Synthesis of substituted 2-heteroarylbenzazol-5-ol derivatives as potential ligands for estrogen receptors

Article abstract of DOI:10.1016/j.tet.2013.05.084

Exposure to estrogen is associated with increased risk of breast and other types of human cancer. One therapeutic goal would be the creation of new molecules that would retain hormonal potency while incorporating features to retard or prevent quinone toxicity. Hence, new structures closely related to ERB-041, a known ERβ selective agonist, were synthesized whereas the phenol ring is substituted with non-quinone forming rings such as pyrazole, 2-pyrimidine-2(1H)-one or pyridine-2(1H)-one. 2-Methyl-5-methoxy-1,3- benzoxazoles (or 1,3-benzothiazole) are key intermediates for the production of the pyrazole and pyrimidine-2(1H)-one analogs. The required 1,3-benzoxazoles were synthesized starting from reduction of 2-nitro-4-methoxyphenols, followed by condensation with trimethyl orthoacetate. Then, the diiminium perchlorate intermediates were prepared from the latter compounds by Vilsmeier-Haack reaction. The reaction of the resulting intermediates with hydrazine hydrate and guanidium chloride afforded the title pyrazole and pyrimidine-2(1H)-ones, respectively. The pyridine analogs were synthesized starting from the reaction of 2-amino-4-methoxyphenols with 6-bromopyridine-3-carboxaldehyde followed by oxidation with DDQ to afford bromopyridines. These compounds were next treated with benzyl alcohol in the presence of potassium tert-butoxide to afford 2-benzyloxypyridine, which in subsequent dealkylation with boron tribromide produced the title pyridine-2-(1H)-ones.

Full text of DOI:10.1016/j.tet.2013.05.084

Tetrahedron 69 (2013) 6076e6082
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted 2-heteroarylbenzazol-5-ol derivatives as
potential ligands for estrogen receptors
*
Sina Rezazadeh, Latifeh Navidpour , Abbas Shafiee
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14176, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Exposure to estrogen is associated with increased risk of breast and other types of human cancer. One
therapeutic goal would be the creation of new molecules that would retain hormonal potency while in-
corporating features to retard or prevent quinone toxicity. Hence, new structures closely related to ERB-
Received 2 March 2013
Received in revised form 9 May 2013
Accepted 20 May 2013
041, a known ERb selective agonist, were synthesized whereas the phenol ring is substituted with non-
Available online 24 May 2013
quinone forming rings such as pyrazole, 2-pyrimidine-2(1H)-one or pyridine-2(1H)-one. 2-Methyl-5-
methoxy-1,3-benzoxazoles (or 1,3-benzothiazole) are key intermediates for the production of the pyr-
azole and pyrimidine-2(1H)-one analogs. The required 1,3-benzoxazoles were synthesized starting from
reduction of 2-nitro-4-methoxyphenols, followed by condensation with trimethyl orthoacetate. Then, the
diiminium perchlorate intermediates were prepared from the latter compounds by VilsmeiereHaack
reaction. The reaction of the resulting intermediates with hydrazine hydrate and guanidium chloride
afforded the title pyrazole and pyrimidine-2(1H)-ones, respectively.
Keywords:
17b-Estradiol
ERB-041
Non-quinone forming ligands
The pyridine analogs were synthesized starting from the reaction of 2-amino-4-methoxyphenols with 6-
bromopyridine-3-carboxaldehyde followed by oxidation with DDQ to afford bromopyridines. These
compounds were next treated with benzyl alcohol in the presence of potassium tert-butoxide to afford 2-
benzyloxypyridine, which in subsequent dealkylation with boron tribromide produced the title pyridine-
2-(1H)-ones.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
substitution at the positions adjacent to the first hydroxyl group
(situated at position three in the A-ring), forming 2-OH estradiol and
The safety of hormone therapies, particularly contraceptives and
hormone replacement therapy (HRT), has been the subject of much
controversy for many years now.1 Epidemiological studies indicate
increased risk of breast and uterine cancers associated with HRT
usage, and contemporary medical practice suggests that women
should minimize their usage of hormone supplements.2 ‘Women’s
Health Initiative’ (WHI) was stopped in 2002 due to an increase in
the reported cases of venous thromboembolism, myocardial in-
farction, stroke and breast cancer.1 In recent years however, many
investigations have focused primarily on the origin of cancer and
the understanding of how sex steroid hormones are so closely re-
lated to breast cancer development.
4-OH estradiol. These metabolites, termed the ‘catechol estrogens’,4
Naturally occurring estrogens, estradiol and estrone, have the
classic steroid structure containing the A, B, C, and D-rings (Fig. 1).
The B, C, and D rings are saturated, but the A-ring is an aromatic
phenol. Phenols are easily metabolized in the liver and elsewhere by
the enzyme cytochrome P450 hydroxylase.2,3 This leads to hydroxyl
WAY202196
ERB-041
* Corresponding author. Fax: þ98 21 6646 1178; e-mail address: navidpur@si-
na.tums.ac.ir (L. Navidpour).
Fig. 1. Representative examples of estrogen receptor ligands.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.084

S. Rezazadeh et al. / Tetrahedron 69 (2013) 6076e6082
6077
can be further metabolized by oxidizing substances present in the
cell, e.g., peroxidase/P450 or tyrosinase/O2,5 or even in the presence
of oxygen, to give the 2,3-quinone and 3,4-quinone.6e15 Catechol
estrogen quinones can react with DNA to form depurinating ad-
ducts. These adducts are released from DNA to generate apurinic
sites. Error-prone base excision repair of this damage maylead tothe
mutations that can initiate breast, prostate and other types of
cancer.
(phenolic) and the 17-position (17
the OeO interatomic distance is 11.0 A, and in general it is thought
b
-OH) in estradiol.3 In estradiol
ꢀ
that for optimum hydrogen bonding this distance should be
11.0ꢀ05 A.27 Aiming to design new non-quinone forming estrogen
ꢀ
analogs, it is thought that fluorination at both ortho-positions on the
A-ring would suppress quinone formation. Hence, to find new ER
b
non-quinone forming ligands, the substitution of phenol ring in
a selective agonist with hetrocycles (or substituted heterocycles)
providing two hydrogen bonding donor and acceptor in neighboring
positions interacting with Glu and Arg on the active site of the re-
ceptor has been investigated. Herein, the synthesis of ERB-041 an-
alogs, whereas the phenol ring is substituted with pyrazole, 2-
hydroxypyrimidine or 2-hydroxypyridine with different sub-
stitutions on 7-position, is reported.
