Sulfur/DABCO Promoted Reductive Coupling/Annulation Cascade Reaction between o -Hydroxy/Amino Nitrobenzenes and Benzaldehydes

Article abstract of DOI:10.1055/s-0039-1690823

Sulfur/DABCO was found to be an efficient reagent in promoting- the reductive coupling/annulation of o -nitrophenols or o -nitroanilines with benzaldehydes. This method represents a simple, straightforward, and green approach to the construction of benz-oxazoles and benzimidazoles.

Full text of DOI:10.1055/s-0039-1690823

SYNTHESIS
0
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1
1
4
3
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2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–H
paper
A
en
M.-H. D. Dang et al.
Paper
Synthesis
Sulfur/DABCO Promoted Reductive Coupling/Annulation Cascade Re-
action between o-Hydroxy/Amino Nitrobenzenes and Benzaldehydes
Minh-Huy Dinh Danga,b
Linh Ho Thuy Nguyenb
Phuong Hoang Tran*a
O
R1
S
S
S
S
NO2
XH
S
S
S
S
R2
N
X
H
R2
R1
DABCO
130 °C, 2 h
a Department of Organic Chemistry, Faculty of Chemistry, University
of Science, Vietnam National University, Ho Chi Minh City (VNU-
HCM) 721337, Vietnam
X: –O–, –NH–
24 examples
5–95% yield
thphuong@hcmus.edu.vn
b Center for innovative Materials and Architectures, Vietnam National
University, Ho Chi Minh City 721337, Vietnam
Received: 14.12.2019
Accepted after revision: 21.01.2020
Published online: 13.02.2020
using superacid hafnium-based metal-organic frameworks8
or phosphonium acidic ionic liquids9 as catalysts. This ap-
proach suffers from a lack of commercially available start-
ing materials and requires expensive catalyst, which pre-
vents it from being applied in large-scale processes. Recent-
ly, a AgPd alloy and defected perovskite-type WO2.72
nanorods were used for efficient one-pot conversion of
nitrophenol/aldehyde into benzoxazole using formic acid as
hydrogen source (Scheme 1).10 However, the protocol suf-
fers from drawbacks such as expensive and unavailable cat-
alyst, and the addition of additives and volatile organic sol-
vent. We report herein a novel, simple, and efficient meth-
od for the synthesis of benzoxazoles and benzimidazoles
from 2-nitrophenols or 2-nitroanilines and benzaldehydes
using available and inexpensive sulfur/DABCO as the cata-
lyst. The prominent features of the current method are sim-
plicity, inexpensive and readily available starting materials,
and a broad scope of substrates.
Initially, we envisioned that treatment of sulfur with
DABCO could give the zwitterion A, which would allow con-
densation of o-nitrophenol with aldehydes and the forma-
tion of benzoxazole scaffolds. To check this hypothesis, we
used the sulfur/DABCO catalyst for the redox condensation
between o-nitrophenol with benzaldehyde, without a hy-
drogen source, at 130 °C. o-Nitrophenol and benzaldehyde
were chosen as model substrates to establish the optimum
reaction conditions. In the absence of sulfur and/or DABCO,
the desired benzoxazole was not formed. Interestingly,
when sulfur was activated with DABCO, benzoxazole was
obtained in good to excellent yields (Table 1).
DOI: 10.1055/s-0039-1690823; Art ID: ss-2019-f0680-op
Abstract Sulfur/DABCO was found to be an efficient reagent in
promoting the reductive coupling/annulation of o-nitrophenols or
o-nitroanilines with benzaldehydes. This method represents a simple,
straightforward, and green approach to the construction of benz-
oxazoles and benzimidazoles.
Key words sulfur, benzimidazole, benzoxazole, reductive coupling,
annulation
The development of new and green pathways to trans-
form functional groups efficiently plays a crucial role in
modern sustainable chemistry.1 In a continuation of our
study on modern sustainable organic synthesis and the de-
velopment of new approaches to the synthesis of biologi-
cally active heterocyclic compounds,2 we want to develop
sustainable methods that comply with the following crite-
ria: (i) the catalyst should be inexpensive and available, (ii)
the process is operationally simple, and (iii) the starting
materials are readily available. In this context, we consid-
ered elemental sulfur, which is readily available, non-toxic,
inexpensive, and easy to handle, as an excellent candidate.3
Interestingly, elemental sulfur is capable of playing multi-
ple roles simultaneously as a redox reagent, starting mate-
rial, and catalyst.3,4 Consequently, the chemistry of elemen-
tary sulfur has attracted much attention in recent years.5
Benzoxazoles and benzimidazoles represent important
classes of fused nitrogen-containing heterocycles that are
found in a wide range of natural products, pharmaceuticals,
and functional materials.6 Traditional methods, such as
condensation of aldehydes with o-aminophenols, require
high reaction temperatures and the presence of strong ac-
ids (Scheme 1).7 Recently, our group reported the synthesis
of benzoxazoles from 2-aminophenols and benzaldehydes
The reaction was best performed at 130 °C in sulfur/
DABCO as an activator (Table 1, entry 7). Conducting the re-
action at higher temperature resulted in decomposition of
the product (entry 13). It should be noted that to obtain
benzoxazoles from o-nitrophenols and aldehydes, the ex-
pensive catalyst (AgPd nanoparticles in the presence of
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M.-H. D. Dang et al.
