Indium-mediated one-pot synthesis of benzoxazoles or oxazoles from 2-nitrophenols or 1-aryl-2-nitroethanones

Article abstract of DOI:10.1016/j.tet.2009.08.059

One-pot reduction-triggered heterocyclizations from 2-nitrophenols to benzoxazoles and from 1-aryl-2-nitroethanones to oxazoles were investigated. In the presence of indium/AcOH in benzene at reflux, 2-nitrophenols and R-C(OMe)₃ (R=H, Me, Ph) produced excellent yields of corresponding benzoxazoles within an hour. Similarly, 1-aryl-2-nitroethanones and Ph-C(OMe)₃ in the presence of indium/AcOH in acetonitrile transformed into the corresponding oxazoles with good yields.

Full text of DOI:10.1016/j.tet.2009.08.059

Tetrahedron 65 (2009) 8821–8831
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Indium-mediated one-pot synthesis of benzoxazoles or oxazoles
from 2-nitrophenols or 1-aryl-2-nitroethanones
,
Jung June Lee a, Jihye Kim a, Young Moo Jun a, Byung Min Lee b, Byeong Hyo Kim a
*
a Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
b Korea Research Institute of Chemical Technology, Taejon 305-600, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2009
Received in revised form 22 August 2009
Accepted 25 August 2009
Available online 28 August 2009
One-pot reduction-triggered heterocyclizations from 2-nitrophenols to benzoxazoles and from 1-aryl-2-
nitroethanones to oxazoles were investigated. In the presence of indium/AcOH in benzene at reflux, 2-
nitrophenols and R–C(OMe)3 (R¼H, Me, Ph) produced excellent yields of corresponding benzoxazoles
within an hour. Similarly, 1-aryl-2-nitroethanones and Ph–C(OMe)3 in the presence of indium/AcOH in
acetonitrile transformed into the corresponding oxazoles with good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
working to utilize indium for efficient reductive organic trans-
formations6 that include various indium-mediated reductive hetero-
N,O-Heteroatom-containing oxazole or benzoxazole ring systems
occur occasionally in nature and oxazole moiety is a popular het-
erocyclic unit of biologically active and pharmaceutically interesting
compounds.1 It has been claimed that oxazole and its derivatives act
as diverse medicinal mediators, such as anti-inflammatory agents,
fungicides, adrenergic antagonists, anti-hypertensive agents, and
anti-ulcer agents.1b More recently, benzoxazole derivatives, such as
UK-1andtheiranalogs,havebeenactivelyinvestigatedastheyexhibit
a wide range of potent anticancer activities against leukemia, lym-
phoma, and certain solid tumor-derived cell lines.2
Thus, various synthetic methods of oxazole and benzoxazole
derivatives have been developed, including one of the most reliable
methods, the Robinson–Gabriel synthesis.1,3 Recent examples of
the oxazole or benzoxazole ring formations include the combina-
torial library synthesis via the condensation of aldehydes with
2-aminophenols/subsequent DDQ-promoted oxidative cyclization
reactions,4a solvent-free microwave irradiation of ketones,4b ru-
thenium and/or gold-catalyzed one-pot reactions of propargylic
alcohols with amides4c or propargylic amides,4d copper-catalyzed
cyclizations of o-halobenzanilides,4e and Cu-nanoparticle catalyzed
oxidative cyclization of Schiff’s bases.4f
cyclizations via the reductive cyclization reaction of nitroarenes
toward nitrogen-containing heterocycles, such as 2,1-benzisoxazo-
les,6a benzimidazoles,6e quinolines,6f indazoles,6g,h andindoles6i when
there is a proper functional group at the ortho position.
Among the indium-mediated reactions we have previously de-
veloped, most are intramolecular heterocyclization reactions that are
preceded by a reduction-triggered one-pot reaction of nitroarenes.
The intermolecular reaction with 2-nitroanilines/benzaldehyde in
the presence of indium and 2-bromo-2-nitropropane was not very
successful, resulting in a mixture of two products.6e More recently,
we discovered an interesting reaction that is a one-pot reaction of
a reduction-triggered aza-Michael type addition of nitroarenes to
vinyl sulfones,7 which is triggered by the reductive reaction of the
nitro group followed by the 1,4-addition of an in situ formed nitrogen
nucleophile to the a,b-unsaturated vinyl sulfones. This implies that
the intermolecular one-pot reductive heterocyclizations of nitro-
arenes should be possible if the reduction of the nitroarene versus the
coupling reaction between the nitroarene substrate and coupling
reagent is properly controlled. Herein we report the one-pot reaction
of indium-reduction-triggered intermolecular heterocyclizations
toward benzoxazoles or oxazoles starting from 2-nitrophenols or
1-aryl-2-nitroethanones and proper orthoesters as a counter-part
coupling reagent.
The applications of indium metal for a wide range of organic
transformations have been receiving increasing interest in the past
decade because of the metal’s eco-friendly green chemistry charac-
teristics.5 Indium metal is stable in air, moreover, the toxicity ob-
served with many metals acting as a single-electron transfer (SET)
agent is little known in indium. Thus, we have been continuously
2. Results and discussion
2.1. Indium-mediated reductive reaction toward
benzoxazoles
For the reductive intermolecular reaction toward benzoxazole
ring formation, orthoesters such as trimethyl orthoformate (1),
* Corresponding author. Fax: þ82 2 942 4635.
E-mail address: bhkim@kw.ac.kr (B.H. Kim).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.059

8822
J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
trimethyl orthoacetate (2), and trimethyl orthobenzoate (3) were
elected as the counter-part of the 2-nitrophenols. In the literature,
there are several examples of benzimidazole production starting
from arylenediamines and orthoesters,8 which were done in the
presence of catalysts such as KSF clay,8a Yb(OTf)3,8b Zeolite,8c
iodine,8d Lewis acids,8e and sulfamic acid.8f Thus, orthoesters should
be good candidates for the coupling reaction if the nitro group on
the 2-nitrophenols that is timely reduced prior to cyclization.
(entry 14) or protic solvents (entries 15 and 16) proceeded poorly.
After the various reaction conditions were examined, the reaction
condition with 2-nitrophenol (1 equiv)/orthoester (4 equiv)/in-
dium (4 equiv)/AcOH (10 equiv) in benzene at reflux (entry 3) was
elected as the most optimized condition.
With the optimum reaction condition obtained, the indium/
acetic acid-promoted intermolecular heterocyclization of 2-nitro-
phenol with orthoester to benzoxazole was applied to hetero-
cyclizations of variously substituted 2-nitrophenols with
orthoesters to verify the synthetic utilization. Thus, heterocycliza-
tions of variously substituted 2-nitrophenols with orthoesters were
OMe
OMe
OMe
1; R = H
2; R = Me
3; R = Ph
R
Various control experiments were examined to determine the
proper reaction condition for the reduction-initiated heterocycliza-
tion of 2-nitrophenols with orthoesters using indium and wide
ranges of Lewis acidoracid additives, such as InCl3, I2, AcOH, and HI or
radical anion-producing 2-bromo-2-nitropropane6a in various sol-
vent systems. Reactions of 2-nitrophenol and orthoester in the
presence of indium/iodine or indium/2-bromo-2-nitropropane usu-
ally produce low yields with the starting 2-nitrophenol recovered.
Reactions of 2-nitrophenol and orthoester in the presence of the
indium/HI, neither organic products nor starting 2-nitrophenol
were recovered from the reactions of 2-nitrophenol and
orthoester as well. Meanwhile, reactions of 2-nitrophenol and
orthoester in the presence of indium/InCl3 in THF/H2O (v/v¼5/1)
at 50 ꢀC for 4 h produced 2-aminophenol in low yield (w10–
15%), instead of the desired benzoxazole product. However, 2-
nitrophenol and orthoester in the presence of indium with
a weak acid such as acetic acid produced the desired benzox-
azole within a short reaction time. For our indium-mediated
intermolecular heterocyclizations, acetic acid seemed to be the
best candidate as an additive for our reductive heterocyclization.
To obtain the optimum conditions for benzoxazole formation,
various reaction conditions in the presence of indium/acetic
acid were examined, as shown in Table 1.
Table 2
Indium/acetic acid-mediated reductive heterocyclization of various 2-nitrophenols
(1 mmol) to trimethyl orthoesters (4 equiv) in the presence of indium (4 equiv) and
acetic acid (10 equiv) in benzene at reflux for 1 h
OH
OMe
R2
OMe
In, AcOH
R1
O
N
+
R1
MeO
R2
Benzene, reflux, 1 hr
NO2
Entry
Substrate
R2
Product
Yielda (%)
1
2
3
H
Me
Ph
69
92
97
OH
(5)
(6)
(7)
O
R2
N
NO2
4
5
6
H
Me
Ph
83
86
97
OH
(8)
(9)
(10)
O
N
R2
R2
MeO
MeO
NO2
OH
MeO
MeO
(11)
(12)
(13)
7
8
9
H
Me
Ph
87
98
98
O
N
NO2
OH
(14)
(15)
(16)
10
11
12
H
Me
Ph
71
O
N
R2
88
96b
NO2
Table 1
Indium-mediated reductive heterocyclizations of 2-nitrophenol (1 mmol) to tri-
methyl orthoacetate under various conditions
13
14
15
H
Me
Ph
73
89
98
OH
(17)
(18)
(19)
O
R2
OH
OMe
O
N
NO2
N
In, AcOH
+
MeO
solvent / temp
NO2
OMe
16
17
18
H
Me
Ph
77
95
98
OH
(20)
(21)
(22)
O
N
4
2
R2
NO2
Entry Molar equiv
Solvent (mL)/Temp (ꢀC)
Time (h) Yielda (%)
4
2
In AcOH
19
20
21
H
Me
Ph
(23)
(24)
(25)
81c
OH
O
94c
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
4
6
4
2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5
3
4
4
4
4
4
4
4
4
4
4
10
10
10
10
10
10
5
20
10
10
10
10
10
10
10
10
Benzene(5)/reflux
Benzene(5)/reflux
Benzene(5)/reflux
Benzene(5)/reflux
Benzene(5)/reflux
Benzene(5)/reflux
Benzene(5)/reflux
Benzene(5)/reflux
Benzene(5)/50
Toluene(5)/reflux
p-Xylene(5)/reflux
CHCl3(5)/reflux
CH3CN(5)/reflux
THF(5)/reflux
6
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
95
95
R2
98b,c
N
Br
Cl
NO2
96(92b)
73
Br
Cl
94
22
23
24
H
Me
Ph
81
(26)
(27)
(28)
OH
O
N
93c
89c
96
87
R2
95b
NO2
9
Tracec
84
10
11
12
13
14
15
16
OH
(29)
(30)
(31)
25
26
27
H
Me
Ph
50
O
82
89
93
R2
70
92b
N
F
F
NO2
OH
F
F
Tracec
Tracec
Trace
MeOH(5)/reflux
MeOH(5), satd NH4Cl(3)/reflux
(32)
(33)
(34)
28
29
30
H
Me
Ph
53
84
94
O
N
R2
a
GC yield with an internal standard.