There are two subtypes of estrogen receptor, ER
, which are members of nuclear receptor. It is hypothesized that
selectivity for ER
can be a desirable therapeutic feature.16e18
a and
ER
b
b
Several groups have investigated a variety of nonsteroidal scaffols
mimicking either the dihydroxy arrangement of the nonselective
estradiol or the moderately ER
potential ER
ligands. Diarylpropylnitriles (DPN),19,20 biphenyl
compounds,21,22 and benzothiazoles/benzoxazoles23,24 exhibited as
b-selective phytoestrogen as
b
The synthetic reactions used for the synthesis of pyrazole, py-
rimidine and pyridine-substituted 1,3-benzoxazol-5-ols or 1,3-
benzothiazol-5-ols are outlined in Schemes 1e3.
much as w70-fold selectivity for ERb. ERB-041 and WAY 202196
S
CH3
N
H3CO
c
3c
X
X
X
X
OH
a
OH
c
O
b
Y
N
N
N
CH3
-
ClO4
H3CO
NO2
N
H3CO
NH2
H3CO
H3CO
1a:X = H
1b: X = Br
2a: X = H (95%)
2b: X = Br (94%)
3a: X = H (80%)
3b: X = Br (82%)
4a: X = H, Y = O
4b: X = Br, Y = O
4c: X = H, Y = S
f
d
X
X
X
Y
N
N
N
Y
N
Y
N
NH
N
e or h
NH2
NH2
H3CO
N
N
HO
H3CO
5a: X = H, Y = O (93%)
5b: X = Br, Y = O (91%)
5c: X = H, Y = S (94%)
7a: X = H, Y = O (88%)
7b: X = Br, Y = O (90%)
7c: X = H, Y = S (85%)
8a: X = H, Y = O (90%)
8b: X = Br, Y = O (94%)
8c: X = H, Y = S (84%)
e
or
h
g
X
X
X
NH
N
O
N
NH
N
O
N
e
Y
NH
O
O
N
H3CO
HO
N
HO
10a: X = H (80%)
10b: X = Br (95%)
9a: X = H (70%)
9b: X = Br (65%)
6a: X = H, Y = O (91%)
6b: X = Br, Y = O (91%)
6c, X = H, Y = S (80%)
Scheme 1. Reagents and conditions: (a) Sn, HCl, EtOH, reflux, overnight; (b) CH3C(OCH3)3, reflux, 12 h; (c) POCl3, DMF, 0 ꢁC to rt, overnight; (d) NH2NH2$H2O, H2O, reflux, 5 min; (e)
BBr3, CH2Cl2, ꢂ78 ꢁC to rt, 24 h; (f) (NH2)2C]N$HCl, (CH3)3COK, (CH3)3COH, 60 ꢁC, overnight; (g) NaNO2, HCl, H2O, AcOH, 0e70 ꢁC, 3 h; (h) AlCl3, dichloroethane, reflux, 3 h.
are two known examples of ER
b
selective agonists (Fig. 1).25
In Scheme 1, two synthetic routes were used to produce pyr-
azole and pyrimidine analogs using a common intermediate
(4aec). The 2-(1H-pyrazol-3-yl)-1,3-benzoxazol-5-ols (6a,b) were
synthesized starting from 2-nitro-4-methoxy phenols (1a,b).
The reduction of 1a,b with tin in acidic media28 followed by con-
densation with trimethyl orthoacetate29 produced 2-methyl-5-
methoxy-1,3-benzoxazoles (3a,b). Pyrazole analogs (5aec) were
prepared via diiminium perchlorate intermediate (4aec) starting
from 3a,b and commercially available 3c by VilsmeiereHaack re-
action. The reaction of 3aec with the cold mixture of phosphorus
oxychloride and DMF followed by treatment with the solution of
NaClO4 produced the latter intermediate.30 The reaction of the
resulting intermediate with hydrazine hydrate in aqueous media
afforded 5aec.30e35 Demethylation of 5aec with boron tribromide
resulted in title compounds 6aec.25
Considering the above approach and as a continuation of our
ongoing study,26 we synthesized new molecules resembling ERB-
041 that would retain hormonal potency while conferring some
features to retard or prevent quinine toxicity. The focus here is on
synthetic structures closely related to ERB-041 wherein the phenol
ring is substituted with non-quinone forming rings such as
pyrazole, 2-hydroxypyrimidine or 2-hydroxypyridine. Further
studies are required to investigate a suitable substitution for
5-hydroxybenzoxazole moiety.
2. Results and discussion
The basic requirements for an estrogen receptor-active phar-
macophore are two H-bonding anchors located near the 3-position

6078
S. Rezazadeh et al. / Tetrahedron 69 (2013) 6076e6082
OH
HO
F
F
HO
F
F
H3CO
NH2
H3CO
F
N
O
F
N
O
j
i
N+
-
ClO4
OCH3
4d
11a (72%)
k
H3CO
H3CO
N
N
O
N
N
N
l
HO
N
N
O
m
O
NH2
O
NH
O
NH
F3C
F3C
F3C
9d (62%)
7d (89%)
10d (91%)
Scheme 2. Reagents and conditions: (i) CF3C(O)]C(OCH3)2, toluene, rt, 0.5 h then 95 ꢁC, 3 h; (j) POCl3, DMF, 0 ꢁC to rt, overnight; (k) (NH2)2C]N$HCl, (CH3)3COK, (CH3)3COH, 60 ꢁC,
overnight; (l) NaNO2, HCl, H2O, AcOH, 0e70 ꢁC, 3 h; (m) BBr3, CH2Cl2, ꢂ78 ꢁC to rt, 24 h.
X
X
X
N
O
N
OH
N
O
N
o
n
OBn
Br
H3CO
H3CO
NH2
H3CO
13a: X = H (93%)
13b: X = Br (96%)
2a: X = H
2b: X = Br
12a: X = H (62%)
12b: X = Br, (67%)
p
X
q
NH
NH
O
N
r
O
NH
O
14b
O
O
O
N
N
HO
HO
HO
15 (86%)
16 (96%)
14a: X = H (92%)
14b: X = Br (90%)
Scheme 3. Reagents and conditions: (n) 6-bromopyridine-3-carbaldehyde, MeOH, rt, overnight then DDQ, CH2Cl2, rt, 1 h; (o) BnOH, (CH3)3COK, THF, rt, overnight; (p) BBr3, CH2Cl2,
ꢂ78 ꢁC to rt, 24 h; (q) CH2]C(CH3)B(OH)2, Pd[Ph3P]4, Cs2CO3, DME, 110 ꢁC, 24 h; (r) H2, Pd/C, rt, 24 h.
