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57
solution, which was stirred for another 1 h. The pyridine was
removed from the solution by mixing the solution with aqueous
cupric sulfate; then the organic phase was extracted using ethyl
acetate. The extract was dried using anhydrous sodium sulfate, and
the solution was evaporated in vacuo. The crude product was
purified by performing column chromatography (SiO2; 2:8 EtOAc/
hexane). The purified product was obtained as colorless and
Synthesis of 1-methylethyl 2-amino-4-(2-methylpropanamido)
benzoate: 1-methylethyl-2-nitro-4-(2-methylpropanamido) ben-
zoate (739 mg, 2.5 mmol) and ammonium chloride (1.038 g,
19.0 mmol) were dissolved in methanol; then zinc powder
(1.65 g, 25 mmol) was added and the mixture was stirred for
19 h. Then the mixture was extracted with ethyl acetate, dried
using anhydrous sodium sulfate, and evaporated in vacuo. The
crude product was purified by performing column chromatogra-
phy (SiO2; 4:6 EtOAc/hexane). The target amine was obtained as a
transparent crystals (85 mg, 73%).1H NMR (400 MHz, CD3Cl)
(1H, s), 7.72 (1H, d, J = 7.8 Hz), 7.65 (1H, brs), 7.35 (2H, m). 13C NMR
(100 MHz, CD3Cl) : 176.60, 138.56, 130.97 (q, J = 32 Hz), 129.15,
d: 7.85
d
brown solid (428.5 mg, 65%). 1H NMR (400 MHz, CD3Cl) : 7.79 (1H,
d
123.7 (q, J = 271 Hz), 123.21, 120.50 (q, J = 4 Hz), 116.88 (q, J = 4 Hz),
36.18, 19.23. IR (KBr) cmꢁ1: 3252, 1664, 1448, 1337. MS (EI) m/z 231
(M+), 212 (M+ ꢁ F), 188 (M+ ꢁ CH(CH3)2), 161 (MH+ ꢁ COCH(CH3)2,
base peak), 71 ((CH3)2CHCO+), 43 ((CH3)2CH+).
d, J = 2.6 Hz), 7.58 (1H, dd, J = 2.6, 8.6 Hz), 6.97 (1H, brs), 6.65 (1H, d,
J = 8.8 Hz), 5.66 (1H, brs), 5.22 (1H, sep, J = 6.2 Hz), 2.48 (1H, sep,
J = 6.9 Hz), 1.37 (6H, d, J = 6.2 Hz), 1.20 (6H, d, J = 6.9 Hz). 13C NMR
(100 MHz, CD3Cl) d: 175.27, 167.12, 147.36, 127.94, 127.07, 122.81,
116.98,110.92, 67.72, 36.09, 21.81,19.50. IR (KBr) cmꢁ1: 3363, 3290,
1656, 1574, 1239. MS (EI) m/z 264 (M+), 221 (M+ ꢁ CH(CH3)2), 152
(MH+ ꢁ COCH(CH3)2, base peak).
2.3.3. Synthesis of N-[4-amino-3-(trifluoromethyl) phenyl]2-
methylpropaneamide (product 4)
Flutamide (0.996 g, 0.36 mmol) and ammonium chloride
(1.079 g, 20.2 mmol) were dissolved in 46 mL methanol, and zinc
powder (3.56 g, 54.6 mmol) was added. The reaction mixture was
stirred for about 1 h at room temperature and filtered. The filtrate
was washed with hot water and extracted with ethyl acetate; then
the extract was dried using anhydrous sodium sulfate. After
evaporation in vacuo, brown crystals of the pure product were
2.4. Internal irradiation experiment
Isolation of N-[4-hydroxy 3-nitro-5-(trifluoromethyl) phenyl]2-
methylpropaneamide (product 2): Flutamide was converted into
product 2 when an aerated acetonitrile solution of the starting
material (1.8 ꢀ 10ꢁ3 M) was irradiated with UV light from a high
pressure mercury arc (UVL-100HA-100P; Riko). The reaction
mixture obtained after photolysis had been performed was
evaporated in vacuo; then the precipitate was purified by
performing column chromatography (SiO2; 2:8 EtOAc/hexane) to
obtained without any purification. 1H NMR (400 MHz, CD3Cl)
7.71 (1H, brs), 7.53 (1H, d, J = 2.3 Hz), 7.41 (1H, dd, J = 2.3, 8.6 Hz), 6.65
(1H, d, J = 8.6 Hz), 2.49 (1H, sep, J = 6.9 Hz), 1.20 (6H, d, J = 6.9 Hz). 13
NMR (100 MHz, CD3Cl) : 175.88, 141.22, 128.25, 126.12, 124.40 (q,
d:
C
d
J = 271 Hz), 118.18 (q, J = 5 Hz), 117.48, 113.51 (q, J = 30 Hz), 36.01,
19.36. IR (KBr) cmꢁ1: 3403, 3273, 1633, 1509, 1102. MS (EI) m/z 246
(M+), 227 (M+ ꢁ F), 176 (MH+ ꢁ COCH(CH3)2, base peak), 71
((CH3)2CHCO+), 43 ((CH3)2CH+).
