Synthesis of 3-Aryl-3-(4-phenoxy)-propionic Acid
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 12 2813
phenyl)-3-phenyl-propionic Acid Ethyl Ester (4). A solution of
1 (135 mg, 0.50 mmol), 1-butanol (37 mg, 0.50 mmol), and PPh3
(157 mg, 0.60 mmol) in THF (3 mL) was treated with DIAD
(107 mg, 0.53 mmol). The reaction was stirred at room temperature
for 7 h. The reaction mixture was concentrated, and the crude
product was purified by column chromatography on silica gel (20:1
3H), 0.99 (d, J ) 6.7 Hz, 3H), 0.93 (t, J ) 7.2 Hz, 3H); MS (ES)
m/z 341 (M + H+).
(3B)-{4-[(2R)-Methyl-butoxy]-phenyl}-3-phenyl-propionic Acid
(22(B, R)). Using 21(B, R) and following the procedure as in the
1
preparation of 3 gave 22(B, R) as a colorless oil film (92%). H
NMR (400 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.81 (d, J )
8.6 Hz, 2H), 4.48 (t, J ) 7.8 Hz, 1H), 3.77 (dd, J ) 9.0, 6.0 Hz,
1H), 3.68 (dd, J ) 9.0, 6.6 Hz, 1H), 3.06 (d, J ) 7.9 Hz, 2H),
1.86-1.76 (m, 1H), 1.60-1.49 (m, 1H), 1.30-1.19 (m, 1H), 0.98
(d, J ) 6.7 Hz, 3H), 0.92 (t, J ) 7.4 Hz, 3H); MS (ES) m/z 335
(M + Na+). Anal. (C20H24O3) C, H, N.
1
hexane/EtOAc) to give 103 mg (63%) of 4 as a colorless oil. H
NMR (300 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.80 (d, J )
6.0 Hz, 2H), 4.49 (t, J ) 6.0 Hz, 1H), 4.02 (q, J ) 6.0 Hz, 2H),
3.91 (t, J ) 6.0 Hz, 2H), 3.01 (d, J ) 6.0 Hz, 2H), 1.73 (tt, J )
6.0, 6.0 Hz, 2H), 1.52-142 (m, 2H), 1.11 (t, J ) 6.0 Hz, 3H),
0.95 (t, J ) 6.0 Hz, 3H); MS (ES) m/z 327 (M + H+).
3-(4-Pentyloxy-phenyl)-3-phenyl-propionic Acid Ethyl Ester
(6). Using 1-pentanol and following the procedure as in the
preparation of 4 gave 6 (69%) as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.80 (d, J ) 8.0 Hz,
2H), 4.49 (t, J ) 7.5 Hz, 1H), 4.02 (q, J ) 6.0 Hz, 2H), 3.90 (t,
J ) 6.0 Hz, 2H), 3.01 (d, J ) 7.5 Hz, 2H), 1.75 (tt, J ) 6.0,
6.0 Hz, 2H), 1.45-1.27 (m, 4H), 1.10 (t, J ) 6.0 Hz, 3H), 0.93 (t,
J ) 6.0 Hz, 3H); MS (ES) m/z 341 (M + H+).
(3B)-{4-[(2S)-Methyl-butoxy]-phenyl}-3-phenyl-propionic Acid
(22(B, S)). Using 21(B, S) and following the procedure as in the
1
preparation of 3 gave 22(B, S) as a white solid (92%). H NMR
(300 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.81(d, J ) 8.6 Hz, 2H),
4.47 (t, J ) 7.8 Hz, 1H), 3.77 (dd, J ) 9.0, 6.0 Hz, 1H), 3.68 (dd,
J ) 9.0, 6.6 Hz, 1H), 3.05 (d, J ) 7.9 Hz, 2H), 1.88-1.76 (m,
1H), 1.60-1.46 (m, 1H), 1.31-1.18 (m, 1H), 0.98 (d, J ) 6.7 Hz,
3H), 0.92 (t, J ) 7.4 Hz, 3H); MS (ES) m/z 335 (M + Na+).
(3A)-{4-[(2R)-Methyl-butoxy]-phenyl}-3-phenyl-propionic Acid
(22(A, R)). Using 21(A, R) and following the procedure as in the
3-[4-(3-Methyl-but-3-enyloxy)-phenyl]-3-phenyl-propionic Acid
Ethyl Ester (18). Using 3-methyl-but-3-en-1-ol and following the
procedure as in the preparation of 4 gave 18 (64%) as a colorless
1
preparation of 3 gave 22(A, R) as a white solid (94%). H NMR
(300 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.81(d, J ) 8.6 Hz, 2H),
4.47 (t, J ) 7.8 Hz, 1H), 3.77 (dd, J ) 9.0, 6.0 Hz, 1H), 3.68 (dd,
J ) 9.0, 6.6 Hz, 1H), 3.05 (d, J ) 7.9 Hz, 2H), 1.88-1.76 (m,
1H), 1.60-1.46 (m, 1H), 1.31-1.18 (m, 1H), 0.98 (d, J ) 6.7 Hz,
3H), 0.92 (t, J ) 7.4 Hz, 3H); MS (ES) m/z 335 (M + Na+).