The 2-aminopyrimidine (8aec) and pyrimidin-2(1H)-one analogs
(10aec) were prepared according to Scheme 1 via the common in-
termediates (4aec). Treatment of the intermediates (4aec) with
guanidinium chloride in the presence of potassium tert-butoxide
furnished 2-aminipyrimidine analogs (7aec). Demethylation of 7aec
with boron tribromide produced the title 2-(2-aminopyrimidin-5-yl)-
1,3-benzoxazol-5-ols (8a,b) and 1,3-benzothiazol-5-ol (8c). Di-
azotization of 7aec followed by heating in acidic media afforded the
2-pyrimidones 9aec. Demethylation of the latter with boron tri-
bromide resulted in title 5-(5-hydroxy-1,3-benzoxazol (or 1,3-
benzothiazol)-2-yl)pyrimidin-2(1H)-one (10aec).
Moreover, it is reported that meta-substitution in the phenol ring
can strongly increase the receptor binding affinity.3 Therefore, the 4-
CF3 substituted pyrimidin-2(1H)-one (10d) was synthesized starting
from 2-aminophenol 2aasshowninScheme2. Thereactionof 2awith
1,1,1,-trifluoro-4,4-dimethoxy-but-3-en-2-one produced substituted
1,3-benzoxazole 11a36,37, which subsequently was reacted with cold
mixture of phosphorus oxychloride and DMF, then treated with
guanidium chloride to afford 7d. Diazotization followed by deme-
thylation with boron tribromide resulted in title compound 10d.
The pyridin-2(1H)-one analogs (14a,b, 15, 16) were prepared
according to Scheme 3. The reaction of 2-amino-4-methoxyphenols
(2a,b) with 6-bromopyridine-3-carboxaldehyde followed by oxi-
dation with DDQ afforded bromopyridines (12a,b).38 Compounds
12a,b were next treated with benzyl alcohol in the presence of
potassium tert-butoxide to afford 2-benzyloxypyridine 13a,b,
which in subsequent dealkylation with boron tribromide produced
the title compound 14a,b. The Suzuki coupling of 14b with iso-
propenylboronic acid resulted in 15. Hydrogenation of the latter
afforded the title compound 16.
In conclusion, aiming at synthesizing non-quinone forming
estrogen analogs, new structures closely related to ERB-041,
a known ERb selective agonist, were prepared, whereas, the phe-
nol ring is substituted with heteroaryl rings, such as pyrazole, 2-
hydroxypyrimidine or 2-hydroxypyridine.
3. Experimental
3.1. General
Chemicals were obtained from commercial sources. Melting
points were measured on a Kofler hot stage apparatus. 1H NMR
spectrawererecordedonaBrukerFT-500MHzorVarianFT-400MHz
spectrometer in CDCl3 or DMSO-d6, and TMS was used as an internal
standard. Infrared (IR) spectra were acquired on a Nicollet Magna
550-FT spectrometer. The Elemental analyses were carried out with
a PerkineElmer model 240-C apparatus. The results of elemental
analyses (C, H, N) were within ꢀ0.4% of the calculated values.
3.1.1. 7-Bromo-5-methoxy-2-methyl-1,3-benzoxazole (3b). 2-Amino-
6-bromo-4-methoxyphenol (2.2 g, 10 mmol) was added to trimethyl
orthoacetate (20 mL) and the mixture was refluxed for 12 h. The

S. Rezazadeh et al. / Tetrahedron 69 (2013) 6076e6082
6079
remaining volatiles were evaporated under reduced pressure. Puri-
fication by flash chromatography (CH2Cl2) gave 3b (1.96 g) as a light
pink solid.
3150 cmꢂ1 (NeH); 1H NMR (DMSO-d6)
d
13.53 (br s, 1H, NH), 9.44
(br,1H, OH), 8.53 (br s,1H), 8.12 (br s,1H), 7.45 (d, J¼8.5 Hz,1H), 6.99
(d, J¼2.0 Hz, 1H), 6.75 (dd, J¼8.5, 2.0 Hz).
Yield, 82%; mp 106e109 ꢁC; IR (KBr)
NMR (CDCl3)
n
1133,1193 cmꢂ1 (CeO); 1H
Anal. Calcd for C10H7N3O2: C, 59.70; H, 3.51; N, 20.89. Found: C,
59.76; H, 3.53; N, 20.81.
d
7.08 (d, J¼2.0 Hz, 1H), 7.05 (d, J¼2.0 Hz, 1H), 3.85 (s,
3H) 2.64 (s, 3H).
Anal. Calcd for C9H8BrNO2: C, 44.66; H, 3.33; N, 5.79. Found: C,
44.73; H, 3.20; N, 5.64.
3.3.3. 7-Bromo-2-(1H-pyrazol-4-yl)-1,3-benzoxazol-5-ol (6b). Yield,
91% (293 mg, cream solid); mp 268e270 ꢁC; IR (KBr)
n
3476
(OeH), 3158 cmꢂ1 (NeH); 1H NMR (DMSO-d6)
d 13.58 (br s, 1H),
3.2. General procedure for the synthesis of 5-methoxy-2-(1H-
pyrazol-4-yl)-1,3-benzoxazole (or 1,3-benzothiazole) (5aec)
9.85 (br s, 1H), 8.37 (br s, 2H), 6.99 (d, J¼1.5 Hz, 1H), 6.96 (d,
J¼1.5 Hz, 1H).
Anal. Calcd for C10H7N3O2: C, 59.70; H, 3.51; N, 20.89. Found: C,
59.58, H, 3.77, N, 21.05.
To dry DMF (5 mL) was added dropwise phosphorus oxychloride
(2.0 mL, 21 mmol) at 5e10 ꢁC with constant stirring. The mixture
was stirred for an additional hour at room temperature. Then, it was
added dropwise to a cooled solution (at 0 ꢁC) of 3aec (6 mmol) in
DMF (5 mL) and the solution was stirred overnight at room tem-
perature. The resulting mixture was poured on crushed ice. After
decomposition of the excess Vilsmeier reagent, a saturated solution
of NaClO4 (4.0 g) was added with stirring. The resulting nearly yel-
low precipitate of the diiminium perchlorate intermediate (4aec)
was filtered and washed with two 15 mL portions of water. The
compound was used in the next step without further purification.