Isolated yield.
Substrate (4) remained (entry 9: 94%, entry 14: 82%, entry 15: 91%).
NO2
b
c
a
Isolated yield.
b
After satd aq NH4Cl work-up, the concentrated organic layer was added to
MeOH/10 M aq NaOH solution (8 mL/2 mL), stirred for 0.5 h at room temperature for
the methyl benzoate removal that overlapped with the product on TLC, and
extracted with CH2Cl2/satd aq NH4Cl.
As shown in Table 1, most reactions in an aprotic solvent, such as
benzene, toluene, p-xylene, chloroform, and acetonitrile did pro-
ceed well at reflux (entries 1–13), whereas the reactions in THF
c
Debrominated benzoxazole trace was detected on GC–MS.

J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
8823
examined using the optimized reaction conditions. In most cases,
the heterocyclization reaction appeared to be generally applicable,
as most of the reactions were completed within 1 h to produce the
corresponding benzoxazoles with reasonable yields (Table 2). In
general, reactions of 2-nitrophenols with trimethyl orthoacetate (2)
or trimethyl orthobenzoate (3) produced excellent yields of ben-
zoxazoles without any electronic effect from the substituent. On the
contrary, the reactions of 2-nitrophenols with trimethyl ortho-
formate (1) produced relatively lower yields of benzoxazoles
compared to the reactions of 2-nitrophenols with 2 or 3. Moreover,
the strong inductive effect significantly lowered the yields (Table 2,
entries 25 and 28), which was not much observed in the reactions
of 2-nitrophenols with 2 or 3. This implies the possibility of mod-
ified intermediate formation prior to cyclization, changes of rate-
determining step in the reaction path, and/or interferences by
undesired intermediate formation. Mechanistic considerations will
be discussed in detail in Section 3.
result in a reduction potential change that would be similar in value
to that of nitroarenes. From the cyclic voltammetric response of
2-nitrophenol (0.10 M) obtained in 0.10 M tetrabutylammonium
tetrafluoroborate in acetonitrile solution (platinum electrode, scan
rate 50 mV/s), the reduction potential of 2-nitrophenol was ob-
served at ꢁ0.99 V (Fig. 1). Similarly, 2-nitro-1-phenylethanone
showed a reduction peak at ꢁ1.08 V at the same cyclic voltam-
metric condition, probably because of the enol-form contribution
as shown in Eq.1, which implies the possibility of successful hetero-
cyclization of reduction-triggered oxazole ring formation similar to
that of benzoxazole ring formation.
R1
R1
O
OH
ð1Þ
NO2
NO2
Thus, a reaction condition similar to that applied to benzoxazole
ring formation was attempted with 2-nitro-1-phenylethanone
with orthoesters. Unfortunately, 2-nitro-1-phenylethanone with
orthoesters in the presence of indium/AcOH in benzene did not work
well and mostly resulted in poor yields of the desired oxazoles.
However, 2-nitro-1-phenylethanone with trimethyl orthobenzoate
did start working after the reaction condition was varied, particularly
by changing the solvent. After the various reactions were examined,
the optimum reaction condition was determined: 2-nitro-1-phenyl-
ethanone (1 mmol) with trimethyl orthobenzoate (4 equiv) in the
presence of indium (4 equiv)/AcOH (10 equiv) in acetonitrile (15 mL)
at reflux, which was analogous to the optimum reaction condition of
benzoxazole synthesis, except for the solvent. This condition pro-
duced the 2,5-diphenyl-substituted oxazole with a good yield (60%,
Scheme 1, Eq. 4), whereas the reactions of 2-nitro-1-phenylethanone
with trimethyl orthoformate or trimethyl orthoacetate failed to
produce a reasonable yield of oxazole formation. The reaction failure
with trimethyl orthoformate or trimethyl orthoacetate presumably
arises from the thermodynamic driving force difference of the pro-
duced oxazoles or the difficulties of the desired intermediate for-
mation, since the conjugative effect of the 5-aryloxazoles (products
from trimethyl orthoformate or trimethyl orthoacetate) is not as
strong as that of 5-aryl-2-phenyl-substituted oxazoles (products from
trimethyl orthobenzoate). Despite the failure with trimethyl ortho-
formate (1) or trimethyl orthoacetate (2), the methodology with
2.2. Indium-mediated reductive reaction toward oxazoles
As reduction-initiated heterocyclizations of 2-nitrophenols with
orthoesters using indium/acetic acid were successful, it may be
worth attempting to carry out the syntheses not only with ben-
zoxazoles, but also with oxazoles from proper substrates using
a similar reaction condition. One of the important key points of
success would be the reduction potential of the substrate, as the
nitro group should first be reduced properly to form the imidate
intermediate prior to heterocyclization. Aliphatic nitro compounds
have less chance for the well-timed reduction, as their reduction
potentials are more negative than those of aromatic nitro com-
pounds. However, aliphatic compounds such as 1-aryl-2-nitro-
ethanones could be good candidates for our reduction-triggered
oxazole ring formation. As shown in Eq. 1, 1-aryl-2-nitroethanones
could be in equilibrium with enol-form via tautomerization be-
cause of the conjugation effect with the aryl group, which may
O
O
H
N
TEA/CH2Cl2
0.5 hr, rt
N
Cl
N
R
+
R
N
A
O
A/DMSO
NaH/DMSO
NO2
MeNO2
0.5 hr, 10 °C --> 12 hrs, rt
R
0.5 hr, 10 °C
Figure 1. Cyclic voltamograms (50 mV/s) of 2-nitrophenol and 2-nitro-1-phenyl-
ethanone (0.10 M) at a Pt electrode in MeCN containing in 0.10 M tetrabutylammonium
tetrafluoroborate electrolyte (reference electrode, Ag/Agþ).
Scheme 2.
O
Ph
R = H
R = Me
R = Ph
(2)
N
Trace
OMe
R
OMe
Ph
O
O
In, AcOH
Ph
Ph
(3)
+
MeO
CH3CN, reflux, 1 hr
N
12%
NO2
O
Ph
(4)
N
60%
Scheme 1.

8824
J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
Table 3
Indium/acetic acid-triggered reductive heterocyclizations of various 2-nitro-1-phenylethanones (1 mmol) to trimethyl orthobenzoate (4 equiv) in the presence of indium
(4 equiv) and acetic acid (10 equiv) in acetonitrile (15 mL) at reflux for 1 h
R
R
OMe
OMe
O
In, AcOH
O
N
MeO
+
CH3CN, reflux, 1 hr
NO2
Entry
1
Substrate
H
Product
Yielda (%)
60
Entry
13
Substrate
Product
Yielda (%)
63b
(35)
(47)
2-Cl
3-Cl
4-Cl
O
N
O
N
Cl
(36)
(48)
Cl
Cl
O
N
2
3
2-OCH3
3-OCH3
O
N
53
55
14
15
68
68
MeO
(37)
MeO
O
N
(49)
O
N
MeO
(50)
4
5
4-OCH3
47
46
16
17
2-F
3-F
O
N
75b
(38)
O
N
F
O
O
(51)
(39)
F
F
3,4-OCH2O
O
N
70
O
N
(52)
6
4-t-buytl
53
18
4-F
66
O
N
(40)
O
N
(53)
(41)
7
8
2-CH3
3-CH3
O
N
66
59
19
20
2-CF3
3-CF3
O
N
73
67
F3C
(42)
F3C
(54)
O
N
O
N
F3C
(43)
9
4-CH3
2-Br
55
21
22
4-CF3
66
(55)
O
N
O
N
(56)
(44)
72b,c
2-I
45d
O
N
10
O
N
Br
I
(45)
Br
Br
11
3-Br
4-Br
67
23
4-Ph
59
O
N
(57)
O
N
12
64c
(46)
O
N
a
Isolated yield.
b
After 1 N aq HCl work-up, the concentrated organic layer was added to MeOH/10 M aq NaOH solution (10 mL/3 mL), stirred for 0.5 h at room temperature for the methyl
benzoate removal that overlapped with the product on TLC, and extracted with CH2Cl2/satd aq NH4Cl.
c
Debrominated 2,5-diphenyloxazole trace was detected on GC–MS.
Deiodinated 2,5-diphenyloxazole was observed on GC–MS (GC yield w5%).
d

J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
8825
OMe
R
OMe
trimethyl orthobenzoate is still worth investigating as the syntheses
of biologically active 2,5-diaryl-substituted oxazole alkaloids, such as
texaline, texamine, and balsoxin have recently been getting more
interest.9
In, AcOH
No reaction
R = H, Me, Ph
MeO
Ph-OH
+
ð5Þ
PhH, reflux
Thus, to develop the 2,5-diaryl-substituted oxazole synthesis,
various 1-aryl-2-nitroethanone precursors were prepared by the
two-step synthesis starting from the corresponding acid chloride as
shown in Scheme 2. The overall yield of the two-step synthesis was
50–79%.
O
Ph
In,XAcOH
O
N
Ph
ð6Þ
O
PhH, reflux
NO2
After the starting 1-aryl-2-nitroethanone substrates were pre-
pared, indium-mediated intermolecular coupling-based oxazole
syntheses were examined. The results are summarized in Table 3.
Most of the reactions worked fairly well and produced the desired
2,5-aryl-substituted oxazoles in yields ranging from 45 to 75%. As
shown in Table 3, reactions performed with differently substituted
1-aryl-2-nitroethanone derivatives seemed to be unaffected by
substitution on the phenyl group. Neither electron-donating nor
electron-withdrawing groups showed any great influence on
product yield, similar to the benzoxazole synthesis. However, it is
worth noting that some of the bromo- (entries 10 and 12) or iodo-
(entry 22) substituted substrates produced a dehalogenated pro-
duct that served as strong evidence of the involvement of radical or
radical anion species in the reaction.
