TfOH-Promoted Decyanative Cyclization toward the Synthesis of 2,1-Benzisoxazoles

Article abstract of DOI:10.1021/acs.joc.1c00091

A novel solvent-free, TfOH-promoted decyanative cyclization approach for the synthesis of 2,1-benzisoxazoles has been developed. The reactions are complete instantly at room temperature and result in the formation of the desired 2,1-benzisoxazoles in a 34-97% isolated yield.

Full text of DOI:10.1021/acs.joc.1c00091

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Article
TfOH-Promoted Decyanative Cyclization toward the Synthesis of
2,1-Benzisoxazoles
Mengge Zhang, Yonggang Meng, Yangang Wu, and Chuanjun Song*
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ABSTRACT: A novel solvent-free, TfOH-promoted decyanative cyclization approach for
the synthesis of 2,1-benzisoxazoles has been developed. The reactions are complete instantly
at room temperature and result in the formation of the desired 2,1-benzisoxazoles in a 34−
97% isolated yield.
Scheme 1. Comparation of Previous and Present Methods
for the Synthesis of 2,1-Benzisoxazoles
INTRODUCTION
■
2,1-Benzisoxazoles (anthranils) are useful building blocks for
the synthesis of drug molecules,1 2-aminoarylketons,2 and
fused heterocyclic molecules such as benzazepines,3 indoles,4
quinolines,5 and acridines.6 Moreover, derivatives of benzisox-
azoles have been found to show antimicrobial,7 antitubulin,8
antifungal,9 and antitumor activities.10 A number of methods
for the synthesis of benzisoxazoles have been developed
(Scheme 1). The condensation of nitrobenzenes and
arylacetonitriles (1)11 and the transition-metal-catalyzed
heterocyclization of (2-amino/nitro)phenylacetylenes (2)12
are limited to the synthesis of 3-aryl-2,1-benzisoxazoles and
3-acyl-2,1-benzisoxazoles, respectively. General methods for
the synthesis of 2,1-benzisoxazoles involve the reductive
heterocyclization of 2-nitroacylbenzenes (3a),13 thermolysis
or metal-catalyzed cyclization of 2-azidoacylbenzenes (3b),14
and acid- or base-catalyzed dehydrative cyclization of 2-
nitrobenzyl compounds (4).15 Among these, the latter method
seems to be the most versatile to access variously substituted
2,1-benzisoxazoles. However, the requirement of prolonged
heating of the acid-catalyzed reaction15a−c limits the functional
group tolerance. As part of our recent interest toward the
synthesis of heterocyclic compounds via C−N and C−O bond
formation under transition-metal-free conditions,16 we herein
report a TfOH-promoted, solvent-free, room temperature,
instant decyanative cyclization approach for the synthesis of
2,1-benzisoxazoles.
RESULTS AND DISCUSSION
■
2-(2-Nitrophenyl)acetonitrile 1a was used as a substrate for
the optimization of reaction conditions. In sharp contrast with
literature reports,15a−c the reaction was complete instantly in
the presence of 8 equiv of TfOH at ambient temperature in
dichloromethane (DCM), which resulted in the formation of
2,1-benzisoxazole-3-carboxylate 2a in an 85% isolated yield
(Table 1, entry 1). No reaction occurred in other solvents
tested (entries 2−5). To our delight, 2a could be isolated in a
91% yield in the absence of the solvent (entry 6). Next, other
acids were inspected under solvent-free conditions (entries 7−
Received: January 13, 2021
Published: May 20, 2021
https://doi.org/10.1021/acs.joc.1c00091
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 7326−7332
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Acid-promoted enolization of 1 provided A, intramolecular
cyclization of which gave B. An attack of the cyanide group by
the hydroxyl group resulted in the formation of C. 2a−u and
2v were formed following a retro-Diels−Alder-type reaction
and an elimination pathway, respectively.
Table 1. Optimization of Reaction Conditions
a
entry
acid (equiv)
TfOH (8.0)
solvent
temp. (°C)
yield (%)
CONCLUSIONS
■
1
2
3
4
5
6
7
8
DCM
MeOH
THF
DMF
MeCN
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
85
b
In summary, we have developed a novel solvent-free, TfOH-
promoted decyanative cyclization approach for the synthesis of
2,1-benzisoxazoles with a broad substrate scope. The reactions
are complete instantly at room temperature to yield the desired
products in moderate to excellent isolated yields.