Then, the iminium perchlorate intermediate (4aec, 1 mmol) was
poured intowater (30 mL) and heated until complete dissolution. Then,
hydrazine hydrate (0.3 mL, 3 mmol) was added to the mixture, it was
heated for 5 min, and the resulting precipitate was filtered, washed
with water, and recrystallized from EtOAc/hexane to give 5aec.
3.3.3.1. Method B. Demethylation of 5-methoxy1,3-benzothiazoles
(5c, 7c or 9c). To a solution of 5c, 7c or 9c (0.35 mmol) in 1,2-
dichloroethane (20 mL) was added AlCl3 (0.465 g, 3.5 mmol). The
mixture was heated at reflux for 3 h. Then the solvent was evapo-
rated under reduced pressure, and cold water was added to the
residue. The resulting mixture was extracted with EtOAc. The or-
ganic phase was dried, evaporated, and purified by preparative TLC
(EtOAc) to give 6c, 8c or 10c.
3.3.4. 2-(1H-Pyrazol-4-yl)-1,3-benzothiazol-5-ol (6c). Yield, 80%
(170 mg, light cream solid); mp 263e265 ꢁC; IR (KBr)
n
3476 (OeH),
3121 cmꢂ1 (NeH); 1H NMR (DMSO-d6)
d 9.62 (br s, 1H, OH), 8.47 (br
s, 1H), 8.05 (br s, 1H), 7.79 (d, J¼8.8 Hz, 1H), 7.27 (d, J¼2.5 Hz, 1H),
6.87 (dd, J¼8.8, 2.5 Hz, 1H).
Anal. Calcd for C10H7N3O2: C, 59.70; H, 3.51; N, 20.89. Found: C,
59.51; H, 3.66, N, 21.02.
3.2.1. 5-Methoxy-2-(1H-pyrazol-4-yl)-1,3-benzoxazole (5a). Yield, 93%
(200 mg, light cream crystal); mp 257e260 ꢁC; IR (KBr)
n
3175 cmꢂ1
(NeH); 1H NMR (DMSO-d6)
d
13.53 (br s, 1H, NH), 8.54 (br s, 1H), 8.12
3.4. Synthesis of 3,3,3-trifluoro-1-(5-methoxy-1,3-
(br s, 1H), 7.45 (d, J¼8.8 Hz, 1H), 6.99 (d, J¼2.5 Hz, 1H), 6.75 (dd, J¼8.8,
benzoxazol-2-yl)prop-1-en-2-ol (11a)
2.5 Hz, 1H), 3.75 (s, 3H).
Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C,
61.12; H, 4.43; N, 19.76.
2-Amino-4-methoxyphenol (2a, 556 mg, 4 mmol) was added
to
a
solution of 1,1,1-trifluoro-4,4-dimethoxybut-3-en-2-one
(735 mg, 4 mmol) in toluene (30 mL). The mixture was stirred
for 3 h at 90e95 ꢁC and was then allowed to cool to room tem-
perature. The solvent was evaporated to dryness under reduced
pressure and the crude product was then purified by flash chro-
matography (EtOAc/hexane; 1:9) to give the desired compound
(747 mg) as a white solid. Yield, 72%; mp 154e157 ꢁC; IR (KBr): 3480
3.2.2. 7-Bromo-5-methoxy-2-(1H-pyrazol-4-yl)-1,3-benzoxazole(5b). Yield,
91% (266 mg, light cream crystal); mp >300 ꢁC; IR (KBr)
n
3150 cmꢂ1
(NeH); 1H NMR (DMSO-d6)
d 13.54 (br s, 1H), 8.38 (br s, 2H), 7.25 (d,
J¼1.5 Hz, 1H), 7.16 (d, J¼1.5 Hz, 1H), 3.81 (s, 3H).
Anal. Calcd for C11H8BrN3O2: C, 44.92; H, 2.74; N, 14.29. Found:
C, 44.74; H, 2.96; N, 14.20.
(OH), 1183, 1132 cmꢂ1 (CF3); 1H NMR (CDCl3)
d
7.38 (d, J¼9.0 Hz,
1H), 7.06 (d, J¼2.5 Hz, 1H), 6.91 (dd, J¼9.0, 2.5 Hz, 1H), 6.02 (s, 1H),
3.2.3. 5-Methoxy-2-(1H-pyrazol-4-yl)-1,3-benzothiazole (5c). Yield,
3.86 (s, 3H).
94% (216 mg, cream crystal); mp 201e203 ꢁC; IR (KBr)
n
3163 cmꢂ1
Anal. Calcd for C11H8F3NO3: C, 50.98; H, 3.11; N, 5.40. Found: C,
50.88; H, 2.96; N, 5.32.
(NeH); 1H NMR (DMSO-d6)
d 13.44 (br s,1H), 8.50 (br s,1H), 8.07 (br
s, 1H), 7.91 (d, J¼8.8 Hz, 1H), 7.49 (d, J¼2.5 Hz, 1H), 7.00 (dd, J¼8.8,
2.5 Hz, 1H), 3.97 (s, 3H).
3.5. General procedure for the synthesis of 2-(2-
aminopyrimidin-5-yl)-5-methoxy-1,3-benzoxazoles (or 1,3-
benzothiazole) (7aed)
Anal. Calcd for C11H9N3OS: C, 57.13; H, 3.92; N, 18.17. Found: C,
56.98; H, 4.05; N, 18.35.
3.3. General procedures for the demethylation
Compounds 4aed (1 mmol) were added to a mixture of gua-
nidinium chloride (190 mg, 2 mmol), potassium tert-butoxide
(200 mg, 1.8 mmol), and tert-butanol (15 mL), and it was heated at
60 ꢁC for 15 h. Then it was cooled to room temperature and added
to cold water. The resulting precipitate was filtered and recrystal-
lized from EtOAc/hexane to give 7aed.
3.3.1. Method A. Demethylation of 5-methoxy-1,3-benzoxazoles
(5a,b,7a,b, 9a,b or 9d). Boron tribromide (1 M in dichloro-
methane, 3 equiv) was added dropwise at ꢂ78 ꢁC to a suspension of
5a,b, 7a,b, 9a,b or 9d (1 mmol) in CH2Cl2 (5 mL). The mixture was
allowed to warm to room temperature and was stirred overnight.
Then it was poured into cold water (50 mL) and the resulting mixture
was neutralized with NaHCO3, extracted three times with EtOAc and
dried over Na2SO4. The solvent was evaporated and the residue was
purified by preparative TLC (EtOAc) to give 6a,b, 8a,b, 10a,b or 10d.