OMe
H
OMe
H
N
In, AcOH
N
N
OMe
Ph-NO2
Ph-NO2
MeO
MeO
+
Ph
Ph
Ph
PhH, reflux
ð7Þ
OMe
R
OMe
N
R
In, AcOH
Ph
+
ð8Þ
OMe
PhH, reflux
R = Me, Ph
As imidate formation during the reductive coupling reactions of
2-nitrophenols with orthoesters was expected from the reaction of
nitroso intermediate and orthoesters, several control experiments
with nitrosobenzene were examined to confirm the reaction in-
termediacy. As we expected, reactions of nitrosobenzene (1 mmol)
with trimethyl orthobenzoate (3, 4 equiv) in the presence of AcOH
(10 equiv)/indium (4 equiv) in benzene (5 mL) at reflux produced
the desired imidate quantitatively within 10 min (Eq. 9). In the
absence of indium, no reaction was observed (Eq. 10). The reaction
of nitrosobenzene in the presence of indium (4 equiv)/AcOH
(10 equiv) in the absence of trimethyl orthobenzoate (3) at benzene
reflux for 0.5 h produced mixtures of aniline, azobenzene, and
azoxybenzene (approximately w3/2/1 by GC analysis, Eq.11). It was
certain that the nitroso anion was involved in the imidate forma-
tion. However, it was difficult to distinguish whether the orthoester
coupled with the nitroso anion species or if the aniline in-
termediate produced the imidate intermediate as aniline coupled
with trimethyl orthobenzoate as readily as with nitrosobenzene
within 0.5 h under the same conditions (Eq. 12).
2.3. Mechanistic considerations
2.3.1. Intermediacy. To elucidate the possible intermediate, several
control reactions were attempted in order to determine the pos-
sibility of coupling between the orthoester and the nitrogen in-
termediate that forms in situ from the reduction of the nitro group.
There were two possibilities for the intermediate formation: one
was the reaction of the phenol group with orthoesters to form an
ester-like intermediate that may cyclize with the reduced nitrogen
intermediate, and the other was that a reduced nitro group first
produces an intermediate, which is then followed by cyclization
with the neighboring hydroxyl group. Thus, the coupling reactions
of phenol with orthoesters and reductive coupling reactions of ni-
trobenzene with orthoesters in the presence of indium and AcOH
were independently examined, which may provide a clue for the
identification of the prior intermediate stage. The various coupling
reactions of phenol with orthoesters failed to elicit a reaction in any
condition (Eq. 5). In addition, pre-prepared 20-nitrophenyloxy
benzoate did not proceed to cyclization in our reductive condition
(Eq. 6). Therefore, the possibility of an initial in situ ester formation
and a follow-up reductive cyclization to the benzoxazole ring could
be eliminated.
OMe
Ph
OMe
In, AcOH
N
Ph
Ph
MeO
Ph-NO
+
ð9Þ
PhH, reflux, 10 min
OMe
OMe
Ph
OMe
AcOH
No reaction
Ph-NO
+
MeO
ð10Þ
PhH, reflux, 1 hr
In contrast, reductive coupling reactions of nitrobenzene with
orthoesters in the presence of indium and AcOH exhibited
interesting results. The reaction of nitrobenzene (1 mmol) with
trimethyl orthoformate (1, 4 equiv) in the presence of AcOH
(10 equiv)/indium (4 equiv) in benzene (5 mL) at reflux transformed
into N,N0-diphenylformamidine with a trace amount of imidate, as
identified by GC–MS (Eq. 7), within 0.5 h. Meanwhile, the reactions
of nitrobenzene (1 mmol)/indium (4 equiv) with trimethyl ortho-
acetate (2, 4 equiv) or trimethyl orthobenzoate (3, 4 equiv) in ben-
zene (5 mL) at reflux produced mostly methyl imidate (Eq. 8) within
0.5 h. The formation of N,N0-diphenylformamidine shown in Eq. 7 is
believed to have arisen from N-phenylformimidate and aniline,
which are formed in situ during the reductive reaction of nitro-
benzene and trimethyl orthoformate. Roberts et al. reported the
N-phenylformimidate formation from the reactions of aniline hydro-
chloride with a large excess of trimethyl orthoformate.10 They also
observed the formation of N,N0-diphenylformamidine. Thus, imi-
date could be an actual intermediate for our reductive one-pot cy-
clization of 2-nitrophenols and orthoesters to the benzoxazole ring
formation.
In, AcOH
Ph-NH2
+
Ph-N=N-Ph
+
Ph-N(O)=N-Ph
Ph-NO
ð11Þ
ð12Þ
PhH, reflux, 0.5 hr
OMe
AcOH
PhH, reflux, 0.5 hr
N
Ph
Ph-NH2
+
MeO
Ph
OMe
Ph
OMe
2.3.2. Relative reactivity. As the reductive coupling step could be
a key step for the reaction rate, the influence of the substituent on
the reductive coupling step was studied. To evaluate the reactivity
difference in the reductive coupling step of the nitro group, sev-
eral competition reactions were examined. Competition reactions
for the relative reactivities of the substituted nitrobenzenes for
the reduction step examined [substrates (0.5 mmol for each)/
trimethyl orthobenzoate (4 equiv)/indium (4 equiv)/AcOH
(10 equiv) in benzene (5 mL) at 50 ꢀC for 0.5 h] revealed about the

8826
J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
same relative reactivity regardless of the substituent, that is, there
was little effect from the electron-donating (methoxy or methyl)
group or the electron-withdrawing group (fluoro) (Eqs. 13–15).
Thus, based on the competition experiments, it was concluded
that there should be no significant reactivity differences in the
reductive coupling step in our cyclization reaction. As all of the
reactions had similar reaction completion times, the cyclization
step also seemed to be unaffected by the electronic effects of the
substituent.
can easily accept an electron from the indium, the radical anion
species formation would trigger the initial reductive reaction,
and the consecutive proton and electron transfer processes may
easily produce a nitroso intermediate.
OMe
Ph
OMe
In, AcOH
O
O
Ph
O
+
+ MeO
Ph
Ph
CH3CN, reflux, 1 hr
N
I
N
I
NO2
56 (45%)
35 (~5%)
ð16Þ
MeO
Ph
MeO
Ph
OMe
Ph
OMe
NO2
NO2
In, AcOH
PhH, 50 °C, 0.5 hr
+
+
MeO
N
N
+
2.3.4. Plausible mechanism. Based on various experiments, a plau-
sible mechanism is proposed in Scheme 3. By the consequent elec-
tron transfers and proton transfers, the nitro group could first
transform into a nitroso intermediate. The nitroso intermediate may
be transformed into the aniline species via electron transfer and
proton transfer processes, if the proton transfer reactions are highly
favorable (path A in Scheme 3), and then it can react further to the
imidate intermediate. Another possibility is the coupling reaction of
the nitroso radical anion with the orthoester to form the imidate
intermediate, as shown in path B in Scheme 3. After the imidate
intermediate is formed by either path A or B, an acid-assisted attack
by the hydroxyl group toward the neighboring imidate group fol-
lowed by the loss of MeOH due to the aromatization driving forces
would produce the benzoxazole ring. A similar reaction path is also
expected for the oxazole ring formation from 1-aryl-2-nitro-
ethanone derivatives.
Rel reactivity ; 0.95 :1.0
ð13Þ
MeO
MeO Ph
Ph
NO
OMe
Ph
OMe
2
NO
2
In, AcOH
PhH, 50°C, 0.5 hr
+
N
+
MeO
N
+
O
MeO
Rel reactivity ;1.0 :1.0
ð14Þ
MeO
MeO
Ph
Ph
OMe
Ph
OMe
NO
NO
2
2
In, AcOH
PhH, 50°C, 0.5 hr
+
MeO
N
+
N
+
F
F
Rel reactivity ;0.90:1.0
3. Conclusion
ð15Þ
In conclusion, we have described a simple and efficient method
for a one-pot reduction-triggered heterocyclization toward ben-
zoxazoles or oxazoles. In the presence of indium/AcOH in benzene
at reflux, 2-nitrophenols and R–C(OMe)3 (R¼H, Me, Ph) produced
corresponding benzoxazoles within an hour with excellent yield.
Similarly, 1-aryl-2-nitroethanones and Ph–C(OMe)3 in the presence
of indium/AcOH in acetonitrile transformed into the corresponding
oxazoles with good yield. Our findings may serve as a foundation
for the development of a new synthetic path toward valuable
benzoxazole and oxazole derivatives.
2.3.3. Evidences of radical anion/radical species. As mentioned
earlier, bromo- (Table 2, entries 19–21 and Table 3, entries 10 and
12) and iodo- (Table 3, entry 22 and Eq. 16) substituted substrates
exhibit a dehalogenated product as a trace (bromo-derivatives)
or a minor (iodo-derivative). Those derivatives are possible by-
products when the radical or radical anion species were involved
during the reaction path.11 Without doubt, indium-mediated
single-electron transfer (SET) processes were involved during the
cyclization reaction. As nitroarenes or 1-aryl-2-nitroethanones
OMe
Path A
MeO
R, H
OMe
OH
N
OH
OH
OH
In/AcOH
In/AcOH
O
O H
R
NO2
NH2
N
H
O
H
Path B
SET
OH
OH
OH
O
O
O
O
R
H
N
OH
N
H
R
N
OH
R
H
SET
- H
R
OH
O
Imidate
N
H
H
O
H
O
O
O
- MeOH
- H
proton
transfer
O
R
R
N
R
N
H
N
H
R = Me, Ph
Scheme 3.

J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
8827
4. Experimental section
110.6; IR (KBr) 3060, 1450, 1244 cmꢁ1; GC–MS m/z (rel intensity)
195 (Mþ, 100), 92 (21), 77 (7), 63 (11).
4.1. General considerations
4.2.4. 5-Methoxybenzoxazole (8)12d. Yield 83%. White solid, mp 49–
52 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.38; 1H NMR (400 MHz,
Most of the chemical reagents were purchased from Aldrich
and, in most cases, were used without further purification. Sol-
vents were purchased and dried using the standard method. 1H
NMR spectra were recorded on a 400 MHz Jeol instrument, and
13C NMR spectra were recorded on a 100 MHz Jeol instrument.
Chemical shifts were reported in parts per million relative to the
residual solvent as an internal standard. HRMS spectra were
recorded on a JEOL JMS-DX 303 mass spectrometer, and GC–MS
spectra were recorded on an Agilent 6890 N GC connected with an
Agilent 5975 mass selective detector. Infrared (IR) spectra were
recorded using MB104 FTIR (ABB Bomem Inc.). Melting points
were determined on an electrothermal apparatus and were un-
corrected. All the major products were isolated by flash column
chromatography on silica gel (230–400 mesh ATSM, purchased
from Merck) with eluents of mixed solvents (ethyl acetate and
hexane).
