Article
J. Agric. Food Chem., Vol. 59, No. 2, 2011 639
3JHH = 7.7 Hz, Ph); 7.64 (d, 1H, 3JHH = 8.0 Hz, Ph); 7.29 (t, 1H, 3JHH
8.0 Hz, Ph); 7.07 (s, 1H, CH); 2.53 (s, 3H, CH3).
=
2.78 mmol) was reacted with sodium hydroxide solution (10 mL, 10%) to
give compound III-4 as a white solid (0.42 g, 91%), distilled at 180 °C
[lit. (27) mp 227-228 °C]; 1H NMR (CDCl3) δ 7.46 (d, 1H, 3JHH=8.2 Hz,
ArH); 7.03 (d, 1H, 3JHH=7.7 Hz, ArH); 6.90 (t, 1H, 3JHH=8.0 Hz, ArH);
6.14 (s, 2H, CH2).
Synthesis of N0-tert-Butyl-N-2-methylbenzofuran-4-carbohydrazide
(II-3). The procedure is the same as for the preparation of N0-tert-butyl-
2-methylbenzofuran-6-carbohydrazide (I-5). First, compound II-1 (0.60 g,
3.4 mmol) was reacted with thionyl chloride (3 mL) to give compound II-2.
Then compound II-2 was reacted with tert-butylhydrazine hydrochloride
(0.52 g, 4.1 mmol) and sodium hydroxide (0.22 g, 7.5 mmol) in dichlor-
omethane (30 mL) and water (4 mL) at -15 °C to give compound II-3 as a
white solid (0.64 g, 72%): mp 108-109 °C; 1H NMR (CDCl3) δ 7.53
(d, 1H, 3JHH =7.7Hz, Ph);7.51(d, 1H,3JHH = 7.2 Hz, Ph); 7.24 (t, 1H, 3JHH
=7.9 Hz, Ph); 6.82 (s, 1H, CH); 2.50 (s, 3H, CH3); 1.19 (s, 9H, C(CH3)3).
Synthesis of Methyl 2,3-Dihydro-2-methylbenzofuran-4-carboxylate
(II-4). The procedure is the same as for the preparation of 2,3-dihydro-
2-methylbenzofuran-6-carboxylate (I-6). Compound I-4a (1.53 g, 8.05
mmol) was reacted with 70 atm of hydrogen at room temperature with
10% palladium on activated carbon (0.2 g, 54% in water) as catalyst and
acetic acid (20 mL) as solvent for 24 h to give compound II-4 as a colorless
oil (0.38 g, 24%): 1H NMR (CDCl3) δ 7.49 (d, 1H, 3JHH = 7.8 Hz, Ph);
7.16 (t, 1H, 3JHH=7.9 Hz, Ph); 6.92 (d, 1H, 3JHH=7.8 Hz, Ph); 4.91-5.00
(m, 1H, CH); 3.89 (s, 3H, OCH3); 3.63-3.70 (m, 1H, CH2); 3.04-3.15 (m,
1H, CH2); 1.47 (d, 3H, 3JHH =6.3 Hz, CH3).
Synthesis of Methyl 2,3-Dihydrobenzo[1,4]dioxine-5-carboxylate (III-
6). After a mixture of 2,3-dihydroxybenzoate III-2 (2.00 g, 11.89 mmol),
potassium carbonate (4.92 g, 35.67 mmol), and N,N-dimethylformamide
(15 mL) had been stirred at room temperature for 2 h, a solution of 1,2-
dibromoethane (2.46 g, 13.08 mmol) in N,N-dimethylformamide (5 mL)
was added dropwise. After 5h of refluxing, water (30 mL) was added to the
reaction mixture, followed by extraction with ethyl acetate (3 ꢀ 50 mL).
The organic layer was washed successively with water (50 mL) and brine
(50 mL) and then dried over anhydrous sodium sulfate. After the solvent
had been removed under vacuum to give compound III-6 as a white crystal
(0.42 g, yield=18%): mp 58-60 °C; 1H NMR (400 MHz, CDCl3) δ 7.38
3
3
(d, 1H, JHH=7.8 Hz, ArH), 7.00 (d, 1H, JHH = 7.8 Hz, ArH), 6.84
3
(t, 1H, JHH = 7.8 Hz, ArH), 4.35-4.36 (m, 2H, OCH2), 4.27-4.29
(m, 2H, OCH2), 3.87 (s, 3H, OCH3).
Synthesis of 2,3-Dihydrobenzo[1,4]dioxine-5-carboxylic Acid (III-7).
