Enantioselective fluorination of ?-ketoesters catalyzed by chiral sodium phosphate: Remarkable enhancement of reactivity by simultaneous utilization of metal enolate and metal phosphate

Article abstract of DOI:10.1246/cl.130934

A highly enantioselective fluorination of ?-ketoesters catalyzed by chiral sodium phosphate is achieved. In this process, the simultaneous formation of sodium enolate and sodium phosphate under basic conditions is the key to achieving excellent selectivity. Indanone derivatives as well as benzofuranone derivatives could be employed in this reaction to afford the fluorinated adducts in good yields with good to excellent enantioselectivities.

Full text of DOI:10.1246/cl.130934

Received: October 5, 2013 | Accepted: October 12, 2013 | Web Released: October 19, 2013
CL-130934
Enantioselective Fluorination of β-Ketoesters Catalyzed by Chiral Sodium Phosphate:
Remarkable Enhancement of Reactivity by Simultaneous Utilization
of Metal Enolate and Metal Phosphate
Keiji Mori, Ayaka Miyake, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8558
(
E-mail: takahiko.akiyama@gakushuin.ac.jp)
O
O O O
A highly enantioselective fluorination of β-ketoesters
catalyzed by chiral sodium phosphate is achieved. In this
process, the simultaneous formation of sodium enolate and
sodium phosphate under basic conditions is the key to achieving
excellent selectivity. Indanone derivatives as well as benzofur-
anone derivatives could be employed in this reaction to afford
the fluorinated adducts in good yields with good to excellent
enantioselectivities.
S
S
Ph
N
F
Ph
(1.5 equiv)
O
O
1
e (10 mol%)
Na2CO3 (1.1 equiv)
F
O
O
O
CO2Me
P
Benzene
CO2Me
X
X
OH
R
R
up to 92% ee
1e
Scheme 1. Enantioselective fluorination of β-ketoesters cata-
lyzed by chiral phosphoric acid.
Because of the increasing importance of fluorinated com-
pounds in pharmaceuticals and pesticides, the introduction of
fluorine atoms in organic molecules has attracted much interest
i) employment of metal phosphate
X
ii) formation of the metal enolate anion
1
in recent years. In particular, there have been numerous moves
M
O
to develop a variety of enantioselective reactions.2
O
O
O
O
O
The catalytic enantioselective fluorination of β-ketoesters
P
M
3
was achieved by Hintermann and Togni in 2000. Although
OMe
excellent enantioselectivity was accomplished with the Ti-
TADDOL catalyst (90% ee), only one substrate with an
extremely bulky 2,4,6-triisopropylphenylmethyl ester was pre-
sented in their report. Recent advances in metal-catalyzed
asymmetric reactions have furthered the applicability of sub-
X
Figure 1. Two solutions for enhancing reactivity.
α-fluoro β-ketoesters, including methyl, ethyl, and benzyl esters,
were obtained in excellent yields with good to excellent
enantioselectivities.
In our initial examination conducted with chiral phosphoric
acid 2 as the catalyst, we found that phosphoric acid itself is not
sufficient to achieve the desired reaction. In spite of our
exhaustive investigations that were aimed at achieving high
selectivities, desired fluorinated adduct 4a was obtained in
modest chemical yield with low selectivity (less than 20% yield,
4
strates. One of the limitations, however, is that bulky t-butyl or
adamantyl esters have to be employed most of the time to
achieve excellent enantioselectivity as methyl ester yields
moderate to low selectivity.
In contrast to the progress made in metal-catalyzed
reactions, the asymmetric fluorination reaction that employs an
organocatalyst still has much room for improvement.5 The first
organocatalytic enantioselective fluorination of β-ketoesters was
developed by Park and Kim,5a in which cinchona alkaloids
worked as a phase-transfer catalyst to afford α-fluoro β-
ketoesters in excellent yields with moderate enantioselectivities.
Quite recently, Maruoka (chiral quaternary ammonium phase-
­7
up to 25% ee).
