SCHEME 3
Experimental Section
Hydrogenation of 5-Fluorouracil (5-FU). 5-Fluorouracil (790
mg, 6.1 mmol) was dissolved in methanol (100 mL) after vigorous
stirring for 1 h. Pd/C (10 wt %, 646 mg, 0.61 mmol) was added,
and the mixture was stirred under a hydrogen atmosphere for 36 h
at room temperature. The reaction mixture was diluted with
methanol, filtered through Celite, and then concentrated. The
product was recrystallized from water, resulting in a white solid
(530 mg, 66%) that was an inseparable 85:15 mixture of 5,6-
dihydro-5-fluorouracil and 5,6-dihydrouracil (as determined by 1H
NMR integration).
1,3-Bis(4-methoxybenzyl)-5-fluorouracil (3). 5-Fluorouracil
(260 mg, 2 mmol) and K2CO3 (663 mg, 4.8 mmol) were added to
an oven-dried 3-necked flask under argon. Anhydrous DMF (5 mL)
was added, and the mixture was stirred for 1 h, resulting in a thick
gel. DMF (2 mL) and 4-methoxybenzyl bromide (0.87 mL, 6 mmol)
were added, and the reaction was stirred for another 24 h until
completion was ascertained by TLC analysis (2:1 hexanes/EtOAc).
The reaction mixture was diluted with EtOAc and washed with
water and brine, dried over MgSO4, filtered, and concentrated.
Purification by silica gel column chromatography (1:1 EtOAc/
hexanes) afforded the product as a white solid (693 mg, 94%). 1H
NMR (CDCl3, 500 MHz) δ 7.50 (m, 2H), 7.22 (m, 2H), 7.14 (d, J
) 5.36 Hz, 1H), 6.89 (m, 2H), 6.85 (m, 2H), 5.10 (s, 2H), 4.83 (s,
2H), 3.81 (s, 3H), 3.79 (s, 3H). 13C NMR (CDCl3, 125 MHz) δ
159.6, 159.0, 157.0 (d, J ) 25.1 Hz), 150.0, 140.8 (d, J ) 235.67
Hz), 130.6, 129.6, 128.1, 126.1, 125.6, 125.3, 114.3, 113.4, 55.0
(d, J ) 14.73 Hz), 51.5, 44.3. HRMS calcd for C20H19FN2O4 [M+]
371.1407, found 371.1423.
SCHEME 4
1,3-Bis(4-methoxybenzyl)uracil (5). Uracil (930 mg, 8.29
mmol) and K2CO3 (2.75 g, 19.89 mmol) were added to an oven-
dried 3-necked flask under argon. Anhydrous DMF (35 mL) was
added, and the mixture was stirred for 18 h, resulting in a thick
gel. 4-Methoxybenzyl bromide (3.6 mL [5 g], 24.87 mmol) was
added, and the reaction was stirred for another 5 days. The reaction
mixture was concentrated and redissolved in water and extracted
with EtOAc. The combined organic layers were washed with water
and brine, dried over MgSO4, filtered, and concentrated. Purification
by silica gel column chromatography (2:1 EtOAc/hexanes) afforded
the product (5) as a white solid (1.066 g, 36%). 1H NMR (CDCl3,
500 MHz) δ 7.47 (m, 2H), 7.21 (m, 2H), 7.08 (d, J ) 7.93 Hz),
6.89 (m, 2H), 6.83 (m, 2H), 5.70 (d, J ) 7.93 Hz), 5.07 (s, 2H),
4.82 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H). 13C NMR (CDCl3, 125
MHz) δ 162.8, 159.6, 158.9, 151.6, 141.5, 130.5, 129.5, 129.0,
127.0, 114.3, 113.5, 101.8, 55.2, 55.0, 51.6, 43.6. HRMS calcd for
C20H20N2O4 [M+] 353.1501, found 353.1501
to afford 5-DHFU, although isolation of this polar product from
the salt byproducts required continuous extraction, performed
according to the following isolation protocol: The reaction
solvent was evaporated from the crude product, and the resulting
solid was redissolved in a small volume (∼20 mL) of water
and then washed briefly with CHCl3 to remove the organic
byproducts. The aqueous layer containing 5-FDHU was then
transferred to a continuous extractor and extracted with EtOAc
for 24-36 h. The extraction solvent was removed by evapora-
tion, and the resulting solid was recrystallized from ethanol to
give very pure 5-DHFU.
1,3-Bis(4-methoxybenzyl)-5,6-dihydro-5-fluorouracil(4).Method
A (hydride reduction of bis-PMB-5-FU): A flask containing a
stir bar and 1,3-(4-methoxybenzyl)-5-fluorouracil (3, 2.05 g, 5.53
mmol) was evacuated and purged with argon three times. Anhy-
drous THF (25 mL) was added, and the reaction was cooled to
-78 °C. L-Selectride (1 M in THF, 6.08 mL, 6.08 mmol) was added
via syringe and stirred for 90 min at -78 °C. Saturated NH4Cl
was added, and then the mixture was warmed to room temperature
and stirred for 30 min. The aqueous layer was extracted with EtOAc,
and the combined organic layers were washed with water and brine,
dried over MgSO4, filtered, and concentrated. Purification by silica
gel column chromatography (1:1 EtOAc/hexanes) afforded the
product 4 as a clear oil (1.44 g, 70%).
Method B (hydride reduction-fluorination of 5): A flask
containing a stir bar and 1,3-(4-methoxybenzyl)uracil (5, 1.26 g,
3.56 mmol) was evacuated and purged with argon three times.
Anhydrous THF (15 mL) was added, and the reaction was cooled
to -78 °C. L-Selectride (1 M in THF, 3.93 mL, 3.93 mmol) was
added via syringe and stirred for 2 h at -78 °C. A solution of
SelectFluor (1.39 g, 3.93 mmol) in anhydrous DMF (5 mL) was
added, and the reaction was slowly warmed to room temperature
and stirred overnight. The solvent was evaporated and redissolved
An alternative method was developed to prepare 5-DHFU
from uracil instead of 5-FU. 5-FU is currently over 10 times
more expensive than uracil, so using uracil as a starting material
has significant cost advantages. Uracil was N-alkylated with
4-methoxybenzyl bromide in a similar manner to 3. The
L-Selectride reduction goes through intermediate 6 (Scheme 4),
and because Kundu et al. were able to alkylate this position,
we wondered whether it could be fluorinated electrophilically.
L-Selectride reduction of 5 followed by treatment with Select-
fluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)) in anhydrous DMF (instead of acidic
workup) gave the desired product (4) in 58% yield, as well as
the protio compound 7, in 25% yield; formation of the latter
product was presumed due to the presence of water in the DMF.
The products were easily separated with silica gel flash
chromatography (1:1 EtOAc/hexanes).
This work demonstrates the first practical chemical syntheses
of 5-DHFU, and it opens possibilities for using this material in
various biological applications.
J. Org. Chem, Vol. 72, No. 22, 2007 8575