Titanium-catalyzed stereoselective geminal heterodihalogenation of β-ketoesters

Article abstract of DOI:10.1021/ol0343459

(Matrix presented) β-Ketoesters can be effectively monofluorinated with F-TEDA using CpTiCl₃ as a catalyst. With the use of this catalyst, the extent of the competing difluorination does not reach 10%. [TiCl₂(TADDOLato)] complexes catalyze the one-pot enantioselective heterodihalogenation of β-ketoesters with F-TEDA and NCS to afford α-chloro-α-fluoro-β-ketoesters in moderate to good yields. The sequence of addition of the halogenating agents determines the sense of chiral induction.

Full text of DOI:10.1021/ol0343459

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1709-1712
Titanium-Catalyzed Stereoselective
Geminal Heterodihalogenation of
â-Ketoesters
Richard Frantz, Lukas Hintermann, Mauro Perseghini, Diego Broggini, and
Antonio Togni*
Department of Chemistry, Swiss Federal Institute of Technology,
ETH Ho¨nggerberg, CH-8093 Zu¨rich, Switzerland
togni@inorg.chem.ethz.ch
Received February 27, 2003
ABSTRACT
â-Ketoesters can be effectively monofluorinated with F-TEDA using CpTiCl3 as a catalyst. With the use of this catalyst, the extent of the
competing difluorination does not reach 10%. [TiCl2(TADDOLato)] complexes catalyze the one-pot enantioselective heterodihalogenation of
â-ketoesters with F-TEDA and NCS to afford r-chloro-r-fluoro-â-ketoesters in moderate to good yields. The sequence of addition of the
halogenating agents determines the sense of chiral induction.
Fluorine-containing organic molecules are becoming increas-
ingly important in medicinal chemistry and as crop protection
agents.1 Besides the fluorination of aromatic groups and the
introduction of perfluoroalkyl chains, the development of
synthetic methods in this area has addressed also stereo-
selective C-F bond-forming reactions.2 In this context, chiral
enantiopure fluorinating reagents3 or chiral starting materials4
have been used. Recently, we reported the first asymmetric
electrophilic fluorination of â-ketoesters with the com-
mercially available fluorinating agent F-TEDA (also called
Selectfluor; 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
[2,2,2]octane bis(tetrafluoroborate)), catalyzed by a [TiCl2-
(TADDOLato)] complex, giving enantioselectivities of up
to 90% ee.5
We also reported the analogous chlorination and bromi-
nation reactions.6 More recently, Sodeoka has shown that
Pd(II) complexes bearing axial-chiral diphosphines catalyze
(3) (a) Differding, E.; Lang, R. E. Tetrahedron Lett. 1988, 29, 6087-
6090. (b) Davis, F. A.; Zhou, P.; Murphy, C. K.; Sundarababu, G.; Qi, H.;
Han, W.; Przeslawski, R. M.; Chen, B.-C.; Carroll, P. J. Org. Chem. 1998,
63, 2273-2280. (c) Liu, Z.; Shibata, N.; Takeuchi, Y. J. Org. Chem. 2000,
65, 7583-7587. (d) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am.
Chem. Soc. 2001, 123, 7001-7009. (e) Mohar, B.; Baudoux, J.; Plaquevent,
J.-C.; Cahard, D. Angew. Chem., Int. Ed. 2001, 40, 4214-4216.
(4) (a) Iwaoka, T.; Murohashi, T.; Sato, M.; Kaneko, C. Tetrahedron:
Asymmetry 1992, 3, 1025-1028. (b) Davis, F. A.; Kasu, P. V. N.
Tetrahedron Lett. 1998, 39, 6135-6138. (c) Enders, D.; Faure, S.; Potthoff,
M.; Runsink, J. Synthesis 2001, 15, 2307-2319.
(5) (a) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39,
4359-4362. (b) Togni, A.; Mezzetti, A.; Barthazy, P.; Becker, C.; Devillers,
I.; Frantz, R.; Hintermann, L.; Perseghini, M.; Sanna, M. Chimia 2001, 55,
801-806. (c) Piana, S.; Devillers, I.; Togni, A.; Rothlisberger, U. Angew.
Chem., Int. Ed. 2002, 41, 979-982. (d) Hintermann, L.; Togni, A. Eur.
Pat. Appl. EP1151980, 2001.
(1) (a) Lowe, K. C.; Powell, R. L J. Fluorine Chem. 2001, 109 (1), and
references therein. (b) Biomedical Frontiers of Fluorine Chemistry; Ojima,
I., McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series 639;
American Chemical Society: Washington, DC, 1996.
(2) (a) For a recent review, see: Mun˜iz, K. Angew. Chem., Int. Ed. 2001,
40, 1653-1656. (b) Asymmetric Fluoroorganic Chemistry: Synthesis,
Application and Future Directions; Ramachandran, P. V., Ed.; ACS
Symposium Series 746; American Chemical Society: Washington, DC,
2000. (c) Enantiocontrolled Synthesis of Fluoro-Organic Compounds.
Stereochemical Challenges and Biomedical Targets; Soloshonok, V. A.,
Ed.; Wiley: New York, 1999. (d) SelectiVe Fluorination in Organic and
Bioorganic Chemistry; Welch, J. T., Ed.; ACS Symposium Series 456;
American Chemical Society: Washington, DC, 1991.
(6) Hintermann, L.; Togni, A. HelV. Chim. Acta 2000, 83, 2425-2435.
10.1021/ol0343459 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003

