Iron(0)-Catalyzed Transfer Hydrogenative Condensation of Nitroarenes with Alcohols: A Straightforward Approach to Benzoxazoles, Benzothiazoles, and Benzimidazoles

Article abstract of DOI:10.1021/acs.joc.0c02191

The iron-catalyzed hydrogen transfer strategy has been applied to the redox condensation of o-hydroxynitrobenzene with alcohol, leading to the formation of benzoxazole derivatives. A wide range of 2-substituted benzoxazoles were synthesized in good to excellent yields without the addition of an external redox agent. A series of control experiments provided a plausible mechanism. Furthermore, the reaction system was successfully extended to the synthesis of benzothiazoles and benzimidazoles.

Full text of DOI:10.1021/acs.joc.0c02191

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Article
Iron(0)-Catalyzed Transfer Hydrogenative Condensation of
Nitroarenes with Alcohols: A Straightforward Approach to
Benzoxazoles, Benzothiazoles, and Benzimidazoles
Ramachandra Reddy Putta, Simin Chun, Seung Hyun Choi, Seok Beom Lee, Dong-Chan Oh,
and Suckchang Hong*
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ABSTRACT: The iron-catalyzed hydrogen transfer strategy has been
applied to the redox condensation of o-hydroxynitrobenzene with alcohol,
leading to the formation of benzoxazole derivatives. A wide range of 2-
substituted benzoxazoles were synthesized in good to excellent yields without
the addition of an external redox agent. A series of control experiments
provided a plausible mechanism. Furthermore, the reaction system was
successfully extended to the synthesis of benzothiazoles and benzimidazoles.
catalyzed cyclization of o-substituted nitrobenzenes with 4-
picoline, alkyl amines, and aryl acetic acids to form 2-aryl
benzazoles.7 Inspired by that report, Gan et al. extended similar
Fe/S redox systems to benzyl chlorides and disulfides.8 Pd-
catalyzed carbonylative coupling of o-substituted nitrobenzenes
with aryl halides has also been reported; however, stoichio-
metric Fe(CO)5 was used as a carbonyl source and reducing
reagent.9 Alcohols have received more attention as reducing
partners because of their availability in a wide range of
structures. Indeed, alcohols have been widely applied in redox
condensations with o-nitrophenols and o-nitroaniline, leading
to the corresponding benzazoles.10 These reactions usually
proceed using a specific metal catalyst or heterogeneous
catalyst. However, the formation of organic waste and the use
of excess alcohols are often major concerns. Therefore, an
efficient synthetic method for these benzazoles from simple and
readily available starting materials is still desirable.
INTRODUCTION
■
Benzazoles (benzoxazoles, benzothiazoles, and benzimidazoles)
are common structures in many natural products and synthetic
drugs. In particular, 2-substituted benzazoles are considered a
core moiety in drug discovery because of their wide range of
biological activities.1 In addition to biological applications,
these compounds have been applied in fluorescent chemo-
sensors2 and other functional materials.3 Because of the
important pharmaceutical and industrial applications, many
synthetic protocols for benzazole derivatives have been
developed. The most straightforward approach involves
condensation of o-hydroxy/mercapto/amino anilines with
carbonyl compounds, in particular, an aldehyde.4 Compared
with labile aldehydes, low-oxidation-level substrates, such as
alcohol and amine, are readily available and usually supplied as
feedstock. Based on these advantages, low-oxidation-level
substrates have been employed in the synthesis of benzazoles
via oxidative annulation, which is initiated by in situ formation
of aldehyde or imine intermediate.5 Moreover, metal-catalyzed
cyclization of o-haloanilides was also reported for the synthesis
of benzazoles.6
Tricarbonyl (η4-cyclopentadienone) iron(0) complexes have
been extensively applied to construct C−N, C−C, and C−O
bonds through a hydrogen-borrowing strategy.11 In this
strategy, alcohol can be applied as both a coupling partner
and a reductant. Using this iron complex, we recently reported
In recent years, redox condensation of nitroarenes with low-
oxidation-level substrates has attracted much attention of
organic chemists. Nitroarenes are usually considered a
precursor of aniline, and they can be reduced to aniline by a
redox process with a low-oxidation-level partner. Redox
condensation provides an efficient synthetic approach to
benzazole motifs from readily available starting materials
through a one-pot reaction. Nguyen et al. developed a Fe/S-
Received: September 10, 2020
https://dx.doi.org/10.1021/acs.joc.0c02191
© XXXX American Chemical Society
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Scheme 1. Synthesis of Benzazoles from Nitroarene through a Redox Strategy
the synthesis of benzimidazoles via acceptorless dehydrogen-
ative coupling of alcohols with 1,2-diaminobenzene.12 Based on
our previous work, we envisioned that nitroarenes could be
applied as a hydrogen acceptor to balance the transfer of
hydrogen. Even if the hydrogenation of CO, CN, and C
C bonds has been reported using this iron complex, a reduction
of nitro group via hydrogen transfer has rarely been investigated
to date. Herein, we report a facile synthesis of 2-substituted
benzazoles by iron-catalyzed transfer hydrogenative annulation
of o-nitrophenol/thiophenol/aniline with alcohols (Scheme 1).
No additional redox reagents were needed, and only water was
generated as a byproduct in this transformation.
carried out using Fe 1 as a catalyst (3 mol %), and the expected
2-phenylbenzoxazole 3aa was isolated in 51% yield along with
2-(benzylamino) phenol 3aa′ (entry 1). We supposed that the
catalyst could mediate imine reduction competitively with the
annulation process. To suppress the formation of 3aa′, catalyst
loading was reduced to 2 mol % and the formation of 3aa′ was
significantly decreased (entry 2). Moreover, o-xylene and
cyclopentyl methyl ether (CPME) afford benzoxazole 3aa
more selectively than toluene (entries 3 and 4). When alcohol
2a was decreased from 2.0 to 1.5 equiv, an excellent yield of 3aa
was achieved without side product 3aa′ (entries 5 and 6).
Further decreasing the quantities of catalyst or alcohol gave a
negative result on the reaction (entries 7 and 8). In addition,
various iron complexes, including commercially available FeCl3·
6H2O and Fe2(CO)9, were screened to determine the best
catalyst in the reaction condition. Among these complexes, Fe 1
showed the highest activity in transfer hydrogenative
condensation (see details in the Supporting Information). All
reactions were carried out under pressure in a sealed tube to
enhance the efficiency of hydrogen transfer, especially for the
reduction of nitro group.
RESULTS AND DISCUSSION
■
We began the optimization study for the transfer hydrogenative
condensation of o-nitrophenol 1a using benzyl alcohol 2a as a
reducing partner (Table 1). The preliminary reaction was
Table 1. Optimization of the synthesis of 2-
a
phenylbenzoxazole
With the optimized conditions, we investigated the substrate
scope for transfer hydrogenative condensation between o-
nitrophenol 1 and alcohol 2 (Table 2). Various benzyl alcohols
afforded the desired benzoxazole products 3ab−al in high
yields (70−97%). In the case of alcohols with strong electron-
withdrawing groups such as CO2Me and CN, benzoxazole
products were obtained in lower yields (3al−an). Generally, an
alcohol with a para-substituent provided the desired products in
a slightly higher yield than that of an alcohol with meta- and
ortho-substituents (3ab−ag). A series of alcohols containing
heterocycles (furan, thiophene, and pyridine) also gave the
corresponding products (3aq−as). In addition to benzylic
alcohols, allyl and alkyl alcohols were explored. Although the
yields were lower than those achieved by benzylic alcohols, the
allyl and alkyl alcohols could afford the desired products (3at,
3au). It is important to note that a small amount of o-
aminophenol, which might be generated in situ by hydro-
genation of 1a, was observed in some cases.
b
yield (%)
entry
2a (equiv)
solvent
3aa
3aa′
c
1
2.0
2.0
2.0
2.0
1.5
1.5
1.5
1.0
toluene
toluene
o-xylene
CPME
51
58
77
74
87
89
67
51
48
25
11
10
2
3
4
5
6
CPME
o-xylene
o-xylene
o-xylene
d
7
8
a
Next, variously substituted o-nitrophenols 1 were used for
transfer hydrogenative condensation with benzyl alcohol 2a.