1
oil. H NMR (300 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.82 (d,
J ) 9.0 Hz, 2H), 4.82 (s, 1H), 4.78 (s, 1H), 4.49 (t, J ) 9.0 Hz,
1H), 4.08-3.99 (m, 2H), 3.01 (d, J ) 9.0 Hz, 2H), 2.47 (t, J )
6.0 Hz, 2H), 1.78 (s, 3H), 1.11 (t, J ) 6.0 Hz, 3H); MS (ES) m/z
361 (M + Na+).
(3A)-{4-[(2S)-Methyl-butoxy]-phenyl}-3-phenyl-propionic Acid
(22(A, S)). Using 21(A, S) and following the procedure as in the
(3B)-{4-[(2R)-Methyl-butoxy]-phenyl}-3-phenyl-propionic Acid
Ethyl Ester (21(B, R)). Using 1(B), which was the second peak
separated from the chiral HPLC (OJ column, using 100% MeOH
as the eluent and 80 mL/min as the flow rate, retention time ∼
22.9 min) of 1, and (R)-2-methyl-butan-1-ol and following the
procedure as in the preparation of 4 gave 21(B, R) as a colorless
oil (44%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.81
(d, J ) 8.7 Hz, 2H), 4.49 (t, J ) 8.0 Hz, 1H), 4.03 (q, J ) 7.1 Hz,
2H), 3.76 (dd, J ) 9.0, 6.0 Hz, 1H), 3.68 (dd, J ) 9.0, 6.6 Hz,
1H), 3.01 (d, J ) 8.0 Hz, 2H), 1.86-1.76 (m, 1H), 1.60-1.49 (m,
1H), 1.30-1.19 (m, 1H), 1.13 (t, J ) 7.1 Hz, 3H), 0.98 (d, J ) 6.7
Hz, 3H), 0.93 (t, J ) 7.2 Hz, 3H); MS (ES) m/z 341 (M + H+).
1
preparation of 3 gave 22(A, S) as a colorless oil film (98%). H
NMR (300 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.81(d, J )
8.6 Hz, 2H), 4.47 (t, J ) 7.8 Hz, 1H), 3.77 (dd, J ) 9.0, 6.0 Hz,
1H), 3.68 (dd, J ) 9.0, 6.6 Hz, 1H), 3.05 (d, J ) 7.9 Hz, 2H),
1.88-1.76 (m, 1H), 1.60-1.46 (m, 1H), 1.31-1.18 (m, 1H), 0.98
(d, J ) 6.7 Hz, 3H), 0.92 (t, J ) 7.4 Hz, 3H); MS (ES) m/z 335
(M + Na+).
3-[4-(3-Methyl-butoxy)-phenyl]-3-phenyl-propionic Acid (20).
A mixture of compound 19 (15 mg, 0.05 mmol) in EtOH (5 mL)
with Pd/C (10% w/w, 20 mg) was shaken under H2 (55 psi) for
5 h in a Parr shaker. Filtration though Celite and concentration
gave the crude. The crude product was purified by column
chromatography on silca gel (20:1 CH2Cl2/MeOH) to give 10 mg
(66%) of the acid 20 as a white solid. 1H NMR (300 MHz, CDCl3)
δ 7.30-7.15 (m, 5H), 7.12 (d, J ) 9.0 Hz, 2H), 6.80 (d, J )
9.0 Hz, 2H), 4.46 (t, J ) 7.5 Hz, 1H), 3.93 (t, J ) 6.0 Hz, 2H),
3.04 (d, J ) 7.5 Hz, 2H), 1.87-1.72 (m, 1H), 1.64 (dt, J ) 6.0,
6.0 Hz, 2H), 0.94 (d, J ) 6.0 Hz, 6H); MS (ES) m/z 335 (M +
Na+).
