5004 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Mor et al.
(CDCl3): δ 1.17-2.06 (m, 10H), 3.58 (m, 1H), 4.93 (br d, 1H),
6.96-7.44 (m, 13H) ppm. IR (Nujol): 3305, 1741, 1709, 1578,
1540 cm-1. Anal. (C25H25NO3) C, H, N.
Cycloh exylca r ba m ic Acid 3′-Ben zyloxyca r bon yla m i-
n obip h en yl-3-yl Ester (4x). A vitreous solid was obtained.
Yield: 86% (0.382 g). MS (EI): m/z 319 (M+), 91 (100). 1H NMR
(CDCl3): δ 1.16-2.06 (m, 10H), 3.58 (m, 1H), 4.97 (br d, 1H),
5.23 (s, 2H), 6.80 (br s, 1H), 7.12 (m, 1H), 7.30-7.41 (m, 11H),
[1,1′;3′,1′′]-Ter p h en yl-3-yl Ca r ba m ic Acid Cycloh exyl
Ester (4n ). White crystals were obtained. Yield: 74% (0.275
g). Mp: 177-179 °C (EtOAc). MS (EI): m/z 371 (M+), 246
7.61 (s, 1H) ppm. IR (Nujol): 3308, 1709, 1606, 1537 cm-1
.
1
(100). H NMR (CDCl3): δ 1.17-2.06 (m, 10H), 3.60 (m, 1H),
Cycloh exylca r ba m ic Acid 4′-Ben zyloxyca r bon yla m i-
n obip h en yl-3-yl Ester (4y). A white solid was obtained.
Yield: 94% (0.418 g). Mp: 195-196 °C (EtOH). MS (EI): m/z
4.95 (br d, 1H), 7.12-7.80 (m, 13H) ppm. IR (KBr): 3301, 2923,
2853, 1744, 1707 cm-1. Anal. (C25H25NO2) C, H, N.
1
319 (M+), 167. H NMR (CDCl3): δ 1.16-2.18 (m, 10H), 3.59
Cycloh exylca r ba m ic Acid 3′-Ben zylbip h en yl-3-yl Es-
ter (4o). White crystals were obtained. Yield: 70% (0.270 g).
Mp: 112-114 °C (EtOH). MS (EI): m/z 260 (M+), 165 (100).
1H NMR (CDCl3): δ 1.20-1.50 (m, 6H), 1.60 (m, 2H), 2.00 (m,
2H), 3.58 (m, 1H), 4.04 (s, 2H), 4.93 (br d, 1H), 7.10-7.50 (m,
13H) ppm. IR (KBr): 3154, 1733, 1602, 1558, 1471 cm-1. Anal.
(C26H27NO2) C, H, N.
(m, 1H), 4.94 (br d, 1H), 5.23 (s, 2H), 6.74 (br s, 1H), 7.09 (m,
1H), 7.32-7.56 (m, 12H) ppm. IR (Nujol): 3332, 1703, 1600,
1540 cm-1
.
Gen er a l P r oced u r e for th e Syn th esis of 3′-(or 4′-)-
Su bstitu ted -3-m eth oxybip h en yls (8a -e,g,h ,j,k ,m -o,q,9)
a n d 3-Su bstitu ted -1-h yd r oxybip h en yls (3i,r -w ). To a
stirred solution of the opportune halobenzene 6a -e,g-k ,m -
o,q-w ,7 (15.5 mmol) in toluene (100 mL) were added Pd-
(PPh3)4 (0.726 g, 0.63 mmol), a solution of Na2CO3 (10.323 g,
97.37 mmol) in H2O (50 mL), and a solution of the suitable
3-methoxyphenyl boronic acid (5a ) (31 mmol) or 3-hydroxy-
phenyl boronic acid (5b) (15.5 mmol) in EtOH (44 mL) under
N2 atmosphere. The mixture was vigorously stirred under
reflux for the opportune time (1 h for 3r -t,v,w ,8b,h ,j,9; 2 h
for 3i,8a ,m ,q; 3 h for 3u ,8c-e,g,k ,n ,o) and cooled, H2O was
added, and the mixture was extracted with CH2Cl2 (EtOAc in
the case of 3i,r ,t,w ,8d ,m ; the acidification of the aqueous
phase with 2 N HCl was necessary for 3r ). The combined
organic layers were dried (Na2SO4) and concentrated. Purifica-
tion of the residue by column chromatography (cyclohexane/
EtOAc 200:1 for 8m ; 98:2 for 8b,h ,n ,o; 97:3 for 8e; 95:5 for
8g,k ; 85:15 for 8q,9; 8:2 for 8a ; 75:25 for 3s; 7:3 for 3u ,8j; 65:
35 for 3t,v; 6:4 for 8d ; 1:1 for 3r ; 7:3 to 6:4 to 1:1 for 3w ; 2:8
for 3i; EtOAc for 8c) gave 8a ,d ,e,g,h ,j,k ,m -o,9 and 3r ,s,v,w
as oils and 8b,c,q and 3i,t,u as solids.
