A convenient one-pot synthesis of N-substituted 2-aminoazole derivatives

Article abstract of DOI:10.1055/s-0032-1316868

A practical protocol for the one-pot synthesis of N-substituted 2-aminoazole derivatives is described, employing simple azole substrates, nitrogen nucleophiles, lithium tert-butoxide as the base, and iodine to mediate carbon-nitrogen bond formation. This method proceeds at room temperature under an air atmosphere using a normal benchtop set-up, or can be performed conveniently using microwave irradiation. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1316868

936▌
PAPER
paper
A Convenient One-Pot Synthesis of N-Substituted 2-Aminoazole Derivatives
One-Pot Synthesis of N-Substituted 2-Aminoazoles
Sirilata Yotphan,* Danupat Beukeaw, Vichai Reutrakul
Center for Catalysis and Center of Excellence for Innovation in Chemistry, Department of Chemistry, Faculty of Science, Mahidol University,
Bangkok 10400, Thailand
Fax +66(2)3547151; E-mail: sirilata.yot@mahidol.ac.th
Received: 22.01.2013; Accepted after revision: 18.02.2013
halogenation of the intermediate anionic species with var-
Abstract: A practical protocol for the one-pot synthesis of N-sub-
ious halide electrophiles, for example, iodine (I2), iodine
stituted 2-aminoazole derivatives is described, employing simple
monochloride (ICl), and carbon tetrachloride (CCl4).11
We have examined the synthesis of N-substituted 2-ami-
azole substrates, nitrogen nucleophiles, lithium tert-butoxide as the
base, and iodine to mediate carbon–nitrogen bond formation. This
method proceeds at room temperature under an air atmosphere us- noazoles starting from simple azoles and nitrogen nucleo-
ing a normal benchtop set-up, or can be performed conveniently us-
ing microwave irradiation.
philes, by combining the in situ C-2 halogenation of
azoles and subsequent nucleophilic attack of different
Key words: N-substituted 2-aminoazoles, iodine, one-pot synthe-
sis, benzoxazole, carbon–nitrogen bond formation
amines on the halogenated azole intermediates into a one-
pot protocol (Scheme 1).
R1
R2
N
R1
X
N
X
N
X
N
base, I2
There are a number of N-substituted 2-aminoazoles that
possess biological and pharmaceutical activities, and
many are employed in medicinal chemistry.1,2 For exam-
ple, 2-aminobenzoxazoles are very common scaffolds in a
wide variety of therapeutic agents for the treatment of
cancer,2 central nervous system (CNS) disorders,3 and in-
somnia.4 Derivatives of 2-aminothiazoles are currently
used as dopamine antagonists for early stage treatment of
Parkinson’s disease, and as anti-inflammatory and antibi-
otic agents.5
H
I
N
R2
X = O, S, NR
R1, R2 = alkyl, aryl
Scheme 1 One-pot synthesis of N-substituted 2-aminoazoles
Benzoxazole (1a) and morpholine (2a) were chosen as
model substrates for the optimization studies in the pres-
ence of various halogenating agents (NCS, NBS, NIS, Br2
and I2) (Scheme 2).12 The reaction using iodine (1.5 equiv)
as the halogenating agent in the presence of 1a (1 mmol,
1 equiv), lithium tert-butoxide (2 equiv), and morpholine
(2a) (5 equiv; added to the mixture after 10 min) in tetra-
hydrofuran, at room temperature under an air atmosphere,
resulted in the highest isolated yield (89%) of the desired
product 3a (purified by column chromatography). Other
halogenating agents (NCS, NBS, NIS and Br2) gave lower
yields under the same reaction conditions (9%, 32%, 67%
and 60%, respectively). It is interesting to note that no
product was obtained in the absence of the halogenating
agent, which further suggested that iodine played an im-
portant role in this transformation.
As a result of the various applications of N-substituted 2-
aminoazoles in medicinal chemistry, the development of
practical, convenient and efficient protocols for their
preparation has been the subject of intense research effort.
Classical methods for the synthesis of N-substituted 2-
aminoazoles employ cyclocondensation reactions (e.g.
the Hantzsch synthesis).6 A more conventional and diver-
gent method involves direct formation of a carbon–nitro-
gen (C–N) bond through a displacement reaction of 2-halo
substituted azoles with amine nucleophiles.7 However,
metal-catalyzed carbon–nitrogen bond formation via
cross-coupling, or carbon–hydrogen (C–H) bond func-
tionalization methods are utilized increasingly in both in-
dustry and academia as potentially powerful and reliable
approaches for the synthesis of these structural motifs.5a,8,9
Oxidative coupling methods involving metal-free carbon–
hydrogen bond functionalization and carbon–nitrogen
bond formation have also been recognized as alternative
and useful synthetic tools.10
LiOt-Bu (2 equiv)
X⎯Y (1.5 equiv)
O
O
N
O
N
N
O
+
THF, 18 h, r.t.
