Copper-catalyzed direct oxidative C-H amination of benzoxazoles with formamides or secondary amines under mild conditions

Article abstract of DOI:10.1021/jo200447x

A facile, efficient, and practical method for copper-catalyzed direct C-H amination of benzoxazoles with formamides or secondary amines has been developed. The system can be performed in the absence of external base and only requires O₂ or even air as oxidant. A variety of substituted benzoxazol-2-amines were synthesized with moderate to excellent yield.

Full text of DOI:10.1021/jo200447x

NOTE
pubs.acs.org/joc
Copper-Catalyzed Direct Oxidative CꢀH Amination of Benzoxazoles
with Formamides or Secondary Amines under Mild Conditions
Yaming Li,* Yusheng Xie, Rong Zhang, Kun Jin, Xiuna Wang, and Chunying Duan*
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology,
Dalian 116024, P. R. China
S Supporting Information
b
ABSTRACT: A facile, efficient, and practical method for copper-catalyzed
direct CꢀH amination of benzoxazoles with formamides or secondary
amines has been developed. The system can be performed in the absence of
external base and only requires O2 or even air as oxidant. A variety of
substituted benzoxazol-2-amines were synthesized with moderate to
excellent yield.
Scheme 1. Transition-Metal-Mediated Amination
he transition-metal-catalyzed selective CꢀN bond forma-
T
tion reaction of azoles is a highly important transformation
in synthetic chemistry since five-membered heterocycles with
amine group are widely employed in biological, pharmaceutical,
and material sciences.1 Classically, methods to synthesize this
skeleton include cyclocondensation reactions from two functio-
nalized precursors (e.g., Hantszch aminothiazole synthesis),2
palladium-catalyzed BuchwaldꢀHartwig coupling,3 and copper-
catalyzed Ullmann and Goldberg couplings.4 Although sig-
nificant advances have been achieved, still there are some
disadvantages, such as high temperature, long reaction time,
poisonous ligands, and noneconomic effects. To find greener and
more efficient methods, direct CꢀH amination of heteroarenes
has been reported successively.5,6 For example, Mori7a and
Schreiber7b independently provided a copper-catalyzed access
to the heteroarylamines in the presence of ligand (Scheme 1A, a).
Miura7c successfully developed a copper-catalyzed amination of
azoles using chloroamines instead of the parent amines, albeit
with the use of the strong base NaO-t-Bu (Scheme 1A, b).
Recently, Chang8 reported a new and efficient access to CꢀH
amination of azoles with stoichiometric amounts of a silver
species and acid as additive (Scheme 1A, c).
During the preparation of this manuscript, Chang9 reported
the Co-catalyzed amination of azoles and the use of tert-butyl
hydroperoxide as oxidant (Scheme 1A, d). On the basis of
the above excellent works and our previous studies on the
copper-catalyzed aminations,10 we describe herein our successful
copper catalyst systems with O2 as oxidant, which can construct
the CꢀN bond of azoles efficiently either by decarboxylative
coupling with formamides or by a direct CꢀH amination
protocol with secondary amines under mild reaction conditions
(Scheme 1B).
As it is known that Cu(II) can oxidate Pd(0) to Pd(II) and O2
can oxidate Cu(I) to Cu(II), we attempted to use Pd(II)/
Cu(II)/O2 as a catalytic system for direct CꢀH amination of
azoles. When the CꢀH amination of benzoxazole with DMF as a
nitrogen source was chosen as a model reaction, only 20% yield
of the amination product of benzoxazole was obtained (Table 1,
entry 1). On the other hand, when Cu(OAc)2 H2O was
3
employed as catalyst, the yield was enhanced to 73% (Table 1,
entry 2). Subsequent studies revealed that the amination pro-
ceeded smoothly with high yields even without Pd(OAc)2
(Table 1, entries 2 and 3), which indicated that Pd(OAc)2 has
almost no effect on the reaction. Acid is essential since only 15%
yield was obtained without addition of acid (Table 1, entry 12).
