Estrogen Receptor â-Selective Radioligand
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 20 6375
combined organic layers were washed by NaHCO3 and brine,
dried over Na2SO4, and concentrated to give clear oil. The
crude product was chromatographed over silica using ether
as eluent to give white solid. (313 mg, 67%): 1H NMR (CDCl3,
300 MHz) δ 1.99 (m, 2H), 3.15 (m, 1H), 3.34-3.58 (m, 2H),
3.758 (s, 3H), 3.761 (s, 3H), 4.01 (d, J ) 6.3 Hz, 1H), 6.79 (m,
4H), 6.98 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 35.8 (CCH2-
CH2OH), 43.8 (CCN), 46.4 (CCH2CH2OH), 55.2 and 55.3
(OCH3), 60.1 (CH2CH2OH), 113.9 and 114.1 (Ph ring CH),
120.2 (CN), 126.4, 129.4 and 129.6 (Ph ring CH), 130.7, 159.0
and 159.3 (Ph ring C). HRMS (FAB): m/z 318.1688 ([M + Li]+,
C19H21NO3Li, calcd 318.1681).
(2R*,3S*)-5-Fluoro-2,3-bis(4-methoxyphenyl)pentane-
nitrile (4a). To a dry CH2Cl2 solution (8 mL) of (2R*,3S*)-5-
hydroxy-2,3-bis(4-methoxyphenyl)pentanenitrile (285 mg, 0.92
mmol) was added (diethylamino)sulfur trifluoride (DAST, 600
µL, 4.58 mmol) dropwise at -76 °C. The mixture was stirred
under Ar atmosphere and allowed to warm to room-temper-
ature overnight. After quenching with saturated NaHCO3 at
0 °C, the solution was diluted with water (15 mL), then
extracted CH2Cl2 (2 × 15 mL), dried over MgSO4, and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica, ethyl acetate/hexane (1:1)) to give a
pale yellow solid. (187 mg, 65%): 1H NMR (CDCl3, 300 MHz)
δ 1.98-2.32 (m, 2H), 3.19 (m, 1H), 3.80 (s, 6H), 4.02 (d, J )
6.9 Hz, 1H), 4.10-5.31 (m, 2H), 6.20 (m, 4H), 7.01 (m, 4H);
13C NMR (CDCl3, 75 MHz) δ 34.1 (d, JCF ) 20.0 Hz, CH2CH2F),
43.8 (CHCN), 46.1 (d, JCF ) 4.1 Hz, CHCH2CH2F), 55.40 and
55.49 (OCH3), 81.6 (d, JCF ) 164.7 Hz, CH2CH2F), 114.2 and
114.3 (Ph ring CH), 120.0 (CN), 126.2, 129.5 and 129.7 (Ph
ring CH), 130.0, 159.3, 159.6. HRMS (FAB): m/z 320.1635 ([M
+ Li]+, C19H20FNO2Li, calcd 320.1638).
(Z)-2,3-Bis(4-(benzyloxy)phenyl)acrylonitrile (1b). The
mixture of 4-(benzyloxy)benzaldehyde (5257 mg, 24.8 mmol),
4-(benzyloxy)phenylacetonitrile (5530 mg, 24.8 mmol), and
NaOMe (156 mg, 2.89 mmol) in dry ethanol (100 mL) was
refluxed for 2 h and cooled to room temperature to produce a
precipitate of white crystals. After removing the solid by
filtration, to the filtrate was added more NaOMe (503 mg, 9.31
mmol), and the mixture was refluxed for 2 h and cooled to room
temperature to precipitate more crystals. After second crop,
the filtrate was concentrated and the residue was redissolved
in CH2Cl2, washed by brine, dried over MgSO4, and concen-
trated. The residue was dissolved in EtOH (80 mL) again, then
NaOMe (579 mg, 10.7 mmol) was added. The mixture was
refluxed for 3 h, then cooled to room temperature to give white
crystals. All crops were washed with a small amount of ethanol
and dried in air. (10.02 g, 97%): 1H NMR (CDCl3, 300 MHz) δ
5.12 (s, 2H), 5.14 (s, 2H), 7.04 (m, 4H), 7.36 (s, 1H), 7.44 (m,
10H), 7.59 (m, 2H), 7.86 (m, 2H); 13C NMR (CDCl3, 75 MHz)
δ 70.4 (OCH2Ph), 108.7 (CH)CCN), 115.4 and 115.5 (Ph ring
CH), 118.8 (CN), 127.2, 127.3, 127.7, 128.35, 128.41, 128.9,
131.1, 136.6, 136.7, 140.2 (CHdCCN), 159.5, 160.6. HRMS
(FAB): m/z 417.1726 ([M]+, C29H23NO2, calcd 417.1729).
