New facile and mild synthesis of 2-substituted oxazolopyridines

Article abstract of DOI:10.1016/j.tetlet.2005.10.109

A new, two-step synthesis of oxazolopyridines is described. The synthesis involving amide formation between o-aminopyridinols and aliphatic or aromatic carboxylic acids followed by condensation with hexachloroethane/ triphenylphosphine takes place at room

Full text of DOI:10.1016/j.tetlet.2005.10.109

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 9001–9004
New facile and mild synthesis of 2-substituted oxazolopyridines
Stefan Heuser,a,* Martine Keenanb and Andreas G. Weicherta
aLilly Forschung GmbH—Division of Eli Lilly Research Laboratories, Essener Bogen 7, 22419 Hamburg, Germany
bLilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
Received 9 September 2005; revised 19 October 2005; accepted 21 October 2005
Available online 8 November 2005
Abstract—A new, two-step synthesis of oxazolopyridines is described. The synthesis involving amide formation between o-amino-
pyridinols and aliphatic or aromatic carboxylic acids followed by condensation with hexachloroethane/triphenylphosphine takes
place at room temperature and thereby gives mild access to all regioisomeric, 2-substituted oxazolopyridines in good yields.
Ó 2005 Elsevier Ltd. All rights reserved.
Benzoxazoles1 and their derivatives2 are widely found in
natural products. Moreover, they find application in
drug discovery as melatonin receptor agonists,3 COX
inhibitors,4 anticancer agents,5 5-HT3 receptor antago-
nists6 and HIV-1 reverse transcriptase inhibitors.7 Inter-
estingly, the oxazolopyridine moiety is far less common
in the literature although it might offer some advantages
from a medicinal chemistry point of view. The pyridine
fragment may provide better water solubility by offering
an additional site for protonation and salt formation or
it might enhance intermolecular interactions with a
target protein by formation of an additional hydrogen
bond. Interested in these potential benefits, we focused
on the synthesis of 2-substituted oxazolopyridines
during the course of one of our research programmes.
A robust, generally applicable synthesis was required
in order to access all of the pyridyl regioisomers.
aldehydes under oxidative conditions is also described.13
Aside from the limitations of functional group tolerance
with some of these routes, access to all of the possible
oxazolopyridyl regioisomers has not been demonstrated
with these methods.
In order to find a milder ring-closing method, we turned
to known oxazole syntheses. The cyclodehydration of
a-acyl-aminoketones, the Robinson–Gabriel synthesis,14
offers good synthetic access towards substituted oxaz-
oles.15 Various extensions and modifications of this pro-
tocol have been described.16 Most noteworthy in this
regard is the work of Wipf who demonstrated that a-
acylaminoaldehydes can be readily cyclodehydrated
using a mixture of triphenylphosphine and iodine,17
although this reagent system is known to have limited
applicability.18 With this in mind, we envisioned a
two-step approach with initial amide formation fol-
lowed by cyclodehydration using the milder combina-
tion of triphenylphosphine and hexachloroethane.19
The few routes to oxazolopyridines described in the lit-
erature are very similar to the numerous benzoxazole
syntheses that have been reported.8 Typically an o-amino-
pyridinol is condensed with a carboxylic acid or deriva-
tive thereof in the presence of a large excess of
polyphosphoric acid at high temperatures.9 Acid labile
groups are not tolerated during the usual aqueous work
up. Use of acid catalysis and lower reaction tempera-
tures have been reported,10,11 as has a base promoted
cyclisation of an o-halogeno amido pyridine at very high
temperature.12 The reaction of o-aminopyridinols with
The synthesis of the required o-aminopyridinols not
commercially available was achieved following known
literature procedures. 3-Aminopyridin-4-ol (1a) was
obtained in excellent yield by catalytic hydrogenation
of 3-nitropyridin-4-ol.11 4-Aminopyridin-3-ol (1b) was
prepared by the method of Chu-Moyer and Berger start-
ing from 4-aminopyridine.20
The amide formation was performed by O-benzotriazol-
1-yl-N,N,N0,N0-tetramethyluronium tetrafluoroborate
(TBTU)-mediated coupling (Scheme 1) of a variety of
carboxylic acids and the four regioisomeric o-aminopy-
ridinols (1a–d).21 With yields of 52–85% the reaction
Keywords: Oxazolopyridines; Heterocycles; Carboxylic acids; 2-Amino-
pyridinol; Solid-phase synthesis.
*
Corresponding author. Tel.: +49 40 52724409; fax: +49 40
52724601; e-mail: heuser_stefan@lilly.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.109

