Catalytic enantioselective fluorination of oxindoles

Article abstract of DOI:10.1021/ja0513077

We have developed a highly efficient catalytic enantioselective fluorination of oxindole derivatives. In the presence of a catalytic amount of chiral Pd complex 2 (2.5 mol %), various substrates, including aryl- and alkyl-substituted oxindoles, were fluor

Full text of DOI:10.1021/ja0513077

Published on Web 06/28/2005
Catalytic Enantioselective Fluorination of Oxindoles
Yoshitaka Hamashima,† Toshiaki Suzuki,† Hisashi Takano,† Yuta Shimura,† and Mikiko Sodeoka*,†,‡,§
Institute of Multidisciplinary Research for AdVanced Materials, Tohoku UniVersity, Miyagi, 980-8577, Japan,
PRESTO, Japan Science and Technology Agency (JST), and RIKEN, Hirosawa, Wako 351-0198, Japan
Received March 2, 2005; E-mail: sodeoka@tagen.tohoku.ac.jp
Table 1. Optimization of the Reaction Conditions
Introduction of fluorine atoms into bioactive compounds is a
common approach to improve the biological activity profile.1
Therefore, catalytic enantioselective fluorination has attracted
growing interest.2 We recently reported efficient fluorination
reactions of â-ketoesters and â-ketophosphonates.3 Several chiral
catalysts for enantioselective fluorination have been developed,4
but in most cases, they were applied only to â-ketoesters, and other
nucleophiles were rarely examined. Therefore, development of novel
reactions applicable to other carbonyl compounds is still required.
BMS 204352 (MaxiPost) 3 developed by Bristol-Myers Squibb
is a promising agent for the treatment of stroke and is undergoing
clinical phase III trial.5 It was reported that replacement of a
hydroxyl group at the 3-position of the oxindole ring by a fluorine
atom played a key role in enhancing its pharmaceutical efficiency.
Because the oxindole ring is widely found among natural products,
its optically active fluorinated derivatives could have many ap-
plications in the field of medicinal chemistry.6,7 Moreover, further
conversion of fluorinated oxindoles would provide access to the
chiral R-fluorophenylacetic acid derivatives 4, which are fluorinated
analogues of important structural components of various drug
candidates. Herein, we wish to report the first example of catalytic
enantioselective fluorination of oxindoles using chiral Pd complexes
1 and 2.
Pd
time
(h)
yield
(%)
eea
(%)
entry
catalyst
5
R1/R2
solvent
1
2
3
4
5
6
7
8b
1
1
1
1
2
2
2
2
5a H/H
THF
THF
IPA
acetone
IPA
60
12
3
3
5
18
12
5
20
53
66
58
90
89
93
95
5
81
88
89
88
76
73
81
5b Boc/H
5b Boc/H
5b Boc/H
5b Boc/H
5c Boc/OMe
5d OC(O)CHPh2/OMe acetone
5e OC(O)-9-Fl/OMe acetone
acetone
a Determined by chiral HPLC analysis. b 9-Fl ) 9-fluorenyl.
Scheme 1. Catalytic Asymmetric Synthesis of BMS 204352
to give 6c in 89% yield with 76% ee (entry 6). Although several
bulkier protecting groups were tested, the observed enantiomeric
excesses were comparable (up to 81% ee) to that in the case of 5c
(entries 7 and 8).
With these results in hand, we applied our reaction to the catalytic
asymmetric synthesis of 3 (Scheme 1).8,10 A starting material 7 was
subjected to the fluorination reaction, and the desired product 8
was isolated in 90% yield with 71% ee. After treatment with TFA,
recrystallization furnished optically pure 3 (>99% ee).
Encouraged by these results, we next examined the generality
of this reaction (Table 2).8 The enantiomeric excess of 6b was
slightly improved (90% ee) when the reaction was conducted at 0
°C (entry 1, see also entries 3 and 7). Regardless of the electronic
nature of the substituents on the aromatic rings, other aryl-
substituted oxindoles (5f-h) were also good substrates (entries
2-5). In addition, the reaction of alkyl-substituted substrates (5i-
m) proceeded well in good yield with high to excellent enantio-
selectivities (75-96% ee) (entries 6-11). Thus, we have developed
an efficient enantioselective fluorination of oxindoles with broad
generality. It should be noted that these reactions are operationally
convenient and can be performed without exclusion of air and
moisture.
Initially, we examined the reaction of the phenyl-substituted
oxindole 5a (Table 1). (S)-DM-BINAP was chosen as a chiral ligand
based on our previous results.3,8 In the presence of 1, the reaction
of 5a with N-fluorobenzenesulfonimide (NFSI) was sluggish, and
negligible asymmetric induction was observed (entry 1). Thus, we
planned to protect the nitrogen moiety of 5a with a t-butoxycarbonyl
(Boc) group, expecting that the N-Boc-protected oxindoles would
be activated effectively to form a configurationally stable Pd enolate.
Gratifyingly, the reaction of 5b in THF afforded the desired product
6b in 53% yield with 81% ee (entry 2). Further optimization
revealed that 2-propanol (IPA) and acetone gave better selectivity
(entries 3 and 4).8 However, the chemical yield was still unsatisfac-
tory (<66%), which was attributed to deprotection of the Boc group
due to the acidic nature of 1. This problem was overcome by using
the less acidic Pd complex 2, and 6b was isolated in 90% yield
without any loss of enantioselectivity (entry 5).9 Next, we assessed
the influence of a methoxy group at the R2 position. Despite the
possible steric interaction, the reaction of 5c proceeded smoothly
