Regioselective synthesis of fluorohydrines via SN2-type ring-opening of epoxides with TBABF-KHF2

Article abstract of DOI:10.1055/s-2003-40865

We found that the ring-opening fluorination of terminal epoxides using TBABF-KHF₂ proceeds with high selectivity through the S_N2 mechanism. As TBABF-KHF₂ is easily obtainable, is stable, and can be used in glassware, it ca

Full text of DOI:10.1055/s-2003-40865

1530
LETTER
Regioselective Synthesis of Fluorohydrines via SN2-Type Ring-Opening of
Epoxides with TBABF–KHF2
R
egioselective Syn
u
thesis of Flu
r
orohydr
i
ine
s
ko Akiyama, Tsuyoshi Fukuhara, Shoji Hara*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066556; E-mail: hara@org-mc.eng.hokudai.ac.jp
Received 4 June 2003
to be less basic than TBAF, also gave a poor result.6 On
Abstract: We found that the ring-opening fluorination of terminal
epoxides using TBABF–KHF2 proceeds with high selectivity
through the SN2 mechanism. As TBABF–KHF2 is easily obtainable,
is stable, and can be used in glassware, it can be a useful reagent for
1-fluoro-2-alkanol synthesis from the terminal epoxides.
the other hand, TBABF reacted with 1a at 100 °C to give
2a in 78% yield with good regioselectivity (90%).7 How-
ever, application of longer reaction time or higher reaction
temperature (120 °C) could not improve the yield, and the
formation of Bu3N was observed after the reaction.
Though TBABF is stable at below 140 °C, after the reac-
tion with epoxides, it changes to the TBAF. The addition
of KHF2 was found to be effective not only to suppress the
formation of Bu3N but also to improve the yield. In the re-
action of 1a with 3 equivalents of TBABF and 0.3 equiv-
alents of KHF2 at 120 °C, 2a was obtained in 92% yield
and with good selectivity (91%).8 Though TBAF–2HF
(TBATF) also showed high reactivity in the reaction with
1a, the regioselectivity was less satisfactory.
Key words: epoxides, fluorohydrine, regioselectivity, ring-open-
ing, tetrabutylammonium bifluoride (TBABF)–KHF2
Ring-opening reaction of epoxides with a fluoride ion has
been widely used to prepare organofluorine compounds.1
Especially, regioselective fluorination of terminal ep-
oxides has attracted much attention because optically ac-
tive fluorohydrines, expected as building blocks for liquid
crystal materials,2 can be prepared from easily accessible,
optically active terminal epoxides by that method. Though
many reagents for regioselective ring-opening fluorina-
tion of terminal epoxides 1 have been reported, only a few
of them successfully obtained good regioselectivity for
1-fluoro-2-alkanols 2 (Equation 1).
Table 1 Fluorination of 1a with Various Reagents
HO
F
O
+
F
OH
Hex
Hex
Hex
1a
3a
2a
HO
F
Fluorination reagenta
TBAFc
Temp (°C)
r.t.
Time (h)
Yield (%)b
0
O
+
F
OH
24
18
18
18
4
R
R
R
1
2
3
TBAF
100
37 (84:16)
36 (72:28)
78 (90:10)
73 (90:10)
97 (78:22)
92 (91:9)
Equation 1
TBAF·5H2O
TBABF
100
100
Schlosser et al. attained high regioselectivity (> 90%) for
2 by i-Pr2NEt–HF,3 and Yoshioka et al. succeeded by us-
ing PBu4F(HF)n.4 However, they each showed only one
example and the generality of their methods was not con-
firmed. Furthermore, a drawback of these methods is that
the reagents are not easily available. We wish to report
here that high regioselectivity (≥90%) for 2 was realized
TBABF
120
TBATF
120
4
d
TBABF–KHF2
120
4
a If otherwise not mentioned, fluorination reagent (3 mmol), 1a