CDCl3)
d
8.06 (s, 1H), 7.47 (d, 1H, J¼8.9 Hz), 7.27 (d, 1H, J¼2.6 Hz),
7.00 (dd, 1H, J¼8.9, 2.6 Hz), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
157.4, 153.2, 144.6, 140.9, 114.5, 111.0, 103.1, 55.9; IR (KBr) 3126,
3012, 2979, 2939, 1480, 1282 cmꢁ1; GC–MS m/z (rel intensity) 149
(Mþ, 100), 134 (61), 119 (6), 107 (28), 91 (3), 79 (28), 63 (6), 51 (11).
4.2.5. 5-Methoxy-2-methylbenzoxazole (9)12e. Yield 96%. Colorless
liquid; TLC (30% ethyl acetate/hexane) Rf 0.35; 1H NMR (400 MHz,
CDCl3)
d
7.34 (d, 1H, J¼9.2 Hz), 7.14 (d, 1H, J¼2.8 Hz), 6.88 (dd, 1H,
J¼9.2, 2.8 Hz), 3.84 (s, 3H), 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
164.5, 157.0, 145.5, 142.3, 112.6, 110.2, 102.6, 55.8, 14.5; IR (KBr)
3072, 3005, 2941, 2835, 1440, 1286 cmꢁ1; GC–MS m/z (rel intensity)
163 (Mþ, 100), 148 (77), 107 (37), 79 (23), 63 (5), 51 (8).
4.2.6. 5-Methoxy-2-phenylbenzoxazole(10)12d. Yield 97%. White solid,
mp 81–84 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.53; 1H NMR
4.2. General procedure for the indium-mediated reductive
reaction of 2-nitrophenols with trimethyl orthoesters
to benzoxazoles
(400 MHz, CDCl3)
J¼8.8 Hz), 7.26 (d, 1H, J¼2.4 Hz), 6.96 (dd, 1H, J¼8.8, 2.4 Hz), 3.87 (s,
3H); 13C NMR (100 MHz, CDCl3)
163.8, 157.4, 145.4, 142.9, 131.4,
d 8.24–8.21 (m, 2H), 7.52–7.51 (m, 3H), 7.46 (d, 1H,
d
128.9, 127.5, 127.3, 113.7, 110.7, 102.9, 55.9; IR (KBr) 3066, 3009, 2979,
2939, 2828, 1477, 1279 cmꢁ1; GC–MS m/z (rel intensity) 225 (Mþ,
100), 210 (68), 182 (4), 107 (19), 79 (18), 63 (4), 51 (9).
2-Nitrophenol derivative (1 mmol) was added to a mixture of
indium powder (459 mg, 4.0 mmol) and acetic acid (0.572 mL,
10 mmol) in benzene (2 mL), and then trimethyl orthoester
(4.0 mmol) in benzene (3 mL) was added. The reaction mixture was
stirred at reflux under a nitrogen atmosphere. After the reaction
was complete, the reaction mixture was diluted with CH2Cl2
(30 mL), filtered through Celite, poured into satd aq NH4Cl solution
(30 mL), and then extracted with CH2Cl2 (30 mLꢂ3). The combined
organic extracts were dried over MgSO4, filtered, and concentrated.
The residue was eluted with ethyl acetate/hexane (v/v¼10/90)
through a silica gel column to give the corresponding benzox-
azoles. Some of the reaction mixture (refer to Table 2) was addi-
tionally treated to remove the methyl benzoate that overlapped
with the product on TLC and column chromatography after the
routine work-up process, i.e., the concentrated organic layer was
added in MeOH/10 M aq NaOH solution (8 mL/2 mL), stirred for
0.5 h at room temperature, and extracted with satd aq NH4Cl/
CH2Cl2. The structures of the benzoxazoles were characterized by
1H NMR, 13C NMR, FTIR, and GC–MS, and were mostly known
compounds.12
4.2.7. 6-Methoxybenzoxazole (11)12f. Yield 87%. White solid, mp
52–54 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.40; 1H NMR
(400 MHz, CDCl3)
d
8.00 (s, 1H), 7.66 (d, 1H, J¼8.8 Hz), 7.09 (d, 1H,
J¼2.3 Hz), 6.99 (dd, 1H, J¼8.8, 2.3 Hz), 3.86 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 158.5, 151.5, 150.9, 133.7, 120.5, 113.1, 95.4, 55.9;
IR (KBr) 3123, 3063, 2838, 1436, 1286 cmꢁ1; GC–MS m/z (rel in-
tensity) 149 (Mþ, 100), 134 (59), 119 (5), 106 (35), 91 (5), 80 (12), 63
(7), 51 (11).
4.2.8. 6-Methoxy-2-methylbenzoxazole (12)12e. Yield 98%. White
solid, mp 60–61 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.31; 1H NMR
(400 MHz, CDCl3)
d
7.52 (d,1H, J¼8.7 Hz), 7.01 (d,1H, J¼2.3 Hz), 6.91
(dd, 1H, J¼8.7, 2.3 Hz), 3.85 (s, 3H), 2.60 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 162.7, 157.7, 151.7, 135.2, 119.3, 111.9, 95.3, 55.9, 14.4; IR
(KBr) 3073, 2979, 2955, 2845, 1488, 1291 cmꢁ1; GC–MS m/z (rel
intensity) 163 (Mþ,100),148 (96),120 (13),106 (28), 79 (13), 51 (14).
4.2.9. 6-Methoxy-2-phenylbenzoxazole (13)12g. Yield 98%. White
solid, mp 66–69 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.55; 1H NMR
4.2.1. Benzoxazole (5)12a. Yield 69%. Colorless liquid; TLC (30% ethyl
acetate/hexane) Rf 0.50; 1H NMR (400 MHz, CDCl3)
d
8.10 (s, 1H),
(400 MHz, CDCl3)
7.49 (m, 3H), 7.11 (d, 1H, J¼2.4 Hz), 6.97 (dd, 1H, J¼8.7, 2.4 Hz), 3.87
(s, 3H); 13C NMR (100 MHz, CDCl3)
162.2, 158.3, 151.6, 135.9, 131.0,
d
8.21–8.19 (m, 2H), 7.65 (d, 1H, J¼8.7 Hz), 7.51–
7.82–7.78 (m, 1H), 7.61–7.57 (m, 1H), 7.41–7.35 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d
152.4, 149.9, 140.0, 125.5, 124.5, 120.6, 110.9; IR
d
(KBr) 3110, 1450, 1235 cmꢁ1; GC–MS m/z (rel intensity) 119 (Mþ,
128.9, 127.4, 127.2, 120.0, 112.8, 95.4, 55.9; IR (KBr) 3069, 2999,
2935, 2835, 1453, 1269 cmꢁ1; GC–MS m/z (rel intensity) 225 (Mþ,
100), 210 (85), 182 (17), 154 (5), 105 (8), 79 (11), 63 (4), 51 (7).
100), 91 (48), 63 (28).
4.2.2. 2-Methylbenzoxazole (6)12b. Yield 92%. Colorless liquid; TLC
(30% ethyl acetate/hexane) Rf 0.47; 1H NMR (400 MHz, CDCl3)
4.2.10. 4-Methylbenzoxazole (14)12h. Yield 71%. Colorless liquid;
TLC (30% ethyl acetate/hexane) Rf 0.52; 1H NMR (400 MHz, CDCl3)
d
7.66–7.64 (m, 1H), 7.47–7.45 (m, 1H), 7.30–7.27 (m, 1H), 2.63
(s, 3H); 13C NMR (100 MHz, CDCl3)
d
163.7, 150.9, 141.5, 124.4,
d
8.07 (s, 1H), 7.41 (d, 1H, J¼7.6 Hz), 7.29 (t, 1H, J¼7.6 Hz), 7.17 (d, 1H,
124.0, 119.4, 110.1, 14.5; IR (KBr) 3058, 2931, 1456, 1242 cmꢁ1
;
J¼7.6 Hz), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 151.7, 149.7,
GC–MS m/z (rel intensity) 133 (Mþ, 100), 104 (19), 78 (14), 63
139.2, 130.9, 125.2, 125.0, 108.2, 16.4; IR (KBr) 3099, 2928, 1460,
1242 cmꢁ1; GC–MS m/z (rel intensity) 133 (Mþ, 100), 104 (25), 78
(40), 63 (5), 51 (17).
(19).
4.2.3. 2-Phenylbenzoxazole (7)12c. Yield 97%. White solid, mp 110–
111 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.68; 1H NMR (400 MHz,
4.2.11. 2,4-Dimethylbenzoxazole (15)12b. Yield 88%. Colorless liquid;
TLC (30% ethyl acetate/hexane) Rf 0.53; 1H NMR (400 MHz, CDCl3)
CDCl3)
7.54–7.52 (m, 3H), 7.37–7.33 (m, 2H); 13C NMR (100 MHz, CDCl3)
163.0, 150.7, 142.1, 131.5, 128.9, 127.6, 127.2, 125.1, 124.5, 120.0,
d 8.27–8.25 (m, 2H), 7.80–7.77 (m, 1H), 7.60–7.56 (m, 1H),
d
7.29 (d, 1H, J¼8.0 Hz), 7.18 (t, 1H, J¼8.0 Hz), 7.09 (d, 1H, J¼8.0 Hz),
d
2.62 (s, 3H), 2.59 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
162.9, 150.6,

8828
J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
140.5, 129.6, 124.6, 124.0, 107.4, 16.4, 14.4; IR (KBr) 3062, 2924,
2854, 1419, 1242 cmꢁ1; GC–MS m/z (rel intensity) 147 (Mþ, 100),
132 (7), 118 (12), 106 (17), 78 (34), 51 (8).
J¼8.5 Hz); 13C NMR (100 MHz, CDCl3)
d 153.5, 149.0, 141.6, 128.8,
123.6, 117.4, 112.2; IR (KBr) 3093, 1447, 1262 cmꢁ1; GC–MS m/z (rel
intensity) 196 (Mþ, 100), 168 (25), 141 (7), 90 (8), 63 (38).
4.2.12. 4-Methyl-2-phenylbenzoxazole (16)12i. Yield 96%. White
solid, mp 94–97 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.67; 1H NMR
4.2.20. 5-Bromo-2-methylbenzoxazole (24)12n. Yield 94%. White
solid, mp 67–69 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.52; 1H NMR
(400 MHz, CDCl3)
1H, J¼8.0, 0.8 Hz), 7.26 (t, 1H, J¼8.0 Hz), 7.16 (dd, 1H, J¼8.0, 0.8 Hz),
2.69 (s, 3H); 13C NMR (100 MHz, CDCl3)
162.2, 150.5, 141.4, 131.2,
130.6, 128.8, 127.6, 127.4, 125.0, 124.7, 107.8, 16.6; IR (KBr) 3061,
2955, 2918, 1443, 1237 cmꢁ1; GC–MS m/z (rel intensity) 209 (Mþ,
100), 180 (13), 105 (8), 78 (15), 51 (5).
d
8.29–8.26 (m, 2H), 7.54–7.51 (m, 3H), 7.42 (dd,
(400 MHz, CDCl3)
d
7.79 (d,1H, J¼1.8 Hz), 7.42 (d,1H, J¼8.6 Hz), 7.40
(dd, 1H, J¼8.6, 1.8 Hz), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
d 165.1, 150.0, 143.1, 127.5, 122.5, 116.8, 111.4, 14.5; IR (KBr) 3093,
3059, 2922, 1453, 1262 cmꢁ1; GC–MS m/z (rel intensity) 210 (Mþ,
100), 182 (3), 169 (6), 141 (9), 132 (10), 104 (25), 91 (7), 63 (29).