X
O
O
NFSI (1.0 equiv)
(10 mol%)
O
O
O
2
F
2
P
CO2Me
Toluene
rt, 24 h
CO Me
OH
5
c
5d
transfer catalyst) and Hu (chiral thiourea catalyst) independ-
ently developed a highly enantioselective fluorination reaction
3a
4a
X
less than 20%
up to 25% ee
2
8
,9
of β-ketoesters. As regards chiral phosphoric acid catalysis,
ð1Þ
Inanaga’s group developed a chiral scandium perfluorobinaphth-
yl phosphate-catalyzed asymmetric reaction of β-ketoesters, in
which moderate to good selectivities were achieved.1 Except
for the work of Hu and Inanaga, excellent selectivity could be
achieved with only a bulky t-butyl group on the ester moiety and
hence, there is a great demand for the development of a new
method that is able to use a large variety of substrates.
To overcome this daunting reactivity issue, improvement of
both catalytic ability and substrate reactivity is required. Based
0
12
13
on the reports of Ishihara and Antilla on the enantioselective
reaction catalyzed by a chiral metal phosphate, we hypothesized
that the following two solutions would meet our purpose
(Figure 1): (1) employment of a metal phosphate in place of
phosphoric acid itself and (2) formation of a metal enolate anion.
We anticipated that the concomitant employment of these two
species would lead to a dramatic enhancement of reactivity.
The simplest way to simultaneously form the above-
mentioned two active species is to add a slight excess (1.1 equiv)
of an inorganic base to the reaction mixture. As expected, the
We wish to report herein an asymmetric fluorination
reaction catalyzed by in situ generated chiral sodium phosphate
derived from chiral phosphoric acid (Scheme 1).11 Two active
species (sodium enolate and sodium phosphate) were formed
simultaneously under basic conditions and the corresponding
Chem. Lett. 2014, 43, 137–139 | doi:10.1246/cl.130934
© 2014 The Chemical Society of Japan | 137

a
Table 2. Substrate scopea
Product Time Yield
Table 1. Screening for catalysts under basic conditions
Na2CO3 (1.1 equiv)
O
O
NFSI (1.0 equiv)
Entry
1
ee
2
(10 mol%)
F
CO2Me
b
Toluene
rt, 24 h
CO2Me
/h
/%
/%
3
a
4a
O
Entry
X
Yield/%
ee/%b
F
4f
48
92
89
CO2Me
1
2
3
4
5
6
2,4,6-(iPr)3C6H2 (2a)
3-CF3-4-NO2C6H3 (2b)
77
97
84
78
87
76
96
20
7
0
9
77
Cl
Br
O
F
2
2
3
4
5
6
7
4g
4h
4i
27
26
37
37
42
33
92
98
85
90
48
98
70
88
92
91
75
42
3,4,5-(MeO) C H (2c)
3
6
2
CO Me
SiPh3 (2d)
O
9-anthryl (2e)
9-anthryl (1e)
9-anthryl (1e)
F
¹79
¹90
CO2Me
O
c
O
7
Cl
Br
F
aUnless otherwise noted, all reactions were performed with
.20 mmol β-ketoester 3, 0.20 mmol NFSI, 0.22 mmol Na2-
CO3, and 10 mol % 2 in toluene (2.0 mL) at room temperature.
CO2Me
O
0
O
F
2
4j
b
CO Me
Enantiomeric excess was determined with a chiral stationary
O
O
c
phase. Benzene was employed as the reaction solvent.
F
4k
4l
CO2Me
S
4
a: Me
4b: Et
4c: Bn
O
O
F
9
6%, 90% ee 90%, 87% ee 74%, 82% ee
CO Me
2
F
R
CO2R
4
d: i-Pr
4e: t-Bu
8
0%, 60% ee 81%, 26% ee
O
4
8
9
F
4m
4n
44
48
63
7
33
29
CO2Bn
O
Figure 2. Effect of the ester group.
O
Ph
OEt
F
Bn
addition of Na2CO3 significantly improved the chemical yield
Table 1). Corresponding product 4a was obtained in good to
aUnless otherwise noted, all reactions were performed with
.20 mmol β-ketoester 3, 0.20 mmol NFSI, 0.22 mmol Na2-
CO3, and 10 mol % 1e in benzene (2.0 mL) at room temper-
ature. bEnantiomeric excess was determined with a chiral
stationary phase.
(
0
excellent chemical yields in all cases (²76%). Fortunately,
phosphoric acid 2e bearing a 9-anthryl group dramatically
improved the selectivity to 77% ee (87% yield, Entry 5). A
slight improvement in selectivity was observed with (S)-
biphenyl-type catalyst 1e (76% yield, ¹79% ee, Entry 6).
