Catalyst-Free Synthesis of Benzofuran Derivatives from Cascade Reactions between Nitroepoxides and Salicylaldehydes

Article abstract of DOI:10.1021/acs.joc.1c00143

Different benzofuran derivatives are synthesized via a catalyst-free reaction between nitroepoxides and salicylaldehydes. In the employed methodology, K2CO3 and DMF have been used at 110 °C, and the reactions were completed after 12 h in 33-84% yields. Th

Full text of DOI:10.1021/acs.joc.1c00143

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Catalyst-Free Synthesis of Benzofuran Derivatives from Cascade
Reactions between Nitroepoxides and Salicylaldehydes
Mohammad A. Ranjbari and Hossein Tavakol*
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ABSTRACT: Different benzofuran derivatives are synthesized via a catalyst-free
reaction between nitroepoxides and salicylaldehydes. In the employed methodology,
K2CO3 and DMF have been used at 110 °C, and the reactions were completed after 12
h in 33−84% yields. The highest yields were obtained using 3-nitrosalicylaldehyde.
Finally, a plausible mechanism was proposed for the reaction, and some evidence was
provided for this mechanism such as the detection of released acetate anion (using
FTIR) and isolation and structure determination of the critical intermediate.
derivatives have antitumor,22 cytotoxic,23 antifungal,24 and
anti-inflammatory25 abilities. Because of the biological and
medicinal importance of benzofuran derivatives, many method-
ologies have been developed to synthesize them. They have
been prepared using C−C coupling reactions,26 oxidative
annulation,27 olefination of phenols,28 Fujiwara−Moritani
arylations,29 cycloaddition of benzoquinones with stilbene
oxides,30 and many other reactions.31−33 However, the
research on the synthesis of benzofuran derivatives using
new starting materials is still open. In this way, the use of mild
conditions, simple methodology, and available materials is
highly desirable.
Herein, in continuation of the recent focus of this research
group on the development of new catalyst-free methodologies
using simple and green media,34,35 the synthesis of benzofuran
derivatives from α-nitroepoxides has been investigated. The
reaction has been designed between salicylaldehyde derivatives
and different α-nitroepoxides. Salicylaldehydes are available
materials, and α-nitroepoxides can be easily prepared from the
condensation of aldehydes with nitroalkanes (both are
available), followed by the epoxidation of the produced C
C double bond.
1. INTRODUCTION
The synthesis and chemistry of α-nitroepoxides were first
developed by Newman and Angier in 1970.1 They could be
easily prepared by the oxidation of β-nitrostyrenes using
different reagents.2 However, until the 21st century, the
development of their chemistry and reactions was limited to a
few reports including their photochemical reactions.3 During
the first three decades, the most essential aspects of these
structures were their reactions in some carbohydrate
derivatives.4 Nevertheless, during the past decade, their
reactions and chemistry have been of wide interest. α-
Nitroepoxides could be rearranged to α-nitroketones5 and α-
hydroxy ketones6 or reduced to β-nitrobenzylamine derivatives
as the precursors for pseudoephedrines.1 Moreover, several
useful syntheses could be started from β-nitrostyrenes to
produce structures of interest.7−10
The most interesting transformation is the ring-opening
reaction by the attack of a nucleophile followed by the release
of the nitro group. In line with this, different nucleophiles such
as dithiocarbamates,11 various amines,12,13 and fluoride and
phenoxy anions1 have been used to perform the ring-opening
reaction. This bifunctional capability of these structures makes
them the right choice for performing complex multicomponent
reactions.14 Noticeably, the use of bifunctional nucleophiles in
the reaction with α-nitroepoxides has been employed for the
synthesis of critical heterocyclic structures.15−20 In agreement
with this, the syntheses of pyrroles, cyclic thioureas, thiazoles,
and quinoxalines have been successfully performed starting
from α-nitroepoxides.