give 43 mg of the photoproduct. 1H NMR (400 MHz, CD3OD)
d:
10.96 (1H, s), 8.60 (1H, d, J = 2.8 Hz), 8.10 (1H, d, J = 2.8 Hz), 7.82 (1H,
s), 2.58 (1H, sep, J = 6.8 Hz) 1.27 (6H, d, J = 6.8 Hz). 13C NMR
(100 MHz, CD3OD)
d: 178.64, 149.52, 135.50, 132.06, 127.18 (q,
J = 5 Hz), 123.66 (q, J = 271 Hz), 121.60 (q, J = 31 Hz), 119.76, 36.98,
2.3.4. Synthesis of 1-methylethyl-2-amino-4-(2-methylpropanamido)
benzoate (product 5)
19.67. IR (KBr) cmꢁ1: 3301, 1671, 1538, 1146. HRMS (FAB+) m/z
The authentic compound matching product 5 was synthesized
using the three-stage procedure described below.
Synthesis of 4-(2-methylpropanamido)-2-nitrobenzoic acid: 2-
methylpropanoyl chloride (0.70 mL, 6.7 mmol) was added drop-
wise to 5-amino-2-nitrobenzoic acid (1.01 g, 5.55 mmol) in
pyridine, and the mixture was stirred for 24 h. The pyridine was
removed by mixing the reaction mixture with aqueous cupric
sulfate, and the organic phase was extracted using ethyl acetate.
The extract was dried using anhydrous sodium sulfate and
evaporated in vacuo. The crude product was purified by performing
column chromatography, although the target amide was not
completely separated from the other products.
Synthesis of 1-methylethyl 2-nitro-4-(2-methylpropanamido)
benzoate: the crude 4-(2-methylpropanamido)-2-nitrobenzoic
acid (1.73 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride (2.63 g, 13.7 mmol), and N,N0-dimethyl-4-amino-
pyridine (1.67 g, 13.7 mmol) were dissolved in 15 mL dimethylfor-
mamide and 2-propanol (1.6 mL, 21 mmol) was gradually added
dropwise to the solution. After a 24 h stirring, the reaction mixture
was extracted with ethyl acetate. The extract was dried using
anhydrous sodium sulfate and the organic phase was evaporated in
vacuo. The crude product was purified by performing column
chromatography (SiO2; 4:6 EtOAc/hexane). The target ester was
obtained as a brown solid (739 mg, 45%). 1H NMR (400 MHz, CD3Cl)
d
: 8.30 (1H, brs), 7.94 (1H, d, J = 8.8 Hz), 7.83 (1H, dd, J = 2.0, 8.8 Hz),
7.79 (1H, d, J = 2.0 Hz), 5.22 (1H, sep, J = 6.4 Hz), 2.53 (1H, sep,
J = 6.8 Hz), 1.31 (6H, d, J = 6.4 Hz), 1.19 (6H, d, J = 6.8 Hz). 13C NMR
(100 MHz, CD3Cl) d: 176.18, 165.87, 143.23, 141.40, 130.53, 125.62,
Fig.1. The time course of absorption spectra for flutamide in (a) aerated acetonitrile
and (b) deaerated acetonitrile. The photoreactions were monitored at 5 min
intervals. The arrows in each spectrum represent the direction in which the
absorption intensity is changing.
120.28, 118.76, 70.70, 36.49, 21.20, 19.18. .MS (EI) m/z 294 (M+), 224
(MH+ ꢁ COCH(CH3)2, base peak), 71 ((CH3)2CHCO+), 43
((CH3)2CH+).