Synthesis of 2-amino-3-hydroxy-4-substituted pyridines via regioselective metalation of 3-(1-ethylpropyl)-[1,3]oxazolo[4,5-b]pyridin-2(3H)-one and application to corticotropin releasing factor1 receptor ligands

Article abstract of DOI:10.1016/j.tetlet.2005.01.067

An efficient route to the preparation of 2-amino-3-hydroxy-4-substituted pyridines is described. The key step involves the regioselective metalation and subsequent alkylation of the [1,3]oxazolo[4,5-b]pyridin-2(3H)-one ring system. Base hydrolysis provides access to a variety of 4-substituted pyridines. This chemistry is proved to be useful for the synthesis of corticotropin releasing factor₁ receptor ligands.

Full text of DOI:10.1016/j.tetlet.2005.01.067

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1683–1686
Synthesis of 2-amino-3-hydroxy-4-substituted pyridines via
regioselective metalation of 3-(1-ethylpropyl)-
[1,3]oxazolo[4,5-b]pyridin-2(3H)-one and application to
corticotropin releasing factor1 receptor ligands
Richard A. Hartz,a,* Kausik K. Nandab and Charles L. Ingallsc
aDiscovery Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
bMerck Research Laboratories, West Point, PA 19486, USA
cWyeth, Pearl River, NY 10965, USA
Received 30 November 2004; revised 12 January 2005; accepted 13 January 2005
Available online 29 January 2005
Abstract—An efficient route to the preparation of 2-amino-3-hydroxy-4-substituted pyridines is described. The key step involves the
regioselective metalation and subsequent alkylation of the [1,3]oxazolo[4,5-b]pyridin-2(3H)-one ring system. Base hydrolysis pro-
vides access to a variety of 4-substituted pyridines. This chemistry is proved to be useful for the synthesis of corticotropin releasing
factor1 receptor ligands.
Ó 2005 Elsevier Ltd. All rights reserved.
During the course of our investigation to identify novel
ligands for corticotropin releasing factor1 (CRF1) recep-
tors1 we sought an efficient method for the preparation
of 4-substituted pyridines. We were particularly inter-
ested in a synthetic route that would be readily amen-
able to the preparation of compounds bearing a phenyl
substituent at the 4-position of the pyridine ring.
be easily hydrolyzed to regenerate the amino and hydr-
oxy groups later in the synthetic route.
The synthesis begins with alkylation of the amino group
of 2-amino-3-hydroxy pyridine (1) with 3-pentanone via
reductive amination (Scheme 1). Subsequent treatment
with triphosgene resulted in the formation of the
[1,3]oxazolo[4,5-b]pyridin-2(3H)-one ring system( 3).
An attempt to directly couple 3 with bromobenzene
via a Negishi coupling reaction resulted in a low yield
of desired product (Table 1, compound 11). Regioselec-
tive metalation with t-BuLi resulted in the formation of
a mixture of the desired lithium anion at the 4-position
of the pyridine ring as well as addition of t-BuLi to the
oxazolidinone carbonyl group resulting in the formation
of 2,2-dimethylpropionic acid 2-(1-ethyl-propylamino)-
pyridin-3-yl ester 16 as the major product in 62% yield
(Fig. 1).5 Cleavage of the C–N bond rather than the
C–O bond is likely a result of the enhanced leaving
group ability of this nitrogen due to resonance stabiliza-
tion of the resulting charge into the neighboring pyr-
idine nitrogen. Within several minutes of isolation, the
product turned blue in color, which was likely due to
trace amounts of air oxidation.
Directed ortho metalation has been widely used for the
regioselective alkylation and arylation of aryl and het-
eroaryl ring systems.2 Our synthetic plan began with
commercially available 2-amino-3-hydroxy pyridine. It
was anticipated that installation of the substituent at
the 4-position could be carried out by a directed ortho
metalation reaction whereby the oxygen at the 3-posi-
tion would serve as a directing group. This plan was
bolstered by the previously reported regioselective
metalation of related heterocyclic ring systems.3,4 The
2-amino and 3-hydroxy groups could be protected as
an oxazolidinone, which would be ideal since it could
Keywords: Regioselective metalation; Pyridine; Corticotropin releasing
factor.
