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4.10. 2-Fluoro-5-hydroxy-b-nitro-styrene(15)
4.13. 2-Fluoro-5-benzyloxyphenyl acetic acid (17)
A mixture of 700 mg (5 mmol) of aldehyde 6, 3.25 ml
(58 mmol) of nitromethane, 825 ml (14 mmol) of glacial
HOAc, and 831 mg (16 mmol) of NH4OAc was sonicated at
22–40 8C until the reaction was complete as shown by TLC.
CH2Cl2 (20 ml) was added and the mixture was washed
successively with water and brine. After drying (Na2SO4),
the solvent was removed to give a yellow solid. This was
purified by flash column chromatography (PE:EtOAc 2:1)
to give 642 mg (3.5 mmol, 70%) of 15 as a yellow solid,
A solution of 320 mg (1.17 mmol) of 16 in 5 ml of MeOH
and 1.5 ml of 30% aqueous NaOH was stirred at room
temperature for 4 h. The reaction mixture was washed twice
with EtOAc, acidified with aqueous HCl, and extracted with
three portions of EtOAc. The organic extracts were com-
bined, washed with brine, and dried (Na2SO4). Evaporation
of the solvent gave 300 mg (99%) of 17 as a white crystals,
mp 126–127 8C. 1H NMR (acetone-d6): d 3.66 (2H, s,
CH2CO2), 5.09 (2H, s, OCH2Ar), 6.9–7.6 (8H, m, ArH)
ppm. MS: CI NH3 m/z (M) 260, (M þ 18) 278, (M þ 35) 295.
1
mp 139–141 8C. H NMR (CDCl3): d 4.97 (1H, s, ArOH),
6.92–6.96 (2H, m, ArH), 7.06 (1H, t, J ¼ 10:2 Hz, ArH),
7.69(1H, d, J ¼ 14:1 Hz, bH), 7.98 (1H, d, J ¼ 13:8 Hz,
aH) ppm. HRMS. Calculated for C8H6NFO3: 183.0332;
found:183.0326.
4.14. 2-Fluoro-5-hydroxyphenylacetic acid (4)
A mixture of 132 mg (0.51 mmol) of 17 and 35 mg of 10%
Pd/C in 35 ml of EtOH was stirred overnight in an atmosphere
of hydrogen gas (balloon). Removal of catalyst and solvent
gave 78 mg (0.45 mmol, 90%) of 4 as a pale solid. Recrys-
4.11. 6-Fluoro-meta-tyramine (2)
1
To a cooled solution of 500 mg (2.7 mmol) of 15 in 10 ml
of anhydrous THF was cautiously added 124 mg (3.2 mmol)
of LiAlH4. The mixture was refluxed for 3 h and then cooled
to 0 8C. To this was cautiously added 10 ml of 1.5 N H2SO4
with stirring. The aqueous layer was separated and its pH
was adjusted to 6 with solid (Li)2CO3. The solution was
heated to boiling and the precipitated Al(OH)3 was
removed by filtration with the aid of filter cell. The clear,
hot filtrate was cooled to room temperature and was
extracted three times with ether. The combined ether layer
was washed with water and brine. After drying (Na2SO4),
the solvent was removed to afford the 203 mg (1.3 mmol,
49%) of 2, identical to the material prepared from
14. HRMS. Calculated for C8H10NFO: 155.0746; found:
155.0744.
tallization (toluene) gave white plates, mp 127–128 8C. H
NMR (CD3OD): d 3.56 (2H, s, CH2CO2), 6.62–6.91 (m, ArH)
ppm. MS: CI m/z (M þ 18) 188, (M þ 35) 205.
4.15. N-cbz-6-fluoro-meta-tyramine (18)
To a solution of 2 (200 mg, 1.3 mmol) in 15 ml of CHCl3
was added 0.24 ml (2.6 mmol) of Et3N at room temperature.
After 10 min, 243 mg (1.4 mmol) of benzyl chloroformate
was added. After stirring the mixture for additional 3 h, the
precipitated solid was removed by filtration and 30 ml of
EtOAc was added to the filtrate. The organic layer was
washed three times with chilled 1 N HCl, dried, and con-
centrated to give a yellow oil. Purification by flash column
chromatography (PE:EtOAc 3:1) gave 285 mg (76%) of 18
as a viscous colorless oil. 1H NMR (CDCl3): d 2.79 (2H, t,
J ¼ 6:6 Hz, CH2CH2), 3.40–3.47 (2H, m, CH2CH2), 5.09
(2H, s, ArCH2), 6.61–6.65 (2H, m, ArH), 6.87 (1H, t, J ¼
9:3 Hz, ArH), 7.34 (5H, m, ArH) ppm. HRMS. Calculated
for C16H16NFO3: 289.1114; found: 289.1105.
4.12. (2-Fluoro-5-benzyloxyphenyl)acetic acid
methyl ester (16)
To a solution of 520 mg (2.15 mmol) of 13 in 6 ml of ether
was added 0.93 ml of MeOH. Dry HCl gas was bubbled
through the solution until saturation. The reaction mixture
was stirred for 2 h at ice bath temperature and then was
stored in a refrigerator for 7 days during which time fine
white crystals of imino ester hydrochloride formed. To the
reaction mixture was added 5 ml of water and the mixture
was stirred at room temperature for 3 h. The layers were
separated and the aqueous layer was extracted with four
portions of ether. The organic layers were combined and
washed successively with a saturated solution of NaHCO3,
water and brine. After drying (Na2SO4), the solvent was
removed, the residue was dissolved in a 1:5 EtOAc:PE
mixture and was filtered through silica gel. Evaporation
of solvent gave 320 mg (1.16 mmol, 54%) of 16 as a clear
liquid. 1H NMR (CDCl3): d 3.64 (2H, s, CH2CO2), 3.71 (3H,
s, OCH3), 5.02 (2H, s, OCH2Ar), 6.86–7.43 (8H, m, ArH)
ppm. MS: FABꢀ m/z (M ꢀ 1) 273, FABþ (M) 274.
4.16. 6-Fluoro-meta-tyramine O-sulfate (3)
A suspension of 60% NaH in oil (30 mg, 0.75 mmol) was
added to a solution of 18 (145 mg, 0.5 mmol) in 5 ml of
DMF. The mixture was stirred for 30 min at room tempera-
ture, at which time the NaH was completed consumed.
The solution was cooled to 0 8C and Me3N–SO3 complex
(278 mg, 1 mmol) was added. After 30 min, the solution was
evaporated under reduced pressure at room temperature to
give 19, which was not further characterized. This was
dissolved in 5 ml of EtOH, 10 mg of 10% Pd on carbon
was added, and the mixture was hydrogenated for 30 min
(balloon). After removal of catalyst and solvent, the residue
was triturated with 95% EtOH (1 ml) and filtered. The
crystals were dissolved in 2 ml of water, the solution
was cooled to 5 8C and acidified with HCl to pH 3–4.