N
H
1a
(1 equiv)
2a
3a
(5 equiv)
Halogenating agent (X⎯Y)
Yield (%)
NCS
NBS
NIS
Br2
9
Based on studies by Daugulis and co-workers, the in situ
halogenation of acidic sp2 C–H bonds in heterocycles and
electron-deficient arenes can be achieved efficiently using
an appropriate alkoxide or phosphate base, followed by
32
67
60
89
0
I2
none
Scheme 2 Effect of different halogenating agents (X–Y)
SYNTHESIS 2013, 45, 0936–0942
Advanced online publication: 08.03.2013
DOI: 10.1055/s-0032-1316868; Art ID: SS-2013-F0068-OP
© Georg Thieme Verlag Stuttgart · New York
The strength of the base also proved to be important in this
reaction. Upon examining the effects of various inorganic
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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One-Pot Synthesis of N-Substituted 2-Aminoazoles
937
Table 2 Effect of Solvents and Concentrationsa
bases (Table 1), lithium tert-butoxide (3 equiv) was found
to be the best (Table 1, entries 2–4). Other stronger bases
(e.g. NaOt-Bu, KOt-Bu, KOMe and NaOH) gave signifi-
cantly lower yields, probably due to decomposition of the
starting benzoxazole (1a) (Table 1, entries 5–8). Low con-
versions were observed when weaker bases such as sodi-
um carbonate (Na2CO3), potassium carbonate (K2CO3),
potassium phosphate (K3PO4) and sodium acetate
(NaOAc) were employed (Table 1, entries 9–12).
LiOt-Bu (3 equiv)
2 (1.5 equiv)
O
O
N
O
N
I
+
N
O
solvent, 18 h, r.t.
N
H
1a
(1 equiv)
2a
3a
(5 equiv)
Entry
Solvent
Concn (M)
Yield (%)b
1
2
THF
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
0.2
0.1
100
39
62
52
10
18
13
9
Table 1 Effect of Inorganic Basesa
1,4-dioxane
Et2O
base (3 equiv)
2 (1.5 equiv)
O
3
O
N
I
O
+
N
O
THF, 18 h, r.t.
N
H
N
4
DMF
1a
2a
3a
5
EtOAc
CH2Cl2
toluene
hexane
THF
(1 equiv)
(5 equiv)
6
Entry
Base
Equiv
Yield (%)b
7
1
2
–
0
1
2
3
3
3
3
3
3
3
3
3
5
34
89
100
34
19
12
15
5
8
LiOt-Bu
LiOt-Bu
LiOt-Bu
NaOt-Bu
KOt-Bu
KOMe
NaOH
9
100
100
73
3
10
11
THF
4
THF
5
a Reaction conditions: benzoxazole (1a) (0.5 mmol, 1 equiv), LiOt-Bu
(3 equiv), I2 (1.5 equiv), morpholine (2a) (5 equiv; added to the mix-
ture after 10 min), r.t.
6
b Yields were determined by GC integration relative to hexamethyl-
benzene (0.1 equiv) as the internal standard.
7
8
9
Na2CO3
K2CO3
K3PO4
NaOAc
(Table 3). This one-pot transformation was complete
(≥99%) in one hour after adding morpholine (at t = 10
min) (Table 3, entry 5). Adding morpholine (2a) before
ten minutes had elapsed resulted in incomplete conversion
of the benzoxazole substrate into the iodide intermediate.
When morpholine (2a) was added at the start of the reac-
tion (t = 0 min), a much lower yield was obtained due to a
competing reaction between 2a and iodine (Table 3, entry
6). In addition, decomposition of the product was not ob-
served under extended reaction times (Table 3, entries 7
and 8).
10
11
12
7
25
9
a Reaction conditions: benzoxazole (1a) (0.5 mmol, 1 equiv), base (0–
3 equiv), I2 (1.5 equiv), THF (0.5 M soln of the benzoxazole sub-
strate), morpholine (2a) (5 equiv; added to the mixture after 10 min),
r.t.
b Yields were determined by GC integration relative to hexamethyl-
benzene (0.1 equiv) as the internal standard.
