I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617
7615
chromatography (dichloromethane–methanol = 19:1) to
4.40. (3RS,4RS)/(3RS,4SR)-4-(4-[2-Dimethylaminoeth-
oxy]phenyl)-4-(3-hydroxyphenyl)-3-phenylbut-1-ene (36)
afford a mixture of geometric isomers of 31 (201 mg,
88%, E/Z = 51/49) as a colorless solid. Each compound
was isolated by thin layer chromatography (benzene–tri-
ethylamine = 19:1) using preparative TLC plates
(Merck, Silica gel 60 F254). [The plate was developed
The coupling product 34 (421 mg, 0.909 mmol) was dis-
solved in a solution of dimethylamine in ethanol (30%,
3 mL). After the reaction mixture had been stirred for
8 h at 110 ꢁC in a sealed vessel, it was cooled down to
room temperature. The residue was diluted with ethyl
acetate and then the solvent was removed by evapora-
tion. The crude product was purified by thin layer chro-
matography (chloroform–methanol = 9:1) to afford a
mixture of diastereomers of 36 (285 mg, 81%) as a color-
less oil; IR (neat): 3402, 3028, 2953, 1599, 1511, 1454,
1
twice in the dark.] (E)-31; H NMR (CDCl3): d 7.34–
6.54 (m, 13H, Ar), 3.92 (t, J = 5.8 Hz, 2H, OCH2),
2.63 (t, J = 5.8 Hz, 2H, NCH2), 2.45 (q, J = 7.0 Hz,
2H, 3-H), 2.34 (s, 6H, NMe2), 0.93 (t, J = 7.0 Hz, 3H,
1
4-H). (Z)-31; H NMR (CDCl3): d 7.34–6.54 (m, 13H,
Ar), 4.08 (t, J = 5.8 Hz, 2H, OCH2), 2.74 (t,
J = 5.8 Hz, 2H, NCH2), 2.48 (q, J = 7.0 Hz, 2H, 3-H),
2.39 (s, 6H, NMe2), 0.93 (t, J = 7.0 Hz, 3H, 4-H).
1244, 1180, 1031, 915, 775, 700 cmꢀ1
;
1H NMR
(CDCl3): d 7.31–6.47 (m, 13H, Ar), 5.91–5.78 (m, 1H,
2-H), 4.89–4.80 (m, 2H, 1-H), 4.20 (d, J = 11.5 Hz,
1H, 4-H), 4.06 and 3.87 (t, J = 5.5 and 5.3 Hz, 2H,
OCH2), 4.02 (dd, J = 7.9, 11.5 Hz, 1H, 3-H), 2.83 and
2.77 (t, J = 5.5 and 5.3 Hz, 2H, NCH2), 2.40 and 2.37
(s, 6H, NMe2); 13C NMR (CDCl3): d 156.7, 156.5,
156.3, 156.0, 144.6, 143.8, 143.5, 140.9, 136.1, 129.6,
129.3, 128.6, 128.4, 128.3, 128.1, 126.2, 125.8, 120.3,
120.0, 115.9, 115.6, 114.4, 114.2, 113.4, 64.9, 64.2,
57.8, 57.4, 56.0, 54.5, 45.2, 44.8; HR MS (ESI) calcd
for C26H30NO2 [M+H]+, 388.2271, found 388.2267.
4.38. 1-(4-Iodophenyl)-1-(4-[2-dimethylaminoeth-
oxy]phenyl)-2-phenylbut-1-ene (32)
The title compound was prepared according to the sim-
ilar procedure for Section 4.37. (E)-32; 1H NMR
(CDCl3): d 7.27–6.47 (m, 13H, Ar), 3.86 (t, J = 5.7 Hz,
2H, OCH2), 2.58 (t, J = 5.7 Hz, 2H, NCH2), 2.37 (q,
J = 7.0 Hz, 2H, 3-H), 2.22 (s, 6H, NMe2), 0.85 (t,
J = 7.0 Hz, 3H, 4-H). (Z)-32; 1H NMR (CDCl3): d
7.27–6.47 (m, 13H, Ar), 4.02 (t, J = 5.7 Hz, 2H,
OCH2), 2.68 (t, J = 5.7 Hz, 2H, NCH2), 2.40 (q,
J = 7.0 Hz, 2H, 3-H), 2.28 (s, 6H, NMe2), 0.85
(t, J = 7.0 Hz, 3H, 4-H).