2. RESULTS AND DISCUSSION
Most of the reported synthetic methodologies for benzofurans
consist of coupling reactions involving expensive (and in many
cases toxic) transition metals. More importantly, there is not
Received: January 19, 2021
Published: March 3, 2021
Despite the synthesis of different nitrogen- and sulfur-
containing heterocycles from α-nitroepoxides, the synthesis of
oxygen-containing heterocycles such as furan or benzofurans
has not been reported using α-nitroepoxides yet. Benzofurans
are an important class of organic compounds with promising
bioactive properties and medicinal significance.21 Their
https://dx.doi.org/10.1021/acs.joc.1c00143
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any report on the synthesis of these compounds from α-
nitroepoxides and salicylaldehydes. In this report, the
suggested reaction has been performed successfully in
catalyst-free conditions using a small amount of solvent. For
the optimization of the reaction conditions, since the presence
of base is vital, various common bases have been examined to
find the best choice. It should be noticed that, because of the
moderate acidity of the salicylaldehyde derivatives (pKa ≈ 8),
the examined bases should have sufficient basicity (pKa of their
conjugate acids should be higher than 9). For this purpose, the
model reaction consists of 2-methyl-2-nitro-3-(3-nitrophenyl)
oxirane (1 mmol), salicylaldehydes (1 mmol), and 3 mmol of
each base in 5 mL of methanol at reflux. The reaction was
followed by TLC, and after 24 h, the product was isolated and
weighed. The results of these experiments are listed in Table 1.
of the best solvent, in addition to methanol (which was
examined in the previous experiments) and solvent-free
conditions, THF, toluene, acetonitrile, water, DMSO, and
DMF (1 mL for the last two solvents and 5 mL for others)
were examined for the model reaction at 80 °C for 12 and 24 h
(entries 1−7). The yields of all reactions were not increased
after 12 h. However, for the first two solvents (and also for
methanol), the reaction was allowed to be continued for 24 h
to ensure this. The highest yield (62%) was obtained using
DMF (entry 7). Then, to increase the yield of the reaction,
higher reaction temperatures were examined using the
previously optimized conditions (K2CO3 as the base and
DMF as the solvent for 12 h) for the model reaction. Among
the three assayed temperatures (entries 8−11), 110 °C (entry
10) gave the highest yield.
After the optimization of the reaction parameters, a series of
new reactions was designed to prepare various benzofuran
derivatives. All of these new reactions were performed at 1 mL
of DMF and using 3 mmol of K2CO3 at 110 °C for 12 h (the
optimized conditions). First, 5-bromo, 5-chloro, 3-methoyxy,
4-(N,N-diethylamino), and 5-fluoro salicylaldehyde derivatives
were reacted with simple and substituted (4-chloro, 4-nitro,
and 3-nitro) nitroepoxides, and 20 different benzofurans were
obtained, as shown in Scheme 1. The yields were between 33%
and 84%, and in general, 3-nitro derivatives of nitroepoxides
gave the highest yields (3e and 3f); the smallest yields are,
respectively, related to the methyl-containing nitroepoxides
(3p and 3q with 33−35% yield), naphthalene nitroepoxides
(3n and 3o with 42−45% yield), and reactions involving 4-
(N,N-diethylamino)salicylaldehyde (3l and 3m with 52−56%
yield). The differences between the yields of the other
derivatives are not meaningful.
After the successful preparation of the mentioned deriva-
tives, some nitroepoxides were reacted with simple salicylalde-
hyde (1c) to prepare three new benzofuran derivatives (3u−
3x), and the results are depicted in Scheme 2. The yields of
these new reactions (64−81%) were comparable with the
previous derivatives, and interestingly, the product of the
reaction with the 3-nitro derivative of nitroepoxide showed the
highest yield.
Table 1. Results of the Optimizations of the Selection of
Base
a
entry
base
urea
pyridine
Et3N
NaOH
KOH
K2CO3
KOtBu
time (h)
yield (%)
1
2
3
4
5
6
7
24
24
24
24
24
24
24
30
a
Reaction conditions: 1 mmol of salicylaldehyde, 1 mmol of
nitroepoxide, and 3 mmol of base with reflux in 5 mL of methanol.
These reactions showed that, among seven examined organic
and inorganic bases, only potassium carbonate afforded the
product (in 30% yield). Therefore, this base was selected for
the next optimization and reactions.
The next optimization attempts were made for the selection
of the best solvent, temperature, and reaction time. The results
of these optimizations are shown in Table 2. For the selection
It seems that proposing the plausible mechanism for this
reaction could be interesting. It is more interesting when one
takes a deep look at the reaction and perceives that, in addition
to the release of the nitro group, the product has two carbons
and two oxygens less than the reactants. These atoms could
belong to the acetate group, and when the reaction was
monitored, the release of the acetate ion was detected (by
recording FTIR of the reaction mixture and observing acetate
ion bands at 1570 and 1650 cm−1). A plausible mechanism
based on this foundation is depicted in Scheme 3. According to
this mechanism, after the deprotonation of the phenolic
hydroxy by the base, it (I1) attacks the benzylic position of the
epoxy for ring-opening. The return of the anionic charge of the
oxyanion leads to the release of the nitro group and the
formation of carbonyl (I2). Then, the hydrogen between
carbonyl and phenolic oxygen is removed by the base, and the
carbanion (I3) attacks the carbonyl group to produce I4.
