Enantioselective α-fluorination and chlorination of β-ketoesters by cobalt catalyst

Article abstract of DOI:10.1246/cl.2010.466

We demonstrated the cobalt-catalyzed asymmetric a-fluorination and a-chlorination of β-ketoesters. Both reactions were achieved using a catalytic amount of Co(acac)2 with (R, R)Jacobsen's salen ligand; α-fluorinated or a-chlorinated products were thus obt

Full text of DOI:10.1246/cl.2010.466

doi:10.1246/cl.2010.466
466
Published on the web March 31, 2010
Enantioselective ¡-Fluorination and Chlorination of ¢-Ketoesters by Cobalt Catalyst
Motoi Kawatsura,* Shunsuke Hayashi, Yuji Komatsu, Shuichi Hayase, and Toshiyuki Itoh*
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
Koyama, Tottori 680-8552
(Received February 12, 2010; CL-100153; E-mail: kawatsur@chem.tottori-u.ac.jp, titoh@chem.tottori-u.ac.jp)
We demonstrated the cobalt-catalyzed asymmetric ¡-fluori-
Table 1. Cobalt catalysts for the ¡-fluorination of ethyl 2-
oxocyclopentanecarboxylate (1a)a
nation and ¡-chlorination of ¢-ketoesters. Both reactions were
achieved using a catalytic amount of Co(acac)2 with (R,R)-
Jacobsen’s salen ligand; ¡-fluorinated or ¡-chlorinated products
were thus obtained with a good enentioselectivity.
O
O
10mol% [Co/L*]
NFSI
CO2Et
CO2Et
*
F
1a
2a
Chiral fluorinated organic compounds are well recognized
as important materials in the field of biological and medicinal
chemistry.1 Recently, the transition metal catalyzed highly
enantioselective ¡-fluorination of ¢-ketoesters has been achiev-
ed by several groups.2 For example, Togni reported the
[TiCl2(TADDOLato)]-catalyzed reaction with Selectfluor, and
they also discovered a ruthenium catalyst system.3 Sodeoka
demonstrated a Pd/BINAP-catalyzed system with N-fluoroben-
zenesulfonimide (NFSI).4 Cahard also described that Cu/Box is
an effective catalyst for the ¡-fluorination of ¢-ketoesters.5
Furthermore, Shibata and Toru attained a high enantioselectivity
with a Ni/dbfox catalyst.6 More recently, a Ni or Mg/N,N,N-
tridentate ligand system was reported by Shibatomi and Iwasa,7
and chiral rare earth perfluorinated organophosphate catalysts
were developed by Inanaga.8 Despite these pioneering studies of
enantioselective fluorination, the development of a new catalyst
system is still required in this area. Recently, we have been
interested in the development of the cobalt-catalyzed asymmetric
reaction, and realized the cobalt/pybox-catalyzed asymmetric
conjugate addition of thiols to ¡,¢-unsaturated carbonyl com-
pounds.9 During the course of the cobalt-catalyzed asymmetric
reactions, we found that the cobalt/Jacobsen’s salen ligand
system exhibited a high enantioselectivity for the ¡-fluorination
of ¢-ketoesters.
We examined the reaction of ethyl 2-oxocyclopentanecar-
boxylate (1a) with NFSI using cobalt catalysts.10 Based on the
results of our previous chiral cobalt catalyzed asymmetric
reaction,9 we tested the ¡-fluorination reaction of ¢-ketoesters
by Co(ClO4)2¢6H2O with (S,S)-ip-pybox. However, the reaction
produced an ¡-fluorinated product with a poor result; i.e., a 55%
yield and 25% enatiomeric excess (Table 1, Entry 1). Reinves-
tigation of the effective combination of a cobalt salt and chiral
ligand revealed that Co(acac)2 with the (R,R)-Jacobsen’s salen
ligand (L2) exhibited a higher enatiomeric excess (60% ee) with
almost the same yield (60%) (Entry 4). The enantioselectivity
was improved when diethyl ether was used as the solvent, but
the yield had decreased to 41% (Entry 5). Fortunately, both the
chemical yield and enantioselectivity of the desired products
significantly increased at lower reaction temperature (Entries 6
and 7), and the best result was obtained at ¹20 °C (84% isolated
yield with 89% ee). According to the reported results of the
metal-catalyzed ¡-fluorination of cyclic ¢-ketoesters by other
groups, it seems that moderately bulky groups, such as tert-
butyl, at the ester functionality are necessary to attain high
H
H
O
N
O
N
N
N
N
tBu
OH HO
tBu
iPr
iPr
tBu
tBu
L1: (S,S)-ip-pybox
L2: (R,R)-Jacobsen's salen ligand
Solv./
Temp (°C) /%b
Yield
Entry [Co]
L
ee/%c
1
2
3
4
5
6
7
Co(ClO4)2¢6H2O L1 THF/rt
Co(ClO4)2¢6H2O L2 THF/rt
55
50
86
60
41
68
84
25
8
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
L1 THF/rt
L2 THF/rt
L2 Et2O/rt
L2 Et2O/0
L2 Et2O/¹20
34
60
73
85
89
aReaction conditions: 1a (0.32 mmol), [Co] (0.032 mmol), L1
or L2 (0.032 mmol), NFSI (0.45 mmol), solvent (1.0 mL).
bIsolated yield. Enantiomeric excess values were determined
c
by GC analysis using Chiraldex G-TA.
enantioselectivity. Actually, most of the reports mainly exam-
ined the tert-butyl esters, and there are only two examples of the
reaction of the ethyl ester,3c,8 which is commercially available.
To the best of our knowledge, the highest enantioselectivity
reported for the reaction of 1a was 76% ee, and it was attained
using a scandium catalyst. It should be emphasized that our
cobalt catalyst is superior to the scandium catalyst for the ¡-
fluorination of the ethyl ester 1a (89% ee, Entry 7).
We used the Co(acac)2/L2 catalyst for the ¡-fluorination of
other ¢-ketoesters. These results are summarized in Table 2. The
ketoester 1b (methyl ester) produced the desired ¡-fluorinated
product with 90% ee (Entry 1). The reaction of 1c (tert-butyl
ester) also exhibited a good enantioselectivity (86% ee). On the
other hand, reduced enantioselectivities were obtained for the
reaction of other cyclic ¢-ketoesters containing six- or seven-
membered rings (1d-1f) (Entries 3-5). We further examined the
reaction of acyclic ¢-ketoester 1g, but both yield and enantio-
selectivity were moderate (Entry 6).11
Furthermore, the Co(acac)2/L2 catalyst worked as a good
system for the the enantioselective ¡-chlorination of 1a with
CF3SO2Cl (TFSC) (Scheme 1).6,12 The reaction was carried out
Chem. Lett. 2010, 39, 466-467
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