3.5.1. 2-(2-Aminopyrimidin-5-yl)-5-methoxy-1,3-benzoxazole
(7a). Yield, 88% (212 mg, white crystal); mp 275e276 ꢁC; IR (KBr)
n
3368, 3320 cmꢂ1 (NH2); 1H NMR (DMSO-d6)
d 8.92 (s, 2H), 7.60 (d,
J¼8.8 Hz, 1H), 7.52 (br s, 2H), 7.27 (d, J¼2.5 Hz, 1H), 6.94 (dd, J¼8.8,
2.5 Hz, 1H), 3.82 (s, 3H).
3.3.2. 2-(1H-Pyrazol-4-yl)-1,3-benzoxazol-5-ol (6a). Yield, 91%
(167 mg, cream solid); mp 298e301 ꢁC; IR (KBr): 3462 (OeH),
Anal. Calcd for C12H10N4O2: C, 59.50; H, 4.16; N, 23.13. Found: C,
59.67; H, 4.03; N, 22.96.

6080
S. Rezazadeh et al. / Tetrahedron 69 (2013) 6076e6082
3.5.2. 2-(2-Aminopyrimidin-5-yl)-7-bromo-5-methoxy-1,3-benzoxazole
n d 12.76
3423 (NeH), 1645 cmꢂ1 (C]O); 1H NMR (DMSO-d6)
(7b). Yield, 90% (290 mg, yellowish-white crystal); mp 269e270 ꢁC; IR
(br, 1H, OH), 8.94 (s, 2H), 7.33 (d, J¼2.0 Hz, 1H), 7.22 (d, J¼2.0 Hz, 1H),
(KBr) n d 8.90 (s, 2H), 7.61
3432, 3380 cmꢂ1 (NH2); 1H NMR (DMSO-d6)
3.84 (s, 3H).
(br s, 2H), 7.29 (d, J¼2.0 Hz, 1H), 7.19 (d, J¼2.0 Hz, 1H), 3.82 (s, 3H).
Anal. Calcd for C12H9BrN4O2: C, 44.88; H, 2.82; N, 17.45. Found:
C, 45.04; H, 2.73; N, 17.31.
Anal. Calcd for C12H8BrN3O3: C, 44.74; H, 2.50; N, 13.05. Found:
C, 44.65; H, 2.53; N, 12.98.
3.6.3. 5-(5-Methoxy-1,3-benzoxazol-2-yl)-6-trifluoromethylpyrimidin-
2(1H)-one (9d). Yield, 62% (240 mg, cream crystal); mp 185e188 ꢁC; IR
3.5.3. 2-(2-Aminopyrimidin-5-yl)-5-methoxy-1,3-benzothiazole(7c). Yield,
85% (220 mg, yellow crystal); mp 258e260 ꢁC; IR (KBr)
n
3477, 3420 cmꢂ1
(KBr) n
3414 (NeH), 1711 (C]O), 1186, 1126 cmꢂ1 (CF3); 1H NMR (DMSO-
(NH2); 1H NMR (DMSO-d6)
d
8.85 (s, 2H), 7.95 (d, J¼8.8 Hz, 1H), 7.53 (d,
d6þD2O) 7.62 (s, 1H), 7.49 (d, J¼8.5 Hz, 1H), 7.16 (s, 1H), 6.88 (d, J¼8.5 Hz,
d
J¼2.5 Hz, 1H), 7.41 (br s, 2H), 7.04 (dd, J¼8.8, 2.5 Hz, 1H), 3.84 (s, 3H).
Anal. Calcd for C12H10N4O2S: C, 55.80; H, 3.90; N, 21.69. Found:
C, 55.97; H, 3.93; N, 21.61.
1H), 3.78 (s, 3H).
Anal. Calcd for C13H8F3N3O3: C, 50.17; H, 2.59; N,13.50. Found: C,
49.97; H, 2.83; N, 13.34.
3.5.4. 2-(2-Amino-4-trifluoromethylpyrimidin-5-yl)-5-methoxy-1,3-
benzoxazole (7d). Yield, 89% (275 mg, brown solid); mp 243e245 ꢁC;
3.6.4. 5-(5-Hydroxy-1,3-benzoxazol-2-yl)pyrimidin-2(1H)-one
(10a). Yield, 80% (277 mg, cream solid); mp >300 ꢁC; IR (KBr)
n 3492,
IR (KBr)
d6)
n
3455, 3367 (NH2), 1190, 1124 cmꢂ1 (CF3); 1H NMR (DMSO-
3406 (NeH, OeH), 1650 cmꢂ1 (C]O); 1H NMR (DMSO-d6þD2O)
d
9.04 (s, 1H), 8.03 (2br s, 2H), 7.67 (d, J¼9.0 Hz, 1H), 7.37 (d,
d
9.05 (s, 2H), 7.55 (d, J¼8.8 Hz, 1H), 7.33 (d, J¼2.5 Hz, 1H), 6.90 (dd,
J¼2.0 Hz, 1H), 7.01 (dd, J¼9.0, 2.0 Hz, 1H), 3.82 (s, 3H).
Anal. Calcd for C13H9F3N4O2: C, 50.33; H, 2.92; N, 18.06. Found:
C, 50.45; H, 3.11; N, 17.97.
J¼8.8, 2.5 Hz, 1H).
Anal. Calcd for C11H7N3O3: C, 57.65; H, 3.08; N, 18.33. Found: C,
57.82; H, 2.90; N, 18.57.
3.5.5. 2-(2-Aminopyrimidin-5-yl)-1,3-benzoxazol-5-ol (8a). Yield, 90%
3.6.5. 5-(5-Hydroxy-7-bromo-1,3-benzoxazol-2-yl)pyrimidin-2(1H)-
(203 mg, cream solid); mp >300 ꢁC; IR (KBr)
n
3475, 3430, 3402 cmꢂ1
one (10b). Yield, 95% (290 mg, light cream solid); mp >300 ꢁC; IR
(NH2, OH); 1H NMR (DMSO-d6)
d
9.49 (br s, 1H), 8.90 (s, 2H), 7.50 (br s,
(KBr)
d6) 12.76 (br s,1H, NH),10.08 (br s, 0.65H, OH), 9.92 (br s, 0.35H, OH),
n
3475, 3623 (NeH, OeH), 1645 cmꢂ1 (C]O); 1H NMR (DMSO-
2H), 7.47 (d, J¼8.75 Hz, 1H), 7.01 (d, J¼2.35 Hz, 1H), 6.77 (dd, J¼8.75,
d
2.35 Hz, 1H).
9.39 (s, 0.65H), 9.31 (s, 0.65H), 8.90 (br s, 0.7H), 7.15 (s, 0.65H), 7.14 (s,
0.65H), 7.03 (s, 0.35H), 7.00 (s, 0.35H).