(2R*,3S*)-2,3-Bis(4-(benzyloxy)phenyl)pent-4-eneni-
trile (2b). To a dry THF solution (35 mL) of (Z)-2,3-bis(4-
(benzyloxy)phenyl)acrylonitrile (3433 mg, 8.22 mmol) and CuI
(157 mg, 0.82 mmol) was added 1 M vinylmagnesium bromide
(10 mL) dropwise at -25 °C. The flask was allowed to warm
to room temperature over 1 h and stirred overnight under Ar
gas atmosphere. The reaction was quenched by saturated NH4-
Cl, and the mixture was stirred for 2 h at 0 °C. After filtering
off the precipitate, the filtrate was concentrated, redissolved
in ethyl acetate, then washed by NaHCO3 solution, dried over
MgSO4, and concentrated. The crude product was recrystal-
lized for 1 h from refluxing ethanol to give a white solid.
Repeated recrystallization from refluxing ethanol gave pure
erythro-2b (1695 mg, 46%): 1H NMR (CDCl3, 300 MHz) δ 3.64
(t, J ) 7.7 Hz, 1H), 3.99 (d, J ) 7.2 Hz, 1H), 5.04 (s, 4H), 5.12
(d, J ) 17 Hz, 1H), 5.26 (d, J ) 10 Hz, 1H), 6.20 (m, 1H), 6.89
(m, 4H), 7.05 (m, 4H), 7.37 (m, 10H); 13C NMR (CDCl3, 75
MHz) δ 43.9 (CHCN), 54.6 (CHCHdCH2), 70.2 (OCH2Ph),
115.15 and 115.19 (Ph ring CH), 118.9 (CHCH)CH2), 120.2
(CN), 126.6, 127.7, 128.20, 128.26, 128.8, 129.2, 129.5, 132.0,
136.3 (CHCHdCH2), 136.9 and 137.1 (OCH2C), 158.2 and
158.6 (COCH2). HRMS (FAB): m/z 452.2184 ([M + Li]+,
C31H27NO2Li, calcd 452.2202).
(2R*,3S*)-2,3-Bis(4-(benzyloxy)phenyl)-5-hydroxypen-
tanenitrile (3b). To a dry THF solution (20 mL) of (2R*,3S*)-
2,3-bis(4-(benzyloxy)phenyl)pent-4-enenitrile (503 mg, 1.13
mmol) was added 1 M BH3‚THF (1.6 mL) dropwise at 0 °C.
The flask was allowed to warm to room temperature slowly
and stirred for 5 h under Ar gas atmosphere. The mixture was
cooled to 0 °C again and quenched by water (2 mL). 3 M NaOH
(4 mL) and 35% H2O2 (4 mL) were added, and the resulting
reaction mixture was stirred for 30 min more in ice bath. The
solution was diluted with water (15 mL) and extracted by ethyl
acetate (2 × 20 mL). The combined organic layer was washed
by saline, dried over MgSO4, and concentrated. The crude
product was chromatographed over silica using ethyl acetate/
hexane (1:1) to give pure product. (228 mg, 44%): 1H NMR
(CDCl3, 300 MHz) δ 2.02-2.26 (m, 2H), 3.19-3.41 (m, 2H),
3.56 (m, 1H), 3.95 (d, J ) 7.2 Hz, 1H), 5.040 (s, 2H), 5.044 (s,
2H), 6.91 (m, 4H), 7.07 (m, 4H), 7.42 (m, 10H); 13C NMR
(CDCl3, 75 MHz) δ 34.6 (CHCH2CH2OH), 44.2 (CHCN), 46.6
(CH2CH2OH), 60.2 (CH2CH2OH), 70.1 (OCH2Ph), 115.1 (Ph
ring CH), 120.4 (CN), 126.6, 127.6, 128.08 and 128.14 (Ph ring
CH), 128.7, 129.35 and 129.40 (Ph ring CH), 131.5, 136.8 and
137.0 (OCH2C), 158.2 and 158.5.