The procedure is the same as for the preparation of 2-methylbenzofuran-6-
carboxylic acid (I-3). Methyl 2,3-dihydrobenzo[1,4]dioxine-5-carboxylate
III-6 (0.42 g, 2.16 mmol) was reacted with sodium hydroxide solution (10
mL, 10%) to give compound III-7 as a white solid (0.38 g, yield = 97%):
mp 202-204 °C [lit. (28) mp 195-196 °C]; 1H NMR (400 MHz, CDCl3) δ
10.27 (br s, 1H, COOH), 7.71 (d, 1H, 3JHH =7.9 Hz, ArH), 7.11 (d, 1H,
3JHH=8.0 Hz, ArH), 6.98 (t, 1H, 3JHH=7.9 Hz, ArH), 4.50-4.52 (m, 2H,
OCH2), 4.36-4.38 (m, 2H, OCH2).
Synthesis of Methyl Octahydro-2-methylbenzofuran-4-carboxylate (V-1).
The procedure is the same as for the preparation of 2,3-dihydro-
2-methylbenzofuran-6-carboxylate (I-6). Compound I-2b (7.00 g, 36.80
mmol) was reacted with 110 atm of hydrogen at 70 °C with 10% palladium
on activated carbon (4.0 g, 54% in water) as catalyst and acetic acid (100
mL) as solvent for 4 days to give compound V-1 as a colorless oil (1.48 g,
24%): 1H NMR (CDCl3) δ 4.04-4.13 (m, 1H, CH); 3.66 (s, 3H, OCH3);
2.66-2.77 (m, 1H, CH); 2.18-2.30 (m, 1H, CH); 1.30-1.97 (m, 9H, CH);
1.21 (d, 3H, 3JHH =6.2 Hz, CH3).
Synthesis of 2,3-Dihydro-2-methylbenzofuran-4-carboxylic Acid (II-5).
The procedure is the same as for the preparation of 2-methylbenzofuran-6-
carboxylic acid (I-3). Methyl 2,3-dihydro-2-methylbenzofuran-4-carbox-
ylate (II-4) (0.38 g, 1.97 mmol) was reacted with sodium hydroxide
solution (5 mL, 10%) to give compound II-5 as a white crystal (0.30 g,
86%): mp 165-166 °C; 1H NMR (CDCl3) δ 7.58 (d, 1H, 3JHH = 7.9 Hz,
3
3
Ph); 7.22 (t, 1H, JHH = 7.6 Hz, Ph); 6.98 (d, 1H, JHH = 7.9 Hz, Ph);
4.96-5.02 (m, 1H, CH); 3.69-3.75 (m, 1H, CH2); 3.14-3.21 (m, 1H,
CH2); 1.49 (d, 3H, 3JHH =6.2 Hz, CH3).
Synthesis of N0-tert-Butyl-N-2,3-dihydro-2-methylbenzofuran-4-carbo-
hydrazide (II-7). The procedure is the same as for the preparation ofN0-tert-
butyl-2-methylbenzofuran-6-carbohydrazide (I-5). First, compound II-5
(0.30 g, 1.68 mmol) was reacted with thionyl chloride (3 mL) to give
compound II-6. Then compound II-6 was reacted with tert-butylhydrazine
hydrochloride (0.26 g, 2.02 mmol) and sodium hydroxide (0.18 g, 5.42
mmol) in dichloromethane (20 mL) and water (5 mL) at -15 °C to give
compound II-7 as a white crystal (0.35 g, 83%): mp 69-70 °C; 1H NMR
(CDCl3) δ 7.17 (t, 1H, 3JHH = 7.9 Hz, Ph); 7.04 (d, 1H, 3JHH = 7.7 Hz,
Ph); 6.88 (d, 1H, 3JHH = 8.0 Hz, Ph); 4.99-5.02 (m, 1H, CH); 3.57-3.64
(m, 1H, CH2); 3.04-3.11 (m, 1H, CH2); 1.48 (d, 3H, 3JHH = 6.2 Hz, CH3);
1.16 (s, 9H, C(CH3)3).
Synthesis of Octahydro-2-methylbenzofuran-4-carboxylic Acid (V-2).
The procedure is the same as for the preparation of 2-methylbenzofuran-6-
carboxylic acid (I-3). Compound V-1 (1.48 g, 7.46 mmol) was reacted with
sodium hydroxide solution (30 mL, 10%) to give compound V-2 as a
colorless oil (1.18 g, 86%): 1H NMR (CDCl3) δ 10.54 (br, 1H, COOH);
4.02-4.17 (m, 1H, CH); 2.70-2.78 (m, 1H, CH); 2.22-2.33 (m, 1H, CH);
1.30-2.06 (m, 9H, CH); 1.23 (d, 3H, 3JHH =6.1 Hz, CH3).