TfOH (8.0)
TfOH (8.0)
TfOH (8.0)
TfOH (8.0)
TfOH (8.0)
conc. HCl (8.0)
MsOH (8.0)
TFA (8.0)
0
0
0
0
b
b
b
91
b
0
0
0
EXPERIMENTAL SECTION
b
■
Melting points were determined on a hot-stage apparatus and were
uncorrected. Infrared spectra were obtained using a Fourier transform
infrared (FT-IR) spectrometer. 1H and 13C NMR spectra were
obtained on a 400 MHz spectrometer. Mass spectra were recorded on
a Q-TOF micro spectrometer. Flash column chromatography was
performed over a silica gel 200−300 mesh.
b
9
10
11
12
13
conc. H2SO4 (8.0)
TfOH (7.0)
TfOH (9.0)
trace
85
89
TfOH (8.0)
81
a
b
General Procedure for the Synthesis of Substrate 1a−r. To
a suspension of potassium tert-butoxide (224 mg, 2.0 mmol, 2.0
equiv) in dimethylformamide (DMF) (5 mL) at 0 °C, acetonitrile
(1.2 mmol, 1.2 equiv) was added over 5 min, followed by 2-
fluoronitrobenzene (1.0 mmol). After addition, the reaction was
heated at 90 °C until completion according to thin-layer
chromatography (TLC) analysis. The cooled mixture was quenched
with saturated aqueous NH4Cl (10 mL) and extracted with ethyl
acetate (3 × 30 mL). The combined organic extracts were washed
with brine (30 mL), dried over anhydrous Na2SO4, and then
concentrated under vacuum. The residue was purified by column
chromatography on a silica gel (200−300 mesh) to give 1a−r.
General Procedure for the Synthesis of Substrate 1s−u. A
mixture of 2-nitrophenylacetonitrile (1.0 mmol) and potassium
carbonate (276 mg, 2.0 mmol, 2.0 equiv) in DMF (5 mL) was
stirred at room temperature for 0.5 h. Alkyl iodine (1.1 mmol, 1.1
equiv) was added. The reaction was stirred at room temperature until
completion according to TLC analysis, and then cooled to 0 °C and
quenched with saturated aqueous NH4Cl (10 mL). The mixture was
extracted with ethyl acetate (3 × 30 mL). The combined organic
extracts were washed with brine (30 mL), dried over anhydrous
Na2SO4, and then concentrated under vacuum. The crude product
was purified by column chromatography on a silica gel (200−300
mesh) to give 1s−u.
Isolated yield. No reaction, starting material recovered.
10). Only trace amount of the desired 2a was obtained when
conc. H2SO4 was used, while no reaction occurred with other
acids. Variation of the equivalent of TfOH (entries 11 and 12)
or lowering the reaction temperature (entry 13) did not
improve the yield of 2a.
With the optimal reaction conditions in hand, we then
examined the TfOH-promoted decyanative cyclization of
various 2-(2-nitrophenyl)acetonitriles for the synthesis of 2,1-
benzisoxazoles. As shown in Table 2, a variety of 2-
methoxycarbonyl-2-(2-nitrophenyl)acetonitriles reacted
smoothly under the reaction conditions to provide 2,1-
benzisoxazole-3-carboxylates 2a−g in excellent isolated yields.
Next, the reactions of the 2-aryl substituted substrates 1h−r
were examined. The desired products 2h−o,q were obtained in
moderate isolated yields. In general, substrates with an
electron-withdrawing-group-substituted phenyl ring gave high-
er product yields than those with an electron-donating-group-
substituted phenyl ring. The reaction of 1p with a 2,6-
dichlorophenyl ring resulted in the formation of 2p in an
excellent isolated yield. It is interesting to notice that the
reaction of 1r with 2-nitrophenyl as well as 2-methyl-6-
nitrophenyl group gave 2r in a 64% isolated yield. No trace of
the alternative product (structure not shown) resulting from
heterocyclization involving the 2-nitrophenyl moiety was
observed. Under the reaction conditions, 3-alkyl-substituted
products 2s−u could also be obtained as expected. Finally, the
reaction of 2-nitrophenylacetonitrile 1v (R  H) yielded 2,1-
benzisoxazole-3-carboxamide 2v in a 65% isolated yield.