Paper
Synthesis
(a) Acid-catalyzed condensation of o-aminophenol with aromatic aldehydes7
Cat. Bronsted
or Lewis acid
OH
CHO
N
O
R'
+
R
R
R'
NH2
(b) Ag48Pd52/WO2.72-catalyzed redox condensation of o-nitrophenol with aromatic aldehydes10
OH
CHO
N
O
R'
Cat. Ag48Pd52/WO2.72
HCOOH
+
R
R
R'
NH2
(c) Sulfur/DABCO-promoted redox condesation of o-nitrophenol with aromatic aldehydes (this work)
R1
O
S8
DABCO
NO2
XH
R2
N
X
+
H
R2
R1
130 °C, 2 h
X: –O –, –NH –
S
S
S
S
- Readily available
- Inexpensive
S
S
S
S
- Easy to handle
sulfur
Scheme 1 Synthetic routes to acid catalysts (a), Ag48Pd52/WO2.72 (b), and our work (c) on the synthesis of 2-arylbenzoxazoles
WO2.72 nanorods) and formic acid as a hydrogen source for
hydrogenation reactions were previously required.10 Most
significantly, in this report, inexpensive and readily avail-
able sulfur/DABCO reagents were sufficient to achieve full
conversion of o-nitrophenols into benzoxazoles.
Once the optimal conditions had been identified, the
scope of the reaction was examined with 24 examples, as
summarized in Scheme 2. The reactions of aromatic alde-
hydes with o-nitrophenol proceeded smoothly with good
to excellent yields (3aa–aj). Various functional benzalde-
hydes such as methyl, tert-butyl, fluoro, chloro, or methoxy
at the p-position were found to be suitable substrates for
the optimized transformation (3aa–af). However, when o-
fluorobenzaldehyde was used, the amount of desired prod-
uct 3ag was greatly reduced due to the formation of 3H-
benzo[c][1,2]dithiole-3-thione (detected by NMR and MS
analyses) as a by-product (see the proposed mechanism be-
low). Similar behavior was found for 2-chlorobenzaldehyde,
which afforded the desired product in low yield (3ah).
However, 2-hydroxybenzaldehyde was reactive under the
current conditions and the desired product was afforded in
up to 95% GC yield. Heterocyclic aldehydes such as pyri-
dine-4-carbaldehyde were also reactive (3aj, 3bi, and 3ci).
When 5-methyl-2-nitrophenol was used, the desired prod-
ucts were obtained in lower yields even when the reaction
time was extended to five hours (3ba, 3bb, 3be, 3bf, and
3bi). A possible explanation for the decrease of yields was
the inductive effect of the methyl group, which decreases
the reactivity of the nitro group. Interestingly, 5-chloro-2-
nitrophenol was successfully condensed under the current
conditions, and the expected products 3ca–ci were ob-
tained in good yields. The benzimidazole products could be
formed exclusively in moderate to good yield in the reac-
tion. The reaction of o-nitrophenol with benzaldehyde was
also carried out on a 10 mmol scale, and the yield was al-
most the same as that on the 1 mmol scale (86% vs. 90%).
Table 1 Optimization of the Reaction Conditionsa
NO2
N
S8 (3 mmol)
R1
OHC
additive
OH
O
1a
2a
3aa
Entry
Additive
Molar
(mmol)
Temp
(°C)
Time
(h)
Yield
(%)b
1
2
triethylamine
1
130
130
130
130
130
130
130
130
80
2
2
2
2
2
2
2
2
2
2
2
2
2
4
0
N,N-dimethylaniline
4-ethylmorpholine
N-methylpyrrolidine
DABCO
1
3
1
trace
4
1
40
50
95
95
96
0
5
0.5
1
6
DABCO
7
DABCO
1.5
2
8
DABCO
9
DABCO
1
10
11
12
13
DABCO
1
100
110
120
140
trace
22
45
75
DABCO
1
DABCO
1
DABCO
1
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), S (3 mmol, 96 mg).
b GC yield.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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M.-H. D. Dang et al.
