Metal-free N-iodosuccinimide-catalyzed mild oxidative C-H bond amination of benzoxazoles

Article abstract of DOI:10.1016/j.tetlet.2012.04.117

A facile, efficient, and mild protocol for the synthesis of aminobenzoxazoles has been developed using direct oxidative C-H bond amination of benzoxazoles with secondary or primary amines. The reaction was performed using catalytic amount of N-iodosuccinimide and aqueous hydrogen peroxide as a green oxidant and in the absence of transition metals. Reaction proceeds smoothly at ambient temperature and requires shorter reaction time to furnish excellent yield of the desired products. Various cyclic, acyclic, and functionalized aliphatic amines were well tolerated under optimized reaction conditions and provided good to excellent yield of the respective aminobenzoxazoles.

Full text of DOI:10.1016/j.tetlet.2012.04.117

Tetrahedron Letters 53 (2012) 3482–3485
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free N-iodosuccinimide-catalyzed mild oxidative C–H bond amination
of benzoxazoles
⇑
Yogesh S. Wagh, Dinesh N. Sawant, Bhalchandra M. Bhanage
Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile, efficient, and mild protocol for the synthesis of aminobenzoxazoles has been developed using
direct oxidative C–H bond amination of benzoxazoles with secondary or primary amines. The reaction
was performed using catalytic amount of N-iodosuccinimide and aqueous hydrogen peroxide as a green
oxidant and in the absence of transition metals. Reaction proceeds smoothly at ambient temperature and
requires shorter reaction time to furnish excellent yield of the desired products. Various cyclic, acyclic,
and functionalized aliphatic amines were well tolerated under optimized reaction conditions and pro-
vided good to excellent yield of the respective aminobenzoxazoles.
Received 22 March 2012
Revised 23 April 2012
Accepted 26 April 2012
Available online 2 May 2012
Keywords:
Green chemistry
Oxidative amination
C–H activation
Ó 2012 Elsevier Ltd. All rights reserved.
Homogeneous catalysis
N-Iodosuccinimide
Catalytic oxidative C–H bond amination reaction of arenes and
heteroarenes is one of the important reactions in synthetic organic
chemistry since, the molecules containing aryl and heteroaryl-
amine units are ubiquitous in biological and pharmaceutical sci-
ences.1 Aryl and heteroarylamines can be synthesized by
palladium-catalyzed N-arylation reaction using heteroaryl ha-
lides,2 that is Buchwald–Hartwig amination. However, transition-
metal-catalyzed N-arylation reaction generates stoichiometric
amount of acid in the reaction medium and also it requires the
use of expensive metals, specialized ligands and long reaction time.
In the past few years transition-metal-catalyzed direct C–H bond
amination of arenes and heteroarenes has attracted great atten-
tion,3 as it enables the synthesis of wide range of functionalized
heterocyclic compounds and is more atom economical as com-
pared with related coupling reaction of heteroaryl halides.
The 2-aminobenzoxazole derivatives are found in a number of
therapeutically important molecules and some 2-(N-alkylpiperazyl)-
benzoxazoles already described as potent 5-HT3-receptor
agonists.4 Also, they are important scaffolds in medicinal chemis-
try. In this regard Monguchi et al.5a and Wang and Schreiber5b
independently developed a copper-catalyzed C–H bond amination
and amidation of azoles. However, the reaction conditions used in
these protocols were quite harsh. Kawano et al. successfully devel-
oped a copper-catalyzed milder protocol for azole amination using
chloroamines,6 however the protocol requires specialized ligands
and stoichiometric amount of base. Afterward, Chang and co-work-
ers developed a milder protocol for azole amination with amines
and amides by using silver salt in the presence of Bronsted acids.7
Although, the reaction conditions were milder, major disadvantage
of this procedure was the use of stoichiometric amount of a silver
species. Next, same author reported another milder protocol by
using catalytic amount of cobalt and manganese based catalysts.8
Despite the fact that the reported protocol overcomes all the draw-
backs of earlier protocols, there was a need to develop this trans-
formation under environmentally benign conditions and ideally
under metal-free conditions. Oxidative C–H bond amination of
benzoxazoles under metal-free conditions is not a well known
reaction.9 Recently, Nachtsceim and co-workers successfully ex-
plored metal-free conditions for oxidative C–H bond amination of
benzoxazoles by using tetrabutylammonium iodide (TBAI) as a cat-
alyst along with peroxide oxidant.9b There is one more report on
metal-free amination by Lamani and Prabhu using molecular io-
dine as a catalyst. In this case, tertiary butyl hydrogen peroxide
(TBHP) was used as an oxidant at room temperature for 12 h.9c
However, both of these metal-free protocols suffer from drawbacks
such as requirement of longer reaction time and lower yields of the
aminated products.