Compared with literature reports concerning acid-catalyzed
cyclization of 2-nitrobenzyl compounds toward the synthesis of
2,1-benzisoxazoles,15a−c it implied that capturing of water
molecule generated during the reaction by the cyano group
might be crucial to the ease of the reaction reported herein
(ambient temperature, instant reaction). Indeed, the yield of
2a dropped to 38% if 1 equiv of water was added to the
mixture of 1a and TfOH (Scheme 2a). Besides, no reaction
occurred when 2-(2-nitrophenyl)acetamide 3a, methyl 2-(2-
nitrophenyl)acetate 3b, or 1-benzyl-2-nitrobenzene 3c was
subjected to the reaction conditions (Scheme 2b).
General Procedure for the Synthesis of 2,1-Benzisoxazoles
2a−v. TfOH (8.0 mmol, 8 equiv) was added to 1a−v (1.0 mmol) at
room temperature. After addition, the reaction was quenched
immediately with saturated aqueous sodium carbonate (20 mL),
and then the mixture was extracted with ethyl acetate (3 × 20 mL).
The combined organic extracts were dried over anhydrous Na2SO4
and filtered. The solvent was evaporated under reduced pressure. The
crude product was purified by column chromatography to give 2a−v.
Methyl benzo[c]isoxazole-3-carboxylate (2a). The crude
product was purified by column chromatography on a silica gel (n-
hexane/ethyl acetate = 30/1). Yellow solid (161 mg, 91%); mp 64−
1
65 °C; H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.8 Hz, 1H),
7.69 (d, J = 9.1 Hz, 1H), 7.37 (ddd, J = 9.1, 6.4, 1.0 Hz, 1H), 7.22
(ddd, J = 8.8, 6.4, 0.6 Hz, 1H), 4.07 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ = 157.6, 157.6, 153.5, 131.33, 128.1, 120.5,
120.5, 116.2, 53.0 ppm; IR (neat): vmax 1731, 1313, 1197 cm−1;
electrospray ionization-high-resolution mass spectrometry (ESI-
HRMS): m/z [M + H]+ calcd for C9H8NO3: 178.0499, found:
178.0497.
Methyl 7-chlorobenzo[c]isoxazole-3-carboxylate (2b). The
crude product was purified by column chromatography on a silica gel
(n-hexane/ethyl acetate = 6/1). White solid (179 mg, 85%); mp 94−
1
Based on the results of the experiments and literature
95 °C; H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 8.8, 0.6 Hz,
reports,15a a plausible mechanism is depicted in Scheme 3.
1H), 7.40 (dd, J = 7.0, 0.6 Hz, 1H), 7.16 (dd, J = 8.8, 7.0 Hz, 1H),
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Table 2. Substrate Scope
111−112 °C; 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 9.2 Hz,
1H), 7.70 (s, 1H), 7.15 (d, J = 9.2 Hz, 1H), 4.07 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ = 157.6, 157.2, 154.2, 137.8,
130.0, 121.9, 118.9, 114.7, 53.1 ppm; IR (neat): vmax 1718, 1298,
1228, 1043 cm−1; ESI-HRMS: m/z [M + H]+ calcd for
C9H735ClNO3: 212.0109, found: 212.0107.
Scheme 2. Control Experiments
Methyl 5-chlorobenzo[c]isoxazole-3-carboxylate (2d). The
crude product was purified by column chromatography on a silica gel
(n-hexane/ethyl acetate = 8/1). White solid (188 mg, 89%); mp
1
111−112 °C; H NMR (400 MHz, CDCl3): δ = 7.90 (s, 1H), 7.67
(d, J = 9.4 Hz, 1H), 7.30 (dd, J = 9.4, 1.8 Hz, 1H), 4.08 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ = 157.3, 156.1, 153.2, 134.4,
133.4, 120.7, 119.0, 117.8, 53.1 ppm; IR (neat): vmax 1728, 1279, 1193
cm−1; ESI-HRMS: m/z [M + H]+ calcd for C9H735ClNO3: 212.0109,
found: 212.0110.