Among different acids, (4-NO2)PhCO2H and PhCO2H were
demonstrated to be better than other acids (Table 1, entries
6ꢀ11). The catalyst Cu(OAc)2 H2O and oxidant O2 are crucial
3
for the amination reaction, which would not take place without
Received: March 1, 2011
Published: May 27, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200447x J. Org. Chem. 2011, 76, 5444–5449
|

The Journal of Organic Chemistry
NOTE
Table 1. Optimization of Reaction Conditions with Amide and Azolea
entry
cat. (equiv)
acid (equiv)
PhCO2H (5)
oxidant
yieldb (%)
1
2
Pd(OAc)2 (0.02), CuBr2 (0.4)
air
20
73
Pd(OAc)2 (0.02), Cu(OAc)2 H2O (0.4)
PhCO2H (5)
air
3
3
Cu(OAc)2 H2O (0.4)
PhCO2H (5)
air
73
3
4
Cu(OAc)2 H2O (0.4)
PhCO2H (5)
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
N2
79
3
5
Cu(OAc)2 H2O (0.2)
PhCO2H (5)
76
3
6
Cu(OAc)2 H2O (0.2)
PhCO2H (2)
70
3
7
Cu(OAc)2 H2O (0.2)
(4-OH)PhCO2H (2)
(4-CH3O)PhCO2H (2)
(4-NO2)PhCO2H (2)
2-PyCO2H (2)
L-proline (2)
15
3
8
Cu(OAc)2 H2O (0.2)
60
3
9
Cu(OAc)2 H2O (0.2)
70
3
10
11
12
13
14
Cu(OAc)2 H2O (0.2)
nd
nd
15
3
Cu(OAc)2 H2O (0.2)
3
Cu(OAc)2 H2O (0.2)
3
PhCO2H (2)
PhCO2H (2)
nd
trace
Cu(OAc)2 H2O (0.2)
3
a Reaction conditions: With 1 (0.5 mmol) and 2 (2 mL), O2 balloon, 130 °C, 12 h. b Isolated yield.
Scheme 2. Copper-Catalyzed Direct CꢀH Amination of
Cu(OAc)2 H2O or oxidant O2 (Table 1, entries 13 and 14).
Through the optimization of the reaction conditions, the best
3
Azoles with Amides*
condition is PhCO2H (5 equiv)/Cu(OAc)2 H2O (40 mol %)/
3
O2 (Table 1, entry 4). While from the viewpoint of economy and
practicality of the catalyst and oxidant in laboratory synthesis and
industrial applications, we chose Cu(OAc)2 H2O (20 mol %) and
3
PhCO2H (2 equiv) and O2 as optimized conditions.
Under the optimized reaction conditions, we investigated the
substrate scope of benzoxazoles in the decarbonylative amination
with amides (Scheme 2). A range of azole derivatives were
obtained with moderate yields. First, DMF reacted with benzox-
azole slightly easier than the N,N-diethylformamide. Second, it
was obvious that benzoxazoles bearing electron-donating groups,
such as methyl and tert-butyl could react much easier than
those bearing electron-withdrawing groups, such as 5-chloro
(Scheme 2, 4bꢀd,gꢀi). Oxazolo[4,5-b]pyridine even failed to
react with formamide or acetamide (Scheme 2, 4e or 4j), which
indicated that there may be a balance between the acidity at
position 2 of azoles and the ability to coordinate with copper.
Lastly, when N,N-dimethylacetamide instead of DMF was
subjected to reaction with benzoxazole under the reaction
conditions, the N,N-dimethyl-2-aminobenzoxazole product was
obtained in 30% yield, indicating that deacetylation is feasible
under the reaction conditions.
* Reaction conditions: azoles (0.5 mmol), amides (2 mL), Cu(OAc)2
H2O (20 mol %), PhCO2H (2 equiv), O2 balloon, 130 °C, 12 h.
a Isolated yield in parentheses. b N,N-Dimethylacetamide as nitrogen
source and solvent.