(1 mmol) and heptane (0.1 mL) were used.
by Bu4N+HF2 (TBABF)–KHF2, prepared from commer-
–
b 19F NMR yield using FCH2CH2OH as an internal standard. In paren-
theses, ratio of 2a:3a obtained by 19F NMR.
cially available Bu4N+F––(TBAF), aq HF, and KHF2. The
application of TBAF to the reaction with 1-octene oxide
(1a) resulted in poor selectivity and chemical yield as
shown in Table 1, and a significant amount of Bu3N was
found after the reaction at 100 °C. As the fluoride ion of
the TBAF is highly basic, Hofmann-type elimination took
place under the reaction conditions and the TBAF decom-
posed to Bu3N, butene, and HF.5 TBAF–5H2O, reported
c 3 mL of 1 M THF solution of TBAF was used.
d TBABF (3 mmol), KHF2 (0.3 mmol) and heptane (0.1 mL) were
used.
The generality of our method for the selective formation
of the terminal fluorides 2 was shown in the reaction with
various terminal epoxides (Table 2). Even in the reaction
with styrene oxide (1b), which is apt to give SN1 product
3b,9a,10 SN2 product 2b was obtained with good selectivi-
ty. Sattler and Haufe reported that in the reaction of Et3N–
(HF)n reagents with ethyl 10,11-epoxy undecanoate (1c),
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1530,1532,ftx,en;U10503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Synthesis of Fluorohydrines
1531
a
available (S)-(–)-styrene oxide (98% ee) as shown in
Scheme 1.11 Interestingly, the minor product, 2-phenyl-2-
fluoroethanol (3b), also kept the optical purity of the start-
ing epoxide. Therefore, both 2b and 3b were formed via
the SN2 mechanism without racemization.12
Table 2 Fluorination of Various Epoxides with TBABF–KHF2
HO
F
O TBABF-KHF2
120 °C
+
R
F
OH
R
R
1
3
2
Substrate
Time (h)
2
Yield of 2 (%)b
2:3c
References
86 (68)
90:10
90:10
–
O
(1) (a) Mascaretti, O. A. Aldrichimica Acta 1993, 26, 47.
(b) Bonini, C.; Righi, G. Synthesis 1994, 225; and the
references cited therein.
(2) Umezawa, J.; Takahashi, O.; Furuhashi, K.; Nohira, H.
Tetrahedron: Asymmetry 1993, 4, 2053.
(3) Suga, H.; Hamatani, T.; Schlosser, M. Tetrahedron 1990,
46, 4247.
(4) Seto, H.; Qian, Z.; Yoshioka, H.; Uchibori, Y.; Umeno, M.
Chem. Lett. 1991, 1185.
Ph
1b
O
6
4
86 (65)
71
EtOOC-(CH2)8
1c
O
(5) (a) Landini, D.; Maia, A.; Rampoldi, A. J. Org. Chem. 1989,
54, 328. (b) Christe, K. O.; Wilson, W. W.; Wilson, R. D.;
Bau, R.; Feng, J. J. Am. Chem. Soc. 1990, 112, 7619.
(6) Albanese, D.; Landini, D.; Penso, M. J. Org. Chem. 1998,
63, 9587.
(7) TBABF was previously used for the halogen exchange
fluorination reaction in polar solvents, see: (a) Bosch, P.;
Camps, F.; Chamorro, E.; Gasol, V.; Guerrero, A.
Tetrahedron Lett. 1987, 28, 4733. (b) Moughamir, K.;
Atmani, A.; Mestdagh, H.; Rolando, C.; Francesch, C.
Tetrahedron Lett. 1998, 39, 7305.
(8) The generated TBAF must be converted to the stable
TBABF again by KHF2 before the decomposition to Bu3N.9
As KHF2 is slightly soluble in the reaction mixture, further
addition of KHF2 was not effective.
(9) (a) Landini, D.; Penso, M. Tetrahedron Lett. 1990, 31,
7209. (b) Landini, D.; Albanese, D.; Penso, M. Tetrahedron
1992, 48, 4163.
1d
4
4
75 (74)
92 (72)
>99:<1
98:2
O
O
tBu
1e
BnO
1f
a 3 Equivalents of TBABF, 0.3 equivalents of KHF2, and 0.1 mL of
heptane were used to 1 (1 mmol).
b 19F NMR yield using FCH2CH2OH as an internal standard, in paren-
theses, isolated yield based on 1.
c Determined by 19F NMR.
(10) Sattler, A.; Haufe, G. J. Fluorine Chem. 1994, 69, 185.