4.2.21. 5-Bromo-2-phenylbenzoxazole (25)12o. Yield 98%. White solid,
mp 117–118 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.72; 1H NMR
4.2.13. 5-Methylbenzoxazole (17)12h. Yield 73%. White solid, mp
49–51 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.53; 1H NMR
(400 MHz, CDCl3)
d
8.24–8.21 (m, 2H), 7.89 (dd, 1H, J¼1.6, 0.8 Hz),
(400 MHz, CDCl3)
d
8.05 (s, 1H), 7.58 (s, 1H), 7.46 (d, 1H, J¼8.3 Hz),
7.57–7.49 (m, 3H), 7.47–7.42 (m, 2H); 13C NMR (100 MHz, CDCl3)
7.20 (d, 1H, J¼8.3 Hz), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 164.1, 149.7, 143.7, 131.9, 129.0, 128.1, 127.8, 126.6, 123.0, 117.3, 111.8;
d
152.6, 148.2, 140.2, 134.4, 126.7, 120.4, 110.3, 21.4; IR (KBr) 3103,
IR (KBr) 3089, 3063, 1444, 1257 cmꢁ1; GC–MS m/z (rel intensity) 272
2925, 2865, 1480, 1259 cmꢁ1; GC–MS m/z (rel intensity) 133 (Mþ,
(Mþ, 100), 246 (8), 194 (5), 166 (5), 91 (4), 77 (6), 63 (15).
100), 104 (19), 78 (33), 63 (5), 51 (15).
4.2.22. 5-Chlorobenzoxazole (26)12h. Yield 81%. White solid, mp
41–44 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.50; 1H NMR
4.2.14. 2,5-Dimethylbenzoxazole (18)12j. Yield 89%. Colorless liquid;
TLC (30% ethyl acetate/hexane) Rf 0.43; 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
8.12 (s, 1H), 7.79 (d, 1H, J¼1.9 Hz), 7.53 (d, 1H,
d
7.42 (s, 1H), 7.33 (d, 1H, J¼8.2 Hz), 7.09 (d, 1H, J¼8.2 Hz), 2.60 (s,
J¼8.7 Hz), 7.39 (dd, 1H, J¼8.7, 1.9 Hz); 13C NMR (100 MHz, CDCl3)
3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
163.8, 149.2, 141.7,
d 153.7, 148.6, 141.2, 130.2, 126.1, 120.6, 111.7; IR (KBr) 3110, 3009,
133.8, 125.4, 119.3, 109.5, 21.4, 14.5; IR (KBr) 3032, 2922, 2861, 1483,
1262 cmꢁ1; GC–MS m/z (rel intensity) 147 (Mþ, 100), 132 (8), 118
(8), 106 (21), 78 (39), 51 (10).
1457, 1262 cmꢁ1; GC–MS m/z (rel intensity) 153 (Mþ, 100), 125 (33),
98 (12), 63 (25).
4.2.23. 5-Chloro-2-methylbenzoxazole (27)12j. Yield 87%. White
solid, mp 61–64 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.52; 1H NMR
4.2.15. 5-Methyl-2-phenylbenzoxazole (19)12k. Yield 98%. White
solid, mp 112–114 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.68; 1H
(400 MHz, CDCl3)
d
7.63 (d,1H, J¼2.0 Hz), 7.39 (d,1H, J¼8.6 Hz), 7.28
NMR (400 MHz, CDCl3)
7.52–7.49 (m, 3H), 7.45 (d, 1H, J¼8.3 Hz), 7.15 (dd, 1H, J¼8.3, 1.0 Hz),
2.47 (s, 3H); 13C NMR (100 MHz, CDCl3)
163.1, 149.0, 142.3, 134.3,
d
8.26–8.21 (m, 2H), 7.55 (m, 1H, J¼1.0 Hz),
(dd, 1H, J¼8.6, 2.0 Hz), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
165.3, 149.7, 142.7, 129.6, 124.7, 119.5, 110.9, 14.5; IR (KBr) 3093,
d
3059, 2925, 1457, 1259 cmꢁ1; GC–MS m/z (rel intensity) 167 (Mþ,
131.3, 128.8, 127.5, 127.3, 126.2, 119.9, 109.9, 21.5; IR (KBr) 3058,
2920, 2860, 1442, 1264 cmꢁ1; GC–MS m/z (rel intensity) 209 (Mþ,
100), 180 (7), 105 (7), 78 (15), 51 (4).
100), 139 (4), 126 (6), 104 (25), 63 (21).
4.2.24. 5-Chloro-2-phenylbenzoxazole (28)12d. Yield 95%. White
solid, mp 110–113 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.68; 1H
4.2.16. 6-Methylbenzoxazole (20)12l. Yield 77%. Colorless liquid; TLC
(30% ethyl acetate/hexane) Rf 0.43; 1H NMR (400 MHz, CDCl3)
NMR (400 MHz, CDCl3)
7.58–7.52 (m, 3H), 7.51 (d, 1H, J¼8.6 Hz), 7.33 (dd,1H, J¼8.6, 2.0 Hz);
13C NMR (100 MHz, CDCl3)
164.3, 149.3, 143.3, 131.9, 130.0, 129.0,
d
8.24–8.22 (m, 2H), 7.74 (d, 1H, J¼2.0 Hz),
d
8.02 (s, 1H), 7.66 (d, 1H, J¼8.0 Hz), 7.38 (s, 1H), 7.19 (d, 1H,
d
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d
152.0, 150.2, 137.8, 136.0,
127.7, 126.7, 125.4, 120.0, 111.3; IR (KBr) 3096, 3066, 3026, 1443,
1262 cmꢁ1; GC–MS m/z (rel intensity) 229 (Mþ, 100), 201 (11), 166
(5), 126 (5), 98 (6), 77 (7), 63 (14).
125.8, 119.8, 111.0, 21.7; IR (KBr) 3110, 3036, 2922, 2861, 1433,
1255 cmꢁ1; GC–MS m/z (rel intensity) 133 (Mþ, 100), 104 (21), 78
(35), 63 (5), 51 (11).
4.2.25. 5-Fluorobenzoxazole (29)12p. Yield 50%. White solid, mp 43–
45 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.54; 1H NMR (400 MHz,
4.2.17. 2,6-Dimethylbenzoxazole (21)12b. Yield 95%. Colorless liquid;
TLC (30% ethyl acetate/hexane) Rf 0.45; 1H NMR (400 MHz, CDCl3)
CDCl3)
d
8.13 (s, 1H), 7.55 (dd, 1H, J¼8.8, 4.4 Hz), 7.49 (dd, 1H, J¼8.4,
d
7.51 (d, 1H, J¼8.2 Hz), 7.27 (s, 1H), 7.10 (d, 1H, J¼8.2 Hz), 2.60 (s,
2.4 Hz), 7.17 (td, 1H, J¼8.8, 2.4 Hz); 13C NMR (100 MHz, CDCl3)
3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
163.1, 151.2, 139.2,
d 161.3 (d), 154.1, 146.3 (d), 141.0 (d), 113.6 (d), 111.3 (d), 107.1 (d); IR
134.6, 125.1, 118.6, 110.3, 21.6, 14.4; IR (KBr) 3032, 2925, 2865, 1436,
1242 cmꢁ1; GC–MS m/z (rel intensity) 147 (Mþ, 100), 132 (8), 118
(11), 106 (19), 91 (4), 78 (43), 63 (6), 51 (15).
(KBr) 3096, 3002, 1480, 1268 cmꢁ1; GC–MS m/z (rel intensity) 137
(Mþ, 100), 109 (38), 82 (33), 63 (9), 56 (4).
4.2.26. 5-Fluoro-2-methylbenzoxazole (30)12j. Yield 70%. Colorless
liquid; TLC (30% ethyl acetate/hexane) Rf 0.48; 1H NMR (400 MHz,
4.2.18. 6-Methyl-2-phenylbenzoxazole (22)12k. Yield 98%. White
solid, mp 99–102 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.66; 1H
CDCl3)
d
7.41 (dd, 1H, J¼8.8, 4.0 Hz), 7.34 (dd, 1H, J¼8.4, 2.4 Hz), 7.05
NMR (400 MHz, CDCl3)
d
8.24–8.21 (m, 2H), 7.64 (d, 1H, J¼8.0 Hz),
(td, 1H, J¼8.8, 2.4 Hz), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3)
7.51–7.49 (m, 3H), 7.36 (s,1H), 7.16 (d,1H, J¼8.0 Hz), 2.49 (s, 3H); 13C
d 165.7, 161.0 (d), 147.3 (d), 142.4 (d), 112.1 (d), 110.4 (d), 106.1 (d),
NMR (100 MHz, CDCl3)
d
162.5, 151.0, 140.0, 135.5, 131.2, 128.8,
14.6; IR (KBr) 3076, 2928, 2858, 1477, 1279 cmꢁ1; GC–MS m/z (rel
127.4, 127.3, 125.8, 119.3, 110.7, 21.8; IR (KBr) 3056, 2918, 2858, 1447,
1244 cmꢁ1; GC–MS m/z (rel intensity) 209 (Mþ, 100), 180 (11), 105
(9), 78 (15), 51 (5).
intensity) 151 (Mþ, 100), 122 (18), 110 (6), 96 (19), 82 (28), 63 (7).