To test the scope of this protocol, the reactions of benzox-
azoles 1a and 1b and different amine nucleophiles 2a–j
were examined (Table 4). The reaction proved to be gen-
eral in nature, allowing the straightforward synthesis of a
number of 2-aminobenzoxazole derivatives. The one-pot
reactions of benzoxazole (1a) and secondary amines 2a–g
resulted in very high yields (80–98%) of the correspond-
ing N-substituted 2-aminoazoles 3a–g. Amines with sul-
fide (2e), N-methyl (2f), and N-tert-butoxycarbonyl (2g)
groups tolerated the present synthetic conditions. The re-
actions of benzoxazole (1a) and primary amines such as
cyclohexylamine (2h) and N-benzylamine (2i) afforded
the corresponding products 3h and 3i in moderate yields
(61% and 45% yields, respectively). Moreover, 8-amino-
quinoline (2j), a less nucleophilic amine, is a viable sub-
strate for this reaction, affording the desired product 3j in
The effects of different solvents and concentrations were
also evaluated (Table 2). Excellent conversions were ob-
tained when tetrahydrofuran (0.2–1 M concentrations of
the benzoxazole substrate) was used as the solvent (Table
2, entries 1, 9 and 10). Other polar aprotic solvents includ-
ing 1,4-dioxane, diethyl ether, N,N-dimethylformamide,
ethyl acetate and dichloromethane were less effective (Ta-
ble 2, entries 2–6). Nonpolar solvents such as toluene and
hexane gave poorer conversions compared to tetrahydro-
furan (Table 2, entries 7 and 8). The addition of salts or
other additives was not necessary for further optimization.
Using the optimized reaction conditions [1a (1 equiv),
LiOt-Bu (3 equiv), I2 (1.5 equiv) THF (0.5 M soln of the
benzoxazole substrate), morpholine (2a) (5 equiv)], the
progress of the reaction was monitored by GC analysis
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 936–942

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S. Yotphan et al.
PAPER
Table 4 One-Pot Synthesis of 2-Aminobenzoxazole Derivativesa
(continued)
Table 3 Monitoring the Reaction Timea
2a
(5 equiv)
LiOt-Bu (3 equiv)
2 (1.5 equiv)
R1
R2
O
O
O
N
I
R1
R2
LiOt-Bu, I2
1a
I
3a
N
+
N
H
time
THF, r.t.
(10 min)
N
(1 equiv)
THF, r.t., 1 h
N
X
X
1a X = H
1b X = Cl
2a–j
3a–l
Entry
Timeb
Yield (%)c
(5 equiv)
(1 equiv)
1
2
3
4
5
6
7
8
1 min
5 min
10 min
30 min
1 h
55
90
Entry Benzoxazole Amine
Product
Yield
(%)b
O
95
HN
N
4
1a
92
N
98
2d
3d
3e
3f
100
31d
100
100
O
N
HN
S
N
N
S
1 h
5
6
7
1a
1a
1a
94
93
83
2 h
2e
O
N
18 h
HN
NMe
NMe
a Reaction conditions: benzoxazole (1a) (0.5 mmol, 1 equiv), LiOt-Bu
(3 equiv), I2 (1.5 equiv), THF (0.5 M soln of the benzoxazole sub-
strate), morpholine (2a) (5 equiv; added to the mixture after 10 min),
r.t.
2f
O
N
HN
NBoc
N
NBoc
b Reaction time following the addition of morpholine (2a).
c Yields were determined by GC integration relative to hexamethyl-
benzene (0.1 equiv) as the internal standard.
2g
3g
O
N
d Morpholine added at t = 0 min.
NH
H2N
8
9
1a
1a
1a
61
45
66
66% yield. Additionally, the reaction of 5-chlorobenzox-
azole (1b) with morpholine (2a) and piperidine (2b) at
room temperature afforded the expected products 3k and
3l in 64% and 65% yields, respectively, after one hour un-
der the optimized reaction conditions. Hence, the pres-
ence of the chloro group at C-5 of the benzoxazole did not
adversely affect the reaction.