467
Table 2. Cobalt-catalyzed ¡-fluorination of ¢-ketoesters (1b-
1g)a
Chem. 2007, 128, 469. b) V. A. Brunet, D. O’Hagan, Angew.
Chem., Int. Ed. 2008, 47, 1179.
O
O
O
O
10 mol% Co(acac)2
3
a) L. Hintermann, A. Togni, Angew. Chem., Int. Ed. 2000,
39, 4359. b) S. Piana, I. Devillers, A. Togni, U.
Rothlisberger, Angew. Chem., Int. Ed. 2002, 41, 979. c) M.
Althaus, C. Becker, A. Togni, A. Mezzetti, Organometallics
2007, 26, 5902.
a) Y. Hamashima, K. Yagi, H. Takano, L. Tamás, M.
Sodeoka, J. Am. Chem. Soc. 2002, 124, 14530. b) Y.
Hamashima, H. Takano, D. Hotta, M. Sodeoka, Org. Lett.
2003, 5, 3225.
10 mol% L2
OR
OR
NFSI (1.4 equiv)
Et2O, 12 h
F
n
n
2b-f
1b: n = 1, R = Me
1c: n = 1, R = tBu
1d: n = 2, R = Me
1e: n = 2, R = Et
1f: n = 3, R = Me
O
O
4
5
Me
OEt
Me
F
2g
O
O
a) J.-A. Ma, D. Cahard, Tetrahedron: Asymmetry 2004, 15,
1007. b) J.-A. Ma, D. Cahard, J. Fluorine Chem. 2004, 125,
1357.
Me
OEt
Me
1g
6
7
N. Shibata, J. Kohno, K. Takai, T. Ishimaru, S. Nakamura, T.
Toru, S. Kanemasa, Angew. Chem., Int. Ed. 2005, 44, 4204.
a) K. Shibatomi, Y. Tsuzuki, S. Nakata, Y. Sumikawa, S.
Iwasa, Synlett 2007, 551. b) K. Shibatomi, Y. Tsuzuki, S.
Iwasa, Chem. Lett. 2008, 37, 1098.
S. Suzuki, H. Furuno, Y. Yokoyama, J. Inanaga, Tetrahe-
dron: Asymmetry 2006, 17, 504.
M. Kawatsura, Y. Komatsu, M. Yamamoto, S. Hayase, T.
Itoh, Tetrahedron 2008, 64, 3488.
Entry
1
Temp/°C
Yield/%b
ee/%c
1
2
3
4
5
6
1b
1c
1d
1e
1f
¹20
¹20
0
74
65
65
65
75
64
90
86
79
75
79
71
0
0
8
9
1g
rt
aReaction conditions: ¢-ketoester (0.32 mmol), Co(acac)2
(0.032 mmol), L2 (0.032 mmol), NFSI (0.45 mmol), diethyl
ether (1.0 mL). bIsolated yield. cEnantiomeric excess values
were determined by GC analysis with a Chiraldex G-TA for 1b
and 1d-1g, or chiral HPLC using Daicel CHIRALPAK AD-H
for 1c.
10 Typical procedure:
A solution of Co(acac)2 (8.2 mg,
0.032 mmol), (R,R)-Jacobsen’s salen ligand (17.5 mg,
0.032 mmol) and NFSI (141 mg, 0.45 mmol) in anhydrous
diethyl ether (1.0 mL) was stirred at ¹20 °C for 10 min. To
this solution was added a ¢-ketoester 1a (50 mg, 0.32 mmol),
then stirred for 12 h. Saturated NH4Cl was added for
quenching, and the water layer was extracted with diethyl
ether (1.0 mL © 3). The combined organic layers were
washed with brine and dried over MgSO4. Removal of the
solvent, followed by flash column chromatography (hexane/