Then, the oxyanion of I4 takes a proton from the conjugated
acid, and the produced intermediate (I5) is attacked by the
hydroxy group to produce I6. Finally, the shown rearrange-
ment in I6 leads to the product (3). The intermediates I4, I5,
and I6 have two asymmetric centers and have been produced
in both cis and trans diastereomers. However, by following the
Table 2. Results of the Optimization of the Solvent and
Reaction Temperature
a
entry
solvent
THF
temp. (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
9
80
80
80
80
80
80
80
100
110
120
24
24
12
12
12
12
12
12
12
12
toluene
acetonitrile
water
32
trace
54
48
62
70
81
80
b
DMSO
solvent-free
b
DMF
b
DMF
b
10
11
DMF
b
DMF
a
Reaction conditions: 1 mmol of salicylaldehyde, 1 mmol of
nitroepoxide, and 3 mmol of base with reflux in 5 mL of solvent.
b
1 mL of solvent was used.
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Scheme 1. Reaction of Various Nitroepoxides with Salicylaldehyde Derivatives
Scheme 2. Reaction of Nitroepoxides with Salicylaldehyde
Scheme 3. Plausible Mechanism for the Studied Reaction
ization data and real spectra of this intermediate (Supporting
Information) completely confirm the formation of this
intermediate and could be considered proof for the proposed
mechanism.
reaction with TLC, it was found that both of these
stereoisomers convert to the product (only at different rates).
To provide more evidence for this mechanism, in the
reaction producing 3i, the intermediate I5 was isolated and its
3. CONCLUSION
In summary, a mild and efficient procedure for the catalyst-free
conversion of nitroepoxides and salicylaldehydes to benzofuran
derivatives was studied. The optimized condition consisted of
1
structure was identified by H and 13C NMR. The character-
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2924, 1486, 1439, 1384, 1094, 792; 1H NMR (400 MHz, chloroform-
d) δ 7.82−7.80 (m, 1H), 7.79−7.77 (m, 1H), 7.73−7.72 (t, J = 1.2
Hz, 1H), 7.47−7.45 (m, 1H), 7.44−7.42 (m, 1H), 7.40 (d, J = 1.2 Hz,
2H), 6.97 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.1, 153.6,
134.9, 131.0, 129.2, 128.4, 127.4, 126.3, 123.6, 116.2, 112.7, 101.1;
known compound.29
3 mmol of K2CO3 as the base, 1 mL of DMF as the solvent,
110 °C temperature, and 12 h. Three different salicylaldehyde
derivatives, including its 5-bromo and 5-chloro derivatives, and
four nitroepoxide derivatives (simple, 3-nitro, 4-nitro, and 4-
chloro) were used, and the yields were between 33% and 84%.
The highest yields were obtained by using the 3-nitro
derivative of nitroepoxide. The plausible mechanism for the
reaction was proposed and confirmed by some evidence such
as finding the released acetate anion and isolating the critical
4.4.2. 5-Bromo-2-(4-nitrophenyl) Benzofuran (3b). Yellow solid
(232 mg, 74% yield), mp 191−193 °C; FT-IR νmax (KBr): 3105,
1
1599, 1517, 1343, 1106, 851; H NMR (400 MHz, chloroform-d) δ
8.40−8.30 (m, 2H), 8.06−7.97 (m, 2H), 7.80−7.78 (m, 1H), 7.50−
7.43 (m, 2H), 7.20 (s, 1H). 13C{1H} NMR (101 MHz, CDzCl3) δ
154.5, 154.1, 147.5, 135.7, 130.6, 128.7, 125.5, 124.4, 124.2, 116.6,
113.0, 104.3; known compound.30
1
intermediate, followed by its analysis by H and 13C NMR.
The major defects of this work are poor atom economy and
using DMF as a nonenvironmentally friendly solvent.
However, since many other reports for the preparation of
benzofurans involve the use of heavy metals or have fewer
atom economies, this work seems better in some aspects.