Electron-rich nitrophenols tend to afford products in higher
yields than electron-deficient nitrophenols (3ba−ea). In
Reaction conditions: 1a (0.4 mmol), 2a (0.4−0.8 mmol), Fe 1 (2
mol %), Me3NO (4 mol %), and solvent (1 mL) in a sealed tube at
150 °C for 24 h. Isolated yield. Fe 1 (3 mol %), Me3NO (6 mol %).
b
c
d
Fe 1 (1.5 mol %), Me3NO (3 mol %).
B
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dimerized disulfide product. When we added 1 equiv of
tBuONa to suppress the dimerization of 4a, the yield of 5aa was
significantly increased to 71% (Scheme 2). 3-Pyridine and 1-
naphthalene were also successfully substituted on the 2-position
of benzothiazole with good yields (5as, 5av).
Table 2. Reaction Scope for Benzoxazoles
Scheme 2. Synthesis of Benzothiazoles
To further extend the reaction system, we employed o-
nitroaniline 6a as a substrate to explore the possibility of
benzimidazole formation (Table 3). While no annulated
Table 3. Optimization Studies for the Synthesis of 2-
a
Phenylbenzimidazole
b
entry
tBuONa (equiv)
solvent
o-xylene
o-xylene
toluene
CPME
1,4-dioxane
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
time (h)
yield (%)
1
2
3
4
5
6
7
24
24
24
24
24
24
42
42
42
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
19
15
45
18
62
75
70
80
c
particular, CN- and COCH3-substituted 1 gave the desired
products in low yields (3ja, 3ka). Although we could not
observe any reduced products, a trace amount of aldol
condensation product was observed in the reaction for 3ka.
These results indicate that the nitrophenol 1 bearing electron-
rich substituents facilitate the transfer hydrogenative annulation
higher than those of electron-withdrawing substituents. If there
was a substituent at the ortho-position to the OH group in
nitrophenol, benzoxazole products were obtained in lower
yields (3ga−ia). No hydrogenated or reduced products were
observed in the reaction containing substituents that could be
affected by hydrogenation, such as halogen, ester, and nitrile.
The tolerance of various functional groups opens the pathway
for further modifications of the benzoxazole products.
Furthermore, the practical utility of the developed method
was demonstrated by the gram-scale reaction of 3ah (73%).
After the successful synthesis of benzoxazoles from o-
nitrophenol, we envisioned that benzothiazole and benzimida-
zoles could also be synthesized by replacing o-nitrophenol with
o-nitrothiophenol/aniline. First, we explored the feasibility of
benzothiazole formation between o-nitrothiophenol 4a and
benzyl alcohol 2a using the above reaction conditions. Freshly
prepared o-nitrothiophenol 4a was used in the reaction since 4a
is unstable and easily undergoes dimerization to 2,2′-
dinitrodiphenyl disulfide itself. However, a low yield of the
desired benzothiazole 5aa was obtained (30%) along with the
8
9
a
Reaction conditions: 6a (0.4 mmol), 2a (0.6 mmol), Fe 1 (2 mol
t
%), Me3NO (4 mol %), BuONa (0.4−0.8 mmol), and solvent (1
mL) in a sealed tube at 150 °C. Isolated yield. 160 °C.
b
c
products could be detected under the standard conditions,
significant amounts of 1,2-diamonobenzene and benzaldehyde,
which can be generated through hydrogen transfer, were
observed (entry 1). Based on our experience and previous
reports,10d,g,12 we expected that a stoichiometric base is
required for the formation of benzimidazole. The screening of
t
bases was followed, and BuONa was found to be the most
appropriate one (entry 2), whereas other bases (tBuOK, KOH,
and K2CO3) gave only trace amounts of benzimidazole 7aa
(results are not shown). Considering the more polar character
of benzimidazole than benzoxazoles and benzothiazoles, we
assumed that solvent may be a crucial factor in the
benzimidazole synthesis. Thus, we examined the solvent effect
and revealed that chlorobenzene is the best solvent (entries 2−
6). A longer reaction time afforded 7aa in higher yield (entry
7), and a slightly diminished yield was observed at a higher
temperature (entry 8). The highest yield of 7aa was obtained by
increasing the quantity of base to 1.5 equiv (entry 9, 80%).
C
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With the optimal conditions in hand, the scope of alcohol
substrates was investigated for the synthesis of benzimidazole
(Table 4). Similar to benzoxazole, benzyl alcohols with
be formed via the C−N bond formation by transfer hydro-
genation between amine 1a′ and alcohol 2a. These experiments
revealed that both hydrogen acceptors and hydrogen donors are
required for iron-catalyzed hydrogen transfer. Furthermore, the
reaction of prereduced 1a′ with preoxidized 2a′ could not
produce the desired product 3aa, and most of starting materials
remained (Scheme 3d). We speculated that imine formation
and cyclization between 1a′ and 2a′ are reversible until the final
oxidative aromatization. Therefore, the iron complex was
determined not only to serve as a hydrogen mediator between
the nitro and alcohol groups but also to be involved in the final
oxidative aromatization to form the desired product 3aa. To
determine the key redox intermediates, secondary alcohol 2w
was applied in the reaction as a reducing partner (Scheme 3e).
Although annulation did not occur, both o-aminophenol 1a′
and ketone 2w′ were directly obtained. This result confirmed
that the alcohol is oxidized into the corresponding carbonyl
intermediate and that the nitro group is reduced to an amino
group in situ by iron-catalyzed hydrogen transfer process.
Based on the above-described experiments, a plausible
mechanism of the transfer hydrogenative condensation for
benzoxazole was proposed, as depicted in Scheme 4. First, the
Table 4. Scope of Alcohols for the Synthesis of
Benzimidazoles
Scheme 4. Proposed Mechanism for the Synthesis of
Benzoxazole
electron-donating groups (7af, 7ah) are more favorable than
those having electron-withdrawing groups (7ag, 7aj). Hetero-
aryl-substituted alcohols also afforded the desired products 7ar
and 7as in satisfactory yields. Notably, any 1,2-disubstituted
benzimidazole products were not observed in the reaction,
which is often problematic in the selective synthesis of
benzimidazole.
Several control experiments were performed to investigate
the reaction mechanism (Scheme 3). When the reaction was
Scheme 3. Mechanism Studies
iron catalyst Fe 1 is activated by Me3NO to form 16-electron
iron species [Fe]. [Fe] mediates the oxidation of alcohol 2a and
generates [Fe]-H2, which reduces nitrophenol 1a to amino-
phenol 1a′. Condensation of the oxidized aldehyde 2a′ with 1a′
produces imine intermediate I, followed by cyclization to form
intermediate II. All steps from 1a′ and 2a′ to intermediate II
are reversible; thus, [Fe]-mediated oxidative aromatization of II
leads to completion of benzoxazole 3aa. In the case of
benzimidazole synthesis, the oxidative aromatization did not
occur with [Fe] alone, and the base helps to complete the
benzimidazole synthesis at this step. As mentioned above, we
carried out in the absence of a catalyst, any products were not
observed (Scheme 3a). This result indicates the vital role of
iron catalyst in the hydrogen transfer. As shown in Scheme 3b,
benzaldehyde 2a′ was applied directly in the reaction instead of
2a. However, nitro reduction of 1a did not occur and no
products were observed. If o-aminophenol 1a′ was treated with
2a, no desired product was detected, and a small amount of
3aa′ was observed (Scheme 3c). N-Benzyl product 3aa′ could
D
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(FAB+) m/z calcd for C13H10NO [M + H]+: 196.0762, found:
196.0759.
also identified 3aa′ as a side product, which might be generated
from imine I by [Fe]-H2 mediated hydrogenation.