2h
3h
3i
O
N
H2N
NH
NH
2i
O
N
NH2
N
Table 4 One-Pot Synthesis of 2-Aminobenzoxazole Derivativesa
N
10
LiOt-Bu (3 equiv)
R1
O
N
O
N
I
2 (1.5 equiv)
R1
R2
2j
3j
N
+
N
H
R2
O
THF, r.t., 1 h
X
X
N
N
O
HN
O
1a X = H
2a–j
3a–l
N
11
12
1b
1b
Cl
64
65
1b X = Cl
(5 equiv)
(1 equiv)
2a
HN
2b
3k
O
N
Entry Benzoxazole Amine
Product
Yield
(%)b
Cl
3l
O
N
O
HN
O
a Reaction conditions: benzoxazole 1 (2 mmol), LiOt-Bu (3 equiv), I2
(1.5 equiv), amine 2a–j (5 equiv; added to the mixture after 10 min),
THF (0.5 M soln of the benzoxazole substrate), r.t., 1 h.
b Yield of isolated product.
1
1a
98
N
2a
3a
3b
3c
O
N
N
N
HN
2
3
1a
1a
87
80
With the less reactive thiazoles (4a,b) and imidazoles
(4c,d), only a small amount of product or no reaction was
observed at room temperature. This could be a result of
the higher pKa values of the C–H bonds at the C-2 posi-
tions of thiazoles and imidazoles.13 A microwave irradia-
tion method was therefore employed to facilitate
2b
HN
2c
O
N
Synthesis 2013, 45, 936–942
© Georg Thieme Verlag Stuttgart · New York

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One-Pot Synthesis of N-Substituted 2-Aminoazoles
939
formation of the desired N-substituted 2-aminoazole de- This procedure could be used as a convenient route to N-
rivatives. The corresponding products 5a–d were ob- substituted 2-aminoazoles, which may show considerable
tained in moderate yields (Table 5, entries 1–4). The potential in medicinal chemistry. Further development of
choice of solvent and temperature were investigated brief- an air-stable catalytic version of this reaction at ambient
ly; heating a mixture of benzothiazole (4a) and morpho- temperature is currently underway.
line (2a) in tetrahydrofuran at 100 °C under microwave
irradiation afforded a 54% yield of the corresponding N-
Unless otherwise specified, all reactions were carried out under an
substituted product 5a (Table 5, entry 1). The N-substitut-
ed 2-aminoazole products 5b,c were obtained in 10% and
33% isolated yields, respectively, via the above-men-
tioned approach (Table 5, entries 2 and 3). Additionally,
the microwave-assisted reaction of caffeine (4d) and mor-
pholine (2a) in N,N-dimethylformamide at 140 °C provid-
ed a 31% yield of the corresponding product 5d (Table 5,
entry 4).
air atmosphere. All reagents were obtained from commercial sup-
pliers and were used without further purification. Tetrahydrofuran
(THF) was dried over alumina under a nitrogen atmosphere. Oven-
dried glassware was used in all cases. Chromatography was per-
formed on silica gel (SiO2), (60 Å SiO2, Merck Grade, 70–230
mesh). GC experiments were carried out with an Agilent 6890N
GC-FID equipped with an Agilent column (HP-1, polysiloxane,
24.5 m × 0.32 mm ID × 0.17 μm). The microwave experiments
were carried out using a single mode microwave reactor (CEM dis-
cover SP system). Melting points were determined on a Mel-Temp
apparatus and are reported uncorrected. IR spectra were recorded on
an FT-IR Spectrum GX (Perkin Elmer), and only partial data are
Table 5 Microwave-Assisted Synthesis of N-Substituted 2-Amino-
azolesa
1
listed. H and 13C NMR spectra were recorded with a Bruker AV-
1) LiOt-Bu, I2 , THF
MW at 100 °C (2 h)
300 spectrometer in CDCl3. NMR chemical shifts are reported in
X
X
N
1
ppm relative to CHCl3 (7.24 ppm for H and 77.0 ppm for 13C).
R
H
R
N
O
N
2) morpholine (2a)
MW at 100 °C (2 h)
High-resolution mass spectrometry was carried out at Mahidol Uni-
versity, Department of Chemistry Micro-Mass Facility.
4a–d
5a–d
(1 equiv)
Compounds 3a–l; General Procedure
Entry
Azole
Product
Yield
(%)b
To an oven-dried and N2-flushed 20 mL scintillation vial, equipped
with a magnetic stir bar, was added a mixture of benzoxazole 1
(2.00 mmol, 1.00 equiv), LiOt-Bu (0.48 g, 6.00 mmol, 3.00 equiv),
and I2 (0.76 g, 3.00 mmol, 1.50 equiv) in THF (4.00 mL, 0.50 M
concentration of substrate). After stirring at r.t. for 10 min, amine 2
(10.0 mmol, 5.00 equiv) was added, and the mixture stirred at r.t. for
an additional 1 h. Following completion of the reaction, deionized
H2O (10 mL) was added and the mixture was extracted with EtOAc
(2 × 15 mL). The combined organic layer was concentrated in vac-
uo, and the crude residue was purified by SiO2 column chromatog-
raphy to afford the benzoxazole derivative.