4.4.3. 5-Bromo-2-phenyl Benzofuran (3c). White solid (194 mg,
71% yield), mp 157−158 °C; FT-IR νmax (KBr): 3100, 1450, 1439,
1
807, 762, 688; H NMR (400 MHz, chloroform-d) δ 7.90−7.85 (m,
2H), 7.73 (dd, J = 1.8, 0.7 Hz, 1H), 7.51−7.46 (m, 2H), 7.44−7.37
(m, 3H), 6.99 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.2,
153.6, 131.2, 129.9, 129.0, 128.9, 127.1, 125.1, 123.5, 116.0, 112.6,
100.6; known compound.26
4. EXPERIMENTAL DETAILS
4.1. Materials and Instruments. The employed solvents and
other materials have been bought from Sigma-Aldrich, Dae-Jung,
Merck, and Fluka companies in high purities (>0.99%, reagent grade),
and most of them were used without further purification. Melting
points were obtained using the Gallen Kamp apparatus. FT-IR spectra
have been recorded using KBr pellets by the JASCO FT-IR
instrument. All 1H NMR and 13C NMR spectra were recorded
using a Bruker Ultrashield 300 MHz NMR instrument with CDCl3 or
DMSO-d6 as solvents. Elemental analyses were performed using a
CHNS Vario EL III analyzer.
4.2. General Procedure for the Synthesis of Nitroepoxide
Derivatives. To a 5 mL round-bottom flask with a magnet, 38 mL of
methanol and 12 mL of nitroalkene were added. The flask was placed
in a 0 °C ice−water bath, and 2.5 mL of hydrogen peroxide solution
(50 v/v%) was added. Then, 3.9 mL of a 2 M solution of NaOH was
added, and the mixture was stirred for 10 min at 0 °C. After this, 10
mL of cold water (5−10 °C) was added to the mixture, and the
organic products were extracted 2× with 30 mL of diethyl ether. The
organic layer was dried using sodium sulfate, and the solvent was
evaporated. The crude product was purified using column
chromatography on silica and a hexane−ethyl acetate (1:10) mixture
as eluent (for all derivatives). All of these products are known, and
their structures were confirmed by comparison of their melting points
with the reports.36−43
4.3. General Procedure for the Synthesis of Benzofuran
Derivatives. To a 10 mL round-bottom flask with a magnet over a
heater−stirrer, one mL of DMF, 3 mmol of K2CO3, and 1 mmol of
salicylaldehyde were added, and the reaction was stirred at room
temperature. After 10 min, 1 mmol of nitroepoxide was added to the
solution, and the temperature was increased to 110 °C using an oil
bath. The reaction progress was followed by TLC (1:10 mixture of
hexane−ethyl acetate) until completion (12 h). Then, the solvent
(DMF) was removed by vacuum distillation, and 5 mL of water was
added. The organic compounds were extracted from the mixture using
15 mL of ethyl acetate (2×). The organic layer was washed with 15
mL of brine (3×) and dried over sodium sulfate, and its solvent was
evaporated. Before the purification of the product, the mixture was
analyzed with FTIR (in some reactions) to find some evidence for the
mechanism of the reaction (as it will be said later, the acetate ion
band has been observed at this step). Then, the crude product was
purified using column chromatography on silica and the hexane−ethyl
acetate (1:10) mixture as eluent (for all derivatives). Among the 23
synthesized products, 19 compounds were characterized using FT-IR,
1H NMR, 13C NMR, and melting points (as described in the next
4.4.4. 5-Chloro-2-(4-nitrophenyl) Benzofuran (3d). Yellow solid
(164 mg, 60% yield), mp 194−195 °C; FT-IR νmax (KBr): 3106,
1597, 1508, 1382, 1345, 1325, 851; 1H NMR (400 MHz, chloroform-
d) δ 8.36−8.31 (m, 2H), 8.03−7.99 (m, 2H), 7.63 (d, J = 1.8 Hz,
1H), 7.50 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 8.7, 2.1 Hz, 1H), 7.20 (d,
J = 0.8 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.6, 153.8,
147.5, 135.7, 130.0, 129.1, 126.0, 125.4, 124.4, 121.1, 112.5, 104.5;
known compound.39
4.4.5. 5-Bromo-2-(3-nitrophenyl) Benzofuran (3e). Pale yellow
solid (267 mg, 84% yield), mp 176−178 °C; FT-IR νmax (KBr): 3102,
1525, 1432, 1351, 1050, 809, 798; 1H NMR (300 MHz, DMSO-d6) δ
8.69 (t, J = 1.9 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.29 (dd, J = 8.2,
1.5 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.75
(s, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.7, 2.1 Hz, 1H).
13C{1H} NMR (76 MHz, DMSO) δ 154.6, 153.8, 149.0, 131.5, 131.4,
131.3, 131.2, 128.6, 124.5, 124.1, 119.6, 116.4, 114.0, 104.5, 40.8,
40.6, 40.3, 40.0, 39.7, 39.4, 39.2; Anal. Calcd (%) for C14H8BrNO3: C,
52.86; H, 2.53; N, 4.40. Found: C, 53.52; H, 2.68; N, 4.61.
