7
774
R. Wisastra et al. / Bioorg. Med. Chem. 21 (2013) 7763–7778
thetic procedure 4. Yield quantitatively determined from the final
yield of product in excess of KOH. R = 0.18 (heptane/EtOAc 1:1
containing 1% acetic acid). The product was more than 95% pure
132.06, 130.69, 116.17, 111.76, 105.95, 72.47, 68.11, 41.28, 39.28,
ꢁ
f
38.27, 31.89, 29.99, 26.67, 23.95, 23.86, 20.90. HRMS: m/z [MꢁH]
31 5
calcd for C24H O 399.2177, found 399.21844.
1
2
as judged from TLC and NMR. H NMR (200 MHz, D O) d 6.95 (d,
J = 8.3, 2H), 6.57 (t, J = 8.5, 1H), 6.43 (d, J = 8.3, 2H), 6.16 (d,
J = 8.5, 1H), 5.91 (d, J = 8.5, 1H), 4.75 (s, 2H), 3.38 (m, 2H), 1.34
(
4.1.23. (3-(Heptyloxy)phenyl)methanol (4b)
The product was obtained using Williamson ether synthesis fol-
lowed by aldehyde reduction of 1-bromoheptane, and 3-hydroxy-
benzaldehyde using synthetic procedure 1. The product was used
m, 2H), 1.06 (m, 12H), 0.71 (t, J = 7.0, 3H).13C NMR (50 MHz, CD3-
OD) d 202.2, 164.24, 160.76, 156.88, 133.10, 131.98, 130.67,
1
3
16.19, 111.48, 109.33, 106.36, 72.41, 69.89, 61.77, 33.83, 31.47,
for the next reaction step without further purification. Yield 94%.
ꢁ
1
1.31, 31.18, 28.10, 27.95, 24.52, 14.22. HRMS: m/z [MꢁH] calcd
Brown solid. R
CDCl
t, J = 6.5, 2H), 1.88–1.67 (m, 3H), 1.55–1.17 (m, 8H), 0.89 (t,
f
= 0.48 (heptane/EtOAc 1:1). H NMR (200 MHz,
for C23
H
29
O
5
385.20205, found 385.20248.
3
) d 7.26–7.18 (m, 1H), 6.96–6.75 (m, 3H), 4.64 (s, 2H), 3.95
(
1
3
4
.1.19. (4-((3,7-Dimethyloctyl)oxy)phenyl)methanol (2d)
The product was obtained using Williamson ether synthesis fol-
3
J = 6.5, 3H). C NMR (50 MHz, CDCl ) d 159.62, 142.67, 129.74,
119.09, 114.01, 113.09, 68.18, 65.48, 31.99, 29.49, 29.27, 26.22,
+
lowed by aldehyde reduction of 1-1-bromo-3,7-dimethyloctane,
and 4-hydroxybenzaldehyde using synthetic procedure 1. The
22.82, 14.34. MS (APPI): m/z 222.2 [M ].
product was used for the next reaction step without further purifi-
4.1.24. 1-(Bromomethyl)-3-(heptyloxy)benzene (5b)
The product was obtained from (3-(heptyloxy)phenyl)methanol
4b using synthetic procedure 2. Therefore product was used for the
1
cation. Yield 92%. Yellow oil. R
NMR (200 MHz, CDCl
4
6
f
= 0.48 (heptane/EtOAc 1:1).
H
3
) d 7.27 (d, J = 8.6, 2H), 6.88 (d, J = 8.6, 2H),
.59 (s, 2H), 3.98 (t, J = 6.5, 2H), 1.88–1.46 (m, 5H), 1.32–1.14 (m,
H), 0.93 (d, J = 6.2, 3H),0.87 (d, J = 6.5, 6H).13C NMR (50 MHz,
) d 158.98, 133.10, 128.82, 114.77, 66.59, 65.27, 39.45,
7.49, 36.40, 30.06, 28.17, 24.86, 22.91, 22.81, 19.86. MS (APPI):
next reaction step without further purification. Yield 86%. Brown
1
solid.