*
Formation of this undesired byproduct was circum-
vented by using a two-step procedure to install the
Corresponding author. Tel.: +1 2036777837; fax: +1 2036777702;
e-mail: richard.hartz@bms.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.067

1684
R. A. Hartz et al. / Tetrahedron Letters 46 (2005) 1683–1686
N
O
N
HN
HO
N
H2N
HO
N
c
a
b
O
e
2
3
1
HN
HO
N
N
N
N
O
N
O
O
d
O
Cl
Br
Cl
4
Cl
Cl
5
6
Scheme 1. Reagents and conditions: (a) 3-pentanone, NaBH3CN, THF, 62%; (b) triphosgene, Et3N, THF 70%; (c) LDA, BrCH2CH2Br, THF, 65%;
(d) Ba(OH)2Æ8H2O, Pd(PPh3)2Cl2, 2,4-dichlorobenzeneboronic acid, DME, H2O, 80%; (e) KOH, EtOH, 87%.
Table 1.
ested in studying the directed metalation of 3 in more
detail. The intermediate lithium anion was subjected to
additional electrophiles as shown in Table 1. Addition
of methyl iodide, several aldehydes, and a Weinreb
amide each proceeded in good yield. Not unexpectedly,
treatment with ethyl iodide resulted only in recovery
of protonated starting material due to competing
elimination.
N
O
N
N
O
N
LDA, Electrophile
THF
O
O
R
3
Compds
Electrophile
BrCH2CH2Br
MeI
R
Yield (%)
4
7
Br
Me
65
78
With 2-amino-3-hydroxy-4-substituted pyridine 6 in
hand, it was elaborated further to the desired products
(Scheme 2) which were tested for CRF1 receptor binding
affinity. Compound 6 was selectively alkylated on either
the amine or hydroxyl groups depending upon the
choice of reaction conditions. Subjection of 6 to formal-
dehyde under reductive amination conditions resulted in
the selective formation of 12; whereas, treatment of 6
OH
CHO
8
9
89
73
OH
CHO
O
O
10
76
11
N
O
11a
PhBr
Ph
a Compound 11 was prepared by a Negishi coupling reaction (t-BuLi,
ZnCl2, Pd(PPh3)4, PhBr).
O
N
O
N
N
N
R1
R2O
c, d
Cl
Cl
HN
O
N
O
Cl
Cl
6 R1 = H, R2 = H
12 R1 = Me, R2 = H
13 R1 = H, R2 = Et
14
a
b
16
Figure 1. Structure of compound 16.
N
O
N
e
phenyl group. Deprotonation with LDA6 followed by
the addition of dibromoethane3 cleanly afforded desired
bromide 4 in 65% yield. Compound 4 was then subjected
to Suzuki coupling conditions to furnish biaryl interme-
diate 5 in good yield. Treatment with NaOH resulted in
hydrolysis of the oxazolidinone to forma 2-amino-3-
hydroxy-4-substituted pyridine (6).
Cl
Cl
15
Scheme 2. Reagents and conditions: (a) HCHO, ZnCl2, NaBH3CN,
MeOH, 60 °C, 34%; (b) K2CO3, EtI, acetone, 81%; (c) K2CO3, methyl
2-bromopropionate, 2-butanone, 74%; (d) p-TsOHÆH2O (cat), toluene,
4 days, 96%; (e) BH3ÆSMe2, THF, 84%.
Having successfully completed the synthesis of the de-
sired 4-substituted pyridyl ring system( 6) we were inter-

R. A. Hartz et al. / Tetrahedron Letters 46 (2005) 1683–1686
1685
(thin film) 2965 (s), 2935 (m), 2875 (m), 1758 (s), 1609 (s),
1500 (s), 1169 (s), 1104 (s) cmÀ1; HRMS (ESI) m/e
265.1918 [(M+H)+, calcd for C15H25N2O2 265.1916].
6. (a) Commins, D. L.; Lamunyon, D. H. Tetrahedron Lett.
1988, 29, 773; (b) Marsais, F.; Le Nard, G.; Queguiner, G.
