5012 J. Agric. Food Chem., Vol. 52, No. 16, 2004
Nihei et al.
and alcohol (1.3 mmol) in THF (10 mL) cooled at 0 °C was added a
solution of DCC (2.0 mmol). After the solution was stirred over-
night at room temperature, the solvent was removed under reduced
pressure. The residue was extracted with ethyl acetate several times
and filtered. The filtrate was washed successively with dilute aque-
ous citric acid solution, saturated aqueous NaHCO3 solution, and
water. The organic layer was dried over Na2SO4 and evaporated. The
crude products were purified by silica gel chromatography (10-40%
AcOEt-hexane), until urea was completely removed. The best yield
(64%) was obtained with butyl 3,4-dihydroxybenzoate. Structures of
the synthesized esters were established by spectroscopic methods (IR,
MS, and NMR). Because of this synthetically easy accessibility, the
construction of a wide range of structurally diverse mimics was made
available for evaluation. Log P values were calculated by Chem Draw
Pro version 4.5 (Cambridge Soft Co., Cambridge, MA) using Crippen’s
fragmentation (10).
8.0, 1H), 7.50 (d, J ) 2.0, 1H), 8.45 (bs, 2H). 13C NMR (100 MHz,
CD3COCD3): δ 14.4, 23.3, 26.8, 29.5, 30.2, 32.6, 64.9, 115.5, 116.9,
122.9, 123.0, 145.4, 150.4, 166.3. IR (Nujol): 3460, 3310, 1670, 1605,
1300, 1230, 1100 cm-1. EI-MS: m/z 294 (M+).
Undecyl 3,4-dihydroxybenzoate (9) was obtained in 50% yield as a
1
colorless powder. H NMR (400 MHz, CD3COCD3): δ 0.83 (t, J )
7.2 Hz, 3H), 1.24 (m, 16H), 1.69 (quin, J ) 6.8 Hz, 2H), 4.18 (t, J )
6.8 Hz, 2H), 6.85 (d, J ) 8.0, 1H), 7.41 (dd, J ) 2.0, 8.0, 1H), 7.46
(d, J ) 2.0, 1H), 8.43 (bs, 2H). 13C NMR (100 MHz, CD3COCD3): δ
14.4, 23.3, 26.8, 29.5, 30.2, 30.3, 32.6, 64.9, 115.5, 116.9, 122.9, 123.0,
145.3, 150.4, 166.3. IR (Nujol): 3490, 3350, 1695, 1615, 1300, 1235,
1105 cm-1. EI-MS: m/z 308 (M+).
Dodecyl 3,4-dihydroxybenzoate (10) was obtained in 33% yield as
a colorless powder. 1H NMR (400 MHz, CD3COCD3): δ 0.86 (t, J )
6.8 Hz, 3H), 1.27 (m, 18H), 1.72 (quin, J ) 6.8 Hz, 2H), 4.22 (t, J )
6.8 Hz, 2H), 6.88 (d, J ) 8.0, 1H), 7.44 (dd, J ) 2.0, 8.0, 1H), 7.50
(d, J ) 2.0, 1H), 8.47 (bs, 2H). 13C NMR (100 MHz, CD3COCD3): δ
14.4, 23.3, 26.8, 29.5, 30.2, 30.3, 32.6, 64.9, 115.5, 116.9, 122.9, 123.0,
145.3, 150.4, 166.3. IR (Nujol): 3480, 3330, 1680, 1615, 1305, 1240,
1105 cm-1. EI-MS: m/z 322 (M+).