3
On the basis of the results of reactions of benzoxazoles with
amides, we believed that amines may directly react with azoles
under low temperature, since decarbonylation releases amine
from amide at high temperature.8 After benzoxazole reacted with
di-n-butylamine at 70 °C for 12 h, the desired product was
obtained in a high GC yield of 89% (Table 2, entry 1) under
the CH3CO2Na conditions the desired product was only
obtained in 54% GC yield (Table 2, entry 5). For the reaction
of benzoxazole with formamide, without addition of acid, the
amination yield decreased from 70% to 15%, while for the
reaction of benzoxazole with di-n-butylamine, without addition
of acid, the yield decreased from 96% to 83% (Table 2, entries 4
and 7). This implied that the reaction process may be a copper-
catalyzed CꢀH activation pathway other than the process of
nucleophilic attack of amine to the intermediate of the proto-
nated azole (Scheme 5). Either copper source or oxidant O2 plays
a crucial role in the reaction process since without copper source
conditions of Cu(OAc)2 H2O (20 mol %), PhCO2H (2equiv),
3
and O2 as oxidant. Other copper salts, CuBr2 and CuCl2 H2O,
3
were less effective than Cu(OAc)2 H2O (Table 2, entries 1ꢀ3),
3
which agreed with the basicity of the anion of the copper salt.
Addition of CH3CO2H instead of PhCO2H enhanced the GC
yields from 89% to 96% (Table 2, entries 1 and 4), while under
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NOTE
Table 2. Optimization of Reaction Conditions of Dibutyla-
mine and Azolea
Scheme 3. Substrate Scope of Amines*
entry additive (equiv)
cat. (equiv)
oxidant yieldb (%)
1
2
3
4
5
6
7
8
9
PhCO2H (2)
PhCO2H (2)
PhCO2H (2)
CH3CO2H (2)
Cu(OAc)2 H2O (0.2)
O2
O2
O2
O2
O2
O2
O2
O2
N2
89
80
84
96
54
95
83
8
3
CuBr2 (0.2)
CuCl2 H2O (0.2)
3
Cu(OAc)2 H2O (0.2)
3
CH3CO2Na (2) Cu(OAc)2 H2O (0.2)
3
CH3CO2H (2)
Cu(OAc)2 (0.2)
Cu(OAc)2 H2O (0.2)
3
CH3CO2H (2)
CH3CO2H (2)
Cu(OAc)2 H2O (0.2)
23
3
a Reaction conditions: With 1 (0.5 mmol), 3 (0.6 mmol), CH3CN
(2 mL), 70 °C, 12 h. b GC yield.
or O2 the desired product yields decreased from 96% to 8% or
from 96% to 23%, respectively (Table 2, entries 8 and 9).
Under the optimized reaction conditions, a variety of amines
were tested for the direct amination of benzoxazole (Scheme 3,
4f, 5aꢀk). The reactions of morpholine, piperidine, di-n-buty-
lamine, 4-methylpiperdine, and diethylamine with benzoxazole
proceeded smoothly to yield the desired products 5aꢀd and 4f in
good yields (55ꢀ85%). Pyrrolidine gave the corresponding
functionalized amine product 5e in a yield of 45% because ofthe
steric hindrance of five-membered ring. Regretfully, diallylamine
afforded the product 5h only in 20% GC yield, which may be
caused by the lower nucleophilicity of diallylamine. Notably,
unsymmetrical amines such as N-methylbenzylamine and
N-methyl-2-chlorobenzylamine gave the products 5f and 5g in
yields of 65% and 57%, respectively. In sharp contrast to the
above results of secondary aliphatic amines, no desired products
were obtained when either primary amines (e.g., 5i, 5j) or
aromatic amine (e.g., 5k) were employed under the reaction
conditions, which may be caused by decrease of nucleophilicity of
amine, and related works are still underway in our group.
Next, the scope of this reaction was investigated with respect
to azole under the same conditions as those shown in Scheme 4
(5c, 6aꢀh). Benzoxazoles bearing the substituents at position 5
were aminated effectively in excellent yield (5c, 6aꢀc, eꢀf,
75ꢀ94% yield). It is also observed that electron-withdrawing
groups attached to the position-5 of benzoxazole resulted in
lower conversion, 5-chlorobenzoxazole yielded the desired products
6c and 6f in 76% and 75% yields, respectively. Oxazolo[4,5-
b]pyridine even gave the product 6d only in 48% yield. In
contrast to benzoxazoles, benzothiazole or N-ethylbenzimida-
zole afforded the desired products 6g and 6h in 15% and 0% GC
yield, respectively. The lower reactivity of those substrates
observed here is may caused by their weaker acidity.
* Reaction conditions: benzoxazoles (0.5 mmol), amines (0.6 mmol),
Cu(OAc)2 H2O (20 mol %), CH2CO2H (2 equiv), O2 balloon, solvent
3
(2 mL), 70 °C, 12 h. a Isolated yield in parentheses. b GC yield.