Cycloh exylca r ba m ic Acid 3′-P r op ylbip h en yl-3-yl Ester
(4p ). Colorless crystals were obtained. Yield: 86% (0.290 g).
Mp: 89-90 °C (petroleum ether). MS (EI): m/z 337 (M+), 212
(100). 1H NMR (CDCl3): δ 0.97 (t, 3H), 1.16-1.79 (m, 10H),
2.04 (m, 2H), 2.65 (t, 2H), 3.59 (m, 1H), 4.94 (br d, 1H), 7.08-
7.43 (m, 8H) ppm. IR (Nujol): 3310, 1736, 1703, 1546 cm-1
Anal. (C22H27NO2) C, H, N.
.
Cycloh exylca r ba m ic Acid 3′-Nitr obip h en yl-3-yl Ester
(4q). Colorless needles. Yield: 75% (0.255 g). Mp: 138-142
°C (EtOH). MS (EI): m/z 215 (M+), 141 (100). 1H NMR
(CDCl3): δ 1.17-2.07 (m, 10H), 3.59 (m, 1H), 4.98 (br d, 1H),
7.21 (m, 1H), 7.45 (m, 3H), 7.61 (t, 1H), 7.92 (d, 1H), 8.22 (m,
1H), 8.45 (m, 1H) ppm. IR (Nujol): 3289, 1744, 1701, 1530,
1344 cm-1. Anal. (C19H20N2O4) C, H, N.
Cycloh exylca r ba m ic Acid 3′-Su lfa m oylbip h en yl-3-yl
Ester (4r ). White crystals which decompose starting from 115
°C (EtOAc/petroleum ether) were obtained. Yield: 26% (0.093
g). MS (EI): m/z 249 (M+), 169 (100). 1H NMR [CD3C(O)CD3]:
δ 1.16-2.05 (m, 10H), 3.48 (br s, 1H), 6.68 (s, 2H), 6.77 (br d,
1H), 7.17 (d, 1H), 7.48 (m, 3H), 7.67 (t, 1H), 7.91 (d, 2H), 8.17
3-Meth oxy-4′-tr iflu or om eth ylbip h en yl (8a ).30 A colorless
oil was obtained. Yield: 95% (3.714 g). MS (EI): m/z 252 (M+,
100). The 1H NMR spectrum is according to literature.30
3-Meth oxy-4′-m eth ylbip h en yl (8b).31 White crystals were
obtained. Yield: 94% (2.889 g). Mp: 75-76 °C (MeOH). MS
(EI): m/z 198 (M+), 69 (100). 1H NMR (CDCl3): δ 2.40 (s, 3H),
3.87 (s, 3H), 6.88 (m, 1H), 7.11-7.52 (m, 7H) ppm. IR (neat):
(s, 1H) ppm. IR (KBr): 3347, 3310, 3262, 1698, 1540 cm-1
.
Anal. (C19H22N2O4‚0.2C6H14) C, H, N.
Cycloh exylca r ba m ic Acid 3′-Acetylbip h en yl-3-yl Ester
(4s). Pearly scales were obtained. Yield: 72% (0.234 g). Mp:
130-132 °C (EtOH). MS (EI): m/z 212 (M+), 197 (100). 1H
NMR (CDCl3): δ 1.17-2.07 (m, 10H), 2.67 (s, 3H), 3.59 (m,
1H), 4.98 (br d, 1H), 7.17 (m, 1H), 7.39-7.58 (m, 4H), 7.79 (d,
1H), 7.95 (d, 1H), 8.17 (s, 1H) ppm. IR (Nujol): 3305, 1736,
1709, 1687, 1600, 1534 cm-1. Anal. (C21H23NO3) C, H, N.
Cycloh exylca r ba m ic Acid 3′-Cya n obip h en yl-3-yl Ester
(4t). White crystals were obtained. Yield: 80% (0.257 g). Mp:
105-107 °C (EtOH) (sealed capillary tube). MS (EI): m/z 320
(M+), 195 (100). 1H NMR (CDCl3): δ 1.22-2.07 (m, 10H), 3.58
(m, 1H), 4.97 (br d, 1H), 7.18 (m, 1H), 7.36-7.86 (m, 7H) ppm.
IR (Nujol): 3305, 2235, 1741, 1703 cm-1. Anal. (C20H20N2O2)
C, H, N.
Cycloh exylca r ba m ic Acid 3′-Hyd r oxybip h en yl-3-yl Es-
ter (4u ). White crystals were obtained. Yield: 45% (0.148 g).