Tridecyl 3,4-dihydroxybenzoate (11) was obtained in 33% yield as
a colorless powder. 1H NMR (400 MHz, CD3COCD3): δ 0.86 (t, J )
6.8 Hz, 3H), 1.27 (m, 20H), 1.72 (quin, J ) 6.8 Hz, 2H), 4.21 (t, J )
6.8 Hz, 2H), 6.88 (d, J ) 8.0, 1H), 7.44 (dd, J ) 2.4, 8.0, 1H), 7.50
(d, J ) 2.4, 1H), 8.47 (bs, 2H). 13C NMR (100 MHz, CD3COCD3): δ
14.4, 23.3, 26.8, 29.5, 30.0, 30.2, 30.3, 30.4, 32.6, 64.9, 115.5, 116.9,
122.9, 123.0, 145.3, 150.4, 166.3. IR (Nujol): 3490, 3350, 1695, 1615,
1300, 1235, 1100 cm-1. EI-MS: m/z 336 (M+).
Tetradecyl 3,4-dihydroxybenzoate (12) was obtained in 36% yield
as a colorless powder. 1H NMR (400 MHz, CD3COCD3): δ 0.88 (t, J
) 7.2 Hz, 3H), 1.27 (m, 22H), 1.73 (quin, J ) 6.8 Hz, 2H), 4.23 (t, J
) 6.8 Hz, 2H), 6.90 (d, J ) 8.0, 1H), 7.46 (dd, J ) 2.0, 8.0, 1H), 7.51
(d, J ) 2.0, 1H), 8.48 (bs, 2H). 13C NMR (100 MHz, CD3COCD3): δ
14.4, 23.3, 26.8, 29.5, 30.2, 30.3, 30.4, 30.5, 32.6, 64.9, 115.5, 116.9,
122.9, 123.0, 145.3, 150.4, 166.3. IR (Nujol): 3480, 3330, 1680, 1615,
1305, 1240, 1105 cm-1. EI-MS: m/z 350 (M+).
Other nonyl benzoates were synthesized as follows (11). A mixture
of benzyloxybenzoic acid (0.60 mmol) (12-17), 1-nonanol (0.66
mmol), and TPP (190 mg, 0.72 mmol) in THF (4 mL) was cooled to
0 °C and treated with DIAD (0.72 mmol). After the mixture was stirred
for 2 h at room temperature, the solvent was removed in vacuo. The
residue was subjected to silica gel chromatography eluted with 1-8%
AcOEt-hexane to give an ester as a white solid, which was used in
the next step without further purification. The ester was hydrogenated
over 20% Pd(OH)2 on carbon (10 mg) in 1% AcOH-AcOEt (4 mL)
for 12 h. Filtration through Celite and concentration followed by silica
gel chromatography (1-40% AcOEt-hexane) gave pure nonyl ben-
zoate in high yield.
Propyl 3,4-dihydroxybenzoate (1) was obtained in 55% yield as a
1
colorless powder. H NMR (400 MHz, CD3COCD3): δ 1.00 (t, J )
7.2 Hz, 3H), 1.75 (sex, J ) 7.2 Hz, 2H), 4.19 (t, J ) 7.2 Hz, 2H), 6.91
(d, J ) 8.0, 1H), 7.46 (dd, J ) 2.0, 8.0, 1H), 7.52 (d, J ) 2.0, 1H),
8.50 (bs, 2H). 13C NMR (100 MHz, CD3COCD3): δ 10.8, 22.8, 66.3,
115.6, 116.9, 122.9, 123.0, 145.3, 150.4, 166.3. IR (Nujol): 3500, 3340,
1680, 1610, 1280, 1235, 1100 cm-1. EI-MS: m/z 196 (M+).
Butyl 3,4-dihydroxybenzoate (2) was obtained in 64% yield as a
1
colorless powder. H NMR (400 MHz, CD3COCD3): δ 0.95 (t, J )
7.2 Hz, 3H), 1.43 (sex, J ) 7.2 Hz, 2H), 1.69 (quin, J ) 7.2 Hz,
2H), 4.22 (t, J ) 7.2 Hz, 2H), 6.88 (d, J ) 8.0, 1H), 7.44 (dd, J ) 2.8,
8.0, 1H), 7.49 (d, J ) 2.8, 1H), 8.49 (bs, 2H). 13C NMR (100 MHz,
CD3COCD3): δ 14.0, 19.9, 31.6, 64.6, 115.6, 116.9, 122.9, 123.0, 145.3,
150.4, 166.3. IR (Nujol): 3490, 3330, 1680, 1610, 1300, 1235, 1100
cm-1. EI-MS: m/z 210 (M+).
