Antiestrogenically Active 1,1,2-tris(4-Hydroxyphenyl)alkenes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 8 1489
Ar′′H-3, Ar′′H-5); 7.06 (AA′BB′ 3J ) 8.7 Hz, 2H, Ar′H-2, Ar′H-
(CdC); 1510 s (CdC). MS (EI, 80 °C): m/z (%) ) 284 [M]+•
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(6.6); 135 H3CO-Ph-CO+ (100).
6); 7.14 (AA′BB′ J ) 8.6 Hz, 2H, Ar′′H-2, Ar′′H-6). IR (KBr,
cm-1): 2955 w (CH2); 2910 w (CH2); 2836 w (OCH3); 1607 s
(CdC); 1573 w (CdC); 1511 s (CdC). MS (EI, 140 °C): m/z
(%) ) 360 [M]+• (100).
1,2-Bis(4-m eth oxyp h en yl)p en ta n on e (1d ). From 1a (5.12
g, 20 mmol), potassium tert-butanolate (3.47 g, 30.9 mmol) and
bromopropane (3.66 g, 29.7 mmol) in THF. The crude product
was purified by column chromatography with diethyl ether/
1,1,2-Tr is(4-m eth oxyp h en yl)bu t-1-en e (2c). Magnesium
(0.26 g, 10.6 mmol) and 4-bromoanisole (1.98 g, 10.6 mmol)
were reacted in dry THF to give the Grignard reagent. 1c (2.03
g, 7.0 mmol) was added and the mixture was refluxed for 12
h. Hydrolysis was carried out by heating the crude carbinol
in 10 mL of H3PO4 for 2 h. The compound was purified by
column chromatography with diethyl ether/ligroine 1:3.
Yield: 2.07 g (5.53 mmol, 79%) of a colorless solid (mp 90 °C).
1H NMR (CDCl3): 0.92 (t, 3H, CH3); 2.45 (q, 2H, CH2); 3.69
(s, 3H, OCH3); 3.76 (s, 3H, OCH3); 3.82 (s, 3H, OCH3); 6.56
(AA′BB′ 3J ) 8.9 Hz, 2H, ArH-3, ArH-5); 6.71 (AA′BB′ 3J )
8.8 Hz, 2H, Ar′H-3, Ar′H-5); 6.78 (AA′BB′ 3J ) 8.9 Hz, 2H,
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ligroine 1:5. Yield: 3.25 g (10.3 mmol, 54%) of a yellow oil. H
NMR (CDCl3): δ ) 0.91 (t, 3H, CH3); 1.27 (m, 2H, CH2CH3);
1.77 (m, 1H, ROC-CHRCH2); 2.15 (m, 1H, ROC-CHRCH2); 3.75
(s, 3H, OCH3); 3.82 (s, 3H, OCH3); 4.46 (t, 1H, CH); 6.81
(AA′BB′ 3J ) 8.7 Hz, 2H, ArH-3, ArH-5); 6.86 (AA′BB′ 3J )
8.9 Hz, 2H, Ar′H-3, Ar′H-5); 7.21 (AA′BB′ 3J ) 8.7 Hz, 2H,
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ArH-2, ArH-6); 7.95 (AA′BB′ J ) 8.9 Hz, 2H, Ar′H-2, Ar′H-
6). IR (film; cm-1): 2957 s (CH2); 2934 s (CH2); 2869 m (OCH3);
2838 m (OCH3); 1671 s (CdO); 1601 s (CdC); 1510 s (CdC).
MS (EI, 60 °C): m/z (%) ) 163 [H3CO-Ph-CH+C2H5] (18.9);
135 H3CO-Ph-CO+ (100).
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ArH-2, ArH-6); 6.87 (AA′BB′ J ) 8.6 Hz, 2H, Ar′′H-3, Ar′′H-
1,2-Bis(4-m eth oxyp h en yl)h exa n on e (1e). From 1a (5.09
g, 19.9 mmol), potassium tert-butanolate (3.41 g, 30.4 mmol)
and bromobutane (4.18 g, 30.5 mmol) in 25 mL of THF. The
crude product was purified by column chromatography with
ether/ligroine 1:5. Yield: 3.16 g (10.1 mmol, 51%) of a yellow
oil. 1H NMR (CDCl3): δ ) 0.86 (t, 3H, CH3); 1.13-1.39 (m,
4H, 2 × CH2); 1.77 (m, 1H, ROC-CHRCH2); 2.15 (m, 1H, ROC-
CHRCH2); 3.75 (s, 3H, OCH3); 3.82 (s, 3H, OCH3); 4.43 (t, 1H,
CH); 6.81 (AA’BB’ 3J ) 8.7 Hz, 2H, ArH-3, ArH-5); 6.86
5); 7.02 (AA′BB′ 3J ) 8.8 Hz, 2H, Ar′H-2, Ar′H-6); 7.14 (AA′BB′
3J ) 8.6 Hz, 2H, Ar′′H-2, Ar′′H-6). IR (KBr, cm-1): 3061 w
(ArH); 3011 w (ArH); 2953 m (CH2); 2833 m (OCH3); 1608 s
(CdC); 1573 w (CdC); 1509 s (CdC). MS (EI, 150 °C): m/z
(%) ) 374 [M]+• (100).