(11) Enantiomeric excess values of (S)-2b and (R)-3b were
determined from 19F NMR after conversion to MTPA esters.
(12) The representative procedure for 2a is as follows: To a 1 M
THF solution of TBAF (30 mL, 30 mmol) in a glass vessel
was added 46% aq HF (1.3 g, 30 mmol) and the volatile part
was removed by evaporator to give a crude TBABF. The
crude TBABF, containing a little water, is storable in a glass
bottle.15 The crude TBABF (845 mg, 3 mmol) and KHF2 (24
mg, 0.3 mmol) were put in a glass vessel and water was
completely removed (for 15 min at 100 °C and 0.55 mmHg).
After cooling to room temperature, heptane (0.1 mL)16 and
1a (1 mmol) were added. The mixture was kept at 120 °C for
4 h and then cooled to room temperature again. To the
reaction mixture, 2 mL of water was added and the mixture
was extracted with ether (2 mL × 3). NMR yield and the
product ratio were determined from 19F NMR using
FCH2CH2OH as an internal standard. Isolation was carried
out by column chromatography (silica gel/hexane–ether)
after concentration. 2a: IR (film) 3390, 2930, 1460 cm–1; 1H
NMR (400 MHz, CDCl3) d 4.50–4.20 (m, 2 H), 3.89–3.86
(m, 1 H), 2.00 (s, 1 H), 1.48–1.43 (m, 3 H), 1.33–1.28 (m, 7
H), 0.89 (t, 3 H, J = 7.0 Hz); 19F NMR (376 MHz, CDCl3) d
–228.81 (dt, J = 18.3 Hz, 47.7 Hz, 1 F); 3a: IR (film) 3365,
2930, 1466 cm–1; 1H NMR (400 MHz, CDCl3) d 4.58 (dm, J
= 50.3 Hz, 1 H), 3.79–3.61 (m, 2 H), 1.88 (t, J = 6.3 Hz, 1
H), 1.75–1.30 (m, 12 H), 0.89 (t, 3 H, J = 6.8 Hz); 19F NMR
(376 MHz, CDCl3) d –190.03 to –190.42 (m, 1 F).
(13) Matsuda, T.; Harada, T.; Nakajima, N.; Itoh, T.; Nakamura,
K. J. Org. Chem. 2000, 65, 157.
the isolation of the corresponding fluorohydrine products
from the amine mixtures was difficult.10 In the reaction of
1c with TBABF–KHF2, the fluorohydrine 2c was ob-
tained in good yield and with high selectivity. From 1-ox-
aspiro[2,5]octane derivative 1e and glycidol derivatives
1f, 2e and 2f were exclusively obtained.
TBABF–KHF2 is applicable to the synthesis of optically
active fluorohydrines, and (S)-2-fluoro-1-phenylethanol
of 98% ee was obtained in 90% yield from commercially
O
TBABF-KHF2
Ph
120 °C, 2 h
98%ee
F
HO
(S)-1b
+
OH
F
Ph
Ph
98% ee
98% ee
(S)-2b : (R)-3b
91
:
9
(S)-2b [α]31D = +56.1 (c = 0.94, MeOH)
{lit.13 [α]23D = +52.5 (c = 0.94, MeOH) }
(R)-3b [α]31D = -48.2 (c =1.08, CHCl3)
{lit.14 [α]24D = -51.75 (c = 5.07, CHCl3)}
Scheme 1
Synlett 2003, No. 10, 1530–1532 © Thieme Stuttgart · New York

1532
Y. Akiyama et al.
LETTER
(14) Takano, S.; Yanase, M.; Ogasawara, K. Chem. Lett. 1989,
1689.
(16) Heptane was used to wash the substrates attached on the wall
of the vessel during the reaction, and in a larger-scale
experiment, the solvent is not necessary.
(15) Complete removal of water gave pure TBABF as a highly
viscous liquid,17 which is difficult to handle. Therefore, it is
better to store the crude TBABF and to remove the water
completely just before use.18 TBABF is commercially
available and TBABF obtained from Tokyo Kasei Kogyo
Co., Ltd. showed the same reactivity.
(17) Spectra data of TBABF thus prepared coincided with the
reported ones; 19F NMR (CD2Cl2, –80 °C) d –151.5 (d, JHF
=
123.0 Hz), lit.19 (CD2Cl2, –80 °C) d –147.5 (d, JHF = 123.3
Hz).
(18) Camps, F.; Chamorro, E.; Casol, V.; Guerrero, A. J. Org.
Chem. 1989, 54, 4294.
(19) Sharma, R. K.; Fry, J. L. J. Org. Chem. 1983, 48, 2112.
Synlett 2003, No. 10, 1530–1532 © Thieme Stuttgart · New York