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M. Waibel et al. / European Journal of Medicinal Chemistry 44 (2009) 3412–3424
gave 13 as pale yellow oil (215 mg, 46% yield) after purification by
BF3$OEt (181
oil (168 mg, 82%) after purification by flash chromatography (25%
EtOAc/hexanes). 1H NMR (500 MHz, CDCl3)
mL, 1.43 mmol) in 4.5 mL CH2Cl2 gave 18 as a colorless
flash chromatography (25% EtOAc/hexanes). 1H NMR (500 MHz,
CDCl3)
d
7.21 (d, J ¼ 8.8, 2H), 6.83 (d, J ¼ 8.8, 2H), 6.80 (d, J ¼ 8.8, 2H),
d
6.96 (d, J ¼ 8.8, 2H),
6.68 (d, J ¼ 8.8, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 3.16 (d, J ¼ 13.5, 1H),
6.88 (d, J ¼ 8.8, 2H), 6.77 (d, J ¼ 8.8, 2H), 6.70 (d, J ¼ 8.8, 2H), 3.77 (s,
3H), 3.74 (s, 3H), 3.04 (dd, J ¼ 13.6, 5.4, 1H), 2.74 (dd, J ¼ 13.6, 9.5,
1H), 2.55–2.51 (m, 1H), 1.87 (qq, J ¼ 6.7, 6.7, 1H), 0.98 (d, J ¼ 6.7, 3H),
3.08 (d, J ¼ 13.5, 1H), 2.11–2.06 (m, 1H), 1.00 (d, J ¼ 6.8, 3H), 0.81 (d,
J ¼ 6.8, 3H); 13C NMR (500 MHz, CDCl3)
d 158.40, 158.12, 136.93,
131.81, 128.69, 127.61, 113.59, 112.99, 78.68, 55.29, 55.24, 44.87,
0.77 (d, J ¼ 6.7, 3H); 13C NMR (500 MHz, CDCl3)
d 157.79, 157.59,
37.71, 18.01, 17.07; MS (CI) m/z 283 (Mþ ꢀ 17, 19).
135.59, 133.61, 130.04, 129.79, 113.46, 113.24, 55.39, 54.31, 38.90,
32.40, 21.53, 19.91; MS (EI) m/z 284 (Mþ, 7).
5.2.1.5. 1,2-Bis-(4-methoxy-phenyl)-hexan-2-ol (14). Use of butyl
magnesium chloride (2.34 mL of a 2 M solution in diethyl ether)
and a reflux time of 4.5 h gave 14 as colorless oil (286 mg, 58% yield)
after purification by flash chromatography (25% EtOAc/hexanes). 1H
5.2.2.5. 1,2-Bis-(4-methoxy-phenyl)-hexane (19). Use of compound
14 (235 mg, 0.75 mmol), Et3SiH (239
(190 L, 1.50 mmol) in 4.5 mL CH2Cl2 gave 19 as a colorless oil
(207 mg, 93%) after purification by flash chromatography (25%
EtOAc/hexanes).1H NMR (500 MHz, CDCl3)
mL, 1.50 mmol) and BF3$OEt
m
NMR (500 MHz, CDCl3)
d
7.22 (d, J ¼ 9.0, 2H), 6.87–6.83 (m, 4H),
6.74 (d, J ¼ 8.6, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.07 (d, J ¼ 13.5, 1H),
2.96 (d, J ¼ 13.5, 1H), 1.93–1.86 (m, 1H), 1.78–1.72 (m, 1H), 1.33–1.19
(m, 3H), 1.07–0.98 (m, 1H), 0.83 (t, J ¼ 7.2, 3H); 13C NMR (500 MHz,
d
7.01 (d, J ¼ 8.6, 2H), 6.92
(d, J ¼ 8.8, 2H), 6.81 (d, J ¼ 8.6, 2H), 6.75 (d, J ¼ 8.8, 2H), 3.79 (s, 3H),
3.76 (s, 3H), 2.80 (dd, J ¼ 13.4, 7.2, 1H), 2.78–2.67 (m, 2H), 1.68–1.61
(m, 1H), 1.59–1.51 (m, 1H), 1.31–1.08 (m, 4H), 0.81 (t, J ¼ 7.3, 3H); 13C
CDCl3) d 158.32, 157.98, 138.06, 131.62, 128.40, 126.64, 113.42, 113.17,
76.44, 55.13, 55.09, 48.80, 41.80, 25.68, 23.02, 14.02; MS (ESI) m/z
NMR (500 MHz, CDCl3) d 157.68, 157.59, 137.45, 133.04, 130.02,
297 (Mþ ꢀ 17, 100).