As shown in Scheme 2, the optically active R-fluoro-R-aryl
acetate 9 was readily obtained by treatment with MeONa in MeOH.8
In view of the versatility of the amine moiety for further function-
alization, this procedure would be useful for the synthesis of various
R-fluorophenylacetate derivatives.
† Tohoku University.
‡ JST.
§ RIKEN.
9
10164
J. AM. CHEM. SOC. 2005, 127, 10164-10165
10.1021/ja0513077 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Fluorination of Oxindoles
solvolysis of 10 should be suppressed to increase the chemical yield,
catalytic asymmetric monofluorination, which is considered to be
difficult under basic conditions, was achieved at a synthetically
useful level.
In conclusion, we have developed a highly efficient catalytic
enantioselective fluorination of oxindoles. This method can provide
various fluorinated compounds, including oxindoles and phenyl-
acetate derivatives, in a highly enantioselective manner. We believe
that the availability of these compounds will be valuable in the
field of medicinal chemistry. Further examination of the scope of
the reaction and mechanistic studies are underway in our laboratory.
time
(h)
yield
(%)
ee
entry
5
R1/R2
tempa
(%)
1
2
3
5b
5f
5f
5g
5h
5i
5i
5j
5k
5l
5m
Ph/H
0 °C
rt
0 °C
rt
rt
rt
0 °C
rt
rt
rt
rt
18
3
18
3
3
5
18
10
2
4
2
96
97
92
94
80
86
85
85
85
72
85
90
86
88
84
75
95
96
92
86
80
75
p-MeC6H4/H
p-MeC6H4/H
p-FC6H4/H
o-MeOC6H4/CF3
Me/H
4
5c
6
Acknowledgment. Y.H. thanks JSPS for a Grant-in-Aid for
Encouragement of Young Scientists (B). We also thank Dr. Saito
of Takasago International Corporation for providing chiral phos-
phine ligands, and Ms. Harada of RIKEN for MS measurements.
This paper is dedicated to Prof. Iwao Ojima on his 60th birthday.
7
8
9
10
11
Me/H
Et/H
CH2C(O)CH3/H
Bn/H
i-Bu/H
Supporting Information Available: Details of optimization of the
reaction conditions, experimental details of the fluorination reaction,
and the spectroscopic characterization of new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
a rt ) 20-23 °C. b Determined by chiral HPLC analysis. c Acetone was
used as a solvent.
Scheme 2. Conversion of 6i
References
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pounds: Chemistry and Applications; Springer: Berlin, 2000. (c) Kirsch,
P. Modern Fluoroorganic Chemistry: Synthesis, ReactiVity, Applications;
Wiley-VCH: Weinheim, Germany, 2004.
Table 3. Catalytic Enantioselective Monofluorination of 10
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time
(h)
yield
(%)
eea
(%)
entry
solvent
product
1
2
3
4
THF
11
12
12
12
43
60
18
18
29
55
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21
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THF/MeOH (1:1)
ClCH2CH2Cl/MeOH (1:1)
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a Determined by chiral HPLC analysis.
Although we could not observe a key intermediate by spectro-
scopic analysis, the high enantioselectivity obtained in this reaction
can be explained by postulating involvement of a chiral Pd enolate
(see Supporting Information).11 The stereochemistry predicted on
the basis of this model was in accord with the absolute stereo-
chemistry observed in the case of BMS compound 3.
(7) For a stoichiometric enantioselective fluorination of oxindoles, see:
Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001,
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(8) For details, see Supporting Information.
(9) In the case of 5i, the enantiomeric excess was also improved. See
Supporting Information.
In contrast to the fluorination of active methine compounds to
give chiral quaternary carbon centers, there has been, to our
knowledge, no successful example of the catalytic asymmetric
synthesis of fluorinated compounds with a tertiary chiral center
having a hydrogen atom.12,13 This fact prompted us to attempt the
enantioselective monofluorination of 10.8 Since the fluorinated
product 11 would be more susceptible to enolization than 10,
racemization of the product was considered unavoidable. Indeed,
an attempt at obtaining 11 resulted in low selectivity (Table 3, entry
1). We envisaged that solvolysis of 11 with alcohol before
racemization would be possible. Racemization of 11 was indeed
significantly suppressed, and the monofluorinated product 12 was
obtained with reasonably high enantioselectivity (entries 2 and 3).
After examining several solvents, we found that the use of
halogenated solvent mixed with MeOH (1:1) afforded 12 with an
excellent enantioselectivity of 93% (entry 4). Although competitive
(10) For stoichiometric reactions, see: (a) Shibata, N.; Ishimaru, T.; Suzuki,
E.; Kirk, K. L. J. Org. Chem. 2003, 68, 2494-2497. (b) Zoute, L.;
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1, 1833-1834.
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Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240-11241 and references
therein.
(12) For noncatalytic examples, see: (a) Davis, F. A.; Han, W. Tetrahedron
Lett. 1992, 33, 1153-1156. (b) Enders, D.; Faure, S.; Potthoff, M.;
Runsink, J. Synthesis 2001, 15, 2307-2319. (c) Greedy, B.; Paris, J.-M.;
Vidal, T.; Gouverneur, V. Angew. Chem., Int. Ed. 2003, 42, 3291-3294.
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