Paper
Synthesis
O
R1
S8
DABCO
NO2
R2
N
H
R2
+
R1
X
130 °C, 2 h
XH
3
1
2
X: –O–, –NH–
O
O
N
O
O
N
N
3ab, 87%
3ac, 82%
O
3aa, 90%
O
O
Cl
F
N
N
N
3ae, 74%
3af, 84%
3ad, 72%
HO
O
A
O
O
N
N
N
N
3ai, 95%a
3aj, 85%
3ag, A = F, 5%a
3ah, A = Cl, 35%a
O
O
O
CH3
H3C
N
N
N
H3C
H3C
H3C
3ba, 71%
3be, 67%
3bb, 73%
O
O
O
N
Cl
N
N
N
Cl
H3C
Cl
3bf, 20%a,b
3bi, 45%a,b
3ca, 92%
O
O
O
CH3
F
N
N
N
Cl
Cl
Cl
3cb, 85%
3cd, 80%
3ce, 90%
H
N
O
O
N
Cl
O
N
N
N
Cl
3da, 70%c
3cf, 55%
3ci, 83%
H
N
H
N
H
N
O
N
N
N
O
O
3dc, 65%c
3ea, 85%c
3ec, 68%c
Scheme 2 Reaction scope and versatility. Reagents and conditions: 1 (1 mmol), 2 (1 mmol), S (3 mmol, 96 mg), DABCO (1 mmol), 130 °C, 2 h. Yields
refer to isolated products unless otherwise noted. a Yields were determined by GC. b 5 h. c 10 h.
To further understand the reaction pathway for the syn-
thesis of benzoxazole, control experiments were carried
out under the optimized conditions. First, each couple of
starting materials was heated together. Reaction of sulfur
with o-nitrophenol and of o-nitrophenol with benzalde-
hyde did not proceed (based on TLC or GCMS analysis). In
contrast, when sulfur was treated with DABCO, a higher
yield of benzoxazole was observed. Although the mecha-
nism of the reaction is not clear at this stage, a proposed
mechanism is presented in Scheme 3. In this scheme the re-
action is suggested to be initiated by attack of sulfur on
DABCO to form zwitterion A. Subsequent attack of this pre-
cursor on benzaldehyde leads to C, which reacts with o-ni-
trophenol to afford nitro polysulfide D.5c Subsequent frag-
mentation of D leads to o-nitrophenyl benzoate E, which
undergoes deoxygenation to give 2-nitrosophenyl benzoate
F. Although the detailed mechanism of the transformation
of F into benzoxazole is not clear at the current time, the
sulfonation and annulation process can occur from the ni-
troso group and carbonyl in benzoate to form intermediate
H.11 The elimination of SO3 molecule of H will give the benz-
oxazole. Furthermore, based on our experiments and on
previous reports, a mechanism of byproduct formation
with halobenzaldehydes is proposed in Scheme 4.
In general, we believe that our protocol is more conve-
nient, simpler and cheaper than previous protocols for the
synthesis of benzoxazoles, which certainly required more
expensive/complex catalysts, an inert atmosphere, and re-
ducing agents or solvents. Moreover, unlike most metal-
catalyzed reactions involving molecular hydrogen or other
stronger reductants, which are generally not compatible
with the aldehyde functional group, our selective reduction
method can be carried out in the presence of different
o-nitrophenols and o-nitroanilines to provide 2-arylbenz-
oxazoles and benzimidazoles under green conditions.
In conclusion, we have developed a new, remarkably
simple, and efficient method for the direct redox condensa-
tion of o-nitrophenols/anilines with aromatic aldehydes us-
ing elemental sulfur in DABCO under solvent- and catalyst-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

D
M.-H. D. Dang et al.
Paper
Synthesis
97%), 2-hydroxybenzaldehyde (purity ≥ 99%), 4-pyridinecarboxalde-
hyde (purity ≥ 97%) were purchased from Sigma-Aldrich. Silica gel
230–400 mesh for flash chromatography, TLC plates (silica gel 60
F254), ethyl acetate (anhydrous, purity ≥ 99%), acetone and n-hexane
(anhydrous, purity ≥ 99.5%) were obtained from Merck. Deuterated
solvents, CDCl3, DMSO-d6 and acetone-d6, were purchased from Cam-
bridge Isotope Laboratories (Andover, MA). All chemicals were used
without further purification.
Equipment and analytical methods
The chemicals were measured by using an Ohaus 80251621 explorer
precision balance. The reactions were conducted on an IKA C-MAG
HS7 magnetic stirrer. The products were analyzed by thin-layer chro-
matography (TCL) performed on F-254 silica gel coated aluminum
plates from Merck. Column chromatography was performed on silica
gel 60, 0.04–0.06 mm (230–400 mesh). Melting points were recorded
with a Buchi B-545 melting point Apparatus.