Changing the reaction solvent from toluene to benzene improved
the selectivity markedly and corresponding adduct 4a was
obtained in 96% yield with ¹90% ee (Entry 7).1
i) without catalyst
NFSI (1.0 equiv)
Na2CO3 (1.1 equiv)
4,15
Benzene
rt, 24 h
O
39%
O
Next, we sought to examine the applicability of this
reaction. A survey of the ester group revealed that a small ester
group was suitable for this asymmetric reaction (Figure 2). High
selectivities were achieved when substrates with ethyl and
benzyl esters were employed (87% ee in 4b, 82% ee in 4c,
respectively). On the other hand, sterically hindered isopropyl
and t-butyl esters led to low selectivities (¯60% ee). These
results suggest that our fluorination reaction may be used
together with hitherto reported methods, in which a bulky ester
group (such as t-butyl ester) exhibited excellent selectivity.
Table 2 lists the results of further examination of the
substrate scope. Here we find that the substituents on the
aromatic ring have an almost negligible effect on the reaction.
The obtained fluorinated adducts 4f and 4g with chloro and
bromo atoms at 5-position had good to excellent selectivities
F
CO2Me
CO2Me
1
e-Na (10 mol%)
3a
4a
4%, 30% ee
NFSI (1.0 equiv)
2
Benzene
rt, 24 h
ii) without Na CO3
2
Scheme 2. Effect of metal phosphate and metal enolate.
with decreased selectivity (42% ee, Entry 7). This is possibly
due to the loss of structural rigidity compared with indanone
derivatives. Further examination revealed that both the aromatic
ring and the ketoester ring structure are important to achieve
high selectivity: both benzyl 2-oxocyclopentanecarboxylate
(3m) and methyl 2-benzyl-3-oxo-3-phenylpropanoate (3n) re-
sulted in low selectivity (33% ee and 29% ee, respectively,
(89% ee and 70% ee, respectively, Entries 1 and 2). This
1
6
method could be applied to ketoesters derived from salicylic
acid to afford corresponding adducts 4h­4j in good yields with
excellent selectivities (88­92% ee, Entries 3­5). Good selectiv-
ity was also observed in thio-analogue 4k (75% ee, Entry 6). In
contrast to the favorable results gained with the five-membered
ring substrates, 6-membered ring substrate 3l gave a product
Entries 8 and 9).
As we have expected, the simultaneous formation of metal
phosphate and metal enolate is crucial for this reaction
(Scheme 2). A low chemical yield was observed in the absence
of a phosphoric acid catalyst (39%, 24 h). When the reaction
was conducted without Na2CO3 (sodium phosphate of 1e was
138 | Chem. Lett. 2014, 43, 137–139 | doi:10.1246/cl.130934
© 2014 The Chemical Society of Japan

2
a) H.-J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Müller, U.
Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637. b) W. K. Hagmann,
J. Med. Chem. 2008, 51, 4359. c) K. L. Kirk, Org. Process Res. Dev. 2008,
12, 305. d) C. Hollingworth, V. Gouverneur, Chem. Commun. 2012, 48,
Cl
O
O O
O
+
N
BF4–
TfO–
+
2
S
S
N
+
N
Ph
N
F
Ph
F
2
929. e) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem., Int. Ed. 2013,
9
6%, 90% ee
45%, 14% ee
no reaction
52, 8214.
3
4
a) L. Hintermann, A. Togni, Helv. Chim. Acta 2000, 83, 2425. b) L.
Hintermann, A. Togni, Angew. Chem., Int. Ed. 2000, 39, 4359.
*
*
Lewis acidic
activation
cf. Toste's model
O
O
P
O
O
For transition-metal-catalyzed fluorination reactions, see: a) Y.
Hamashima, K. Yagi, H. Takano, L. Tamás, M. Sodeoka, J. Am. Chem.
Soc. 2002, 124, 14530. b) R. Frantz, L. Hintermann, M. Perseghini, D.
Broggini, A. Togni, Org. Lett. 2003, 5, 1709. c) Y. Hamashima, H.
Takano, D. Hotta, M. Sodeoka, Org. Lett. 2003, 5, 3225. d) N. Shibata, T.
Ishimaru, T. Nagai, J. Kohno, T. Toru, Synlett 2004, 1703. e) N. Shibata,
J. Kohno, K. Takai, T. Ishimaru, S. Nakamura, T. Toru, S. Kanemasa,
Angew. Chem., Int. Ed. 2005, 44, 4204. f) S. M. Kim, H. R. Kim, D. Y.
