Metal-free synthesis of 2-aminobenzoxazoles using hypervalent iodine reagent

Article abstract of DOI:10.1016/j.tetlet.2012.12.127

A facile, simple, mild, and metal-free protocol for the synthesis of 2-aminobenzoxazoles has been developed via C-H bond amination of benzoxazoles with amines through a ring-opening and subsequent ring-closure approach. The reaction was performed in two steps wherein nucleophilic addition of amines across benzoxazoles takes place in the absence of any reagent or catalyst under solvent-free condition, followed by oxidative ring closure using 2-iodoxybenzoic acid as a hypervalent iodine reagent. Various cyclic, acyclic, and functionalized aliphatic amines were well tolerated under optimized reaction conditions and provided good to excellent yield of respective 2-aminobenzoxazoles.

Full text of DOI:10.1016/j.tetlet.2012.12.127

Tetrahedron Letters 54 (2013) 1290–1293
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free synthesis of 2-aminobenzoxazoles using hypervalent iodine reagent
⇑
Yogesh S. Wagh, Neelam J. Tiwari, 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, simple, mild, and metal-free protocol for the synthesis of 2-aminobenzoxazoles has been
developed via C–H bond amination of benzoxazoles with amines through a ring-opening and subsequent
ring-closure approach. The reaction was performed in two steps wherein nucleophilic addition of amines
across benzoxazoles takes place in the absence of any reagent or catalyst under solvent-free condition,
followed by oxidative ring closure using 2-iodoxybenzoic acid as a hypervalent iodine reagent. Various
cyclic, acyclic, and functionalized aliphatic amines were well tolerated under optimized reaction
conditions and provided good to excellent yield of respective 2-aminobenzoxazoles.
Received 13 October 2012
Revised 24 December 2012
Accepted 26 December 2012
Available online 9 January 2013
Keywords:
2-Aminobenzoxazoles
Oxidative amination
C–H activation
Ó 2013 Elsevier Ltd. All rights reserved.
2-Iodoxybenzoic acid
Benzoxazoles
Oxidative C–H functionalization reactions are of great interest
in organic synthesis as they have high atom-efficiency compared
to related cross-coupling reactions using organometallic com-
pounds.1 Oxidative C–H bond amination reaction of heteroaro-
matic compounds is particularly important because of its
applications in the synthesis of biologically active molecules and
advanced organic materials.2 These heteroaromatic compounds
such as 2-aminobenzoxazoles can be synthesized by oxidative
C–H bond amination of benzoxazoles with a variety of amines.3
Such types of 2-aminobenzoxazole derivatives are invariably found
in a number of therapeutically important molecules and some
2-(N-alkylpiperazyl)benzoxazoles have already been described as
potent 5-HT3-receptor agonists.4 These 2-aminobenzoxazoles can
be synthesized by palladium-catalyzed N-arylation reaction of 2-
halo derivatives of benzoxazoles with amines.5 However, use of
expensive metals, specialized ligands, harsh reaction conditions,
and long reaction time are the major drawbacks of N-arylation
reaction. In comparison with N-arylation, amination by C–H acti-
vation is more attractive as it can directly couple C–H of heteroar-
omatic compound with N–H of amines and can take place without
ligands under milder reaction conditions. In this direction various
metal-catalysts such as Ag(I), Co(II), Mn(II), Fe(III), and Cu(II) are
reported for the oxidative C–H bond amination of azoles.6 How-
ever, metal catalysts themselves have some drawbacks like they
are expensive and not environmentally benign. They are needed
to remove at trace levels for pharmaceutical applications. Hence,
some metal-free protocols using various non-metal catalysts such
as TBAI, I2, TEMPO, and NIS have been designed by several reseach-
ers.7 Furthermore, Chang and co-workers explored DIB as a hyper-
valent iodine reagent for the oxidative C–H bond amination of
benzoxazoles at room temperature.8 Nowadays, hypervalent
iodine reagents are extensively employed for a variety of chemical
transformations and particularly as oxidative reagents. Because of
ready availability, convenience of use, unique oxidizing properties,
and eco-friendly features they are widely utilized in the synthesis
of complex natural products of biological interest.9 Recently,
2-iodoxybenzoic acid (IBX) has become an alternative oxidizing
agent for various metal based oxidants.10
Although there are many reports on oxidative C–H bond amina-
tion of benzoxazoles, the reported protocols still suffer from some
drawbacks such as necessity of stoichiometric amount of acid/base
additive and co-oxidant. Also, they either require harsh reaction
conditions or it takes more time at room temperature for comple-
tion of the reaction. Hence, there is a need to develop a protocol
which works at milder reaction condition and metal-free condi-
tions in shorter reaction time.
In this context, herein we report oxidative C–H bond amination
of benzoxazoles with amines in the presence of IBX as a hyperva-
lent iodine reagent (Scheme 1). Here, 2-aminobenzoxazoles have
been successfully synthesized in two steps.
First step is direct nucleophilic addition of secondary amine at
C-2 position of benzoxazole at 25 °C under solvent-free and aerobic
conditions and gives ring opened amidine intermediate 3. Further
in the second step cyclization of this intermediate 3 takes place by
using IBX reagent at 25 °C within 5-30 min to give 2-aminobenzox-
azoles 4.11
⇑
Corresponding author. Tel.: +91 22 33612601; fax: +91 22 33611020.
E-mail addresses: bhalchandra_bhanage@yahoo.com, bm.bhanage@gmail.com
Benzoxazole (1a) and morpholine (2a) were selected as model
substrates for the optimization of the ring-opening and subsequent
(B.M. Bhanage).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.127