Pentyl 3,4-dihydroxybenzoate (3) was obtained in 51% yield as a
colorless powder. 1H NMR (500 MHz, CDCl3): δ 0.92 (t, J ) 7.0 Hz,
3H), 1.39 (m, 4H), 1.75 (quin, J ) 7.0 Hz, 2H), 4.28 (t, J ) 7.0 Hz,
2H), 6.30 (bs, 2H), 6.92 (d, J ) 8.5, 1H), 7.57 (dd, J ) 2.0, 8.5, 1H),
7.70 (d, J ) 2.0, 1H). IR (Nujol): 3500, 3360, 1695, 1615, 1295, 1235,
1100 cm-1. FAB-MS: m/z 225 (M + H+).
Hexyl 3,4-dihydroxybenzoate (4) was obtained in 33% yield as a
1
colorless powder. H NMR (400 MHz, CD3COCD3): δ 0.85 (t, J )
6.8 Hz, 3H), 1.29 (m, 4H), 1.40 (m, 2H), 1.68 (quin, J ) 6.8 Hz,
2H), 4.18 (t, J ) 6.8 Hz, 2H), 6.85 (d, J ) 8.0, 1H), 7.41 (dd, J ) 2.0,
8.0, 1H), 7.46 (d, J ) 2.0, 1H), 8.45 (bs, 2H). 13C NMR (100 MHz,
CD3COCD3): δ 14.3, 23.2, 26.4, 30.6, 32.2, 64.9, 115.6, 116.9, 122.9,
123.0, 145.3, 150.4, 166.3. IR (Nujol): 3510, 3350, 1680, 1610, 1280,
1240, 1100 cm-1. EI-MS: m/z 238 (M+).
Heptyl 3,4-dihydroxybenzoate (5) was obtained in 35% yield as a
1
colorless powder. H NMR (400 MHz, CD3COCD3): δ 0.88 (t, J )
6.8 Hz, 3H), 1.32 (m, 8H), 1.72 (quin, J ) 6.8 Hz, 2H), 4.21 (t, J )
6.8 Hz, 2H), 6.89 (d, J ) 8.4, 1H), 7.44 (dd, J ) 2.0, 8.4, 1H), 7.50
(d, J ) 2.0, 1H), 8.50 (bs, 2H). 13C NMR (100 MHz, CD3COCD3): δ
14.3, 23.2, 26.7, 29.5, 29.7, 32.5, 64.9, 115.5, 116.9, 122.9, 123.0, 145.3,
150.4, 166.3. IR (Nujol): 3500, 3340, 1685, 1610, 1300, 1230, 1105
cm-1. EI-MS: m/z 252 (M+).
Nonyl 2-hydroxybenzoate (16) was obtained in 86% yield as a
1
colorless oil. H NMR (500 MHz, CDCl3): δ 0.88 (t, J ) 7.0 Hz,
3H), 1.29 (m, 8H), 1.36 (m, 2H), 1.44 (quin, J ) 6.5 Hz, 2H),
1.78 (quin, J ) 6.5 Hz, 2H), 4.34 (t, J ) 6.5 Hz, 2H), 6.88 (td, J )
1.0, 7.5, 9.0 Hz, 1H), 6.98 (dd, J ) 1.0, 9.0 Hz, 1H), 7.45 (td, J ) 2.0,
7.5, 9.0 Hz, 1H), 7.84 (dd, J ) 2.0, 7.5 Hz, 1H), 10.84 (s, 1H). 13C
NMR (125 MHz, CDCl3): δ 14.1, 22.7, 26.0, 28.6, 29.2, 29.5, 31.6,
65.5, 112.7, 117.6, 119.1, 129.9, 135.6, 161.7, 170.2. IR (CCl4): 3180,
2900, 1670, 1475, 1290, 1240, 1200, 1145, 1075 cm-1. EI-MS: m/z
264 (M+).