S
S
N
N
O
1
2
54
10
N
4a
4b
5a
S
N
S
N
O
N
5b
2-(Morpholin-4-yl)benzoxazole (3a)10a–e
Me
Me
Compound 3a was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and morpholine (2a) (0.87 g, 10.0 mmol). The crude residue
was purified by flash column chromatography (SiO2, hexane–
EtOAc, 4:1) to afford pure compound 3a (0.40 g, 98%) as a yellow-
orange solid.
1H NMR (300 MHz, CDCl3): δ = 7.41–7.38 (m, 1 H), 7.30–7.28 (m,
1 H), 7.20 (dt, J = 7.8, 1.2 Hz, 1 H), 7.06 (dt, J = 7.8, 1.2 Hz, 1 H),
3.86–3.83 (m, 4 H), 3.73–3.70 (m, 4 H).
N
N
N
O
3
4
33
N
N
4c
5c
O
O
Me
Me
Me
O
Me
O
N
N
N
N
N
O
19 (31c)
N
N
N
N
13C NMR (75 MHz, CDCl3): δ = 162.1, 148.7, 142.7, 124.1, 120.9,
Me
Me
116.4, 108.8, 66.2, 45.7.
HRMS (ESI): m/z [M + H]+ calcd for C11H13N2O2: 205.0977; found:
205.1001.
4d
5d
a Reaction conditions: azole 4 (2 mmol, 1 equiv), LiOt-Bu (3 equiv),
I2 (1.5 equiv), morpholine (2a) (5 equiv), THF (0.5 M soln of the
azole substrate).
2-(Piperidin-1-yl)benzoxazole (3b)10a–e
b Yield of isolated product.
Compound 3b was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and piperidine (2b) (0.85 g, 10.0 mmol). The crude residue
was purified by flash column chromatography (SiO2, hexane–
EtOAc, 4:1) to afford pure compound 3b (0.35 g, 87%) as a pale
yellow solid.
c Yield obtained after MW irradiation at 140 °C in DMF.
In summary, we have reported an efficient protocol for the
synthesis of azole derivatives bearing a nitrogen substitu-
ent at C-2, starting from simple azoles and nitrogen nu-
cleophiles using iodine and lithium tert-butoxide to
mediate carbon–nitrogen bond formation. This transfor-
mation can be carried out under an air atmosphere, or can
be performed conveniently using microwave irradiation,
demonstrating good scope and functional group tolerance.
1H NMR (300 MHz, CDCl3): δ = 7.37–7.35 (m, 1 H), 7.29–7.23 (m,
1 H), 7.16 (dt, J = 7.8, 1.2 Hz, 1 H), 7.00 (dt, J = 7.8, 1.2 Hz, 1 H),
3.67 (br s, 4 H), 1.69 (br s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 162.4, 148.6, 143.3, 123.8, 120.2,
115.9, 108.5, 46.5, 25.2, 24.0.
HRMS (ESI): m/z [M + H]+ calcd for C12H15N2O: 203.1184; found:
203.1210.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 936–942

940
S. Yotphan et al.
PAPER
2-(Pyrrolidin-1-yl)benzoxazole (3c)10a,c,d
1H NMR (300 MHz, CDCl3): δ = 7.40–7.38 (m, 1 H), 7.30–7.27 (m,
1 H), 7.22–7.17 (m, 1 H), 7.09–7.03 (m, 1 H), 3.71–3.68 (m, 4 H),
3.60–3.57 (m, 4 H), 1.51 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 162.0, 154.6, 148.7, 142.8, 124.1,
120.9, 116.4, 108.8, 80.4, 45.4, 28.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H22N3O3: 304.1661; found:
304.1655.
Compound 3c was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and pyrrolidine (2c) (0.71 g, 10.0 mmol). The crude residue
was purified by flash column chromatography (SiO2, hexane–
EtOAc, 4:1) to afford pure compound 3c (0.30 g, 80%) as an off-
white solid.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.36 (m, 1 H), 7.29–7.25 (m,
1 H), 7.16 (dt, J = 7.8, 1.2 Hz, 1 H), 7.00 (dt, J = 7.8, 1.2 Hz, 1 H),
3.70–3.64 (m, 4 H), 2.07–2.03 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 161.0, 149.0, 143.6, 123.8, 120.0,
115.9, 108.5, 47.4, 25.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H13N2O: 189.1028; found:
189.1052.
