A general and efficient synthesis of 2-substituted oxazolopyridines

Article abstract of DOI:10.1055/s-0028-1088149

Starting from commercially available halonitropyridines and haloaminopyridines, 2-substituted-oxazolo[5,4-b]pyridines, and 2-aryl-oxazolo[4,5-b]pyridines were synthesized in good yields by using a Cu(I)-mediated cyclization of halopyridylamides as a key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088149

1172
LETTER
A General and Efficient Synthesis of 2-Substituted Oxazolopyridines
S
ynthesis of 2-Sub
a
stituted O
x
n
azolopyridines Xu,a Xianfang Xu,b Zongliang Liu,a Li-Ping Sun,*a Qidong Youa
a
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. of China
Fax +86(25)83271351; E-mail: chslp@cpu.edu.cn
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. of China
b
Received 21 November 2008
Me
N
Abstract: Starting from commercially available halonitropyridines
and haloaminopyridines, 2-substituted-oxazolo[5,4-b]pyridines,
and 2-aryl-oxazolo[4,5-b]pyridines were synthesized in good yields
by using a Cu(I)-mediated cyclization of halopyridylamides as a
key step.
N
Me
O
N
N
N
O
N
N
N
H
H
Key words: copper-catalyzed cyclization, synthesis, heterocycles,
oxazolo[5,4-b]pyridines, oxazolo[4,5-b]pyridines
histamine H3-antagonist
factor IIa/Xa inhibitor
Cl
Figure 1 Selected examples of bioactive oxazolopyridines
Oxazoles are stable heterocyclic scaffolds often found in
natural products and widely used in medicinal chemistry.
Benzoxazoles are important heterocycles from different
areas of biologically activities as targets in drug discov-
ery.1 As an analogue of benzoxazole, oxazolopyridines,
such as oxazolo[5,4-b]pyridine and oxazolo[4,5-b]pyri-
dine, have also been reported to have many biological
properties such as antimicrobial,2a anticancer,2b anti-
inflammatory,2c analgesic,2d anticoagulant agents,2e and
histamine H3-antagonists (Figure 1).2f However, there are
only a few synthetic routes for the preparation of oxazol-
opyridines. To date, the most common method employs
aminohydroxypyridines as substrates, which condensed
with carboxylic acid derivatives under strong acidic con-
ditions, such as boric acid, polyphosphoric acid, and aro-
matic carboxylic acids at high reaction temperature.3
Another approach uses the reaction of haloaminopy-
ridines with polyphosphoric acid or trimethylsilylpoly-
phosphate ester.4 In most cases, these procedures suffer
from one or more limitations such as harsh reaction con-
ditions, long reaction time, low yields of the products, and
co-occurrence of several side reactions.3,4 Hence, the de-
velopment of flexible, efficient, and simple methodology
is still needed for the synthesis of 2-substituted oxazolo-
pyridines.
Commercially available halonitro- or haloaminopyridines
were chosen as starting materials for the synthesis of 2-
substituted oxazolo[5,4-b]pyridines 3. The halonitro-
pyridines were reduced under SnCl2·2H2O to give the 2-
chloro-3-aminopyridine 1. As illustrated in Scheme 1,
precursors 2 were readily obtained by the acylation of 1
with aromatic acid chloride. Our investigation then fo-
cused on the intramolecular C–O cyclization reaction of
chloropyridylamides 2 to give oxazolopyridines 3. Initial
experiments were carried out on a model substrate N-(2-
chloropyridin-3-yl)benzamide (2a). The catalytic system
CuI, 1,10-phenanthroline, and Cs2CO3 was used to gener-
ate 3a in low conversion of 2a. For copper-catalyzed C–O
and C–N bond-formation reaction, the ligand bound to
copper has an important role which can alter both the sol-
ubility and the stability of copper–ligand complex.6 Sev-
eral attempts were performed by screening different
ligands. The use of CuI (5 mol%), 1,10-phenanthroline
(10 mol%), and K2CO3 (2.0 equiv) in toluene refluxing for
six hours under nitrogen atmosphere afforded 3a in 55%
yield. Increasing the amount of base and ligand did not
lead to an improvement of product yield. The use of N,N¢-
dimethylethylenediamine (10 mol%) with CuI (5 mol%),
and K2CO3 (2.0 equiv) in toluene over six hours resulted
in 3a in a slightly better yield (75%). The use of ethylene-
diamine did not work well. Other different reaction pa-
rameters such as solvent, base amount, and ligand amount
were also performed. Finally the optimal conditions for
the ring closure of 2 were to conduct the reaction using
CuI (5 mol%), N,N¢-dimethylethylenediamine (10 mol%),
and K2CO3 (2.0 equiv) in refluxing toluene over 12 hours
under nitrogen atmosphere.