2-(Benzylamino)phenol (3aa′). Following the general procedure A
with 1a (55.6 mg) and 2a (0.8 mmol, 83 μL), 3aa′ was obtained as
colorless oil (8.8 mg, 11% yield). Eluent: n-hexane/ethyl acetate (90/
CONCLUSIONS
■
1
In conclusion, we have described the iron-catalyzed transfer
hydrogenative condensation of nitroarenes with alcohol for the
synthesis of benzazoles. Tricarbonyl (η4-cyclopentadienone)
iron(0) complexes have been applied in a hydrogen transfer
strategy between nitro and alcohol functionalities. This is a
pioneering work on the reduction of nitro group via hydrogen
transfer using this type of iron complex. A wide range of
benzoxazole derivatives were synthesized in good to excellent
yields. A plausible mechanism for benzoxazole formation was
presented based on the control experiments. The main
advantages of the developed method are that no additional
oxidants or reductants were required, and only water was
generated as a stoichiometric byproduct. Moreover, the
reaction system was successfully extended to the synthesis of
benzothiazoles and benzimidazoles. Therefore, this method-
ology provides an efficient alternative for the synthesis of
benzazole derivatives. Further extension to access other types of
N-heterocycles using an iron-catalyzed hydrogen transfer
strategy is under investigation in our research group.
10). H NMR (400 MHz, CDCl3) δ 7.34−7.41 (m, 4H), 7.26−7.30
(m, 1H), 6.84 (t, J = 7.4 Hz, 1H), 6.62−6.73 (m, 3H), 4.63 (s, 1H),
4.36 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 143.5, 139.5, 137.1,
128.713, 127.7, 127.3, 121.9, 117.9, 114.4, 112.6, 48.7. HRMS (FAB+)
m/z calcd for C13H13NO [M + H]+: 199.0997, found: 199.0993.
2-(o-Tolyl)benzo[d]oxazole (3ab). Following the general proce-
dure A with 1a (55.6 mg) and 2b (73.3 mg), 3ab was obtained as a
white solid (70 mg, 84% yield). Mp 69−71 °C. Eluent: n-hexane/ethyl
1
acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.17−8.19 (m, 1H),
7.81 (dd, J = 5.7, 3.4 Hz, 1H), 7.60 (q, J = 3.1 Hz, 1H), 7.35−7.42 (m,
5H), 2.82 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.5, 150.4,
142.2, 139.0, 131.9, 131.0, 130.1, 126.3, 126.2, 125.1, 124.5, 120.2,
110.6, 22.4. HRMS (FAB+) m/z calcd for C14H12NO [M + H]+:
210.0919, found: 210.0912.
2-(2-Fluorophenyl)benzo[d]oxazole (3ac). Following the general
procedure A with 1a (55.6 mg) and 2c (65 μL), 3ac was obtained as a
white solid (59.9 mg, 70% yield). Mp 97−99 °C. Eluent: n-hexane/
ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.25 (td, J = 7.5,
1.7 Hz, 1H), 7.83−7.85 (m, 1H), 7.61−7.64 (m, 1H), 7.51−7.54 (m,
1H), 7.38−7.41 (m, 2H), 7.30−7.34 (m, 1H), 7.26−7.28 (m, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 160.9 (d, J = 256.8 Hz), 159.5 (d,
J = 4.8 Hz), 150.6, 141.9, 133.2 (d, J = 8.7 Hz), 130.6, 125.6, 124.6 (d,
J = 2.9 Hz), 124.6, 120.5, 117.2 (d, J = 21.1 Hz), 115.6 (d, J = 10.5
Hz), 110.81. 19F NMR (376 MHz, CDCl3) δ −110.0. HRMS (FAB+)
m/z calcd for C13H9FNO [M + H]+: 214.0668, found: 214.0664.
2-(m-Tolyl)benzo[d]oxazole (3ad). Following the general proce-
dure A with 1a (55.6 mg) and 2d (73.3 mg), 3ad was obtained as a
white solid (71.2 mg, 85% yield). Mp 81−83 °C. Eluent: n-hexane/
ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 8.06
(d, J = 7.8 Hz, 1H), 7.77−7.79 (m, 1H), 7.57−7.60 (m, 1H), 7.42 (t, J
= 7.5 Hz, 1H), 7.35 (dt, J = 9.5, 3.7 Hz, 3H), 2.46 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 163.4, 150.9, 142.2, 138.9, 132.5, 129.0,
128.3, 127.1, 125.2, 124.9, 124.7, 120.1, 110.7, 21.5. HRMS (FAB+)
m/z calcd for C14H12NO [M + H]+: 210.0919, found: 210.0915.
2-(3-Fluorophenyl)benzo[d]oxazole (3ae). Following the general
procedure A with 1a (55.6 mg) and 2e (65 μL), 3ae was obtained as a
white solid (64.0 mg, 75% yield). Mp 91−93 °C. Eluent: n-hexane/
EXPERIMENTAL SECTION
■
General Information. All catalytic reactions were carried out
under an argon atmosphere using a sealed tube. Iron complexes Fe 1−
5 and Fe 6 were prepared according to the literature.13,14 All
commercially available reagents and solvents (purchased from Sigma-
Aldrich, TCI, Alfa Aesar, and Acros Organics) were used without
further purification unless otherwise noted. Reactions were monitored
by thin-layer chromatography on a silica gel 60 F254 plate using UV
illumination at 254 nm. Column chromatography was performed on
silica gel (230−400 mesh) using a mixture of n-hexane/ethyl acetate or
dichloromethane (DCM)/methanol as eluents. Nuclear magnetic
resonance (1H NMR, 13C NMR, 19F NMR) spectra were measured on
JEOL JNM-ECZ400s [400 MHz (1H), 100 MHz (13C), 376 MHz
(19F)] using CDCl3 or DMSO-d6 as solvent. The chemical shifts are
given in parts per million (ppm) on the delta (δ) scale. The solvent
peak was used as a reference value, for 1H NMR: CDCl3 = 7.26 ppm,
DMSO-d6 = 2.50 ppm; for 13C{1H} NMR: CDCl3 = 77.16 ppm,
DMSO-d6 = 39.52 ppm. Coupling constants (J) are expressed in hertz
(Hz). IR spectra were recorded on a JASCO, FT/IR-4200 infrared
spectrophotometer and are reported in cm−1. All high-resolution mass
spectra (HRMS) were acquired under fast atom bombardment (FAB)
mode on a JMS-700 MStation mass spectrometer using a double-
1
ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.05−8.07 (m,
1H), 7.94−7.98 (m, 1H), 7.78−7.80 (m, 1H), 7.59−7.61 (m, 1H),
7.51 (td, J = 8.0, 5.6 Hz, 1H), 7.37−7.41 (m, 2H), 7.25 (dt, J = 9.1, 1.6
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.0 (d, J = 245.3 Hz),
161.9 (d, J = 3.8 Hz), 150.9, 142.0, 130.8 (d, J = 7.7 Hz), 129.3 (d, J =
8.6 Hz), 125.6, 124.9, 123.4 (d, J = 2.9 Hz), 120.3, 118.6 (d, J = 21.0
Hz), 114.7 (d, J = 24.0 Hz), 110.8. 19F NMR (376 MHz, CDCl3) δ
−111.7. HRMS (FAB+) m/z calcd for C13H9FNO [M + H]+:
214.0668, found: 214.0672.
focusing magnetic sector. Melting points were measured on a Bu
540 melting point apparatus and were not corrected.
̈
chi B-
2-(p-Tolyl)benzo[d]oxazole (3af). Following the general procedure
A with 1a (55.6 mg) and 2f (73.3 mg), 3af was obtained as a white
solid (73.5 mg, 88% yield). Mp 115−117 °C. Eluent: n-hexane/ethyl
Synthesis of Benzoxazoles. General Procedure A. A mixture of
o-nitrophenol (0.4 mmol, 1.0 equiv), alcohol (0.6 mmol, 1.5 equiv), Fe
1 (3.35 mg, 0.008 mmol), and Me3NO (1.2 mg, 0.016 mmol) was
placed in a dried 10 mL sealed tube. The tube was degassed and
backfilled with argon three times; then, o-xylene (1 mL) was added
using a syringe under argon flow. The reaction tube was capped, and
then the mixture was stirred and heated at 150 °C in an oil bath for 24
h. After completion, the reaction mixture was cooled to room
temperature and volatiles were removed under reduced pressure. The
residue was purified by silica gel column chromatography using n-
hexane/ethyl acetate as an eluent to afford the desired benzoxazole
derivatives 3.