Synthesis of Methyl 2,3-Dihydroxybenzoate (III-2). A mixture of 2,3-
dihydroxybenzoic acid III-1 (15.00 g, 97.33 mmol), methanol (150 mL),
and sulfuric acid (2.00 g) was refluxed for 10 h. After the solvent had been
removed under vacuum, the residue was crystallized by petroleum ether
(60-90 °C) and ethyl acetate (v/v=3:1) to give compound III-2 as a pink
Synthesis of N0-tert-Butyl-N-octahydro-2-methylbenzofuran-4-carbo-
hydrazide (V-4). The procedure is the same as for the preparation of N0-tert-
butyl-2-methylbenzofuran-6-carbohydrazide (I-5). First, compound V-2
(1.18 g, 6.41 mmol) was reacted with thionyl chloride (2 mL) to give
compound V-3. Then compound V-3 was reacted with tert-butylhydrazine
hydrochloride (0.96 g, 7.69 mmol) and sodium hydroxide (0.57 g, 14.1
mmol) in dichloromethane (50 mL) and water (5 mL) at -15 °C to give
compound V-4 as a white crystal (0.70 g, 43%): mp 68-70 °C; 1H NMR
(CDCl3) δ 3.98-4.14 (m, 1H, CH); 3.50 (br, 1H, NH); 2.65-2.73 (m, 1H,
1
solid (14.50 g, yield = 88%): mp 79-80 °C [lit. (25) mp 83-85 °C]; H
NMR (400 MHz, CDCl3) δ 10.91 (s, 1H, OH), 7.38 (d, 1H, 3JHH = 8.1 Hz,
ArH), 7.12 (d, 1H, 3JHH=7.4 Hz, ArH), 6.81 (t, 1H, 3JHH = 8.0 Hz, ArH),
5.65 (s, 1H, OH), 3.97 (s, 3H, OCH3).
Synthesis of Methyl Benzo[1,3]dioxole-4-carboxylate (III-3). After a
mixture of 2,3-dihydroxybenzoate III-2 (2.00 g, 11.89 mmol), potassium
carbonate (4.92 g, 35.67 mmol), N,N-dimethylformamide (15 mL) had
been stirred at room temperature for 12 h, a solution of diiodomethane
(3.50 g, 13.08 mmol) in N,N-dimethylformamide (10 mL) was added
dropwise. After 5 h of stirring at 60 °C, water (25 mL) was added to the
reaction mixture, followed by extraction with ethyl acetate (3 ꢀ 25 mL).
The organic layer was washed with water (2ꢀ25 mL) and then dried over
anhydrous sodium sulfate. After the solvent had been removed under
vacuum, the residue was purified by column chromatography on silica gel
using a mixture of petroleum ether (60-90 °C) and ethyl acetate (v/v=3:1)
as the eluent to give compound III-3 as a white crystal (0.65 g, 30%): mp
CH); 2.30-2.38 (m, 1H, CH); 1.45-1.88 (m, 9H, CH); 1.30 (d, 3H, 3JHH
=
6.1 Hz, CH3); 1.09 (s, 9H, C(CH3)3).
General Synthetic Procedure for Target Compounds N0-tert-
Butyl-N0-substituted-benzoyl-N-[di(octa)hydro]benzofurancarbo-
hydrazide (Ia, Ib, IIa-IIg, and Va). The solution of substituted-
benzoyl chloride (0.61 mmol) in dichloromethane (10 mL) was added
dropwise to a stirred mixture of N0-tert-butyl-N-carbohydrazide (I-5, I-9,
II-3, II-7, and V-4, 0.61 mmol), triethylamine (0.07 g, 0.67 mmol), and
dichloromethane (10 mL) in an ice bath. After stirring at room tempera-
ture overnight, dichloromethane (20 mL) was added. The reaction mixture
was washed successively with water (3 ꢀ 15 mL) and brine (15 mL) and
then dried over anhydrous sodium sulfate. After evaporation of the
solvent, the residue was purified by recrystallization or column chroma-
tography on a silica gel to afford the target compounds Ia, Ib, IIa-IIg, and
Va as colorless crystals. The physical properties and HRMS of these
66-68 °C [lit. (26) mp 71-73 °C]; 1H NMR (CDCl3) δ 7.40 (d, 1H, 3JHH
=
8.2 Hz, ArH); 6.96 (d, 1H, 3JHH =7.7 Hz, ArH); 6.85 (t, 1H, 3JHH =8.0
Hz, ArH); 6.09 (s, 2H, CH2); 3.91 (s, 3H, CH3).
Synthesis of Benzo[1,3]dioxole-4-carboxylic Acid (III-4). The proce-
dure is the same as for the preparation of 2-methylbenzofuran-6-car-
boxylic acid (I-3). Methyl benzo[1,3]dioxole-4-carboxylate III-3 (0.50 g,
1
compounds (Ia, Ib, IIa-IIg, and Va) are listed in Table 1, and their H
NMR data are listed in Table 2.