128.59, 113.47, 113.33, 55.13, 55.11, 47.28, 43.09, 35.33, 29.73, 22.69,
13.99; MS (EI) m/z 298 (Mþ, 9).
5.2.2. General procedure for the dehydroxylation of 1,2-bis-(4-
methoxy-phenyl)-alkan-2-ols
5.2.3. General procedure for the deprotection of methoxy groups
with BBr3
The starting material was dissolved in CH2Cl2 and the mixture
was brought to 0 ꢁC. Et3SiH was added and after 2 min BF3$OEt was
added dropwise. The reaction was stirred for 30 min at 0 ꢁC,
quenched with water and extracted three times with EtOAc. The
organic extracts were dried over Na2SO4 and the solvent was
removed under vacuum.
The starting material was dissolved in CH2Cl2 and brought to
0 ꢁC unless stated otherwise. BBr3 was added dropwise and the
mixture was brought to rt and stirred for 17 h. The reaction was
brought to 0 ꢁC, quenched with water and extracted three times
with EtOAc. The organic extracts were dried over Na2SO4 and the
solvent was removed under vacuum.
5.2.2.1. 1,2-Bis-(4-methoxy-phenyl)-propane (15). Use of compound
10 (337 mg, 1.24 mmol), Et3SiH (394
(314 L, 2.48 mmol) in 5 mL CH2Cl2 gave 15 as a white solid (313 mg,
quant. yield, mp 68 ꢁC) after purification by flash chromatography
(25% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3)
m
L, 2.48 mmol) and BF3$OEt
5.2.3.1. 1,2-Bis-(4-hydroxy-phenyl)-propane (21). Use of compound
15 (286 mg, 1.12 mmol) and BBr3 (3.35 mL of a 1 M solution in
CH2Cl2) in 11 mL CH2Cl2 gave 21 as a white solid (209 mg, 82%, mp
173–174 ꢁC) after purification by flash chromatography (50% EtOAc/
m
d
7.09 (d, J ¼ 8.6,
2H), 6.98 (d, J ¼ 8.8, 2H), 6.83 (d, J ¼ 8.8, 2H), 6.78 (d, J ¼ 8.6, 2H),
3.79 (s, 3H), 3.78 (s, 3H), 2.95–2.88 (m, 1H), 2.84 (dd, J ¼ 13.5, 6.6,
1H), 2.69 (dd, J ¼ 13.5, 6.6, 1H), 1.21 (d, J ¼ 6.9, 3H); 13C NMR
hexanes). 1H NMR (400 MHz, acetone-d6)
d 8.02 (s, OH), 7.01 (d,
J ¼ 8.5, 2H), 6.91 (d, J ¼ 8.5, 2H), 6.72 (d, J ¼ 8.5, 2H), 6.68 (d, J ¼ 8.5,
2H), 2.91–2.82 (m, 1H), 2.76 (dd, J ¼ 13.3, 6.7, 1H), 2.65 (dd, J ¼ 13.3,
8.0, 1H), 1.14 (d, J ¼ 6.8, 3H); 13C NMR (400 MHz, acetone-d6)
(500 MHz, CDCl3)
d 157.74, 157.71, 139.15, 133.00, 130.04, 127.92,
113.59, 113.42, 55.18, 44.30, 41.11, 21.26; MS (EI) m/z 256 (Mþ, 9).
d 156.24, 138.74, 132.60, 130.80, 128.68, 115.74, 115.59, 44.95, 41.97,
21.79; MS (EI) m/z 228 (Mþ, 7). HRMS (EI) calcd for C15H16O2:
228.1150, found 228.1145. Anal. C15H16O2 (C, H).
