hydroxy ketones derived from benzaldehydes possessing
electron-donating groups22 at ortho-, para-, and meta-
positions and aliphatic aldehydes, such as hydrocinnamal-
dehyde and cyclohexanecarboxaldehyde were olefinated
to demonstrate the generality of the process for difluori-
nated R-pyrones.
Scheme 3. Preparation of Z-4,4-Difluoropent-2-enoate
The following benzyloxy alcohols 1 derived from the
corresponding aldehydes [shown in brackets] were con-
verted to the corresponding 5,5-difluoro-5,6-dihydropy-
ran-2-ones in 20-39% overall yields in six steps: 3-
(benzyloxy)-2,2-difluoro-1-(4-methoxyphenyl)-but-3-
en-1-ol (1b) [4-methoxybenzaldehyde], 3-(benzyloxy)-2,
2-difluoro-1-p-tolylbut-3-en-1-ol (1c) [p-tolualdehyde],
and [3-(benzyloxy)-2,2-difluoro-1-(3-methoxyphenyl)-but-
3-en-1-ol (1d) [3-methoxybenzaldehyde], as well as
3-(benzyloxy)-1-(2,6-dimethylphenyl)-2,2-difluorobut-3-
en-1-ol (1e) [2,6-dimethylbenzaldehyde], 5-(benzyloxy)-4,
Scheme 4. Preparation of δ,δ-Difluoro-R-pyrone
(24) (a) Otaka, A.; Watanabe, J.; Yukimasa, A.; Watanabe, H.;
Kinoshita, T.; Oishi, S.; Tamamura, H.; Fujii, N. J. Org. Chem. 2004,
69, 1634. (b) Also see: Kitazume, T.; Tsukamoto, T.; Yoshimura, K.
Chem. Commun. 1994, 1355.
(25) A typical experimental procedure for the preparation of 6a is as
follows. (a) Preparation of 4-(tert-butyldimethylsilyloxy)-3,3-difluoro-4-
phenylbutan-2-one (3a): 2,6-Lutidine (0.55 mL, 4.65 mmol) was added to
a solution of 3,3-difluoro-4-hydroxy-4-phenylbutan-2-one (2a) (0.31 g,
1.55 mmol) in CH2Cl2 (6 mL) at 0 °C, followed by dropwise addition of
TBDMSOTf (0.72 mL, 3.10 mmol), and the mixture was stirred at 0 °C
for 3 h, and at RT for 3 h. The reaction mixture was diluted with CH2Cl2
and washed with saturated aqueous NH4Cl (8 mL). The organic layer
was washed with brine, dried (anhyd. MgSO4), filtered, and concen-
trated. The residue was purified by flash silica chromatography (hexane/
EtOAc = 95/5) to yield 3a as a colorless liquid (0.45 g, 94%). (b)
Preparation of Z-methyl 5-(tert-butyldimethylsilyloxy)-4,4-difluoro-
3-methyl-5-phenylpent-2-enoate (4a): To a solution of 18-crown-6
(0.85 g, 3.18 mmol) in THF (11 mL), at -78 °C, was added bis(2,2,2-
trifluoroethyl)(methoxycarbonylmethyl)phosphonate (0.36 mL,
1.59 mmol) and a solution of KN(TMS)2 (0.5 M in toluene, 4.12 mL,
2.06 mmol). The homogeneous mixture was stirred at that temperature
for 15 min, followed by the addition of a solution of 3a (0.50 g,
1.59 mmol) in THF (3 mL) and further stirring for 30 min and at
-40 °C for 18 h. The reaction was allowed to warm to RT and quenched
with sat. aqueous NH4Cl (10 mL). The organics were extracted with
Et2O (3 ꢀ 20 mL) and the combined Et2O layers were washed with sat.
