Scheme 1
DFMBA and its application to the synthesis of optically-active
fluorohydrin derivatives.
When ethylene glycol (1a) was subjected to a reaction with
2.4 equiv. of DFMBA in heptane at 98 uC for 1 h, the meta-
methylbenzoyl ester of 2-fluoroethanol (2a) was obtained in 79%
yield. Only one hydroxy group of 1a was fluorinated, the other
being esterified by DFMBA. When the reaction was carried out
under microwave irradiation (MW), the reaction was complete in
10 min and 2a was obtained in 73% yield.
Scheme 2
In a similar manner, optically-active fluorohydrin derivatives
could be obtained from commercially available, optically-active
2,3-butanediol (1i) and 1,2-diphenylethanediol (1j) with high
diastereoselectivities. In nature, many compounds, such as sugars,
have optically-active diol functions. When a manitol derivative, 1k,
was subjected to reaction with DFMBA, a monofluorinated
product, 2k, was obtained with high diastereoselectivity.{
Under similar conditions, various 1,2-diols (1a,c,d) and 1,3-diols
(1b,e,f) could be converted to their corresponding fluorohydrin
derivatives in good yields, as shown in Table 1. When an
unsymmetrical diol (1f) was used, a mixture of two regioisomers
were obtained non-selectively. On the other hand, the reaction of
1,12-dodecanediol (1g), in which the hydroxy groups are well
Notes and references
{ General procedure for the monofluorination of diols using DFMBA: A
mixture of diol (1 mmol), DFMBA (2.2 mmol) and solvent (1 ml) in a
Teflon2 PFA vessel was heated using microwaves6 or an oil bath, at the
temperature and time shown in Table 1. After completion of the reaction,
the mixture was poured into aqueous NaHCO3 and extracted with ether 3
times. The combined organic phases were dried over MgSO4, concentrated
under reduced pressure and purified by column chromatography (silica gel,
hexane–ether) to give the monofluoride product 2.
separated from each other by methylene groups, gave
difluorinated product in good yield.
a
As special care is not required to terminate the reaction at
the monofluorination stage, the reaction seems to proceed
through
a cyclic intermediate, after which the remaining
hydroxy group is converted to an ester group, inert to DFMBA
(Scheme 1).
1 K. Dax, M. Albert, J. Ortner and B. J. Paul, Carbohydr. Res., 2000, 327,
47.
2 K. W. Pankiewicz, Carbohydr. Res., 2000, 327, 87.
When an optically-active (2S,4S)-2,4-pentandiol (1h) was
subjected to DFMBA, a monofluorinated product, 2h, was
obtained in 75% yield with high diastereoselectivity. In order to
examine the stereochemistry of the reaction, 1h was converted to
the monomesylate 3. Monofluorination of 3 was carried out with
inversion of stereochemistry by using tetrabutylammonium
fluoride (TBAF?5H2O)7 to give (2S,4R)-4-fluoro-2-pentanol
meta-methylbenzoyl ester. As this compound’s 1H and 19F
NMR spectra, and optical rotation8 coincided with those of 2h,
fluorination of alcohols by DFMBA was found to also proceed
with inversion of stereochemistry. Starting from (2R,4R)-1h,
(2R,4S)-2h was obtained selectively (Scheme 2).
3 G. Haufe, J. Fluorine Chem., 2004, 125, 875.
4 C. Ye and J. M. Shreeve, J. Fluorine Chem., 2004, 125, 1869.
5 D. F. Shellhamer, D. T. Anstine, K. M. Gallego, B. R. Ganesh,
A. A. Hanson, K. A. Hanson, R. D. Henderson, J. M. Prince and
V. L. Heasley, J. Chem. Soc., Perkin Trans. 2, 1995, 861.
6 S. Kobayashi, A. Yoneda, T. Fukuhara and S. Hara, Tetrahedron Lett.,
2004, 45, 1287; S. Kobayashi, A. Yoneda, T. Fukuhara and S. Hara,
Tetrahedron, 2004, 60, 6923.
7 D. Albanese, D. Landini and M. Penso, J. Org. Chem., 1998, 63, 9587.
8 (2R, 4S)-2h, prepared by reaction with TBAF?5H2O, was contaminated
with about 10% of olefinic by-products, which were difficult to separate.
We believe this must be the reason why it had a larger optical rotation
value than 2h itself, prepared from 1h and DFMBA.
3590 | Chem. Commun., 2005, 3589–3590
This journal is ß The Royal Society of Chemistry 2005
Yoneda, Atsushi
