Terphenyls and 3,5-Diaryl Isoxazole DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4801
tetrakis triphenylphosphine palladium, and the mixture was heated
to reflux under argon atmosphere for 3 h. The suspension was
cooled, filtered, and washed with dichloromethane (40 mL). Water
phase was then acidified and extracted with diethyl ether. Purifica-
tion of the residue of ether extracts gave the O-protected terphenyl
products.
isoxazol-3-yl]-benzoic Acid Methyl Ester (23c). Yield 44%. 1H
NMR δ 1.76 (s, 6H), 2.01 (s, 9H), 2.35 (s, 3H), 3.37 (dd, J )
16.7, J ) 8.6, 1H), 3.76 (dd, J ) 16.7, J ) 11, 1H), 3.93 (s, 3H),
5.76 (dd, J ) 11, J ) 8.6, 1H), 7.01 (d, J ) 8.2, 1H), 7.24 (dd, J
) 8.2, J ) 2, 1H), 7.36 (d, J ) 2, 1H), 7.65 (d, J ) 6.6, 2H), 8.07
(d, J ) 6.7, 2H).
General Procedure for Isoxazoles. To a solution of the isoxazo-
line (0.25 mmol) in carbon tetrachloride (10 mL), N-bromosuccin-
imide (66 mg, 0.37 mmol) was added and the mixture was gently
refluxed for 3 h. Hydrogen bromide was slowly liberated. The
cooled solution was filtered from the precipitated succinimide,
washed with 5% aqueous sodium hydroxide and then with water
until the organic phase became clear. The organic layer was dried
and the solvent removed in vacuo. The residue was chromato-
graphed on silica gel (ethyl acetate-light petroleum).
General Procedure for Removal of the Benzyl-Protection
Group. To a solution of the appropriate benzyl protected derivative
(0.11 mmol) in abs EtOH (15 mL) was added Pd/C 5% (catalytic
amount). The reaction was stirred in hydrogen atmosphere for 15 h.
The mixture was filtered over celite and the solution evaporated.
The residue was chromatographed on silica gel (light petroleum-
ethyl acetate).
4-Hydroxy-3-tricyclo[3.3.1.10,0]dec-1-yl-[1,1′;4′,1′′]terphenyl-4′′-
carboxylic Acid (13). Yield 40%; mp 300 °C (dec.). 1H NMR
(DMSO-d6) δ 1.71 (s, 6H), 2.01 (s, 9H), 5.76 (s, 1H), 7.46-7.52
(m, 4H), 7.72-7.82 (m, 5H), 8.01 (d, J ) 8.2, 2H), 12.96 (br, 1H).
Anal. (C29H28O3) C, H.
4-[3-(4-Methoxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-isoxazol-
5-yl]-benzoic Acid Methyl Ester (26a). Yield 81%. 1H NMR δ 1.80
(s, 6H), 2.15 (s, 9H), 3.90 (s, 3H), 3.96 (s, 3H), 6.90 (s, 1H), 6.97
(d, J ) 8.2, 1H), 7.66-7.75 (m, 2H), 7.92 (d, J ) 8.4, 2H) 8.16
(d, J ) 8.4, 2H).
4-Hydroxy-3-tricyclo[3.3.1.10,0]dec-1-yl-[1,1′;3′,1′′]terphenyl-4′′-
carboxylic acid (14). Yield 35%; mp 263-265 °C. 1H NMR δ 1.80
(s, 6H), 2.11 (s, 3H), 2.19 (s, 6H), 5.12 (s, 1H), 6.76 (d, J ) 8.0,
1H), 7.34 (dd, J ) 8.0, J ) 1.8, 1H), 7.48-7.60 (m, 4H), 7.73-7.77
(m, 3H), 8.20 (d, J ) 8.0, 2H), 12.47 (br, 1H). Anal. (C29H28O3)
C, H.
Acetic Acid 4-[5-(4-Nitro-phenyl)-isoxazol-3-yl]-2-tricyclo-
1
[3.3.1.10,0]dec-1-yl-phenyl Ester (26b). Yield 54%. H NMR δ
1.72 (s, 6H), 2.02 (s, 9H), 2.33 (s, 3H), 6.92 (s, 1H), 7.07 (d, J )
8.4, 1H), 7.62 (dd, J ) 8.4, J ) 2.2, 1H), 7.82 (d, J ) 2.2, 1H),
7.93-7.97 (m, 2H), 8.28-8.33 (m, 2H).