4.2.27. 5-Fluoro-2-phenylbenzoxazole (31)4e. Yield 92%. White
solid, mp 117–119 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.69; 1H
NMR (400 MHz, CDCl3) d .23–8.21 (m, 2H), 7.56–7.51 (m, 3H), 7.50
4.2.19. 5-Bromobenzoxazole (23)12g. Yield 81%. White solid, mp 40–
42 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.41; 1H NMR (400 MHz,
(ddd, 1H, J¼8.0, 4.4, 0.4 Hz), 7.45 (ddd, 1H, J¼8.4, 2.4, 0.4 Hz), 7.09
CDCl3)
d
8.10 (s, 1H), 7.94 (s, 1H), 7.52 (d, 1H, J¼8.5 Hz), 7.48 (d, 1H,
(ddd, 1H, J¼9.2, 8.8, 2.4 Hz); 13C NMR (100 MHz, CDCl3)
d 164.7,

J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
8829
161.3 (d), 147.0 (d), 143.0 (d), 131.8, 128.9, 127.6, 126.8, 112.8 (d),
110.8 (d), 106.5 (d); IR (KBr) 3110, 3073, 3046, 1436, 1272 cmꢁ1; GC–
MS m/z (rel intensity) 213 (Mþ,100),185 (20),110 (5), 82 (14), 63 (5).
(0.566 mL, 10 mmol) in acetonitrile (10 mL), and then trimethyl
orthoester (4.0 mmol) in acetonitrile (5 mL) was added. The re-
action mixture was stirred at reflux under a nitrogen atmosphere.
After the reaction was complete, the reaction mixture was diluted
with CH2Cl2 (30 mL), filtered through Celite, poured into 1 N HCl
solution (30 mL), and then extracted with CH2Cl2 (30 mLꢂ3). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated. The residue was eluted with ethyl acetate/hexane
(v/v¼2/98) through a silica gel column to give the corresponding
2,5-diaryloxazoles. Some of the reaction mixture (refer to Table 3)
was additionally treated to remove the methyl benzoate that
overlapped with the product on TLC and column chromatography
after the routine work-up process, i.e., the concentrated mixture
was added to MeOH/10 M aq NaOH solution (10 mL/3 mL), stirred
for 0.5 h at room temperature, and extracted with satd aq NH4Cl/
CH2Cl2 again. The structures of the 2,5-diaryloxazoles were char-
acterized by 1H NMR, 13C NMR, FTIR, and GC–MS for known com-
pounds.13 Elemental analysis or HRMS data were additionally
obtained for the unknown compounds.
4.2.28. 6-Fluorobenzoxazole (32)12p. Yield 53%. White solid, mp 53–
54 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.52; 1H NMR (400 MHz,
CDCl3)
d
8.09 (s, 1H), 7.75 (dd, 1H, J¼8.8, 5.2 Hz), 7.33 (dd, 1H, J¼8.0,
2.4 Hz), 7.16 (ddd, 1H, J¼9.2, 8.8, 2.4 Hz); 13C NMR (100 MHz, CDCl3)
d
160.2 (d), 153.0 (d), 150.0 (d), 136.3 (d), 121.0 (d), 112.9 (d), 99.0
(d); IR (KBr) 3103, 3016, 1487, 1286 cmꢁ1; GC–MS m/z (rel intensity)
137 (Mþ, 100), 109 (42), 82 (28), 63 (7).
4.2.29. 6-Fluoro-2-methylbenzoxazole (33)12j. Yield 84%. Colorless
liquid; TLC (30% ethyl acetate/hexane) Rf 0.42; 1H NMR (400 MHz,
CDCl3)
d
7.58 (dd,1H, J¼8.8, 4.8 Hz), 7.20 (dd, 1H, J¼8.0, 2.4 Hz), 7.06
(ddd, 1H, J¼9.6, 8.8, 2.4 Hz), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
164.3 (d), 161.4 (d), 150.9 (d), 137.8 (d), 119.6 (d), 112.0 (d), 98.4 (d),
14.4; IR (KBr) 3075, 2934, 2857, 1477, 1286 cmꢁ1; GC–MS m/z (rel
intensity) 151 (Mþ, 100), 122 (23), 96 (25), 82 (19), 63 (8).
4.2.30. 6-Fluoro-2-phenylbenzoxazole (34)12c. Yield 94%. White
solid, mp 111–112 ꢀC; TLC (30% ethyl acetate/hexane) Rf 061; 1H
5.2.1. 2,5-Diphenyloxazole (35)13a. Yield 60%. White solid, mp 75–
77 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.50; 1H NMR (400 MHz,
NMR (400 MHz, CDCl3)
d
8.24–8.20 (m, 2H), 7.71 (dd, 1H, J¼8.8,
CDCl3)
d
8.12–8.09 (m, 2H), 7.73 (dd, 2H, J¼8.4, 1.2 Hz), 7.50–7.42
4.8 Hz), 7.56–7.49 (m, 3H), 7.32 (dd, 1H, J¼8.0, 2.4 Hz), 7.13 (ddd, 1H,
(m, 6H), 7.35–7.31 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
161.1, 151.3,
J¼9.6, 8.8, 2.4 Hz); 13C NMR (100 MHz, CDCl3)
d
163.7 (d), 161.9 (d),
130.3, 128.9, 128.8, 128.4, 128.0, 127.5, 126.3, 124.2, 123.5; IR (KBr)
3063, 3039, 1481, 1133 cmꢁ1; GC–MS m/z (rel intensity) 221 (Mþ,
100), 193 (13), 165 (48), 116 (10), 89 (18), 77 (15), 63 (11), 51 (10).
150.8 (d), 138.4 (d), 131.6, 128.9, 127.5, 126.9, 120.3 (d), 112.6 (d),
98.8 (d); IR (KBr) 3066, 1477, 1255 cmꢁ1; GC–MS m/z (rel intensity)
213 (Mþ, 100), 185 (18), 110 (7), 82 (9), 63 (5).
5.2.2. 5-(2-Methoxyphenyl)-2-phenyloxazole(36)13b. Yield 53%. White
solid, mp 129–131 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.50; 1H NMR
(400 MHz, CDCl3)
5. General procedure for the indium-mediated reductive
reaction of the 2-nitro-1-phenylethanones trimethyl
orthoalkylates to oxazoles
d
8.14 (dd, 2H, J¼8.4, 2.0 Hz), 7.90 (dd, 1H, J¼7.6,
1.6 Hz), 7.65 (s,1H), 7.50–7.44 (m, 3H), 7.32 (ddd,1H, J¼8.4, 7.6,1.6 Hz),
7.09 (td, 1H, J¼7.6, 1.2 Hz), 7.00 (dd, 1H, J¼8.4, 1.2 Hz), 3.97 (s, 3H); 13C
5.1. Preparation of the 2-nitro-1-phenylethanones starting
from acyl chlorides
NMR (100 MHz, CDCl3) d 160.0, 155.7, 147.8, 130.1, 129.0, 128.7, 127.6,
127.6, 126.3, 125.8, 120.8, 117.3, 110.9, 55.4; IR (KBr) 3151, 3069, 3009,
2965, 2841, 1495, 1130 cmꢁ1; GC–MS m/z (rel intensity) 251 (Mþ,100),
208 (8), 195 (18), 167 (6), 133 (28), 118 (10), 105 (21), 89 (11), 77 (24),
63 (5), 51 (5).
5.1.1. Step 1. Imidazole (6.0 mmol) and triethylamine (6.0 mmol)
were dissolved in dry CH2Cl2 (25 mL), and acyl chloride (5 mmol)
was slowly added to the stirred solution. The mixture was stirred
for 0.5 h at room temperature. The mixture was filtered, and the
solution was rapidly washed with cold water (150 mLꢂ3). The or-
ganic phase was dried with MgSO4, filtered, and concentrated,
yielding the crude N-acylimidazoles. The crude N-acylimidazoles
were used for the synthesis of 2-nitro-1-phenylethanones without
further purification.
5.2.3. 5-(3-Methoxyphenyl)-2-phenyloxazole (37). Yield 55%. White
solid, mp 97–98 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.53; 1H NMR
(400 MHz, CDCl3)
d 8.12–8.09 (m, 2H), 7.50–7.45 (m, 3H), 7.43 (s,
1H), 7.37 (t, 1H, J¼7.6 Hz), 7.32 (dt, 1H, J¼7.6, 1.2 Hz), 7.25 (dd, 1H,
J¼2.4,1.2 Hz), 6.70 (ddd,1H, J¼7.6, 2.4,1.2 Hz), 3.87 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 161.1, 160.0, 151.1, 130.3, 130.0, 129.2, 128.8,
127.4, 126.2, 123.7, 116.7, 113.9, 109.7, 55.3; IR (KBr) 3095, 2995,
2954, 2832, 1483, 1131 cmꢁ1; GC–MS m/z (rel intensity) 251 (Mþ,
100), 208 (11), 195 (9), 181 (20), 165 (13), 153 (9), 116 (9), 89 (11), 77
(14), 63 (6), 51 (5). Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N,
5.57. Found: C, 76.48; H, 5.35; N, 5.60.
5.1.2. Step 2. A mixture of the nitromethane (5.0 mmol) and so-
dium hydride (11 mmol) in DMSO (25 mL) was stirred for 0.5 h,
while the temperature was maintained at 10 ꢀC. The crude N-acyl-
imidazole (5.0 mmol) in DMSO (25 mL) was added dropwise to the
resulting solution, and the mixture was stirred for 30 min at 10 ꢀC
and then at room temperature for 12 h. The mixture was diluted
with ethyl acetate (150 mL), poured into 1 N HCl (150 mL), and then
extracted with ethyl acetate (150 mLꢂ3). The combined organic
extracts were washed with cold water (150 mLꢂ3), dried over
MgSO4, filtered, and concentrated. The residue was eluted with
dichloromethane/hexane (v/v¼50/50) through a silica gel column
to give the corresponding 2-nitro-1-phenylethanones, which were
used as starting substrates for the oxazole synthesis.
5.2.4. 5-(4-Methoxyphenyl)-2-phenyloxazole (38)13c. Yield 47%.
White solid, mp 88–89 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.41;
1H NMR (400 MHz, CDCl3)
d
8.10 (dd, 2H, J¼8.0, 1.6 Hz), 7.66–7.63
(m, 2H), 7.49–7.42 (m, 3H), 7.32 (s, 1H), 6.98–6.95 (m, 2H), 3.84 (s,
3H); 13C NMR (100 MHz, CDCl3)
160.6, 159.8, 151.3, 130.1, 128.8,
d
127.6, 126.1, 125.7, 121.9, 120.9, 114.4, 55.3; IR (KBr) 3042, 3016,
2965, 2835, 1503, 1175 cmꢁ1; GC–MS m/z (rel intensity) 251 (Mþ,
100), 236 (29), 196 (12), 181 (12), 153 (6), 112 (6), 77 (18).
5.2. Indium-mediated reductive reaction of 2-nitro-1-
phenylethanones with trimethyl orthoesters
to 2,5-diaryloxazoles
5.2.5. 5-Benzo[1,3]dioxol-5-yl-2-phenyloxazole (39)9a. Yield 46%.