Scheme 3 Proposed mechanism
Fourier transform infrared (FT-IR) spectra were measured on a Bruker
E400 FT-IR spectrometer using potassium bromide pellets. Nuclear
magnetic resonance (1H and 13C NMR) spectra were acquired on a
Bruker advance II 500 MHz NMR spectrometer. Chemical shifts were
quoted in parts per million (ppm) and referenced to the appropriate
solvent peak. Gas chromatography-mass spectrometry (GC-MS) mea-
surements were carried out on an Agilent GC System 7890 equipped
with a mass selective detector (Agilent 5973N) and a capillary DB-
5MS column (30 m × 250 μm × 0.25 μm).
General Procedure
To a round-bottomed flask equipped with a magnetic stirrer was se-
quentially added o-nitrophenol or o-nitroaniline (1 mmol), aldehyde
(1 mmol), sulfur (3 mmol, 96 mg), and DABCO (1,4-diazabicyclo-
[2.2.2]octane; 1 mmol, 112 mg). The reaction mixture was stirred at
130 °C for 2 h under air. Upon completion, the reaction mixture was
dissolved in EtOAc, and the residual sulfur was removed. The crude
mixture was purified by a silica gel column (petroleum ether/EtOAc,
from 95:5 to 90:10) to give the expected product.
Scheme 4 Proposed mechanism for by-product formation with substi-
tution of halo groups at the ortho-position
2-Phenylbenzoxazole (3aa)
Yield: 90% (175 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 102–103.5 °C.
free conditions. This strategy is capable of providing a wide
range of 2-arylbenzoxazoles and 2-arylbenzimidazoles, is
highly versatile, and has great potential for industrial appli-
cation. Moreover, the present method is highlighted for the
simplicity and efficiency in affording benzoxazoles and
benzimidazoles from simple, available and inexpensive
starting materials. Further studies on the mechanism and
scope of the reaction are in progress.
FT-IR (KBr): 3059, 2925, 2854, 1775, 1615, 1551, 1475, 1448, 1285,
1240 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.28–8.26 (m, 2 H), 7.80–7.77 (m, 1 H),
7.60–7.58 (m, 1 H), 7.55–7.52 (m, 3 H), 7.38–7.34 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 163.2, 150.9, 142.2, 131.7, 129.0,
127.8, 127.3, 125.3, 124.7, 120.1, 110.7.
GC-MS (EI, 70 eV): m/z = 195 [M]+.
2-(4-Methylphenyl)benzoxazole (3ab)
Materials
Yield: 87% (181 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 113–114.5 °C.
Sulfur (purity ≥ 99.5%), triethylamine (purity ≥ 98%), N-methylpyroli-
dine (purity ≥98%), 1,4-diazabicyclo[2.2.2]octane (purity ≥ 97%), 4-
ethylmorpholine (purity ≥ 97%), N,N-dimethylaniline (purity ≥ 98%),
2-nitrophenol (purity ≥ 97%), 4-methyl-2-nitrophenol (purity ≥ 99%),
4-chloro-2-nitrophenol (purity ≥ 97%), 2-nitroaniline (purity ≥ 98%),
5-methoxy-2-nitroaniline (purity ≥ 97%), benzaldehyde (purity ≥
99%), 4-methylbenzaldehyde (purity ≥ 97%), 4-methoxybenzaldehyde
(purity ≥ 98%), 4-fluorobenzaldehyde (purity ≥ 97%), 4-chlorobenz-
aldehyde (purity ≥ 98%), 4-tert-butylbenzaldehyde (purity ≥ 95%),
2-fluorobenzaldehyde (purity ≥ 97%), 2-chlorobenzaldehyde (purity ≥
FT-IR (KBr): 3056, 2920, 2854, 1728, 1620, 1554, 1499, 1450,
1242 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.15 (d, J = 8.0 Hz, 2 H), 7.77–7.75 (m,
1 H), 7.58–7.56 (m, 1 H), 7.35–7.32 (m, 4 H), 2.44 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 163.5, 150.8, 142.3, 142.2, 129.8,
127.8, 125.1, 124.7, 124.5, 120.0, 110.6, 21.8.
GC-MS (EI, 70 eV): m/z = 209 [M]+.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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M.-H. D. Dang et al.
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Synthesis
2-(4-Methoxyphenyl)benzoxazole (3ac)
13C NMR (125 MHz, CDCl3):  = 161.1, 150.8, 141.8, 133.7, 132.1,
132.0, 131.5, 127.1, 126.5, 125.7, 124.8, 120.7, 110.9.
GC-MS (EI, 70 eV): m/z = 229 [M]+.
Yield: 82% (184 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 120–122 °C.
FT-IR (KBr): 3050, 2924, 2849, 1615, 1501, 1450, 1420, 1244.