1,1,2-Tr is(4-m et h oxyp h en yl)p en t -1-en e (2d ). Magne-
sium (0.4 g, 16.3 mmol) and 4-bromoanisole (2.99 g, 16.0 mmol)
were reacted in THF to give the Grignard reagent. 1,2-Bis(4-
methoxyphenyl)pentanone 1d (3.25 g, 10.9 mmol) in 20 mL of
dry THF was added and heated for 14 h. Decomposition with
35 mL of HBr (47%) and column chromatography with diethyl
ether/ligroine 1:3 gave 1.8 g (4.64 mmol, 43%) of colorless
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(AA′BB′ J ) 8.9 Hz, 2H, Ar′H-3, Ar′H-5); 7.21 (AA′BB′ J )
8.7 Hz, 2H, ArH-2, ArH-6); 7.95 (AA′BB′ 3J ) 8.9 Hz, 2H, Ar′H-
2, Ar′H-6). IR (Film; cm-1): 3003 w (ArH); 2955 s (CH2); 2932
s (CH2); 2859 m (OCH3); 2840 m (OCH3); 1671 s (CdO); 1601
s (CdC); 1510 s (CdC). MS (EI, 110 °C): m/z (%) ) 312 [M]+•
(4.7); 135 [H3CO-Ph-CO+] (100).
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crystals (mp 91 °C). H NMR (CDCl3): 0.81 (t, 3H, CH3); 1.26
(m, 2H, CH2CH3); 2.38 (m, 2H, dCR-CH2); 3.69 (s, 3H, OCH3);
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3.76 (s, 3H, OCH3); 3.82 (s, 3H, OCH3); 6.55 (AA′BB′ J ) 8.8
Meth od C: 1,1,2-Tr is(4-m eth oxyp h en yl)eth en e (2a ). A
solution of 1a (1.3 g, 5.05 mmol) in dry THF was added
dropwise to a solution of 4-methoxyphenylmagnesium bromide
(1.41 g, 7.5 mmol) in THF, which was generated before from
4-bromoanisole and Mg (0.19 g, 7.8 mmol). The mixture was
refluxed for 12 h and then decomposed with ice and acetic acid
(6 N). The solvent was removed under reduced pressure and
the remaining aqueous layer was extracted with diethyl ether.
The combined organic extracts were washed with saturated
NaHCO3 solution and water, dried over Na2SO4, and the
solvent was removed to give the crude carbinol. After dissolu-
tion in dry THF it was added dropwise to ice cold 47% HBr.
The mixture was warmed to room temperature and stirred for
2 h, then poured onto ice, and extracted with dichloromethane.
The organic extracts were washed with NaHCO3 solution and
water. After the extracts were dried over Na2SO4, the solvent
was removed and the remaining product was purified by
column chromatography on silica gel with diethyl ether/
ligroine 1:1. Yield: 0.99 g (2.86 mmol, 57%) of a colorless solid
(mp 93-95 °C). 1H NMR (CDCl3): δ ) 3.75 (s, 3H, OCH3); 3.81
Hz, 2H, ArH-3, ArH-5); 6.67 (AA′BB′ 3J ) 8.6 Hz, 2H, Ar′H-3,
Ar′H-5); 6.79 (AA′BB′ 3J ) 8.8 Hz, 2H, ArH-2, ArH-6); 6.87
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(AA′BB′ J ) 8.6 Hz, 2H, Ar′′H-3, Ar′′H-5); 7.01 (AA′BB′ J )
8.6 Hz, 2H, Ar′H-2, Ar′H-6); 7.15 (AA′BB′ 3J ) 8.6 Hz, 2H,
Ar′′H-2, Ar′′H-6). IR (KBr, cm-1): 3029 w (ArH); 2953 m (CH2);
2836 w (OCH3); 1607 s (CdC); 1573 w (CdC); 1510 s (CdC).
MS (EI, 130 °C): m/z (%) ) 388 [M]+• (100).