Synthesis 1982, 235, and references cited therein.
with K2CO3 and ethyl iodide resulted in the selective
alkylation of the phenol oxygen to form 13. It was also
possible to prepare bicyclic compounds by taking
advantage of the differential reactivity of the amine
and phenol groups on the pyridine ring. Treatment of
6 with 2-bromomethylpropionate7 followed by heating
in toluene in the presence of p-TsOH (4 days) resulted
in the formation of 14. The amide was then reduced with
BH3ÆSMe2 to form 15 in good yield.8
7. Wimmer, Z.; Saman, D.; Francke, W. Helv. Chim. Acta
1994, 77, 502.
8. Characterization data for compounds 2–15 follows: com-
pound 2: yellow solid; mp 112–113 °C; 1H NMR
(300 MHz, CDCl3) d 7.52 (d, J = 5.5 Hz, 1H), 6.81 (d,
J = 7.3 Hz, 1H), 6.41–6.37 (m, 1H), 4.95 (br, 1H), 3.94–
3.85 (m, 1H), 1.68–1.46 (m, 4H), 0.91 (t, J = 7.3 Hz, 6H);
HRMS (ESI) m/e 181.1343 [(M + H)+, calcd for
C10H17N2O 181.1341]; 3: colorless oil; 1H NMR
(300 MHz, CDCl3) d 8.09 (dd, J = 5.5, 1.5 Hz, 1H), 7.40
(dd, J = 7.7, 1.1 Hz, 1H), 7.03 (dd, J = 7.7, 5.2 Hz, 1H),
4.25–4.15 (m, 1H), 2.26–2.14 (m, 2H), 1.96–1.82 (m, 2H),
0.89 (t, J = 7.3 Hz, 6H); HRMS (ESI) m/e 207.1141
[(M+H)+, calcd for C11H15N2O2 207.1134]; compound
Compounds 12, 13, and 15 were tested for their binding
affinity to the CRF1 receptor. Compounds 12 and 13
were found to be inactive (Ki > 10,000 nM); however,
compound 15 showed moderately potent binding affinity
(Ki = 111 10 nM, n = 4) for the CRF1 receptor. Bind-
ing affinities were determined in a CRF1 receptor
binding titration assay using rat frontal cortex
homogenate, in which inhibition of specific binding of
[
125I]ovine–CRF by our test compounds was measured
1
4: colorless solid; mp 83.5–84.5 °C; H NMR (300 MHz,
to determine their receptor binding affinity.9,10
CDCl3) d 7.91 (d, J = 5.5 Hz, 1H), 7.19 (d, J = 5.8 Hz,
1H), 4.21–4.12 (m, 1H), 2.24–2.11 (m, 2H), 1.95–1.81 (m,
2H), 0.89 (t, J = 7.7 Hz, 6H); HRMS (ESI) m/e 285.0236
[(M+H)+, calcd for C11H14N2O2Br 285.0239]; compound
5: blue-green solid; 1H NMR (300 MHz, CDCl3) d 8.15 (d,
J = 5.4 Hz, 1H), 7.57 (d, J = 1.4 Hz, 1H), 7.43–7.36 (m,
2H), 7.09 (d, J = 5.5 Hz, 1H), 4.26–4.18 (m, 1H), 2.29–2.16
(m, 2H), 1.99–1.85 (m, 2H), 0.93 (t, J = 7.3 Hz, 6H);
LRMS (APCI) m/e 351.1 [(M+H)+, calcd for C17H17-
N2O2Cl2 351.1]; compound 6: green amorphous solid;
1H NMR (300 MHz, CDCl3) d 6.63 (d, J = 5.2 Hz,
1H), 7.53 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.4, 1.8 Hz,
1H), 7.28 (d, J = 8.1 Hz, 1H), 6.28 (d, J = 5.1 Hz, 1H),
4.88 (br, 1H), 3.98 (br, 1H), 1.71–1.49 (m, 4H), 0.94 (t,
J = 7.3 Hz, 6H); HRMS (ESI) m/e 325.0888 [(M+H)+,
calcd for C16H19N2OCl2 325.0874]; compound 7: colorless
In conclusion, the preparation of 2-amino-3-hydroxy-4-
substituted pyridines was carried out by the regioselec-
tive metalation of the [1,3]oxazolo[4,5-b]pyridin-2(3H)-
one ring system( 3) as a key step. Suzuki coupling
followed by base hydrolysis furnished the 4-substituted
pyridine intermediate, which was subsequently con-
verted to the desired products. This method appears to
be general, allowing ready access to a variety of 2-ami-
no-3-hydroxy-4-substituted pyridines, and was also di-
rectly applicable to our investigation of CRF1 receptor
ligands.