Copper-mediated C–O and C–N bond formation is an im-
portant transformation and has been widely used in the
synthesis of heterocycles.6 Recently Glorius described a
one-pot synthesis of oxazolo[4,5-b]pyridines by using
Cu-catalyzed domino C–N and C–O cross-coupling of
primary amide with dihalopyridines.5 In connection with
our studies on diversity-oriented synthesis of bioactive
heterocyclic compounds, herein we report a practical and
efficient method for the formation of 2-substituted oxazo-
lo[5,4-b]pyridines and oxazolo[4,5-b]pyridines.
With the optimized conditions, we synthesized a number
of 2-substituted oxazolo[5,4-b]pyridines 3a–n in moder-
ate or good yields (Table 1). However, aliphatic- or pyri-
dine-substituted amide gave low yields (Table 1, entries
SYNLETT 2009, No. 7, pp 1172–1174
x
x.
x
x.
2
0
0
9
Advanced online publication: 20.03.2009
DOI: 10.1055/s-0028-1088149; Art ID: W18108ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Substituted Oxazolopyridines
1173
Br
Me
H
N
Me
Br
NH2
RCOCl, DMAP
R
O
N
O
RCOCl, Py
CuI, ligand
R
CH2CI2
0 °C to r.t.
NH2
N
CH2CI2
0 °C to r.t.
O
N
N
H
base
R
Cl
N
N
Cl
N
4
5
1
2
3
Me
CuI (5 mol%), 1,10-Phen (10 mol%)
Cs2CO3 (2.0 equiv), THF, 24 h
O
N
Scheme 1 Synthetic route of 2-substituted oxazolo[5,4-b]pyridines 3
R
N
12 and 13). Furthermore, halo-substituted chloropyridyl
benzamides could help the cyclization to afford corre-
sponding products in good yields (Table 1, entries 2, 7, 8,
and 10). In addition, replacement of the 4-substituted
group of benzene ring with meta or ortho groups de-
creased the product yields (Table 1, entries 2, 3, 7–9).8
6
Scheme 2 Synthetic route to oxazolo[4,5-b]pyridines 6
Table 2 Synthesis of Oxazolo[4,5-b]pyridines 6
Entry
R
Product9
Yield (%)a
Table 1 Synthesis of 2-Substituted Oxazolo[5,4-b]pyridines 3a
1
2
3
4
5
6
Ph
6a
6b
6c
6d
6e
6f
90
94
88
90
89
86
Entry
1
R
Product9
3a
Yield (%)b
4-MeOC6H4
4-IC6H4
4-t-BuC6H4
4-BrC6H4
naphthyl
Ph
75
91
73
61
61
66
78
74
63
76
55
28
35
2
4-ClC6H4
4-MeOC6H4
4-t-BuC6H4
4-i-BuC6H4
4-i-PrC6H4
3-ClC6H4
2-ClC6H4
2-MeOC6H4
2,3,4-F3C6H4
3,4,5-(MeO)3C6H4
2-pyridyl
Et
3b
3c
3
4
3d
3e
5
a Isolated yields.
6
3f
In conclusion, we have developed an efficient and appli-
cable protocol for the synthesis of 2-substituted oxazo-
lo[5,4-b]pyridines and oxazolo[4,5-b]pyridines by the use
of a copper-catalyzed cyclization reaction. Introduction of
other functional groups at the C-2 position could be
achieved by selecting the appropriate carboxylic acids or
acyl chlorides. This strategy could also be adapted for the
synthesis of other bioactive heterocycles.
7
3g
8
3h
3i
9
10
11
12
13
3j
3k
3l
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
3m
a Reaction conditions of cyclization: CuI (5 mol%), DMEDA (10
mol%), and K2CO3 (2.0 equiv) in refluxing toluene.
b Isolated yield.
Acknowledgment
This work was supported by the Natural Science Foundation of
We also developed a Cu-mediated synthetic route to oxa- China (20742003) and was partially supported by a research grant
provided by China Pharmaceutical University (211083).
zolo[4,5-b]pyridines under similar reaction conditions.
Scheme 2 illustrates the synthesis of oxazolo[4,5-b]py-
ridines 6 starting from 2-amino-3-bromo-5-methyl-pyri-
dine 4. The key step was the ring-closure reaction of
bromopyridylamides 5, which was obtained from the acyl-
ation reaction of 4. Comparing to those of chloropyridyl-
References and Notes
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of 1,10-phenanthroline as the ligand in excellent yields,
and high reaction temperature was not required. The bro-
mide precursor were more active than chloride precursors,
which were consistent with those reported in literature.7
The reaction conditions could tolerate both electron-
donating and electron-withdrawing substituents on phenyl
ring of pyridylamide 5 (Table 2, entries 2–5).8
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Synlett 2009, No. 7, 1172–1174 © Thieme Stuttgart · New York

1174
D. Xu et al.
LETTER
further purified by flash chromatography over silica gel
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column with PE–EtOAc (5:1) to give the pure product 3a.
(9) Selected Spectral Data
Compound 3a: mp 101–102 °C. Rf = 0.55 (EtOAc–PE, 1:2).
