C. J. Easton et al.
water (5.5 mL) were treated with 4-tert-butylbenzohydroximinoyl chlor-
ide (1.1 mol equiv dissolved in 0.1 mL ethanol), and the mixtures were
stirred at 258C for 1 h before triethylamine (1.2 mol equiv) was added
over a period of 1 h. The mixtures were then stirred for 15 h before being
diluted with water/ethanol (1:4, v/v, 20 mL), washed with ethyl acetate
(330 mL), and concentrated under reduced pressure. The residues were
dissolved in aqueous sodium hydroxide (0.5m, 10 mL) and the solutions
were stirred at 258C for 2 h before being acidified with HCl and extract-
ed with ethyl acetate (330 mL). The extracts were dried (MgSO4) and
concentrated under reduced pressure, and the resulting residues were an-
alyzed by 1H NMR spectroscopy to determine the ratios of the cycload-
ducts 24x–z and 25x–z.
THF, and under much more dilute conditions, the isoxazoles 24x and 25x
were produced in the ratio 1:25.
3-(4-tert-Butylphenyl)-5-methyl-2-isoxazoline-5-carboxylic acid (25y):
The crude product obtained by using the general procedure comprised
only the acid 25y and none of the regioisomer 24y, as determined by
comparison with an authentic sample, obtained as described above. Chro-
matography of the crude product on silica, with elution by 0–2% metha-
nol in dichloromethane containing 1% acetic acid gave the isoxazoline
25y as a colorless solid (38%). M.p. 163–1668C partial, 195–1998C;
1H NMR (300 MHz, CDCl3): d=7.58 (d, J=8.9 Hz, 2H), 7.43 (d, J=
8.9 Hz, 2H), 3.88 (d, J=17.1 Hz, 1H), 3.28 (d, J=17.1 Hz, 1H), 1.76 (s,
3H), 1.32 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=175.2, 157.2,
154.3, 126.7, 125.8, 125.5, 85.8, 45.2, 34.9, 31.1, 23.21 ppm; MS (EI): m/z
(%): 261 (43) [M]+, 246 (56), 216 (76), 202 (54), 174 (85), 160 (62), 144
(100), 116 (68); elemental analysis calcd (%) for C15H19NO3: C 68.94, H
7.33, N 5.36; found: C 68.75, H 7.27, N 5.22.
3-(4-tert-Butylphenyl)-2-isoxazoline-4-carboxylic acid (24x): By using the
general procedure, the acids 24x and 25x were obtained as a 20:1 mix-
ture. The acid 25x was identified by comparison with an authentic
sample, obtained as described below. Chromatography of the mixture on
silica, with elution by 0–2% methanol in dichloromethane containing
1% acetic acid gave 24x as a colorless solid (43%). M.p. 116–1198C;
1H NMR (300 MHz, CDCl3): d=7.70 (d, J=8.7 Hz, 2H), 7.43 (d, J=
8.7 Hz, 2H), 4.86 (dd, J=5.8, 8.7 Hz, 1H), 4.63 (dd, J=8.7, 10.8 Hz, 1H),
4.51 (dd, J=5.8, 10.8 Hz, 1H), 1.33 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3): d=174.8, 154.8, 153.9, 126.9, 125.8, 125.2, 77.2, 73.4, 34.9,
31.1 ppm; MS (EI): m/z (%): 247 (33) [M]+, 232 (100); HRMS m/z:
calcd for C14H17NO3: 247.1208; found: 247.1205.
