exhibit potential therapeutic activities.4 Therefore, the
development of efficient and eco-safe protocols for the
construction of these heterocycles is highly desirable.
reagents. Furthermore, these protocols demonstrate poor step
efficiency, which makes them unattractive from a sustain-
ability point of view. Solvent-free reactions have drawn
considerable attention because of their environmentally
benign character.10 Carbon disulfide, the sulfur analogue of
carbon dioxide, is a valuable C1 building block and solvent
used in the chemical industries for the production of materials
such as rayon and cellophane and for the synthesis of a wide
range of organosulfur compounds including dithiocarba-
mates, xanthates and thioureas. Notably, CS2 is more reactive
towards nucleophiles due to the weaker p-donor ability of the
sulfido centres, which renders the carbon more electrophilic.11
In view of the above and as a part of our ongoing
explorations,12 we have envisioned and undertaken a straight-
forward connective route for the preparation of 2-aminoben-
zoxazoles using a one-pot reaction of 2-aminophenol, carbon
disulfide, and amines without a catalyst and a solvent.
2-Aminobenzoxazoles have been prepared by the nucleo-
philic displacement of 2-substituted benzoxazoles with an
amine,5a–c cyclodesulfurization of 2-hydroxyarylthioureas,5d,5e
and also via direct amination of benzoxazoles.5f,5g More
importantly, 2-aminobenzoxazoles can be expediently synthe-
sized from 2-aminophenol by three versatile routes (Fig. 1) viz.
a) preparation of polymer-bound 2-mercaptobenzoxazole
resins by the reaction of Merrifield resin with 2-aminophenols
and CS2 in the presence of N,N9-diisopropylcarbodiimide (DIC)
in CH3CN, followed by further oxidation of the resulting resin
2. Results and discussion
Our initial studies were aimed at optimizing the reaction
conditions by using a model reaction involving piperidine (1a),
carbon disulfide (2), and 2-aminophenol (3a). The findings are
given in Table 1. To our delight the reaction proceeded
smoothly in the absence of catalyst and solvent to selectively
afford the target 2-piperidobenzoxazole (4a) in 71% yield at
100 uC after five hours (Table 1, entry 1). A modest increase in
the reaction temperature (110 uC), however, brought about a
considerable enhancement in the product yield (90%) in three
hours (Table 1, entry 2). Increasing the temperature further
did not increase the yield of the reaction (Table 1, entry 3). To
study the effect of base on the yield of the reaction, a series of
bases, viz. K2CO3, Na2CO3 and Cs2CO3 were screened and it
was found that they did not improve the yield of the reaction
and subsequent treatment with amines,6 b)
a reaction
involving tetramethyl orthocarbonate, an amine and 2-amino-
phenol,7 and c) by the reaction of aryl isothiocyanates with
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi
221005, India. E-mail: knsingh@bhu.ac.in
Electronic supplementary information (ESI) available. See DOI: 10.1039/
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c3ra41189c
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toluene (Table 1, entries 7–15) were tried but none of them
could match the end result of the solvent free conditions.
With the optimized conditions in hand (Table 1, entry 2),
the scope and versatility of the method was then extended to a
variety of amine and 2-aminophenol partners. As shown
illustrated in Table 2, a range of amines such as piperidine
(1a),
morpholine
(1b),
N,N-diethylamine
(1c),
N,N-dimethylamine (1d), N-methylbenzylamine (1e), n-hexyla-
mine (1f), cyclopropylamine (1g), n-butylamine (1h),
N,N-dibutylamine (1i), cyclohexylamine (1j), tert-butylamine
(1k), 2-phenylethylamine (1l), benzylamine (1m) and
N,N-dipropylamine (1n) underwent smooth reaction with
carbon disulfide (2) and different 2-aminophenols viz.
2-aminophenol (3a), 4-methyl-2-aminophenol (3b) and
4-nitro-2-aminophenol (3c) to deliver a series of 2-aminoben-
zoxazole derivatives (4a–4u) in moderate to excellent yields
(56–96%). An electron withdrawing substituent installed at the
4-position of 2-aminophenol increased the yield of the reaction
considerably (Table 2, entries 18–21), while an electron-
donating substituent decreased the yield of the reaction
(Table 2, entries 15–17). Aromatic primary and secondary
amines failed to produce the desired 2-aminobenzoxazoles.
Anilines bearing different substituents (–OCH3, –CH3, and –Cl)
were screened as reaction partners along with CS2 and
2-aminophenol, but none of them afforded the desired
product (entries 22–24). However, the formation of small
amounts of symmetrically substituted thiourea was observed
at 110 uC after 3 h. Reactions were also carried out with amino
group-containing heterocycles, such as 2-aminopyridine and
2-aminothiophene, in the presence of CS2, and 2-aminophe-
nol, resulting in no desired product formation (entries 25 and
26). However, the formation of trace amounts of symmetrically
substituted thiourea was observed in the case of 2-aminopyr-
idine at 110 uC after 3 h. Heterocyclic secondary amines such
as pyrrole, imidazole, and pyrazole were also tested as amine
variants along with CS2, and 2-aminophenol, with no
corresponding product formation (entries 27–29). Aliphatic
secondary amines participated more rapidly in these transfor-
mations. When aliphatic primary amines were used, formation
of the corresponding symmetrically substituted thiourea was
invariably observed as a side product, however, no such
product formation was noticed in the case of secondary
amines, in accordance with the reported literature.13 Primary
amines with a phenyl ring at a- or b- position demonstrated a
marked yield loss (entries 12 and 13). It is interesting to note
that the desired product was not formed at all in the case of
cyclopropylamine (1g), rather 2-mercaptobenzoxazole (6) was
observed as the main product along with the symmetrically
substituted thiourea. To improve the environmental friendli-
ness of our methodology, efforts were made to trap the evolved
Fig. 1 Approaches for the synthesis of 2-aminobenzoxazoles.