Scheme 4. Substrate Scope of Azoles*
* Reaction conditions: azoles (0.5 mmol), amines (0.6 mmol), Cu-
The interesting experiment results obtained above could help
us elucidate the mechanistic details of the present reaction. First,
the role of acid in the reaction of benzoxazoles with amines is less
important than that with amides, indicating that acid plays an
important role in the release of amine from amides by decarbo-
nylation other than CꢀH activation. Second, whether azoles
(OAc)2 H2O (20 mol %), CH3CO2H (2 equiv), O2 balloon, CH2CN
3
(2 mL), 70 °C, 12 h. a Isolated yield in parentheses. b GC yield.
catalyst and O2 oxidant were crucial, which was observed from
the great diminishment of the desired product yield in the
absence of copper source or O2. Third, it was also observed that
electron-donating groups attached to azoles resulted in higher
reacted with amines or with amides, both Cu(OAc)2 H2O
3
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NOTE
Scheme 5. Possible Mechanism for Copper-Catalyzed Direct
CꢀH Amination of Azoles
General Procedure for Copper-Catalyzed Direct Amina-
tion of Benzoxazoles with Secondary Amines. A dried Schlenk
test tube containing a magnetic stirring bar was charged under air with
benzoxazole (0.5 mmol), amine (0.6 mmol), Cu(OAc)2 H2O (20 mol %),
3
CH3CO2H (2 equiv), and CH3CN (2 mL). Then the O2 was
introduced to the tube to form an O2 balloon, the tube was sealed,
and the mixture was treated at 70 °C for 12 h. The resulting mixture
was allowed to cool to room temperature and washed with a saturated
solution of NaHCO3, extracted with ethyl acetate for three times. The
combined organic layers were dried with Na2SO4 and concentrated
under reduced pressure. The resulting residue was purified by column
chromatography on silica gel with EtOAc/petroleum (1/1ꢀ1/30) to
provide the desired product.
N,N-Dimethylbenzoxazol-2-amine8 (4a). The title compound was
prepared according to the general procedure for amination of benzox-
1
azoles with formamides to give a yellow solid: 70% isolated yield; H
NMR (400 MHz, CDCl3) δ (ppm): 7.36 (d, J = 7.6 Hz, 1H), 7.24 (d, J =
7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 3.18 (s,
6H); 13C NMR (100 MHz, CDCl3) δ (ppm): 163.0, 149.0, 143.3, 123.9,
120.3, 116.0, 108.7, 37.8; HRMS (ESI) calcd for C9H10N2O [M þ H]þ
163.0871, found 163.0867.
N,N,5-Trimethylbenzoxazol-2-amine8 (4b). The title compound was
prepared according to the general procedure for amination of benzox-
azoles with formamides to give a light yellow solid: 53% isolated yield;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.15 (s, 1H), 7.10 (d, J = 8.0 Hz,
1H), 6.78 (d, J = 8.0 Hz, 1H), 3.16 (s, 6H), 2.37 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 163.3, 147.3, 143.8, 133.5, 120.9, 116.5, 108.0,
37.7, 21.6; GCꢀMS (EI) m/z = 176 [M]þ.
conversion in the CꢀH amination reactions of azoles with
amines or amides, which implied that there is a balance between
the acidity at position 2 of azoles and the ability to coordinate with
copper. Therefore, a plausible pathway similar to the reaction of
tertiary amine reported by Huang11 can be proposed (Scheme 5).
At the beginning of the reaction, the copper catalyst is oxidized by
oxygen to form [LnCunþ1] composed of the copper salt and
molecular oxygen.11,12 Then the copper species coordinates with
the secondary amine and give the intermediate A by elimination
of water assisted by CH3CO2H. Second, intermediate A coordi-
nates to azole to give B, and its subsequent deprotonation/
rearrangement yields C and regenerates CH3CO2H. Lastly, C
affords product by reductive elimination and regenerate the
copper catalyst to complete the catalytic cycle.7b,c
In conclusion, an efficient and copper-catalyzed direct CꢀH
amination of azoles with amides or secondary amines as nitrogen
group sources has been developed in good to excellent yields.