White solid, mp 144–146 ꢀC; TLC (30% ethyl acetate/hexane) Rf
0.57; 1H NMR (400 MHz, CDCl3)
d
8.09 (dd, 2H, J¼8.0, 2.0 Hz), 7.49–
7.42 (m, 3H), 7.30 (s, 1H), 7.24 (dd, 1H, J¼8.0, 1.6 Hz), 7.17 (d, 1H,
2-Nitro-1-phenylethanone derivative (1 mmol) was added to
a mixture of indium powder (459 mg, 4.0 mmol) and acetic acid
J¼1.6 Hz), 6.88 (d, 1H, J¼8.0 Hz), 6.00 (s, 2H); 13C NMR (100 MHz,
CDCl3)
d 160.6, 151.1, 148.2, 147.9, 130.2, 128.8, 127.5, 126.1, 122.4,

8830
J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
122.2, 118.3, 108.8, 104.8, 101.4; IR (KBr) 3113, 3009, 2922, 1483,
1105 cmꢁ1; GC–MS m/z (rel intensity) 265 (Mþ, 100), 237 (9), 180
(14), 152 (28), 133 (5), 119 (6), 105 (5), 89 (5), 76 (8), 63 (5).
122.3; IR (KBr) 3120, 3039, 1477, 1135 cmꢁ1; GC–MS m/z (rel in-
tensity) 298 (Mþ, 100), 270 (5), 243 (8), 192 (8), 165 (61), 154 (6), 116
(11), 89 (28), 77 (5), 63 (9).
5.2.6. 5-[4-(1,1-Dimethylethyl)phenyl]-2-phenyloxazole (40)13d. Yield
53%. Colorless liquid; TLC (30% ethyl acetate/hexane) Rf 0.58; 1H NMR
5.2.13. 5-(2-Chlorophenyl)-2-phenyloxazole (47)13e. Yield 63%. White
solid, mp 79–80 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.61; 1H NMR
(400 MHz, CDCl3)
7.44 (m, 5H), 7.40 (s, 1H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3)
160.9, 151.7, 151.4, 130.2, 128.8, 127.5, 126.2, 125.8, 125.2, 124.0,
d
8.12–8.10 (m, 2H), 7.67 (d, 2H, J¼8.3 Hz), 7.50–
(400 MHz, CDCl3)
d
8.13–8.11 (m, 2H), 7.92 (dd,1H, J¼8.0,1.6 Hz), 7.88
(s, 1H), 7.51–7.47 (m, 4H), 7.39 (td, 1H, J¼8.0, 1.2 Hz), 7.28 (ddd, 1H,
d
J¼8.0, 7.6, 1.6 Hz); 13C NMR (100 MHz, CDCl3)
d 160.9, 147.8, 130.7,
122.9, 34.7, 31.2; IR (KBr) 3123, 3083, 2953, 2868, 1487, 1133 cmꢁ1
;
130.5, 128.9, 128.8, 128.4, 128.4, 127.6, 127.2, 127.0, 126.8, 126.4; IR
(KBr) 3173, 3076, 3039, 1487, 1144 cmꢁ1; GC–MS m/z (rel intensity)
255 (Mþ,100), 227 (8), 200 (11),165 (85),139 (6),116 (13), 89 (28), 77
(7), 63 (9), 51 (5).
GC–MS m/z (rel intensity) 277 (Mþ, 59), 262 (100), 234 (15), 131 (8),
117 (12), 103 (7).
5.2.7. 5-(2-Methylphenyl)-2-phenyloxazole (41)9b. Yield 66%. White
solid, mp 72–74 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.54; 1H NMR
5.2.14. 5-(3-Chlorophenyl)-2-phenyloxazole (48)13f. Yield 68%. White
solid, mp 119–120 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.54; 1H
NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
7.46 (m, 3H), 7.35 (s, 1H), 7.33–7.25 (m, 3H), 2.54 (s, 3H); 13C NMR
(100 MHz, CDCl3) 160.8, 150.7, 134.9, 131.2, 130.3, 128.8, 128.4,
d
8.13–8.10 (m, 2H), 7.79 (d, 1H, J¼7.2 Hz), 7.51–
d
8.11–8.09 (m, 2H), 7.70 (t, 1H, J¼1.2 Hz),
d
7.59 (ddd, 1H, J¼8.0, 2.0, 1.2 Hz), 7.51–7.46 (m, 4H), 7.38 (t, 1H,
127.5, 127.3, 126.8, 126.3, 126.2, 126.2, 21.9; IR (KBr) 3163, 3066,
2952, 2858, 1486, 1151 cmꢁ1; GC–MS m/z (rel intensity) 235 (Mþ,
100), 206 (10), 179 (20), 165 (7), 131 (10), 104 (15), 89 (10), 77 (11).
J¼8.0 Hz), 7.31 (ddd, 1H, J¼8.0, 2.0, 1.2 Hz); 13C NMR (100 MHz,
CDCl3)
d 161.6, 149.8, 135.0, 130.6, 130.2, 129.6, 128.8, 128.3, 127.1,
126.4, 124.4, 124.1, 122.2; IR (KBr) 3107, 3059, 3032, 1487, 1141 cmꢁ1
;
GC–MS m/z (rel intensity) 255 (Mþ, 100), 227 (8), 192 (9), 165 (52),
5.2.8. 5-(3-Methylphenyl)-2-phenyloxazole (42)13e. Yield 59%. White
solid, mp120–121 ꢀC;TLC (30%ethyl acetate/hexane)Rf 0.53; 1H NMR
116 (15), 89 (24), 75 (7), 63 (8).
(400 MHz, CDCl3)
d
8.12 (dd, 2H, J¼7.7,1.8 Hz), 7.53–7.42 (m, 5H), 7.42
5.2.15. 5-(4-Chlorophenyl)-2-phenyloxazole (49)13c. Yield 68%. White
solid, mp 110–111 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.52; 1H
(s, 1H), 7.34 (t, 1H, J¼7.6 Hz), 7.16 (d, 1H, J¼7.6 Hz), 2.41 (s, 3H); 13C
NMR (100 MHz, CDCl3)
d
161.0, 151.4, 138.6, 130.2, 129.2, 128.8, 128.8,
NMR (400 MHz, CDCl3)
d
8.10–8.08 (m, 2H), 7.65–7.62 (m, 2H), 7.51–
161.3,
127.9, 127.5, 126.2, 124.8, 123.3, 121.4, 21.4; IR (KBr) 3103, 3056, 2952,
2915, 1487, 1131 cmꢁ1; GC–MS m/z (rel intensity) 235 (Mþ, 100), 207
(11), 179 (16), 165 (40), 116 (8), 103 (8), 89 (11), 77 (8), 63 (5).
7.45 (m, 3H), 7.44–7.39 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
150.2, 134.1, 130.5, 129.2, 128.8, 127.2, 126.5, 126.3, 125.4, 123.8; IR
(KBr) 3123, 3059, 1481, 1132 cmꢁ1; GC–MS m/z (rel intensity) 255
(Mþ, 100), 227 (8), 200 (11), 165 (56), 116 (9), 89 (21), 75 (5), 63 (8).
5.2.9. 5-(4-Methylphenyl)-2-phenyloxazole (43)9b. Yield 55%. White
solid, mp 85–86 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.59; 1H NMR
5.2.16. 5-(2-Fluorophenyl)-2-phenyloxazole (50). Yield 75%. White
solid, mp 103–104 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.63; 1H
NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
8.11 (dd, 2H, J¼7.9, 1.6 Hz), 7.62 (d, 2H, J¼8.0 Hz),
7.50–7.44 (m, 3H), 7.39 (s, 1H), 7.25 (d, 2H, J¼8.0 Hz), 2.38 (s, 3H); 13C
d
8.13–8.11 (m, 2H), 7.88 (td, 1H, J¼7.6,
NMR (100 MHz, CDCl3)
d
160.8, 151.5, 138.5, 130.2, 129.6, 128.8, 127.6,
1.6 Hz), 7.59 (d, 1H, J¼4.0 Hz), 7.51–7.45 (m, 3H), 7.33–7.23 (m, 2H),
126.2, 125.3, 124.2, 122.8, 21.3; IR (KBr) 3126, 3026, 2989, 2955, 1476,
1133 cmꢁ1; GC–MS m/z (rel intensity) 235 (Mþ, 100), 207 (11), 179
(12), 165 (42), 116 (5), 103 (6), 91 (9), 77 (6), 63 (5).
7.19 (ddd, 1H, J¼11.2, 7.6,1.6 Hz); 13C NMR (100 MHz, CDCl3)
d 160.9,
160.1 (d), 145.6 (d), 130.5, 129.4 (d), 128.8, 127.8 (d), 127.3, 126.4,
126.0 (d), 124.5 (d), 116.6 (d), 116.1 (d); IR (KBr) 3079, 3066, 3042,
1487, 1138 cmꢁ1; GC–MS m/z (rel intensity) 239 (Mþ, 100), 211 (13),
183 (74), 123 (7), 107 (14), 89 (16), 75 (6), 63 (9), 51 (5); HRMS (EI)
calcd for C15H10FNO 239.0746, found 239.0741.
5.2.10. 5-(2-Bromophenyl)-2-phenyloxazole (44). Yield 72%. White
solid, mp 70–72 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.69; 1H NMR
(400 MHz, CDCl3)
d
8.13–8.10 (m, 2H), 7.95 (s,1H), 7.86 (dd,1H, J¼8.0,
1.6 Hz), 7.69 (dd, 1H, J¼8.0, 1.2 Hz), 7.51–7.46 (m, 3H), 7.43 (ddd, 1H,
5.2.17. 5-(3-Fluorophenyl)-2-phenyloxazole (51). Yield 70%. White
solid, mp 88–90 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.57; 1H NMR
(400 MHz, CDCl3) d 8.12–8.08 (m, 2H), 7.51–7.45 (m, 5H), 7.05 (tdd,
J¼8.0, 7.6, 1.2 Hz), 7.20 (ddd, 1H, J¼8.0, 7.6, 1.6 Hz); 13C NMR
(100 MHz, CDCl3)
d
161.1,148.7,134.2,130.5,129.2,128.8,128.4,128.1,
128.1, 127.5,127.2,126.4,119.9; IR (KBr) 3167, 3066,1471,1142 cmꢁ1
;
1H, J¼9.2, 2.4, 1.2 Hz); 13C NMR (100 MHz, CDCl3)
d 164.3 (d), 161.5,
150.1 (d), 130.6, 130.6 (d), 130.0 (d), 128.8, 127.2, 126.3, 124.4, 119.8
GC–MS m/z (rel intensity) 298 (Mþ, 85), 192 (7), 165 (100), 116 (11),
89 (31), 77 (11), 63 (9), 51 (5). Anal. Calcd for C15H10BrNO: C, 59.52;
H, 3.57; N, 4.57. Found: C, 60.02; H, 3.36; N, 4.67.