(Table 1, entries 4–6). In order to observe the effect of solvent
on the reaction, various polar and non-polar solvents such as
DMF, CH3CN, THF, 1,4-dioxane, DCE, DMSO, H2O, NMP and
Table 1 Optimization of reaction conditionsa
Entry
Base
Solvent
T/uC
Time (h)
Yield (%)b
1.
2.
3.
4.
5.
6.
7.
8.
—
—
—
K2CO3
Na2CO3
CS2CO3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
100
110
120
110
110
110
110
80
65
100
85
110
100
110
110
5
3
3
3
3
3
10
10
10
10
10
10
10
10
10
71
90
90
89
90
87
80
65
40
68
54
45
trace
49
60
DMF
CH3CN
THF
1,4-Dioxane
DCE
DMSO
H2O
NMP
Toluene
9.
10.
11.
12.
13.
14.
15.
H2S by
using N,N9-dicyclohexylcarbodiimide
(DCC).
Unfortunately, the utilization of DCC significantly decreased
the yield of the product, probably due to the formation of side
products arising from the reaction of 2-aminophenol with
DCC.
a
b
Using 1a (1.5 mmol), 2 (1.5 mmol) and 3a (1 mmol). Isolated
yield based on 2-aminophenol.
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Table 2 Substrate scope for the one-pot synthesis of 2-amino benzoxazolesa
Entry Amine (1)
One carbon surrogate (2)
2-Aminophenol (3)
Product (4)
Yield (%)b
a
b
Using 1 (1.5 mmol), 2 (1.5 mmol) and 3 (1 mmol) at 110 uC for 3 h. Isolated yield based on 2-aminophenol.
1.
1a CS2
1b CS2
1c CS2
1d CS2
1e CS2
1f CS2
1g CS2
1h CS2
1i CS2
2
2
2
2
2
2
2
2
2
2
2
2
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
4a 90
2.
4b 87
3.
4c
85
4.
4d 80
5.
4e 79
6.
4f
75
0
7.
4g
8.
4h 75
9.
4i
4j
69
67
10.
11.
12.
1j
CS2
1k CS2
4k 65
1l
CS2
4l
60
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Table 2 (Continued)
Entry Amine (1)
One carbon surrogate (2)
1m CS2
2-Aminophenol (3)
Product (4)
Yield (%)b
13.
2
2
2
2
2
2
2
2
2
2
2
2
3a
3a
3b
3b
3b
3c
3c
3c
3c
3a
3a
3a
4m 56
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
1n CS2
1a CS2
1c CS2
1i CS2
1b CS2
1c CS2
1a CS2
1d CS2
1o CS2
1p CS2
1q CS2
4n 75
4o 77
4p 70
4q 63
4r
4s
4t
94
90
96
4u 80
4v
4w
4x
0
0
0
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Table 2 (Continued)
Entry Amine (1)
One carbon surrogate (2)
1r CS2
2-Aminophenol (3)
Product (4)
Yield (%)b
25.
2
3a
4y
0
26.
27.
1s CS2
2
2
3a
3a
4z
0
0
1t CS2
4aa
28.
29.
1u CS2
2
2
3a
3a
4ab
4ac
0
0
1v CS2
Based upon isolation of products and the existing
literature, a plausible reaction pathway is outlined in Fig. 2.
The formation of symmetrically substituted thiourea as a side
product suggests the involvement of dithiocarbamate (5) as an
intermediate. To confirm the presence of dithiocarbamate (5)
during the course of reaction, a control experiment was
conducted using a secondary amine (1a) and CS2 alone under
the optimized set of conditions, proving the formation of
intermediate 5. To further confirm the intermediacy of 5, an
additional experiment was carried out with a large excess of
primary aliphatic amine 1l and CS2, which afforded the
symmetrically substituted thiourea (8) as main product.
3. Experimental section
3.1 General remarks
1H and 13C NMR spectra were run on a JEOL AL300 FTNMR
spectrometer at 300 MHz and 75 MHz respectively, at a
temperature of 300 K. NMR chemical shifts are expressed in d
values with reference to tetramethylsilane (TMS) as an internal
standard.
All reagents were procured from Aldrich, USA, and were
used without further purification. The solvents were purified
and dried according to standard methods prior to use. All
reactions were carried out under an atmosphere of air.
Reactions were monitored using thin-layer chromatography
(TLC) carried out on silica gel 60/Kieselguhr F254 pre-coated
on aluminium sheets (thickness 0.2 mm), commercially
available from Merck, using ultra-violet light as the visualizing
agent and I2 as the developing agent.
Fig. 2 Plausible mechanism of the reaction.
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Acknowledgements
We thank Council of Scientific and Industrial Research (CSIR),
New Delhi and Department of Biotechnology (DBT), New Delhi
for financial assistance.
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