A rapid method for the preparation of 2-substituted oxazolo[4,5-b]pyridines using microwave-assisted direct condensation reactions

Article abstract of DOI:10.1016/j.tetlet.2007.01.161

The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assisted heating is a fast method for producing libraries based on fused 2-substituted oxazolo[4,5-b]pyridines in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2007.01.161

Tetrahedron Letters 48 (2007) 2295–2298
A rapid method for the preparation of 2-substituted
oxazolo[4,5-b]pyridines using microwave-assisted
direct condensation reactions
Mikko J. Myllym a¨ ki and Ari M. P. Koskinen*
Laboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland
Received 20 November 2006; revised 23 January 2007; accepted 31 January 2007
Available online 3 February 2007
Abstract—The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assisted heating is
a fast method for producing libraries based on fused 2-substituted oxazolo[4,5-b]pyridines in moderate to good yields.
ꢀ
2007 Elsevier Ltd. All rights reserved.
Oxazoles are rigid and stable structures often found in
natural products and widely used in medicinal chemis-
try. 2-Phenylbenzoxazoles have traditionally been syn-
thesized by heating amino alcohols with benzoic acids
N
N
R
O
1
1
in the presence of polyphosphoric acid or trimethylsilyl
2
polyphosphate as dehydrating reagents. Activated acids
Figure 1.
such as orthoesters and acid anhydrides have been used
in the preparation of 2-phenyl-pyrido- and pyrimidino-
oxazoles. Our interest lay in the preparation of
3
satisfactory yield (83%). The same method was then
applied for 2-amino-3-hydroxypyridine 4 giving com-
pound 1a in 58% yield. Scheme 1.
2
-phenyloxazolo[4,5-b]pyridines (1, Fig. 1) with different
substituents on the phenyl ring. Zhuravlev presented a
convenient method to prepare these compounds using
palladium catalyzed C-2 arylation of oxazolo[4,5-b]pyr-
Microwave irradiation has previously been applied in
6
4
condensation reactions by Bougrin et al. and we
idine. We particularly wanted to find a rapid way to
decided to apply this method for the preparation of
prepare these compounds via direct condensations of
benzoic acids as starting materials.
ꢀ
1a. The reactions were carried out in a CEM Discover
microwave reactor with varying parameters (Table 1).
Reaction times were shortened dramatically, and the
best results were obtained without solvent, catalyst or
water scavenger with 2 min hold time at 250 ꢁC, giving
We first explored the method published by Terashima
5
and Ishii in which boric acid is used as the catalyst to
carry out the condensations. Refluxing 3-hydroxy-
benzoic acid 2a and 2-aminophenol 3 with 100 mol %
of boric acid in m-xylene for 18 h with a Dean–Stark
apparatus for water removal gave only a 13% yield of
compound 5. Addition of Na SO to the reaction mix-
1a in 77% isolated yield (entry 7).
We applied the optimized reaction conditions to differ-
ent aromatic and aliphatic acids and the results of
screening are shown in Table 2.
2
4
ture to scavenge the water produced in the reaction
chemically increased the yield to 37%. Eventually, carry-
ing out the reaction at higher temperature (200 ꢁC) and
under pressure (50 psi) in an autoclave overnight gave a
For some acids the selected temperature (250 ꢁC) was
too high and resulted in low yields. These reactions were
tested at lower temperature, improving the yield in sev-
eral cases (entries 3, 4, 6, 7, 8). Some low-yielding reac-
tions were also repeated in the presence of boric acid,
since it has been reported to catalyze the condensation
under normal heating reactions. Surprisingly, boric acid
Keywords: Direct condensation; Oxazolo[4,5-b]pyridine; Microwaves.
*
Corresponding author. Tel.: +358 9 451 2526; fax: +358 9 451
538; e-mail: ari.koskinen@hut.fi
2
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.161

2296
M. J. Myllym a¨ ki, A. M. P. Koskinen / Tetrahedron Letters 48 (2007) 2295–2298
O
OH
X
NH2
HO
X
N
A, B or C
OH
OH
O
2
a
3, X= CH
, X= N
1
a, X= N
4
5, X= CH
Scheme 1. Reagents and conditions: 2a (415 mg, 3 mmol, 100 mol %), 3 (330 mg, 3 mmol, 100 mol %), boric acid (185 mg, 3 mmol, 100 mol %),
xylene (30 mL). Methods and yields: (A), reflux with a Dean–Stark trap, 18 h, 13% for 5; (B), Na SO , reflux 18 h, 37% for 5; (C), autoclave, 200 ꢁC,
0 psi, 18 h, 83% for 5 and 58% for 1a.
2
4
5
Table 1. Optimization of the condensation reaction of 3-hydroxybenzoic acid 2a and 2-aminopyridin-3-ol 4
O
OH
OH
N
NH2
N
MW
N
O
HO
OH
2a
4
1a
a
b
Entry
Solvent
Temperature and power
Other reagents
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
m-Xylene
Toluene
—
—
—
—
—
—
200 ꢁC/300 W
160 ꢁC/1st 150 W, 2nd 300 W
200 ꢁC/150 W
200 ꢁC/300 W
200 ꢁC/200 W
250 ꢁC/300 W
250 ꢁC/300 W
250 ꢁC/300 W
H
H
H
—
—
—
—
—
3
3
3
BO
BO
BO
3
3
3
, Na
, Na
, Na
2
2
2
SO
SO
SO
4
4
4
15
2 · 15
15
15
15
1
25
0
c
13
67
40
69
77
12
2
10
a
b
c
Hold time is the time at a specific temperature. Ramp time varied from 3 to 10 min.
Isolated yields.
Only the starting materials were detected.
Table 2. The condensation reactions of 2-amino-3-pyridine 4 with acids 2
N
NH2
N
N
R
2
a-j (1.0 eq)
MW
O
OH
4
1
a
Entry
1
Acid
Time (min)
2
T (ꢁC)
Product
Yield (%)
O
OH
N
OH
N
O
2a
250
1a
1b
1c
1d
1e
77
HO
O
O
N
N
N
O
2
3
4
5
2b
2c
2d
2e
2
250
170
170
250
60 (60)
Trace (44)
67
HO
HO
N
O
4 · 2
OMe
OMe
Cl
O
O
Cl
N
N
N
O
3
3
HO
HO
N
O
56
Cl
Cl

