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Xiong et al.
2-Amino-5-methoxybenzonitrile (7)
To a stirred solution of 6 (5.15 g, 28.4 mmol) in anhydrous EtOAc (30 mL) was added 10%
Pd-C (0.5 g), and the mixture was hydrogenated under atmospheric pressure of hydrogen
◦
for 3.5 h at 25 C. The mixture was passed through the Celite pad and the solid was rinsed
with EtOAc (2 × 5 mL). The combined filtrate was concentrated in vacuo to afford 7 (4.24
◦
9
◦
g, 99% yield, 99% purity by GC) as a light yellow solid, m.p. 46–47 C ( Lit: 47 C);
1
H-NMR (400 MHz, CDCl3): δ 6.96 (dd, J = 8.8, 2.8 Hz, 1H, H-4), 6.85 (d, J = 2.8 Hz,
1
(
H, H-6), 6.69 (d, J = 8.8 Hz, 1H, H-3), 4.23 (s, 2H, NH2), 3.73 (s, 3H, OCH3), EI-MS
+
+
+
1
m/z): 148(M ), 133(M -CH3), 105(M -CH3-CO). The H-NMR is agreement with the
9
data given in the literature.
2-Amino-5-methoxypropiophenone (8)
To a stirred solution of Grignard reagent [prepared from ethyl bromine (12.45 g, 114.1
mmol) and magnesium powder (2.88 g, 119.7 mmol) in dry THF (20 mL) with stirring
at reflux for 50 min under nitrogen] was added a solution of 7 (4.2 g, 28.5 mmol) in dry
◦
THF (25 mL), while the internal reaction temperature was maintained below 5 C. After
completion of the addition, the reaction mixture was stirred at room temperature for 6
◦
h, then cooled to 0 C, and the reaction was quenched by adding 15% aq. HCl (30 mL).
The resulting mixture was stirred at room temperature for 2 h, and the pH of the aqueous
solution was adjusted to 7 by adding 30% aq. NaOH, then extracted with EtOAc (3 ×
1
5 mL). The organic layer was washed with water (2 × 10 mL) and saturated aq. NaCl
(10 mL), then dried over Na2SO4. The solvent was concentrated in vacuo and dried under
◦
reduced pressure for 5 h at 40 C to give a mixture of 8 and 9 (5.02 g, 8/9 = 90:10, ratio
of GC purity) as a pale yellow solid, and the crude product was recrystallized from EtOH
◦
10
to provide 4.2 g (80% yield) of pure 8 as pale yellow needles, m.p. 63.5–64.5 C ( Lit:
◦
1
6
6 C) H-NMR (400 MHz, DMSO): δ 7.22 (d, J = 2.8 Hz, 1H, H-6), 6.98 (dd, J = 9.2,
2
.8 Hz, 1H, H-4), 6.82 (s, 2H, NH2), 6.74 (d, J = 8.8 Hz, 1H, H-3), 3.71 (s, 3H, OCH3),
+
2.96 (q, J = 21.6 Hz, 2H, CH2), 1.07 (t, J = 14.4 Hz, 3H, CH3), EI-MS (m/z): 179(M ),
+ + +
1
164(M -CH3), 150(M -CH2CH3),122(M -COCH2CH3). The H-NMR is agreement with
10
the data given in the literature.
Although compound 2 was obtained directly from the mixture of 8/9 (see below),
◦
Compound 9 was isolated as a white solid, mp. 127.4–128.6 C, via purification by column
1
chromatography on silica gel (20:1 petroleum ether/ethyl acetate). H-NMR (400 MHz,
CDCl3): δ 6.7 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.8, 2.8 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H),
1
3
3
.70 (s, 3H), 2.09 (q, J = 14.8 Hz, 2H), 0.95 (t, J = 14.4, 3H). C-NMR (400 MHz, CDCl3):
δ 153.1(C N), 137.6(C-O), 128.5(C-N), 117.7(C-1), 113.6(C-3), 110.5(C-4), 67.2(C-6),
5.7(-OCH3), 32.5(-CH2 of Et), 7.9(-CH3 of Et). EI-MS (m/z): 322(M ), 307(M -CH3),
+
+
5
2
+
92(M -CH3- CH3).
Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.58; H, 6.82; N,
8.61
2-Amino-5-hydroxypropiophenone (2)
A mixture of 8 and 9 (4.73 g, 26.3 mmol) in 47% aq. HBr (30 mL) was stirred under
◦
reflux for 3.5 h, and cooled to 5 C, stirring was continued at this temperature for 1 h. The