4.41. 1-(4-[2-Dimethylaminoethoxy]phenyl)-1-(3-
hydroxyphenyl)-2-phenylbut-1-ene (2, droloxifene)
4.39. (3RS,4RS)/(3RS,4SR)-4-[4-(2-Chloroeth-
oxy)phenyl]-4-[3-(pivaloyloxy)phenyl]-3-phenylbut-1-ene
(34)
To a solution of potassium tert-butoxide (373 mg,
3.32 mmol) in DMSO (1 mL) at room temperature was
added a solution of 36 (199 mg, 0.512 mmol) in DMSO
(1 mL). The reaction mixture was stirred for 2 h at 50 ꢁC
and then poured into saturated aqueous ammonium
chloride at 0 ꢁC. The mixture was extracted with diethyl
ether, and the organic layer was washed with brine,
dried over sodium sulfate. After filtration of the mixture
and evaporation of the solvent, the crude product was
purified by thin layer chromatography (ammoniacal
chloroform–methanol = 19:1) to afford (E)-droloxifene
((E)-2) (97.4 mg, 49%) and (Z)-droloxifene ((Z)-2)
(74.5 mg, 38%) as colorless solids, respectively. (E)-2;
mp 161–162 ꢁC; IR (KBr): 3422, 2979, 1608, 1592,
To a suspension of hafnium tetrachloride (490 mg,
1.53 mmol) and trimethylsilyl trifluoromethanesulfonate
(34.0 mg, 0.153 mmol) in b-chlorophenetole (1 mL) at
room temperature with cooling by a water bath to main-
tain the settled temperature was added a mixture of
cinnamyltrimethylsilane (583 mg, 3.06 mmol) and 3-
pivaloyloxybenzaldehyde (316 mg, 1.53 mmol) in b-
chlorophenetole (1 mL). The reaction mixture was stirred
for 2 h at room temperature and then poured into satu-
rated aqueous sodium hydrogencarbonate at 0 ꢁC. The
mixture was extracted with diethyl ether, and the organic
layer was washed with brine, dried over sodium sulfate.
After filtration of the mixture and evaporation of the sol-
vent, the crude product was purified by column chroma-
tography (hexane–ethyl acetate = 9:1) followed by thin
layer chromatography (toluene–hexane = 17:3) to afford
a mixture of isomers of 34 (308 mg, 43%, (o-)/
(p-) = 2:98, (3RS,4RS)/(3RS,4SR) = ca. 55:45) as a color-
less oil; IR (neat): 2974, 1750, 1609, 1587, 1511, 1480,
1509, 1470, 1444, 1287, 1243, 1173, 1116, 785 cmꢀ1
;
1H NMR (CDCl3): d 7.36–6.54 (m, 13H, Ar), 3.98 (t,
J = 5.5 Hz, 2H, OCH2), 2.74 (t, J = 5.5 Hz, 2H,
NCH2), 2.41 (q, J = 7.3 Hz, 2H, 3-H), 2.34 (s, 6H,
NMe2), 0.92 (t, J = 7.3 Hz, 3H, 4-H); 13C NMR
(CDCl3): d 157.3, 157.2, 144.7, 144.5, 142.1, 138.8,
136.6, 132.4, 130.0, 129.4, 128.7, 127.1, 122.1, 117.1,
114.0, 113.7, 65.7, 58.5, 45.6, 29.6, 13.7; HR MS (ESI)
calcd for C26H30NO2 [M+H]+, 388.2271, found
388.2269. (Z)-2; mp 146–149 ꢁC; IR (KBr): 3422, 2953,
1664, 1606, 1591, 1508, 1445, 1286, 1236, 1174, 1022,
1
1453, 1244, 1146, 1116, 1032, 914, 698 cmꢀ1; H NMR
(CDCl3): d 7.31–6.63 (m, 13H, Ar), 5.93–5.86 (m, 1H,
2-H), 4.94–4.90 (m, 2H, 1-H), 4.24–4.05 (m, 2H, 3-H, 4-
H), 4.18 and 4.07 (t, J = 6.0 Hz, 2H, OCH2), 3.77 and
3.69 (t, J = 6.0 Hz, 2H, ClCH2), 1.34 and 1.33 (s, 9H,
t-Bu); 13C NMR (CDCl3): d 176.9, 176.8, 156.6, 156.2,
151.0, 144.4, 140.3, 140.2, 136.1, 136.0, 129.8, 129.7,
129.4, 129.3, 129.0, 128.6, 128.4, 128.2, 125.7, 125.6,
121.4, 119.1, 119.0, 116.5, 114.6, 114.4, 68.0, 67.9, 56.1,
54.3, 41.9, 39.0, 27.2, 27.1; HR MS (ESI) calcd for
C29H32ClO3 [M+H]+, 463.2035, found 463.2038.
770 cmꢀ1 1H NMR (CDCl3): d 7.22–6.55 (m, 13H,
;
Ar), 5.70 (br, 1H, OH), 4.08 (t, J = 5.7 Hz, 2H,
OCH2), 2.76 (t, J = 5.7 Hz, 2H, NCH2), 2.43 (q,
J = 7.3 Hz, 2H, 3-H), 2.33 (s, 6H, NMe2), 0.92 (t,
J = 7.3 Hz, 3H, 4-H); 13C NMR (CDCl3): d 157.3,
156.2, 143.9, 143.3, 141.8, 138.0, 136.1, 130.6, 130.5,
128.8, 127.2, 125.6, 121.5, 116.7, 114.0, 113.4, 65.5,
58.0, 45.5, 29.0, 13.5; HR MS (ESI) calcd for
C26H30NO2 [M+H]+, 388.2271, found 388.2280.