1
solid; mp 65–66 °C, H NMR (300 MHz, CDCl3) d 7.96
Acknowledgements
(d, J = 5.5 Hz, 1H), 6.86 (d, J = 5.8 Hz, 2H), 4.23–4.13 (m,
1H), 2.39 (s, 3H), 2.28–2.13 (m, 2H), 1.94–1.80 (m, 2H),
0.89 (t, J = 7.3 Hz, 6H); LRMS (APCI) m/e
221.1[(M+H)+, calcd for C12H17N2O2 221.1]; compound
8: light yellow solid; mp 115.5–116.5 °C, 1H NMR
(300 MHz, CDCl3) d 8.08 (d, J = 5.5 Hz, 1H), 7.51 (dd,
J = 8.4, 1.8 Hz, 2H), 7.42–7.31 (m, 3H), 7.24 (d,
J = 5.5 Hz, 1H), 6.15 (s, 1H), 4.21–4.13 (m, 1H), 2.23–
2.09 (m, 3H), 1.92–1.83 (m, 2H), 0.88 (t, J = 7.7 Hz, 6H);
HRMS (ESI) m/e 313.1543 [(M+H)+, calcd for
C18H21N2O3 313.1552]; 9: pale blue oil; 1H NMR
(300 MHz, CDCl3) d 8.07 (d, J = 5.5 Hz, 1H), 7.14 (d,
J = 5.5 Hz, 1H), 4.98 (t, J = 6.6 Hz, 1H), 4.23–4.13 (m, H),
2.53 (br, H), 2.23–2.11 (m, H), 1.94–1.80 (m, 4H), 0,99 (t,
J = 7.3 Hz, 3H), 0.87 (t, J = 7.4 Hz, 6H); LRMS (APCI)
m/e 265.0 [(M+H)+, calcd for C14H21N2O3 265.2];
We thank Ge Zhang and Anne Marshall for the rat
CRF receptor binding data for compounds 12, 13, and
15.
References and notes
1. (a) Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med.
Chem. 2000, 43, 1641; (b) Keller, P. A.; Elfick, L.; Garner,
J.; Morgan, J.; McCluskey, A. Bioorg. Med. Chem. 2000,
8, 1213; (c) McCarthy, J. R.; Heinrichs, S. C.; Grigoriadis,
D. E. Curr. Pharm. Design 1999, 5, 289.
2. For a review of the metalation of p-deficient heteroaro-
matic compounds see: Marais, F.; Queguiner, G. Tetra-
hedron 1983, 39, 2009.
1
compound 10: pale blue oil; H NMR (300 MHz, CDCl3)
3. Flouzat, C.; Savelon, L.; Guillaumet, G. Synthesis 1992,
842.
4. (a) Lever, O. W., Jr.; Werblood, H. M.; Russell, R. K.
Tetrahedron Lett. 1993, 34, 203; (b) Flouzat, C.; Guilla-
umet, G. J. Heterocyclic Chem. 1991, 28, 899.