In this context, to design more environmentally benign, mild,
and greener methods for the oxidative C–H bond amination of
benzoxazole and continuation of our research work on amination
reaction,10 herein we report an efficient and mild metal-free proto-
col for the oxidative C–H bond amination of benzoxazoles by using
catalytic amount of N-iodosuccinimide (NIS) and aq H2O2 as a
⇑
Corresponding author. Tel.: +91 22 33612601; fax: +91 22 33611020.
E-mail addresses: bm.bhanage@gmail.com, bhalchandra_bhanage@yahoo.com
(B.M. Bhanage).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.117

Y. S. Wagh et al. / Tetrahedron Letters 53 (2012) 3482–3485
3483
NIS (5 mol%),
AcOH (2 equiv),
greener oxidant and acetic acid as an additive at room temperature
in acetonitrile solvent (Scheme 1).11
R1
R2
R1
R2
O
N
O
N
R
H
+
N
HN
R
Aq. H2O2 (2 equiv)
ACN, RT
For the optimization of reaction conditions, benzoxazole (1a)
and morpholine (2a) were chosen as model substrates in the pres-
ence of catalytic amount of NIS, H2O2 as an oxidant and acetic acid
as an additive. Influence of various reaction conditions like sol-
vents, time, temperature, and catalyst loading was studied to get
optimize reaction conditions (Table 1). Influence of various polar
as well as non-polar solvents has been studied on the oxidative
amination of benzoxazole with morpholine (Table 1, entries 1–9)
and it reveals that the reaction does not have any significant im-
pact on the nature of solvent and it gave moderate to good yields
in most of the solvents (Table 1, entries 1–8). It gives 82% yield
of product 3a even under solvent-free condition (Table 1, entry
9). Acetonitrile was found to be the best solvent among various sol-
vents screened as it resulted in excellent yield of 3a (Table 1, entry
8). Further, we also performed the reaction at room temperature
and checked the yield at different time intervals (2–12 h) (Table
1, entries 8, 10–11). It was observed that the reaction completed
within 4 h and gave excellent yield of 3a (Table 1, entry 11). Next,
we studied the effect of reaction temperature on reaction outcome
and we have performed the reaction at different reaction temper-
atures ranging from room temperature to 80 °C by continuous
monitoring on GC (Table 1, entries 11, 12–14). It was observed that
reaction proceeded smoothly at room temperature within 4 h and
gave excellent yield of 3a (Table 1, entry 11). With further increase
in the reaction temperature, it gave significant enhancement in the
reaction rate and requires just 1 h for the completion of reaction at
80 °C (Table 1, entry 14). In an effort to evolve the best loading of a
catalyst for oxidative C–H bond amination, the reactions with var-
ious catalysts loading were carried out (Table 1, entries 11 and 15).