(d), 115.3 (d), 111.2 (d); IR (KBr) 3105, 3079, 3059, 1489, 1196 cmꢁ1
;
GC–MS m/z (rel intensity) 239 (Mþ, 100), 211 (15), 183 (62), 116 (19),
89 (17), 75 (5), 63 (17); HRMS (EI) calcd for C15H10FNO 239.0746,
found 239.0743.
5.2.11. 5-(3-Bromophenyl)-2-phenyloxazole (45). Yield 67%. White
solid, mp 116–117 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.57; 1H NMR
(400 MHz, CDCl3)
d
8.12–8.08 (m, 2H), 7.86 (t,1H, J¼1.6 Hz), 7.64 (ddd,
5.2.18. 5-(4-Fluorophenyl)-2-phenyloxazole (52). Yield 66%. White
solid, mp 101–103 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.53; 1H
1H, J¼8.0, 1.6, 1.2 Hz), 7.52–7.44 (m, 5H), 7.32 (t, 1H, J¼8.0 Hz); 13C
NMR (100 MHz, CDCl3)
d
161.6, 149.7, 131.2, 130.6, 130.4, 129.9, 128.8,
NMR (400 MHz, CDCl3)
7.45 (m, 3H), 7.38 (s, 1H), 7.17–7.11 (m, 2H); 13C NMR (100 MHz,
CDCl3) 163.9 (d), 161.1, 150.4, 130.4, 128.8, 127.4, 126.3, 126.1 (d),
d 8.11–8.07 (m, 2H), 7.72–7.67 (m, 2H), 7.51–
127.1, 127.0, 126.4, 124.4, 123.1, 122.6; IR (KBr) 3105, 3056, 1486,
1139 cmꢁ1; GC–MS m/z (rel intensity) 298 (Mþ,100),192 (9),165 (57),
116 (17), 89 (29), 76 (8), 63 (11). Anal. Calcd for C15H10BrNO: C, 59.52;
H, 3.57; N, 4.67. Found: C, 60.01; H, 3.37; N, 4.63.
d
124.4 (d), 123.1, 116.2 (d); IR (KBr) 3130, 3063, 3042, 1503,
1131 cmꢁ1; GC–MS m/z (rel intensity) 239 (Mþ, 100), 211 (19), 183
(59), 123 (5), 107 (11), 95 (11), 75 (4), 63 (5); HRMS (EI) calcd for
C15H10FNO 239.0746, found 239.0746.
5.2.12. 5-(4-Bromophenyl)-2-phenyloxazole (46)13c. Yield 64%. White
solid, mp 110–112 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.50; 1H
NMR (400 MHz, CDCl3)
2H), 7.50–7.46 (m, 3H), 7.44 (s, 1H); 13C NMR (100 MHz, CDCl3)
161.4, 150.3, 132.1, 130.5, 128.8, 127.3, 126.9, 126.3, 125.6, 124.0,
d
8.11–8.08 (m, 2H), 7.59 (br s, 2H), 7.57 (br s,
5.2.19. 5-(2-Trifluoromethylphenyl)-2-phenyloxazole (53). Yield
73%. White solid, mp 46–47 ꢀC; TLC (30% ethyl acetate/hexane)
d
Rf 0.61; 1H NMR (400 MHz, CDCl3)
d 8.14–8.09 (m, 2H), 7.82 (d,

J.J. Lee et al. / Tetrahedron 65 (2009) 8821–8831
8831
2H, J¼8.0 Hz), 7.65 (t, 1H, J¼8.0 Hz), 7.51–7.45 (m, 5H); 13C NMR
Jacob, M. R.; Reynolds, M. B.; Kerwin, S. M. Bioorg. Med. Chem. 2002, 10, 3997–
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(100 MHz, CDCl3)
d 162.0, 147.9, 132.0, 130.6, 129.6, 128.8, 128.6,
127.9 (q), 127.7 (q), 127.2 (q), 127.1, 126.9 (q), 126.4, 126.4; IR
(KBr) 3187, 3063, 1490, 1125 cmꢁ1; GC–MS m/z (rel intensity)
289 (Mþ, 100), 233 (32), 214 (23), 158 (5), 145 (9), 116 (19), 89
(11), 63 (5); HRMS (EI) calcd for C16H10F3NO 289.0714, found
289.0714.
5.2.20. 5-(3-Trifluoromethylphenyl)-2-phenyloxazole (54). Yield 67%.
White solid, mp 132–133 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.60;
1H NMR (400 MHz, CDCl3)
d 8.14–8.10 (m, 2H), 7.95 (br s,1H), 7.88 (d,
1H, J¼6.8 Hz), 7.60–7.46 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 161.8,
149.8, 132.1 (q), 131.1, 129.5, 128.9, 128.8, 127.9 (q), 127.2, 127.1, 126.4,
124.9 (q), 124.7, 120.9 (q); IR (KBr) 3123, 3066, 1488, 1125 cmꢁ1; GC–
MS m/z (rel intensity) 289 (Mþ, 100), 270 (6), 261 (7), 233 (6), 165
(28), 145 (9), 116 (11), 89 (10); HRMS (EI) calcd for C16H10F3NO
289.0714, found 289.0713.
5.2.21. 5-(4-Trifluoromethylphenyl)-2-phenyloxazole (55)13g. Yield
66%. White solid, mp 113–115 ꢀC; TLC (30% ethyl acetate/hexane)
Rf 0.64; 1H NMR (400 MHz, CDCl3)
d 8.15–8.10 (m, 2H), 7.83 (d, 2H,
J¼8.3 Hz), 7.71 (d, 2H, J¼8.3 Hz), 7.55 (s, 1H), 7.54–7.48 (m, 3H); 13C
NMR (100 MHz, CDCl3) d 162.0, 149.8, 131.2, 130.7, 130.6 (q), 128.9,
128.0 (q), 127.1, 126.5, 126.0 (q), 125.2, 124.2; IR (KBr) 3120, 3049,
1476, 1108 cmꢁ1; GC–MS m/z (rel intensity) 289 (Mþ, 100), 261 (8),
233 (8), 165 (25), 145 (9), 116 (10), 89 (9).
5.2.22. 5-(2-Iodophenyl)-2-phenyloxazole (56). Yield 45%. White
solid, mp 104–106 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.52; 1H
7. Lee, S. J.; Lee, J. J.; Kim, C.-H.; Jun, Y. M.; Lee, B. M.; Kim, B. H. Tetrahedron Lett.
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242; (b) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 6646–6647;
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5824–5825; (e) Nishioka, H.; Ohmori, Y.; Iba, Y.; Tsuda, E.; Harayama, T.
Heterocycles 2004, 64, 193–198; (f) Sanfilippo, P. J.; Urbanski, M.; Press, J. B.;
Hajos, Z. G.; Shriver, D. A.; Scott, C. K. J. Med. Chem. 1988, 31, 1778–1785; (g)
El-Sheikh, M. I.; Marks, A.; Biehl, E. R. J. Org. Chem. 1981, 46, 3256–3259; (h)
Mohammadpoor-Baltork, I.; Khosropour, A. R.; Hojati, S. F. Monatsh. Chem.
2007, 138, 663–667; (i) Pottorf, R. S.; Chadha, N. K.; Katkevics, M.; Ozola, V.;
Suna, E.; Ghane, H.; Regberg, T.; Player, M. R. Tetrahedron Lett. 2003, 44, 175–
178; (j) Said, N. PCT Int. Appl. 2008, 59; CAN 148: 428491; (k) Viirre, R. D.;
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Lynch, J. K.; Mulhern, M. M.; Judd, A. S.; Freeman, J. C.; Gao, J.; Souers, A. J.;
Zhao, G.; Wodka, D.; Falls, H. D.; Brodjian, S.; Dayton, B. D.; Reilly, R. M.;
Swanson, S.; Su, Z.; Martin, R. L.; Leitza, S. T.; Houseman, K. A.; Diaz, G.;
Collins, C. A.; Sham, H. L.; Kym, P. R. Bioorg. Med. Chem. Lett. 2007, 17, 874–
878; (m) Kunz, K. R.; Taylor, E. W.; Hutton, H. M.; Blackburn, B. J. Org. Prep.
Proced. Int. 1990, 22, 613–618; (n) Gershon, H.; Clarke, D. D.; Gershon, M.
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NMR (400 MHz, CDCl3)
d
8.14–8.11 (m, 2H), 8.01 (d, 1H, J¼8.0 Hz),
7.86 (s, 1H), 7.71 (dd, 1H, J¼8.0, 1.2 Hz), 7.51–7.42 (m, 4H), 7.06 (td,
1H, J¼8.0, 1.2 Hz); 13C NMR (100 MHz, CDCl3)
d 161.3, 150.7, 141.0,
132.7, 130.5, 129.7, 129.2, 128.8, 128.2, 127.3, 127.2, 126.4, 94.1; IR
(KBr) 3156, 3066, 1467, 1141 cmꢁ1; GC–MS m/z (rel intensity) 347
(Mþ, 100), 192 (8), 165 (47), 89 (24), 77 (9), 63 (7). Anal. Calcd for
C15H10INO: C, 51.90; H, 2.90; N, 4.03. Found: C, 51.92; H, 2.87; N, 4.04.
5.2.23. 5-Biphenyl-4-yl-2-phenyloxazole (57)13a. Yield 59%. White
solid, mp 165–166 ꢀC; TLC (30% ethyl acetate/hexane) Rf 0.66; 1H
NMR (400 MHz, CDCl3)
d
8.13 (d, 2H, J¼6.8 Hz), 7.79 (d, 2H,
J¼8.4 Hz), 7.68 (d, 2H, J¼8.4 Hz), 7.63 (d, 2H, J¼7.6 Hz), 7.51–7.44
(m, 6H), 7.38 (t, 1H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d 161.2,
151.0,141.1, 140.2,130.3, 128.9, 128.8, 127.6, 127.5,127.4, 126.9, 126.9,
126.3, 124.6, 123.6; IR (KBr) 3130, 3066, 3032, 1484, 1140 cmꢁ1; GC–
MS m/z (rel intensity) 297 (Mþ, 100), 269 (10), 241 (36), 165 (19),
152 (13), 134 (8).
Acknowledgements
This work was supported by the Korean Government through
a Korea Research Foundation Grant (MOEHRD, KRF-2005-C00250).
Y.M.J. acknowledges Kwangwoon University for his 2009 sabbatical
leave.
References and notes
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