L. Wu / Journal of Fluorine Chemistry 132 (2011) 367–372
371
rearrangement and fluoride-promoted aldol addition, which
afforded a facile, ‘‘one-pot’’ process to -hydroxy- -difluor-
1.25 mmol), was added 2 mL freshly distilled CH2Cl2. The dark-red
heterogeneous solution was stirred for 10 min at r.t. before the
b
a,a
oketone derivatives with good to excellent yields. We are presently
investigating the application of this tandem reaction to a novel
intermolecular cyclization.
solution of 178 mg trifluoroacetyltriphenylsilane (5), 86 mL
allylbromide in 3 mL CH2Cl2 was injected. When the dark-red
solution faded to colorless, and the magnesium powder disap-
peared (about 2 h), the solution of 53 mg benzaldehyde, 540 mg
TBAT (0.5 mmol) in 5 mL CH2Cl2 was dropwisely added at 0 8C.
After the addition was complete, the solution was kept at room
temperature for another 2 h. The reaction was terminated by
addition of aqueous NH4Cl and extracted with ethyl acetate.
Further purification was achieved by column chromatography
(with ethyl acetate: hexanes = 1:5 as eluent), which afforded aldol
adduct 3 as colorless oil with 86% yield.
4. Experimental
4.1. General experimental procedures
Solvents and reagents were reagent grade and used without
purification unless otherwise noted. Tetrahydrofuran (THF) was
distilled over sodium and benzophenone and stored under argon.
CH2Cl2 was distilled over CaH2 and stored with molecular sieves.
Trifluoroethanol, chlorosilanes, aldehydes were distilled under
vacuum and stored under nitrogen. LDA was prepared from fresh
distilled (i-Pr)2NH with commercial n-BuLi (2.5 M hexane solu-
tion). Magnesium powder and zinc dust obtained from Aldrich
Corp. were used without further activation. All reactions were
carried out in oven dried glassware under nitrogen or argon unless
otherwise specified. All 1H NMR (400 MHz) spectra were recorded
on a Bruker-DMX 400 using CDCl3 solution in the presence of
tetramethylsilane (TMS) as an internal standard and are reported
4.3.1. 2,2-Difluoro-1-hyroxy-1-phenylhex-5-en-3-one (3)
As colorless oil in 86% yield, 1HNMR (CDCl3)
d
2.75 (brs, 1H),
3.76 (d, J = 6.5 Hz, 2H), 5.18–5.25 (m, 1H), 5.77–5.91 (m, 1H), 6.16
(d, J = 16.2 Hz, 1H), 6.54 (d, J = 16.2 Hz, 1H), 7.36–7.50 (m, 5H). 19
F
NMR (CDCl3)
d 116.15 (dd, J = 271, 7.5 Hz, 1F), 125. 65 (dd, J = 271,
16.7 Hz, 1F). HRMS (FAB+): Calc’d for C12H12F2O2: 226.0805; found:
226.0816.
4.3.2. 2,2-Difluoro-1-hyroxy-1-(p-tolyl)hex-5-en-3-one (3-1)
in ppm (
d
). 19F NMR spectra are given in ppm upfiled with CCl3F as
As colorless oil in 87% yield, 1HNMR (CDCl3)
d 2.35 (s, 3H), 2.74
the internal standard and CDCl3 as the solvent. Coupling constants
are reported in hertz (Hz). Spectral splitting patterns are
designated as s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; and br, broad. High and low resolution fast atom
bombardment (FAB) measurements were made with a JEOL JMS-
AX505HA mass spectrometer.
(brs, 1H), 3.77 (d, J = 6.5 Hz, 2H), 5.16–5.23 (m, 1H), 5.75–5.90 (m,
1H), 6.16 (d, J = 16.3 Hz, 1H), 6.54 (d, J = 16.3 Hz, 1H), 7.18 (d,
J = 7.2 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H). 19F NMR (CDCl3)
d 115.75
(dd, J = 271, 7.5 Hz, 1F), 124.60 (dd, J = 271, 16.7 Hz, 1F). HRMS
(FAB+): Calc’d for C13H14F2O2: 240.0962; found: 240.0965.
4.3.3. 2,2-Difluoro-1-hyroxy-1-(4-methoxyphenyl)hex-5-en-3-one
4.2. Preparation of trifluoroacetyltriphenylsilane (5)
(3-2)
As colorless oil in 73% yield, 1HNMR (CDCl3)
d 2.74 (brs, 1H),
To a round-bottom flask (flame-dried, three-neck with a
septum cap, 100 mL) under an argon atmosphere, containing
THF (5 mL), 2,2,2-trifluoroethanol (500 mg, 5 mmol), chlorotri-
phenylsilane (1.47 g, 5 mmol), and HMPA (0.5 mL) in a dry ice/
acetone bath, was added dropwise a freshly prepared solution of
LDA (17.5 mmol, 3.5 equiv., in 100 mL of THF). After the addition
was complete, the solution was kept at ꢀ78 8C for 4 h, then
warmed up and stirred at r.t. overnight. 1.5 equiv. of TMSCl was
injected slowly into the above solution via syringe at 0 8C. After
being stirred for 4 h at room temperature, the reaction was
terminated by addition of distilled water and extracted with
hexanes. The organic layer was separated, washed with saturated
brine, and dried over anhydrous Na2SO4. After the removal of the
drying agent by filtration, the solvent was evaporated and the
residue was purified by flash column chromatography (100%
hexanes) to afford the difluorovinylsilyenolate intermediate 4 with
75% yield.
