Synthesis of 2-aminobenzoxazoles via copper-catalyzed electrophilic amination of benzoxazoles with O-benzoyl hydroxylamines

Article abstract of DOI:10.1016/j.tet.2013.05.127

An efficient copper-catalyzed electrophilic amination of benzoxazoles with O-benzoyl hydroxylamines is described, employing CuCl catalyst, PPh₃ ligand, and LiO^tBu base. This simple air-stable copper catalysis enables the preparation of various 2-aminobenzoxazole derivatives at room temperature in good yields.

Full text of DOI:10.1016/j.tet.2013.05.127

Tetrahedron 69 (2013) 6627e6633
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Synthesis of 2-aminobenzoxazoles via copper-catalyzed
electrophilic amination of benzoxazoles with O-benzoyl
hydroxylamines
*
Sirilata Yotphan , Danupat Beukeaw, Vichai Reutrakul
Center for Catalysis and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Department of Chemistry, Faculty of Science, Mahidol University,
Bangkok 10400, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient copper-catalyzed electrophilic amination of benzoxazoles with O-benzoyl hydroxylamines is
described, employing CuCl catalyst, PPh3 ligand, and LiOtBu base. This simple air-stable copper catalysis
enables the preparation of various 2-aminobenzoxazole derivatives at room temperature in good yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 23 March 2013
Received in revised form 15 May 2013
Accepted 28 May 2013
Available online 4 June 2013
Keywords:
Copper catalysis
Electrophilic amination
CeN bond formation
Benzoxazole
O-Benzoyl hydroxylamine
1. Introduction
CeN bonds. This strategy allows the effective amination of both
organometallic reagents11 and heteroaromatic CeH bonds.12
A number of 2-aminoazoles (2-N-substituted azoles) possess
biological and pharmaceutical activities. They are employed widely
as a building block for the development of promising drug candi-
dates.1,2 Particularly, 2-aminobenzoxazoles are ubiquitous scaffolds
in a wide variety of therapeutic agents for a treatment of CNS dis-
orders,3 insomnia,4 and Alzheimer’s disease.5
Miura and co-workers recently reported the copper-catalyzed
direct amination of electron-deficient heteroaryl substrates with
chloroamines and hydroxylamines.13 The use of these electrophilic
amine reagents under copper catalysis enables the successful for-
mation of heteroaryleamino linkages at room temperature. Herein,
we reported an alternative and straightforward synthetic approach
to access 2-aminobenzoxazoles and their derivatives under atmo-
spheric conditions by using the readily prepared O-benzoyl hy-
droxylamines as electrophilic amine reagents.11d,14
Due to their significance, the development of versatile
and practical protocols to achieve
a
variety of these
2-aminobenzoxazoles and other 2-aminoazole derivatives has been
the subject of intense research effort. Over the past decade, the
transition metal-catalyzed carbonenitrogen (CeN) bond cross-
coupling reactions, particularly BuchwaldeHartwig as well as Ull-
man couplings provide powerful, efficient, and reliable approaches
for the synthesis of these structural motifs.6 Recent methods in-
volving the catalytic carbonehydrogen (CeH) bond functionaliza-
tion and CeN bond formation were also recognized as the
potentially useful synthetic tools for these structural moieties.7,8
Additionally, an umpolung9 electrophilic amination10 using
a reagent of type R2Nþ, such as halogenated amine, hydroxylamine,
oxaziridine, and hydrazine, provides a practical tool to construct
2. Results and discussion
We initiated the studies by choosing benzoxazole 1 and
O-benzoyl hydroxylamine 2a as substrates for the optimization
under the atmospheric conditions (Table 1). To our delight, this
reaction was complete within 1 h even at room temperature as
monitored by GC analysis.15 We screened various copper salts
(Table 1, entries 1e7), and a combination of CuCl/PPh3/LiOtBu in
THF showed higher catalytic activities (entry 3). No reaction was
observed in the absence of copper and only 31% yield of product 3a
was obtained in the absence of PPh3 ligand (entries 8e10). The use
of phen (1,10-phenanthroline) and bipy (2,20-bipyridine) ligands
led to lower yields, 36 and 21%, respectively (entries 11 and 12).
* Corresponding author. Tel.: þ662 201 5154; fax: þ662 354 7151; e-mail
address: sirilata.yot@mahidol.ac.th (S. Yotphan).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.127

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S. Yotphan et al. / Tetrahedron 69 (2013) 6627e6633
Table 1
Table 3
Effect of copper source and liganda
Optimization of reaction conditionsa
CuX (10 mol%)
ligand (10 mol%)
LiOtBu (2 equiv)
CuCl (cat)
PPh3 (cat)
O
N
O
N
O
O
N
O
O
LiOtBu (3 equiv)
+
+
H
N
H
N
N
N
solvent
Ph
O
THF
N
Ph
O
1
2a
3a
1
2a
3a
(1 equiv)
(1.5 equiv)
(1 equiv)
(1.5 equiv)
Entry
Copper salt
Ligand
Yieldb (%)
Entry
CuCl (mol %)
PPh3 (mol %)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuBr
CuCl
CuBr2
CuCl2
Cu(OAc)2
Cu(OTf)2
d
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
d
55
40
60
17
58
50
50
0
1
2
3
4
5
6
7
8
9
10
10
20
5
2
5
5
5
5
5
10
20
5
THF
THF
THF
THF
80
68
88
62
95
83
81
72
21
18
2
10
10
10
10
10
10
THF
Toluene
Dioxane
Acetonitrile
DMF
9
d
PPh3
d
0
10
11
12
CuCl
CuCl
CuCl
31
36
21
5
DMSO
Phen
Bipy
a
Conditions: benzoxazole 1 (0.5 mmol, 1 equiv), 2a (1.5 equiv), CuCl (cat), PPh3
(cat), LiOtBu (3 equiv), solvent (2 mL), rt, 1 h.
a
b
Conditions: benzoxazole 1 (0.5 mmol, 1 equiv), 2a (1.5 equiv), CuX (10 mol %),
Yields were determined by GC integration relative to hexamethylbenzene
ligand (10 mol %), LiOtBu (2 equiv), THF (2 mL), rt, 1 h.