4.4.6. 5-Chloro-2-(3-nitrophenyl) Benzofuran (3f). Pale yellow
1
solid (219 mg, 80% yield), mp 182−184 °C; H NMR (300 MHz,
DMSO-d6) δ 8.72−8.66 (m, 1H), 8.40 (ddd, J = 7.8, 1.6, 0.9 Hz, 1H),
8.29 (ddd, J = 8.2, 2.3, 0.9 Hz, 1H), 7.89−7.73 (m, 4H), 7.43 (dd, J =
8.9, 2.2 Hz, 1H). 13C{1H} NMR (76 MHz, DMSO) δ 154.8, 153.4,
148.9, 131.5, 131.3, 131.3, 130.6, 128.4, 125.9, 124.1, 121.5, 119.6,
113.5, 104.6; Anal. Calcd (%) for C14H8ClNO3: C, 61.44; H, 2.95; N,
5.12. Found: C, 62.31; H, 2.34; N, 4.78.
4.4.7. 5-Chloro-2-(4-chlorophenyl) Benzofuran (3g). White solid
(203 mg, 77% yield), mp 154−155 °C; FT-IR νmax (KBr): 3084,
1730, 1484, 1442, 1090, 811, 800; 1H NMR (300 MHz, DMSO-d6) δ
8.01−7.92 (m, 2H), 7.77 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.7 Hz,
1H), 7.64−7.57 (m, 2H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 8.7,
2.2 Hz, 1H). 13C{1H} NMR (76 MHz, DMSO) δ 156.1, 153.3, 134.3,
130.9, 129.7, 128.6, 128.2, 127.1, 125.2, 121.2, 113.2, 102.9; known
compound.40
4.4.8. 5-Chloro-2-phenyl Benzofuran (3h). White solid (149 mg,
65% yield), mp 152−153 °C; FT-IR νmax (KBr): 2913, 1606, 1432,
1
1345, 879; H NMR (300 MHz, DMSO-d6) δ 7.99−7.91 (m, 2H),
7.75 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.59−7.51 (m,
2H), 7.50−7.42 (m, 2H), 7.36 (dd, J = 8.7, 2.3 Hz, 1H). 13C{1H}
NMR (76 MHz, DMSO) δ 157.3, 153.2, 131.0, 129.8, 129.7, 129.6,
128.1, 125.4, 125.0, 121.0, 113.2, 102.2; known compound.40
4.4.9. 2-(4-Chlorophenyl)-7-Methoxybenzofuran (3i). White solid
(173 mg, 67% yield), mp 73−74 °C; FT-IR νmax (KBr): 2947, 1591,
1487, 1093, 800, 727; 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J =
8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.49 (s, 1H), 7.27−7.16 (m,
2H), 6.98 (dd, J = 7.3, 1.7 Hz, 1H), 3.99 (s, 3H). 13C{1H} NMR (76
MHz, DMSO) δ 154.4, 145.4, 143.9, 133.7, 130.7, 129.6, 129.1,
126.8, 124.6, 113.8, 107.9, 103.5, 56.3; known compound.45
sections), and their structures were confirmed by the comparison of
their melting points and spectra with the reports. For the unknown
products, in addition to the above analyses, elemental analyses were
recorded to confirm their structures.
4.4. Spectral and Physical Data for All Synthesized
Compounds. 4.4.1. 5-Bromo-2-(4-chlorophenyl) Benzofuran (3a).
White solid (228 mg, 74% yield), mp 176−178 °C; T-IR νmax (KBr):
4.4.10. 7-Methoxy-2-(3-nitrophenyl) Benzofuran (3j). Yellow
solid (188 mg, 70% yield), mp 144−143 °C; FT-IR νmax (KBr):
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1
1521, 1494, 1344, 1101, 727; H NMR (300 MHz, chloroform-d) δ
1720, 1458, 1176, 954, 802; H NMR (300 MHz, chloroform-d) δ
7.81 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 3H), 7.27 (dd, J = 8.5,
2.6 Hz, 1H), 7.09−6.99 (m, 2H). 13C{1H} NMR (76 MHz,
chloroform-d) δ 159.4 (d, J = 238.4 Hz), 156.6, 151.2, 134.75,
129.9 (d, J = 10.9 Hz), 129.1, 128.6, 126.2, 112.2 (d, J = 26.5 Hz),
111.8 (d, J = 9.7 Hz), 106.4 (d, J = 25.1 Hz), 101.9 (d, J = 4.1 Hz);
known compound.46
8.74 (t, J = 1.9 Hz, 1H), 8.28−8.17 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H),
7.29−7.17 (m, 3H), 6.90 (dd, J = 6.8, 2.1 Hz, 1H), 4.10 (s, 3H).