The use of inexpensive copper catalyst and O2 even air as the
oxidant is a green and significant practical advantage. This
reaction can be performed in the absence of an external base at
70 °C. The present reaction provides a powerful tool for the
synthesis of 2-aminoazole derivatives.
5-tert-butyl-N,N-dimethylbenzoxazol-2-amine (4c). The title com-
pound was prepared according to the general procedure for amination of
benzoxazoles with formamides to give a yellow solid: 64% isolated yield;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.43 (s, 1H), 7.15 (d, J = 8.4 Hz,
1H), 7.03 (d, J = 8.4 Hz, 1H), 3.16 (s, 6H), 1.33 (s, 9H); 13C NMR (100
MHz, CDCl3) δ (ppm) 163.3, 147.3, 147.0, 143.3, 117.4, 113.2, 107.7,
37.7, 34.8, 31.8; HRMS (ESI) calcd for C13H18N2O [M þ H]þ
219.1497, found 219.1493; mp 70ꢀ72 °C.
5-Chloro-N,N-dimethylbenzoxazol-2-amine8 (4d). The title com-
pound was prepared according to the general procedure for amination of
benzoxazoles with formamides to give a yellow solid: 42% isolated yield;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.28 (s, 1H), 7.12 (d, J = 8.4 Hz,
1H), 6.94 (d, J = 8.4 Hz, 1H), 3.18 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 163.8, 147.7, 145.1, 129.2, 120.0, 116.1, 109.1, 37.7;
GCꢀMS (EI) m/z = 196 [M]þ.
N,N-Diethylbenzoxazol-2-amine11 (4f). The title compound was
prepared according to the general procedure for amination of benzox-
azoles with formamides and amines to give a yellow liquid in 52% and
84% isolated yield, respectively: 1H NMR (400 MHz, CDCl3) δ (ppm)
7.35 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H),
6.97 (t, J = 8.0 Hz, 1H), 3.55ꢀ3.60 (q, 4H), 1.27 (t, J = 7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 162.0, 148.7, 143.5, 123.6, 119.8,
115.6, 108.4, 42.8, 13.4; GCꢀMS (EI) m/z = 190 [M]þ.
’ EXPERIMENTAL SECTION
5-tert-Butyl-N,N-diethylbenzoxazol-2-amine (4g). The title com-
pound was prepared according to the general procedure for amination
of benzoxazoles with formamides to give a yellow liquid: 54% isolated
yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.43 (s, 1H), 7.15 (d, J =
8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 3.53ꢀ3.58 (q, 4H), 1.33 (s, 9H),
1.26 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.5,
147.2, 146.8, 143.4, 117.1, 113.0, 107.6, 43.0, 34.8, 31.9, 13.8; HRMS
(ESI) calcd for C15H22N2O [M þ H]þ 247.1810, found 247.1805.
N,N-Diethyl-5-methylbenzoxazol-2-amine (4h). The title com-
pound was prepared according to the general procedure for amination
of benzoxazoles with formamides to give a yellow liquid: 49% isolated
yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.14 (s, 1H), 7.10 (d, J =
8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.53ꢀ3.58 (q, 4H), 2.37 (s, 3H),
General Procedure for Copper-Catalyzed Amination of
Benzoxazoles with Formamides. A dried Schlenk test tube
containing a magnetic stirring bar was charged under air with benzox-
azole (0.5 mmol), formamide (2 mL), Cu(OAc)2 H2O (20 mol %), and
3
acid additive (2 equiv). Then O2 was introduced to the tube to form an
O2 balloon, the tube was sealed, and the mixture was treated at 130 °C
for 12 h. The resulting mixture was allowed to cool to room temperature,
washed with a saturated solution of NaHCO3, and extracted with ethyl
acetate three times. The combined organic layers were dried with
Na2SO4 and concentrated under reduced pressure. The resulting residue
was purified by column chromatography on silica gel with EtOAc/
petroleum (1/2ꢀ1/30) to provide the desired product.
