1032
A. D. Clark et al.
Ethyl 4-Nitrobenzoylacetate
recrystallized from a mixture of dichloromethane and hexane, giving
the desired product as a yellow powder, m.p. 181–183°C (339 mg,
67%) (Found: M+•, 248.0436. C11H8N2O5 requires M+•, 248.0433). 1H
n.m.r. ␦ 2.50, s, 3H; 5.81, s, 1H; 7.76, d, J 11 Hz, 2H; 8.31, d, J 11 Hz,
2H. 13C n.m.r. ␦ 22.27, CH3; 97.56, C 4; 122.90, ArCH; 129.39, ArCH;
The general procedure of Rathke20 was modified, as 4-nitrobenzoyl
chloride was found to be too reactive under the standard reaction con-
ditions, reacting both with the N-isopropylcyclohexylamine to give the
amide, and with the ethyl 4-nitrobenzoylacetate to afford the bis adduct,
diethyl 3-hydroxy-3-(4-nitrophenyl)pentanedioate. Accordingly it was
replaced with ethyl 4-nitrobenzoate.
133.11, ArC; 148.76, C 3; 157.91, ArC; 164.79, CO; 164.97, CO.
max
1759, 1747, 1725, 1518, 1348 cm–1. Mass spectrum m/z 249 (M+1,
1%), 208 (6.9), 206 (5.4), 204 (4.2), 148 (6.2), 147 (3.6), 101 (12), 75
(13), 43 (100).
To a rapidly stirred solution of N-isopropylcyclohexylamine (4.30
ml, 26.18 mmol) in tetrahydrofuran (25 ml) under nitrogen at –80°C
was added n-butyllithium (1.6 M, 16.4 ml), followed after 10 min by
ethyl acetate (2.55 ml, 26.18 mmol). The mixture was maintained
below –80°C for 5 min, after which time ethyl 4-nitrobenzoate (5.11 g,
26.18 mmol) was introduced. The mixture was stirred at –80°C for 10
min, then quenched with 20% hydrochloric acid (25 ml) and briefly
shaken with ether (20 ml) and water (20 ml). The organic layer was
removed, dried and concentrated, affording the product as a pale yellow
solid, m.p. 65–70oC (lit.21 73–74oC) (5.36 g, 86%), which was used
without further purification.
2-Acetyl-3-phenyl[3-13C]isoxazol-5(2H)-one
3-Phenyl[3-13C]isoxazol-5(4H)-one (400 mg, 2.48 mmol) and
acetic anhydride (4 ml) were heated at 100°C for 17 h. The solvent was
removed under reduced pressure and the crude product recrystallized
from a mixture of dichloromethane and hexane, giving the desired
product as colourless needles (339 mg, 67%), m.p. 132–134°C (lit.11
137–138°C). 13C n.m.r. ␦ 22.89, CH3; 96.26, d, J 70.6 Hz, CH; 127.38,
d, J 62.0 Hz, ArC; 128.20, d, J 4.8 Hz, ArCH; 128.54, d, J 2.9 Hz,
ArCH; 131.44, ArCH; 160.35, CO; 161.12, C 3*; 165.59, d, J 51.5 Hz,
CO.
3-(4-Nitrophenyl)isoxazol-5(4H)-one
Ethyl 4-nitrobenzoylacetate (734 mg, 3.80 mmol) and hydroxyl-
amine hydrochloride (800 mg, 11.5 mmol) were heated in water (4 ml)
at 100°C for 5 min. Ethanol (4.5 ml) was added and heating continued
for 30 min. The mixture was cooled, and then chilled. Filtration afforded
the pure product as a yellow powder, m.p. 145–148°C (402 mg, 66%)
Pyrolysis of 2-Acetyl-3-phenylisoxazol-5(2H)-one
(i) At 600°C.