2-Phenylbenzo[d]oxazole (3aa). Following the general procedure
A with 1a (55.6 mg) and 2a (62 μL), 3aa was obtained as a white solid
(69.5 mg, 89% yield). Mp 103−105 °C. Eluent: n-hexane/ethyl acetate
(97/3). 1H NMR (400 MHz, CDCl3) δ 8.26−8.28 (m, 2H), 7.79 (q, J
= 3.0 Hz, 1H), 7.60 (q, J = 3.0 Hz, 1H), 7.52−7.55 (m, 3H), 7.35−
7.38 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.2, 150.9,
142.2, 131.7, 129.0, 127.8, 127.3, 125.2, 124.7, 120.1, 110.7. HRMS
1
acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz,
2H), 7.75−7.77 (m, 1H), 7.56−7.58 (m, 1H), 7.32−7.36 (m, 4H),
2.45 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 150.8, 142.3,
142.2, 129.8, 127.7, 125.0, 124.6, 124.5, 120.0, 110.6, 21.8. HRMS
(FAB+) m/z calcd for C14H12NO [M + H]+: 210.0919, found:
210.0914.
2-(4-Fluorophenyl)benzo[d]oxazole (3ag). Following the general
procedure A with 1a (55.6 mg) and 2g (65 μL), 3ag was obtained as a
white solid (76.1 mg, 89% yield). Mp 97−99 °C. Eluent: n-hexane/
1
ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.25−8.28 (m,
2H), 7.76−7.78 (m, 1H), 7.57−7.59 (m, 1H), 7.35−7.38 (m, 2H),
7.20−7.24 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.9 (d, J =
250.1 Hz), 162.3, 150.9, 142.2, 129.9 (d, J = 9.5 Hz), 125.3, 124.8,
123.6 (d, J = 3.9 Hz), 120.1, 116.3 (d, J = 22.0 Hz), 110.7. 19F NMR
(376 MHz, CDCl3) δ −107.4. HRMS (FAB+) m/z calcd for
C13H9FNO [M + H]+: 214.0668, found: 214.0660.
E
https://dx.doi.org/10.1021/acs.joc.0c02191
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Article
2-(4-Methoxyphenyl)benzo[d]oxazole (3ah). Following the gen-
eral procedure A with 1a (55.6 mg) and 2h (82.9 mg), 3ah was
obtained as a white solid (87 mg, 97% yield). Mp 102−104 °C. Eluent:
a white solid (45.1 mg, 51% yield). Mp 203−205 °C. Eluent: n-
hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.34 (dd,
J = 6.9, 1.8 Hz, 2H), 7.79−7.81 (m, 3H), 7.60 (q, J = 3.1 Hz, 1H),
7.39−7.43 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.0,
151.0, 142.0, 132.8, 131.2, 128.0, 126.3, 125.2, 120.7, 118.3, 114.8,
111.0. IR (neat) υ 3065, 2308, 1652, 1507, 1216, 750, 689, 669 cm−1.
HRMS (FAB+) m/z calcd for C14H9N2O [M + H]+: 221.0715, found:
221.0716.
2-(Benzo[d][1,3]dioxol-5-yl)benzo[d]oxazole (3ao). Following the
general procedure A with 1a (55.6 mg) and 2o (91.3 mg), 3ao was
obtained as a white solid (83.1 mg, 87% yield). Mp 150−152 °C.
Eluent: n-hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ
7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.72−7.74 (m, 1H), 7.70 (d, J = 1.4 Hz,
1H), 7.54−7.56 (m, 1H), 7.32−7.34 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H),
6.07 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 150.8, 150.7,
148.4, 142.3, 124.9, 124.7, 123.0, 121.3, 119.9, 110.6, 108.9, 107.8,
101.9. HRMS (FAB+) m/z calcd for C14H10NO3 [M + H]+: 240.0661,
found: 240.0658.
2-(Naphthalen-2-yl)benzo[d]oxazole (3ap). Following the general
procedure A with 1a (55.6 mg) and 2p (94.9 mg), 3ap was obtained as
a white solid (79.3 mg, 81% yield). Mp 111−113 °C. Eluent: n-
hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.79 (s,
1H), 8.33 (dd, J = 8.7, 1.4 Hz, 1H), 7.99 (q, J = 4.3 Hz, 2H), 7.91 (q, J
= 3.0 Hz, 1H), 7.82 (q, J = 3.0 Hz, 1H), 7.57−7.65 (m, 3H), 7.39 (q, J
= 3.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 151.0,
142.4, 134.9, 133.1, 129.1, 128.9, 128.3, 128.7, 128.0, 127.7, 125.3,
124.8, 124.5, 124.1, 120.2, 110.8. HRMS (FAB+) m/z calcd for
C17H12NO [M + H]+: 246.0919, found: 246.0916.
1
n-hexane/ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.20
(dd, J = 7.1, 2.1 Hz, 2H), 7.73−7.75 (m, 1H), 7.55−7.57 (m, 1H),
7.31−7.34 (m, 2H), 7.04 (dd, J = 6.9, 1.8 Hz, 2H), 3.90 (s, 3H)
13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 162.4, 150.8, 142.4, 129.5,
124.7, 124.5, 119.8, 119.7, 114.5, 110.5, 55.6. HRMS (FAB+) m/z
calcd for C14H12NO2 [M + H]+: 226.0868, found: 226.0864.
Procedure for the Gram-Scale Synthesis of 3ah. A mixture of o-
nitrophenol 1a (1.0 g, 7.19 mmol), 4-methoxy benzyl alcohol 2h (1.49
g, 10.79 mmol), Fe 1 (60.17 mg, 2 mol %), and Me3NO (21.60 mg, 4
mol %) was placed in a dried 100 mL sealed tube. The tube was
degassed and backfilled with argon three times; then, o-xylene (18 mL)
was added using a syringe under argon flow. The reaction tube was
capped, and then the mixture was stirred and heated at 150 °C in an oil
bath for 24 h. After completion, the reaction mixture was cooled to
room temperature and volatiles were removed under reduced pressure.
The residue was purified by silica gel column chromatography using n-
hexane/ethyl acetate (97/3) as an eluent to afford the corresponding
benzoxazole 3ah (1.18 g, 73% yield) (1.25 g, 77% for 42 h).
2-(4-Chlorophenyl)benzo[d]oxazole (3ai). Following the general
procedure A with 1a (55.6 mg) and 2i (85.5 mg), 3ai was obtained as a
white solid (86.1 mg, 94% yield). Mp 150−152 °C. Eluent: n-hexane/
ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.20 (dt, J = 8.9,
2.2 Hz, 2H), 7.76−7.79 (m, 1H), 7.58−7.60 (m, 1H), 7.51 (dt, J = 9.0,
2.3 Hz, 2H), 7.36−7.39 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ
162.2, 150.9, 142.2, 137.9, 129.4, 129.0, 125.8, 125.5, 124.9, 120.2,
110.8. HRMS (FAB+) m/z calcd for C13H9ClNO [M + H]+: 230.0373,
found: 230.0372.
2-(Furan-2-yl)benzo[d]oxazole (3aq). Following the general
procedure A with 1a (55. 6 mg) and 2q (52 μL), 3aq was obtained
as a white solid (37.2 mg, 50% yield). Mp 87−89 °C. Eluent: n-
2-(4-Bromophenyl)benzo[d]oxazole (3aj). Following the general
procedure A with 1a (55.6 mg) and 2j (112.3 mg), 3aj was obtained as
a white solid (91.1 mg, 83% yield). Mp 156−158 °C. Eluent: n-
hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J
= 8.7 Hz, 2H), 7.76−7.79 (m, 1H), 7.68 (dd, J = 8.9, 2.1 Hz, 2H),
7.58−7.60 (m, 1H), 7.37 (td, J = 3.3, 2.1 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3) δ 162.3, 150.9, 142.1, 132.4, 129.2, 126.4, 126.2, 125.5,
124.9, 120.3, 110.8. HRMS (FAB+) m/z calcd for C13H9BrNO [M +
H]+: 273.9868, found: 273.9858.
1
hexane/ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 7.75−
7.77 (m, 1H), 7.67 (s, 1H), 7.55−7.57 (m, 1H), 7.36 (dt, J = 7.0, 2.2
Hz, 2H), 7.28 (t, J = 2.5 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 6.61−6.63
(m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 155.4, 150.3, 145.9,
142.7, 141.8, 125.4, 125.0, 120.3, 114.4, 112.4, 110.7. HRMS (FAB+)
m/z calcd for C11H8NO2 [M + H]+: 186.0555, found: 186.0561.