Kim, Org. Lett. 2005, 7, 2309. g) T. Suzuki, T. Goto, Y. Hamashima, M.
Sodeoka, J. Org. Chem. 2007, 72, 246. h) J. Nie, H.-W. Zhu, H.-F. Cui,
M.-Q. Hua, J.-A. Ma, Org. Lett. 2007, 9, 3053. i) N. Shibata, H. Yasui, S.
Nakamura, T. Toru, Synlett 2007, 1153. j) K. Shibatomi, Y. Tsuzuki, S.
Iwasa, Chem. Lett. 2008, 37, 1098. k) V. A. Brunet, D. O’Hagan, Angew.
Chem., Int. Ed. 2008, 47, 1179. l) D. S. Reddy, N. Shibata, T. Horikawa,
S. Suzuki, S. Nakamura, T. Toru, M. Shiro, Chem.®Asian J. 2009, 4,
O
Lewis basic
activation
electrostatic
interaction
Lewis basic
activation
P
O
Na
Pa
O
O–
O
Bz
N
Na
H
O
S
O
+
O
F
N
N+
O
N
F
S
O
R
Cl
Ph
OMe
A
B
Figure 3. Examination of fluorinating reagent and proposed
transition state model.
prepared in situ), corresponding adduct 4a was obtained in 24%
yield with 30% ee.
Quite recently, Toste’s group achieved a chiral sodium
phosphate-catalyzed enantioselective fluorination of enamide
derived from indanone under almost identical reaction con-
ditions to our method (ent-2a, Selectfluor , Na2CO3, hexane,
room temperature).
obtained in low yield with very low enantioselectivity (45%,
4% ee) with Selectfluor under our optimum conditions. In
addition, the reaction did not proceed to completion when N-
fluoropyridinium triflate was used.10 These results clearly
indicate that the transition state of the present reaction is totally
different from that of Toste’s group (B in Figure 3). Based on the
above arguments, we assumed that our fluorination reaction
would proceed via twelve-membered ring transition state model
A as shown in Figure 3, wherein sodium phosphate worked as
a bifunctional catalyst [(1) Lewis basic activation of sodium
enolate moiety by phosphoryl oxygen and (2) Lewis acidic
activation of sulfonyl group of NFSI by sodium atom of
phosphate moiety].
In summary, a highly enantioselective fluorination of β-
ketoesters was achieved based on a chiral metal phosphate
strategy. A variety of substrates derived from indanone and
benzofuranone could be employed in this reaction to afford
fluorinated adducts in good yields with good to excellent
selectivities. Further investigation to develop novel reactions by
use of the simultaneous formation of metal phosphate and metal
enolate is under way in our laboratory.
1411. m) M. Kawatsura, S. Hayashi, Y. Komatsu, S. Hayase, T. Itoh,
Chem. Lett. 2010, 39, 466.
5
6
For the organocatalyzed asymmetric fluorination of β-ketoesters, see: a)
D. Y. Kim, E. J. Park, Org. Lett. 2002, 4, 505. b) D. Enders, M. R. M.
Hüttl, Synlett 2005, 991. c) X. Wang, Q. Lan, S. Shirakawa, K. Maruoka,
Chem. Commun. 2010, 46, 321. d) J. Xu, Y. Hu, D. Huang, K.-H. Wang,
C. Xu, T. Niu, Adv. Synth. Catal. 2012, 354, 515.
Other examples of asymmetric fluorination catalyzed by organocatalysts.
For aldehydes and ketones: a) N. Shibata, E. Suzuki, Y. Takeuchi, J. Am.
Chem. Soc. 2000, 122, 10728. b) D. D. Steiner, N. Mase, C. F. Barbas, III,
Angew. Chem., Int. Ed. 2005, 44, 3706. c) T. D. Beeson, D. W. C.
MacMillan, J. Am. Chem. Soc. 2005, 127, 8826. d) P. Kwiatkowski, T. D.
Beeson, J. C. Conrad, D. W. C. MacMillan, J. Am. Chem. Soc. 2011, 133,
μ
1
1b
However, desired compound 4a was
μ
1
1738. For allylsilanes: e) T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda,
S. Nakamura, T. Toru, M. Shiro, Angew. Chem., Int. Ed. 2008, 47, 4157.
f) S. C. Wilkinson, O. Lozano, M. Schuler, M. C. Pacheco, R. Salmon,
V. Gouverneur, Angew. Chem., Int. Ed. 2009, 48, 7083. For indole
fluorocyclization: g) O. Lozano, G. Blessley, T. M. del Campo, A. L.