(0.1 equiv) as the internal standard.
b
Yields were determined by GC integration relative to hexamethylbenzene
(0.1 equiv) as the internal standard.
conditions (Table 4). The reactions of benzoxazole 1 with cyclic and
acyclic O-benzoyl hydroxylamines (2aeg) derived from secondary
alkylamines underwent smooth amination affording the corre-
sponding 2-aminobenzoxazole derivatives 3aeg in moderate to
excellent isolated yields (entries 1e7). An additional oxygen or
sulfur heteroatom in the O-benzoyl hydroxylamine structure is well
tolerated, as shown by the successful reaction using morpholine 2d
or thiomorpholine 2e derivatives (entries 4 and 5). The Boc 2f and
benzyl 2g protecting groups on nitrogen are also compatible (en-
tries 6 and 7). Therefore, further functionalization after the
deprotection would be possible. On the other hand, copper-
catalyzed electrophilic amination reaction of benzoxazole 1 and
O-benzoyl hydroxylamine derived from primary amines showed
somewhat lower efficiency. O-Benzoyl hydroxylamine 2h, which
was derived from tert-butylamine, provided 16% isolated yield of
C-2 aminated benzoxazole product 3h (entry 8). No reaction or only
small amount of desired product was observed when using other
primary amines derived O-benzoyl hydroxylamine reagents (e.g.,
entries 9 and 10).15
We also studied the substrate scope of benzoxazoles and other
derivatives of azoles (Table 5). Under the optimized conditions, the
copper-catalyzed reactions of methylbenzoxazoles (4a and 4b) and
O-benzoyl hydroxylamine 2a afforded the corresponding C-2 ami-
nated benzoxazole products 5a and 5b in high yields (86% and 73%,
respectively; entries 1 and 2). In case of 5-phenylbenzoxazole
substrate 4c, excellent isolated yield of product 5c was obtained
(90%; entry 3). Moreover, the presence of chloro and nitro groups
on the aromatic portion of benzoxazole substrates 4d and 4e did
not have much significant effect in the reaction, therefore, amina-
tion reaction also proceeded without any difficulties furnishing
products 5d and 5e in good yields (66% and 61%; entries 4 and 5).
Interestingly, oxadiazole substrate 4f can be converted to the cor-
responding C-2 aminated product 5f with good efficiency (72%
isolated yield; entry 6). Conversely, other azoles such as benzo-
thiazole 4g and N-methyl benzimidazole 4h do not react under
these conditions (entries 7 and 8). Only a small amount (less than
5%) of desired C-2 aminated azole was detected by GCeMS when
LiOtBu was replaced by a stronger KOtBu base. This could be a result
of the higher pKa values of the CeH bonds at C-2 position of thia-
zoles and imidazoles.7a,16
We also studied the effect of inorganic base (Table 2, entries
1e8) and equivalency (entries 2, 9, and 10). The results in Table 2
showed that 3 equiv of LiOtBu can furnish product 3a in very high
yield (entry 10). On the other hand, other stronger bases such as
NaOtBu, KOtBu, and NaOH, or weaker bases such as K3PO4, Cs2CO3,
and NaOAc resulted in significantly lower yields or no reaction.
Table 2
Effect of inorganic basea
CuCl (10 mol%)
PPh3 (10 mol%)
base
O
N
O
N
O
+
H
N
N
Ph
O
THF
1
2a
3a
(1 equiv)
(1.5 equiv)
Entry
Base
Equiv
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
d
d
2
2
2
2
2
2
2
1
3
0
60
19
0
LiOtBu
NaOtBu
KOtBu
NaOH
K3PO4
Cs2CO3
NaOAc
LiOtBu
LiOtBu
0
<2
<2
0
49
80
a
Conditions: benzoxazole 1 (0.5 mmol, 1 equiv), 2a (1.5 equiv), CuCl (10 mol %),
PPh3 (10 mol %), base (1e3 equiv), THF (2 mL), rt, 1 h.
b
Yields were determined by GC integration relative to hexamethylbenzene
(0.1 equiv) as the internal standard.
Subsequent investigation of ratio of Cu to PPh3 and solvent effect
(Table 3, entries 1e10) established the combination of CuCl (5 mol %),
PPh3 (10 mol %), LiOtBu (3 equiv) in THF at rt for 1 h as the best
catalytic conditions providing 3a in 95% yield (Table 3, entry 5). Good
yields of product 3a can also be obtained when using 1,4-dioxane,
toluene, and acetonitrile as solvent (Table 3; entries 6e8), whereas
DMF and DMSO were much less effective (entries 9 and 10).
To test the generality of this protocol, reactions of benzoxazole 1
and a variety of O-benzoyl hydroxylamines (2aej) were next ex-
amined for the C-2 amination under the optimized reaction
The plausible mechanism would involve (1) an initial com-
plexation of copper salt with phosphine and tert-butoxide to

S. Yotphan et al. / Tetrahedron 69 (2013) 6627e6633
6629
Table 4
Table 5
Copper-catalyzed electrophilic amination of benzoxazole 1 with various O-benzoyl
Copper-catalyzed electrophilic amination of benzoxazole derivatives with O-ben-
hydroxylaminesa
zoyl hydroxylamine 2aa
CuCl (5 mol%)
PPh3 (10 mol%)
CuCl (5 mol%)
PPh3 (10 mol%)
O
R'
N
O
N
R'
LiOtBu (3 equiv)
O
N
X
LiOtBu (3 equiv)
O
X
N
H
N
H
+
+
R
N
R
N
Ph
O
R''
THF, rt
1 h
THF, rt
1h
Ph
O
N
4a⎯h
R''
2a
5a⎯h
1
2a
j
3a
j
(1 equiv)
(1.5 equiv)
(1 equiv)
(1.5 equiv)
Entry
1
Azole
Product
Yieldb (%)
Entry
O-Benzoyl hydroxylamine
Product
Yieldb (%)
91
H3C
H3C
O
N
O
N
O
N
O
N
N
N
86
73
90
66
61
1
N
Ph
Ph
O
2a
4a
5a
3a
O
N
O
N
O
O
2
3
4
5
N
N
2
3
4
40
74
54
H3C
H3C
O
2b
N
4b
5b
3b
O
O
N
O
N
O
N
N
Ph
Cl
Ph
Cl
N
N
N
4c
5c
Ph
Ph
O
2c
3c
O
N
O
N
N
O
O
4d
5d
O
2d
O
O
N
N
N
O2N
O2N
O
O
S
4e
5e
N
S
5
N
45
Ph
Ph
N
Ph
O
2e
O
N
O
N
3e
N
6
7
72
0c
N
N
O
N
4f
5f
O
NBoc
N
NBoc
6
7
50
75
N
S
N
S
Ph
O
2f
N
3f
N
5g
4g
O
CH3
N
O
N
CH3
N
CH3
Ph
O
N
N
N
N
CH3
NH
2g
8
0c
N
3g
O
O
N
4h
5h
H
N
a
8
9
16
Conditions: benzoxazoles 4aeh (1 mmol, 1 equiv), 2a (1.5 equiv), CuCl (5 mol %),
Ph
O
PPh3 (10 mol %), LiOtBu (3 equiv), THF (4 mL), rt, 1 h.