The yield of reaction was observed to decrease with a decrease in
catalyst loading from 5 mol % to 2 mol % (Table 1, entries 15). The
5 mol % loading of NIS was the optimum amount of catalyst for
the reaction (Table 1, entry 11). Thus, the optimized reaction con-
ditions are: 1a (1.0 mmol), 2a (2.0 mmol), NIS (5 mol %), H2O2
(2.0 mmol), and AcOH (2.0 mmol) in acetonitrile at room tempera-
ture for 4 h.
3
1
2
R = H/CH3, R1, R2 = H/alkyl
Scheme 1. NIS catalyzed oxidative amination of benzoxazole.
Table 1
Optimization of oxidative C–H bond amination reaction conditionsa
NIS (5 mol%),
O
N
O
AcOH (2 equiv),
H
N
O
+
HN
O
Aq. H2O2 (2 equiv)
ACN, RT
N
3
1
2
Entry Solvent
Influence of solvent
NIS (mol %) Temperature (°C) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
EtOAc
Dioxane
DMF
CH3Cl
Methanol 5.0
Toluene
Hexane
CH3CN
Neat
5.0
5.0
5.0
5.0
rt
rt
rt
rt
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
12
12
72
75
88
84
89
81
67
98
82
5.0
5.0
5.0
5.0
Influence of temperature and time
10
11
12
13
14
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5.0
5.0
5.0
5.0
5.0
rt
rt
40
60
80
2
4
2
1.5
1
82
98
95
96
96
Influence of catalyst concentration
15 CH3CN 2.0
rt
4
86
a
Reaction condition: 1a (1 mmol), 2a (2.0 mmol), acetic acid (2.0 mmol), aq H2O2
(2.0 mmol, 30% aq solution), solvent (5 mL).
b
GC yield.
Table 2
Oxidative C–H amination of benzoxazoles with various aminesa
Entry
Benzoxazole (1)
Amine (2)
Product (3)
Time (h)
4
Yieldb (%)
98
O
O
HN
HN
HN
HN
O
N
N
N
N
O
1
2a
N
N
O
1a
3a
2
3
4
5
6
1a
1a
1a
1a
1a
6
8
94
85
85
90
96
2b
N
O
3b
2c
N
O
3c
N
N
12
6
2d
N
O
3d
O
O
HN
HN
N
N
N
N
N
N
2e
N
O
3e
5
Ph
2f
N
O
Ph
3f
N
N
NH
7
8
1a
1a
5
6
97
2g
N
3g
O
N
HN
82
2h
3h
(continued on next page)

3484
Y. S. Wagh et al. / Tetrahedron Letters 53 (2012) 3482–3485
Table 2 (continued)
Entry
Benzoxazole (1)
Amine (2)
Product (3)
Time (h)
8
Yieldb (%)
83
nBu
HN
nBu
nBu
O
N
N
9
1a
N
O
nBu
2i
3i
HN
10
1a
1a
1a
4
6
92
80
Ph
2j
N
Ph
3j
O
N
HN
N
11
2k
3k
3l
H2N
O
Ph
NH
NH
2l
12
13
12
12
82
81
N
O
Ph
H2N
2m
1a
N
3m
3n
O
O
N
O
14
15
16
2a
2b
2d
5
6
6
94
91
86
N
N
O
1b
N
N
1b
1b
N
O
3o
N
N
3p
O
N
N
17
1b
2 k
6
92
3q
a
Reaction condition: 1 (1 mmol), 2 (2 mmol), NIS (5.0 mol %), acetic acid (2 mmol), aq H2O2 (2 mmol, 30% aq solution), acetonitrile (5 mL) at rt.