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NOTE
1.26 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.4,
147.0, 143.8, 133.4, 120.6, 116.3, 107.9, 43.0, 21.6, 13.8; HRMS (ESI)
calcd for C12H16N2O [M þ H]þ 205.1341, found 205.1338.
isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.37ꢀ7.39
(m, 2H), 7.14ꢀ7.26 (m, 5H), 7.01 (t, J = 8.0 Hz, 1H), 4.87 (s, 2H),
3.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.9, 149.1,
143.5, 134.0, 133.5, 129.8, 128.9, 128.4, 127.2, 124.1, 120.6, 116.3, 108.9,
51.4, 35.8; HRMS (ESI) calcd for C15H13ClN2O [M þ H]þ 273.0795,
found 273.0798; mp 82ꢀ84 °C.
5-Chloro-N,N-diethylbenzoxazol-2-amine (4i). The title compound
was prepared according to the general procedure for amination of
benzoxazoles with formamides to give a yellow liquid: 29% isolated
yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.29 (s, 1H), 7.12
(d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.54ꢀ3.59 (q, 4H), 1.28
(t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.0, 147.5,
145.1, 129.1, 119.8, 115.9, 109.0, 43.0, 13.5; HRMS (ESI) calcd for
C11H13ClN2O [M þ H]þ 225.0795, found 225.0788.
N,N-Dibutyl-5-methylbenzoxazol-2-amine (6a). The title com-
pound was prepared according to the general procedure for direct
amination of benzoxazoles with amines to give a white solid: 94%
isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.15 (s, 1H), 7.09
(d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 3.48 (t, J = 7.6 Hz, 4H), 2.37
(s, 3H), 1.60ꢀ1.67 (m, 4H), 1.32ꢀ1.41 (m, 4H), 0.95 (t, J = 7.2 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.8, 146.9, 143.9, 133.2,
120.4, 116.2, 107.8, 48.3, 30.1, 21.5, 20.0, 13.9; HRMS (ESI) calcd for
C16H24N2O [M þ H]þ 261.1967, found 261.1969; mp 73ꢀ75 °C.
5-tert-Butyl-N,N-dibutylbenzoxazol-2-amine (6b). The title com-
pound was prepared according to the general procedure for direct
amination of benzoxazoles with amines to give a yellow liquid: 84%
isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (s, 1H), 7.14
(d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 3.49 (t, J = 7.2 Hz, 4H),
1.61ꢀ1.68 (m, 4H), 1.33ꢀ1.40 (m, 13H), 0.95 (t, J = 7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 162.9, 147.1, 146.7, 143.5, 116.9,
113.0, 107.5, 48.3, 34.8, 31.9, 30.2, 20.0, 13.9; HRMS (ESI) calcd for
C19H30N2O [M þ H]þ 303.2436, found 303.2444.
2-Morpholinobenzoxazole7c (5a). The title compound was prepared
according to the general procedure for direct amination of benzoxazoles
1
with amines to give a yellow solid: 55% isolated yield; H NMR (400
MHz, CDCl3) δ (ppm) 7.38 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H),
7.17 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 3.81 (t, J = 4.4 Hz, 4H),
3.68 (t, J = 4.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.1,
148.8, 142.9, 124.2, 121.0, 116.6, 108.9, 66.3, 45.8; HRMS (ESI) calcd
for C11H12N2O2 [M þ H]þ 205.0977, found 205.0977.
2-(Piperidin-1-yl)benzoxazole7c (5b). The title compound was pre-
pared according to the general procedure for direct amination of
benzoxazoles with amines to give a yellow solid: 84% isolated yield;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.34 (d, j = 8.0 Hz, 1H), 7.21 (d,
J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H),
3.61ꢀ3.62 (m, 4H), 1.63 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 162.3, 148.6, 143.3, 123.7, 120.2, 115.9, 108.5, 46.5, 25.1, 24.0;
GCꢀMS (EI) m/z = 202 [M]þ.
N,N-Dibutyl-5-chlorobenzoxazol-2-amine (6c). The title compound
was prepared according to the general procedure for direct amination of
benzoxazoles with amines to give a yellow solid: 76% isolated yield; 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.28 (s, 1H), 7.11 (d, J = 8.4 Hz,
1H), 6.91 (d, J = 8.4 Hz, 1H), 3.48 (t, J = 7.6 Hz, 4H), 1.60ꢀ1.68 (m,
4H), 1.32ꢀ1.41 (m, 4H), 0.96 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 163.4, 147.4, 145.2, 129.0, 119.6, 115.8, 108.9, 48.4,
30.1, 20.0, 13.9; HRMS (ESI) calcd for C15H21ClN2O [M þ H]þ
281.1421, found 281.1425; mp 63ꢀ65 °C.