2h
3h
b
Isolated yields after purification by chromatography.
No reaction was detected by TLC/GCeMS.
c
O
O
n-Bu
H
N
<5c
NH
Ph
Ph
O
2i
n-Bu
N
3i
O
O
N
H
NH
N
10
0
O
3j
2j
a
Conditions: benzoxazole 1 (1 mmol, 1 equiv), 2aej (1.5 equiv), CuCl (5 mol %),
PPh3 (10 mol %), LiOtBu (3 equiv), THF (4 mL), rt, 1 h.
b
Isolated yields after purification by chromatography.
Detected by GCeMS.
c
generate copper(I)-tert-butoxide complex 6, (2) formation of the
key intermediate azole-cuprate 7 assisted by anionic tert-butoxide
(OtBu) ligand,17 (3) oxidative addition of complex 7 with O-benzoyl
hydroxylamine by single electron transfer process to generate an
intermediate 8 in higher oxidation state,18 (4) reductive elimination
of 8 to form new CeN bond of 2-aminobenzoxazole product and
regenerate active copper species to resume the catalytic cycle
(Scheme 1).13b Further efforts to study the detailed mechanism and
expand the reaction scope of this chemistry are currently under
investigation.
Scheme 1. Proposed plausible mechanism of the Cu-catalyzed electrophilic amination
of benzoxazoles and O-benzoyl hydroxylamines.

6630
S. Yotphan et al. / Tetrahedron 69 (2013) 6627e6633
3. Conclusion
orthoformate and ethanol byproduct were removed from the res-
idue under reduced pressure. The crude product was further pu-
rified by silica gel (SiO2) column chromatography to yield the
desired substituted azole. All physical data of 4c and 4e were in
agreement with those reported in the literature.8d
In conclusion, we have disclosed an efficient synthetic protocol
for the copper-catalyzed amination reaction of benzoxazoles and O-
benzoyl hydroxylamines. This umpolung electrophilic amination
strategy can be carried out under atmospheric conditions with
good scope and functional group compatibility. This transformation
allows the facile synthesis of a number of 2-aminobenzoxazole
derivatives and serves as an alternative and convenient synthetic
route to 2-aminobenzoxazoles, which are employed widely in
medicinal chemistry.
4.2.3. General procedure for the synthesis of compounds 3aeh and
5aef. A 20 mL oven-dried and N2-flushed scintillation vial equip-
ped with a magnetic stir bar was charged with benzoxazole or azole
starting material (1.00 mmol,1.00 equiv), O-benzoyl hydroxylamine
(1.50 mmol, 1.50 equiv), CuCl (5.0 mg, 0.05 mmol, 0.05 equiv), PPh3
(26.0 mg, 0.10 mmol, 0.10 equiv), LiOtBu (0.24 g, 3.00 mmol,
3.00 equiv), and tetrahydrofuran (THF) (4.00 mL, 0.25 M concen-
tration of substrate). The vial was capped, and the reaction mixture
was stirred at room temperature for 1 h. Upon completion, distilled
deionized H2O (10 mL) was added, and the mixture was extracted
with EtOAc (2ꢀ15 mL). The solution was concentrated in vacuo, and
the crude product was purified by SiO2 column chromatography to
afford a corresponding benzoxazole derivative. All physical data of
the known compounds were in agreement with those reported in
the literature.8a,8d,13,14,22
4. Experimental section
4.1. General methods
Unless otherwise specified, all reactions were carried out under air
atmosphere. All reagents were obtained from commercial suppliers
and used without further purification. Oven-dried glasswarewasused
ꢀ
in all cases. Chromatography was performed on silica gel (SiO2; 60 A
silica gel, Merck Grade, 70e230 Mesh). GC experiments were carried
out with an Agilent 6890N GC-FID on chromatograph equipped with
an Agilent column (HP-1, polysiloxane, 24.5 mꢀ0.32 mm IDꢀ0.17
m
m).
4.3. Analytical data for compounds 2aej, 3aeh, 4c, 4e, 5aef
1H and 13C NMR spectra were measured with Bruker AV-300 or
AV-500 spectrometers in CDCl3. NMR chemical shifts are reported in
parts per million (ppm) relative to CHCl3 (7.24 ppm for 1H and
77.0 ppm for 13C). IR spectra were recorded on an FTIR Spectrum GX
(Perkin Elmer), and only partial data are listed. Melting points were
determined on a Mel-Temp apparatus and are uncorrected. High-
resolution mass spectroscopy analyses were carried out by Mahidol
University, Department of Chemistry Micro-Mass Facility.
4.3.1. Piperidin-1-yl benzoate (2a).11d Benzoyl hydroxylamine 2a
was prepared from benzoyl peroxide (3.03 g, 12.5 mmol, 1.00 equiv)
and piperidine (1.28 g, 15.0 mmol, 1.20 equiv) following the general
procedure for the preparation of O-benzoyl hydroxylamines. The
crude product was further purified by flash column chromatogra-
phy (SiO2, Hex/EtOAc¼4:1) to afford pure compound 2a (1.90 g,
75%) as a colorless solid. 1H NMR (300 MHz, CDCl3):
d 7.91e7.89 (m,
2H), 7.47e7.42 (m, 1H), 7.35e7.29 (m, 2H), 3.48e3.27 (m, 2H),
2.68e2.66 (m, 2H), 1.74e1.70 (m, 4H). 1.65e1.45 (m, 1H), 1.17e1.12
4.2. General procedure for the synthesis of compounds 2e5
(m, 1H). 13C{1H} NMR (75 MHz, CDCl3):
d 164.8, 132.9, 129.6, 129.4,
4.2.1. General procedure for the preparation of O-benzoyl hydroxyl-
amines 2aej.11d,14 A 100-mL, one-necked, round-bottomed flask
equipped with a magnetic stir bar was charged with benzoyl per-
oxide (3.03 g, 12.5 mmol, 1.00 equiv), dipotassium hydrogen
phosphate (3.27 g, 18.8 mmol, 1.50 equiv), and N,N-dime-
thylformamide (30 mL). The suspension was stirred and amine
(15.0 mmol, 1.20 equiv) was added via syringe in one portion. The
flask was capped with a septum and the reaction mixture was
stirred at room temperature for 1e24 h, during, which time
a gradual change in coloration of the reaction mixture occurred.