9002
S. Heuser et al. / Tetrahedron Letters 46 (2005) 9001–9004
An alternative synthesis of 13 employing isobutyryl
chloride (9) proceeded in 75% yield (entry 11).
OH
OH
HO
R
TBTU, NEt3
(DMF), rt
O
N
+
N
O
R
NH2
N
H
The key cyclisation step was achieved at room temper-
ature in dichloromethane using the triphenylphoshine–
hexachloroethane combination, with the triphenyl-
phosphonium halide being formed prior to addition
of the amide22 (Scheme 2). Even under such mild
conditions, all regioisomeric oxazolopyridines were
obtained in moderate to high yields after purification
(Table 2).
1a-d
2-8
10a-g, 11-13
Scheme 1. TBTU-mediated amide formation between o-amino-pyrid-
inols 1a–d and carboxylic acids derivatives 2–8.
proceeded quite satisfactorily (Table 1), the only excep-
tion being entry 10 where no product could be isolated.
Table 1. Amide-formation between o-aminopyridinols 1a–d and carboxylic acid derivatives 2–9
Entry
1a
o-Aminopyridinol
Carboxylic acid derivative
Product
Yield (%)
70
OH
OH
HO
H
NH2
N
2
1a
10a
O
O
O
N
N
OH
OH
H
N
NH2
HO
2a
3a
4a
5a
72
72
80
67
3
1a
10b
10c
O
N
N
OH
OH
H
N
NH2
HO
4
1a
O
O
O
N
N
OH
OH
H
N
NH2
HO
5
1a
10d
O
N
N
OH
OH
H
N
NH2
HO
6
1a
10e
O
O
O
N
N
OH
OH
H
N
H
N
H
O
NH2
HO
N
O
6a
52
58
1a
10f
7
O
O
O
N
N
O
O
O
O
OH
OH
N
HN
O
HN
O
NH2
7a
H
N
1a
10g
8
HO
HO
N
O
O
O
O
NH2
NH
N
OH
8a
64
3
1b
11
OH
N
H
N
NH2
HO
HO
Cl
9a
85
0
3
3
12
1c
O
OH
OH
N
N
N
O
O
N
N
OH
OH
O
10a
11b
1d
1d
13
13
N
H
NH2
OH
OH
O
9
75
N
N
H
NH2
O
a 1.2 equiv TBTU, 2.8 equiv NEt3, in DMF at rt after 16 h using 1 equiv of carboxylic acid.
b 1 equiv NEt3, in CH2Cl2 at rt after 16 h using 1 equiv of isobutyryl chloride.