5.2.2.2. 1,2-Bis-(4-methoxy-phenyl)-butane (16). Use of compound
11 (330 mg, 1.05 mmol), Et3SiH (320
(253 L, 2.01 mmol) in 5 mL CH2Cl2 gave 16 as a colorless oil
(249 mg, 88%) after purification by flash chromatography (25%
EtOAc/hexanes). 1H NMR (400 MHz, CDCl3)
mL, 2.01 mmol) and BF3$OEt
m
5.2.3.2. 1,2-Bis-(4-hydroxy-phenyl)-butane (6). Use of compound
16 (250 mg, 0.93 mmol) and BBr3 (2.79 mL of a 1 M solution in
CH2Cl2) in 10 mL CH2Cl2 gave 6 as a white solid (209 mg, quant.
yield,) after purification by flash chromatography (50% EtOAc/
hexanes). The analytical data of compound 6 were consistent with
the data published previously [30].
d
7.01 (d, J ¼ 8.8, 2H),
6.94 (d, J ¼ 8.6, 2H), 6.82 (d, J ¼ 8.8, 2H), 6.77 (d, J ¼ 8.6, 2H), 3.79 (s,
3H), 3.77 (s, 3H), 2.82–2.74 (m, 2H), 2.67–2.58 (m,1H),1.76–1.65 (m,
1H), 1.61–1.50 (m, 1H), 0.76 (t, J ¼ 7.1, 3H); 13C NMR (400 MHz,
CDCl3) d 157.68, 157.56, 137.11, 133.04, 130.02, 128.64, 113.45, 113.33,
55.14, 49.08, 42.72, 28.36, 12.11; (EI) m/z 270 (Mþ, 11).
5.2.3.3. 1,2-Bis-(4-hydroxy-phenyl)-pentane (22). Use of compound
17 (203 mg, 0.71 mmol) and BBr3 (2.14 mL of a 1 M solution in
CH2Cl2) in 7 mL CH2Cl2 gave 22 as a white solid (157 mg, 86%, mp
99–100 ꢁC) after purification by flash chromatography (50% EtOAc/
5.2.2.3. 1,2-Bis-(4-methoxy-phenyl)-pentane (17). Use of compound
12 (306 mg, 1.02 mmol), Et3SiH (325
(259 L, 2.04 mmol) in 5 mL CH2Cl2 gave 17 as a white solid
(233 mg, 88%, mp 34 ꢁC) after purification by flash chromatography
(25% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3)
mL, 2.04 mmol) and BF3$OEt
m
hexanes). 1H NMR (500 MHz, acetone-d6)
d 8.00 (s, OH), 6.95 (d,
J ¼ 8.6, 2H), 6.86 (d, J ¼ 8.4, 2H), 6.71 (d, J ¼ 8.4, 2H), 6.65 (d, J ¼ 8.6,
d
7.02 (d, J ¼ 8.8,
2H), 2.81–2.66 (m, 3H), 1.64–1.49 (m, 2H), 1.21–1.09 (m, 2H), 0.78
2H), 6.94 (d, J ¼ 8.6, 2H), 6.81 (d, J ¼ 8.8, 2H), 6.76 (d, J ¼ 8.6, 2H),
3.79 (s, 3H), 3.77 (s, 3H), 2.84–2.69 (m, 3H), 1.67–1.50 (m, 2H), 1.22–
1.10 (m, 2H), 0.83 (t, J ¼ 7.3, 3H); 13C NMR (400 MHz, CDCl3)
(d, J ¼ 7.3, 3H); 13C NMR (500 MHz, acetone-d6)
d 156.31, 156.19,
136.96, 132.63, 130.83, 129.42, 115.74, 115.57, 47.86, 43.77, 38.76,
21.26, 14.29; MS (ESI) m/z 255 (Mþ ꢀ 1, 81). HRMS (ESI) calcd for
C17H19O2: 255.1385, found 255.1389 Anal. C17H20O2 (C, H).
d
157.64, 157.55, 137.37, 133.00, 130.00, 128.56, 113.44, 113.31, 55.11,
47.04, 43.07, 37.84, 20.62, 14.06; MS (EI) m/z 284 (Mþ, 12).
5.2.3.4. 1,2-Bis-(4-hydroxy-phenyl)-3-methyl-butane (23). Use of
compound 18 (139 mg, 0.49 mmol) and BBr3 (1.48 mL of a 1 M
solution in CH2Cl2) in 5 mL CH2Cl2 gave 23 as a white solid
5.2.2.4. 1,2-Bis-(4-methoxy-phenyl)-3-methyl-butane (18). Use of
compound 13 (215 mg, 0.72 mmol), Et3SiH (228 mL, 1.43 mmol) and