(2R*,3S*)-2,3-Bis(4-(benzyloxy)phenyl)-5-fluoropen-
tanenitrile (4b). To a solution of (2R*,3S*)-2,3-bis(4-(benzyl-
oxy)phenyl)-5-hydroxypentanenitrile (157 mg, 0.34 mmol) in
dry CH2Cl2 (6 mL) was added (diethylamino)sulfur trifluoride
(DAST, 222 µL, 1.69 mmol) dropwise at -76 °C. The mixture
was stirred under Ar gas and allowed to warm to room-
temperature overnight. The flask was cooled to 0 °C again and
quenched by saturated NaHCO3. The solution was diluted by
water (15 mL), then extracted by CH2Cl2, dried over MgSO4,
and concentrated. The crude product was recrystallized in
refluxing ethanol to give pale yellow crystal. (83 mg, 53%): 1H
NMR (CDCl3, 300 MHz) δ 2.02-2.50 (m, 2H), 3.24 (m, 1H),
3.97 (d, J ) 6.6 Hz, 1H), 4.06-4.51 (m, 2H), 5.06 (s, 4H), 6.93
(m, 4H), 7.09 (m, 4H), 7.42 (m, 10H); 13C NMR (CDCl3, 75
MHz) δ 32.5 (d, JCF ) 20.5 Hz, CH2CH2F), 44.1 (CHCN), 46.1
(d, JCF ) 4.5 Hz, CHCH2CH2F), 70.2 (OCH2Ph), 81.4 (d, JCF
)
165.1 Hz, CH2CH2F), 115.3 (Ph ring CH), 120.1 (CN), 126.4,
127.6, 128.17, 128.22, 128.7, 129.4, 130.9, 136.8 and 137.0
(OCH2C), 158.4 and 158.7 (COCH2).
(2R*,3S*)-5-Fluoro-2,3-bis(4-hydroxyphenyl)pentane-
nitrile (5). To a clearly dissolved solution of (2R*,3S*)-2,3-
bis(4-(benzyloxy)phenyl)-5-fluoropentanenitrile (83 mg, 0.18
mmol) in ethyl acetate (15 mL) was added 10% Pd/C (106 mg),
and the mixture was stirred under H2 gas for 4 h. The Pd/C
catalyst was filtered off through a Celite plug and washed with
small amount of ethyl acetate and MeCN. After concentration,
the residue was purified by flash chromatography (silica, ethyl
acetate/hexane (1:1) to give a clear oil. (39 mg, 77%): 1H NMR
(acetone-d6, 300 MHz) δ 2.04-2.48 (m, 2H), 3.22 (m, 1H), 4.04-
4.48 (m, 2H), 4.19 (d, J ) 8.1 Hz, 1H), 6.75 (m, 4H), 7.04 (m,
4H), 8.41 (b s, 2H); 13C NMR (acetone-d6, 75 MHz) δ 34.0 (d,
JCF ) 19.4 Hz, CH2CH2F), 44.0 (CCN), 46.6 (d, JCF ) 5.7 Hz,
CCH2CH2F), 82.3 (d, JCF ) 162.8 Hz, CH2CH2F), 116.2 and
116.3 (Ph ring CH), 121.4 (CN), 126.7, 130.4 (Ph ring CH),
130.6, 157.5 and 158.0 (Ph ring C). HRMS (ESI): m/z 286.1232
([M + H]+, C17H17FNO2, calcd 286.1243). Rf ) 0.58 (silica, ethyl
acetate:hexane ) 3:1).
(2R*,3S*)-2,3-Bis(4-hydroxyphenyl)pent-4-enenitrile (6).
To a solution of (2R*,3S*)-2,3-bis(4-methoxyphenyl)pent-4-
enenitrile (473 mg, 1.61 mmol) in anhydrous CH2Cl2 was added
1 M BBr3 (7 mL) in portions at 0 °C. The solution was allowed
to warm to room temperature slowly and stirred overnight.
The reaction was quenched by water (2 mL) at 0 °C. The
mixture was diluted by ethyl acetate (30 mL), then washed
by brine solution, dried over MgSO4, and concentrated com-
pletely under vacuum to give a pale yellow solid. (422 mg,
99%): 1H NMR (acetone-d3, 300 MHz) δ 3.76 (t, J ) 8.3 Hz,
1H), 4.33 (d, J ) 8.4 Hz, 1H), 4.98 (m, 2H), 6.01 (m, 1H), 6.80
(m, 4H), 7.11 (m, 4H), 8.30 (s, 1H), 8.46 (s, 1H); 13C NMR