Thompson, G. T. Giuffredi, M. Bettati, M. Walker, R. Borman, V.
Gouverneur, Angew. Chem., Int. Ed. 2011, 50, 8105. For diester: h) D. S.
Reddy, N. Shibata, J. Nagai, S. Nakamura, T. Toru, S. Kanemasa, Angew.
Chem., Int. Ed. 2008, 47, 164.
7
8
For reviews on asymmetric fluorination reaction, see: a) See ref 1a. b) S.
Lectard, Y. Hamashima, M. Sodeoka, Adv. Synth. Catal. 2010, 352, 2708.
a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem., Int. Ed.
2004, 43, 1566. b) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126,
5356.
9
1
For reviews on chiral phosphoric acid catalysis, see: a) T. Akiyama, J.
Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999. b) T. Akiyama, Chem.
Rev. 2007, 107, 5744. c) M. Terada, Chem. Commun. 2008, 4097. d) M.
Terada, Synthesis 2010, 1929.
For scandium perfluorinated phosphate-catalyzed asymmetric fluorination
of β-ketoesters, see: S. Suzuki, H. Furuno, Y. Yokoyama, J. Inanaga,
Tetrahedron: Asymmetry 2006, 17, 504.
0
11
For the asymmetric fluorination reaction catalyzed by chiral sodium
phosphate (“anionic chiral phase-transfer catalyst” strategy), see: a) V.
Rauniyar, A. D. Lackner, G. L. Hamilton, F. D. Toste, Science 2011, 334,
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Trans-
formation Organocatalysis” from MEXT, Japan, a Grant-in-Aid
Scientific Research from JSPS.
1
1
681. b) R. J. Phipps, K. Hiramatsu, F. D. Toste, J. Am. Chem. Soc. 2012,
34, 8376. c) T. Honjo, R. J. Phipps, V. Rauniyar, F. D. Toste, Angew.
Chem., Int. Ed. 2012, 51, 9684.
1
2
3
a) M. Hatano, T. Ikeno, T. Matsumura, S. Torii, K. Ishihara, Adv. Synth.
Catal. 2008, 350, 1776. b) M. Hatano, K. Moriyama, T. Maki, K. Ishihara,
Angew. Chem., Int. Ed. 2010, 49, 3823.
a) Z. Zhang, W. Zheng, J. C. Antilla, Angew. Chem., Int. Ed. 2011, 50,
1135. b) W. Zheng, Z. Zhang, M. J. Kaplan, J. C. Antilla, J. Am. Chem.
Soc. 2011, 133, 3339. c) G. K. Ingle, Y. Liang, M. G. Mormino, G. Li,
F. R. Fronczek, J. C. Antilla, Org. Lett. 2011, 13, 2054. d) G. Li, T. Liang,
L. Wojtas, J. C. Antilla, Angew. Chem., Int. Ed. 2013, 52, 4628.
This paper is dedicated to Professor Teruaki
Mukaiyama in celebration of the 40th anniversary of the
Mukaiyama aldol reaction.
1
References and Notes
1
a) P. M. Pihko, Angew. Chem., Int. Ed. 2006, 45, 544. b) G. K. S. Prakash,
P. Beier, Angew. Chem., Int. Ed. 2006, 45, 2172. c) C. Bobbio, V.
Gouverneur, Org. Biomol. Chem. 2006, 4, 2065. d) N. Shibata, T.
Ishimaru, S. Nakamura, T. Toru, J. Fluorine Chem. 2007, 128, 469. e) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008,
14 Examination of various counter cations revealed that Na2CO3 is the best
choice. See Supporting Information for details.
15 The absolute configuration of 4a was determined by the comparison of
optical rotation of the reported datum in ref 5c.
16 Supporting Information is available electronically on the CSJ-Journal Web
site, http://www.csj.jp/journals/chem-lett/index.html.
37, 320. f) X.-L. Qiu, X.-H. Xu, F.-L. Qing, Tetrahedron 2010, 66, 789.
Chem. Lett. 2014, 43, 137–139 | doi:10.1246/cl.130934
© 2014 The Chemical Society of Japan | 139