N,N-Dibutylbenzoxazol-2-amine7c (5c). The title compound was
prepared according to the general procedure for direct amination of
benzoxazoles with amines to give a yellow liquid: 85% isolated yield; 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, J = 8.0 Hz, 1H), 7.22 (d, J =
8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 3.46ꢀ3.50
(t, 4H), 1.60ꢀ1.68 (m, 4H), 1.32ꢀ1.41 (m, 4H), 0.95 (t, J = 7.6 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.6, 148.7, 143.7, 123.7,
119.8, 115.7, 108.4, 48.3, 30.1, 20.0, 13.8; GCꢀMS (EI) m/z = 246
[M]þ.
N,N-Dibutyloxazolo[4,5-b]pyridin-2-amine (6d). The title com-
pound was prepared according to the general procedure for direct
amination of benzoxazoles with amines to give a yellow liquid: 48%
isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.19 (S, 1H), 7.39
(d, J = 7.6 Hz, 1H), 6.84ꢀ6.87 (m, 1H), 3.54 (t, J = 7.2 Hz, 4H),
1.64ꢀ1.71 (m, 4H), 1.33ꢀ1.43 (m, 4H), 0.96 (t, J = 7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 164.1, 158.8, 144.4, 141.4, 115.0,
114.4, 48.5, 30.1, 20.0, 13.9; HRMS (ESI) calcd for C14H21N3O [M þ
H]þ 248.1763, found 248.1764.
2-(4-Methylpiperdin-1-yl)benzoxazole (5d). The title compound
was prepared according to the general procedure for direct amination
of benzoxazoles with amines to give a white solid: 83% isolated yield; 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.34 (d, J = 7.6 Hz, 1H), 7.22 (d, J =
8.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 4.25 (d, J =
13.2 Hz, 2H), 3.02 (t, J = 12 Hz, 2H), 1.71 (d, J = 12.8 Hz, 2H),
1.57ꢀ1.60 (m, 1H), 1.19ꢀ1.30 (m, 2H), 0.96 (d, j = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 162.4, 148.7, 143.4, 123.8, 120.2,
116.0, 108.5, 46.0, 33.6, 21.8; HRMS (ESI) calcd for C13H16N2O [M þ
H]þ 217.1341, found 217.1340; mp 65ꢀ67 °C.
N-Benzyl-N,5-dimethylbenzoxazol-2-amine (6e). The title com-
pound was prepared according to the general procedure for direct
amination of benzoxazoles with amines to give a yellow solid: 78%
1
isolated yield; H NMR (400 MHz, CDCl3) δ (ppm) 7.25ꢀ7.32 (m,
2-(Pyrrolidin-1-yl)benzoxazole13 (5e). The title compound was pre-
pared according to the general procedure for direct amination of benzox-
azoles with amines to give a white solid: 45% isolated yield; 1H NMR (400
MHz, CDCl3) δ (ppm) 7.36 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H),
7.14 (t, J= 7.6 Hz, 1H), 6.98 (t, J= 7.6 Hz, 1H), 3.64 (t, J = 6.4 Hz, 4H), 2.02
(t, J = 6.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 161.1, 149.1,
143.7, 123.9, 120.1, 116.0, 108.6, 47.5, 25.7; GCꢀMS (EI) m/z=188[M]þ.
N-Benzyl-N-methylbenzoxazol-2-amine13 (5f). The title compound
was prepared according to the general procedure for direct amination of
benzoxazoles with amines to give a yellow solid: 65% isolated yield; 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.39 (d, J = 7.6 Hz, 1H), 7.23ꢀ7.34
(m, 6H), 7.17 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 4.74 (s, 2H),
3.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.0, 149.0,
143.6, 136.5, 128.8, 127.8, 127.7, 124.0, 120.5, 116.2, 108.8, 53.9, 35.2;
GCꢀMS (EI) m/z = 238 [M]þ.
5H), 7.18 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.70
(s, 2H), 3.08 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 163.1, 147.2, 143.7, 136.5, 133.6, 128.7, 127.7, 127.6, 121.0,
116.6, 108.1, 53.8, 35.1, 21.6; HRMS (ESI) calcd for C16H16N2O [M þ
1] 253.1341, found 253.1342; mp 55ꢀ57 °C.