Y. S. Wagh et al. / Tetrahedron Letters 54 (2013) 1290–1293
1291
R2
R3
R2
IBX, DCM,
HN
R1
N
N
R1
R1
25 °C, 5-30 min
R2
R3
N
O
N
O
R3
2
N
O
25-60 °C,
15-60 min
OH
O
IBX =
1
3
4
I
O
R
1 = H, CH3; R2, R3 = alkyl
HO
Scheme 1. Oxidative C–H amination of benzoxazoles.
Table 1
Optimization of reaction conditionsa
ious solvents such as CH2Cl2, CHCl3, CH3CN, THF, toluene, and
DMSO were screened to find the best solvent for oxidative ring
closing reaction of 3a (Table 1, entries 7–11). CH2Cl2 was found
to be the best among all the above solvents screened and furnished
95% yield of 4a. Also, it has been observed that the reaction pro-
vides comparative yield after decrease in reaction time up to
5 min at 25 °C (Table 1, entry 12). Hence, the optimized reaction
conditions for ring closing reaction of 3a to 4a are: IBX (1 equiv)
in CH2Cl2 solvent at 25 °C for 5 min.
O
N
N
N
O
N
O
OH
3a
4a
Entry
Reagent
Solvent
Time (min)
Yieldb (%)
1
2
3
4
KIO3
KIO4
HIO4
IBX
H2O2
O2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
10
10
10
10
60
60
10
10
10
10
10
5
65
60
55
95
—
These optimized reaction conditions were then applied for the
synthesis of various 2-aminobenzoxazoles by ring opening reac-
tion of benzoxazole with various amines and then subsequent oxi-
dative ring closing reaction mediated by IBX reagent (Table 2).
Initially various cyclic amines such as morpholine, piperidine,
and pyrrolidine were treated with 1a for ring opening reaction at
25 °C under solvent-free conditions (Table 2, entries 1–3). All these
amines reacted smoothly with 1a and provided respective amidine
adducts in excellent yields. Then the respective 2-aminobenzoxaz-
oles were synthesized in good to excellent yields by subsequent
cyclization of these amidines using IBX in CH2Cl2 at 25 °C. Further,
the other cyclic amines bearing various functional groups like N-
methylpiperazine, 1-(piperazin-1-yl)ethanone, N-benzylpipera-
zine, and 1,2,3,4-tetrahydroisoquinoline were also treated with
1a under optimized reaction conditions (Table 2, entries 4–7).
However, the ring opening reactions of these amines need to be
performed at 60 °C to get higher yields of respective amidine ad-
duct. The further cyclization of these amidine adducts occurred
smoothly under optimized reaction conditions and provided good
to excellent yield of respective 2-aminobenzoxazoles. Acyclic sec-
ondary amines such as diethylamine, dibutylamine, and N-
methyl-1-phenylmethanamine also turned out to be facile reac-
tants (Table 2, entries 8–10). However, they require higher reaction
temperatures and longer duration of time to obtain full conversion
in the ring-opening step. The reaction of these amines (2h, 2i, and
2j) with 1a was performed at 60 °C and it proceeded efficiently to
give adduct 3h, 3i, and 3j respectively, which subsequently cy-
clized to form 4h, 4i, and 4j respectively with good to excellent
overall yields.
To widen the applicability of the present protocol, we provided
5-methylbenzoxazole substrate for oxidative C–H bond amination
with various cyclic amines such as morpholine, piperidine, and
N-methylpiperazine (Table 2, entries 10–13). All these cyclic
amines tolerated very well and afforded good to excellent yields
in the ring opening as well as IBX mediated cyclization step.
In conclusion, we have developed an efficient metal-free method-
ology for oxidative C–H bond amination of benzoxazoles with amines
by ring-opening and subsequentring-closing inthe presenceofIBX as
a hypervalent iodine reagent. IBX as a source of oxidizing agent gave
the most significant results. Secondary amines can be concluded as
the best substrates for this reaction at ambient temperature and pres-
sure. The overall reaction is highly attractive from a synthetic point of
view, since the reaction conditions are milder and free from acids,
5c
6d
7
—
IBX
92
10
8
—
28
94
8
9
IBX
IBX
CH3CN
THF
10
11
12
IBX
IBX
IBX
Toluene
DMSO
CH2Cl2
a
Reaction conditions: 3a (0.5 mmol) and hypervalent iodine reagents (1 equiv)
at 25 °C.
b
GC yield.
c
30% aqueous solution of H2O2.
1 atm O2 pressure.
d
oxidative ring-closing reaction (Table 1). Chang and co-worker
demonstrated such type of ring opening of azoles under neat and
mild conditions to give the amidine adducts.8 Later, Studer and
co-worker observed amidine formation for the reaction of benzox-
azoles with amines in the presence of TfOH or Sc(OTf)3.7c Hence,
we treated 1a with 2a for ring opening reaction to give amidine
and it was observed that the reaction proceeded smoothly at
25 °C and required only 15 min for completion under an air atmo-
sphere and solvent-free conditions with 98% yield of 3a. The reac-
tion completion was constantly monitored using thin layer
chromatography. One significant visual observation during the
reaction course was the phase change from liquid to semisolid/so-
lid indicating the maximum formation of intermediate 3a.
Next, the oxidative ring closing reaction of 3a–4a was opti-
mized with the help of various reaction conditions such as screen-
ing of various reagents, solvents, and reaction time (Table 1).
Various iodine reagents such as KIO3, KIO4, HIO4, and IBX as well
other normal oxidants such as dihydrogen dioxide and oxygen
were screened for the ring closing reaction of 3a to 4a in CH2Cl2
solvent at 25 °C under an air atmosphere (Table 1, entries 1–6). It
has been observed that IBX shows excellent activity and offered
95% overall yield of 4a. Other iodine reagents gave lower yields
of 4a in comparison with IBX. Dihydrogen dioxide and oxygen
were found to be inactive for the ring closing of 3a in to 4a under
present reaction conditions (Table 1, entries 5 and 6). Further var-