2-(Thiophen-2-yl)benzo[d]oxazole (3ar). Following the general
procedure A with 1a (55.6 mg) and 2r (57 μL), 3ar was obtained as a
white solid (64.2 mg, 80% yield). Mp 104−106 °C. Eluent: n-hexane/
ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J = 1.7
Hz, 1H), 7.73−7.75 (m, 1H), 7.54−7.57 (m, 2H), 7.33−7.36 (m, 2H),
7.20 (dd, J = 4.8, 3.9 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
159.2, 150.6, 142.1, 130.4, 130.1, 129.8, 128.4, 125.2, 124.9, 119.9,
110.6. HRMS (FAB+) m/z calcd for C11H8NOS [M + H]+: 202.0327,
found: 202.0326.
2-(4-Iodophenyl)benzo[d]oxazole (3ak). Following the general
procedure A with 1a (55.6 mg) and 2k (140.5 mg), 3ak was obtained
as a white solid (105.2 mg, 82% yield). Mp 168−170 °C. Eluent: n-
1
hexane/ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 7.96−
7.99 (m, 1H), 7.87−7.90 (m, 1H), 7.76−7.78 (m, 1H), 7.57−7.59 (m,
1H), 7.37 (td, J = 3.4, 1.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ 162.5, 150.9, 142.1, 138.4, 129.1, 126.8, 125.6, 124.9, 120.3, 110.8,
98.6. HRMS (FAB+) m/z calcd for C13H9INO [M + H]+: 321.9729,
found: 321.9728.
2-(Pyridin-3-yl)benzo[d]oxazole (3as). Following the general
procedure A with 1a (55.6 mg) and 2s (58 μL), 3as was obtained
as a white solid (68.2 mg, 87% yield). Mp 112−114 °C. Eluent: n-
hexane/ethyl acetate (90/10). 1H NMR (400 MHz, CDCl3) δ 9.48 (d,
J = 0.9 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.52 (dt, J = 7.9, 1.9 Hz,
1H), 7.80−7.82 (m, 1H), 7.61−7.64 (m, 1H), 7.48 (ddd, J = 8.0, 4.8,
0.9 Hz, 1H), 7.39−7.43 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ
160.8, 152.2, 150.8, 148.9, 141.9, 134.8, 125.8, 125.0, 123.8, 123.6,
120.4, 110.9. HRMS (FAB+) m/z calcd for C12H9N2O [M + H]+:
197.0715, found: 197.0716.
2-(4-(Trifluoromethyl)phenyl)benzo[d]oxazole (3al). Following
the general procedure A with 1a (55.6 mg) and 2l (82 μL), 3al was
obtained as a white solid (83.1 mg, 79% yield). Mp 142−144 °C.
Eluent: n-hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ
8.38 (d, J = 8.2 Hz, 3H), 7.79−7.82 (m, 5H), 7.62 (td, J = 3.7, 1.7 Hz,
2H), 7.39−7.42 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.6,
151.0, 142.0, 133.1 (q, J = 32.5 Hz), 130.6, 128.0, 126.1 (q, J =3.8 Hz),
125.9, 125.2−119.8 (q, J =270.2), 120.5, 110.9. 19F NMR (376 MHz,
CDCl3) δ −62.9. HRMS (FAB+) m/z calcd for C14H9F3NO [M + H]+:
264.0636, found: 264.0631.
Methyl 4-(Benzo[d]oxazol-2-yl)benzoate (3am). Following the
general procedure A with 1a (55.6 mg) and 2m (99.7 mg), 3am was
obtained as a white solid (61.0 mg, 60% yield). Mp 193−195 °C.
Eluent: n-hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ
8.33−8.35 (m, 2H), 8.20 (d, J = 8.7 Hz, 2H), 7.80−7.82 (m, 1H),
7.61−7.63 (m, 1H), 7.40 (dd, J = 6.1, 2.6 Hz, 2H), 3.97 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 166.5, 162.1, 151.0, 142.1, 132.7,
131.8, 130.3, 127.6, 125.9, 125.0, 120.5, 110.9, 52.6. IR (neat) υ 3072,
1718, 1540, 1456, 1260, 1108 cm−1. HRMS (FAB+) m/z calcd for
C15H12NO3 [M + H]+: 254.0814, found: 254.0817.
2-Styrylbenzo[d]oxazole (3at). Following the general procedure A
with 1a (55.6 mg) and 2t (80.5 mg), 3at was obtained as a white solid
(27.8 mg, 31% yield). Mp 83−85 °C. Eluent: n-hexane/ethyl acetate
(97/3). 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 16.5 Hz, 1H), 7.72
(q, J = 3.1 Hz, 1H), 7.60−7.62 (m, 2H), 7.52−7.55 (m, 1H), 7.38−
7.45 (m, 3H), 7.34 (td, J = 3.5, 1.8 Hz, 2H), 7.09 (d, J = 16.5 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 150.6, 142.3, 139.6, 135.3,
129.9, 129.1, 127.7, 125.4, 124.7, 120.0, 114.1, 110.5. HRMS (FAB+)
m/z calcd for C15H12NO [M + H]+: 222.0919, found: 222.0924.
2-Cyclohexylbenzo[d]oxazole (3au). Following the general
procedure A with 1a (55.6 mg) and 2u (74 μL), 3au was obtained
as a white solid (23.2 mg, 29% yield). Mp 37−39 °C. Eluent: n-
1
4-(Benzo[d]oxazol-2-yl)benzonitrile (3an). Following the general
procedure A with 1a (55.6 mg) and 2n (79.9 mg), 3an was obtained as
hexane/ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 7.67−
7.69 (m, 1H), 7.46−7.49 (m, 1H), 7.26−7.31 (m, 2H), 2.95 (qd, J =
F
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7.5, 3.8 Hz, 1H), 2.15−2.19 (m, 2H), 1.87 (dt, J = 12.7, 3.6 Hz, 2H),
1.67−1.76 (m, 3H), 1.25−1.49 (m, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 170.6, 150.7, 141.4, 124.5, 124.1, 119.8, 110.4, 38.1, 30.6,
25.9, 25.8. HRMS (FAB+) m/z calcd for C13H16NO [M + H]+:
202.1232, found: 202.1235.
6-Methyl-2-phenylbenzo[d]oxazole (3ba). Following the general
procedure A with 1b (61.3 mg) and 2a (62 μL), 3ba was obtained as a
white solid (75.3 mg, 90% yield). Mp 93−95 °C. Eluent: n-hexane/
ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.24 (td, J = 4.0,
1.6 Hz, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.51 (q, J = 3.3 Hz, 3H), 7.38 (s,
1H), 7.15−7.18 (m, 1H), 2.50 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.7, 151.2, 140.0, 135.7, 131.4, 129.0, 127.6, 127.5, 125.9,
119.5, 110.9, 21.9. HRMS (FAB+) m/z calcd for C14H12NO [M + H]+:
210.0919, found: 210.0920.
116.7 (d, J = 6.7 Hz), 115.8 (d, J = 19.1 Hz). 19F NMR (376 MHz,
CDCl3) δ −131.6. HRMS (FAB+) m/z calcd for C13H8BrFNO [M +
H]+: 291.9773, found: 291.9777.
2-Phenylnaphtho[2,1-d]oxazole (3ia). Following the general
procedure A with 1i (75.7 mg) and 2a (62 μL), 3ia was obtained as
a white solid (53.9 mg, 55% yield). m.p 122−124 °C. Eluent: n-
1
hexane/ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.31−
8.36 (m, 3H), 7.99 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.80
(d, J = 8.6 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.53−7.58 (m, 4H).
13C{1H} NMR (100 MHz, CDCl3) δ 162.6, 146.6, 138.8, 131.9, 131.3,
129.1, 128.9, 127.6, 127. 5, 127.0, 125.8, 125.6, 120.5, 120.3, 118.8.
HRMS (FAB+) m/z calcd for C17H12NO [M + H]+: 246.0919, found:
246.0915.
2-Phenylbenzo[d]oxazole-5-carbonitrile (3ja). Following the
general procedure A with 1j (65.7 mg) and 2a (62 μL), 3ja was
obtained as a white solid (52.7 mg, 60% yield). m.p 196−198 °C.