N-Benzyl-5-chloro-N-methylbenzoxazol-2-amine14 (6f). The title
compound was prepared according to the general procedure for direct
amination of benzoxazoles with amines to give a yellow solid: 75%
1
isolated yield; H NMR (400 MHz, CDCl3) δ (ppm) 7.26ꢀ7.32 (m,
6H), 7.12 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.70 (s, 2H), 3.09
(s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.7, 147.6, 145.0,
136.1, 129.2, 128.8, 127.9, 127.7, 120.1, 116.2, 109.2, 53.8, 35.1; HRMS
(ESI) calcd for C15H13ClN2O [M þ H]þ 273.0795, found 273.0793.
5-Methylbenzoxazole: light yellow solid; 62% isolated yield; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.04 (s, 1H), 7.55 (s, 1H), 7.40
(d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 2.42 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 152.5, 148.0, 140.1, 134.1, 126.5, 120.2, 110.0,
21.2; GCꢀMS (EI) m/z = 133 [M]þ.
N-(2-Chorobenzyl)-N-methylbenzoxazol-2-amine (5g). The title
compound was prepared according to the general procedure for direct
amination of benzoxazoles with amines to give a yellow solid: 57%
5448
dx.doi.org/10.1021/jo200447x |J. Org. Chem. 2011, 76, 5444–5449

The Journal of Organic Chemistry
NOTE
5-tert-Butylbenzoxazole: yellow liquid; 94% isolated yield; 1H NMR
(400 MHz, CDCl3) yellow liquid δ (ppm) 8.06 (s, 1H), 7.81 (s, 1H),
7.43ꢀ7.50 (m, 2H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 152.7, 148.2, 148.1, 140.0, 123.5, 117.1, 110.1, 35.0, 31.9;
GCꢀMS (EI) m/z = 175 [M]þ.
(7) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178.
(c) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010,
132, 6900.
(8) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed.
2009, 48, 9127.
5-Chlorobenzoxazole: light yellow solid; 53% isolated yield; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.12 (s, 1H), 7.78 (s, 1H), 7.51
(d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 153.8, 148.6, 141.2, 130.2, 126.1, 120.7, 111.8;
GCꢀMS (EI) m/z = 153 [M]þ.
(9) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed.
2010, 49, 9899.
(10) (a) Wang, H. F.; Li, Y. M.; Sun, F. F.; Feng, Y.; Jin, K.; Wang,
X. N. J. Org. Chem. 2008, 73, 8639. (b) Li, Y.; Wang, H.; Jiang, L.; Sun, F.;
Fu, X.; Duan, C. Eur. J. Org. Chem. 2010, 6967.
(11) Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. Org. Lett. 2011, 13,
522.
(12) (a) Lewis, E. A.; Tolman, W. B. Chem. Rev. 2004, 104, 1047. (b)
Kunishita, A.; Ishimaru, H.; Nakashima, S.; Ogura, T.; Itoh, S. J. Am.
Chem. Soc. 2008, 130, 4244. (c) Zhang, C.; Jiao, N. Angew. Chem., Int. Ed.
2010, 49, 6174.
1
Oxazolo[4,5-b]pyridine. light yellow solid; 90% isolated yield; H
NMR (400 MHz, CDCl3) δ (ppm) 8.64 (s, 1H), 8.39 (s, 1H), 7.94 (d,
J = 8.0 Hz, 1H), 7.37ꢀ7.40 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 155.4, 154.5, 147.0, 142.1, 120.8, 119.1; GC-MS (EI) m/z =
120 [M]þ.
(13) Cioffi, C. L.; Lansing, J. J.; Yuksel, H. J. Org. Chem. 2010, 75,
7942.
’ ASSOCIATED CONTENT
(14) Masatoshi, Y.; Yasuo, T.; Kyoto, H.; Kuniko, H. Chem. Pharm.
Bull. 1984, 32, 3053.
S
Supporting Information. Experimental procedures, char-
b
acterization data, and copies of 1H and 13C NMR spectra for the
aminated products. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: ymli@dlut.edu.cn; cyduan@dlut.edu.cn.
’ ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (Project Nos. 20876021, 20923006) and
the Education Department of Liaoning Province (2009S021).
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