N-Cyclohexylbenzoxazole-2-amine (3h)14
Compound 3h was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and cyclohexylamine (2h) (1.00 g, 10.0 mmol). The crude
residue was purified by flash column chromatography (SiO2, hex-
ane–EtOAc, 4:1) to afford pure compound 3h (0.26 g, 61%) as an
orange-brown solid.
N,N-Diethylbenzoxazole-2-amine (3d)10a–e
1H NMR (300 MHz, CDCl3): δ = 7.37 (d, J = 7.8 Hz, 1 H), 7.25 (d,
J = 7.8 Hz, 1 H), 7.16 (dt, J = 7.8, 1.2 Hz, 1 H), 7.03 (dt, J = 7.8, 1.2
Hz, 1 H), 5.36 (br s, 1 H), 3.76 (br s, 1 H), 2.17–2.13 (m, 2 H), 1.83–
1.76 (m, 2 H), 1.70–1.64 (m, 1 H), 1.49–1.21 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 161.5, 148.3, 143.0, 123.8, 120.5,
116.0, 108.6, 52.0, 33.4, 25.4, 24.7.
Compound 3d was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and diethylamine (2d) (0.73 g, 10.0 mmol). The crude resi-
due was purified by flash column chromatography (SiO2, hexane–
EtOAc, 4:1) to afford pure compound 3d (0.35 g, 92%) as a yellow
oil.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.36 (m, 1 H), 7.28–7.24 (m,
1 H), 7.16 (dt, J = 7.8, 1.2 Hz, 1 H), 6.99 (dt, J = 7.8, 1.2 Hz, 1 H),
3.60 (q, J = 7.2 Hz, 4 H), 1.30 (t, J = 7.2 Hz, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O: 217.1341; found:
217.1337.
N-Benzylbenzoxazole-2-amine (3i)14
13C NMR (75 MHz, CDCl3): δ = 162.2, 148.8, 143.6, 123.7, 119.9,
Compound 3i was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and benzylamine (2i) (1.07 g, 10.0 mmol). The crude residue
was purified by flash column chromatography (SiO2, hexane–
EtOAc, 4:1) to afford pure compound 3i (0.20 g, 45%) as a pale yel-
low solid.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.20 (m, 6 H), 7.19–7.15 (m,
1 H), 7.09 (dt, J = 7.8, 1.2 Hz, 1 H), 6.96 (dt, J = 7.8, 1.2 Hz, 1 H),
5.72 (br s, 1 H), 4.60 (s, 2 H).
115.8, 108.4, 42.9, 13.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H15N2O: 191.1184; found:
191.1213.
2-(Thiomorpholin-4-yl)benzoxazole (3e)
Compound 3e was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and thiomorpholine (2e) (1.03 g, 10.0 mmol). The crude res-
idue was purified by flash column chromatography (SiO2, hexane–
EtOAc, 4:1) to afford pure compound 3e (0.41 g, 94%) as a yellow
solid; mp 90.2–92.0 °C.
13C NMR (75 MHz, CDCl3): δ = 162.0, 148.5, 142.8, 137.7, 128.8,
127.8, 127.6, 123.9, 120.9, 116.4, 108.8, 47.1.
IR (film): 3436, 2921, 1655, 1578, 1460, 1401, 1263, 1149, 969,
879, 796, 754, 741, 570, 425 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.30–7.27 (m, 1 H), 7.19–7.17 (m,
1 H), 7.10 (dt, J = 7.8, 1.2 Hz, 1 H), 6.95 (dt, J = 7.8, 1.2 Hz, 1 H),
3.94–3.89 (m, 4 H), 2.68–2.64 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 161.7, 148.7, 142.9, 124.0, 120.7,
116.3, 108.7, 48.0, 26.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2O: 225.1028; found:
225.1025.
N-(Quinolin-8-yl)benzoxazol-2-amine (3j)
Compound 3j was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and 8-aminoquinoline (2j) (1.44 g, 10.0 mmol). The crude
residue was purified by flash column chromatography (SiO2, hex-
ane–EtOAc, 4:1) to afford pure compound 3j (0.35 g, 66%) as a pale
yellow solid; mp 127.2–128.1 °C.
HRMS (ESI): m/z [M + H]+ calcd for C11H13N2OS: 221.0749;
found: 221.0745.