Eluent: n-hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ
8.25−8.27 (m, 2H), 8.08 (s, 1H), 7.66−7.69 (m, 2H), 7.54−7.61 (m,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.2, 153.2, 142.7, 132.6,
129.2, 129.2, 128.1, 126.1, 124.6, 118.9, 111.9, 108.6. IR (neat) υ 3062,
2224, 1619, 1551, 1261, 788, 705, 689 cm−1. HRMS (FAB+) m/z calcd
for C14H9N2O [M + H]+: 221.0715, found: 221.0713.
1-(2-Phenylbenzo[d]oxazol-5-yl)ethan-1-one (3ka). Following
the general procedure A with 1k (72.5 mg) and 2a (62 μL), 3ka
was obtained as a white solid (19.7 mg, 21% yield). Mp 145−147 °C.
Eluent: n-hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ
8.38 (d, J = 0.9 Hz, 1H), 8.27 (dd, J = 7.8, 1.8 Hz, 2H), 8.06 (dd, J =
8.7, 1.8 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.55−7.57 (m, 3H), 2.70 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.3, 164.7, 153. 9, 142.5,
134.6, 132.2, 129.2, 128.0, 126.7, 126.0, 121.1, 110.8, 26.9. IR (neat) υ
3067, 2920, 1675, 814, 722, 688 cm−1. HRMS (FAB+) m/z calcd for
C15H12NO2 [M + H]+: 238.0868, found: 238.0861.
6-Fluoro-2-phenylbenzo[d]oxazole (3ca). Following the general
procedure A with 1c (62.8 mg) and 2a (62 μL), 3ca was obtained as a
white solid (66.7 mg, 78% yield). m.p 109−111 °C. Eluent: n-hexane/
1
ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.21−8.24 (m,
2H), 7.70 (q, J = 4.6 Hz, 1H), 7.52−7.56 (m, 3H), 7.32 (dd, J = 7.8,
2.3 Hz, 1H), 7.08−7.14 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
163.6 (d, J = 2.9 Hz), 160.8 (d, J = 242.5 Hz), 150.8 (d, J = 14.3 Hz),
138.6, 131.8, 129.1, 127.6, 127.0, 120.4 (d, J = 9.5 Hz), 112.7 (d, J =
24.8 Hz), 98.8 (d, J = 27.7 Hz). 19F NMR (376 MHz, CDCl3) δ
−115.0. HRMS (FAB+) m/z calcd for C13H9FNO [M + H]+:
214.0668, found: 214.0670.
5-Methyl-2-phenylbenzo[d]oxazole (3da). Following the general
procedure A with 1d (61.3 mg) and 2a (62 μL), 3da was obtained as a
white solid (74.6 mg, 89% yield). Mp 101−103 °C. Eluent: n-hexane/
1
ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.23−8.26 (m,
2H), 7.56 (s, 1H), 7.50−7.53 (m, 3H), 7.45 (d, J = 7.9 Hz, 1H), 7.16
(dd, J = 8.6, 1.2 Hz, 1H), 2.49 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 163.2, 149.1, 142.4, 134.5, 131.5, 129.0, 127.7, 127.5, 126.3,
120.0, 110.0, 21.6. HRMS (FAB+) m/z calcd for C14H12NO [M + H]+:
210.0919, found: 210.0918.
Synthesis of Benzothiazoles. Preparation of o-Nitrothiophenol
4a.15 To a suspension of o-nitrophenyl disulfide (1 g, 3.25 mmol) in
25 mL of dry tetrahydrofuran (THF), PPh3 (1.28 g, 4.88 mmol), 2-
mercaptoethanol (0.23 mL, 3.25 mmol), and H2O (0.6 mL, 32.5
mmol) were added. The solution was stirred at 50 °C for 8 h, then
cooled to rt. The mixture was concentrated, redissolved in dichloro-
methane (DCM), washed with brine, dried over Na2SO4, and
evaporated. The resulting orange oil was purified by silica gel column
chromatography using n-hexane/ethyl acetate (90/10) as an eluent to
afford the bright-yellow solid 4a (834 mg, 83% yield). 1H NMR (400
MHz, CDCl3) δ 8.26 (d, J = 8.2 Hz, 1H), 7.44 (dd, J = 4.8, 1.1 Hz,
2H), 7.27−7.31 (m, 1H), 4.02 (s, 1H).
5-Fluoro-2-phenylbenzo[d]oxazole (3ea). Following the general
procedure A with 1e (62.8 mg) and 2a (62 μL), 3ea was obtained as a
white solid (51.8 mg, 61% yield). m.p 104−106 °C. Eluent: n-hexane/
ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J = 7.6,
2.1 Hz, 2H), 7.50−7.56 (m, 4H), 7.45 (dd, J = 8.6, 2.4 Hz, 1H), 7.09
(td, J = 9.2, 2.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.9,
160.3 (d, J = 237.7 Hz), 147.2, 143.1 (d, J = 13.4 Hz), 132.0, 129.1,
127.8, 127.1 (d, J = 12.4 Hz), 112.9 (d, J = 25.8 Hz), 111.0 (d, J = 10.5
Hz), 106.6 (d, J = 24.8 Hz). 19F NMR (376 MHz, CDCl3) δ −117.6.
HRMS (FAB+) m/z calcd for C13H9FNO [M + H]+: 214.0668, found:
214.0667.
General Procedure B. To a predried 10 mL sealed tube, o-
nitrothiophenol 4a (0.4 mmol, 1.0 equiv), alcohol 2 (0.6 mmol, 1.5
equiv), Fe 1 (3.35 mg, 0.008 mmol), Me3NO (1.2 mg, 0.016 mmol),
4-Methyl-2-phenylbenzo[d]oxazole (3fa). Following the general
procedure A with 1f (61.3 mg) and 2a (62 μL), 3fa was obtained as a
white solid (70.3 mg, 84% yield). Mp 90−92 °C. Eluent: n-hexane/
t
and BuONa (38.50 mg, 0.4 mmol, 1.0 equiv) were added. The tube
1
ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.29−8.31 (m,
was degassed and backfilled with argon three times; then, o-xylene (1
mL) was added using a syringe under argon flow. The reaction tube
was capped, and then the mixture was stirred and heated at 150 °C in
an oil bath for 24 h. After completion, the reaction mixture was cooled
to room temperature and volatiles were removed under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy using n-hexane/ethyl acetate as an eluent to afford the desired
benzothiazole derivatives 5.
2H), 7.53−7.56 (m, 3H), 7.43 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 7.6 Hz,
1H), 7.17 (d, J = 8.6 Hz, 1H), 2.71 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.4, 150.7, 141.6, 131.4, 130.741, 128.944, 127.741, 127.6,
125.2, 124.9, 108.0, 16.7. HRMS (FAB+) m/z calcd for C14H12NO [M
+ H]+: 210.0919, found: 210.0922.
7-Methyl-2-phenylbenzo[d]oxazole (3ga). Following the general
procedure A with 1g (61.3 mg) and 2a (62 μL), 3ga was obtained as a
yellow solid (63.4 mg, 76% yield). Mp 88−90 °C. Eluent: n-hexane/
2-Phenylbenzo[d]thiazole (5aa). Following the general procedure
B with 4a (62.1 mg) and 2a (62 μL), 5aa was obtained as a white solid
(60.2 mg, 71% yield). Mp 114−116 °C. Eluent: n-hexane/ethyl acetate
1
ethyl acetate (97/3). H NMR (400 MHz, CDCl3) δ 8.27−8.29 (m,
2H), 7.60 (d, J = 7.9 Hz, 1H), 7.54 (q, J = 2.4 Hz, 3H), 7.24−7.27 (m,
2H), 7.15 (d, J = 7.3 Hz, 1H), 2.60 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.9, 150.2, 141.8, 131.6, 129.0, 127.7, 127.5, 126.3, 124.6,
121.3, 117.5, 15.4. HRMS (FAB+) m/z calcd for C14H12NO [M + H]+:
210.0919, found: 210.0922.
1
(97/3). H NMR (400 MHz, CDCl3) δ 8.07−8.12 (m, 3H), 7.91−
7.93 (m, 1H), 7.48−7.52 (m, 4H), 7.37−7.42 (m, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 168.2, 154.3, 135.2, 133.7, 131.1, 129.1, 127.8,
126.4, 125.3, 123.4, 121.7. HRMS (FAB+) m/z calcd for C13H10NS [M
+ H]+: 212.0534, found: 212.0538.