4-Hydroxy-3-tricyclo[3.3.1.10,0]dec-1-yl-[1,1′;2′,1′′]terphenyl-4′′-
carboxylic Acid (15). Yield 47%; mp 179-181 °C. 1H NMR
(CD3OD) δ 1.86 (s, 6H), 1.92 (s, 9H), 5.49 (s, 1H), 6.60 (d, J )
8.1, 1H), 6.70 (d, J ) 2.1, 1H), 6.86 (dd, J ) 8.1, J ) 2.1, 1H),
7.09 (d, J ) 8.1, 2H), 7.35-7.40 (m, 4H), 7.86 (d, J ) 8.1, 2H),
12.3 (br, 1H). Anal. (C29H28O3) C, H.
4-[3-(4-Acetoxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-isoxazol-5-
yl]-benzoic Acid Methyl Ester (26c). Yield 81%. 1H NMR δ 1.80
(s, 6H), 2.15 (s, 9H), 3.90 (s, 3H), 3.96 (s, 3H), 6.90 (s, 1H), 6.97
(d, J ) 8.2, 1H), 7.66-7.75 (m, 2H), 7.92 (d, J ) 8.4, 2H) 8.16
(d, J ) 8.4, 2H).
4-[5-(4-Methoxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-isoxazol-
3-yl]-benzoic Acid Methyl Ester (27a). Yield 62%. 1H NMR δ 1.80
(s, 6H), 2.14 (s, 9H), 3.89 (s, 3H), 3.95 (s, 3H), 6.75 (s, 1H), 6.96
(d, J ) 8.4, 1H), 7.65-7.70 (m, 2H), 7.95 (d, J ) 8.4 Hz, 2H),
8.15 (d, J ) 8.4, 2H).
General Procedure for Isoxazolines. A mixture of N-chlorosuc-
cinimide (174 mg, 1.3 mmol), pyridine (2 drops) and oxime (1.3
mmol) in anhydrous CHCl3 (15 mL) was stirred for 1 h at 50-60
°C. Olefin (1.4 mmol) was then added followed by triethylamine
(0.27 mL, 1.95 mmol) in CHCl3 (5 mL). After stirring at 25 °C for
20 min, water was added and the organic phase was washed with
2.5% HCl and water, then dried and evaporated under reduced
pressure. The residue was chromatographed on silica gel (ethyl
acetate-light petroleum).
Acetic Acid 4-[3-(4-Nitro-phenyl)-isoxazol-5-yl]-2-tricyclo-
[3.3.1.10,0]dec-1-yl-phenyl Ester (27b). Yield 81%. H NMR δ
1
1.81 (s, 6H), 2.07 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 6.86 (s, 1H),
7.14 (dd, J ) 8.0, J ) 2.0, 1H), 7.84 (d, J ) 2.0, 1H), 8.05-8.07
(m, 2H), 8.34-8.37 (m, 2H).
4-[3-(4-Methoxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-4,5-dihy-
dro-isoxazol-5-yl]-benzoic Acid Methyl Ester (21a). Yield 80%. 1H
NMR δ 1.76 (s, 6H), 2.09 (s, 9H), 3.30 (dd, J ) 16.1, J ) 7.9,
1H), 3.76-3.93 (m, 7H), 5.75 (dd, J ) 11.2, J ) 7.9, 1H), 6.87 (d,
J ) 8.4, 1H), 7.42-7.49 (m, 3H), 7.62 (s, 1H), 7.65 (d, J ) 6.6,
2H), 8.04 (dd, J ) 8.2, J ) 1.8, 2H).
4-[5-(4-Acetoxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-isoxazol-3-
yl]-benzoic Acid Methyl Ester (27c). Yield 65%. 1H NMR δ 1.61
(s, 6H), 2.08 (s, 9H), 2.40 (s, 3H), 3.96 (s, 3H), 6.84 (s, 1H), 7.13
(d, J ) 8.4, 1H), 7.69 (dd, J ) 8.4, J ) 2.1, 1H), 7.84 (d, J ) 2.1,
1H), 7.95 (d, J ) 8.3, 2H), 8.15 (d, J ) 8.3, 2H).
Acetic Acid 4-[5-(4-Nitro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-
tricyclo[3.3.1.10,0]dec-1-yl-phenyl Ester (21b). Yield 42%. 1H NMR
δ 1.78 (s, 6H), 2.01 (s, 6H), 2.09 (s, 3H), 2.37 (s, 3H), 3.29 (dd, J
) 16.4, J ) 7.2, 1H), 3.88 (dd, J ) 16.8, J ) 11.2, 1H), 5.83 (dd,
J ) 10.8, J ) 7.2, 1H), 7.04 (d, J ) 8.4, 1H), 7.46 (dd, J ) 8.4,
J ) 2.0, 1H), 7.55-7.58 (m, 2H), 7.74 (d, J ) 2.0, 2H), 8.22-8.25
(m, 2H).