2-(2-Hydroxylphenyl)benzoxazole (3ai)
1H NMR (500 MHz, CDCl3):  = 8.20 (d, J = 8.5 Hz, 2 H), 7.75–7.73 (m,
1 H), 7.56–7.54 (m, 1 H), 7.33–7.31 (m, 2 H), 7.03 (d, J = 8.5 Hz, 2 H),
3.88 (s, 3 H).
Yield: 95% (202 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 120–122 °C.
13C NMR (125 MHz, CDCl3):  = 163.3, 162.6, 150.8, 142.1, 129.7,
124.8, 124.7, 119.7, 119.7, 114.6, 110.6, 55.6.
FT-IR (KBr): 2921, 2851, 1630, 1587, 1543, 1487, 1452, 1244,
1155 cm–1
.
1H NMR (500 MHz, CDCl3):  = 11.5 (s, 1 H), 8.04 (dd, J = 8.0, 1.5 Hz,
1 H), 7.75–7.73 (m, 1 H), 7.62–7.61 (m, 1 H), 7.46–7.43 (m, 1 H), 7.41–
7.37 (m, 2 H), 7.13 (dd, J = 8.0, 1.5 Hz, 1 H), 7.03–7.00 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 133.72, 127.29, 125.54, 125.17,
119.72, 119.43, 117.59, 110.82.
GC-MS (EI, 70 eV): m/z = 225 [M]+.
2-(4-Fluorophenyl)benzoxazole (3ad)
Yield: 72% (153 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 102–104 °C.
GC-MS (EI, 70 eV): m/z = 213 [M]+.
FT-IR (KBr): 3061, 2925, 1619, 1584, 1582, 1542, 1473, 1448, 1247,
1225 cm–1
.
2-(Pyridin-4-yl)benzoxazole (3aj)
1H NMR (500 MHz, CDCl3):  = 8.28–8.25 (m, 2 H), 7.78–7.76 (m, 1 H),
Yield: 85% (80 mg); analytical TLC on silica gel (9:1 n-hexane/EtOAc);
7.59–7.57 (m, 1 H), 7.37–7.35 (m, 2 H), 7.24–7.20 (m, 2 H).
orange solid; mp 100–102 °C.
13C NMR (125 MHz, CDCl3):  = 165.0 (d, J = 251 Hz), 162.3, 150.9,
142.2, 130.0 (d, J = 8.8 Hz), 130.0 (d, J = 255.1 Hz), 125.0 (d, J =
59.5 Hz), 123.7 (d, J = 3.3 Hz), 120.1, 116.3 (d, J = 22 Hz), 110.7.
FT-IR (KBr): 3460, 2946, 1628, 878 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.82 (d, J = 5.0 Hz, 2 H), 8.09 (d, J =
5.0 Hz, 2 H), 7.83 (d, J = 7.5 Hz, 1 H), 7.63 (d, J = 7.5 Hz, 1 H), 7.42 (m,
2 H).
GC-MS (EI, 70 eV): m/z = 213 [M]+.
2-(4-tert-Butylphenyl)benzoxazole (3ae)
13C NMR (125 MHz, CDCl3):  = 161.0, 151.1, 150.9, 141.9, 134.6,
126.5, 125.3, 121.2, 120.9, 111.1.
GC-MS (EI, 70 eV): m/z = 196 [M]+.
Yield: 74% (186 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 107–108 °C.
FT-IR (KBr): 3059, 2927, 1728, 1547, 1452, 1429, 1287, 1239 cm–1
.
2-(2-Fluorophenyl)benzoxazole (3ag)
1H NMR (500 MHz, CDCl3):  = 8.29 (dt, J = 8.5, 2.0 Hz, 2 H), 7.78–7.76
(m, 1 H), 7.59–7.57 (m, 1 H), 7.55 (dt, J = 8.5, 2.0 Hz, 2 H), 7.36–7.33
(m, 2 H), 1.38 (s, 9 H).
Yield: 5% (10 mg); analytical TLC on silica gel (9:1 n-hexane/EtOAc);
white solid; mp 100–102 °C.
13C NMR (125 MHz, CDCl3):  = 163.4, 155.4, 150.8, 142.1, 127.7,
126.1, 125.1, 124.7, 124.4, 120.0, 110.7, 35.2, 31.3.
FT-IR (KBr): 3061, 2925, 1719, 1584, 1582, 1542, 1473, 1448, 1247,
1225 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.24 (td, J = 7.5, 2.0 Hz, 1 H), 7.85–7.83
(m, 1 H), 7.63–7.61 (m, 1 H), 7.55–7.51 (m, 1 H), 7.40–7.37 (m, 2 H),
7.33–7.32 (m, 1 H), 7.30–7.27 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 162.0, 156.0, 150.7, 141.9, 133.25 (d,
J = 8.6 Hz), 130.7 (d, J = 1.1 Hz), 125.6, 124.8, 124.63 (d, J = 3.8 Hz),
120.52, 117.32 (d, J = 21.3 Hz), 115.7 (d, J = 10.4 Hz), 110.8.