Methyl 4-chlorobenzo[c]isoxazole-3-carboxylate (2e). The
crude product was purified by column chromatography on a silica gel
(n-hexane/ethyl acetate = 8/1). White solid (173 mg, 82%); mp 87−
4.08 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 157.2,
156.1, 155.0, 130.5, 128.3, 122.3, 121.6, 119.4, 53.2 ppm; IR (neat):
vmax 1715, 1268, 1213 cm−1; ESI-HRMS: m/z [M + H]+ calcd for
C9H735ClNO3: 212.0109, found: 212.0106.
Methyl 6-chlorobenzo[c]isoxazole-3-carboxylate (2c). The
crude product was purified by column chromatography on a silica gel
(n-hexane/ethyl acetate = 8/1). White solid (200 mg, 95%); mp
1
88 °C; H NMR (400 MHz, CDCl3): δ = 7.59 (dd, J = 8.5, 1.1 Hz,
1H), 7.24−7.19 (m, 2H), 4.03 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3): δ = 158.6, 157.1, 154.8, 131.2, 128.4, 125.4, 118.4,
115.1, 53.3 ppm; IR (neat): vmax 1733, 1262, 1181 cm−1; ESI-HRMS:
m/z [M + H]+ calcd for C9H735ClNO3: 212.0109, found: 212.0106.
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Scheme 3. Proposed Mechanism
Methyl 6-nitrobenzo[c]isoxazole-3-carboxylate (2f). The
crude product was purified by column chromatography on a silica
gel (n-hexane/ethyl acetate = 8/1). Yellow solid (200 mg, 90%); mp
153−154 °C; 1H NMR (400 MHz, CDCl3): δ = 8.73 (dd, J = 1.8, 0.9
Hz, 1H), 8.14 (dd, J = 9.5, 0.9 Hz, 1H), 8.01 (dd, J = 9.5, 1.8 Hz,
1H), 4.13 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ =
156.9, 156.4, 155.7, 150. 2, 123.2, 121.6, 121.0, 114.4, 53.5 ppm; IR
(neat): vmax 1720, 1268, 1213 cm−1; ESI-HRMS: m/z [M + H]+ calcd
for C9H7N2O5: 223.0349, found: 223.0357.
(neat): vmax 2976, 2842, 1267, 1030 cm−1; ESI-HRMS: m/z [M + H]+
calcd for C13H979BrNO: 273.9862, found: 273.9860.
3-(2-Chlorophenyl)benzo[c]isoxazole (2k). The crude product
was purified by column chromatography on a silica gel (n-hexane/
ethyl acetate = 25/1). Yellow solid (117 mg, 51%); mp 67−68 °C; 1H
NMR (400 MHz, CD3OD): δ = 9.29−9.27 (m, 1H), 9.24−9.22 (m,
1H), 9.19−9.16 (m, 2H), 9.14−9.07 (m, 2H), 8.98 (ddd, J = 9.0, 6.4,
1.0 Hz, 1H), 8.68 (ddd, J = 9.1, 6.4, 0.8 Hz, 1H) ppm; 13C{1H} NMR
(100 MHz, CD3OD): δ = 164.6, 158.5, 134.0, 133.2, 132.8, 132.6,
132.0, 128.7, 128.2, 126.0, 121.9, 117.6, 115.7 ppm; IR (neat): vmax
2956, 2852, 1251, 1021 cm−1; ESI-HRMS: m/z [M + H]+ calcd for
C13H935ClNO: 230.0367, found: 230.0364.
3-(3-Chlorophenyl)benzo[c]isoxazole (2l). The crude product
was purified by column chromatography on a silica gel (n-hexane/
ethyl acetate = 50/1). White solid (112 mg, 49%); mp 85−86 °C; 1H
NMR (400 MHz, CDCl3): δ = 7.98 (s, 1H), 7.90−7.88 (m, 1H), 7.79
(d, J = 8.9 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.50−7.43 (m, 2H),
7.33 (ddd, J = 9.1, 6.4, 0.9 Hz, 1H), 7.09 (ddd, J = 8.9, 6.4, 0.7 Hz,
1H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 162.8, 158.0,
135.4, 130.9, 130.7, 130.3, 130.0, 126.5, 125.4, 124.7, 120.3, 115.8,
114.8 ppm; IR (neat): vmax 2966, 2862, 1256, 1021 cm−1; ESI-HRMS:
m/z [M + H]+ calcd for C13H935ClNO: 230.0367, found: 230.0364.