Deionized water (50 mL) was added and the contents were stirred
vigorously for 30 min. The reaction mixture was transferred to
a separatory funnel and extracted with EtOAc (1ꢀ40 mL). The or-
ganic phase was collected and washed with saturated aqueous
NaHCO3 solution (2ꢀ25 mL). All of the aqueous fractions were
combined and extracted with EtOAc (2ꢀ25 mL). All of the organic
fractions were combined and washed with 30 mL of deionized
water, 25 mL of brine, dried over Na2SO4, filtered, and concentrated
by rotary evaporation. The resulting crude product was purified by
flash column chromatography to give the corresponding O-benzoyl
hydroxylamine 2. All physical data of the known compounds were
in agreement with those reported in the literature.11d,11l,14,19,20
128.3, 57.5, 25.0, 23.3. HRMS (ESIþ, m/z) Calcd for C12H15NO2Na
[MþNa]þ 228.1000. Found 228.1001.
4.3.2. Pyrrolidin-1-yl benzoate (2b). Benzoyl hydroxylamine 2b
was prepared from benzoyl peroxide (3.03 g, 12.5 mmol, 1.00 equiv)
and pyrrolidine (1.07 g, 15.0 mmol, 1.20 equiv) following the gen-
eral procedure for the preparation of O-benzoyl hydroxylamines.
The crude product was further purified by flash column chroma-
tography (SiO2, Hex/EtOAc¼4:1) to afford pure compound 2b
(1.19 g, 50%) as an off-white solid. Mp¼66.2e66.6 ꢁC. 1H NMR
(300 MHz, CDCl3):
7.42e7.37 (m, 2H), 3.31e3.26 (m, 4H), 1.93 (s, 4H). 13C{1H} NMR
(75 MHz, CDCl3): 165.2, 132.9, 129.5, 129.4, 128.3, 57.7, 22.2. IR
d 7.96e7.92 (m, 2H), 7.55e7.49 (m, 1H),
d
(film): 3423, 2978, 1719, 1598, 1452, 1315, 1259, 1092, 1071, 1021,
948, 785, 719 cmꢂ1. HRMS (ESIþ, m/z) Calcd for C11H13NO2Na
[MþNa]þ 214.0844. Found 214.0847.
4.3.3. O-Benzoyl-N,N-diethyl hydroxylamine (2c).11d Benzoyl hy-
droxylamine 2c was prepared from benzoyl peroxide (3.03 g,
12.5 mmol, 1.00 equiv) and diethylamine (1.10 g, 15.0 mmol,
1.20 equiv) following the general procedure for the preparation of O-
benzoyl hydroxylamines. The crude product was further purified by
flash column chromatography (SiO2, Hex/EtOAc¼4:1) to afford pure
compound 2c (1.42 g, 59%) as a colorless oil. 1H NMR (300 MHz,
4.2.2. General procedure for the preparation of 6-substituted ben-
zoxazoles (4c and 4e).8d,21 Most of benzoxazole substrates 4 used in
this study are commercially available except 4c and 4e.
CDCl3):
d 7.99e7.96 (m, 2H), 7.48e7.45 (m, 1H), 7.38e7.33 (m, 2H),
2.98 (q, J¼7.2 Hz, 4H), 1.11 (t, J¼7.2 Hz, 6H). 13C{1H} NMR (75 MHz,
A 100-mL, one-necked, round-bottomed flask equipped with
CDCl3):
d
165.6, 132.7, 129.4, 129.1, 128.1, 53.1, 11.5. HRMS (ESIþ, m/z)
a
magnetic stir bar was charged with the corresponding
Calcd for C11H15NO2Na [MþNa]þ 216.1000. Found 216.1019.
2-aminophenol derivative (5.00 mmol, 1.00 equiv) and triethyl
orthoformate (8.50 mL, 60.0 mmol, 12.0 equiv). The reaction mix-
ture was carefully heated to 150 ꢁC for 6 h. Upon completion, the
reaction mixture was cooled to room temperature and the excess
4.3.4. Morpholino benzoate (2d).11d Benzoyl hydroxylamine 2d was
prepared from benzoyl peroxide (3.03 g, 12.5 mmol, 1.00 equiv) and
morpholine (1.31 g, 15.0 mmol, 1.20 equiv) following the general

S. Yotphan et al. / Tetrahedron 69 (2013) 6627e6633
6631
procedure for the preparation of O-benzoyl hydroxylamines. The
crude product was further purified by flash column chromatogra-
phy (SiO2, Hex/EtOAc¼4:1) to afford pure compound 2d (1.97 g,
hydroxylamines. The crude product was further purified by flash
column chromatography (SiO2, Hex/EtOAc¼4:1) to afford pure
compound 2i (1.50 g, 62%) as a colorless oil. 1H NMR (300 MHz,
76%) as a white solid. 1H NMR (300 MHz, CDCl3):
d
7.96 (d, J¼7.5 Hz,
CDCl3): d 8.01e7.99 (m, 2H), 7.86 (br s, 1H), 7.57e7.54 (m, 1H),
2H), 7.55e7.50 (m, 1H), 7.42e7.37 (m, 2H), 3.91e3.77 (m, 4H),
7.45e7.42 (m, 2H), 3.12 (t, J¼7.5 Hz, 2H),1.62e1.56 (m, 2H),1.45e1.38
3.42e3.38 (m, 2H), 3.02e2.99 (m, 2H). 13C{1H} NMR (75 MHz,
(m, 2H), 0.93 (t, J¼7.5 Hz, 3H).13C{1H} NMR (75 MHz, CDCl3):
d 166.9,
CDCl3):
d
164.5, 133.1, 129.3, 129.0, 128.4, 65.7, 56.9. HRMS (ESIþ, m/
133.2, 129.4, 129.3, 128.5, 52.3, 29.2, 20.2, 13.9. IR (film): 3236, 2961,
2874,1722,1452,1272,1068,1026, 710 cmꢂ1. HRMS (ESIþ, m/z) Calcd
for C11H15NO2Na [MþNa]þ 216.1000. Found 216.1002.
z) Calcd for C11H13NO3Na [MþNa]þ 230.0793. Found 230.0794.