IR (film): 3446, 3358, 3061, 1642, 1577, 1531, 1456, 1334, 1240,
1165, 1003, 974, 822, 787, 737, 634, 587, 422 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.61 (s, 1 H), 8.76–8.74 (m, 1 H),
8.65 (dd, J = 7.8, 1.2 Hz, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.56–7.48
(m, 2 H), 7.40–7.36 (m, 2 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.17 (dt,
J = 7.5, 1.2 Hz, 1 H), 7.07 (dt, J = 7.5, 1.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 157.5, 148.2, 147.7, 142.8, 138.1,
136.3, 134.2, 128.1, 127.5, 124.1, 122.1, 121.8, 120.3, 117.6, 113.9,
109.1.
2-(4-Methylpiperazin-1-yl)benzoxazole (3f)10a–c
Compound 3f was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and 1-methylpiperazine (2f) (1.00 g, 10.0 mmol). The crude
residue was purified by flash column chromatography (SiO2,
EtOAc–MeOH, 4:1) to afford pure compound 3f (0.40 g, 93%) as a
brown oil.
1H NMR (300 MHz, CDCl3): δ = 7.29 (d, J = 7.5 Hz, 1 H), 7.18 (d,
J = 7.8 Hz, 1 H), 7.09 (dt, J = 7.5, 0.9 Hz, 1 H), 6.95 (dt, J = 7.8, 0.9
Hz, 1 H), 3.65 (t, J = 5.1 Hz, 4 H), 2.44 (t, J = 5.1 Hz, 4 H), 2.27 (s,
3 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H12N3O: 262.0980; found:
262.0976.
13C NMR (75 MHz, CDCl3): δ = 162.0, 148.6, 142.9, 123.8, 120.5,
116.1, 108.6, 54.0, 46.1, 45.3.
5-Chloro-2-(morpholin-4-yl)benzoxazole (3k)10a
Compound 3k was prepared from 5-chlorobenzoxazole (1b) (0.31
g, 2.00 mmol) and morpholine (2a) (0.87 g, 10.0 mmol). The crude
residue was purified by flash column chromatography (SiO2, hex-
ane–EtOAc, 4:1) to afford pure compound 3k (0.30 g, 64%) as a
pale yellow solid.
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 2.1 Hz, 1 H), 7.09 (d,
J = 8.4 Hz, 1 H), 6.93 (dd, J = 8.4, 2.1 Hz, 1 H), 3.77–3.73 (m, 4 H),
3.63–3.60 (m, 4 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H16N3O: 218.1293; found:
218.1283.
tert-Butyl 4-(Benzoxazol-2-yl)piperazine-1-carboxylate (3g)10d
Compound 3g was prepared from benzoxazole (1a) (0.24 g, 2.00
mmol) and tert-butyl piperazine-1-carboxylate (2g) (1.86 g, 10.0
mmol). The crude residue was purified by flash column chromatog-
raphy (SiO2, hexane–EtOAc, 4:1) to afford pure compound 3g (0.50
g, 83%) as a yellow solid.
Synthesis 2013, 45, 936–942
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of N-Substituted 2-Aminoazoles
941
13C NMR (75 MHz, CDCl3): δ = 162.8, 147.3, 144.3, 129.4, 120.8,
116.6, 109.3, 66.1, 45.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H12ClN2O2: 239.0587;
found: 239.0583.
1-Methyl-2-(morpholin-4-yl)benzimidazole (5c)16
Compound 5c was prepared from 1-methylbenzimidazole (4c) (g,
2.00 mmol) and morpholine (2a) (0.87 g, 10.0 mmol) via micro-
wave irradiation in THF at 100 °C. The crude residue was purified
by flash column chromatography (SiO2, EtOAc–MeOH, 9:1) to af-
ford pure compound 5c (0.14 g, 33%) as an off-white solid.
5-Chloro-2-(piperidin-1-yl)benzoxazole (3l)10d
1H NMR (300 MHz, CDCl3): δ = 7.64–7.62 (m, 1 H), 7.29–7.28 (m,
1 H), 7.24–7.22 (m, 2 H), 3.93 (t, J = 4.8 Hz, 4 H), 3.65 (s, 3 H),
3.35 (t, J = 4.8 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ = 157.6, 141.3, 135.7, 121.8, 121.4,
118.2, 108.4, 66.6, 50.6, 30.4.
HRMS (ESI): m/z [M + H]+ calcd for C1H16N3O: 218.1293; found:
218.1286.
