Table 1. Asymmetric R-Fluorination of R-Chloro-β-keto Estera
Scheme 1. Synthetic Strategy for Chiral Fluorinated Molecules
timeb
[h]
yieldc
[%]
eed
[%]
entry
Lewis acid
solvent
1
2
3
4e
5
6
7
Ni(ClO4)2 6H2O
benzene
benzene
benzene
benzene
benzene
CH2Cl2
Et2O
18
22
38
11
8
57
54
81
36
82
61
72
0
6
3
Mg(OTf)2
Zn(OTf)2
induction. Nucleophilic substitution of the chlorine moiety
in the resulting compounds affords a variety of R-fluoro-R-
heteroatom-substituted esters. In 2003, Togni and co-
workers demonstrated the asymmetric synthesis of R-
chloro-R-fluoro-β-keto esters by this sequential double
halogenation in one-pot operation in the presence of
Ti-TADDOLate catalyst with up to 65% ee.3a,5 With the
aim of achieving high asymmetric induction, we attempted
to carry out gem-chlorofluorination in the presence of a
new chiral Lewis acid catalyst, which we synthesized from
a 2-pyridyl monooxazoline ligand (SPYMOX)6 having a
spiro-fused axial chiral binaphthyl backbone (Scheme 2).
80
76
90
52
60
Cu(ClO4)2 6H2O
3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
11
13
a All reactions were carried out at 40 °C (bath temperature) with 3
equiv of NFSI in the presence of a chiral catalyst prepared from 12 mol %
of 1 and 10 mol % of Lewis acidic metal. b All reactions were quenched
after the complete consumption of 2 unless otherwise noted. c Isolated
yield. d Determined by chiral HPLC analysis. e About 50% of the
starting material remained unreacted.
The high asymmetric induction ability of our new catalyst
in the fluorination prompted us to proceed to the next stage,
the one-pot asymmetric gem-chlorofluorination of β-keto
esters. In the first step, β-keto ester 4a was chlorinated with
N-chlorosuccinimide (NCS) in the presence of a 1/Cu(OTf)2
complex. After the complete consumption of 4a by TLC
monitoring, NFSI was added to the reaction mixture.
Fluorination was conducted at 40 °C for 8 h to afford the
desired product 3a in 70% yield (over 2 steps) along with the
R,R-dichlorinated form in approximately 5% yield (Table 2,
entry 1). To our delight, the optical purity of 3a in this one-
pot reaction was sufficiently high (90% ee), and the sense of
enantioselection was the same as that in the fluorination of
monochloro ester 2 (Table 1, entry 5). This implied that the
stereochemical outcome of this double halogenation is
determined by the fluorination step. Several β-keto esters
were subjected to gem-chlorofluorination under similar
reaction conditions. As summarized in Table 2, various R-
chloro-R-fluoro-β-keto esters, including aliphatic, aromatic,
and heterocyclic ketoesters, were successfully synthesized
with good to high optical purity (79À92% ee).9
Scheme 2. Preparation of Chiral Spiro Lewis Acid Catalyst
We started our investigation by screening various Lewis
acids for the enantioselective R-fluorination of R-chloro-β-
keto ester 2 with N-fluorobenzenesulfonimide (NFSI).7,8
As shown in Table 1, the copper(II) triflate complex of
SPYMOX (1) was very effective for asymmetric fluorina-
tion of 2 in benzene; in this case, the desired R-chloro-R-
fluoro-β-keto ester 3a was obtained in high yield and
enantioselectivity (entry 5; 90% ee).
(5) A method for asymmetric chlorination of β-keto esters with a Ti-
TADDOLate catalyst: Hintermann, L.; Togni, A. Helv. Chim. Acta
2000, 83, 2425.
(6) For the synthesis of SPYMOX and its application in palladium-
catalyzed asymmetric allylic alkylation, see: Shibatomi, K.; Muto, T.;
Sumikawa, Y.; Narayama, A.; Iwasa, S. Synlett 2009, 241.
Next, we extended the enantioselective gem-chlorofluor-
ination to several β-keto phosphonates 5. As shown in
Table 3, the 1/Cu(OTf)2 complex was very effective for this
reaction; thus, the desired R-chloro-R-fluoro-β-keto phos-
phonates 6aÀf were isolated in moderate to good yields
with high enantioselectivity (85À92% ee).9 It is noteworthy
(7) Although the field of asymmetric R-fluorination of active methine
compounds is progressing steadily, there are only a few known catalysts
that achieve high enantioselectivity (over 90% ee) in the fluorination of
acyclic β-keto esters or β-keto phosphonates. For successful examples
with acyclic substrates, see: (a) Hintermann, L.; Togni, A. Angew.
Chem., Int. Ed. 2000, 39, 4359. (b) Hamashima, Y.; Yagi, K.; Takano,
(9) We have confirmed that the optical purity of gem-chlorofluoro
carbonyl compounds 3a, 3b, 3d, and 6a does not change even after
chromatographic purification using achiral silica gel or solvent evapora-
tion. Therefore, we conclude that the enantiomers do not undergo self-
disproportionation during the purification process. For enantiomers
self-disproportionation effect of perfluorinated compounds, see:(a)
Soloshonok, V. A. Angew. Chem., Int. Ed. 2006, 45, 766. (b) Soloshonok,
V. A.; Ueki, H.; Yasumoto, M.; Mekala, S.; Hirschi, J. S.; Singleton,
D. A. J. Am. Chem. Soc. 2007, 129, 12112. (c) Ueki, H.; Yasumoto, M.;
Soloshonok, V. A. Tetrahedron: Asymmetry 2010, 21, 1396.
ꢀ
H.; Tamas, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530. (c)
Hamashima, Y.; Suzuki, T.; Shimura, Y.; Shimizu, T.; Umebayashi, N.;
Tamura, T.; Sasamoto, N.; Sodeoka, M. Tetrahedron Lett. 2005, 46,
1447. (d) Kim, S. M.; Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7, 2309. (e)
Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanema-
sa, S. Angew. Chem., Int. Ed. 2008, 47, 164. (f) Bernardi, L.; Jørgensen,
K. A. Chem. Commun. 2005, 1324. (g) See also ref 4.
(8) For a review on the asymmetric functionalization at a haloge-
nated prochiral carbon, see: Shibatomi, K. Synthesis 2010, 2679.
Org. Lett., Vol. 13, No. 11, 2011
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