Octyl 3,4-dihydroxybenzoate (6) was obtained in 36% yield as a
1
colorless powder. H NMR (400 MHz, CD3COCD3): δ 0.83 (t, J )
6.8 Hz, 3H), 1.25 (m, 8H), 1.40 (m, 2H), 1.68 (quin, J ) 6.8 Hz,
2H), 4.18 (t, J ) 6.8 Hz, 2H), 6.85 (d, J ) 8.4, 1H), 7.40 (dd, J ) 2.0,
8.4, 1H), 7.46 (d, J ) 2.0, 1H), 8.44 (bs, 2H). 13C NMR (100 MHz,
CD3COCD3): δ 14.3, 23.3, 26.8, 29.5, 30.0, 30.5, 32.5, 64.9, 115.5,
116.9, 122.9, 123.0, 145.3, 150.4, 166.3. IR (Nujol): 3510, 3350, 1685,
1610, 1300, 1235, 1105 cm-1. EI-MS: m/z 266 (M+).
Nonyl 3-hydroxybenzoate (17) was obtained in 89% yield as a
colorless solid. 1H NMR (500 MHz, CDCl3): δ 0.88 (t, J ) 7.0
Hz, 3H), 1.29 (m, 8H), 1.35 (m, 2H), 1.43 (quin, J ) 6.5 Hz, 2H),
1.76 (quin, J ) 6.5 Hz, 2H), 4.31 (t, J ) 6.5 Hz, 2H), 5.47 (s, 1H),
7.05 (td, J ) 1.0, 2.0, 8.0 Hz, 1H), 7.31 (t, J ) 8.0 Hz, 1H), 7.57 (dd,
J ) 2.0, 2.5 Hz, 1H), 7.61 (td, J ) 1.0, 2.5, 8.0 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 14.1, 22.7, 25.0, 26.9, 28.7, 29.2, 29.5, 31.9,
65.4, 116.3, 120.1, 122.0, 129.7, 131.9, 155.7, 166.7. IR (CCl4): 3590,
3420, 2900, 1700, 1680, 1435, 1270, 1200, 1090 cm-1. EI-MS: m/z
264 (M+).
Nonyl 3,4-dihydroxybenzoate (7) was obtained in 41% yield as a
colorless powder. 1H NMR (500 MHz, CDCl3): δ 0.88 (t, J ) 7.0 Hz,
3H), 1.27 (m, 10H), 1.42 (m, 2H), 1.74 (quin, J ) 7.0 Hz, 2H), 4.28
(t, J ) 7.0 Hz, 2H), 6.33 (bs, 2H), 6.91 (d, J ) 8.5, 1H), 7.55 (dd, J
) 2.0, 8.5, 1H), 7.68 (d, J ) 2.0, 1H). IR (Nujol): 3470, 3330, 1685,
1605, 1285, 1225, 1095 cm-1. FAB-MS: m/z 281 (M + H+).
Decyl 3,4-dihydroxybenzoate (8) was obtained in 36% yield as a
1
colorless powder. H NMR (400 MHz, CD3COCD3): δ 0.86 (t, J )
Nonyl 4-hydroxybenzoate (18) was obtained in 85% yield as a
1
7.2 Hz, 3H), 1.27 (m, 12H), 1.44 (m, 2H), 1.72 (quin, J ) 6.8 Hz,
2H), 4.22 (t, J ) 6.8 Hz, 2H), 6.88 (d, J ) 8.0, 1H), 7.44 (dd, J ) 2.8,
colorless solid. H NMR (500 MHz, CDCl3): δ 0.88 (t, J ) 7.0 Hz,
3H), 1.28 (m, 8H), 1.36 (m, 2H), 1.44 (quin, J ) 6.5 Hz, 2H), 1.77