13C{1H} NMR (76 MHz, CDCl3) δ 153.3, 148.8, 145.5, 144.5, 132.1,
130.5, 130.4, 129.8, 124.1, 122.9, 119.8, 113.7, 107.4, 103.9, 77.5,
77.0, 76.6, 56.1. Anal. Calcd (%) for C15H11NO4: C, 66.91; H, 4.12;
N, 5.20. Found: C, 66.08; H, 4.21; N, 5.40.
4.4.19. 5-Fluoro-2-(3-nitrophenyl) Benzofuran (3t). Yellow solid
(187 mg, 77% yield), mp 124−125 °C; FT-IR νmax (KBr): 1525,
1471, 1452, 1352, 1186, 1130, 792, 732; 1H NMR (300 MHz,
chloroform-d) δ 8.72 (t, J = 2.0 Hz, 1H), 8.24 (ddd, J = 8.2, 2.3, 1.0
Hz, 1H), 8.18 (dt, J = 7.9, 1.3 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.52
(dd, J = 9.0, 4.1 Hz, 1H), 7.35−7.30 (m, 1H), 7.19 (s, 1H), 7.11 (td, J
= 9.1, 2.6 Hz, 1H). 13C{1H} NMR (76 MHz, chloroform-d) δ 159.5
(d, J = 239.3 Hz), 154.9, 151.38, 148.8, 131.8, 130.4, 129.9, 129.5 (d,
J = 11.1 Hz), 123.2, 119.8, 113.2 (d, J = 26.5 Hz), 112.1 (d, J = 9.6
Hz), 106.8 (d, J = 25.1 Hz), 103.7 (d, J = 4.1 Hz); known compound
(CAS Registry Number: 1238315-03-1).
4.4.20. 2-(3-Nitrophenyl) Benzofuran (3u). Pale yellow solid (194
mg, 81% yield), mp 134−135 °C; FT-IR νmax (KBr): 3084, 1527,
1449, 1348, 800, 762; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J =
1.9 Hz, 1H), 8.39 (d, J = 7.9 Hz, 1H), 8.26 (dd, J = 8.2, 1.6 Hz, 1H),
7.83 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.76−7.68 (m, 2H), 7.45−7.37
(m, 1H), 7.37−7.28 (m, 1H). 13C{1H} NMR (76 MHz, DMSO) δ
155.0, 153.2, 149.0, 131.8, 131.3, 131.3, 1289.0, 126.0, 124.1, 123.6,
122.2, 119.3, 111.9, 105.0; known compound.41
4.4.11. 7-Methoxy-2-(4-nitrophenyl) Benzofuran (3k). Yellow
solid (201 mg, 75% yield), mp 171−172 °C; FT-IR νmax (KBr):
2925, 1595, 1514, 1332, 1272, 852, 730; 1H NMR (300 MHz,
chloroform-d) δ 8.33 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz, 2H),
7.31−7.18 (m, 3H), 6.91 (dd, J = 6.8, 2.1 Hz, 1H), 4.10 (s, 3H).
13C{1H} NMR (76 MHz, CDCl3) δ 153.4, 147.3, 145.5, 144.9, 136.1,
130.3, 125.3, 124.3, 113.8, 107.7, 105.4, 77.5, 77.0, 76.6, 56.1; known
compound.44
4.4.12. N,N-Diethyl-2-(4-nitrophenyl) Benzofuran-6-amine (3l).
Red crystal (173 mg, 56% yield), mp 155−157 °C; FT-IR νmax (KBr):
1602, 1521, 1344, 1282, 1112, 862; 1H NMR (300 MHz, chloroform-
d) δ 8.29 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 8.7
Hz, 1H), 7.15 (s, 1H), 6.81 (s, 1H), 6.76 (dd, J = 8.7, 2.3 Hz, 1H),
3.48 (q, J = 7.0 Hz, 4H), 1.26 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (76
MHz, CDCl3) δ 158.2, 150.6, 147.6, 146.1, 137.0, 124.4, 123.9, 121.9,
117.9, 110.3, 105.7, 93.4, 77.4, 77.0, 76.6, 45.0, 12.6; known
compound (PubChem ID: 16460625).