4.3.5. Thiomorpholino benzoate (2e). Benzoyl hydroxylamine 2e
was prepared from benzoyl peroxide (3.03 g, 12.5 mmol,1.00 equiv)
and thiomorpholine (1.55 g, 15.0 mmol, 1.20 equiv) following the
general procedure for the preparation of O-benzoyl hydroxyl-
amines. The crude product was further purified by flash column
chromatography (SiO2, Hex/EtOAc¼4:1) to afford pure compound
2e (1.77 g, 69%) as an off-white solid. Mp¼80.9e81.8 ꢁC. 1H NMR
4.3.10. O-Benzoyl-N-isopropylhydroxylamine (2j). Benzoyl hydrox-
ylamine 2j was prepared from benzoyl peroxide (3.03 g, 12.5 mmol,
1.00 equiv) and isopropylamine (1.23 g, 15.0 mmol, 1.20 equiv)
following the general procedure for the preparation of O-benzoyl
hydroxylamines. The crude product was further purified by flash
column chromatography (SiO2, Hex/EtOAc¼4:1) to afford pure
compound 2j (1.71 g, 77%) as a colorless oil. 1H NMR (300 MHz,
(300 MHz, CDCl3):
7.45e7.40 (m, 2H), 3.65 (br s, 2H), 3.22 (br s, 2H), 2.86 (br s, 4H). 13C
{1H} NMR (75 MHz, CDCl3):
164.4, 133.2, 129.4, 129.1, 128.4, 57.7,
d 8.00e7.97 (m, 2H), 7.58e7.53 (m, 1H),
CDCl3):
d 7.99e7.96 (m, 2H), 7.63 (br s, 1H), 7.50e7.48 (m, 1H),
d
7.41e7.35 (m, 2H), 3.31 (sep, J¼6.3 Hz, 1H), 1.13 (d, J¼6.3 Hz, 6H). 13C
26.6. IR (film): 3439, 2961, 2925, 1732, 1598, 1452, 1317, 1267, 1247,
1183, 1090, 1067, 979, 712 cmꢂ1. HRMS (ESIþ, m/z) Calcd for
C11H13NO2SNa [MþNa]þ 246.0565. Found 246.0567.
{1H} NMR (75 MHz, CDCl3):
d 166.6, 133.1, 129.1, 129.0, 128.4, 52.1,
19.7. IR (film): 3237, 2974, 1721, 1601, 1452, 1317, 1271, 1091, 1067,
1026, 708 cmꢂ1. HRMS (ESIþ, m/z) Calcd for C10H13NO2Na [MþNa]þ
202.0844. Found 202.0839.
4.3.6. tert-Butyl 4-(benzoyloxy)piperazine-1-carboxylate
(2f).11l Benzoyl hydroxylamine 2f was prepared from benzoyl per-
oxide (3.03 g, 12.5 mmol, 1.00 equiv) and tert-butyl piperazine-1-
carboxylate (2.79 g, 15.0 mmol, 1.20 equiv) following the general
procedure for the preparation of O-benzoyl hydroxylamines. The
crude product was further purified by flash column chromatography
(SiO2, Hex/EtOAc¼4:1) to afford pure compound 2f (2.74 g, 72%) as
4.3.11. 2-(Piperidin-1-yl)benzoxazole (3a).8a Compound 3a was
prepared from benzoxazole 1 (0.12 g, 1.00 mmol, 1.00 equiv) and
piperidin-1-yl benzoate 2a (0.31 g, 1.50 mmol, 1.50 equiv) following
the general procedure. The crude product was further purified by
flash column chromatography (SiO2, Hex/EtOAc¼4:1) to afford pure
compound 3a (0.18 g, 91%) as an off-white solid. 1H NMR (300 MHz,
a white solid. 1H NMR (300 MHz, CDCl3):
d
7.99e7.95 (m, 2H),
7.58e7.49 (m, 1H), 7.46e7.36 (m, 2H), 3.99 (br s, 1H), 3.40 (br s, 2H),
3.29 (br s, 2H), 2.89 (br s, 2H). 13C{1H} NMR (75 MHz, CDCl3):
164.5,
CDCl3):
d
7.37e7.35 (m,1H), 7.29e7.23 (m,1H), 7.16 (dt, J¼7.8,1.2 Hz,
1H), 7.00 (dt, J¼7.8, 1.2 Hz, 1H), 3.67 (br s, 4H), 1.69 (br s, 6H). 13C
d
{1H} NMR (75 MHz, CDCl3):
d 162.4, 148.6, 143.3, 123.8, 120.2, 115.9,
154.4, 133.2, 129.4, 129.0, 128.4, 80.2, 55.8, 42.0, 28.3. HRMS (ESIþ,
108.5, 46.5, 25.2, 24.0. HRMS (ESIþ, m/z) Calcd for C12H15N2O
m/z) Calcd for C16H22N2O4Na [MþNa]þ 329.1477. Found 329.1469.
[MþH]þ 203.1184. Found 203.1203.
4.3.7. O-Benzoyl-N-benzyl-N-methylhydroxylamine (2g).19 Benzoyl
hydroxylamine 2g was prepared from benzoyl peroxide (3.03 g,
12.5 mmol, 1.00 equiv) and N-methyl-1-phenylmethanamine
(1.93 g, 15.0 mmol, 1.20 equiv) following the general procedure
for the preparation of O-benzoyl hydroxylamines. The crude
product was further purified by flash column chromatography
(SiO2, Hex/EtOAc¼9:1) to afford pure compound 2g (1.96 g, 65%) as
4.3.12. 2-(Pyrrolidin-1-yl)benzoxazole (3b).8a Compound 3b was
prepared from benzoxazole 1 (0.12 g, 1.00 mmol, 1.00 equiv) and
pyrrolidin-1-yl benzoate 2b (0.29 g, 1.50 mmol, 1.50 equiv) fol-
lowing the general procedure. The crude product was further pu-
rified by flash column chromatography (SiO2, Hex/EtOAc¼4:1) to
afford pure compound 3b (0.08 g, 40%) as an off-white solid. 1H
NMR (300 MHz, CDCl3):
(dt, J¼7.8, 1.2 Hz, 1H), 7.00 (dt, J¼7.8, 1.2 Hz, 1H), 3.70e3.64 (m, 4H),
2.07e2.03 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3):
161.0, 149.0,
d 7.39e7.36 (m, 1H), 7.29e7.25 (m, 1H), 7.16
a pale yellow solid. 1H NMR (300 MHz, CDCl3):
d
8.09e8.05 (m, 2H),
7.64e7.55 (m, 1H), 7.52e7.25 (m, 7H), 4.16 (s, 2H), 2.92 (s, 3H). 13C
{1H} NMR (75 MHz, CDCl3):
164.9, 135.5, 132.8, 129.4, 129.3, 128.9,
d
d
143.6, 123.8, 120.0, 115.9, 108.5, 47.4, 25.6. HRMS (ESIþ, m/z) Calcd
128.4, 128.1, 127.7, 65.1, 46.1. HRMS (ESIþ, m/z) Calcd for
for C11H13N2O [MþH]þ 189.1028. Found 189.1055.