similar fluorinations with NFSI.7 This latter reagent has been
used successfully also in fluorinations carried out under
conditions of asymmetric phase-transfer catalysis.8
Scheme 1. Mono- and Difluorination of â-Ketoesters
Very few methods for the preparation of R-chloro-R-
fluoro-â-ketoesters are known.9 For example, Chambers
reported the direct fluorination of ethyl-2-chloro acetoacetate
using fluorine in the presence of formic acid.9b The same
starting material was fluorinated using N-fluorobis[(tri-
fluoromethyl)sulfonyl]-imide as reported by DesMarteau.9d
To the best of our knowledge, no catalytic stereoselective
reaction leading to R-chloro-R-fluoro-â-ketoesters has ever
been described in the literature. A collateral problem is
related to the selectivity toward monohalogenation of active
methylene compounds, which is still quite challenging.10
In the first stage of our work, we investigated the reaction
of the R-unsubstituted â-ketoesters depicted in Figure 1 with
the incorporation of chlorine from the catalyst, as previously
reported.6
Inspection of the results collected in Table 1 clearly
indicates that the simple organometallic complex CpTiCl3
constitutes an excellent catalyst, affording the highest degree
of chemoselection.11 Product ratios reach a value of 32:1
(â-ketoester 1h) in favor of the monofluorinated derivative,
as determined by 19F NMR of the crude reaction mixtures.
Surprisingly, chemoselectivity is much lower when using the
more sophisticated chiral catalysts 3 and 4, with a minimum
extent of difluorination of ca. 10-12%. Also, the mono-
Table 1. Monofluorination of â-Ketoesters
ratio
b
substrate catalyst yielda 2F /2F 2
δ
19F (ppm)c
1a
1a
1a
1b
1b
1b
1c
1b
1d
1d
1e
1e
1f
TiCl4
CpTiCl3
4
CpTiCl3
3
4
CpTiCl3
4
CpTiCl3
4
CpTiCl3
4
CpTiCl3
4
CpTiCl3
4
CpTiCl3
4
CpTiCl3
4
CpTiCl3
4
6:1
20:1
8.3:1
11:1
8:1
-190.7/-108.8
80%
66%
Figure 1. â-Ketoesters as substrates for catalytic halogenation
reactions used in this study.
-193.2/-113.9
6:1
88%
39%
71%
51%
67%
n.d.
15:1
10:1
18:1
4.4:1
30:1
6.5:1
30:1
8:1
21:1
7.8:1
32:1
9:1
10.7:1
5.7:1
20:1
4.7:1
21:1
-195.7/-114.3
-193.6/-113.9
-196.0/-114.5
-193.0/-113.4
-196.0/-114.4
-193.6/-113.3
-192.8; -193.1/-114.1
-194.6/-114.5
-191.0/-108.7
1 equiv of F-TEDA in acetonitrile and in the presence of 5
mol % titanium catalyst (TiCl4, CpTiCl3, (R,R)-3, or (R,R)-
4; see Scheme 1 and Table 1).
These reactions generally lead to the formation of mixtures
of the monofluorinated and difluorinated products 2F and
2F2, respectively, often accompanied by a small amount of
the chlorofluorinated derivative 2ClF, the latter arising from
1f
1g
1g
1h
1h
1i
1i
1j
1j
1k
(7) Hamashima, Y.; Yagi, K.; Takano, H.; Tama´s, L.; Sodeoka, M. J.
Am. Chem. Soc. 2002, 124, 14530-14531.
(8) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545-547.
(9) (a) Elkik, E.; Imbeaux-Oudotte, M. Tetrahedron Lett. 1978, 3793-
3796. (b) Chambers, R. D.; Greenhall, M. P.; Hutchinson, J. Tetrahedron
1996, 52, 1-8. (c) Chambers, R. D.; Hutchinson, J. J. Fluorine Chem. 1998,
92, 45-52. (d) Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991, 56,
4925-4929.
68%
n.d.
(10) (a) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada,
K.; Tomita, K. J. Am. Chem. Soc. 1990, 112, 8563-8575. (b) Davis, F. A.;
Han, W.; Murphy, C. K. J. Org. Chem. 1995, 60, 4730-4737. (c) Umemoto,
T.; Nagayoshi, M.; Adachi, K.; Tomizawa, G. J. Org. Chem. 1998, 63,
3379-3385. (d) Poss, A. J.; Shia, G. A. Tetrahedron Lett. 1999, 40, 2673-
2676.
CpTiCl3
66%
a After column chromatographic purification. b Ratios of mono- and
difluorinated products, as determined by 19F NMR. 19F NMR measured
b
in CDCl3, relative to CFCl3.
1710
Org. Lett., Vol. 5, No. 10, 2003