3-(4-Chlorophenyl)benzo[c]isoxazole (2m). The crude prod-
uct was purified by column chromatography on a silica gel (n-hexane/
ethyl acetate = 10/1). White solid (96 mg, 42%); mp 143−144 °C;
1H NMR (400 MHz, CDCl3): δ = 7.97−7.93 (m, 2H), 7.78 (d, J =
8.9 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.55−7.51 (m, 2H), 7.33 (ddd,
J = 9.1, 6.4, 0.9 Hz, 1H), 7.08 (ddd, J = 8.9, 6.4, 0.7 Hz, 1H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ = 163.3, 158.0, 136.5, 130.9,
129.7, 127.8, 126.9, 125.1, 120.4, 115.8, 114.6 ppm; IR (neat): vmax
2926, 2852, 1250, 1022 cm−1; ESI-HRMS: m/z [M + H]+ calcd for
C13H935ClNO: 230.0367, found: 230.0364.
Methyl 6-methylbenzo[c]isoxazole-3-carboxylate (2g). The
crude product was purified by column chromatography on a silica gel
(n-hexane/ethyl acetate = 10/1). Yellow solid (170 mg, 89%); mp
1
67−68 °C; H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 9.0 Hz,
1H), 7.42 (s, 1H), 7.07 (d, J = 9.0 Hz, 1H), 4.07 (s, 3H), 2.43 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 158.3, 157.7, 153.0,
141.9, 131.6, 119.9, 119.5, 113.6, 52.9, 22.6 ppm; IR (neat): vmax
1708, 1295, 1229 cm−1; ESI-HRMS: m/z [M + H]+ calcd for
C10H10NO3: 192.0655, found: 192.0654.
3-Phenylbenzo[c]isoxazole (2h). The crude product was
purified by column chromatography on a silica gel (n-hexane/ethyl
1
acetate = 2/1). Yellow liquid (68 mg, 35%); H NMR (400 MHz,
CDCl3): δ = 8.03−8.00 (m, 2H), 7.83 (d, J = 8.9 Hz, 1H), 7.61 (d, J
= 9.1 Hz, 1H), 7.57−7.53 (m, 2H), 7.51−7.46 (m, 1H), 7.32 (ddd, J
= 9.1, 6.4, 0.8 Hz, 1H), 7.05 (ddd, J = 8.9, 6.4, 0.6 Hz, 1H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ = 164.5, 157.9, 130.8, 130.4,
129.4, 128.5, 126.7, 124.7, 120.7, 115.6, 114.5 ppm; IR (neat): vmax
2924, 2852, 1632 cm−1; ESI-HRMS: m/z [M + H]+ calcd for
C13H10NO: 196.0757, found: 196.0754.
3-(2-Methoxyphenyl)benzo[c]isoxazole (2i). The crude prod-
uct was purified by column chromatography on a silica gel (n-hexane/
1
ethyl acetate = 10/1). Yellow liquid (77 mg, 34%); H NMR (400
MHz, CDCl3): δ = 7.83 (dd, J = 7.7, 1.7 Hz, 1H), 7.74 (d, J = 8.9 Hz,
1H), 7.59 (d, J = 9.1 Hz, 1H), 7.49 (ddd, J = 9.1, 7.4, 1.7 Hz, 1H),
7.30 (ddd, J = 9.1, 6.4, 1.0 Hz, 1H), 7.13 (td, J = 7.7, 1.0 Hz, 1H),
7.08 (d, J = 8.4 Hz, 1H), 6.98 (ddd, J = 8.9, 6.4, 0.8 Hz, 1H), 3.94 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 163.5, 157.9,
156.5, 132.0, 130.6, 130.6, 123.4, 122.7, 121.2, 117.8, 116.1, 115.2,
111.8, 55.7 ppm; IR (neat): vmax 2924, 2854, 1251, 1021 cm−1; ESI-
HRMS: m/z [M + H]+ calcd for C14H12NO2: 226.0863, found:
226.0860.
