4248 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Meyers et al.
trituration with ether and filtration. The filtrate was concen-
trated and purified by flash chromatography (benzene) to give
olefin 62a as a pale yellow tinted oil (145 mg, 0.471 mmol,
79%). A trace of the minor olefin isomer was observed in the
1H NMR spectra.
(EI) calcd for C15H13O2F3: 282.0865, found 282.0868. Anal.
(C15H13O2F3) C, H.
3,3,4,4,4-P e n t a flu o r o -1,2-b i s (4-h y d r o x y p h e n y l)-
bu ta n e (64b). Fluoroalkane 63b (84.7 mg, 0.235 mmol) was
demethylated with BBr3 (0.500 mmol, 2.1 equiv) according to
method C (basic workup). Flash chromatography (50% EtOAc/
hexanes) afforded 64b as a clear oil which solidified upon
storage at -20 °C to give a white solid (76 mg, 0.229 mmol,
3,3,4,4,4-P en t a flu or o-1,2-b is(4-m et h oxyp h en yl)b u t -1-
en e (62b). Olefin 62b was prepared according to method G
from NaOMe (171 mg, 3.17 mmol, 1.2 equiv), phosphonium
salt 60 (1.11 g, 2.64 mmol, 1.0 equiv), and ketone 61b (671
mg, 2.64 mmol, 1.0 equiv). Flash chromatography (benzene)
furnished methyl 4-methoxybenzoate (132 mg, 0.793 mmol,
30%) as a byproduct and the desired olefin 62b as a white solid
and a single isomer (228 mg, 0.636 mmol, 24%): mp 89.5-
1
97%): mp 82-84 °C; H NMR (500 MHz, acetone-d6) δ 8.35
(s, 1H), 8.06 (s, 1H), 7.09 (d, J ) 8.4, 2H), 6.85 (AA′ of AA′XX′,
J AX ) 8.6, J AA′ ) 2.5, 2H), 6.74 (d, J ) 8.8, 2H), 6.60 (XX′ of
AA′XX′, J AX ) 8.6, J XX′ ) 2.5, 2H), 3.58 (dtd, J ) 23.9, 11.5,
3.3, 1H), 3.30 (dd, J ) 13.8, 3.3, 1H), 3.02 (dd, J ) 13.7, 11.8,
1H); 13C NMR (125 MHz, acetone-d6) δ 158.1, 156.7, 131.7,
131.0, 129.2, 125.2 (d, J ) 6.5), 120.3 (qt, J ) 286, 37, CF2CF3),
117.2 (tq, J ) 256, 35, CF2CF3), 116.1, 115.8, 49.6 (t, J ) 20,
CHCF2), 33.9; MS (EI) m/z 332 (M+, 6), 225 (M - ArCH2, 2),
107 (ArCH2, 100). HRMS (EI) calcd for C16H13O2F5: 332.0836,
found 332.0841. Anal. (C16H13O2F5) C, H.
1
91.5 °C; H NMR (500 MHz, CDCl3) δ 7.19 (d, J ) 8.6, 2H),
7.12 (s, 1H), 6.95 (d, J ) 8.8, 2H), 6.94 (d, J ) 8.8, 2H), 6.70
(d, J ) 9.0, 2H), 3.85 (s, 3H), 3.76 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 160.0, 159.8, 135.5 (t, J ) 8.5, CHdCCF2), 131.8,
131.6, 126.5, 126.4 (t, J ) 21, CH)CCF2), 125.2, 119.4 (qt, J
) 285, 40, CF2CF3), 114.4, 113.7, 113.3 (tq, J ) 255, 37, CF2-
CF3), 55.1; MS (EI) m/z 358 (M+, 100). HRMS (EI) calcd for
Meth yl 2,3-Bis(4-h yd r oxyp h en yl)p r op ion a te (66). A
solution of ester 65 (104 mg, 0.346 mmol, 1 equiv) in CH2Cl2
(5 mL) was added to a solution of AlBr3 (767 mg, 2.88 mmol,
8 equiv) and EtSH (1.24 mL, 16.7 mmol) in CH2Cl2 (5 mL) at
0 °C. After 1 h at 0 °C, the reaction was quenched with MeOH
and evaporated under a stream of nitrogen overnight. The
resulting solid was partitioned between 1 M HCl and EtOAc,
and the aqueous layer was extracted with EtOAc. The com-
bined organic layers were washed with water and brine, dried
over Na2SO4, and concentrated to yield a brown oil. The
product was passed though a silica plug (50% EtOAc/hexanes)
to afford 66 as a beige solid (66.0 mg, 0.242 mmol, 70%). An
analytical sample was obtained by recrystallization from
EtOAc/hexanes: mp 86-88 °C;1H NMR (500 MHz, acetone-
d6) δ 8.27 (br s, 1H), 8.12 (br s, 1H), 7.15 (AA′ of AA′XX′, J AX
C
18H15O2F5: 358.0992, found 358.0986.