CDCl
1.65(m, 2H), 1.34–1.15 (m, 8H), 0.89 (t, J = 6.5, 3H). C NMR
(50 MHz, CDCl ) d 159.41, 129.63, 119.81, 114.36, 105.23, 68.05,
2.65, 32.01, 29.53, 29.36, 26.24, 22.84, 14.31. MS (ESI): m/z
R
f
= 0.71 (heptane/EtOAc 1:1).
H
NMR (200 MHz,
CDCl
3
3
)7.32–6.27 (m, 4H), 4.76 (s, 2H), 3.92 (t, J = 6.4, 2H), 1.72-
13
3
+
m/z 264.1 [M ].
3
3
+
4
(
.1.20. 1-(Bromomethyl)-4-((3,7-dimethyloctyl)oxy)benzene
3d)
The product was obtained from (4-((3,7-dimethyloc-
285.0 [M ].
4.1.25. 5-((3-(Heptyloxy)benzyl)oxy)-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (13b)
tyl)oxy)phenyl)methanol 2d using synthetic procedure 2. The
product was used for the next reaction step without further purifi-
The product was obtained from 5-hydroxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one 1, and 1-(bromomethyl)-3-(heptyl-
oxy)benzene 5b using synthetic procedure 3. The product was
purified using column chromatography with heptane/EtOAc 16:1
cation. Yield quantitative. Light yellow oil. R
f
= 0.75 (heptane/
) d 7.30 (d, J = 8.6, 2H), 6.85
d, J = 8.6, 2H), 4.49 (s, 2H), 3.98 (t, J = 6.5, 2H), 1.87–1.46 (m,
1
EtOAc 1:1). H NMR (200 MHz, CDCl
3
(
4
6
6
2
H), 1.32–1.10 (m, 6H), 0.93 (d, J = 6.2, 3H), 0.87 (d, J = 6.4,
(v/v) as eluent. Yield 58%. White solid. R
f
= 0.29 (heptane/EtOAc
1
3
1
H). C NMR (50 MHz, CDCl
3
) d 159.46, 130.60, 129.88, 114.95,
5:1). H NMR (200 MHz, CDCl ) d 7.42–7.35 (m, 2H), 7.25 (d,
3
6.59, 39.45, 37.47, 36.35, 34.30, 30.04, 28.18, 24.86, 22.92,
J = 7.5, 1H), 7.04 (d, J = 7.5, 1H), 6.83 (d, J = 7.9, 1H), 6.70–6.49 (m,
2H), 5.22 (s, 2H), 3.99 (t, J = 6.4, 2H), 1.87–1.68 (m, 2H) 1.56 (s, 6H),
+
2.82, 19.85. MS (ESI): m/z 247.1 [M–Br] .
1
3
1
3
.42– 1.12 (m, 8H), 0.89 (t, J = 6.5, 3H). C NMR (50 MHz, CDCl ) d
4
4
.1.21. 5-((4-((3,7-Dimethyloctyl)oxy)benzyl)oxy)-2,2-dimethyl-
H-benzo[d][1,3]dioxin-4-one (12d)
The product was obtained from 5-hydroxy-2,2-dimethyl-4H-
160.53, 159.77, 158.23, 158.01, 138.02, 136.48, 129.73, 118.57,
114.61, 112.43, 109.67, 107.36, 105.46, 70.74, 68.19, 32.00, 29.50,
29.29, 26.26, 25.85, 22.82, 14.30. MS (APPI): m/z 399.2 [M+H] .