GC-MS (EI, 70 eV): m/z = 251 [M]+.
2-(4-Chlorophenyl)benzoxazole (3af)
Yield: 84% (175 mg); analytical TLC on silica gel (95:5 n-hexane/
EtOAc); white solid; mp 148–150 °C.
FT-IR (KBr): 3061, 2925, 1610, 1584, 1582, 1542, 1473, 1448, 1247,
GC-MS (EI, 70 eV): m/z = 213 [M]+.
1225 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.24 (d, J = 8.5 Hz, 2 H), 8.27–8.22 (m,
2 H), 7.77 (m, 1 H), 7.71–7.69 (m, 1 H), 7.64 (d, J = 8.5 Hz, 2 H), 7.46–
7.39 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 161.73, 150.81, 142.08, 137.23,
129.34, 128.99, 125.93, 125.59, 124.85, 120.02, 110.70.
5-Methyl-2-phenylbenzoxazole (3ba)
Yield: 71% (148 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 112–115 °C.
FT-IR (KBr): 2918, 1626, 1552, 1445, 1263 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.26–8.24 (m, 2 H), 7.56 (s, 1 H), 7.53–
7.51 (m, 3 H), 7.45 (d, J = 8.5 Hz, 1 H), 7.16 (d, J = 8.5 Hz, 1 H), 2.49 (s,
3 H).
13C NMR (125 MHz, CDCl3):  = 163.3, 149.2, 142.5, 134.5, 131.5,
129.0, 127.7, 127.5, 126.4, 120.1, 110.1, 21.6.
GC-MS (EI, 70 eV): m/z = 229 [M]+.
2-(2-Chlorophenyl)benzoxazole (3ah)
Yield: 35% (80 mg); analytical TLC on silica gel (95:5 n-hexane/
EtOAc); white solid; mp 100–102 °C.
GC-MS (EI, 70 eV): m/z = 209 [M]+.
FT-IR (KBr): 2925, 1608, 1584, 1569, 1533, 1470, 1452, 1343, 1237,
1185 cm–1
.
5-Methyl-2-(4-methyl-phenyl)benzoxazole (3bb)
1H NMR (500 MHz, CDCl3):  = 8.15 (dd, J = 8.0, 2.0 Hz, 1 H), 7.87–7.85
Yield: 73% (163 mg); analytical TLC on silica gel (9:1 n-hexane/
(m, 1 H), 7.63–7.62 (m, 1 H), 7.59–7.57 (m, 1 H), 7.48–7.37 (m, 4 H).
EtOAc); white solid; mp 138–140 °C.
FT-IR (KBr): 3304, 2921, 2856, 1616, 1555, 1499, 1332, 1262 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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Synthesis
1H NMR (500 MHz, CDCl3):  = 8.13 (d, J = 8.0 Hz, 2 H), 7.54 (s, 1 H),
7.43 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 8.0 Hz,
1 H), 2.48 (s, 3 H), 2.44 (s, 3 H).
FT-IR (KBr): 2953, 1610, 1551, 1479, 1448, 1258 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.12 (d, J = 8.5 Hz, 2 H), 7.72 (d, J =
2.0 Hz, 1 H), 7.47 (d, J = 8.5 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.30 (dd,
J = 8.5, 2.0 Hz, 1 H), 2.44 (s, 3 H).
13C NMR (125 MHz, acetone-d6):  = 163.2, 149.2, 142.7, 142.3, 134.5,
129.9, 127.5, 126.3, 124.8, 119.9, 110.1, 20.9, 20.8.
GC-MS (EI, 70 eV): m/z = 223 [M]+.
13C NMR (125 MHz, acetone-d6):  = 165.6, 150.5, 144.6, 143.8, 130.8,
130.6, 128.6, 126.2, 125.0, 120.5, 112.8, 21.7.
GC-MS (EI, 70 eV): m/z = 243 [M]+.
5-Methyl-2-(4-tert-butylphenyl)benzoxazole (3be)
Yield: 67% (178 mg); analytical TLC on silica gel (9:1 n-hexane/
5-Chloro-2-(4-fluorophenyl)benzoxazole (3cd)
EtOAc); white solid; mp 148–150 °C.
Yield: 80% (197 mg); analytical TLC on silica gel (9:1 n-hexane/
FT-IR (KBr): 3107, 2963, 2930, 2871, 1729, 1621, 1532, 1460,
EtOAc); white solid; mp 156–157 °C.
1269 cm–1
.