3-(3-(Trifluoromethyl)phenyl)benzo[c]isoxazole (2n). The
crude product was purified by column chromatography on a silica
gel (n-hexane/ethyl acetate = 10/1). Yellow solid (153 mg, 58%); mp
1
114−115 °C; H NMR (400 MHz, CDCl3): δ = 7.27 (s, 1H), 8.21
(d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.76−7.68 (m, 2H),
7.65 (d, J = 9.1 Hz, 1H), 7.36 (ddd, J = 9.1, 6.4, 0.9 Hz, 1H), 7.13
(ddd, J = 8.9, 6.4, 0.7 Hz, 1H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ = 162.7, 158.1, 132.0 (JF‑C = 32.7 Hz), 131.0, 130.0, 129.7
3-(2-Bromophenyl)benzo[c]isoxazole (2j). The crude product
was purified by column chromatography on a silica gel (n-hexane/
(JF‑C = 1.2 Hz), 129.2, 126.8 (JF‑C = 3.7 Hz), 125.7, 123.8 (JF‑C
270.9 Hz), 123.4 (JF‑C = 3.9 Hz), 120.1, 116.0, 115.0 ppm; IR (neat):
max 2960, 2923, 2848, 1318, 1107 cm−1; ESI-HRMS: m/z [M + H]+
=
1
ethyl acetate = 10/1). Yellow liquid (120 mg, 44%); H NMR (400
v
MHz, CD3OD): δ = 9.40 (dd, J = 8.0, 1.0 Hz, 1H), 9.20 (dd, J = 7.7,
1.8 Hz, 1H), 9.17−9.11 (m, 3H), 9.07−9.02 (m, 1H), 8.97 (ddd, J =
9.1, 6.4, 1.0 Hz, 1H), 8.66 (ddd, J = 8.9, 6.4, 0.7 Hz, 1H) ppm;
13C{1H} NMR (100 MHz, CD3OD): δ = 165.9, 158.4, 135.2, 133.4,
133.1, 132.6, 130.3, 129.1, 126.0, 123.2, 121.8, 117.4, 115.7 ppm; IR
calcd for C14H9F3NO: 264.0631, found: 264.0627.
Methyl 4-(benzo[c]isoxazol-3-yl)benzoate (2o). The crude
product was purified by column chromatography on a silica gel (n-
hexane/ethyl acetate = 6/1). Yellow solid (139 mg, 55%); mp 152−
153 °C; 1H NMR (400 MHz, CDCl3): δ = 8.23−8.20 (m, 2H), 8.11−
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8.08 (m, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.35
(ddd, J = 9.1, 6.4, 0.9 Hz, 1H), 7.12 (ddd, J = 8.9, 6.4, 0.8 Hz, 1H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 166.4, 163.1, 158.0,
132.2, 131.3, 130.9, 130.6, 126.4, 125.6, 120.4, 116.0, 115.4, 52.6
ppm; IR (neat): vmax 1719, 1277, 1102 cm−1; ESI-HRMS: m/z [M +
H]+ calcd for C15H12NO3: 254.0812, found: 254.0811.
(100 MHz, DMSO-d6): δ = 157.7, 157.2, 157.0, 131.9, 127.1, 121.0,
118.2, 115.2 ppm; IR (neat): vmax 3380, 3170, 1698, 1670 cm−1; ESI-
HRMS: m/z [M + H]+ calcd for C8H7N2O2: 163.0502, found:
163.0499.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00091.
■
3-(2,6-Dichlorophenyl)benzo[c]isoxazole (2p). The crude
product was purified by column chromatography on a silica gel (n-
hexane/ethyl acetate = 15/1). Yellow solid (254 mg, 97%); mp 101−
102 °C; 1H NMR (400 MHz, CDCl3): δ = 7.68−7.65 (m, 1H), 7.51−
7.49 (m, 2H), 7.45−7.41 (m, 1H), 7.38−7.32 (m, 2H), 7.04 (ddd, J =
8.7, 6.4, 0.7 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ =
160.6, 157.2, 136.5, 132.4, 131.0, 128.7, 126.7, 124.9, 120.3, 117.7,
115.7 ppm; IR (neat): vmax 2966, 2852, 1251, 1021 cm−1; ESI-HRMS:
m/z [M + H]+ calcd for C13H835Cl2NO: 263.9977, found: 263.9974.