3-(4-tert-Butylphenyl)-4-methyl-2-isoxazoline-5-carboxylic acid (25z): By
using the general procedure, the acids 24z and 25z were obtained as a
1:1 mixture. The acid 24z was identified by comparison with an authentic
sample, obtained as described above. Chromatography of the mixture on
silica, with elution by 0–2% methanol in dichloromethane containing
1% acetic acid gave 25z as a colorless solid (10%). M.p. 132–1368C;
1H NMR (300 MHz, CDCl3): d=7.62 (d, J=8.7 Hz, 2H), 7.45 (d, J=
8.7 Hz, 2H), 4.79 (d, J=3.9 Hz, 1H), 4.06 (dq, J=3.9, 7.2 Hz, 1H), 1.45
(d, J=7.2 Hz, 3H), 1.33 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=
172.3, 160.9, 154.1, 127.2, 125.9, 124.4, 84.3, 77.2, 34.9, 31.1, 18.3 ppm; MS
(EI): m/z (%): 261 (30) [M]+, 246 (82), 216 (21), 144 (42), 84 (95), 66
(100), 57 (59); elemental analysis calcd (%) for C15H19NO3: C 68.94, H
7.33, N 5.36; found: C 68.72, H 7.06, N 5.26.
3-(4-tert-Butylphenyl)-4-methyl-2-isoxazoline-4-carboxylic acid (24y): By
using the general procedure, the acids 24y and 25y were obtained as a
1:10 mixture (55%). The acid 25y was identified by comparison with an
authentic sample, obtained as described below. In addition to the reso-
nances for the acid 25y, the 1H NMR spectrum of the mixture showed
signals characteristic of the regioisomer 24y. 1H NMR (300 MHz,
CDCl3): d=7.62 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 4.84 (d, J=
7.8 Hz, 1H), 4.37 (d, J=7.8 Hz, 1H), 1.66 (s, 3H), 1.32 ppm (s, 9H).
Methyl 3-(4-tert-butylphenyl)-2-isoxazoline-5-carboxylate and methyl 3-
(4-tert-butylphenyl)-2-isoxazoline-4-carboxylate: Methyl acrylate (65 mg,
0.76 mmol) and 4-tert-butylbenzohydroximinoyl chloride (40 mg,
0.19 mmol) were dissolved in THF (5 mL). The mixture was stirred at
258C and triethylamine (21 mg, 0.21 mmol) dissolved in THF (1 mL) was
added over a period of 20 h. The solution was then concentrated under
3-(4-tert-Butylphenyl)-5-methyl-2-isoxazoline-4-carboxylic acid (24z):
The crude product obtained by using the general procedure comprised of
only the acid 24z and none of the regioisomer 25z, as determined by
comparison with an authentic sample, obtained as described below. Chro-
matography of the crude product on silica, with elution by 0–2% metha-
nol in dichloromethane containing 1% acetic acid gave the isoxazoline
24z as a colorless solid (42%). M.p. 113–1158C; 1H NMR (300 MHz,
CDCl3): d=7.65 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 5.11 (m,
1H), 4.07 (d, J=5.7 Hz, 1H), 1.44 (d, J=6.3 Hz, 3H), 1.32 ppm (s, 9H);
13C NMR (125 MHz, CDCl3): d=172.9, 153.6, 153.5, 126.7, 125.8, 125.7,
82.1, 59.8, 34.8, 31.1, 20.8 ppm; MS (EI): m/z (%): 261 (43) [M]+, 24 6
(100), 202 (17), 160 (14), 57 (7); elemental analysis calcd (%) for
C15H19NO3: C 68.94, H 7.33, N 5.36; found: C 68.70, H 7.43, N 5.25.
1
reduced pressure and the residue was analyzed by H NMR spectroscopy.
This showed the presence of the title 3,5- and 3,4-disubstituted isoxazo-
lines in the ratio 25:1. The crude product was dissolved in dichlorome-
thane (10 mL) and the solution was washed with water (315 mL), dried
(MgSO4), and concentrated under reduced pressure. Chromatography of
the residue on silica, with elution by 0–10% ethyl acetate in hexanes
gave methyl 3-(4-tert-butylphenyl)-2-isoxazoline-5-carboxylate as a color-
less oil (26 mg, 53%). 1H NMR (300 MHz, CDCl3): d=7.61 (d, J=
8.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 5.18 (dd, J=10.2, 7.8 Hz, 1H), 3.81
(s, 3H), 3.64(m, 2H), 1.33 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=
170.8, 155.9, 154.0, 126.7, 125.7, 125.6, 77.8, 52.8, 39.1, 34.9, 31.1 ppm; MS
(EI): m/z (%): 261 (72) [M]+, 246 (100), 202 (91), 91 (32); HRMS m/z:
calcd for C15H19NO3: 261.1365; found: 261.1363. In addition to the reso-
General procedure for reactions of the acids 23x–z with 4-tert-butylben-
zonitrile oxide (2a): Solutions of the acids 23x–z (1.29 mmol) and 4-tert-
butylbenzohydroximinoyl chloride (1.42 mmol) in THF (15 mL) were
treated with triethylamine (1.55 mmol) in THF (1 mL) over a period of
20 h, then they were concentrated under reduced pressure. The residues
were analyzed by 1H NMR spectroscopy to determine the ratios of for-
mation of the cycloadducts 24x–z and 25x–z, before they were dissolved
in dichloromethane (20 mL). These solutions were washed with water
(250 mL) containing 1% acetic acid, dried (MgSO4), and concentrated
under reduced pressure.
