124 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Duplantier et al.
(1.50 g, 7.39 mmol), triphenylphosphine (2.13 g, 8.13 mmol),
and (S)-(-)-endo-norborneol (0.83 g, 7.39 mmol) in anhydrous
THF (25 mL) at 25 °C was added diethyl azodicarboxylate (1.4
mL, 8.9 mmol). After 18 h the mixture was diluted with ether
(350 mL) and washed with 1 N NaOH, water, and brine.
Concentration provided a yellow oil which was triturated with
1:1 ether/hexane to remove triphenylphosphine oxide. The
filtrate was concentrated and chromatographed (1:9 ethyl
acetate/hexane) to afford 1.75 g (80%) of a clear colorless oil:
gas evolution had ceased, ether was added and the mixture
was concentrated. Chromatography through a short column
of basic alumina eluted with 1:3 petroleum ether/ether afforded
4.4 g (97%) of a yellow oil: 1H NMR (300 MHz, CDCl3) δ 1.95
(quintet, J ) 7.6 Hz, 2H), 2.33 (t, J ) 7.3 Hz, 2H), 2.72 (t, J )
7.7 Hz, 2H), 3.80 (s, 3H), 3.84 (d, J ) 2.1 Hz, 1H), 4.10 (d, J
) 2.0 Hz, 1H), 6.81 (d, J ) 8.72 Hz, 1H), 7.14-7.32 (m, 7H);
MS m/z 347.
1-(5-Br om o-2-m eth oxyp h en oxy)-1-(3-p h en ylp r op yl)cy-
clop r op a n e (2k ). To a stirred solution of 2j (4.4 g, 12.7 mmol)
in anhydrous ether (8 mL) was added methylene iodide (3.7
g, 14.0 mmol) followed by zinc-copper couple (0.84 g, 14.0
mmol) and iodine (5 mg). After heating at reflux for 17 h, the
mixture was filtered and washed with ether. The combined
ether washings were washed with saturated aqueous am-
monium chloride, sodium bicarbonate, and brine. Concentra-
tion and chromatography (1:9 ethyl acetate/hexane) afforded
3.2 g (71%) of a colorless oil. 1H NMR (300 MHz, CDCl3) δ
0.73 (dd, J ) 5.9, 7.4 Hz, 2H), 1.04 (dd, J ) 5.6, 6.9 Hz, 2H),
1.76-1.87 (m, 4H), 2.63 (t, J ) 7.0 Hz, 2H), 3.81 (s, 3H), 6.73
(d, J ) 8.5 Hz, 1H), 7.02 (dd, J ) 2.2, 8.7 Hz, 1H); HRMS
calcd for C19H21BrO2 360.0725, found 360.0714.
1
[R]D -23.1° (c ) 1.59, CHCl3); H NMR (300 MHz, CDCl3) δ
1.1 (m, 3H), 1.5 (m, 3H), 1.8 (m, 2H), 2.32 (m, 1H), 2.49 (d, J
) 4.6 Hz, 1H), 3.80 (s, 3H), 4.14 (d, J ) 6.5 Hz, 1H), 6.71 (d,
J ) 8.5 Hz, 1H), 6.92 (d, J ) 2.3 Hz, 1H), 6.98 (dd, J ) 8.5,
2.3 Hz, 1H). Anal. (C14H17O2Br) C, H.
1
4-Br om o-2-cyclop en toxya n isole (2a ):21 colorless oil; H
NMR (250 MHz; CDCl3) δ 1.59-1.70 (m, 2H), 1.80-2.06 (m,
6H), 3.85 (s, 3H), 4.65-4.76 (m, 1H), 6.69 (d, J ) 8.4 Hz, 1H),
6.99 (m, 2H).
(S)-exo-2-(5-Br om o- 2-m eth oxyp h en oxy)bicyclo[2.2.1]-
h ep ta n e (2b). See 2c for 1H NMR and purification method:
colorless oil; [R]D +21.8° (c ) 1.42, CHCl3). Anal. (C14H17O2-
Br) C, H.