Isolated yield.
b
The scope and generality of the present protocol were explored
very well and afforded excellent yields of respective aminobenzox-
azoles 3n, 3o, 3p, and 3q (Table 2, entries 14–17).
under optimized reaction conditions for the oxidative C–H bond
amination reaction between different types of cyclic/acyclic ali-
phatic, secondary as well as primary amines with benzoxazole (Ta-
ble 2, entries 1–15). Morpholine, piperidine, and pyrrolidine were
treated with benzoxazole. All these substrates reacted effectively
and gave excellent yields of respective aminobenzoxazoles 3a, 3b,
and 3c (Table 2, entries 1–3). Furthermore we succeeded to synthe-
size 2-piperazylbenzoxazoles 3d, 3e, and 3f in excellent yields (85%,
90% and 96%) starting from N-methyl, N-acyl, and N-benzylpipera-
zine (Table 2, entries 4–6). 2-(N-Alkylpiperazyl)benzoxazoles of
this type were already described as potent 5-HT3-receptor ago-
nists.4 Treatment of 1,2,3,4-tetrahydroisoquinoline with benzoxaz-
ole gives 97% yield of desired aminated product 3g within 5 h only
(Table 2, entry 7). Next, we treated various aliphatic acyclic second-
ary amines such as diethylamine, dibutylamine, and N-methylben-
zylamine with benzoxazole and observed the good to excellent
yields (82–92%) of respective aminobenzoxazoles 3h, 3i, and 3j (Ta-
ble 2, entries 8–10). Diallylamine also well tolerated under the
present optimized reaction conditions and provided 80% yield of
N,N-diallylbenzoxazol-2-amine as one of the synthetically useful
compound (Table 2, entry 11).
After getting successful results in C–H bond amination of sec-
ondary aliphatic amines, various primary aliphatic amines like
benzylamine and n-butylamine were also studied (Table 2, entries
12–13). These substrates reacted sluggishly as compared with sec-
ondary aliphatic amines and provided 82% and 81% yields of 3l and
3m, respectively. The effect of various amines on C–H bond amina-
tion of benzoxazoles shows that the more nucleophilic amines re-
act faster to give higher yields of respective aminobenzoxazoles. In
order to broaden the synthetic potential of present protocol a
derivative of benzoxazole i.e. 5-methylbenzoxazole was treated
with a variety of aliphatic secondary amines like morpholine,
piperidine, N-methylpiperazine, and diallylamine under optimized
reaction conditions. However all these amine substrates tolerated
In conclusion, we have developed an efficient and metal-free
protocol for oxidative amination of benzoxazoles having mild
reaction conditions and require less amount of economical and
easily available NIS catalyst. The ambient reaction temperature,
lower reaction time, and easy to handle H2O2 as an oxidant make
this C–H bond amination protocol more resourceful for future
applications. Variety of aliphatic amines has been successfully uti-
lized to synthesize respective aminobenzoxazoles with excellent
yield.
Acknowledgments
The author (Y.S.W.) is greatly thankful to the Council of Scien-
tific and Industrial Research (CSIR), India for providing
fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
117.
References and notes
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11. General procedure for oxidative amination of benzoxazole: In a 25 mL two-
necked round bottomed flask benzoxazole (1.0 mmol), AcOH (2.0 mmol),
amine (2.0 mmol), and NIS (0.05 mmol) were added. The cold aqueous solution
of H2O2 (2.0 mmol) was slowly added to the above suspension followed by
5 mL acetonitrile. Then the above mixture was kept under stirring condition till
the completion of reaction. The progress of the reaction was monitored using
gas chromatography. After completion of reaction the reaction mixture was
extracted with ethyl acetate and treated with saturated solution of Na2CO3.
Then consecutive water washing was given to the organic layer. The organic
layer was separated, dried over anhydrous sodium sulphate followed by
removal of solvent under reduced pressure. The reaction mixture was analyzed
using a gas chromatography (Perkin Elmer, Clarus 400) equipped with a flame
ionization detector (FID) and capillary column. The crude product was purified
by column chromatography (silica gel, 100–200 mesh; petroleum ether/ethyl
acetate, 90:10) to afford pure products. All the prepared compounds were
confirmed by comparing with their authentic samples and were characterized
by GC–MS (Shimadzu QP 2010), 1H NMR (Varian 500 MHz).
8. Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49, 9899–
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