4.4.13. N,N-Diethyl-2-(3-nitrophenyl) Benzofuran-6-amine (3m).
Red crystal (161 mg, 52% yield), mp 98−99 °C; FT-IR νmax (KBr):
2966, 1631, 1625, 1525, 1506, 1357, 1344, 1118, 794, 734; 1H NMR
(300 MHz, chloroform-d) δ 8.63 (t, J = 2.0 Hz, 1H), 8.16−8.01 (m,
2H), 7.58 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.08 (s, 1H),
6.85 (s, 1H), 6.76 (d, J = 8.4 Hz, 1H), 3.47 (q, J = 7.1 Hz, 4H), 1.26
(t, J = 7.0 Hz, 6H). 13C{1H} NMR (76 MHz, CDCl3) δ 157.7, 148.8,
147.2, 132.8, 131.9, 129.6, 129.3, 121.6, 121.5, 120.9, 118.7, 110.2,
103.7, 93.8, 77.5, 77.0, 76.6, 45.0, 12.6. Anal. Calcd (%) for
C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 68.94; H, 5.58; N,
9.20.
4.4.14. 5-Chloro-2-(naphthalen-1-yl) Benzofuran (3n). Pale
yellow solid (117 mg, 42% yield), mp 74−75 °C; FT-IR νmax
(KBr): 3053, 1689, 1444, 1261, 798, 773; 1H NMR (300 MHz,
chloroform-d) δ 8.53−8.42 (m, 1H), 8.04−7.86 (m, 3H), 7.75−7.52
(m, 5H), 7.34 (dd, J = 8.7, 2.2 Hz, 1H), 7.07 (s, 1H). 13C{1H} NMR
(76 MHz, CDCl3) δ 157.2, 153.4, 133.9, 130.6, 130.4, 129.9, 128.7,
128.5, 127.8, 127.5, 127.1, 126.2, 125.3, 125.3, 124.5, 120.5, 112.3,
105.4, 77.5, 77.0, 76.6; known compound (PubChem ID: 91689946).
4.4.15. 5-Bromo-2-(naphthalen-1-yl) Benzofuran (3o). Pale
yellow solid (145 mg, 45% yield), mp 72−73 °C; FT-IR νmax
(KBr): 3037, 1703, 1651, 1444, 1259, 1176, 790, 763; 1H NMR
(300 MHz, chloroform-d) δ 8.52−8.41 (m, 1H), 8.02−7.95 (m, 2H),
7.92 (dd, J = 7.2, 1.2 Hz, 1H), 7.83 (dd, J = 1.9, 0.7 Hz, 1H), 7.71−
7.56 (m, 3H), 7.56−7.42 (m, 2H), 7.07 (s, 1H). 13C{1H} NMR (76
MHz, CDCl3) δ 157.0, 153.7, 133.9, 131.0, 130.6, 129.9, 128.7, 127.7,
127.5, 127.2, 127.1, 126.2, 125.3, 125.3, 123.6, 116.0, 112.7, 105.3,
77.4, 77.0, 76.6; known compound (PubChem ID: 91689945).
4.4.16. 3-Methyl-2-(3-nitrophenyl) Benzofuran (3p). Yellow solid
(83 mg, 33% yield), mp 77−79 °C; FT-IR νmax (KBr): 2923, 1525,
1348, 808, 750, 734, 676; 1H NMR (300 MHz, chloroform-d) δ 8.72
(t, J = 2.0 Hz, 1H), 8.23 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 8.18 (dt, J =
7.9, 1.4 Hz, 1H), 7.69 (t, J = 8.1 Hz, 1H), 7.65−7.53 (m, 2H), 7.45−
7.30 (m, 2H), 2.60 (s, 3H). 13C{1H} NMR (76 MHz, CDCl3) δ
153.9, 148.6, 148.0, 133.1, 131.9, 130.7, 129.7, 125.4, 122.8, 122.2,
121.2, 119.8, 113.8, 111.2, 9.6; known compound.42
4.4.21. 2-(4-Nitrophenyl) Benzofuran (3v). Yellow solid (167 mg,
70% yield), mp 182−184 °C; FT-IR νmax (KBr): 3085, 1600, 1517,
1
1344, 1110, 852, 752; H NMR (300 MHz, DMSO-d6) δ 8.43−8.33
(m, 2H), 8.26−8.16 (m, 2H), 7.85−7.66 (m, 3H), 7.44 (td, J = 8.4,
7.8, 1.4 Hz, 1H), 7.34 (td, J = 7.5, 0.9 Hz, 1H). 13C{1H} NMR (76
MHz, DMSO) δ 155.3, 153.4, 147.4, 136.1, 128.9, 126.5, 126.0,
124.9, 124.2, 122.4, 111.9, 106.6; known compound.37
4.4.22. 2-(4-Chlorophenyl) Benzofuran (3w). White solid (172
mg, 75% yield), mp 147−148 °C; FT-IR νmax (KBr): 3055, 1486,
1449, 1384, 1093, 804, 749, 585; 1H NMR (400 MHz, chloroform-d)
δ 7.85−7.79 (m, 2H), 7.63−7.59 (m, 1H), 7.57−7.52 (m, 1H), 7.47−
7.41 (m, 2H), 7.36−7.30 (m, 1H), 7.30−7.24 (m, 1H), 7.04 (d, J =