3-(Thiophen-3-yl)benzo[c]isoxazole (2q). The crude product
was purified by column chromatography on a silica gel (n-hexane/
ethyl acetate = 30/1). Yellow solid (80 mg, 40%); mp 89−90 °C; 1H
NMR (400 MHz, CDCl3): δ = 7.98 (dd, J = 3.0, 1.2 Hz, 1H), 7.74−
7.70 (m, 2H), 7.57 (d, J = 9.1 Hz, 1H), 7.50 (J = 5.1, 3.0 Hz, 1H),
7.30 (ddd, J = 9.1, 6.4, 0.9 Hz, 1H), 7.03 (ddd, J = 8.8, 6.4, 0.7 Hz,
1H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 157.3, 156.1,
153.2, 134.4, 133.4, 120.7, 119.0, 117.8, 53.1 ppm; IR (neat): vmax
2922, 2850, 1250, 1021 cm−1; ESI-HRMS: m/z [M + H]+ calcd for
C11H8NOS: 202.0321, found: 202.0320.
4-Methyl-3-(2-nitrophenyl)benzo[c]isoxazole (2r). The crude
product was purified by column chromatography on a silica gel (n-
hexane/ethyl acetate = 10/1). White solid (163 mg, 64%); mp 110−
111 °C; 1H NMR (400 MHz, CDCl3): δ = 8.28−8.26 (m, 1H), 7.83−
7.75 (m, 2H), 7.63−7.60 (m, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.22 (dd,
J = 9.1, 6.5 Hz, 1H), 6.74 (d, J = 6.5 Hz, 1H) ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ = 161.4, 157.9, 148.7, 133.3, 133.1, 131.8,
131.6, 130.4, 125.3, 124.3, 124.3, 117.4, 113.3, 19.3 ppm; IR (neat):
vmax 2924, 2852, 1630 cm−1; ESI-HRMS: m/z [M + H]+ calcd for
C14H11N2O3: 255.0764, found: 255.0766.
sı
1H and 13C NMR spectra for compounds 2a−v (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Chuanjun Song − College of Chemistry and Green Catalysis
Center, Zhengzhou University, Zhengzhou 450001, China;
orcid.org/0000-0001-7733-578X; Email: chjsong@
zzu.edu.cn
Authors
Mengge Zhang − College of Chemistry and Green Catalysis
Center, Zhengzhou University, Zhengzhou 450001, China
Yonggang Meng − College of Chemistry and Green Catalysis
Center, Zhengzhou University, Zhengzhou 450001, China
Yangang Wu − College of Chemistry and Green Catalysis
Center, Zhengzhou University, Zhengzhou 450001, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00091
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful to NSFC-Henan (U1804283) for
financial support.
3-Methylbenzo[c]isoxazole (2s). The crude product was
■
purified by column chromatography on a silica gel (n-hexane/ethyl
1
acetate = 8/1). Colorless oil (77 mg, 58%); H NMR (400 MHz,
CDCl3): δ = 7.51−7.48 (m, 1H), 7.43−7.41 (m, 1H), 7.25 (ddd, J =
9.1, 6.4, 0.9 Hz, 1H), 6.91 (dd, J = 8.8, 6.4 Hz, 1H), 2.78 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 165.8, 157.2, 130.9,
122.9, 120.0, 115.8, 115.0, 12.1 ppm; IR (neat): vmax 2922, 2859, 1072
cm−1; ESI-HRMS: m/z [M + H]+ calcd for C8H8NO: 134.0600,
found: 134.0596.
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ethyl acetate = 6/1). White solid (105 mg, 65%); mp 209−210 °C;
1H NMR (400 MHz, DMSO-d6): δ = 8.64 (s, 1H), 8.18 (s, 1H), 7.95
(d, J = 8.8 Hz, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.49 (ddd, J = 9.1, 6.4,
0.9 Hz, 1H), 7.26 (ddd, J = 8.8, 6.4, 0.9 Hz, 1H) ppm; 13C{1H} NMR
7330
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