C15H15NO2Na [MþNa]þ 264.1000. Found 264.0984.
4.3.13. N,N-Diethylbenzoxazole-2-amine (3c).8a Compound 3c was
prepared from benzoxazole 1 (0.12 g, 1.00 mmol, 1.00 equiv) and O-
benzoyl-N,N-diethyl hydroxylamine 2c (0.29 g, 1.50 mmol,
1.50 equiv) following the general procedure. The crude product was
further purified by flash column chromatography (SiO2, Hex/
EtOAc¼4:1) to afford pure compound 3c (0.14 g, 74%) as a yellow oil.
4.3.8. O-Benzoyl-N-(tert-butyl)hydroxylamine (2h).20 Benzoyl hy-
droxylamine 2h was prepared from benzoyl peroxide (3.03 g,
12.5 mmol, 1.00 equiv) and tert-butylamine (1.10 g, 15.0 mmol,
1.20 equiv) following the general procedure for the preparation of O-
benzoyl hydroxylamines. The crude product was further purified by
flash column chromatography (SiO2, Hex/EtOAc¼4:1) to afford pure
compound 2h (1.95 g, 87%) as a colorless oil. 1H NMR (300 MHz,
1H NMR (300 MHz, CDCl3):
d 7.38e7.36 (m, 1H), 7.28e7.24 (m, 1H),
7.16 (dt, J¼7.8,1.2 Hz,1H), 6.99 (dt, J¼7.8,1.2 Hz,1H), 3.60 (q, J¼7.2 Hz,
CDCl3):
d
8.02e8.01 (m, 2H), 7.66 (br s, 1H), 7.56e7.54 (m, 1H),
4H), 1.30 (t, J¼7.2 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3):
d 162.2,
7.46e7.43 (m, 2H), 1.22 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3):
148.8, 143.6, 123.7, 119.9, 115.8, 108.4, 42.9, 13.4. HRMS (ESIþ, m/z)
d
166.8, 133.2, 129.3, 129.2, 128.5, 56.1, 26.6. IR (film): 3224, 2976,
Calcd for C11H15N2O [MþH]þ 191.1184. Found 191.1210.
1720, 1452, 1366, 1271, 1222, 1093, 1068, 1026, 996, 708 cmꢂ1. HRMS
(ESIþ, m/z) Calcd for C11H16NO2 [MþH]þ 194.1181. Found 194.1186.
4.3.14. 2-Morpholinobenzoxazole (3d).8a Compound 3d was pre-
pared from benzoxazole 1 (0.12 g, 1.00 mmol, 1.00 equiv) and
morpholino benzoate 2d (0.31 g, 1.50 mmol, 1.50 equiv) following
the general procedure. The crude product was further purified by
flash column chromatography (SiO2, Hex/EtOAc¼4:1) to afford pure
compound 3d (0.11 g, 54%) as a pale yellow solid. 1H NMR
4.3.9. O-Benzoyl-N-butylhydroxylamine (2i). Benzoyl hydroxyl-
amine 2i was prepared from benzoyl peroxide (3.03 g, 12.5 mmol,
1.00 equiv) and n-butylamine (1.50 mL, 15.0 mmol, 1.20 equiv) fol-
lowing the general procedure for the preparation of O-benzoyl

6632
S. Yotphan et al. / Tetrahedron 69 (2013) 6627e6633
(300 MHz, CDCl3):
d
7.41e7.38 (m, 1H), 7.30e7.28 (m, 1H), 7.20 (dt,
CDCl3): d 152.9, 149.4, 140.7, 140.6, 138.6, 128.7, 127.5, 127.2, 125.1,
J¼7.8, 1.2 Hz, 1H), 7.06 (dt, J¼7.8, 1.2 Hz, 1H), 3.86e3.83 (m, 4H),
118.9, 110.8. HRMS (ESIþ, m/z) Calcd for C13H10NO [MþH]þ
3.73e3.70 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3):
d
162.1, 148.7,
196.0762. Found 196.0760.
142.7, 124.1, 120.9, 116.4, 108.8, 66.2, 45.7. HRMS (ESIþ, m/z) Calcd
for C11H13N2O2 [MþH]þ 205.0977. Found 205.0998.
4.3.20. 5-Nitrobenzoxazole (4e).8d Compound 4e was prepared
from 2-amino-4-nitrophenol (0.77 g, 5.00 mmol, 1.00 equiv) and
triethyl orthoformate (8.50 mL, 60.0 mmol, 12.0 equiv) following
the general procedure. The crude product was further purified by
flash column chromatography (SiO2, Hex/EtOAc¼3:1) to afford pure
compound 4e (0.42 g, 85%) as a yellow solid. 1H NMR (300 MHz,
4.3.15. 2-Thiomorpholinobenzoxazole (3e).22 Compound 3e was
prepared from benzoxazole 1 (0.12 g, 1.00 mmol, 1.00 equiv) and
thiomorpholino benzoate 2e (0.33 g, 1.50 mmol, 1.50 equiv) fol-
lowing the general procedure. The crude product was further pu-
rified by flash column chromatography (SiO2, Hex/EtOAc¼4:1) to
afford pure compound 3e (0.10 g, 45%) as a pale yellow solid.
CDCl3):
d
8.70 (d, J¼2.4 Hz, 1H), 8.36 (dd, J¼9.0, 2.4 Hz, 1H), 8.25 (s,
1H), 7.70 (d, J¼9.0 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3):
d 155.0,
Mp¼90.5e91.4 ꢁC. 1H NMR (300 MHz, CDCl3):
d
7.30e7.27 (m, 1H),
153.4, 145.4, 140.5, 121.6, 117.1, 111.2. HRMS (ESIþ, m/z) Calcd for
7.19e7.17 (m, 1H), 7.10 (dt, J¼7.8, 1.2 Hz, 1H), 6.95 (dt, J¼7.8, 1.2 Hz,
C7H4N2O3Na [MþNa]þ 187.0120. Found 187.0128.
1H), 3.94e3.89 (m, 4H), 2.68e2.64 (m, 4H). 13C{1H} NMR (75 MHz,
CDCl3):
d
161.7, 148.7, 142.9, 124.0, 120.7, 116.3, 108.7, 48.0, 26.7. IR
4.3.21. 6-Methyl-2-(piperidin-1-yl)benzoxazole (5a).8d Compound
5a was prepared from 6-methylbenzoxazole 4a (0.13 g, 1.00 mmol,
1.00 equiv) and piperidin-1-yl benzoate 2a (0.31 g, 1.50 mmol,
1.50 equiv) following the general procedure. The crude product was
further purified by flash column chromatography (SiO2, Hex/
EtOAc¼4:1) to afford pure compound 5a (0.19 g, 86%) as a white
(film): 3436, 2921, 1655, 1578, 1460, 1401, 1263, 1149, 969, 879, 796,
754, 741, 570, 425 cmꢂ1. HRMS (ESIþ, m/z) Calcd for C11H13N2OS
[MþH]þ 221.0749. Found 221.0741.