d 8.17 (d, J = 5.5 Hz, 1H), 7.48 (d, J = 5.5 Hz, 1H), 4.28–
4.18 (m, 1H), 4.14–4.08 (m, 1H), 2.38 (q, J = 8.0 Hz, 4H),
2.28–2.09 (m, 3H), 1.98–1.83 (m, 1H), 0.89 (t, J = 7.7 Hz,
6H); LRMS (ESI) m/e 289.1540 [(M+H)+, calcd for
1
C16H21N2O3 289.1540]; compound 11: blue oil; H NMR
5. The structure of compound 16 was confirmed by a COSY
experiment in addition to the following characterization
data for this compound: blue oil; 1H NMR (400 MHz,
CDCl3) d 7.93 (dd, J = 5.1, 1.5 Hz, 1H), 7.17 (dd, J = 7.5,
1.5 Hz, 1H), 6.51 (dd, J = 7.8, 2.8 Hz, 1H), 4.11 (d,
J = 8.1 Hz, 1H), 4.02–3.97 (m, 1H), 1.64–1.55 (m, 2H),
1.54–1.41 (m, 2H), 1.37 (s, 9H), 0.88 (t, J = 7.3 Hz, 6H);
13C NMR (100 MHz, CDCl3) d 175.99, 151.39, 144.62,
132.96, 128.06, 111.37, 52.26, 39.37, 27.20, 26.95, 9.79; IR
(300 MHz, CDCl3) 8.15 (d, J = 5.8 Hz, 1H), 7.90 (dd,
J = 6.6, 2.1 Hz, 2H), 7.58–7.44 (m, 3H), 7.28 (d,
J = 5.5 Hz, 1H), 4.29–4.20 (m, 1H), 2.38–2.20 (m, 2H),
2.00–1.82 (m, 2H), 0.94 (t, J = 7.3 Hz, 6H); HRMS (ESI)
m/e 283.1450 [(M+H)+, calcd for C17H19N2O2 283.1447];
12: light green solid; mp 72.6–73.2 °C; 1H NMR
(300 MHz, CDCl3) d 7.98 (d, J = 5.1 Hz, 1H), 7.53 (d,
J = 1.8 Hz, 1H), 7.36–7.28 (m, 2H), 6.87 (d, J = 5.1 Hz,
1H), 2.99–2.95 (m, 1H), 2.71 (s, 3H), 1.69–1.52 (m, 4H),

1686
R. A. Hartz et al. / Tetrahedron Letters 46 (2005) 1683–1686
0.92 (t, J = 7.3 Hz, 6H); HRMS (ESI) m/e 339.1024
1H), 5.1 (m, 1H), 4.66 (q, J = 6.5 Hz, 1H), 2.31 (m, 2H),
1.91 (sept, J = 7.3 Hz, 2H), 1.51 (d, J = 7.0 Hz, 1H),
0.89 (t, J = 7.4 Hz, 6H); HRMS (ESI) m/e 379.0980
[(M+H)+, calcd for C17H21N2OCl2 339.1031]. Anal.
Calcd for C17H20N2OCl2: C, 60.18; H, 5.94; N, 8.27.
Found: C, 60.27; H, 5.90; N, 8.16; compound 13: dark
blue oil; 1H NMR (300 MHz, CDCl3)d 7.85 (d, J = 5.5 Hz,
1H), 7.51 (m, 1H), 7.30 (d, J = 1.1 Hz, 2H), 6.35 (d,
J = 5.1 Hz, 1H), 4.85 (d, J = 9.2 Hz, 1H), 4.07–4.00 (m,
1H), 3.53 (q, J = 6.9 Hz, 2H), 1.72–1.49 (m, 4H), 1.10 (t,
J = 7.0 Hz, 3H), 0.95 (t, J = 7.3 Hz, 6H); HRMS (ESI) m/e
353.1216 [(M+H)+, calcd for C18H23N2OCl2 353.1187].
Anal. Calcd for C18H22N2OCl2: C, 61.20; H, 6.29; N, 7.94.
Found: C, 61.06; H, 6.31; N, 7.71; compound 14: dark oil;
1H NMR (300 MHz, CDCl3) d 8.04 (d, J = 4.8 Hz, 1H),
7.52 (d, J = 2.1 Hz, 1H), 7.35 (m, 1H), 7.25 (d, J = 4 Hz,
[(M+H)+,
calcd
for
C19H21Cl2N2O2
379.2797];
1
compound 15: colorless oil; H NMR (300 MHz, CDCl3)
d 7.74 (d, J = 5.1 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.30
(m, 2H), 6.32 (d, J = 5.1 Hz, 1H), 4.86 (m, 1H), 4.15 (m,
1H), 3.30 (dd, J = 12.0, 2.2 Hz, 1H), 3.02 (m, 1H), 1.64 (m,
4H), 1.28 (d, J = 6.2 Hz, 3H), 0.93 (t, J = 7.3 Hz, 6H);
HRMS (ESI) m/e 365.1169 [(M+H)+, calcd for
C19H23N2OCl2 365.2962].
9. Schumacher, R. W.; Davidson, B. S. Tetrahedron 1999, 55,
935.
10. Desouza, E. B. Neuroscience 1987, 7, 88.