FT-IR (KBr): 3061, 2922, 1610, 1551, 1481, 1450, 1331, 1260, 1227.
1H NMR (500 MHz, CDCl3):  = 8.17 (d, J = 8.5 Hz, 2 H), 7.55–7.53 (m,
2 H), 7.44 (d, J = 8.5 Hz, 1 H), 7.14 (dd, J = 8.5, 1.0 Hz, 1 H), 2.48 (s,
3 H), 1.38 (s, 9 H).
13C NMR (125 MHz, acetone-d6):  = 162.9, 155.0, 149.0, 142.5, 134.3,
127.2, 126.1, 126.0, 124.6, 119.7, 109.9, 34.7, 30.5, 20.5.
1H NMR (500 MHz, CDCl3):  = 8.25–8.23 (m, 2 H), 7.73 (d, J = 2.0 Hz,
1 H), 7.49 (d, J = 8.5 Hz, 1 H), 7.32 (dd, J = 8.5, 2.0 Hz, 1 H), 7.24–7.20
(m, 2 H).
13C NMR (125 MHz, acetone-d6):  = 166.0 (d, J = 250 Hz), 164.3,
150.5, 144.3, 131.1 (d, J = 9.0 Hz), 130.6, 126.3, 124.2, 120.5, 117.2 (d,
J = 22.4 Hz), 112.7.
GC-MS (EI, 70 eV): m/z = 265 [M]+.
GC-MS (EI, 70 eV): m/z = 247 [M]+.
5-Methyl-2-(4-chlorophenyl)benzoxazole (3bf)
Yield: 20% (48 mg); analytical TLC on silica gel (9:1 n-hexane/EtOAc);
5-Chloro-2-(4-tert-butylphenyl)benzoxazole (3ce)
white solid; mp 150–151 °C.
FT-IR (KBr): 3050, 2957, 2849, 1615, 1501, 1450, 1420, 1287 cm–1
Yield: 90% (256 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 137–138 °C.
.
1H NMR (500 MHz, CDCl3):  = 8.15 (d, J = 8.5 Hz, 2 H), 7.53 (s, 1 H),
7.47 (d, J = 8.5 Hz, 2 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.16 (d, J = 8.5 Hz,
1 H), 2.48 (s, 3 H).
FT-IR (KBr): 2957, 2902, 2866, 1611, 1552, 1493, 1457, 1262 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.16 (d, J = 9.0 Hz, 2 H), 7.73 (d, J =
2.0 Hz, 1 H), 7.54 (d, J = 9.0 Hz, 2 H), 7.48 (d, J = 9.0 Hz, 1 H), 7.30 (dd,
J = 9.0, 2.0 Hz, 1 H), 1.38 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 162.3, 149.2, 142.4, 137.7, 134.7,
129.3, 128.9, 126.6, 126.0, 120.1, 110.1, 21.6.
GC-MS (EI, 70 eV): m/z = 243 [M]+.
13C NMR (125 MHz, acetone-d6):  = 165.5, 156.7, 150.6, 144.6, 130.6,
128.6, 127.2, 126.2, 125.0, 120.5, 112.8, 35.9, 31.5.
GC-MS (EI, 70 eV): m/z = 285 [M]+.
5-Methyl-2-(pyridin-4-yl)benzoxazole (3bi)
Yield: 45% (94 mg); analytical TLC on silica gel (9:1 n-hexane/EtOAc);
5-Chloro-2-(4-chlorophenyl)benzoxazole (3cf)
orange solid; mp 129–130 °C.
FT-IR (KBr): 3406, 2921, 1612, 1537, 1414, 1344, 1068, 808 cm–1
Yield: 55% (144 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 195–197 °C.
.
1H NMR (500 MHz, CDCl3):  = 8.80 (d, J = 5.5 Hz, 2 H), 8.07 (dd, J = 5.5,
1.5 Hz, 2 H), 7.60 (s, 1 H), 7.49 (d, J = 8.5 Hz, 1 H), 7.24 (dd, J = 8.5,
1.0 Hz, 1 H), 2.51 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 160.8, 150.7, 149.3, 142.1, 135.2,
134.8, 127.7, 121.1, 120.6, 110.4, 21.6.
FT-IR (KBr): 2913, 1727, 1550, 1448, 1245 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.16 (d, J = 8.5 Hz, 2 H), 7.74 (d, J =
1.5 Hz, 1 H), 7.51–7.48 (m, 3 H), 7.33 (dd, J = 8.5, 1.5 Hz, 1 H).
13C NMR (125 MHz, acetone-d6):  = 149.6, 143.4, 137.7, 129.8, 129.4,
129.2, 125.7, 125.5, 119.7, 111.9.
GC-MS (EI, 70 eV): m/z = 210 [M]+.
GC-MS (EI, 70 eV): m/z = 263 [M]+.
