J. R. Cashman et al. / Bioorg. Med. Chem. 17 (2009) 337–343
341
(iodine). Flash chromatography was done on (60 Å) pore silica gel
from E. Merck (Darmstadt, Germany). 1H NMR (300 MHz) spectra
were determined on a Varian Mercury 300 instrument in the indi-
cated solvent. Low resolution mass spectra (LRMS) were recorded
on a Hitachi M8000. High resolution mass spectra (HRMS) were
obtained with a Micromass LCT time of flight mass spectrometer
at the University of Montana Mass Spectral Facility (Missoula,
MT) using ESI.
J = 3.6, 4.5Hz, 1H), 2.89 (t, J = 7.2Hz, 2H), 2.16 (m, 1H), 1.97 (m,
1H), 1.31 (bs, 2H).
4.1.5. N0-(R)-[1-(1-Naphthyl)ethyl]-N-(S)-3-[4-(triflouromethyl)
phenoxy]-3-phenylpropylurea, (R)-4
(R)-Norfluoxetine (44 mg, 0.15 mmol, 1.1 equiv) and (R)-(ꢀ)-1-
(1-naphthyl)ethyl isocyanate (27 mg, 0.14 mmol, 1.0 equiv) was
placed in a vial containing toluene (0.8 mL). The mixture was stir-
red at room temperature for 13 h and then concentrated in vacuo
to afford a light yellow oil. The product was purified with PTLC
on silica and eluted with EtOAc/Hexane (1:3, v:v, Rf = 0.3). 1H
NMR (CDCl3, 500 MHz) d 8.22–7.21 (m, 14 H), 6.71 (d, J = 8.7 Hz,
2H), 5.53 (t, J = 6.6 Hz, 1H), 5.01–4.93 (m, 1H), 4.60 (bt, 1H), 3.22
(m, 2H), 2.04–1.96 (m, 2H) 1.54 (d, J = 6.9 Hz, 3H). The enantiopu-
rity of (R)-4 was calculated to be 98% based on the benzylic methyl
group at d 1.54.
4.1.2. (R)- or (S)-1-Chloro-3-(4-trifluormethyl-phenoxy)-3-
phenyl-propane (1)
Into a flame dried round bottom flask purged with Ar(g) was
placed PPh3 (368 mg, 1.4 mmol, 1.2 equiv) and 1.5 mL of THF.
To this solution was added DIAD (284 mg, 1.4 mmol, 1.2 equiv)
and the mixture was stirred at rt for 20 min. The
a,a,a-trifluoro-
methyl-p-cresol (190 mg, 1.2 mmol, 1.0 equiv) dissolved in 0.5 mL
THF and was added via syringe and the reaction was stirred at rt
for 4 h until a light precipitate formed and the solution turned
greenish in color. The chiral alcohol (200 mg, 1.2 mmol, 1.0 equiv)
dissolved in 0.5 mL THF was then added via syringe and the pre-
cipitate and color dissipated within 3 min after addition. The mix-
ture was then stirred at rt overnight and then concentrated to an
oil. The crude oil was chromatographed on silica with 5% EtOAc/
Hexanes (v:v) as an eluent to afford the pure product as a clear
4.1.6. N0-(S)-[1-(1-Naphthyl)ethyl]-N-(S)-3-[4-(triflouromethyl)
phenoxy]-3-phenylpropylurea (S)-4
(S)-Norfluoxetine (44 mg, 0.15 mmol, 1.1 equiv) and (R)-(ꢀ)-1-
(1-naphthyl)ethyl isocyanate (27 mg, 0.14 mmol, 1.0 equiv) was
placed in a vial containing toluene (0.75 mL). The mixture was stir-
red at room temperature for 13 h and then concentrated in vacuo
to afford a light yellow oil. The product was purified with PTLC
on silica and eluted with EtOAc/Hexane (1:3, v:v, Rf = 0.3). 1H
NMR (CDCl3, 500 MHz) d 8.22–7.21 (m, 14H), 6.71 (d, J = 8.7 Hz,
2H), 5.53 (t, J = 6.6 Hz, 1H), 5.01–4.93 (m, 1H), 4.60 (bt, 1H), 3.22
(m, 2H), 2.04–1.96 (m, 2H) 1.61 (d, J = 6.9 Hz, 3H). The enantiopu-
rity of (S)-4 was calculated to be 99% based on the benzylic methyl
group at d 1.61.
oil (242 mg, 66%); 1H NMR (CDCl3, 300 MHz):
d 7.47 (d,
J = 8.7 Hz, 2H), 7.36 (m, 5H), 6.94 (d, J = 8.7 Hz, 2H), 5.46 (dd,
J = 3.9, 4.7 Hz, 1H), 3.83 (m, 1H), 3.62 (m, 1H), 2.51 (m, 1H),
2.25 (m, 1H).