5-Bromo-7-fluoro-2-phenylbenzo[d]oxazole (3ha). Following the
general procedure A with 1h (94.4 mg) and 2a (62 μL), 3ha was
obtained as a white solid (52.4 mg, 45% yield). m.p 157−159 °C.
Eluent: n-hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ
8.26 (d, J = 6.7 Hz, 2H), 7.71 (s, 1H), 7.53−7.59 (m, 3H), 7.27−7.30
(m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 148.0, 145.9 (d,
J = 104.4 Hz), 137.4, 132.5, 129.2, 128.2, 126.2, 119.2 (d, J = 11.0 Hz),
2-(Pyridin-3-yl)benzo[d]thiazole (5as). Following the general
procedure B with 4a (62.1 mg) and 2s (58 μL), 5as was obtained
as a white solid (52.1 mg, 61% yield). Mp 129−131 °C. Eluent: n-
hexane/ethyl acetate (90/10). 1H NMR (400 MHz, CDCl3) δ 9.30 (d,
J = 1.8 Hz, 1H), 8.73 (q, J = 2.0 Hz, 1H), 8.40 (td, J = 5.1, 2.7 Hz, 1H),
8.11 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.52−7.56 (m, 1H),
G
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Article
7.42−7.47 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.7,
154.1, 151.8, 148.8, 135.1, 134.7, 129.8, 126.8, 125.9, 123.9, 123.6,
121.9. HRMS (FAB+) m/z calcd for C12H9N2S [M + H]+: 213.0486,
found: 213.0490.
7.60 (s, 2H), 7.22 (td, J = 6.4, 3.5 Hz, 2H). 13C{1H} NMR (100 MHz,
DMSO-d6) δ 150.2, 132.0, 129.4, 128.4, 123.3, 122.5. HRMS (FAB+)
m/z calcd for C13H10BrN2 [M + H]+: 273.0027, found: 273.0024.
2-(Benzo[d][1,3]dioxol-5-yl)-1H-benzo[d]imidazole (7ao). Fol-
lowing the general procedure C with 6a (55.3 mg) and 2o (91.3
mg), 7ao was obtained as a white solid (67.6 mg, 71% yield). Mp 250−
2-(Naphthalen-1-yl)benzo[d]thiazole (5av). Following the general
procedure B with 4a (62.1 mg) and 2v (94.9 mg), 5av was obtained as
a white solid (75.0 mg, 72% yield). Mp 126−128 °C. Eluent: n-
hexane/ethyl acetate (97/3). 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J
= 8.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.93−8.01 (m, 4H), 7.54−
7.65 (m, 4H), 7.44−7.48 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ 167.8, 154.3, 135.6, 134.2, 131.2, 131.0, 130.8, 129.5, 128.6, 127.8,
126. 7, 126.4, 126.0, 125.4, 125.1, 123.7, 121.6. HRMS (FAB+) m/z
calcd for C17H12NS [M + H]+: 262.0690, found: 262.0692.
Synthesis of Benzimidazoles. General Procedure C. A 10 mL
sealed tube was charged with o-nitroaniline 6a (0.4 mmol, 1.0 equiv),
alcohol 2 (0.6 mmol, 1.5 equiv), Fe 1 (3.35 mg, 0.008 mmol), Me3NO
(1.2 mg, 0.016 mmol), and tBuONa (57.66 mg, 0.6 mmol, 1.5 equiv).
The tube was degassed and backfilled with argon three times; then,
chlorobenzene (1 mL) was added using a syringe under argon flow.
The reaction tube was capped, and then the mixture was stirred and
heated at 150 °C in an oil bath for 42 h. After completion, the reaction
mixture was cooled to room temperature and volatiles were removed
under reduced pressure. The resulting residue was purified by silica gel
column chromatography using n-hexane/ethyl acetate or dichloro-
methane/methanol as an eluent to provide the desired benzimidazoles
7.
2-Phenyl-1H-benzo[d]imidazole (7aa). Following the general
procedure C with 6a (55.3 mg) and 2a (62 μL), 7aa was obtained
as a white solid (62.4 mg, 80% yield). Mp 291−293 °C. Eluent: n-
hexane/ethyl acetate (4/1). 1H NMR (400 MHz, DMSO-d6) δ 12.90
(s, 1H), 8.17 (d, J = 6.9 Hz, 2H), 7.47−7.59 (m, 5H), 7.20 (td, J = 6.5,
3.8 Hz, 2H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 151.2, 130.2,
129.8, 129.0, 126.5, 122.1. HRMS (FAB+) m/z calcd for C13H11N2 [M
+ H]+: 195.0922, found: 195.0924.
2-(p-Tolyl)-1H-benzo[d]imidazole (7af). Following the general
procedure C with 6a (55.3 mg) and 2f (73.3 mg), 7af was obtained as
a white solid (66.5 mg, 80% yield). Mp 265−267 °C. Eluent: n-
hexane/ethyl acetate (4/1). 1H NMR (400 MHz, DMSO-d6) δ 12.82
(s, 1H), 8.07 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 7.3 Hz, 1H), 7.51 (d, J =
7.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 7.19 (dd, J = 8.7, 6.0 Hz, 2H),
2.38 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 151.4, 143.8,
139.6, 135.0, 129.5, 127.5, 126.4, 122.4, 121.6, 118.7, 111.2, 21.0.
HRMS (FAB+) m/z calcd for C14H13N2 [M + H]+: 209.1079, found:
209.1076.
1
252 °C. Eluent: n-hexane/ethyl acetate (4/1). H NMR (400 MHz,
DMSO-d6) δ 12.73 (s, 1H), 7.71 (td, J = 8.9, 1.4 Hz, 2H), 7.62 (d, J =
6.7 Hz, 1H), 7.49 (d, J = 6.7 Hz, 1H), 7.18 (q, J = 4.5 Hz, 2H), 7.09 (d,
J = 8.0 Hz, 1H), 6.12 (s, 2H). 13C{1H} NMR (100 MHz, DMSO-d6) δ
151.1, 148.7, 147.9, 143.7, 134.9, 124.3, 122.3, 121.56, 120.9, 118.6,
111.1, 108.8, 106.5, 101.6. HRMS (FAB+) m/z calcd for C14H11N2O2
[M + H]+: 239.0821, found: 239.0815.
2-(Thiophen-2-yl)-1H-benzo[d]imidazole (7ar). Following the
general procedure C with 6a (55.3 mg) and 2r (57 μL), 7ar was
obtained as a white solid (47.3 mg, 59% yield). Mp 280−282 °C.
1
Eluent: n-hexane/ethyl acetate (4/1). H NMR (400 MHz, DMSO-
d6) δ 12.93 (s, 1H), 7.83 (d, J = 3.7 Hz, 1H), 7.72 (d, J = 4.3 Hz, 1H),
7.54 (s, 2H), 7.19−7.24 (m, 3H). 13C{1H} NMR (100 MHz, DMSO-
d6) δ 147.0, 133.7, 128.8, 128.3, 126. 7, 122.6, 121.8, 118.5, 111.1.
HRMS (FAB+) m/z calcd for C11H9N2S [M + H]+: 201.0486, found:
201.0484.
2-(Pyridin-3-yl)-1H-benzo[d]imidazole (7as). Following the gen-
eral procedure C with 6a (55.3 mg) and 2s (58 μL), 7as was obtained
as a white solid (49.4 mg, 63% yield). Mp 254−256 °C. Eluent:
dichloromethane/methanol (98/2). 1H NMR (400 MHz, DMSO-d6)
δ 13.10 (s, 1H), 9.35 (d, J = 1.8 Hz, 1H), 8.67 (dd, J = 4.9, 1.2 Hz, 1H),
8.49 (dt, J = 7.9, 1.8 Hz, 1H), 7.57−7.72 (m, 3H), 7.24 (d, J = 4.3 Hz,
2H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 150.5, 148.9, 147.5,
143.7, 135.0, 133.8, 126.2, 124.0, 123.0, 122.0, 119.1, 111.512. HRMS
(FAB+) m/z calcd for C12H10N3 [M + H]+: 196.0875, found:
196.0874.