Anal. Calcd for C11H6BrN3O3: C, 42.88; H,1.96; N,13.64. Found: C,
43.12; H, 2.12; N, 13.50.
Anal. Calcd for C11H8N4O2: C, 57.89; H, 3.53; N, 24.55. Found: C,
58.10; H, 3.69; N, 24.36.
3.5.6. 2-(2-Aminopyrimidin-5-yl)-7-bromo-1,3-benzoxazol-5-ol
(8b). Yield, 94% (290 mg, cream solid); mp >300 ꢁC; IR (KBr)
n
3415,
3.6.6. 5-(5-Hydroxy-1,3-benzoxazol-2-yl)-6-trifluoromethylpyrimidin-
2(1H)-one (10d). Yield, 91% (270 mg, light cream solid); mp
3487, 3327 cmꢂ1 (NH2, OH); 1H NMR (DMSO-d6)
d 9.88 (br s, 1H), 8.89
(s, 2H), 7.59 (br s, 2H), 7.03 (d, J¼1.9 Hz, 1H), 6.99 (d, J¼1.9 Hz, 1H).
Anal. Calcd for C11H7BrN4O2: C, 43.02; H, 2.30; N,18.24. Found: C,
43.21; H, 2.06; N, 18.13.
183e186 ꢁC; IR (KBr)
n 3487, 3376 (NeH, OeH), 1717 (C]O) 1183,
1132 cmꢂ1 (CF3); 1H NMR (DMSO-d6þD2O)
d 7.60 (s, 1H), 7.39 (d,
J¼8.5 Hz, 1H), 6.94 (s, 1H), 6.73 (d, J¼8.5 Hz, 1H).
Anal. Calcd for C12H5BrF3N3O3: C, 38.32; H, 1.34; N, 11.17. Found:
C, 38.48; H, 1.11; N, 11.29.
3.5.7. 2-(2-Aminopyrimidin-5-yl)-1,3-benzothiazol-5-ol (8c). Yield, 84%
(203 mg, cream solid); mp >300; IR (KBr)
n
3475, 3452, 3416 cmꢂ1
(NH2, OH); 1H NMR (DMSO-d6)
d
9.75 (br s,1H, OH), 8.83 (s, 2H), 7.84 (d,
3.7. General procedure for the synthesis of
2-(6-bromopyridin-3-yl)-5-methoxy-1,3-benzoxazoles
(12a,b)
J¼9.0 Hz, 1H), 7.39 (br s, 2H, NH2), 7.30 (d, J¼2.0 Hz, 1H), 6.9 (dd, J¼9.0,
2.0 Hz, 1H).
Anal. Calcd for C11H8N4OS: C, 54.09; H, 3.30; N, 22.94. Found: C,
53.90; H, 3.46; N, 23.10.
To a solution of 2-amino-4-methoxyphenol derivative (2a,b,
2.15 mmol) in dry methanol was added 6-bromo-3-pyri-
dinecarboxaldehyde (400 mg, 2.15 mmol). The resulting mixture
was stirred at room temperature overnight and then solvent was
evaporated to dryness under reduced pressure. The residue was
taken up in CH2Cl2 (10 mL) and DDQ (550 mg, 1.1 equiv) was added.
After stirring at room temperature for 45 min, the resulting mixture
was diluted with CH2Cl2 (10 mL) and washed sequentially with
saturated Na2CO3 (2ꢃ10 mL) and brine (10 mL). The organic layer
was dried over Na2SO4 and evaporated to give a brown solid. The
crude was purified by flash chromatography (CH2Cl2/hexane; 1:1) to
give 12a,b.
3.6. General procedure for the synthesis of 5-(5-methoxy-1,3-
benzoxazol-2-yl)pyrimidin-2(1H)-one (9a,b or 9d)
To an ice cooled suspension of 7a,b or 7d (1 mmol) in acetic acid/
water (30 mL, 1:1) was added hydrochloric acid (37 percent, 2 mL)
and then a solution of NaNO2 (5 equiv) in water over 10 min. The
mixture was heated to 70 ꢁC for 3 h. It was cooled to room tem-
perature, neutralized with NaHCO3, extracted with EtOAc, dried over
Na2SO4, and the solvent was evaporated under reduced pressure.
The residue was recrystallized from EtOAc/hexane to give 9a,b or 9d.
3.6.1. 5-(5-Methoxy-1,3-benzoxazol-2-yl)pyrimidin-2(1H)-one
3.7.1. 2-(6-Bromopyridin-3-yl)-5-methoxy-1,3-benzoxazole
(9a). Yield, 61% (148 mg, cream crystal); mp 270 ꢁC (dec); IR (KBr)
n
(12a). The physical and spectral data of 12a was similar to those reported.38
1
3416 (NeH), 1619 cmꢂ1 (C]O); H NMR (DMSO-d6)
d 9.48 (br s, 1H,
OH), 8.93 (s, 2H), 7.61 (d, J¼9.0 Hz, 1H), 7.29 (d, J¼2.5 Hz, 1H), 6.96 (dd,
3.7.2. 7-Bromo-2-(6-bromopyridin-3-yl)-5-methoxy-1,3-
J¼9.0, 2.5 Hz, 1H), 3.80 (s, 3H).
benzoxazole (12b). Yield, 67% (555 mg, light cream solid); mp
Anal. Calcd for C12H10N3O3: C, 59.26; H, 3.73; N, 17.28. Found: C,
59.43; H, 3.90; N, 17.41.
210e212 ꢁC; 1H NMR (CDCl3)
d
9.22 (d, J¼2.5 Hz, 1H), 8.36 (dd,
J¼8.0, 2.5 Hz, 1H), 7.69 (d, J¼8.5 Hz, 1H), 7.21 (d, J¼2.0 Hz, 1H), 7.19
(d, J¼2.0 Hz, 1H), 3.88 (s, 3H).
3.6.2. 5-(7-Bromo-5-methoxy-1,3-benzoxazol-2-yl)pyrimidin-2(1H)-
one (9b). Yield, 65% (210 mg, cream crystal); mp 202e204 ꢁC; IR (KBr)
Anal. Calcd for C13H8Br2N2O2: C, 40.66; H, 2.10; N, 7.29. Found: C,
40.79; H, 2.26; N, 7.15.