3.76 (d, J = 6.5 Hz, 2H), 3.84 (s, 3H), 5.20–5.31 (m, 1H), 5.78–5.95
(m, 1H), 6.18 (d, J = 16 Hz, 1H), 6.50 (d, J = 16 Hz, 1H), 6.89 (d,
J = 7.2 Hz, 2H), 7.35 (d, J = 7.2 Hz, 2H). 19F NMR (CDCl3)
d 110 (dd,
J = 271, 7.5 Hz, 1F), 121. 3 (dd, J = 271, 16.7 Hz, 1F). HRMS (FAB+):
Calc’d for C13H14F2O3: 256.0911; found: 256.0920.
4.3.4. 2,2-Difluoro-1-hyroxy-1-(o-tolyl)hex-5-en-3-one (3-3)
As colorless oil in 82% yield, 1HNMR (CDCl3)
d 2.36 (s, 3H), 2.75
(brs, 1H), 3.76 (d, J = 6.5 Hz, 2H), 5.16–5.23 (m, 1H), 5.75–5.90 (m,
1H), 6.16 (d, J = 16.3 Hz, 1H), 6.54 (d, J = 16.3 Hz, 1H), 7.19–7.39 (m,
4H). 19F NMR (CDCl3)
d 115.73 (dd, J = 271, 7.5 Hz, 1F), 124.61 (dd,
J = 271, 16.7 Hz, 1F). HRMS (FAB+): Calc’d for C13H14F2O2:
240.0962; found: 240.0968.
4.3.5. 2,2-Difluoro-1-hyroxy-1-(4-(dimethylamino)phenyl)hex-5-
en-3-one (3-4)
As colorless oil in 80% yield, 1HNMR (CDCl3)
d 2.76 (brs, 1H),
To a solution of Selectfluor1 (266 mg, 0.75 mmol) in 5 mL of
acetonitrile was added a solution of compound 4 (0.5 mmol) in
2 mL of dichloromethane at 0 8C. The resulting mixture was stirred
at room temperature for 24 h. The reaction was quenched by the
addition of 5 mL water, and then extracted with dichloromethane
(5 mL ꢁ2). The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated. The product trifluoroacetyltriphenylsi-
lane (5) was purified by silica gel column chromatography using
100% hexane to afford white solids as 86% yield. Substrates 6, 7, 8,
9, 10 were synthesized with the similar procedure. All these NMR
data were consistent with the literature reported values [11].
3.10 (s, 6H), 3.77 (d, J = 6.5 Hz, 2H), 5.19–5.28 (m, 1H), 5.76–5.93
(m, 1H), 6.20 (d, J = 16.2 Hz, 1H), 6.45 (d, J = 16.2 Hz, 1H), 6.90 (d,
J = 7.2 Hz, 2H), 7.30 (d, J = 7.2 Hz, 2H). 19F NMR (CDCl3)
d 113.26
(dd, J = 271, 7.5 Hz, 1F), 123.1 (dd, J = 271, 16.6 Hz, 1F).
HRMS (FAB+): Calc’d for C14H17F2NO2: 269.1227; found:
269.1219.
4.3.6. Methyl 4-(2,2-difluoro-1-hydroxy-3-oxohex-5-en-1-
yl)benzoate (3-5)
As colorless oil in 86% yield, 1HNMR (CDCl3)
d 2.77 (brs, 1H),
3.76 (d, J = 6.5 Hz, 2H), 3.90 (s, 3H), 5.23–5.35 (m, 1H), 5.76–5.93
(m, 1H), 6.23 (d, J = 16.1 Hz, 1H), 6.54 (d, J = 16.1 Hz, 1H), 7.29 (d,
J = 7.3 Hz, 2H), 7.95 (d, J = 7.3 Hz, 2H). 19F NMR (CDCl3)
d 118.62
4.3. General procedure for the tandem reaction
(dd, J = 271, 7.5 Hz, 1F), 127.6 (dd, J = 271, 16.6 Hz, 1F).
HRMS (FAB+): Calc’d for C14H14F2O4: 284.0860; found:
284.0871.
A flame dried 15 mL vial under argon atmosphere, containing
6 mg Cp2TiCl2 (5 mol%) and 30 mg magnesium powder (2.5 equiv.,