halogenated products obtained using the chiral catalysts did
not display any appreciable level of enantiomeric enrichment,
obviously because of the dual enolization/racemization
activity of the Ti complexes.
Scheme 2. Consecutive Halogenations of â-Ketoesters
One of the racemic products obtained with catalyst 4 could
be isolated in crystalline form and subjected to an X-ray
structural study.12 An ORTEP view of this compound is
shown in Figure 2. In the solid state, the compound is not
Table 2 summarizes the results obtained in these one-pot
experiments, which gave invariably quantitative conversions.
Table 2. Catalytic Enantioselective Heterodihalogenationa
catalyst/
sequence
selectivity
(ee)
substrate
yieldb
analysis
Figure 2. ORTEP view (30% probability ellipsoids) of 2fF
(hydrogen atoms are omitted for clarity).
1a
1a
1d
1d
1d
1d
1e
1e
1i
4/F f Cl
4/Cl f F
3/F f Cl
3/Cl f F
4/F f Cl
4/Cl f F
4/F f Cl
4/Cl f F
4/F f Cl
4/Cl f F
4/F f Cl
4/Cl f F
80%
53%
nd
nd
nd
32%
33%
44%
32%
35% (49%c)
52% (51%c)
65% (45%c)
57% (55%c)
∼4% de
59% de
24%
14.84/18.13d
14.84/18.13d
89.4/91.0e
89.4/91.0e
89.4/91.0e
89.4/91.0e
enolized and the C-F distance of 1.367(3) Å reflects typical
values.13 It is, however, noteworthy that both carbonyl groups
assume a nearly syn planar orientation with respect to the
C-F bond, as illustrated by the torsion angles O2-C4-
C3-F and O1-C2-C3-F of 8.9 and 15.2°, respectively.14
We next turned our attention to the selective catalytic
heterodihalogenation of â-ketoesters to form R-chloro-R-
fluoro-â-ketoesters by changing the sequence of addition of
the halogenating agents (Scheme 2). Thus, in the first
protocol (F f Cl), a fluorination reaction with F-TEDA in
the presence of a catalytic amount of one of the two titanium
complexes 3 and 4 was performed. The intermediate was
then enantioselectively chlorinated by NCS. In the second
protocol (Cl f F) the halogenation sequence was inverted.15
nd
65%
60%
45%
nd
nd
nd
124.2/127.9e
124.2/128.9e
-123.0/-123.1f
-123.0/-123.1f
23.7/25.0e
1i
1j
1j
25.5%
23.7/25.0e
a Reaction conditions: 0.25 mmol of substrate in CH3CN, 5 mol %
catalyst. Quantitative conversions (NMR and TLC). b Yields are given for
compounds isolated after column chromatography. c Reactions carried out
with the isolated monohalogenated products 2dCl, 2dF, and 2eCl, 2eF,
respectively. d Determined by chiral HPLC analysis on a Daicel Chiralcel
OJ 25 cm column. Retention times in min of minor/major enantiomer. See
Supporting Information for details. e Determined by chiral GC on a Supelco
â-dex column. Retention times in min of minor/major enantiomer. See
Supporting Information for details. 19F NMR chemical shifts minor/major
f
diastereoisomers.
(11) For a recent example of monobrominations catalyzed by Mg(ClO4)2,
see: Yang, D.; Yan, Y.-L.; Lui, B. J. Org. Chem. 2002, 67, 7429-7431.
(12) Crystallographic data for the structure reported in this paper have
been deposited at the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC 195249. Copies of the data can be obtained
free of charge upon application to CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK (fax, (+44) 1223 762910; e-mail, deposit@ccdc.cam.ac.uk).
(13) Orpen, A. G.; Brammer, L.; Allen, F. H. Kennard, O. Watson, D.
G. Taylor, R. In Structure Correlation; Bu¨rgi, H.-B., Dunitz, J., Eds.;
VCH: Weinheim, Germany, 1994; Vol. 2, Appendix A, p 751.
(14) For a recent paper discussing conformational effects due to fluorine,
see: Briggs, C. R. S.; O’Hagan, D.; Howard, J. A. K.; Yufit, D. S. J.
Fluorine Chem. 2003, 119, 9-13.
(15) General Procedure: F f Cl Sequence. F-TEDA (0.28 mmol) was
added to a solution of â-ketoester (0.25 mmol) and the titanium complex
(0.0125 mmol) in CH3CN (3 mL) at room temperature. The completion of
the first halogenation reaction was monitored by 1H NMR. A second portion
of the catalyst (0.0125 mmol) and NCS (0.28 mmol) were then added, and
the reaction mixture was stirred until complete conversion. After the addition
of MTBE, the mixture was filtered, the liquid phase concentrated, and the
residue chromatographed on silica to afford the product in an analytically
pure form as an oily material.
Enantioselectivities were as high as 65% ee in the case of
substrate 1e, using catalyst 4. In the case of the menthyl ester
1i a diastereoselectivity up to 59% de was observed. It is
interesting to note that the reaction of the isolated monoha-
logenation intermediate does not afford the same selectivity
as the one-pot procedure. The reasons for the observed
deviation are not apparent. Despite full consumption of the
â-ketoesters in all dihalogenation experiments, the isolation
of the pure chlorofluoro products turned out to be difficult.
Thus, the isolated yields were only moderate (45-65% and
in one case up to 80%). Two main factors are responsible
for this: (1) the relatively low chemoselectivity of the chiral
catalysts 3 or 4, affording in the first step the dichloro or
difluoro derivative as contaminating byproducts, respectively,
Org. Lett., Vol. 5, No. 10, 2003
1711