4-Br om o-2-(2-in d a n yloxy)a n isole (2d ): purified by chro-
matography (95:5 hexane/ethyl acetate) followed by recrystal-
lization from methanol; 76% yield; white solid; mp 116-117
Gen er a l P r oced u r e B. P a lla d iu m -Ca ta lyzed Bia r yl
Cou plin g. (R)-(+)-4-[4-Meth oxy-3-(5-ph en ylpen t-2-yloxy)-
p h en yl]ben zoic Acid (10). To a stirred solution of 2f (2.0 g,
5.7 mmol) in anhydrous THF (30 mL) at -78 °C was added
dropwise a 2.5 M solution of n-BuLi in hexanes (2.80 mL, 7.0
mmol). After 30 min a 1 M solution of ZnCl2 in THF (7.0 mL,
7.0 mmol) was added, and the mixture was warmed to ambient
temperature over 30 min before adding tetrakis(triphenylphos-
phine)palladium(0) (0.42 g, 0.36 mmol) and methyl 4-bro-
mobenzoate (1.32 g, 5.7 mmol). After stirring at ambient
temperature over 3 h, the mixture was concentrated and
chromatographed (1:3 ether/hexane) to give 1.2 g (50%) of a
yellow oil (MS m/z 418). The oil was dissolved in a mixture of
ethanol (15 mL) and 1 N NaOH (12 mL) and heated to reflux.
After 1.5 h the ethanol was removed under reduced pressure,
water (20 mL) was added, and the mixture was extracted with
ether before being acidified to pH ∼2 with 6 N HCl. The
resulting suspension was extracted with methylene chloride,
and the combined organics were washed with water and brine.
Concentration provided 1.04 g (45% from 2f) of a white solid:
mp 159-160 °C; [R]D +33.3° (CHCl3); 1H NMR (250 MHz;
CDCl3) δ 1.34 (d, J ) 6.2 Hz, 3H), 1.59-1.94 (m, 4H), 2.67 (t,
J ) 7.1 Hz, 2H), 3.89 (s, 3H), 4.38-4.50 (m, 1H), 6.94 (d, J )
8.3 Hz, 1H), 7.10-7.29 (m, 7H), 7.59 (d, J ) 8.2 Hz, 2H), 8.15
(d, J ) 8.2 Hz, 2H). Anal. (C25H26O4) C, H.
1
°C; H NMR (300 MHz, CDCl3) δ 3.23 (dd, J ) 3.7, 16.7 Hz,
2H), 3.40 (dd, J ) 6.6, 16.7 Hz, 2H), 3.78 (s, 3H), 5.15 (m, 1H),
6.74 (d, J ) 9.1 Hz, 1H), 7.05 (m, 2H), 7.21 (m, 4H). Anal.
(C16H15BrO2) C, H.
4-Br om o-2-(4-p h en ylbu toxy)a n isole (2e): purified by
chromatography (4:1 hexane/ethyl acetate); 95% yield; yellow
oil; 1H NMR (250 MHz, CDCl3) δ 1.75-1.92 (m, 4H), 2.70 (t, J
) 7.0 Hz, 2H), 3.84 (s, 3H), 3.99 (t, J ) 6.3 Hz, 2H), 6.73 (d, J
) 8.5 Hz, 1H), 6.95-7.10 (m, 2H), 7.19-7.39 (m, 5H). Anal.
(C17H19BrO2) C, H.
(R)-4-Br om o-2-(5-p h en yl-2-p en toxy)a n isole (2f): puri-
fied by chromatography (4:1 hexane/ethyl acetate); 80% yield;
colorless oil; [R]D +9.05° (CHCl3); 1H NMR (250 MHz, CDCl3)
δ 1.31 (d, J ) 6.1 Hz, 3H), 1.61-1.98 (m, 4H), 2.62-2.69 (m,
2H), 3.82 (s, 3H), 4.28-4.38 (m, 1H), 6.73 (d, J ) 8.6 Hz, 1H),
6.96-7.05 (m, 2H), 7.16-7.21 (m, 3H), 7.24-7.32 (m, 2H).
Anal. (C18H21BrO2): H; C: calcd, 61.90; found, 59.77.
(S)-4-Br om o-2-(5-p h en yl-2-p en toxy)a n isole (2g): color-
less oil; [R]D -9.0° (CHCl3); 1H NMR identical with 2f. Anal.
(C18H21BrO2) H; C: calcd, 61.90; found, 61.18.
4-Br om o-2-(5-p h en ylp en toxy)a n isole (2h ): purified by
chromatography (4:1 hexane/ethyl acetate); 98% yield; 1H NMR
(300 MHz, CDCl3) δ 1.51 (m, 2H), 1.71 (m, 2H), 1.88 (m, 2H),
2.66 (t, J ) 7.6 Hz, 2H), 3.84 (s, 3H), 3.98 (t, J ) 6.8 Hz, 2H),
6.73 (d, J ) 8.5 Hz, 1H), 7.01 (m, 2H), 7.19 (m, 3H), 7.31 (m,
2H). Anal. (C18H21BrO2) C, H.