4.3.16. tert-Butyl 4-(benzoxazol-2-yl)piperazine-1-carboxylate
(3f).8d Compound 3f was prepared from benzoxazole 1 (0.12 g,
1.00 mmol, 1.00 equiv) and tert-butyl 4-(benzoyloxy)piperazine-1-
carboxylate 2f (0.46 g, 1.50 mmol, 1.50 equiv) following the general
procedure. The crude product was further purified by flash column
chromatography (SiO2, Hex/EtOAc¼4:1) to afford pure compound
3f (0.15 g, 50%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3):
solid. 1H NMR (300 MHz, CDCl3):
d
7.18 (d, J¼7.8 Hz,1H), 7.00 (s, 1H),
6.90 (d, J¼7.8 Hz, 1H), 3.59 (s, 4H), 2.35 (s, 3H), 1.63 (s, 6H). 13C{1H}
NMR (75 MHz, CDCl3): d 162.1, 148.6, 140.7, 130.1, 124.3, 115.1, 108.8,
46.4, 25.1, 24.0, 21.2. HRMS (ESIþ, m/z) Calcd for C13H16N2ONa
[MþNa]þ 239.1160. Found 239.1162.
d
7.40e7.38 (m, 1H), 7.30e7.27 (m, 1H), 7.22e7.17 (m, 1H), 7.09e7.03
(m, 1H), 3.71e3.68 (m, 4H), 3.60e3.57 (m, 4H), 1.51 (s, 9H). 13C{1H}
NMR (75 MHz, CDCl3): 162.0, 154.6, 148.7, 142.8, 124.1,120.9, 116.4,
4.3.22. 5-Methyl-2-(piperidin-1-yl)benzoxazole (5b).8d Compound
5b was prepared from 5-methylbenzoxazole 4b (0.13 g, 1.00 mmol,
1.00 equiv) and piperidin-1-yl benzoate 2a (0.31 g, 1.50 mmol,
1.50 equiv) following the general procedure. The crude product was
further purified by flash column chromatography (SiO2, Hex/
EtOAc¼4:1) to afford pure compound 5b (0.16 g, 73%) as a white
d
108.8, 80.4, 45.4, 28.4. HRMS (ESIþ, m/z) Calcd for C16H21N3O3Na
[MþNa]þ 326.1481. Found 326.1478.
4.3.17. N-Benzyl-N-methylbenzoxazol-2-amine (3g).8a Compound
3g was prepared from benzoxazole
1.00 equiv) and O-benzoyl-N-benzyl-N-methylhydroxylamine 2g
(0.36 g, 1.50 mmol, 1.50 equiv) following the general procedure.
The crude product was further purified by flash column chroma-
tography (SiO2, Hex/EtOAc¼7:1) to afford pure compound 3g
(0.18 g, 75%) as a colorless solid. 1H NMR (300 MHz, CDCl3):
solid. 1H NMR (300 MHz, CDCl3):
d
7.06 (s, 1H), 7.02 (d, J¼8.1 Hz,
1
(0.12 g, 1.00 mmol,
1H), 6.72 (d, J¼8.1 Hz, 1H), 3.57 (s, 4H), 2.31 (s, 3H), 1.60 (s, 6H). 13C
{1H} NMR (75 MHz, CDCl3):
d 162.6, 146.8, 143.5, 133.4, 120.9, 116.4,
107.9, 46.6, 25.2, 24.1, 21.5. HRMS (ESIþ, m/z) Calcd for C13H17N2O
[MþH]þ 217.1341. Found 239.1346.
4.3.23. 5-Phenyl-2-(piperidin-1-yl)benzoxazole (5c).8d Compound
5c was prepared from 5-phenylbenzoxazole 4c (0.20 g, 1.00 mmol,
1.00 equiv) and piperidin-1-yl benzoate 2a (0.31 g, 1.50 mmol,
1.50 equiv) following the general procedure. The crude product was
further purified by flash column chromatography (SiO2, Hex/
EtOAc¼4:1) to afford pure compound 5c (0.25 g, 90%) as a colorless
d
7.40e7.25 (m, 7H), 7.18 (t, J¼6.6 Hz, 1H), 7.01 (t, J¼6.6 Hz, 1H),
4.75 (s, 2H), 3.12 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3):
d
162.9,
148.9, 143.5, 136.3, 128.6, 127.6, 127.5, 123.8, 120.3, 116.0, 108.6,
53.8, 35.0. HRMS (ESIþ, m/z) Calcd for C15H15N2O [MþH]þ
239.1184. Found 239.1195.
solid. 1H NMR (300 MHz, CDCl3):
d 7.65e7.50 (m, 3H), 7.40 (t,
4.3.18. N-(tert-Butyl)benzoxazol-2-amine (3h).23 Compound 3h
was prepared from benzoxazole 1 (0.12 g, 1.00 mmol, 1.00 equiv)
and O-benzoyl-N-(tert-butyl)hydroxylamine (2h) (0.29 g,
1.50 mmol, 1.50 equiv) following the general procedure. The crude
product was further purified by flash column chromatography
(SiO2, Hex/EtOAc¼4:1) to afford pure compound 3h (0.03 g, 16%) as
J¼7.8 Hz, 2H), 7.33e7.14 (m, 3H), 3.74e3.50 (m, 4H), 1.65 (s, 6H). 13C
{1H} NMR (75 MHz, CDCl3):
d 162.8, 148.3, 144.0, 141.7, 137.6, 128.5,
127.2, 126.8, 119.6, 114.7, 108.4, 46.6, 25.1, 24.0. HRMS (ESIþ, m/z)
Calcd for C18H18N2ONa [MþNa]þ 301.1317. Found 301.1329.