0.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.9, 154.8,
134.3, 129.1, 129.0, 126.1, 124.6, 123.1, 121.0, 111.2, 101.8; known
compound.38
4.4.23. 2-(3-Methoxyphenyl) Benzofuran (3x). White oil (143 mg,
64% yield), mp; FT-IR νmax (KBr): 2923, 1571, 1488, 1454, 1238,
1
779, 750; H NMR (300 MHz, chloroform-d) δ 7.67−7.57 (m, 2H),
7.53 (dt, J = 7.7, 1.3 Hz, 1H), 7.49 (dd, J = 2.6, 1.5 Hz, 1H), 7.45−
7.26 (m, 3H), 7.08 (s, 1H), 6.97 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 3.95
(s, 3H). 13C{1H} NMR (76 MHz, CDCl3) δ 160.0, 155.8, 154.9,
131.8, 129.9, 129.2, 124.4, 123.0, 120.9, 117.6, 114.5, 111.2, 110.2,
101.7, 77.5, 77.1, 76.7, 55.4; known compound.43
4.4.24. 1-(3-Hydroxy-2-(3-nitrophenyl)-2,3-Dihydrobenzofuran-
2-yl) Ethane-1-one (Intermediate I5). 1H NMR (400 MHz,
chloroform-d) δ 8.56 (t, J = 2.1 Hz, 1H), 8.18 (ddd, J = 8.2, 2.3,
1.0 Hz, 1H), 8.05 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 7.56 (t, J = 8.0 Hz,
1H), 7.41−7.35 (m, 2H), 7.20 (d, J = 8.1 Hz, 1H), 7.04 (td, J = 7.5,
1.0 Hz, 1H), 5.48 (s, 1H), 3.31 (d, J = 3.9 Hz, 1H), 2.44 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 207.0, 158.6, 148.3, 139.6,
132.1, 131.6, 129.6, 126.3, 125.6, 123.6, 122.8, 121.1, 111.0, 81.4,
28.2.
ASSOCIATED CONTENT
4.4.17. 3-Methyl-2-(4-nitrophenyl) Benzofuran (3q). Yellow solid
(88 mg, 35% yield), mp 133−134 °C; FT-IR νmax (KBr): 1597, 1510,
1338, 1097, 854, 738; 1H NMR (300 MHz, chloroform-d) δ 8.38 (d, J
= 9.0 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.56
(d, J = 8.1 Hz, 1H), 7.42 (td, J = 8.2, 7.7, 1.4 Hz, 1H), 7.34 (td, J =
7.5, 1.1 Hz, 1H), 2.61 (s, 3H). 13C{1H} NMR (76 MHz, CDCl3) δ
154.2, 148.2, 146.6, 137.5, 130.7, 126.6, 125.9, 124.1, 122.9, 119.9,
115.4, 111.3, 77.5, 77.0, 76.6, 9.9; known compound.42
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00143.
NMR spectra for all reported compounds (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3a−x as well as IR spectra (ZIP)
4.4.18. 2-(4-Chlorophenyl)-5-Fluorobenzofuran (3s). White solid
(182 mg, 74% yield), mp 123−124 °C; FT-IR νmax (KBr): 2925,
4760
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pubs.acs.org/joc
Article
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Regioselective Opening of Nitroepoxides with Unsymmetrical
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(16) Agut, J.; Vidal, A.; Rodríguez, S.; González, F. V. Dynamic
Kinetic Asymmetric Ring-Opening/Reductive Amination Sequence of
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AUTHOR INFORMATION
Corresponding Author
Hossein Tavakol − Department of Chemistry, Isfahan
University of Technology, Isfahan 84156-83111, Iran;
orcid.org/0000-0002-3296-9575; Email: h_tavakol@
iut.ac.ir
■
Author
Mohammad A. Ranjbari − Department of Chemistry, Isfahan
University of Technology, Isfahan 84156-83111, Iran
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00143
Funding
The authors clearly state that no funding has been used in this
work.
Notes
The authors declare no competing financial interest.
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