M. J. Myllym a¨ ki, A. M. P. Koskinen / Tetrahedron Letters 48 (2007) 2295–2298
2297
Table 2 (continued)
a
Entry
Acid
Time (min)
2
T (ꢁC)
Product
Yield (%)
O
N
N
O
6
2f
170
1f
82
HO
O
O
N
N
N
O
7
HO
HO
2g
2h
2
4
170
170
1g
1h
Trace (18)
58 (40)
CN
CN
N
O
8
9
CF3
CF
3
O
O
N
N
N
O
N
O
2i
2j
12
2
250
250
1i
1j
85 (51)
34 (20)
HO
Me
1
0
Me
OH
a
Isolated yields. Yields in parentheses are for reactions using 100 mol % of boric acid.
was found both to increase the yield in some cases
Microwave-assisted reactions were carried out using a
CEM Discover microwave reactor. A glass tube
(10 mL) was loaded with 2a (110 mg, 1.0 mmol) and 4
TM
(
entries 3, 7) and also to decrease it in others (entries
, 9, 10).
8
(138 mg, 1.0 mmol) and placed into the microwave reac-
When 2- and 4-hydroxy-, 4-dimethylamino-, 2-chloro-,
-acetyl-, and 2-, 3- and 4-nitrobenzoic acids were
subjected to the same reaction conditions, none of the
desired products were obtained. The main products
isolated from the reactions of 4 with 2-, and 4-hydroxy-
tor and irradiated (initially 300 W) at 250 ꢁC for 2 min.
After cooling to rt the residual tan solid was dissolved in
EtOAc (10 mL). The mixture was evaporated close to
dryness and purified by flash chromatography and
recrystallization (EtOAc–Hex, 1:1) giving 1a (165 mg,
4
and 4-dimethylaminobenzoic acid were the decarbox-
77%) as a white solid: mp 203–204 ꢁC, R (EtOAc) 0.5;
f
1
1
ylated products (phenol or N,N-dimethylaniline,
H
H NMR (DMSO, 400 MHz) 10.02 (s, 1H), 8.55 (dd,
NMR). This implies that the presence of a strong elec-
tron donor in the 2- or 4-position of the carboxylic acid
results in decarboxylation rather than condensation.
With the remaining acids there was no clear main
product, only a tar-like material or recovered starting
materials.
1H, J = 4.9, 1.4 Hz), 8.24 (dd, 1H, J = 8.2, 1.4 Hz),
7.69 (app dt, 1H, J = 7.7, 1.2 Hz), 7.64 (t, 1H,
J = 2.0 Hz), 7.48–7.43 (m, 2H), 7.08 (ddd, 1H, J = 8.2,
2.5, 0.9 Hz).
Acknowledgement
In summary, 2-substituted oxazolo[4,5-b]pyridines are
easily produced by microwave-assisted direct condensa-
tion. The reactions are fast and operationally simple
The National Technology Agency, TEKES, is gratefully
acknowledged for funding.
(
solvent-free conditions, easy work-up).
General procedure. The synthesis of 1a via method C and
Supplementary data
MW-assisted reaction is presented to illustrate the pro-
TM
cedures. Method C: To a 100 mL steel Parr pressure
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
vessel, 3-hydroxybenzoic acid 2a (415 mg, 3.0 mmol),
2
-aminopyridin-3-ol 4 (330 mg, 3.0 mmol), H BO
3 3
2007.01.161.
(
185 mg, 3.0 mmol), Na SO4 (4 g, 28 mmol) and m-
2
xylene (30 mL) were added. The vessel was closed and
heated overnight at 200 ꢁC. The pressure inside the ves-
sel was 50 psi. The mixture was cooled to rt, poured into
References and notes
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3
1
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dried with Na SO , filtered and evaporated. The result-
2
4
ing tan solid was recrystallized from EtOAc–Hex (1:1,
0 mL) to yield 1a (370 mg, 58%) as a white solid.
5

2298
M. J. Myllym a¨ ki, A. M. P. Koskinen / Tetrahedron Letters 48 (2007) 2295–2298
2
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