Olefin 62b was also prepared according method H from
LHMDS (600 mL of 1.0 M THF solution, 1.0 equiv), phospho-
nium salt 60 (250 mg, 0.597 mmol, 1.0 equiv), and ketone 61b
(157 mg, 0.618 mmol, 1.03 equiv). Flash chromatography
(benzene) afforded olefin 62b as a white solid (104 mg, 0.289
mmol, 48%, dr ) 94:6).
3,3,3-Tr iflu or o-1,2-bis(4-m eth oxyph en yl)pr opan e (63a).
Olefin 62a (136 mg, 0.440 mmol) was hydrogenated over 10%
Pd/C (10 mg) in EtOH (5 mL) under a hydrogen atmosphere
overnight (15 h). The mixture was purged with nitrogen,
filtered through Celite with EtOAc, and concentrated. Filtra-
tion through a plug of silica gel (10% EtOAc/hexanes) gave
63a as a clear oil (119 mg, 0.383 mmol, 87%): 1H NMR (500
MHz, CDCl3) δ 7.12 (AA′ of AA′XX′, J AX ) 8.7, J AA′ ) 2.6, 2H),
6.88 (AA′ of AA′XX′, J AX ) 8.7, J AA′ ) 2.6, 2H), 6.82 (XX′ of
) 8.5, J AA′ ) 2.0, 2H), 6.99 (AA′ of AA′XX′, J AX ) 9.0, J AA′
)
2.5, 2H), 6.67 (XX′ of AA′XX′, J AX ) 9.0, J XX′ ) 2.0, 2H), 6.68
(XX′ of AA′XX′, J AX ) 8.5, J XX′ ) 2.0, 2H), 3.75 (X of ABX, dd,
J ) 9.0, 7.0, 1H), 3.53 (s, 3H), 3.75, (X of ABX, dd, J ) 9.0,
7.0, 1H), 3.22 (AB of ABX, nA ) 1606, nB ) 1427, J AB ) 13.7,
J AX ) 8.9, J BX ) 6.6, 2H); 13C NMR (125 MHz, acetone-d6) δ
173.7, 156.5, 155.7, 130.3, 130.2, 130.1, 129.2, 115.4, 115.1,
60.3, 52.8, 39.0; MS (EI) m/z 272.2 (M+, 44); HRMS (EI) calcd
for C16H16O4: 272.1049, found 272.1042. Anal. (C16H16O4‚0.3
H2O) C, H.
AA′XX′, J AX ) 8.8, J XX′ ) 2.6, 2H), 6.71 (XX′ of AA′XX′, J AX
)
8.7, J XX′ ) 2.6, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.41 (dqd, J )
11.0, 9.3, 3.9, 1H), 3.29 (dd, J ) 14.0, 4.0, 1H), 3.01 (dd, J )
14.0, 11.1, 1H); 13C NMR (125 MHz, CDCl3) δ 159.3, 158.1,
130.2, 129.9, 129.8, 126.9 (q, J ) 281, CF3), 126.3, 113.9, 113.7,
55.1, 55.1, 51.6 (q, J ) 26, CHCF3), 34.7; MS (EI) m/z 310 (M+,
5), 189 (M - ArCH2, 4), 121 (ArCH2, 100). HRMS (EI) calcd
for C17H17O2F3: 310.1181, found 310.1189.
2,3-Bis(4-h ydr oxyph en y)l-N-pr opyl pr opion am ide (67a).
A 1.0 M solution of BBr3 in CH2Cl2 (4 mL, 4 mmol, 6 equiv)
was added to a solution of ester 65 (206 mg, 0.686 mmol, 1
equiv) in CH2Cl2 (10 mL) at -78 °C. The solution was allowed
to warm to room temperature overnight. The reaction was
quenched with excess propylamine (12.5 mL, 120 mmol). The
reaction mixture was concentrated, the partitioned between
EtOAC and water. The organic layer was washed twice with
water, once with brine, dried over Na2SO4, and concentrated.
Flash chromatography (5% MeOH/CHCl3) yielded the desired
product as a beige solid (133 mg, 0.443 mmol, 65%). mp 193-
195 °C; 1H NMR (500 MHz, acetone-d6) δ 7.20 (AA′ of AA′XX′,
J AX ) 8.0, J AA′ ) 3.5, 2H), 7.07 (br t, J ) 5.5, 1H), 6.99 (AA′ of
AA′XX′, J AX ) 8.5, J AA′ ) 3.0, 2H), 6.74 (XX′ of AA′XX′, J AX
3,3,4,4,4-P e n t a flu o r o -1,2-b i s (4-m e t h o x y p h e n y l)-
bu ta n e (63b). Olefin 62b (193 mg, 0.539 mmol) was hydro-
genated over 10% Pd/C by the procedure described for 63a .