2-Acetyl-3-phenylisoxazol-5(2H)-one (100 mg,
0.49 mmol) was pyrolysed by sublimation (80°C, 0.1 mmHg) through
the f.v.p. furnace by the general procedure,9 with methanol in the cold
trap. The contents of the trap were heated for 2 min and the product
mixture (71 mg) was then separated by radial chromatography on silica
to give 2-methyl-4-phenyloxazole (42 mg, 54%), acetanilide (12 mg,
18%), benzonitrile (5.4 mg, 11%), dimethyl malonate (3.0 mg, 5%), 2-
phenylpropionitrile (trace; identified by g.c.–m.s. only) and phenylace-
tonitrile (7.8 mg, 14%). The identity of each fraction was confirmed by
1H and 13C n.m.r. spectroscopy, and by g.c.–m.s. comparison with
authentic samples.
1
(Found: M+•, 206.0327. C9H6N2O4 requires M+•, 206.0328). H n.m.r.
(1: 6 CDCl3/(CD3)2SO) ␦ 5.41 s, 2H; 7.95, m, 2H; 8.30, m, 2H. 13C
n.m.r. (1 :6 CDCl3/(CD3)2SO) ␦ 32.76, C4; 122.65, ArCH; 126.09,
ArCH; 126.70, ArC; 147.27, ArC; 160.70, C 3; 173.89, CO. max 1816,
1524, 1351, 1319 cm–1. Mass spectrum m/z 208 (M+2, 5.4%), 207 (11),
206 (72), 164 (23), 148 (100), 118 (14), 102 (46), 90 (26).
2-Acetyl-3-(4-chlorophenyl)isoxazol-5(2H)-one
3-(4-Chlorophenyl)isoxazol-5(4H)-one (667 mg, 3.40 mmol) and
acetic anhydride (10 ml) were heated at 100°C for 15 h. The solution
was chilled, a process depositing the crude product as a crystalline
solid, which was recrystallized from ethanol. This gave the title com-
pound as faintly pink needles, m.p. 147–149°C (226 mg, 28%).
Evaporation of the acetic anhydride gave a further 60% after recrystal-
lization (Found: C, 55.6; H, 3.5; N, 5.8; M+•, 237.0194. C11H8ClNO3
requires C, 55.6; H, 3.4; N, 5.9%; M+•, 237.0193). 1H n.m.r. ␦ 2.48, s,
3H; 5.59, s, 1H; 7.44, m, 4H. 13C n.m.r. ␦ 22.97, CH3; 96.62, CH; 126.0,
ArC; 128.69, ArCH; 129.99, ArCH; 137.91, ArC; 160.04, C 3; 165.54,
CO; 165.78, CO. max 3107, 1784, 1732, 1601, 1412, 1284 cm–1. Mass
spectrum m/z 239 (M+2, 2.5%), 238 (1.4), 237 (7.0), 197 (2.7), 195
(7.7), 152 (1.6), 150 (3.4), 139 (8.6), 138 (4.5), 137 (9.8), 43 (100).
(ii) At 700°C. 2-Acetyl-3-phenylisoxazol-5(2H)-one (100 mg,
0.49 mmol) was pyrolysed to give a product (60 mg) which contained
2-methyl-4-phenyloxazole (30 mg, 38%), acetanilide (11 mg, 17%),
benzonitrile (4.7 mg, 9%), dimethyl malonate (1.3 mg, 2%), 2-phenyl-
propionitrile (1 mg, 2%), phenylacetonitrile (11 mg, 19%) and iso-
quinoline (0.6 mg, 1%).
(iii) At 750°C. 2-Acetyl-3-phenylisoxazol-5(2H)-one (100 mg,
0.49 mmol) was pyrolysed to give a product (42 mg) consisting of 2-
methyl-4-phenyloxazole (15 mg, 20%), acetanilide (6.5 mg, 10%), ben-
zonitrile (8.0 mg, 16%), dimethyl malonate (2.3 mg, 7%),
2-phenylpropionitrile (1.5 mg, 2%), phenylacetonitrile (7.2 mg, 13%)
and isoquinoline (1 mg, 2%).