ethyl acetate = 2/1), afforded the desired product 2a as a
colorless oil (47 mg, 84%). The enantiomeric purity was
determined to be 89% ee by GC analysis with a Chiraldex G-
TA (initial temperature 60 °C, final temperature 165 °C, rate
3 °C min¹1, inj. temperature 160 °C, det. temperature 100 °C:
t(R) = 26.0 min, t(S) = 30.5 min). ½¡ꢀ2D5 85.8 (c 0.56, CHCl3)
O
O
10 mol% Co(acac)2
10 mol% L2
CO2Et
CO2Et
*
Cl
TFSC (1.4 equiv)
toluene, r.t., 12 h
3a
1a
without MS 4A: 16% yield, 75% ee
with MS 4A:
62% yield, 88% ee
Scheme 1.
25
in toluene at room temperature, and the desired chlorinated
product was obtained with a 75% ee, but the yield was
insufficient (16%). Fortunately, both the yield and enantiose-
lectivity increased to 62% and 88% ee by the addition of
molecular sieves 4A.
In conclusion, we demonstrated the cobalt-catalyzed asym-
metric ¡-fluorination and ¡-chlorination of ¢-ketoesters. Both
of these desired reactions were catalyzed by a chiral cobalt
catalyst, which was prepared from Co(acac)2 with (R,R)-
Jacobsen’s salen ligand, and the ¡-fluorinated or ¡-chlorinated
products were obtained with good enantioselectivities.
(89% ee) {lit.3c ½¡ꢀD 169.0 (c 1.53, CHCl3) (99.7% ee)}.
1H NMR (500 MHz, CDCl3): ¤ 1.32 (t, J = 7.2 Hz, 3H),
2.01-2.19 (m, 2H), 2.28-2.39 (m, 1H), 2.48-2.60 (m, 3H),
4.30 (q, J = 7.2 Hz, 2H). 13C NMR (125 MHz, CDCl3): ¤
14.00, 18.02 (d, J = 2.9 Hz), 33.88 (d, J = 21.1 Hz), 35.68,
62.33, 94.61 (d, J = 199.6 Hz), 167.44 (d, J = 26.8 Hz),
207.52 (d, J = 16.2 Hz). 19F NMR (470 MHz, CDCl3, inter-
nal standard: C6F6): ¤ ¹2.39 (t, J = 18.8 Hz).
11 We also examined the fluorination reactions of 2-methoxy-
carbonyl-1-indanone and 2-ethoxycarbonyl-1-indanone by
Co(acac)2/L2 catalyst, but the enantioselectivities were 55%
ee (98% yield) and 50% ee (94% yield), respectively.
12 a) M. Marigo, N. Kumaragurubaran, K. A. Jørgensen,
Chem.®Eur. J. 2004, 10, 2133. b) H. Ibrahim, F. Kleinbeck,
A. Togni, Helv. Chim. Acta 2004, 87, 605. c) L. Hintermann,
A. Togni, Helv. Chim. Acta 2000, 83, 2425.
References and Notes
1
2
a) B. E. Smart, J. Fluorine Chem. 2001, 109, 3. b) J.-A. Ma,
D. Cahard, Chem. Rev. 2004, 104, 6119. c) H. Ibrahim, A.
Togni, Chem. Commun. 2004, 1147.
a) N. Shibata, T. Ishimaru, S. Nakamura, T. Toru, J. Fluorine
Chem. Lett. 2010, 39, 466-467
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/