S. Heuser et al. / Tetrahedron Letters 46 (2005) 9001–9004
9003
a sterically bulky R group (entry 3) does not dramati-
cally decrease the yield of desired product. Furthermore,
it is noteworthy that the reaction conditions allow for
the presence of acid labile protecting groups such as
the Boc-group (entries 6 and 7) thereby circumventing
problems with existing methods summarised herein.
OH
O
N
C2Cl6, PPh3, NEt3
(CH2Cl2), rt
O
N
N
R
R
N
H
10a-g, 11-13
14a-g, 15-17
Scheme 2. Oxazolopyridine synthesis by cyclodehydration of amides
10a–g, 11–13.
In several examples, the moderate isolated yields of the
oxazolopyridine originate from the difficult removal of
triphenylphosphonium oxide (entries 7, 8 and 10). To
facilitate purification of the products we used polymer-
bound triphenylphosphine and piperidinomethyl-poly-
styrene HL resin. The reactions took place in good to
excellent yields with a much easier work up (entries 5,
7, 8 and 10, brackets). The crude products obtained by
concentration of the reaction mixtures after 16 h were
purified by simple filtration through a short pad of
silica.
Table 2. Oxazolopyridine synthesis by cyclodehydration of amides
10a–g, 11–13 with PPh3/C2Cl6/NEt3
Entry Substrate Product
Yield (%)
83a
O
1
2
3
4
10a
10b
10c
10d
14a
N
N
N
N
N
O
91a
78a
93a
14b
N
O
In summary, we have developed a novel, very mild
synthesis of 2-substituted oxazolopyridines, giving easy
access to all pyridyl regioisomers. The synthesis from
readily available carboxylic acids and o-aminopyridinols
seems to be generally applicable and tolerant of a variety
of functional groups, and is, to the best of our knowl-
edge, the first time the triphenylphosphine–hexachloro-
ethane reagent system has been used for the synthesis
of oxazoloarenes. Moreover, the method described here-
in provides access to substituted oxazolopyridines not
previously accessible via traditional procedures. The
application of this method to the synthesis of benzoxaz-
oles and other azabenzoxazoles such as oxazolopyrimi-
dines is ongoing in our laboratories.
14c
N
O
14d
N
O
N
5
6
10e
10f
84a (95)b
14e
N
N
O
O
N
73a
14f
O
N
H
Acknowledgements
O
O
N
14g
7
10g
50a (71)b
O
O
The authors would like to thank Peter J. Callow for the
measurement of high resolution mass spectra and Sven
Dro¨ge for excellent HPLC-support. Moreover, fruitful
discussions with Richard E. Rathmell, Simon J. Rich-
ards and Erich Seger during the course of the project
are highly appreciated.
N
N
N
H
O
N
8
11
12
13
41a (77)b
15
N
N
O
9
88a
16
17
N
O
References and notes
10
41a (74)b
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a Isolated yield, 2.5 equiv C2Cl6, 3 equiv PPh3, 8 equiv NEt3 in CH2Cl2
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9004
S. Heuser et al. / Tetrahedron Letters 46 (2005) 9001–9004
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MeOH in CH2Cl2) yielded 270 mg (1.39 mmol, 70%)
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white solid; 1H NMR: (300 MHz, DMSO-d6):
d
3
(ppm) = 0.91 (t, J = 7.3 Hz, 3H), 1.33 (m, 2H), 1.57 (m,
3
3
2H), 2.45 (t, J = 7.4 Hz, 2H), 6.26 (d, J = 7.1 Hz, 1H),
7.66 (dd, 3J = 7.1 Hz, 4J = 1.4 Hz, 1H), 8.72 (d,
4J = 1.4 Hz, 1H), 8.97 (br s, 1H), 11.46 (br s, 1H); 13C
NMR: (75 MHz, DMSO-d6): d (ppm) = 13.9, 21.9, 27.5,
35.8, 112.9, 124.3, 129.1, 135.5, 170.1, 171.8.
22. Typical procedure: Add triphenylphosphine (1.09 g,
4.16 mmol) and NEt3 (842 mg, 1.17 mL, 8.32 mmol) to a
solution of hexachloroethane (820 mg, 3.46 mmol) in
10 mL CH2Cl2 and stir the resulting mixture at room
temperature for 5 min. Add solid amide 10a and stir at
ambient temperature for 1 h. Add 50 mL CH2Cl2 and
wash successively with 5 mL saturated NH4Cl solution,
5 mL satd NaHCO3 solution and 10 mL brine. Drying
over Na2SO4, filtration and concentration of the organic
phase gives a brown oil. Purification of the obtained
residue by flash chromatography on silica gel (eluting with
hexanes!80% tert-butylmethyl ether in hexanes) provided
203 mg (1.15 mmol, 83%) 2-butyl-oxazolo[4,5-c]pyridine
(11a) as a white solid; mp: 42–43 °C; 1H NMR: (300 MHz,
CDCl3): d (ppm) = 0.96 (t, 3J = 7.3 Hz, 3H), 1.45 (m, 2H),
1.87 (m, 2H), 2.95 (t, 3J = 7.6 Hz, 2H), 7.43 (dd,
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8.98 (br s, 1H); 13C NMR: (75 MHz, CDCl3):
d
(ppm) = 13.6, 22.2, 28.2, 28.6, 106.2, 139.1, 142.3, 145.0,
155.9, 168.2; MS (EI, 70 eV): m/z (%) = 176 (7), 161 (3),
147 (27), 134 (100); ESI-HRMS: m/z calcd for
(C10H12N2O+H+) = 177.1022, m/z found = 177.1023.