(iv) At 800°C. 2-Acetyl-3-phenylisoxazol-5(2H)-one (100 mg,
0.49 mmol) gave a product (17 mg) containing 2-methyl-4-phenyloxa-
zole (2.7 mg, 3%), acetanilide (2.2 mg, 3%), benzonitrile (2.2 mg, 4%),
2-phenylpropionitrile (0.6 mg, 1%), phenylacetonitrile (4.6 mg, 8%)
and isoquinoline (4.7 mg, 7%).
2-Acetyl-3-(4-methoxyphenyl)isoxazol-5(2H)-one
3-(4-Methoxyphenyl)isoxazol-5(2H)-one (576 mg, 3.00 mmol) and
acetic anhydride (5 ml) were heated at 100°C for 15 h. The mixture was
chilled and the crystalline product collected by filtration, then recrys-
tallized from ethanol, giving the desired product as colourless needles,
m.p. 131–133°C (189 mg, 27%). A further 57% could be obtained from
the acetic anhydride (Found: C, 61.5; H, 4.6; N, 6.0%; M+•, 233.0691.
C12H11NO4 requires C, 61.8; H, 4.75; N, 6.0%; M+•, 233.0688). 1H
n.m.r. ␦ 2.43, s, 3H; 3.83, s, 3H; 5.52, s, 1H; 6.92, d, J 9 Hz, 2H; 7.47,
d, J 9 Hz, 2H. 13C n.m.r. ␦ 22.70, CH3; 54.95, OCH3; 94.70, C 4; 113.31,
ArCH; 119.14, ArC; 130.35, ArCH; 161.03, C 3; 162.03, ArC; 165.41,
CO; 165.29, CO. max 1778, 1724, 1612 cm–1. Mass spectrum m/z 233
(M, 1.4%), 191 (7.3), 165 (2.9), 150 (2.2), 135 (18), 133 (4.7), 123
(3.9), 43 (100).
Pyrolysis of 2-Acetyl-3-phenyl[3-13C]isoxazol-5(2H)-one
2-Acetyl-3-phenyl[3-13C]isoxazol-5(2H)-one (100 mg, 0.49 mmol)
was pyrolysed at 600°C by the general method. The product mixture
1
(71 mg) was analysed by g.c.–m.s. and by H and 13C n.m.r. spec-
troscopy. 2-Methyl-4-phenyl[4-13C]oxazole (62 mg, 78%) and
acetanilide (8 mg, 12%) were isolated by chromatography; the presence
of [cyano-13C]benzonitrile (1.5 mg, 2%) and phenyl[1-13C]acetonitrile
(2.2 mg, 4%) was deduced by g.c.–m.s.
At 750oC the product mixture contained 2-methyl-4-phenyl[4-
13C]oxazole (4%), acetanilide (12%), [cyano-13C]benzonitrile (25%),
[1-13C]isoquinoline (1.3%), phenyl[1-13C]acetonitrile (18%) and a
trace of dimethyl malonate, labelled at one carbonyl carbon.
2-Acetyl-(4-nitrophenyl)isoxazol-5(2H)-one
3-(4-Nitrophenyl)isoxazol-5(4H)-one (400 mg, 2.48 mmol) and
acetic anhydride (4 ml) were heated at 100°C for 17 h. The solvent was
removed under reduced pressure and the crystalline crude product
2-Methyl-4-phenyl[4-13C]oxazole. 1H n.m.r. ␦ 2.51, s, 3H; 7.29, t,
J 7.2 Hz, 1H; 7.39, t, J 7.5 Hz, 2H; 7.70, m, 2H; 7.80, d, J 14.4 Hz, 1H.
13C n.m.r. ␦ 13.79, d, J 3.4 Hz; 125.45, d, J 2.03 Hz, ArCH; 127.98,
* Resonances bearing asterisks indicate 13C labelling at this position.