2-(Naphthalen-1-yl)-1H-benzo[d]imidazole (7av). Following the
general procedure C with 6a (55.3 mg) and 2v (94.9 mg), 7av was
obtained as a white solid (75.1 mg, 77% yield). Mp 254−256 °C.
1
Eluent: n-hexane/ethyl acetate (4/1). H NMR (400 MHz, DMSO-
d6) δ 12.94 (s, 1H), 9.11 (d, J = 8.6 Hz, 1H), 8.01−8.11 (m, 3H), 7.79
(d, J = 6.7 Hz, 1H), 7.58−7.71 (m, 4H), 7.27 (s, 2H). 13C{1H} NMR
(100 MHz, DMSO-d6) δ 151.4, 143.940, 134.5, 133.6, 130.5, 130.2,
128.4, 127.9, 127.5, 127.1, 126.4, 125.3, 122.7, 121.6, 119.1, 111.4.
HRMS (FAB+) m/z calcd for C17H13N2 [M + H]+: 245.1079, found:
245.1081.
Experimental Procedure for the Reaction of Secondary Alcohol
2w with 1a. A mixture of o-nitrophenol 1a (55.6 mg, 0.4 mmol),
benzhydrol 2w (110.5 mg, 0.6 mmol), Fe 1 (3.35 mg, 0.008 mmol),
and Me3NO (1.20 mg, 0.016 mmol) was placed in a dried 10 mL
sealed tube. The tube was degassed and backfilled with argon three
times; then, o-xylene (1.0 mL) was added using a syringe under argon
flow. The reaction tube was capped, and then the mixture was stirred
and heated at 150 °C in an oil bath for 24 h. After completion, the
reaction mixture was cooled to room temperature and volatiles were
removed under reduced pressure. The residue was purified by silica gel
column chromatography using n-hexane/ethyl acetate (5−25%) as an
eluent to afford o-aminophenol 1a′ (10.0 mg, 23% yield based on 1a)
and benzophenone 2w′ (59.1 mg, 54% yield based on 2w).
2-Aminophenol (1a′).16 Brown solid. Eluent: n-hexane/ethyl
2-(4-Fluorophenyl)-1H-benzo[d]imidazole (7ag). Following the
general procedure C with 6a (55.3 mg) and 2g (65 μL), 7ag was
obtained as a white solid (67.4 mg, 79% yield). Mp 250−252 °C.
1
Eluent: n-hexane/ethyl acetate (4/1). H NMR (400 MHz, DMSO-
d6) δ 12.90 (s, 1H), 8.22 (td, J = 6.1, 2.2 Hz, 2H), 7.65 (d, J = 7.4 Hz,
1H), 7.52 (d, J = 7.4 Hz, 1H), 7.37−7.42 (m, 2H), 7.20 (dd, J = 8.4,
6.3 Hz, 2H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 163.2 (d, J =
246.3 Hz), 150.6, 128.8 (d, J = 8.6 Hz), 126.8 (d, J = 2.9 Hz), 122.4,
116.2 (d, J = 22.3 Hz). 19F NMR (376 MHz, DMSO-d6) δ −111.1.
HRMS (FAB+) m/z calcd for C13H10N2F [M + H]+: 213.0828, found:
213.0828.
2-(4-Methoxyphenyl)-1H-benzo[d]imidazole (7ah). Following the
general procedure C with 6a (55.3 mg) and 2h (82.9 mg), 7ah was
obtained as a white solid (76.1 mg, 85% yield). Mp 225−227 °C.
1
acetate (75/25). H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H),
6.62 (d, J = 8.0 Hz, 1H), 6.50−6.58 (m, 2H), 6.37 (td, J = 7.4, 1.2 Hz,
1
1H), 4.44 (s, 2H).
Eluent: n-hexane/ethyl acetate (4/1). H NMR (400 MHz, DMSO-
Benzophenone (2w′).17 White solid. Eluent: n-hexane/ethyl
d6) δ 12.75 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 6.7 Hz, 1H),
7.49 (d, J = 6.7 Hz, 1H), 7.17 (d, J = 4.9 Hz, 2H), 7.11 (d, J = 8.6 Hz,
2H), 3.84 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.6,
151.4, 143.940, 135.0, 128.0, 122.7, 122.1, 121.5, 118.5, 114.4, 111.1,
55.4. HRMS (FAB+) m/z calcd for C14H13N2O[M + H]+: 225.1028,
found: 225.1027.
1
acetate (95/5). H NMR (400 MHz, CDCl3) δ 7.80−7.82 (m, 4H),
7.57−7.61 (m, 2H), 7.49 (t, J = 7.6 Hz, 4H).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02191.
■
sı
2-(4-Bromophenyl)-1H-benzo[d]imidazole (7aj). Following the
general procedure C with 6a (55.3 mg) and 2j (112.3 mg), 7aj was
obtained as a white solid (69.2 mg, 63% yield). Mp 277−279 °C.
1H and 13C NMR spectra and results of catalyst screening
(PDF)
1
Eluent: n-hexane/ethyl acetate (4/1). H NMR (400 MHz, DMSO-
d6) δ 12.99 (s, 1H), 8.12 (dt, J = 9.0, 2.1 Hz, 2H), 7.76−7.79 (m, 2H),
H
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AUTHOR INFORMATION
Corresponding Author
Suckchang Hong − Research Institute of Pharmaceutical
Sciences, College of Pharmacy, Seoul National University, Seoul
08826, Republic of Korea; orcid.org/0000-0003-4975-
9192; Email: schong17@snu.ac.kr
■
Authors
Ramachandra Reddy Putta − BK 21 Plus Project, College of
Pharmacy, Seoul National University, Seoul 08826, Republic of
Korea
Simin Chun − Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea
Seung Hyun Choi − Research Institute of Pharmaceutical
Sciences, College of Pharmacy, Seoul National University, Seoul
08826, Republic of Korea
Seok Beom Lee − Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea
Dong-Chan Oh − Natural Products Research Institute, College of
Pharmacy, Seoul National University, Seoul 08826, Republic of
Korea; orcid.org/0000-0001-6405-5535
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02191
Author Contributions
(3) (a) Qian, Z.; Yang, M.; Li, R.; Li, D.; Zhang, J.; Xiao, Y.; Li, C.;
Yang, R.; Zhao, N.; Xu, J. Fire-resistant, ultralight, superelastic and
thermally insulated polybenzazole aerogels. J. Mater. Chem. A 2018, 6,
20769−20777. (b) Wu, C. C.; Tsay, P. Y.; Cheng, H. Y.; Bai, S. J.
Polarized luminescence and absorption of highly oriented, fully
conjugated, heterocyclic aromatic rigid-rod polymer poly-p-phenyl-
enebenzobisoxazole. J. Appl. Phys. 2004, 95, 417−423. (c) Tamargo-
Martínez, K.; Villar-Rodil, S.; Paredes, J. I.; Martínez-Alonso, A.;
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
Tascon, J. M. D. Studies on the Thermal Degradation of Poly (p-
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(2018R1C1B6005607 and 2018R1A4A1021703) and Creative-
Pioneering Researchers Program through Seoul National
University (SNU).
phenylene benzobisoxazole). Chem. Mater. 2003, 15, 4052−4059.
(d) Xue, P.; Chen, P.; Jia, J.; Xu, Q.; Sun, J.; Yao, B.; Lu, R. A
triphenylamine-based benzoxazole derivative as a high-contrast
piezofluorochromic material induced by protonation. Chem. Commun.
2014, 50, 2569−2571. (e) Wee, D.; Yoo, S.; Kang, Y. H.; Kim, Y. H.;
Ka, J. W.; Cho, S. Y.; Lee, C.; Ryu, J.; Yi, M. H.; Jang, K. S. Poly(imide-
benzoxazole) gate insulators with high thermal resistance for solution-
processed flexible indium-zinc oxide thin-film transistors. J. Mater.
Chem. C 2014, 2, 6395−6401. (f) Xu, Y.; Xiao, L.; Sun, S.; Pei, Z.; Pei,
Y.; Pang, Y. Switchable and selective detection of Zn2+ or Cd2+ in living
cells based on 3′-O-substituted arrangement of benzoxazole-derived
fluorescent probes. Chem. Commun. 2014, 50, 7514−7516.
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