S. Rezazadeh et al. / Tetrahedron 69 (2013) 6076e6082
6081
3.8. General procedure for the synthesis of 2-(6-
benzyloxypyridin-3-yl)-5-methoxy-1,3-benzoxazole (13a,b)
overnight. The resulting mixture was filtered through Celite and
concentrated under reduced pressure, purified by preparative TLC
(EtOAc) to give 16 (38 mg) as a brown solid. Yield, 96%; mp
To a mixture of benzyl alcohol (130 mg, 1.2 mmol), potassium
tert-butoxide (130 mg, 1.16 mmol) in dry THF (10 mL) was added
12a,b (1 mmol). The resulting mixture was stirred at room temper-
ature for 12 h and then poured into cold water. The precipitated solid
was filtered and recrystallized from CH2Cl2/hexane to give 13a,b.
246e249 ꢁC; IR (KBr)
n
3506, 3405 (NeH, OeH), 1657 (C]O),
1387 cmꢂ1 (doublet, eCH(CH3)2); 1H NMR (CD3OD)
d
8.30 (s, 0.5H),
8.25 (d, J¼8.5 Hz, 0.5H), 7.67e7.55 (m, 1.5 H), 6.87 (s, 1H), 6.73
(s, 1H), 6.65 (d, J¼8.5 Hz, 0.5H), 3.50e3.47 (m, 1H), 1.39 (d,
J¼7.0 Hz, 6H).
Anal. Calcd for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C,
66.80, H, 5.37, N, 10.22.
3.8.1. 2-(6-Benzyloxypyridin-3-yl)-5-methoxy-1,3-benzoxazole (13a). Yield,
93% (283 mg, light cream crystal); mp 178e180 ꢁC; 1H NMR (DMSO-d6)
d
8.96 (d, J¼2.2 Hz, 1H), 8.40 (dd, J¼8.7, 2.2 Hz, 1H), 7.67 (d, J¼8.9 Hz, 1H),
Acknowledgements
7.34e7.49 (m, 6H), 7.10 (d, J¼8.7 Hz, 1H), 6.99 (dd, J¼8.9, 2.5 Hz, 1H), 5.46
(s, 2H), 3.82 (s, 3H).
This work was supported by a grant from Research Council of
Tehran University of Medical Sciences.
Anal. Calcd for C20H16N2O3: C, 72.28; H, 4.85; N, 8.43. Found: C,
72.11; H, 4.99; N, 8.24.
References and notes
3.8.2. 7-Bromo-2-(6-benzyloxypyridin-3-yl)-5-methoxy-1,3-
benzoxazole (13b). Yield, 96% (394 mg, light cream crystal); mp
1. Mueck, A. O. J. Reproduktionsmed. Endokrinol. 2010, 7, 220.
2. Wright, J. S.; Shadnia, H.; Anderson, J. M.; Durst, T.; Asim, M.; El-Salfiti, M.;
Choueiri, C.; Pratt, M. A. C.; Ruddy, S. C.; Lau, R.; Carlson, K. E.; Katzenellenb-
ogen, J. A.; O’Brien, P. J.; Wan, L. J. Med. Chem. 2011, 54, 433.
3. O’Brien, P. J. Chem. Biol. Interact. 1991, 80, 1.
160e163 ꢁC; 1H NMR (DMSO-d6)
d
8.94 (s,1H), 8.37 (d, J¼7.8 Hz,1H),
7.24e7.48 (m, 6H), 7.10 (s, 1H), 7.09 (s, 1H), 5.46 (s, 2H), 3.83 (s, 3H).
Anal. Calcd for C20H15BrN2O3: C, 58.41; H, 3.68; N, 6.81. Found: C,
58.18; H, 3.83; N, 19.45.
4. Sarabia, S. F.; Zhu, B. T.; Kurosawa, T.; Tohma, M.; Liehr, J. G. Chem. Res. Toxicol.
1997, 10, 767.
5. Pezzella, A.; Lista, L.; Napolitano, A.; d’Ischia, M. Chem. Res. Toxicol. 2005, 18,
1413.
6. Cavalieri, E.; Chakravarti, D.; Guttenplan, J.; Hart, E.; Ingle, J.; Jankowiak, R.;
Muti, P.; Rogan, E.; Russo, J.; Santen, R.; Sutter, T. Biochim. Biophys. Acta-Rev.
Cancer 2006, 1766, 63.
7. Zhang, F.; Chen, Y.; Pisha, E.; Shen, I.; Xioong, Y.; van Breemen, R. B.; Bolton, J. L.
Chem. Res. Toxicol. 1999, 12, 204.
8. Bolton, J. L. Toxicology 2002, 177, 55.
9. Liu, X.; Yao, J.; Pisha, E.; Yang, Y.; Hua, Y.; van Breemen, R. B.; Bolton, J. L. Chem.
3.8.3. 5-(5-Hydroxy-1,3-benzoxazol-2-yl)pyridin-2(1H)-one (14a). It
was prepared starting from 13a and according to method A. Yield, 92%
(210 mg, light cream solid); mp >300 ꢁC; IR (KBr)
n
3476 (OH),
1638 cmꢂ1 (C]O); 1H NMR (DMSO-d6)
d 12.22 (br s,1H), 9.48 (br s,1H),
8.18 (d, J¼2.5 Hz,1H), 8.04 (dd, J¼9.6, 2.5 Hz,1H), 7.47 (d, J¼8.7 Hz,1H),
7.00 (d, J¼2.2 Hz,1H), 6.77 (dd, J¼8.7, 2.2 Hz,1H), 6.50 (d,1H, J¼9.6 Hz).
Anal. Calcd for C12H8N2O3: C, 63.16; H, 3.53; N, 12.28. Found: C,
62.92; H, 3.69; N, 12.42.
Res. Toxicol. 2002, 15, 512.
10. Liu, X.; Zhang, F.; Liu, H.; Burdette, J. E.; Li, Y.; Cassia, R. O.; Pisha, M.; Yao, J.; van
Breemen, R. B.; Swanson, S. M.; Bolton, J. L. Chem. Res. Toxicol. 2003, 16, 741.
11. Yu, L.; Liu, H.; Li, W.; Zhang, F.; Luckie, C.; van Breemen, R. B.; Thatcher, G. R. J.;
Bolton, J. L. Chem. Res. Toxicol. 2004, 17, 879.
12. Cavalieri, E. L.; Rogan, E. G.; Chakravarti, D. Cell. Mol. Life Sci. 2002, 59, 665.
13. Cavalieri, E.; Rogan, E.; Chakravarti, D. Methods Enzymol. 2004, 382B, 293
Quinones and Quinone Enzymes.