Flash chromatography (10% EtOAc/hexanes) gave 63b as a
clear oil (119 mg, 0.330 mmol, 61%): 1H NMR (500 MHz,
CDCl3) δ 7.06 (d, J ) 8.4, 2H), 6.81 (d, J ) 8.8, 2H), 6.79 (d,
J ) 8.8, 2H), 6.68 (d, J ) 8.8, 2H), 3.78 (s, 3H), 3.72 (s, 3H),
3.28-3.43 (m, 2H), 2.98 (dd, J ) 13.8, 11.7, 1H); 13C NMR (125
MHz, CDCl3) δ 159.2, 158.1, 130.5, 130.0, 129.7, 125.7 (d, J )
7), 119.3 (qt, J ) 287, 37, CF2CF3), 115.9 (tq, J ) 257, 36,
CF2CF3), 113.8, 113.6, 55.1, 49.5 (t, J ) 21, CHCF2), 33.8; MS
(EI) m/z 360 (M+, 7), 239 (M - ArCH2, 3), 121 (ArCH2, 100).
HRMS (EI) calcd for C18H17O2F5: 360.1149, found 360.1139.
Anal. (C18H17O2F5) C, H.
3,3,3-Tr iflu or o-1,2-bis(4-h yd r oxyp h en yl)p r op a n e (64a ).
Fluoroalkane 63a (98 mg, 0.317 mmol) was demethylated with
BBr3 (0.951 mmol, 3 equiv) according to method C (basic
workup). Flash chromatography (40% EtOAc/hexanes) afforded
64a as a clear oil which solidified upon prolonged standing at
room temperature to give a white solid (83.1 mg, 0.294 mmol,
93%): mp 115-117.5 °C; 1H NMR (500 MHz, acetone-d6) δ
8.34 (s, 1H), 8.07 (s, 1H), 7.14 (AA′ of AA′XX′, J AX ) 8.6, J AA′
) 2.6, 2H), 6.91 (AA′ of AA′XX′, J AX ) 8.6, J AA′ ) 2.6, 2H),
6.76 (XX′ of AA′XX′, J AX ) 8.7, J XX′ ) 2.6, 2H), 6.63 (XX′ of
AA′XX′, J AX ) 8.6, J XX′ ) 2.6, 2H), 3.64 (dqd, J ) 11.3, 9.7,
4.1, 1H), 3.23 (dd, J ) 14.0, 4.1, 1H), 3.04 (dd, J ) 14.0, 11.3,
1H); 13C NMR (125 MHz, acetone-d6) δ 158.0, 156.7, 131.4,
130.9, 129.4, 128.3 (q, J ) 282, CF3), 125.9, 116.0, 115.8, 51.6
(q, J ) 26, CHCF3), 34.7 (d, J ) 1.9, CH2CF3); MS (EI) m/z
282 (M+, 3), 175 (M - ArCH2, 3), 107 (ArCH2, 100). HRMS
)8.5, J XX′ ) 3.5, 2H), 6.68 (XX′ of AA′XX′, J AX ) 9.0, J XX′
)
3.0, 2H), 3.57 (X of ABX, dd, J ) 9.0, 6.0, 1H), 3.03 m, 2H),
3.22 (AB of ABX, nA ) 1640, nB ) 1376, J AB ) 13.4, J AX ) 9.1,
J BX ) 6.0, 2H), 1.33 (sextet, J ) 7.4, 2H); 13C NMR (125 MHz,
acetone-d6) δ 174.3, 157.4, 156.8, 133.0, 132.0, 131.0, 129.0,
116.1, 115.0, 55.2, 41.8, 40.1, 23.6, 11.8; MS (EI) m/z 299 (M+,-
11), 193 (M - ArCH2, 100); HRMS (EI) calcd for C18H21NO3
299.1521, found 299.1518. Purity > 96% (HPLC).
N,N-Diet h yl-2,3-b is(4-h yd r oxyp h en yl)p r op ion a m id e
(67b). Amide 67b was prepared as described for 67a using
diethylamine as the quenching agent. Flash chromatography
(50% EtOAc/hexane) yielded the product as a white crystalline
1
solid (188 mg, 0.377 mmol, 56%). mp 219-221 °C; H NMR
(500 MHz, acetone-d6) δ 8.23 (s, 1H), 8.06 (s, 1H), 7.19 (AA′ of
AA′XX′, J AX ) 8.6, J AA′ ) 2.0, 2H), 7.00 (AA′ of AA′XX′, J AX
)
8.4, 2H), 6.76 (XX′ of AA′XX′, J AX )8.5, J XX′ ) 3.0, 2H), 6.68