5-Chloro-2-phenylbenzoxazole (3ca)
5-Chloro-2-(pyridin-4-yl)benzoxazole (3ci)
Yield: 92% (210 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 102–104 °C.
Yield: 83% (190 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); orange solid; mp 152–153 °C.
FT-IR (KBr): 3061, 1612, 1551, 1443, 1333, 1265 cm–1
.
FT-IR (KBr): 3431, 2922, 1612, 1568, 1539, 1449, 1057, 874 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.24–8.22 (m, 2 H), 7.75 (d, J = 1.5 Hz,
1 H), 7.55–7.53 (m, 3 H), 7.50–7.49 (m, 1 H), 7.32 (dd, J = 8.5, 1.5 Hz,
1 H).
13C NMR (125 MHz, acetone-d6):  = 165.3, 150.6, 144.5, 133.1, 130.7,
130.2, 128.6, 127.7, 126.4, 120.7, 112.9.
1H NMR (500 MHz, CDCl3):  = 8.83 (d, J = 5.5 Hz, 2 H), 8.07 (dd, J = 4.5,
1.5 Hz, 2 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.41 (dd,
J = 8.5, 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 162.0, 150.8, 149.6, 143.0, 134.2,
130.9, 126.9, 121.3, 120.8, 111.9.
GC-MS (EI, 70 eV): m/z = 229 [M]+.
GC-MS (EI, 70 eV): m/z = 230 [M]+.
5-Chloro-2-(4-methylphenyl)benzoxazole (3cb)
2-Phenylbenzimidazole (3da)
Yield: 85% (206 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 148–150 °C.
Yield: 70% (136 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp 293–294 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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M.-H. D. Dang et al.
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Synthesis
FT-IR (KBr): 3411, 1540, 1450, 1408, 967, 774 cm–1
1H NMR (500 MHz, DMSO-d6):  = 8.18 (d, J = 7.5 Hz, H), 7.60–7.54 (m,
4 H), 7.51–7.48 (m, 1 H), 7.22–7.19 (m, 2 H).
13C NMR (125 MHz, DMSO-d6):  = 151.2, 130.2, 129.8, 128.9, 126.4,
.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690823.
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122.1.
GC-MS (EI, 70 eV): m/z = 194 [M]+.
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2-(4-Methoxyphenyl)benzimidazole (3dc)
Yield: 65% (145 mg); analytical TLC on silica gel (9:1 n-hexane/
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FT-IR (KBr): 3395, 3055, 1452, 1406, 1274, 741 cm–1
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6-Methoxy-2phenylbenzimidazole (3ea)
Yield: 85% (190 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); white solid; mp >300 °C.
1H NMR (500 MHz, CDCl3):  = 8.03 (dd, J = 8.0, 1.5 Hz, 2 H), 7.51 (d, J =
9.0 Hz, 1 H), 7.47–7.42 (m, 3 H), 7.08 (d, J = 1.5 Hz, 1 H), 6.90 (dd, J =
9.0, 1.5 Hz, 1 H), 3.83 (s, 3 H).
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129.1, 126.3, 55.8.
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6-Methoxy-2-(4-methoxyphenyl)benzimidazole (3ec)
Yield: 68% (173 mg); analytical TLC on silica gel (9:1 n-hexane/
EtOAc); orange solid; mp >300 °C.
1H NMR (500 MHz, CDCl3):  = 7.93 (s, 2 H), 7.36 (s, 1 H), 6.95 (s, 1 H),
6.84 (s, 2 H), 6.74 (s, 1 H), 3.72 (s, 6 H).
13C NMR (125 MHz, CDCl3):  = 161.0, 156.5, 151.6, 128.0, 122.3,
115.6, 114.4, 113.9, 112.0, 97.6, 55.7, 55.3.
GC-MS (EI, 70 eV): m/z = 254 [M]+.
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3H-Benzo[c][1,2]dithiole-3-thione
Obtained as a by-product in the reaction of 2-nitrophenol and 2-fluoro-
benzaldehyde.
Analytical TLC on silica gel (9:1 n-hexane/EtOAc); orange solid; mp
96–98 °C.
1H NMR (500 MHz, CDCl3):  = 8.22 (d, J = 8.2 Hz, 1 H), 7.73 (d, J =
8.2 Hz, 1 H), 7.70–7.66 (m, 1 H), 7.47–7.44 (m, 1 H).
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126.0, 124.3.
GC-MS (EI, 70 eV): m/z = 184 [M]+.
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Acknowledgment
We thank Duy-Khiem Nguyen Chau (North Carolina State University,
USA) and MSc Mai Hoang Ngoc Do (IPH-HCM) for their help.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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M.-H. D. Dang et al.
Paper
Synthesis
(e) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Org.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H