4.1.3. (R)- or (S)-1-Phthalimide-3-(4-trifluormethyl-phenoxy)-
3-phenyl-propane (2)
4.1.7. 6-(3,4-Dimethoxy-benzoyl)-cyclohex-3-enecarboxylic
acid (5)
Into a 20 mL vial was placed (R)- or (S)-1-chloro-3-(4-trifluo-
romethyl-phenoxy)-3-phenyl-propane (1) (468 mg, 1.5 mmol, 1.0
equiv), NaI (10 mg), potassium phthalimide (550 mg, 3.0 mmol,
2.0 equiv) and DMSO (3 mL). The vial was then placed in a 70 °C
oil bath and stirred for 13 h. When the reaction was complete as
judged by TLC the reaction was cooled to rt and stopped with
H2O. The resulting solution was placed in a separatory funnel
and extracted with EtOAc (3ꢂ 25 mL). The organic layers were
combined and washed with brine, dried over Na2SO4, filtered
through paper, and then concentrated to give a light yellow solid.
The crude material was purified with silica chromatography with
25% EtOAc/Hexanes (v:v) as an eluent to afford pure product as a
light yellow solid (461 mg, 73%); 1H NMR (CDCl3, 300 MHz): d
7.81 (m, 2H), 7.70 (m, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.31 (m, 5H),
6.81 (d, J = 8.7 Hz, 2H), 5.28 (dd, J = 3.9, 5.5Hz, 1H), 3.95 (m, 2H),
2.43 (m, 1H), 2.22 (m, 1H).
A solution of Grignard reagent, 3,4-dimethoxyphenylmagne-
sium bromide (59 mmol, 0.3 M) in THF was added dropwise to
an ice-cooled solution of cis-1,2,3,6-tetrahydrophthalic anhydride
in THF (120 mL) over a 1 h period. After the addition was complete,
the resulting mixture was stirred for another 30 min at 0 °C. The
reaction mixture was allowed to warm to rt and stirred overnight.
The mixture was stopped with sat. NH4Cl and the pH adjusted to 2
with concentrated HCl(aq) and extracted with diethyl ether. The or-
ganic layer was washed with water and extracted with 1 M NaOH.
The combined aqueous extract was acidified with concentrated
HCl and extracted with EtOAc (3ꢂ 100 mL). The organic layers
were combined and dried over MgSO4, filtered, and concentrated
under reduced pressure to afford an oil. The oil was dissolved
CH2Cl2 and filtered through silica gel to remove the dicarboxylic
acid formed during workup. The product was recrystallized from
diethyl ether to afford pure product (1.6 g, 10%); mp = 109 °C;
LRMS ESI [MꢀH]ꢀ calcd for C16H18O5 289, found m/z 289; 1H
NMR (CDCl3, 500 MHz): d 7.60–7.53 (m, 2H), 6.92 (d, J = 8.4Hz,
1H), 5.84–5.82 (m, 1H), 5.71–5.68 (m, 1H), 4.03–4.00 (m, 1H),
3.98 (s, 3H), 3.95 (s, 1H), 3.10–3.07 (m, 1H), 2.90–2.84 (m, 1H),
2.54–2.44 (m, 3H).
4.1.4. (R)- or (S)-Norfluoxetine (3)
Into a vial was placed (R)- or (S)-1-phthalimide-3-(4-trifluoro
methyl-phenoxy)-3-phenyl-propane (2) (142 mg, 0.3 mmol, 1.0
equiv) and DCM (1 mL). The solution was stirred until all of the
phthalimide was dissolved. MeOH (1 mL) followed by hydrazine
monohydrate was added to the vial and the reaction was stirred
at rt for 8 h while a creamy white precipitate formed. When the
reaction was complete it was concentrated in vacuo to a white so-
lid, dissolved in DCM and transferred to a separatory funnel and
extracted with H2O. The solution was re-extracted with DCM
(1ꢂ 25 mL) and then the aqueous layer was made basic (pH 12)
with 10 M NaOH and extracted again with DCM (2ꢂ 25 mL). The
organic layers were combined and washed with brine, dried over
Na2SO4, filtered through paper, and concentrated to give a yellow
oil (97 mg, 99%). The resulting material was pure enough to use
in the following reaction; 1H NMR (CDCl3, 300 MHz): d 7.43 (d,
J = 8.7 Hz, 2H), 7.29 (m, 5H), 6.90 (d, J = 8.7 Hz, 2H), 5.32 (dd,
4.1.8. 4-(3,4-Dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-
phthalazin-1-one (6)
A mixture of 5 (610 mg, 2.1 mmol, 1.0 equiv) and hydrazine hy-
drate (168 mg, 5.3 mmol, 2.5 equiv) in EtOH (10 mL) was refluxed
for 4 h. The mixture was then cooled to rt and concentrated under
reduced pressure to afford a white precipitate. The precipitate was
dissolved in EtOAc and washed with Na2SO4(aq), 1 N HCl(aq), and
water. The organic layer was then dried over MgSO4, filtered, and
concentrated to give a white precipitate. The precipitate was
recrystallized in EtOH to afford the product as white crystals
(376 mg, 63%); HRMS ESI [M+H]+ calcd for C16H18N2O3 287.3385,