14. Zahid, M.; Kohli, E.; Saeed, M.; Rogan, E.; Cavalieri, E. Chem. Res. Toxicol. 2006,
19, 164.
15. Liehr, J. G. Hum. Reprod. Update 2001, 10, 273.
3.8.4. 5-(7-Bromo-5-hydroxy-1,3-benzoxazol-2-yl)pyridin-2(1H)-one
(14b). It was prepared starting from 13b and according to method
A. Yield, 90% (277 mg, light cream solid); mp 276e280 ꢁC; IR (KBr)
n
3422 (OH), 1669 cmꢂ1 (C]O); 1H NMR (DMSO-d6)
d 10.11 (br s,
0.5H), 9.54 (br s, 0.5H), 9.07 (d, J¼1.5 Hz, 0.5H), 8.38 (dd, J¼8.3,
1.5 Hz, 0.5H), 8.18 (d, J¼1.5 Hz, 0.5H), 8.00 (dd, J¼9.5, 1.5 Hz, 0.5H),
7.89 (d, J¼8.3 Hz, 0.5H), 7.14 (s, 0.5H), 7.13 (s, 0.5H), 7.02 (s, 0.5H),
7.00 (s, 0.5H), 6.51 (d, J¼9.5 Hz, 0.5H).
16. Kuiper, G. G. J.; Carlsson, B.; Grandien, K.; Enmark, E.; Haggblad, J.; Nilsson, S.;
Gustafsson, J. Endocrinology 1997, 138, 863.
17. Kuiper, G. G. J.; Lemmen, J. G.; Carlsson, B.; Corton, J. C.; Safe, S. H.; van der Saag,
P. T.; van der Burg, B.; Gustafsson, J. Endocrinology 1998, 139, 4252.
18. Dahlman-Wright, K.; Cavailles, V.; Fuqua, S. K.; Jordan, V. C.; Katzenellenbogen,
J. A.; Korach, K. S.; Maggi, A.; Muramatsu, M.; Parker, M. G.; Gustafsson, J.-A.
Pharmacol. Rev. 2006, 58, 773.
Anal. Calcd for C12H7BrN2O3: C, 46.93; H, 2.30; N, 9.12. Found: C,
50.12; H, 2.14; N, 9.01.
3.9. Synthesis of 5-(7-isopropenyl-5-hydroxy-1,3-benzoxazol-
2-yl)pyridin-2(1H)-one (15)
19. Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 4230.
20. Sun, J.; Baudry, J.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Mol.
Endocrinol. 2003, 17, 247.
21. Miller, C. P.; Collini, M. D.; Harris, H. A. Bioorg. Med. Chem. Lett. 2003, 13, 2399.
22. (a) Korach, K. S.; Sarver, O.; Chae, K.; McLachlan, J. A.; McKinney, J. D. Mol.
Pharmacol. 1998, 33, 120; (b) Edsall, R. J.; Harris, H. A.; Manas, E. S.; Mewshaw,
R. E. Bioorg. Med. Chem. 2003, 11, 3457.
To a stirred suspension of 14b (92 mg, 0.3 mmol), iso-
propenylboronic acid (77 mg, 0.9 mmol) and Pd[Ph3P]4 (20 mg) in
dimethoxyethane (2 mL) was added a solution of Cs2CO3 (1 mL,
2 M) and the resulting mixture was heated at 110 ꢁC for 24 h under
argon. It was cooled, diluted with water, extracted with EtOAc and
dried over Na2SO4 and the solvent was evaporated under reduced
pressure. The residue was purified by preparative TLC to give 15
23. Barlaam, B.; Bernstein, P.; Dantzman, C.; Warwick, P. WO 2002051821, 2002.
24. Bernstein, P. WO 2003025930, 2003.
25. Malamas, M. S.; Manas, E. S.; MaDevitt, R. E.; Gunawan, I.; Xu, Z. B.; Collini, M.
D.; Miller, C. P.; Dinh, T.; Henderson, R. A.; Keith, J. C., Jr.; Harris, H. A. J. Med.
Chem. 2004, 47, 5021.
26. Allahyari-Devin, M.; Abedi, B.; Navidpour, L.; Shafiee, A. J. Iran. Chem. Soc. 2013,
10, 43.
(69 mg, light brown solid). Yield, 86%; mp 152e155 ꢁC; IR (KBr)
n
3467, 3414 (NeH, OeH), 1664 cmꢂ1 (C]O); 1H NMR (CD3OD)
d
8.30
27. (a) Anstead, G. M.; Carlson, K. E.; Katzenellenbogen, J. A. Steroids 1997, 62, 268;
(b) Ekena, K.; Weis, K. E.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S. J. Biol.
Chem. 1997, 272, 5069; (c) Carlson, K. E.; Choi, I.; Gee, A.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. Biochemistry 1997, 36, 14897; (d) De Angelis, M.; Stossi,
F.; Carlson, K. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem.
2005, 48, 1132.
(dd, J¼8.5, 1.5 Hz, 1H), 8.22 (d, J¼1.5 Hz, 1H), 6.99 (s, 1H), 6.88 (s,
1H), 6.68 (d, J¼8.5 Hz, 1H), 5.85 (s, 1H), 5.44 (s, 1H), 2.27 (s, 3H).
Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C,
67.02, H, 4.73, N, 10.27.
28. Clarke, H. T.; Hartman, W. W. Organic Syntheses; 1941; Collect. 1455.
29. Zablocki, J.; Ibrahim, P. N.; Shenk, K.; Elzin, E.; Palle, V. U.S. 6,573,264, 2003.
30. Nair, J. S.; Rajasekharan, K. N. Indian J. Chem., Sect. B 2004, 43, 1944.
31. Helliwell, M.; Afghan, A.; Baradarani, M. M.; Joule, J. A. Acta Crystallogr. 2006,
E62, o737.
3.10. Synthesis of 5-(7-isopropyl-5-hydroxy-1,3-benzoxazol-
2-yl)pyridin-2(1H)-one (16)
Compound 15 (40 mg, 0.15 mmol) in methanol (5 mL) was hy-
drogenated over Pd/C (10%, 8 mg) under atmospheric pressure
32. Baradarani, M. M.; Afghan, A.; Zebarjadi, F.; Hasanzadeh, K.; Joule, J. A. J. Het-
erocycl. Chem. 2006, 43, 1591.

6082
S. Rezazadeh et al. / Tetrahedron 69 (2013) 6076e6082
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