940
D. Zhang et al. / Journal of Fluorine Chemistry 130 (2009) 938–941
then stirred at room temperature for 20 min and heated under
reflux for another 2 h. After being cooled to room temperature, ice-
water (10 ml) and H2SO4 (10 ml, 2 M) was added to the mixture in
the ice-water bath. The organic layer was separated and the
aqueous layer was extracted with Et2O (2Â 20 ml). The combined
organic extract was dried over anhydrous MgSO4, filtered and the
solvent was removed under reduced pressure to give alcohol 1 as
colorless liquid (6.1 g, 91%). 1H NMR (500 MHz, CDCl3)
d (ppm):
3.30 (br, 1H, –OH), 4.69 (s, 2H, –CH2), 7.01–7.08 (m, 1H, ArH).
4.2. Preparation of 2,3,4,5,6-pentafluorobenzyl alcohol (4)
Scheme 3.
Table 1
Freshly fused ZnCl2 (0.33 g, 2.4 mmol), NaBH4 (0.2 g, 4.8 mmol)
and dry diglyme (20 ml) was added to a dried 100 ml three-necked
flask fitted with a reflux condenser and connected to a mercury
bubbler. The mixture was stirred for 24 h at room temperature.
Then pentafluorobenzoic acid (1.1 g, 5.2 mmol) dissolved in dry
diglyme was added. The mixture was stirred and heated under
reflux for 5 h. The solvent was distilled off and recycled. The excess
hydride was quenched with H2SO4 (10 ml, 2 M). Then the reaction
mixture was treated with anhydrous K2CO3 and was extracted
with CH2Cl2 (3Â 10 ml). The organic layer was dried on Na2SO4,
filtered and solvent was removed to give the alcohol 4 of crude
product (0.8 g, 86%). After the crude product was purified by silica
gel column, a white solid was obtained. m.p.: 34–37 8C (lit. oil
a
The solvent effect of the reduction of pentafluorobenzoic acid using Zn(BH4)2
.
Entry
Solvent
Condition
Yield
1
2
3
Tetrahydrofuran
Dioxane
Reflux, 24 h
Reflux, 24 h
Reflux, 5 h
0
Trace
86%b
Diglyme
a
The molar quantity of pentafluorobenzoic acid and Zn(BH4)2 was 5.2 and
2.4 mmol respectively and 20 ml of solvent was used.
b
Isolated yield.
failure of the reaction. So perhaps breaking the B–F bond in the
intermediate was a key to the success of this reduction process
(Scheme 3).
When using dioxane as the solvent which has high boiling
point, trace amount of target product was observed by TLC.
However, when using diglyme which has higher boiling point,
2,3,4,5,6-pentafluorobenzyl alcohol 4 was successfully obtained in
86% yield (Table 1).
[19]). 1H NMR (500 MHz, CDCl3)
d (ppm): 4.82 (s, 2H, –CH2).
4.3. Preparation of 1,2,4,5-tetrafluoro-3-(methoxymethyl)benzene
(5)
The same method was used in the reduction of 2,3,5,6-
tetrafluoro-4-(methoxymethyl)benzoic acid 6 and 2,3,5,6-tetra-
fluoroterephthalic acid to give the corresponding alcohol in good
yields (Sections 4.5 and 4.7).
2,3,5,6-Tetrafluorobenzyl alcohol 1 was methylated to obtain
2,3,5,6-tetrafluoro-4-(methoxymethyl)benzene 5. The compound 5
was treated by n-BuLi and carbon dioxide to prepare the acid 6. The
acid6 was reacted withzinc borohydridetogive2,3,5,6-tertrafluoro-
4-(methoxymethyl)benzyl alcohol 3. After hydroxyl group of alcohol
1 was protected as its THP ether, the compound 7 was treated by n-
BuLi and CH3I to prepare the methylated compound that was
deprotected using TsOH and ethanol to give one of our target
molecule, 2,3,5,6-tertrafluoro-4-methyl-benzyl alcohol 2.
The compound 1 (8.4 g, 47 mmol), finely ground NaOH (1.87 g,
47 mmol) and 40 ml CH2Cl2 was added to a round-bottom flask. The
mixture was stirred in an ice-water bath for 30 min. After a small
amount of benzyltrimethylammonium chloride was added, the
mixture was stirred for another 30 min. Then dimethyl sulfate
(4.5 ml, 47 mmol) diluted in 10 ml CH2Cl2 was added dropwise. The
mixture was stirred for 2 h at 4–5 8C. After that, the mixture was
filtered and washed with water. The filtrate was separated and the
aqueous layer was extracted with CH2Cl2 (2Â 10 ml). The combined
organic layer was dried and solvent was removed under reduced
pressure to give crude product. The crude product was distilled
(37 8C/170 Pa; lit. 138 8C/760 mmHg[24])togivethecompound5as
colorless liquid (6.8 g, 75%). 1H NMR (500 MHz, CDCl3)
d(ppm): 3.40
(s, 3H, –OCH3), 4.46 (s, 2H, –CH2), 7.04–7.06 (m, 1H, ArH).
3. Conclusion
4.4. Preparation of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzoic
acid (6)
In conclusion, we developed a novel synthetic route for the
preparation of polyflurorobenzyl alcohols from pentafluoroben-
zoic acid. The route was shortened by direct reduction of
polyfluorobenzoic acid using zinc borohydride as a reductive
agent.
Under N2 atmosphere, a mixture of the compound 5 (2.4 g,
12 mmol) and 30 ml ether was cooled to À78 8C. n-BuLi (5 ml,
2.57 M, 12 mmol) was added dropwise for 20 min. The mixture
was stirred for 1 h. Then dry CO2 was bubbled into the reaction
system for 1 h and the temperature was kept at about À60 8C. After
that, the mixture was warmed to room temperature and dry CO2
was bubbled into reaction system for another 40 min. The solution
of HCl (10 ml, 6 M) was added to the mixture. After simple work-up
procedure, the compound 6 was obtained as oil (1.8 g, 66%), which
was used for the next step directly. The oil was purified by silica gel
column (ethyl acetate) to give a white solid. m.p.: 93–95 8C (lit. 92–
95 8C [25]).
4. Experimental
Boiling points and melting points were uncorrected. Melting
points were measured on a Yanaco Mp-500 instrument. 1H NMR
spectra were obtained at 500 MHz (IMOVA-500) using Me4Si as an
internal standard. All reactions were monitored by TLC.
4.1. Preparation of 2,3,5,6-tetrafluorobenzyl alcohol (1)
LiAlH4 (2.0 g, 52 mmol) and dried ether (40 ml) was added to a
dry 100 ml three-necked flask fitted with a reflux condenser and a
dropping funnel under N2 atmosphere. Pentafluorobenzoic acid
(7.8 g, 37 mmol) dissolved in dry ether was added dropwise to the
mixture for 20 min in an ice-water bath. The reaction mixture was
4.5. Preparation of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl
alcohol (3)
The reaction was carried out as described in Section 4.2.
Zn(BH4)2 (10 mmol) and 2,3,5,6-tetrafluoro-4-(methoxymethyl)-