1
nances for the 3,5-disubstituted isoxazoline, the H NMR spectrum of the
mixture showed signals characteristic of the 3,4-disubstituted regioisom-
er; 1H NMR (300 MHz, CDCl3): d=4.82 (dd, J=6.0, 8.8 Hz, 1H), 4.63
(dd, J=8.8, 11.4Hz, 1H), 4.51 ppm (dd, J=6.0, 11.4Hz, 1H).
p-Nitrophenyl acrylate (26): 1,3-Dicyclohexylcarbodiimide (1.03 g,
5.0 mmol) was added to a solution of p-nitrophenol (556 mg, 4.0 mmol)
and acrylic acid (23x; 0.27 mL, 4.0 mmol) in freshly distilled dichlorome-
thane (20 mL). 4-(Dimethylamino)pyridine (50 mg) was then added, and
the mixture was stirred at 258C for 18 h before being filtered. The filtrate
was concentrated under reduced pressure. The residue was chromato-
graphed on silica, with elution by 5–25% ethyl acetate in hexanes, to
give the ester 26 as a cream-colored solid (417 mg, 54%). M.p. 63–658C
(lit.[91] 61–648C); 1H NMR (300 MHz, CDCl3): d=8.30 (d, J=9.3 Hz,
2H), 7.34(d, J=9.3 Hz, 2H), 6.67 (d, J=17.1 Hz, 1H), 6.34(dd, J=10.5,
17.1 Hz, 1H), 6.11 ppm (dd, J=10.5 Hz, 1H); MS (EI): m/z (%): 193
(20) [M]+, 55 (100).
3-(4-tert-Butylphenyl)-2-isoxazoline-5-carboxylic acid (25x): By using the
general procedure, the acids 24x and 25x were obtained as a 1:20 mix-
ture. The acid 24x was identified by comparison with an authentic
sample, obtained as described above. Chromatography of the crude prod-
uct mixture on silica, with elution by 0–2% methanol in dichloromethane
containing 1% acetic acid, afforded 25x as a colorless solid (46%). M.p.
109–1128C; 1H NMR (300 MHz, CDCl3): d=7.61 (d, J=8.4Hz, 2H),
7.44 (d, J=8.4Hz, 2H), 5.20 (t, J=8.6 Hz, 1H), 3.70 (m, 2H), 1.33 ppm
(s, 9H); 13C NMR (75 MHz, CDCl3): d=172.1, 156.9, 154.7, 126.9, 125.9,
124.9, 77.2, 39.6, 35.0, 31.1 ppm; MS (EI): m/z (%): 247 (59) [M]+, 232
(95), 202 (100), 175 (42), 160 (71); elemental analysis calcd (%) for
C14H17NO3: C 67.51, H 6.96, N 5.62; found: C 67.47, H 6.94, N 5.47.
When the reaction was repeated in water/methanol (1:1, v/v) instead of
m-Nitrophenyl acrylate: The title compound was obtained by using the
procedure described above for the preparation of the para isomer, except
that m-nitrophenol was used as the starting alcohol. The ester was isolat-
ed as a cream-colored solid (465 mg, 60%). M.p. 35–368C (lit.[91] 34–
8578
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8571 – 8580