General Procedure for Ester Hydrolysis. A mixture of ester (1
mmol), methanol (10 mL), water (6-7 mL), and lithium hydroxide
(40 mg, 1.5 mmol or double amount for acetyl derivatives) was
allowed to stand at 50-60 °C for 24 h. The solution was
concentrated in vacuo to remove methanol, and the remaining
aqueous solution was extracted with diethyl ether to separate trace
amounts of unreacted ester. The aqueous solution was acidified with
1 M hydrochloric acid and extracted with three portions of ethyl
acetate. The combined organic extracts were washed with saturated
aqueous sodium chloride and dried. Removal of the solvent under
reduced pressure afforded a residue, which was chromatographed
on silica gel (eluent: ethyl acetate-light petroleum).
4-[3-(4-Acetoxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-4,5-dihydro-
isoxazol-5-yl]-benzoic Acid Methyl Ester (21c). Yield 82%. 1H
NMR δ 1.77 (s, 6H), 2.02 (s, 9H), 2.37 (s, 3H), 3.30 (dd, J )
16.3, 7.7, 1H), 3.83 (dd, J ) 16.5, J ) 11, 1H), 3.92 (s, 3H), 5.79
(dd, J ) 11, J ) 7.6, 1H), 7.04 (d, J ) 8.3, 1H), 7.43-7.50 (m,
3H), 7.55 (d, J ) 2, 1H), 8.05 (d, J ) 8.2, 2H).
4-[3-(4-Hydroxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-4,5-dihy-
dro-isoxazol-5-yl]-benzoic Acid (24). Yield 90%; mp 251-253 °C
(dec). 1H NMR (DMSO-d6) δ 1.72 (s, 6H), 2.06 (s, 9H), 3.27-3.39
(m, 1H), 3.86 (dd, J ) 17.1, J ) 11, 1H), 5.75 (dd, J ) 10.7, J )
7.4, 1H), 6.82 (d, J ) 8.4, 1H), 7.34 (d, J ) 8.4, 1H), 7.44-7.51
(m, 3H), 7.95 (d, J ) 8, 2H), 9.86 (s, 1H), 12.98 (br, 1H). Anal.
(C26H27NO4), C, H, N.
4-[5-(4-Methoxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-4,5-dihy-
dro-isoxazol-3-yl]-benzoic Acid Methyl Ester (23a). Yield 53%. 1H
NMR δ 1.76 (s, 6H), 2.07 (s, 9H), 3.36 (dd, J ) 16.4, J ) 8.6,
1H), 3.65-3.83 (m, 4 H), 3.93 (s, 3H), 5.72 (dd, J ) 11,2, J )
8.6, 1H), 6.86 (d, J ) 8.8, 1H), 7.19-7.24 (m, 2H), 7.77 (d, J )
8.1, 2H), 8.07 (d, J ) 8.2, 2H).
Acetic Acid 4-[3-(4-Nitro-phenyl)-4,5-dihydro-isoxazol-5-yl]-2-
tricyclo[3.3.1.10,0]dec-1-yl-phenyl Ester (23b). Yield 45%. 1H NMR
δ 1.76 (s, 6H), 2.0 (s, 6H), 2.08 (s, 3H), 2.35 (s, 3H), 3.44 (dd, J
) 17.0, J ) 8.0, 1H), 3.78 (dd, J ) 17.0, J ) 11.0, 1H), 5.80 (dd,
J ) 11.0, J ) 8.0, 1H), 7.0 (d, J ) 8.4, 1H), 7.22 (dd, J ) 8.2, J
) 1.1, 1H), 7.85 (d, J ) 9.0, 2H), 8.27 (d, J ) 9.0, 2H).
4-[5-(4-Acetoxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-4,5-dihydro-
4-[5-(4-Hydroxy-3-tricyclo[3.3.1.10,0]dec-1-yl-phenyl)-4,5-dihy-
dro-isoxazol-3-yl]-benzoic Acid (25). Yield 94%; mp 240-242 °C
(dec). 1H NMR (DMSO-d6) δ 1.71 (s, 6H), 2.05 (s, 9H), 3.38-3.46
(m, 1H), 3.79 (dd, J ) 16.4, J ) 11.2, 1H), 5.63 (dd, J ) 11.2, J
) 8.3, 1H), 6.77 (d, J ) 8.1, 1H), 7.03-7.10 (m, 2H), 7.82 (d, J
) 8.3, 2H), 8.0 (d, J ) 8.3, 2H), 9.43 (s, 1H), 12.90 (br, 1H).
Anal. (C26H27NO4), C, H, N.