and (2) the very similar chromatographic behavior of main-
and byproducts, leading to relatively large losses of material
when working on a small scale (0.25 mmol of â-ketoester).
Although the selectivities are not very high in absolute
terms, the most important finding of this study is that the
sequence of addition of the halogenating agents determines
the sense of chiral induction. In other words, given one
enantiomeric form of the catalyst, it is possible to form either
enantiomer of the product preferentially just by choosing the
order of the two halogenation steps in this one-pot tandem
process. This is a very rare observation in asymmetric
catalysis.16 It is, however, easily explained by assuming that
the first halogen is introduced in a nonstereoselective manner
(vide supra) and that the overall stereochemical outcome is
solely determined by the second halogenation step. Given
that for the catalysts derived from (R,R)-TADDOLs the major
product enantiomer is formed via Si-side attack of the
halogenating agent onto the coordinated enolate,5c we assign
the absolute configuration (S)- to the preferred enantiomer
obtained via the F f Cl sequence (and (R)- for the Cl f F
sequence).
We are currently trying to improve the stereoselectivity
of this unique double-halogenation reaction, as well as
investigating the reactivity and potential use as chiral building
blocks of these dihalocompounds.
Supporting Information Available: Experimental condi-
tions and spectroscopic and analytical characterization of
â-ketoesters and mono- and dihalogenated â-ketoesters. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) A comparable situation was reported for the enantioselective double
alkylation of aldimine Schiff bases derived from glycine under phase-transfer
catalytic conditions. See: Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka,
K. J. Am. Chem. Soc. 2000, 122, 5228-5229. We thank one of the reviewers
for drawing our attention to this.
OL0343459
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Org. Lett., Vol. 5, No. 10, 2003