IR (KBr): 2913, 1617, 1544 cm–1. 1H NMR (300 MHz,
CDCl3): d = 8.38 (dd, J = 5.1, 1.5 Hz, 1 H), 8.34 (d, J = 1.5
Hz, 1 H), 8.34 (d, J = 2.1 Hz, 1 H), 8.10 (dd, J = 7.8, 1.5 Hz,
1 H), 7.55–7.62 (m, 3 H), 7.36–7.41 (m, 1 H). MS (EI):
m/z = 196 [M]+. Anal. Calcd for C12H8N2O: C, 73.46; H,
4.11; N, 14.28. Found: C, 73.46; H, 4.43; N, 14.18.
Compound 3i: mp 79–81 °C. Rf = 0.38 (EtOAc–PE, 1:2). IR
(KBr): 2924, 1602, 1523 cm–1. 1H NMR (300 MHz, CDCl3):
d = 8.35 (dd, J = 4.2, 1.5 Hz, 1 H), 8.21 (dd, J = 7.8, 1.5 Hz,
1 H), 8.12 (dd, J = 7.8, 1.5 Hz, 1 H), 7.53–7.56 (m, 1 H),
7.32–7.37 (m, 1 H), 7.10–7.16 (m, 2 H), 4.05 (s, 3 H). MS
(EI): m/z = 226 [M]+. Anal. Calcd for C13H10N2O2: C, 69.02;
H, 4.46; N, 12.38. Found: C, 68.67; H, 4.34; N, 12.38.
Compound 3k: mp 172–174 °C. Rf = 0.42 (EtOAc–PE, 1:2).
IR (KBr): 1496, 1620, 1223 cm–1. 1H NMR (300 MHz,
CDCl3): d = 8.34 (dd, J = 4.5, 1.5 Hz, 1 H), 8.05 (dd, J = 7.8,
1.5 Hz, 1 H), 7.54 (s, 2 H), 7.33–7.37 (m, 1 H), 4.04 (s, 9 H).
MS (EI): m/z = 286 [M]+. Anal. Calcd for C15H14N2O4: C,
62.93; H, 4.93; N, 9.79; Found: C, 63.12; H, 4.74; N, 9.78.
Compound 6a: mp 163–164 °C. Rf = 0.38 (EtOAc–PE, 1:2).
IR (KBr): 2920, 1670, 1580 cm–1. 1H NMR (300 MHz,
CDCl3): d = 8.56 (s, 1 H), 8.46 (dd, J = 1.5, 7.2 Hz, 2 H),
7.81 (s, 1 H), 7.75–7.65 (m, 3 H), 2.65 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 165.1, 154.4, 147.3, 132.3, 130.6, 129.0,
128.0, 126.7, 118.5, 18.9. ESI-MS: m/z = 211 [M+ + 1].
Anal. Calcd for C13H10N2O: C, 74.27; H, 4.79; N, 13.33.
Found: C, 74.05; H, 4.77; N, 13.28.
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D.; Sliwa, H. Synth. Commun. 1992, 22, 2891.
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(8) Typical Procedure for the Synthesis and Purification of
3a
Compound 6b: mp 165–167 °C. Rf = 0.35 (EtOAc–PE, 1:2).
IR (KBr): 2918, 1620, 1550 cm–1.1H NMR (300 MHz,
CDCl3): d = 8.57 (s, 1 H), 8.32 (d, J = 8.4 Hz, 2 H), 8.01 (d,
J = 8.3 Hz, 2 H), 7.84 (s, 1 H), 3.95 (s, 1 H), 2.64 (s, 3 H).
ESI-MS: m/z = 241 [M+ + 1]. Anal. Calcd for C13H10N2O: C,
69.99; H, 5.03; N, 11.66. Found: C, 69.78; H, 4.98; N, 11.69.
Compound 6c: mp 193–194 °C. Rf = 0.32 (EtOAc–PE, 1:2).
IR (KBr): 2918, 1610, 1560 cm–1.1H NMR (300 MHz,
CDCl3): d = 8.59 (s, 1 H), 8.16 (d, J = 8.7 Hz, 2 H), 8.04 (d,
J = 8.1 Hz, 2 H), 7.84 (s, 1 H), 2.64 (s, 3 H). 13C NMR (75
Hz, CDCl3): d = 164.3, 154.2, 147.7, 143.3, 138.4, 130.9,
129.3, 126.2, 118.6, 99.5, 18.9. ESI-MS: m/z = 337 [M+ + 1].
Anal. Calcd for C13H9IN2O: C, 46.45; H, 2.70, N, 8.33.
Found: C, 46.53; H, 2.75; N, 8.40.
To a mixture of 2a (2.0 mmol), CuI (0.1 mmol), N,N¢-
dimethylethylenediamine (0.2 mmol), and K2CO3 (4.0
mmol) was added dry toluene (5.0 mL) under a nitrogen
atmosphere. The reaction was refluxed for 12 h and then
allowed to cool to r.t. The crude mixture was added to 10 mL
H2O and then was extracted by CH2Cl2 (2 × 20 mL). The
organic layer was dried over anhyd Na2SO4 and
concentrated in vacuo to give the crude product, which was
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