aq. NaHCO3 solution, dried (anhyd. MgSO4), filtered, and concen-
trated. The residue was purified by flash silica chromatography (hexane/
EtOAc = 95/5) to provide 4a as a colorless oil (0.51 g, 86%). (c)
Preparation of Z-methyl 4,4-difluoro-5-hydroxy-3-methyl-5-phenylpent-
2-enoate (5a): HF-pyridine complex (70%, 3.7 mL) was added to a
solution of 4a (0.14 g, 0.39 mmol) in THF (10 mL) at 0 °C, and the
solution was stirred at RT for 18 h. The reaction was cautiously
quenched with sat. aq. NaHCO3 solution (9 mL) and extracted with
EtOAc (3 ꢀ 10 mL). The combined extracts were washed with water and
brine, dried (anhyd. MgSO4), filtered, and concentrated. The residue
was purified by flash silica chromatography (hexane/Et2O = 1/1) to
provide 5a as a colorless oil (0.08 g, 80%). (d) Preparation of 5,5-difluoro-
4-methyl-6-phenyl-5,6-dihydro-2H-pyran-2-one (6a): A mixture of 5a
(58 mg, 0.23 mmol) and 2 M NaOH solution (0.34 mL) in THF
(1.9 mL) was stirred for 2 h at RT and the mixture was concentrated
to provide a light yellow solid. This was acidified with aq. 2 M HCl and
extracted with Et2O (3 ꢀ 5 mL). The organic layer was washed with
brine, dried (anhyd. MgSO4), filtered, and concentrated to obtain the
crude β-hydroxy acid as a light yellow oil (90 mg). 2,4,6-Trichloroben-
zoyl chloride (0.07 mL, 0.41 mmol) was added to a mixture of the above
β-hydroxy acid (90 mg, 0.37 mmol) and triethylamine (0.07 mL,
0.48 mmol) in THF (3.5 mL) and the mixture was stirred for 2 h at
RT. After removal of triethylamine hydrochloride, the filtrate was
diluted with toluene (25 mL) and added to a refluxing solution of
4-dimethylaminopyridine (0.18 g, 1.48 mmol) in toluene (35 mL) over
a period 1.5 h. The reaction mixture was refluxed for 15 h, cooled to RT,
then diluted with Et2O, washed with 3% aq. HCl (2 ꢀ 15 mL), water, sat.
aq. NaHCO3 solution, and water, dried (anhyd. MgSO4), filtered and
concentrated. The residue was purified by flash silica chromatography
(hexane/Et2O = 1/1) to provide δ-lactone 6a as a white solid (35 mg,
69%), mp 112-113 °C.
prepare the difluorinated pyrone. The standard deprotec-
tion of the TBS ether with TBAF resulted in poor yields of
the hydroxy ester 5a. Hydrolysis with a catalytic amount of
p-TSA and cyclization20 in refluxing toluene did not go to
completion even after 2 days.
Deprotection of the TBS ether was then examined with
HF-pyridine in THF, which yielded the δ-hydroxy ester
5a in 80% yield (Scheme 4). Sodium hydroxide-mediated
hydrolysis provided the crude δ-hydroxy acid, in quanti-
tative yield, which was subjected to cyclization under
Yamaguchi conditions21 to achieve the targeted R-pyrone
6a in 69% yield.
The successful synthesis of the difluoro-R-pyrone from
1a was then extended to a series of 3-(benzyloxy)-2,2-difluoro-
but-3-en-1-ols (1b-g), after conversion to the correspond-
ing R,R-difluoro β-hydroxy ketones (2b-g). Thus, the
(20) Aurell, M. J.; Ceita, L.; Mestres, R.; Parra, M.; Tortajada, A.
Tetrahedron 1995, 51, 3915.
(21) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(22) Attempts to debenzylate the benzyloxy alcohols 1, prepared via
the fluoroallylboration of benzaldehyde bearing electron-withdrawing
groups, such as p-fluoro, p-chloro, and p-trifluoromethyl groups, re-
sulted in dehalogenation along with debenzylation forming 2a, 2a, and
2c, respectively. Debenyzlation of the benzyloxy alcohol derived from
p-nitrobenzaldehyde resulted in the formation of the corresponding
p-amino compound, 3,3-difluoro-4-hydroxy-4-(4-aminophenyl)butan-
2-one.
(23) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733.
1304
Org. Lett., Vol. 13, No. 6, 2011