1,1,2-Tr is(4-m eth oxyp h en yl)h ex-1-en e (2e). Magnesium
(0.12 g, 4.8 mmol) and 4-bromoanisole (0.84 g, 4.5 mmol) were
reacted in THF to form the Grignard reagent. 1,2-Bis(4-
methoxyphenyl)hexanone 1e (0.96 g, 3.1 mmol) was added and
the mixture refluxed for 12 h. The carbinol was decomposed
with 10 mL of 85% H3PO4 and the product isolated by column
chromatography with diethyl ether/ligroine 1:5. Yield: 0.8 g
(2 mmol, 65%) of a colorless oil. 1H NMR (CDCl3): 0.78 (t, 3H,
CH3); 1.17-1.34 (m, 4H, 2 × CH2); 2.4 (t, 2H, CdCRCH2); 3.69
(s, 3H, OCH3); 3.76 (s, 3H, OCH3); 3.82 (s, 3H, OCH3); 6.56
(AA′BB′ 3J ) 8.7 Hz, 2H, ArH-3, ArH-5); 6.71 (AA′BB′ 3J )
8.6 Hz, 2H, Ar′H-3, Ar′H-5); 6.78 (AA′BB′ 3J ) 8.7 Hz, 2H,
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ArH-2, ArH-6); 6.87 (AA′BB′ J ) 8.7 Hz, 2H, Ar′′H-3, Ar′′H-
(s, 3H, OCH3); 3.84 (s, 3H, OCH3); 6.68 (AA′BB′ J ) 8.8 Hz,
5); 7.02 (AA′BB′ 3J ) 8.6 Hz, 2H, Ar′H-2, Ar′H-6); 7.14 (AA′BB′
3J ) 8.7 Hz, 2H, Ar′′H-2, Ar′′H-6). IR (KBr, cm-1): 3031 w
(ArH); 2955 s (CH2); 2934 s (CH2); 2834 m (OCH3); 1608 s (Cd
C); 1573 w (CdC); 1509 s (CdC). MS (EI, 90 °C): m/z (%) )
402 [M]+• (100).
2H, ArH-3, ArH-5); 6.78 (s, 2H, CH); 6.84 (AA′BB′ 3J ) 8.8
Hz, 2H, ArH-2, ArH-6); 6.87 (AA′BB′ 3J ) 8.6 Hz, 2H, Ar′H-3,
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Ar′H-5); 6.96 (AA′BB′ J ) 8.7 Hz, 2H, Ar′′H-3, Ar′′H-5); 7.12
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(AA′BB′ J ) 8.6 Hz, 2H, Ar′H-2, Ar′H-6); 7.24 (AA′BB′ J )
8.7 Hz, 2H, Ar′′H-2, Ar′′H-6). IR (KBr, cm-1): 3001 w (ArH);
2957 w (CH2); 2930 w (CH2); 2836 w (OCH3); 1605 s (CdC);
1571 m (CdC); 1511 s (CdC). MS (EI, 140 °C): m/z (%) ) 346
[M]+• (100).
Meth od D: 1,1,2-Tr is(4-h yd r oxyp h en yl)eth en e (3a ). A
solution of 2a (0.34 g, 1.0 mmol) in dry dichloromethane was
cooled to -52 °C. Under nitrogen, BBr3 (2.25 g, 9.0 mmol) in
dry dichloromethane was added dropwise. After 0.5 h the
cooling was removed and the reaction mixture was stirred at
room temperature for 3 days. After that, dry methanol was
added under cooling and the solvents were removed under
reduced pressure for at least three times. The crude product
was recrystallized from CH2Cl2. Yield: 0.1 g (0.34 mmol, 34%)
of a dark red solid (mp 168 °C). 1H NMR (CDCl3): δ ) 6.6-
7.2 (m, 13H, ArH, CH); 8.2-8.4 (3s, 3H, ArOH). IR (KBr, cm-1):
3441 br, s (OH); 3394 br, s (OH); 3073 m (ArH); 3025 m (ArH);
2936 m (CH2); 1608 s (CdC); 1511 s (CdC). MS (EI, 160 °C):
m/z (%) ) 304 [M]+• (73.4); 94 (100). Anal. (C20H16O3) C H.
1,1,2-Tr is(4-m eth oxyp h en yl)p r op -1-en e (2b). The Grig-
nard reagent was synthesized from magnesium (0.25 g, 10.1
mmol) and 4-bromoanisole (1.89 g, 10.1 mmol) in 15 mL of
dry THF. 1,2-Bis(4-methoxyphenyl)propanone 1b (1.82 g, 6.7
mmol) in 20 mL abs. THF were added and the mixture was
refluxed for 12 h. After 2 h of hydrolysis with 27 mL of HBr,
the crude product was purified by column chromatography
with diethyl ether/ligroine 1:10. Yield: 1.84 g (5.12 mmol, 76%)
of pink crystals (mp 116 °C). 1H NMR (CDCl3): 2.10 (s, 3H,
CH3); 3.70 (s, 3H, OCH3); 3.75 (s, 3H, OCH3); 3.82 (s, 3H,
OCH3); 6.58 (AA′BB′ 3J ) 8.8 Hz, 2H, ArH-3, ArH-5); 6.69
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(AA′BB′ J ) 8.7 Hz, 2H, Ar′H-3, Ar′H-5); 6.79 (AA′BB′ J )
8.8 Hz, 2H, ArH-2, ArH-6); 6.87 (AA′BB′ 3J ) 8.6 Hz, 2H,
1,1,2-Tr is(4-h yd r oxyp h en yl)p r op -1-en e (3b). From 2b
(0.36 g, 1.0 mmol). Yield: 0.2 g (0.6 mmol, 60%) of a pink