5-Br om o-2-m eth oxyp h en yl 4-p h en ylbu tyr a te (2i). To
a stirred solution of 5-bromoguaiacol (5.0 g, 24.6 mmol) and
4-DMAP (10 mg) in pyridine (25 mL) at 0 °C was added
phenylbutyryl chloride (6.7 g, 36.9 mmol) dropwise over 10
min. An exotherm was observed, and a white precipitate
formed during the addition. After stirring for 2 h at room
temperature, the reaction was quenched with water (5 mL)
and the mixture diluted with a 1:3 mixture of ethyl acetate/
hexane (250 mL). The mixture was then washed with 1 N
HCl (100 mL × 3), saturated aqueous bicarbonate, and brine,
dried over sodium sulfate, and filtered. Concentration and
chromatography (1:5 ethyl actetate/hexane) provided 8.3 g
(97%) of a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 2.09
(quintet, J ) 7.5 Hz, 2H), 2.60 (t, J ) 7.3 Hz, 2H), 2.77 (t, J )
7.6 Hz, 2H), 3.81 (s, 3H), 6.84 (d, J ) 8.8 Hz, 1H), 7.16-7.35
(m, 7H); MS m/z 348 and 350.
2-(5-Br om o-2-m eth oxyph en oxy)-5-ph en yl-1-pen ten e (2j).
Tebbe reagent (prepared from titanocene dichloride and tri-
methyl aluminum) (30 mL of a 0.55 M solution in toluene) was
added dropwise to a stirred solution of 5-bromo-2-methoxy-
phenyl 4-phenylbutyrate (2i) (4.55 g, 13.0 mmol) and pyridine
(0.25 mL) in a mixture of anhydrous THF (10 mL) and
anhydrous toluene (30 mL) at 0 °C. The reaction mixture was
warmed to ambient temperature for 2 h and recooled to 0 °C,
and the reaction was quenched with 3N NaOH (6 mL). After
4-(4-Meth oxy-3-cyclop en toxyp h en yl)ben zoic a cid (4):
recrystallized from ethyl acetate/hexane; 31% yield from 2a ;
1
white crystalline solid; mp 230-232 °C; H NMR (250 MHz;
CDCl3) δ 1.58-1.69 (m, 2H), 1.80-2.06 (m, 6H), 3.91 (s, 3H),
4.81-4.93 (m, 1H), 6.96 (d, J ) 8.3 Hz, 1H), 7.16-7.23 (m,
2H), 7.65 (d, J ) 8.5 Hz, 2H), 8.16 (d, J ) 8.5 Hz, 2H). Anal.
(C19H20O4) C, H.
3-(4-Meth oxy-3-cyclop en toxyp h en yl)ben zoic a cid (5):
recrystallized from ethyl acetate/hexane; 35% yield from 2a ;
1
white crystalline solid; mp 149-151 °C; H NMR (250 MHz;
CDCl3) δ 1.60-1.71 (m, 2H), 1.81-2.09 (m, 6H), 3.91 (s, 3H),
4.86-4.91 (m, 1H), 6.96 (d, J ) 8.2 Hz, 1H), 7.12-7.18 (m,
2H), 7.48-7.55 (m, 1H), 7.75-7.81 (m, 1H), 8.05-8.10 (m, 1H),
8.30 (m, 1H). Anal. (C19H20O4) C, H.
(S)-(+)-exo-4-[3-(Bicyclo[2.2.1]h ep t -2-yloxy)-4-m et h -
oxyph en yl]ben zoic acid (6): recrystallized from ethyl acetate/
hexane; 47% yield from 2b; white silvery crystals; mp 230-
232 °C; [R]D +23.5° (c ) 1.05, THF); 1H NMR (250 MHz;
DMSO-d6) δ 1.1 (m, 3H), 1.5 (m, 3H), 1.61 (m, 1H), 1.8 (m,
1H), 2.28 (m, 1H), 2.38 (m, 1H), 3.79 (s, 3H), 4.39 (d, J ) 5.9
Hz, 1H), 7.05 (d, J ) 8.4 Hz, 1H), 7.20 (d, 2.0 Hz, 1H), 7.26
(dd, J ) 8.3, 2.0 Hz, 1H), 7.75 (d, J ) 8.3 Hz, 2H), 7.98 (d, J
) 8.2 Hz, 2H), 12.9 (br s, 1H). Anal. (C21H22O2) C, H.
(R)-(-)-exo-4-[3-(Bicyclo[2.2.1]h ep t -2-yloxy)-4-m et h -
oxyph en yl]ben zoic acid (7): recrystallized from ethyl acetate/
hexane; 42% yield from 2c; silvery white crystals; mp 234-
236 °C; [R]D -25.1° (c ) 0.89, THF). Anal. (C21H22O2) C, H.
4-[4-Meth oxy-3-(2-in d a n yloxy)p h en yl]ben zoic a cid (8):
recrystallized from ethanol; 54% yield from 2d ; white crystal-