Mp: 68-70 °C (EtOAc/hexane). MS (EI): m/z 186 (M+), 157
(100). 1H NMR (CDCl3): δ 1.20-1.50 (m, 6H), 1.70 (m, 2H),
2.00 (m, 2H), 3.55 (m, 1H), 4.95 (br d, 1H), 5.10 (br s, 1H),
6.80 (m, 1H), 7.05 (m, 1H), 7.15 (m, 2H), 7.40 (m, 4H) ppm. IR
(KBr): 3390, 2927, 2852, 1708, 1650 cm-1. Anal. (C19H21NO3‚
0.2EtOAc) C, H, N.
3055, 3006, 1611, 1584, 1567, 1519, 1486 cm-1
.
3′-Meth oxybiph en yl-4-car boxylic Acid Am ide (8c). White
crystals were obtained. Yield: 55% (1.937 g). Mp: 198-200
°C (EtOH). MS (EI): m/z 227 (M+), 199 (100). 1H NMR
(CDCl3): δ 3.90 (s, 3H), 5.60 (br s, 1H), 6.10 (br s, 1H), 6.95
(dd, 1H), 7.17 (m, 2H), 7.37 (t, 1H), 7.67 (d, 2H), 7.89 (d, 2H)
ppm.
3′-Meth oxybip h en yl-4-yl Am in e (8d ).32 A yellow oil was
obtained. Yield: 57% (1.760 g). MS (EI): m/z 199 (M+, 100),
1
156. H NMR (CDCl3): δ 3.86 (s and br s, 5H), 6.74-7.44 (m,
8H) ppm. IR (neat): 3457, 3370, 3218, 3033, 3001, 2952, 2936,
1600 cm-1
.
4′-F lu or o-3-m eth oxybip h en yl (8e).33 A colorless oil was
obtained. Yield: 62% (1.943 g). MS (EI): m/z 202 (M+), 133
(100).
3-Meth oxy-3′-tr iflu or om eth ylbip h en yl (8g). A colorless
oil was obtained. Yield: 93% (3.636 g). MS (EI): m/z 252 (M+),
1
69 (100). H NMR (CDCl3): δ 3.89 (s, 3H), 6.93-7.84 (m, 8H)
ppm. IR (neat): 3071, 3001, 2952, 2838, 1600, 1578, 1486, 1464
Cycloh exylca r ba m ic Acid 3′-Hyd r oxym eth ylbip h en yl-
3-yl Ester (4v). Colorless tablets were obtained. Yield: 64%
(0.208 g). Mp: 137-140 °C (EtOH). MS (EI): m/z 325 (M+),
cm-1
.
3-Meth oxy-3′-m eth ylbip h en yl (8h ).34 A pink oil was
obtained. Yield: 95% (2.919 g). MS (EI): m/z 198 (M+), 155
(100).
1
153 (100). H NMR (CDCl3): δ 1.17-2.06 (m, 11H), 3.59 (m,
1H), 4.76 (s, 2H), 4.98 (br d, 1H), 7.13 (m, 1H), 7.34-7.54 (m,
6H), 7.59 (s, 1H) ppm. IR (KBr): 3446, 3272, 3061, 1709, 1595,
1540 cm-1. Anal. (C20H23NO3) C, H, N.
3′-Meth oxybip h en yl-3-yl Am in e (8j). A yellow oil was
obtained. Yield: 94% (2.903 g). MS (EI): m/z 199 (M+, 100),
156. 1H NMR (CDCl3): δ 3.87 (s and br s, 5H), 6.69 (s, 1H),
6.86-7.38 (m, 7H) ppm. IR (neat): 3457, 3365, 3213, 3033,
Cycloh exylca r ba m ic Acid 3′-(2-Hyd r oxyeth yl)bip h en -
yl-3-yl Ester (4w ). White crystals were obtained. Yield: 13%
(0.044 g). Mp: 106 °C (acetone/petroleum ether). MS (EI): m/z
2963, 2936, 1622, 1600, 1578 cm-1
.
1
214, 82 (100). H NMR [CD3C(O)CD3]: δ 1.29-1.97 (m, 11H),
3′-F lu or o-3-m eth oxybip h en yl (8k ).35 A pale yellow oil
was obtained. Yield: 83% (2.602 g). MS (EI): m/z 202 (M+,
100). 1H NMR (CDCl3): δ 3.89 (s, 3H), 6.91-7.43 (m, 8H) ppm.
2.88 (t, 2H), 3.47 (m, 1H), 3.80 (t, 2H), 6.73 (br s, 1H), 7.06-
7.54 (m, 8H) ppm. IR (Nujol): 3457, 3305, 3256, 1712, 1709,
1562, 1535 cm-1. Anal. (C21H25NO3) C, H, N.
IR (neat): 3071, 2995, 2963, 2936, 2838, 1608, 1587 cm-1
.