General Procedure for the Synthesis of 27, 32, and 37. 3-(3-
Fluoro-phenyl)-3-(4-methoxy-phenyl)-propionic Acid Ethyl Es-
ter (27). Tetrabutylammonium bromide (1.64 g) was melted at 130
°C. Compound 25 (618 mg, 3.0 mmol), 1-bromo-3-fluoro-benzene
(788 mg, 4.5 mmol), Pd(OAc)2 (20 mg, 0.09 mmol), and then
tetrabutylammonium acetate (2.26 g, 7.5 mmol) were added. The
mixture was stirred at 130 °C for 30 h. Water was added to the
cooled mixture and it was extracted with hexane thrice. The
combined extracts were washed with water (×2) and brine and dried
over Na2SO4. The reaction mixture was concentrated, and the crude
product was purified by column chromatography (10:1 hexane/
EtOAc) to give 839.2 mg of a mixture containing 26. The mixture
(826 mg) was dissolved in EtOH (50 mL) with Pd/C (10% w/w,
450 mg) and then was shaken under H2 in a Parr shaker overnight.
Filtration through Celite and concentrated. The crude product was
purified by column chromatography on silica gel (20:1 hexane/
EtOAc) to give 421 mg (46% for 2 steps) of 27 as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.26-7.20 (m, 1H), 7.14 (d, J )
8.0 Hz, 2H), 7.01 (d, J ) 8.0 Hz, 1H), 6.92-6.84 (m, 2H), 6.83
(d, J ) 8.0 Hz, 2H), 4.49 (t, J ) 7.8 Hz, 1H), 4.04 (q, J ) 8.0 Hz,
2H), 3.77 (s, 3H), 2.99 (d, J ) 7.8 Hz, 2H), 1.12 (t, J ) 8.0 Hz,
3H); MS (ES) m/z 325 (M + Na+).
(3B)-{4-[(2S)-Methyl-butoxy]-phenyl}-3-phenyl-propionic Acid
Ethyl Ester (21(B, S)). Using 1(B) and (S)-2-methyl-butan-1-ol
and following the procedure as in the preparation of 4 gave 21(B,
1
S) as a colorless oil (81%). H NMR (300 MHz, CDCl3) δ 7.30-
7.10 (m, 7H), 6.81(d, J ) 8.7 Hz, 2H), 4.49 (t, J ) 8.0 Hz, 1H),
4.03 (q, J ) 7.1 Hz, 2H), 3.77 (dd, J ) 9.0, 6.0 Hz, 1H), 3.68 (dd,
J ) 9.0, 6.6 Hz, 1H), 3.01 (d, J ) 8.1 Hz, 2H), 1.86-1.76 (m,
1H), 1.60-1.49 (m, 1H), 1.30-1.19 (m, 1H), 1.11 (t, J ) 7.1 Hz,
3H), 0.99 (d, J ) 6.7 Hz, 3H), 0.93 (t, J ) 7.2 Hz, 3H); MS (ES)
m/z 341 (M + H+); [R]D ) 5.5 (c 1, CHCl3).
(3A)-{4-[(2R)-Methyl-butoxy]-phenyl}-3-phenyl-propionic Acid
Ethyl Ester (21(A, R)). Using 1(A), which was the first peak
separated from the chiral HPLC (OJ column, using 100% MeOH
as the eluent and 80 mL/min as the flow rate, retention time ∼
19.1 min) of 1, and (R)-2-methyl-butan-1-ol and following the
procedure as in the preparation of 4 gave 21(A, R) as a colorless
oil (50%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.10 (m, 7H), 6.81-
(d, J ) 8.7 Hz, 2H), 4.49 (t, J ) 8.0 Hz, 1H), 4.03 (q, J ) 7.1 Hz,
2H), 3.77 (dd, J ) 9.0, 6.0 Hz, 1H), 3.68 (dd, J ) 9.0, 6.6 Hz,
1H), 3.01 (d, J ) 8.1 Hz, 2H), 1.86-1.76 (m, 1H), 1.60-1.48 (m,
1H), 1.30-1.15 (m, 1H), 1.11 (t, J ) 7.1 Hz, 3H), 0.99 (d, J ) 6.7
Hz, 3H), 0.93 (t, J ) 7.2 Hz, 3H); MS (ES) m/z 341 (M + H+).
(3A)-{4-[(2S)-Methyl-butoxy]-phenyl}-3-phenyl-propionic Acid
Ethyl Ester (21(A, S)). Using 1(A) and (S)-2-methyl-butan-1-ol
and following the procedure as in the preparation of 4 gave 21(A,
1
S) as a colorless oil (76%). H NMR (300 MHz, CDCl3) δ 7.30-
7.10 (m, 7H), 6.81(d, J ) 8.7 Hz, 2H), 4.49 (t, J ) 8.0 Hz, 1H),
4.03 (q, J ) 7.1 Hz, 2H), 3.77 (dd, J ) 9.0, 6.0 Hz, 1H), 3.68 (dd,
J ) 9.0, 6.6 Hz, 1H), 3.01 (d, J ) 8.1 Hz, 2H), 1.86-1.76 (m,
1H), 1.60-1.49 (m, 1H), 1.30-1.19 (m, 1H), 1.11 (t, J ) 7.1 Hz,