+
benzo[d][1,3]dioxin-4-one 1, and 1-(bromomethyl)-4-((3,7-dime-
thyloctyl)oxy)benzene 3d using synthetic procedure 3. The product
was purified using column chromatography with heptane/EtOAc
4.1.26. 2-((3-(Heptyloxy)benzyl)oxy)-6-hydroxybenzoic acid
(24b)
1
9:1 (v/v) as eluent. Yield 68%. White solid. R
f
= 0.35 (heptane/
) d 7.46–7.26 (m, 3H), 6.92
d, J = 8.6, 2H), 6.65 (d, J = 8.5, 1H), 6.54 (d, J = 8.5, 1 H), 5.18 (s,
The product was obtained from 5-((3-(heptyloxy)benzyl)oxy)-
2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one 13b using synthetic
procedure 5. Yield quantitative. Yellow oil. R = 0.42 (heptane/
f
1
EtOAc 4:1). H NMR (200 MHz, CDCl
(
3
2
0
H), 3.98 (t, J = 6.5, 2H), 1.84–1.5 (m, 10H), 1.32–1.14 (m, 6H),
EtOAc 1:1 containing 1% acetic acid). The product was more than
95% pure as judged from TLC and NMR. H NMR (200 MHz,
.93 (d, J = 6.2, 3H), 0.87 (d, J = 6.4, 6H).13C NMR (50 MHz, CDCl
)
1
3
d 160.69, 159.10, 158.23, 157.99, 136.40, 128.53, 128.25, 114.82,
6
DMSO-d ) d 7.26–7.19 (m, 2H), 7.08 (d, J = 7.5, 1H), 7.04 (d,
1
2
09.57, 107.61, 105.41, 70.89, 66.56, 39.45, 37.49, 36.40, 30.05,
8.17, 25.85, 24.85, 22.91, 22.81, 19.86. MS (APPI): m/z 440.4 [M ].
J = 7.5, 1H), 6.79 (d, J = 8.11H), 6.31 (d, J = 8.2, 2H), 5.04 (s, 2H),
3.95 (t, J = 6.4, 2H), 1.73 - 1.63 (m, 2H), 1.36–1.18 (m, 8H), 0.87
+
1
3
(
6
t, J = 7.0, 3H). C NMR (50 MHz, DMSO-d ) d 170.28, 164.46,
4
.1.22. Potassium 2-((4-((3,7-dimethyloctyl)oxy)benzyl)oxy)-6-
159.34, 158.66, 139.68, 130.82, 129.05, 118.77, 113.03, 110.05,
hydroxybenzoate (23d)
The product was obtained from 5-((4-((3,7-dimethyloc-
tyl)oxy)benzyl)oxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one
109.85, 102.77, 69.61, 67.26, 31.26, 28.75, 28.48, 25.55, 22.07,
ꢁ
13.96. HRMS: m/z [MꢁH] calcd for C21
25 5
H O 357.17075, found
357.17114.
1
2d using synthetic procedure 4. The compound is racemic at its
asymmetric carbon. Yield quantitatively determined from the final
yield of product in excess of KOH. Orange solid. R = 0.54 (heptane/
EtOAc 1:1 containing 1% acetic acid). The product was more than
4.1.27. (3-(Nonyloxy)phenyl)methanol (4c)
f
The product was obtained using Williamson ether synthesis fol-
lowed by aldehyde reduction of 1-bromoheptane, and 3-hydroxy-
benzaldehyde using synthetic procedure 1. The product was used
1
9
5% pure as judged from TLC and NMR. H NMR (200 MHz, CD
3
OD)
d 7.42 (d, J = 8.7, 2H), 7.05 (t, J = 8.2, 1H), 6.95–6.85 (m, 2H), 6.43–
for the next reaction step without further purification. Yield 89%.
1
6
1
.38 (m, 2H), 5.03 (s, 2H), 3.99 (t, J = 6.7 2H), 1.92–1.48 (m, 4H),
R
f
= 0.54 (heptane/EtOAc 1:1). H NMR (200 MHz, CDCl
3
) d 7.22
1
3
.40–1.16 (m, 6H), 0.95 (d, J = 6.2, 3H), 0.89 (d, J = 6.5, 6H).
C
(t, J = 7.8, 1H), 6.89 (s, 1H), 6.85–6.72 (m, 2H), 4.59 (s, 2H), 3.92
(t, J = 6.5, 2H), 2.32 (s, 1H), 1.79–1.69 (m, 2H), 1.42–1.28 (m,
NMR (50 MHz, CD
3
OD) d 202.3, 164.42, 161.42, 160.86, 132.74,