Compound 3l was prepared from 5-chlorobenzoxazole (1b) (0.31 g,
2.00 mmol) and piperidine (2b) (0.85 g, 10.0 mmol). The crude res-
idue was purified by flash column chromatography (SiO2, hexane–
EtOAc, 4:1) to afford pure compound 3l (0.31 g, 65%) as a pale yel-
low solid.
1H NMR (300 MHz, CDCl3): δ = 7.27 (d, J = 2.1 Hz, 1 H), 7.09 (d,
J = 8.4 Hz, 1 H), 6.92 (dd, J = 8.4, 2.1 Hz, 1 H), 3.62 (br s, 4 H),
1.67 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 163.0, 147.2, 144.8, 129.0, 119.8,
115.9, 108.9, 46.2, 25.1, 23.8.
1,3,7-Trimethyl-8-(morpholin-4-yl)-3,7-dihydro-1H-purine-
2,5-dione (5d)17
Compound 5d was prepared from caffeine (4d) (0.39 g, 2.00 mmol)
and morpholine (2a) (0.87 g, 10.0 mmol) via microwave irradiation
in DMF at 140 °C. The crude residue was purified by flash column
chromatography (SiO2, EtOAc) to afford pure compound 5d (0.18
g, 31%) as a white solid; mp 160.9–161.7 °C.
HRMS (ESI): m/z [M + H]+ calcd for C11H12ClN2O: 237.0795;
found: 237.0793.
Compounds 5a–d; General Procedure
To an oven-dried and N2-flushed 35 mL microwave vial equipped
with a magnetic stir bar, was added a mixture of azole 4 (2.00 mmol,
1.00 equiv), LiOt-Bu (0.48 g, 6.00 mmol, 3.00 equiv), and I2 (0.76
g, 3.00 mmol, 1.50 equiv) in THF or DMF (4.00 mL, 0.50 M con-
centration of substrate). After stirring at r.t. for 1 min, the vial was
capped and the mixture was heated at 100 °C or 140 °C for 2 h in a
single mode microwave reactor. Morpholine (2a) (0.87 g, 10.0
mmol, 5.00 equiv) was added and the mixture was then heated in the
microwave reactor at 100 °C or 140 °C for an additional 2 h. After
the reaction was complete, deionized H2O (10 mL) was added, and
the mixture was extracted with EtOAc (2 × 15 mL). The combined
organic layer was concentrated in vacuo, and the crude residue was
purified by SiO2 column chromatography to afford the desired prod-
uct.
IR (film): 3447, 2964, 2865, 1702, 1660, 1513, 1444, 1284, 1215,
1119, 971, 912, 749, 519 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.79 (t, J = 4.7 Hz, 4 H), 3.70 (s,
3 H), 3.46 (s, 3 H), 3.33 (s, 3 H), 3.20 (t, J = 4.8 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ = 155.9, 155.0, 151.7, 147.3, 105.5,
66.3, 50.0, 32.4, 29.7, 27.8.
HRMS (ESI): m/z [M + H]+ calcd for C12H18N5O3: 280.1410; found:
280.1405.
Acknowledgment
This work was supported financially by the Thailand Research Fund
(TRF Grant MRG5580039), the Faculty of Science, Mahidol Uni-
versity, and Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Commission on Higher Education, Ministry of
Education. The authors also thank the Department of Chemistry and
Center of Instrumental Facility (CIF) at the Faculty of Science, Ma-
hidol University for assistance with experiments.
2-(Morpholin-4-yl)benzothiazole (5a)15
Compound 5a was prepared from benzothiazole (4a) (0.27 g, 2.00
mmol) and morpholine (2a) (0.87 g, 10.0 mmol) via microwave ir-
radiation in THF at 100 °C. The crude residue was purified by flash
column chromatography (SiO2, hexane–EtOAc, 3:1) to afford pure
compound 5a (0.24 g, 54%) as an off-white solid.
1H NMR (300 MHz, CDCl3): δ = 7.54–7.48 (m, 2 H), 7.22 (dt,
J = 7.8, 1.2 Hz, 1 H), 7.01 (dt, J = 7.8, 1.2 Hz, 1 H), 3.76–3.72 (m,
4 H), 3.54–3.41 (m, 4 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
13C NMR (75 MHz, CDCl3): δ = 168.9, 152.4, 130.5, 126.0, 121.6,
120.7, 119.3, 66.2, 48.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H13N2OS: 221.0749;
found: 221.0740.
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Synthesis 2013, 45, 936–942
© Georg Thieme Verlag Stuttgart · New York