1292
Y. S. Wagh et al. / Tetrahedron Letters 54 (2013) 1290–1293
Table 2
Oxidative C–H bond amination of benzoxazoles with aminesa,b
Entry Benzoxazole
Amine (2)
Intermediate (3)
Time
(min)
Yieldc
(%)
Product (4)
Time
(min)
Yieldc
(%)
(1)
N
N
O
O
HN
HN
O
N
N
O
N
N
2a
1
15
20
15
60
98
98
5
5
95
92
95
86
O
4a
OH
3a
1a
N
O
2b
N
N
N
4b
2
3
4
1a
1a
1a
OH
3b
N
O
HN
HN
N
N
2c
4c
99
10
20
OH
3c
N
N
O
N
N
N
N
N
N
2d
96d
4d
OH
3d
O
O
O
N
O
HN
HN
N
N
N
N
N
2e
2f
4e
5
1a
N
60
95d
30
82
OH
3e
Ph
N
O
N
N
N
N
N
N
N
Ph
97d
99d
92d
30
5
80
97
86
Ph
4f
6
7
8
1a
1a
1a
60
60
60
OH
3f
N
O
N
N
N
NH
2g
4g
OH
3g
N
O
HN
N
2h
4h
4i
10
OH
3h
3i
nBu
nBu
nBu
N
nBu
N
O
N
N
HN
HN
N
nBu
9
1a
1a
60
60
95d
99d
10
5
83
92
nBu
2i
OH
N
N
O
N
Ph
10
2j
Ph
4j
Ph
N
OH
3j
O
N
O
O
N
N
N
O
N
N
4k
11
12
13
2a
2b
2d
20
20
60
98
96
5
6
94
91
86
1b
OH
3k
O
N
N
N
N
4l
1b
OH
3l
N
O
N
N
N
1b
93d
10
4m
OH
3m
a
b
c
Condition for amidine formation: 1 (0.50 mmol) and 2 (0.75 mmol), neat at 25 °C for above mentioned time under an air atmosphere.
Condition for 2-aminobenzoxazoles formation: 3 (0.5 mmol) and IBX (1 equiv) in DCM at 25 °C for above mentioned time under an air atmosphere.
Isolated yield.
Reaction performed at 60 °C.
d

Y. S. Wagh et al. / Tetrahedron Letters 54 (2013) 1290–1293
1293
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11. Typical experimental procedure: Round bottom flask was charged with
benzoxazole (1a, 0.5 mmol) and morpholine (2a, 0.75 mmol) and the
solution was stirred in the absence of solvent for 30 min at 25 °C under an
air atmosphere. The crude product mixture was then diluted with CH2Cl2
(20 mL), washed with
a
saturated solution of NaCl, (3 Â 10 mL) and the
aqueous layer was again extracted with CH2Cl2 (3 Â 10 mL). The combined
organic layers were dried over Na2SO4 and concentrated under reduced
pressure to obtain pure amidine intermediate 3a in 98% yield. After dissolving
this amidine adduct in dichloromethane (3 mL), IBX (1.0 equiv) was added, and
the reaction mixture was stirred for 5 min at 25 °C under an air atmosphere.
The mixture was then diluted with CH2Cl2 (20 mL), washed with a saturated
solution of NaHCO3 (3 Â 10 mL), and the aqueous layer was extracted with
CH2Cl2 (3 Â 10 mL). The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The resulting residue was purified by
column chromatography on silica gel to afford desired product 4a in 95% yield.
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, JEOL JMTC-270/54/SS (JASTEC 400 MHz)) (see
Supplementary data).