4.3.24. 5-Chloro-2-(piperidin-1-yl)benzoxazole (5d).8d Compound
5d was prepared from 5-chlorobenzoxazole 4d (0.15 g, 1.00 mmol,
1.00 equiv) and piperidin-1-yl benzoate 2a (0.31 g, 1.50 mmol,
1.50 equiv) following the general procedure. The crude product was
further purified by flash column chromatography (SiO2, Hex/
EtOAc¼4:1) to afford pure compound 5d (0.16 g, 66%) as a pale
an off-white solid. 1H NMR (300 MHz, CDCl3):
d
7.31 (d, J¼7.5 Hz,
1H), 7.17 (d, J¼7.5 Hz, 1H), 7.09e7.06 (m, 1H), 6.96e6.94 (m, 1H),
5.20 (br s, 1H), 1.43 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3):
160.8,
d
148.1, 143.2, 123.7, 120.6, 116.4, 108.5, 52.0, 29.2. HRMS (ESIþ, m/z)
Calcd for C11H14N2ONa [MþNa]þ 213.1004. Found 213.1015.
yellow solid. 1H NMR (300 MHz, CDCl3):
d
7.28 (d, J¼2.1 Hz,1H), 7.12
(d, J¼8.4 Hz, 1H), 6.94 (dd, J¼8.4, 2.1 Hz, 1H), 3.63 (s, 4H), 1.67 (s,
6H). 13C{1H} NMR (75 MHz, CDCl3):
163.0, 147.3, 144.8,129.1, 119.8,
4.3.19. 5-Phenylbenzoxazole (4c).8d Compound 4c was prepared
from 2-amino-4-phenylphenol, 90% Aldrich technical grade (1.00 g,
5.00 mmol, 1.00 equiv) and triethyl orthoformate (8.50 mL,
60.0 mmol, 12.0 equiv) following the general procedure. The crude
product was further purified by flash column chromatography
(SiO2, Hex/EtOAc¼3:1) to afford pure compound 4c (0.39 g, 79%) as
d
116.0, 109.0, 46.5, 25.2, 23.9. HRMS (ESIþ, m/z) Calcd for
C12H13ClN2ONa [MþNa]þ 259.0614. Found 259.0607.
4.3.25. 5-Nitro-2-(piperidin-1-yl)benzoxazole (5e).8d Compound 5e
was prepared from 5-nitrobenzoxazole 4e (0.16 g, 1.00 mmol,
1.00 equiv) and piperidin-1-yl benzoate 2a (0.31 g, 1.50 mmol,
a colorless solid. 1H NMR (300 MHz, CDCl3):
d
8.11 (s, 1H), 7.99 (s,
1H), 7.66e7.57 (m, 4H), 7.50e7.31 (m, 3H). 13C{1H} NMR (75 MHz,

S. Yotphan et al. / Tetrahedron 69 (2013) 6627e6633
6633
4. (a) Whitman, D. B.; Cox, C. D.; Breslin, M. J.; Brashear, K. M.; Schreier, J. D.;
Bogusky, M. J.; Bednar, R. A.; Lemaire, W.; Bruno, J. G.; Hartman, G. D.; Reiss, D. R.;
Harrell, C. M.; Kraus, R. L.; Li, Y.; Garson, S. L.; Doran, S. C.; Prueksaritanont, T.; Li, C.;
Winrow, C. J.; Koblan, K. S.; Renger, J. J.; Coleman, P. J. Chem. Med. Chem. 2009, 4,
1069; (b) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Schreier, J. D.; McGaughey, G. B.;
Bogusky, M. J.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A.; Lemaire, W.; Bruno,
J. G.; Reiss, D. R.; Harrell, C. M.; Murphy, K. L.; Garson, S. L.; Doran, S. M.;
Prueksaritanont, T.; Anderson, W. B.; Tang, C.; Roller, S.; Cabalu, T. D.; Cui, D.;
Hartman, G. D.; Young, S. D.; Koblan, K. S.; Winrow, C. J.; Renger, J. J.;
Coleman, P. J. J. Med. Chem. 2010, 53, 5320.
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Re, N.; Fracchiolla, G.; Laghezza, A.; Tortorella, P.; Montanari, R.; Novellino, E.;
Mazza, F.; Crestani, M.; Loiodice, F. J. Med. Chem. 2010, 53, 4354.
6. Selected references: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805; (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534; (c)
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A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
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(a) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49, 2282; (b) Chen, X.;
Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790; (c)
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13, 3754; (b) Iamani, M.; Prabhu, K. R. J. Org. Chem. 2011, 76, 7938; (c) Wagh, Y.
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1.50 equiv) following the general procedure. The crude product was
further purified by flash column chromatography (SiO2, Hex/
EtOAc¼4:1) to afford pure compound 5e (0.15 g, 61%) as an orange
solid. 1H NMR (300 MHz, CDCl3):
d
8.01 (d, J¼2.1 Hz, 1H), 7.85 (dd,
J¼8.7, 2.1 Hz, 1H), 7.18 (d, J¼8.7 Hz, 1H), 3.60 (br s, 4H), 1.63 (s, 6H).
13C{1H} NMR (75 MHz, CDCl3):
d
163.7, 152.7, 145.0, 144.4, 116.6,
111.1, 107.9, 46.6, 25.2, 23.8. HRMS (ESIþ, m/z) Calcd for
C12H13N3O3Na [MþNa]þ 270.0855. Found 270.0868.
4.3.26. 2-Phenyl-5-(piperidin-1-yl)-1,3,4-oxadiazole (5f).8d Compo-
und 5f was prepared from 2-phenyl-1,3,4-oxadiazole 4f (0.15 g,
1.00 mmol, 1.00 equiv) and piperidin-1-yl benzoate 2a (0.31 g,
1.50 mmol, 1.50 equiv) following the general procedure. The crude
product was further purified by flash column chromatography
(SiO2, Hex/EtOAc¼4:1) to afford pure compound 5f (0.16 g, 72%) as
a white solid. 1H NMR (300 MHz, CDCl3):
d
7.95e7.83 (m, 2H),
7.49e7.38 (m, 3H), 3.61e3.52 (m, 4H), 1.69 (br s, 6H). 13C{1H} NMR
(75 MHz, CDCl3): d 164.2, 158.9, 130.3, 128.7, 125.5, 124.7, 47.0, 24.8,
23.6. HRMS (ESIþ, m/z) Calcd for C13H15N3ONa [MþNa]þ 252.1113.
Found 252.1102.
9. Seebach, D.; Enders, D. Angew. Chem., Int. Ed. Engl. 1975, 14, 15.
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This work was financially supported by Thailand Research Fund
(TRF Grant MRG5580039), Faculty of Science, Mahidol University,
and Center of Excellence for Innovation in Chemistry (PERCH-CIC),
Commission on Higher Education, Ministry of Education. The authors
also thank Department of Chemistry and Center of Instrumental
Facility (CIF) at Faculty of Science, Mahidol University for facilities.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.127.
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