Synthesis of 3-phenylbenzo[c]isoxazoles
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 6, June, 2019
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(Carom), 120.7 (Carom), 124.7 (—CH=), 126.8 (—CH=), 128.6
(Carom), 129.4 (Carom), 130.4 (Carom), 130.8 (Carom), 158.0
(=C—O), 164.6 (C=N). MS, m/z (Irel (%)): 196 (13), 195 (71)
[M]+, 168 (12), 167 (90), 166 (44), 140 (24), 139 (37), 105 (20),
92 (16), 77 (100), 64 (14), 63 (22), 51 (36), 50 (17). Found (%):
C, 80.12; H, 4.73; N, 7.05. C13H9NO. Calculated (%): C, 79.98;
H, 4.65; N, 7.17.
5-Bromo-3-phenylbenzo[c]isoxazole (2b). Yield 107 mg
(99%), yellow crystals. M.p. 114 °C. 1Н NMR, δ: 7.37 (dd, 1 H,
H(6), J = 9.4 Hz, J = 1.6 Hz); 7.61—7.49 (m, 4 H); 8.00—7.95
(m, 2 H); 8.03 (dd, 1 Harom, J = 1.7 Hz, J = 0.9 Hz). 13C NMR,
δ: 115.5 (—CH=), 117.3 (Carom), 118.4 (Carom), 122.7 (—CBr=),
126.7 (—CH=), 128.0 (Carom), 129.5 (Carom), 130.8 (Carom),
134.7 (Carom), 156.4 (=C—O), 164.3 (C=N). MS, m/z (Irel (%)):
275 (29) [M(81Br)]+, 273 (29) [M(79Br)]+, 194 (22), 166 (54),
165 (9), 164 (8), 140 (17), 139 (23), 105 (14), 89 (9), 88 (15), 87
(9), 77 (100), 76 (13), 75 (10), 74 (11), 63 (15), 62 (16), 51 (43),
50 (12). Found (%): C, 57.23; H, 3.01; N, 4.93. C13H8BrNO.
Calculated (%): C, 56.96; H, 2.94; N, 5.11.
Benzo[c]isoxazoles were obtained in a series of solvents
with a change in temperature and duration of hetero-
cyclization in the absence of catalysts. We have found that
during thermolysis of 2-azidobenzophenones 1a—c, benzo-
[c]isoxazoles 2a—c are formed with quantitative yields in
o-, m-, p-xylenes (Scheme 2). A decrease in the product
yield was observed when changing the solvent: toluene
(70%), benzene (50%), DMF (30%). The yields of com-
pounds 2a—c were significantly lower when the flask was
overheated above 140 °C, or in moist solvents.
During the thermolysis of azidobenzaldehyde 1d, benzo-
[c]isoxazole was formed in trace amounts, while 2-azido-
benzoic acid esters 1e,f remained intact under these
conditions. In the presence of water, esters 1e,f underwent
thermolysis with the formation of a number of products
with low yields, the main of which were the correspond-
ing amines.
As discussed earlier,20—22 the formation of the N—O
bond of the isoxazole cycle occurs during 6π-electro-
cyclization with the nucleophilic attack of the carbonyl
oxygen atom on the nitrene atom and the simultaneous
elimination of the nitrogen molecule. An indirect evidence
of this assumption is the thermal stability of esters 1e,f,
which is explained by the low nucleophilicity of the ester
oxygen atom. In wet solvents, a competitive nucleophilic
attack of water on the nitrene nitrogen atom of the azide
group changes the reaction path and causes decrease in
the yield of benzo[c]isoxazoles.
5-Iodo-3-phenylbenzo[c]isoxazole (2c). Yield 126 mg (98%),
light pink crystals. M.p. 120 °C. 1Н NMR, δ: 7.40 (dd, 1 H,
H (6), J = 9.4 Hz, J = 1.0 Hz); 7.61—7.48 (m, 4 H); 7.98 (dt, 2 H,
J = 8.1 Hz, J = 1.2 Hz); 8.29 (d, 1 Harom, J = 1.2 Hz). 13C NMR,
δ: 89.2 (—CI=), 116.6 (Carom), 117.2 (—CH=), 126.8 (—CH=),
128.0 (Carom), 129.5 (Carom), 129.7 (Carom), 130.8 (Carom), 139.3
(Carom), 156.3 (=C—O), 163.9 (C=N). MS, m/z (Irel (%)): 322
(10), 321 (100) [M]+, 194 (24), 167 (10), 166 (72), 165 (8), 164
(7), 140 (20), 139 (27), 105 (8), 89 (7), 88 (6), 83 (9), 77 (61),
76 (6), 74 (5), 70 (6), 63 (8), 62 (9), 51 (22). Found (%):
C, 48.73; H, 2.63; N, 4.23. C13H8INO. Calculated (%): C, 48.62;
H, 2.51; N, 4.36.
This work was financially supported by the Ministry of
Education and Science of the Russian Federation within
the framework of the basic part of the state assignment
of the State University of Nizhni Novgorod (Project
No. 4.5706.2017/BC).
Experimental
1Н and 13C NMR spectra were recorded on a Varian 400 MR
spectrometer (400 and 100 MHz, respectively) in CDCl3. The
chemical shifts are given relative to the solvent peak (CDCl3:
7.26 ppm for 1H and 77.16 ppm for 13C). Mass spectra were
recorded on the Thermo Electron DSQ II device, EI ionization
(70 eV), direct input. A control of azide conversion and accu-
mulation of the reaction products was carried out by HPLC on
a Shimadzu LC-20AD instrument with an SPD-M20A detector,
20 μL loop (Discovery C-18 column, 5 μm, d = 3 mm, l = 25 cm,
gradient elution of the ethanol (10%)—water (90%) system with
a linear decrease in 25 minutes to 0% water and continu-
ing elution with ethanol for 60 minutes. The flow rate was
0.15 mL min–1). Elemental analysis was performed on a Vario
Micro cube Elementar CHNS analyzer. Aromatic azides were
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synthesized according to the procedure described in19
.
Synthesis of 3-phenylbenzo[c]isoxazoles 2a—c (general pro-
cedure). In dry o-xylene (2 mL), azide 1a—c (0.4 mmol) was
stirred in an oil bath at 135 °C for 1 h without air moisture access.
The solvent was removed under reduced pressure, the product
was recrystallized from hexane.
3-Phenylbenzo[c]isoxazole (2a). Yield 77 mg (99%), yellow
crystals. M.p. 52 °C. 1Н NMR, δ: 7.06 (dd, 1 H, H (5), J = 8.9 Hz,
J = 6.4 Hz); 7.33 (dd, 1 H, H (6), J = 9.0 Hz, J = 6.4 Hz);
7.53—7.46 (m, 1 H); 7.59—7.53 (m, 2 H); 7.62 (d, 1 Harom
,
,
J = 9.1 Hz); 7.84 (d, 1 Harom, J = 8.8 Hz); 8.03 (dd, 2 Harom
J = 7.1 Hz, J = 1.4 Hz). 13C NMR, δ: 114.5 (—CH=), 115.7