Enantioselective Pd-catalyzed allylation reaction of fluorinated silyl enol ethers

Article abstract of DOI:10.1021/ja067501q

An enantioselective Pd-catalyzed allylation reaction of fluorinated silyl enol ethers is reported. This reaction provides a stereoselective and efficient approach to allylated tertiary α-fluoroketones from achiral fluorinated precursors. A variety of cycl

Full text of DOI:10.1021/ja067501q

Published on Web 01/11/2007
Enantioselective Pd-Catalyzed Allylation Reaction of Fluorinated Silyl Enol
Ethers
EÄ tienne Be´langer, Katy Cantin, Olivier Messe, Me´lanie Tremblay, and Jean-Franc¸ois Paquin*
Canada Research Chair in Organic and Medicinal Chemistry, De´partement de chimie,
UniVersite´ LaVal, Que´bec, QC, Canada G1K 7P4
Received October 19, 2006; E-mail: jean-francois.paquin@chm.ulaval.ca
The presence of a fluorine atom can often modify the activity
of a bioactive molecule by changing its solubility, lipophilicity,
metabolic stability, conformation, hydrogen-bonding ability, or
chemical reactivity.1 Thus, the number of drugs or agrochemicals
Figure 1. Enantioselective access to tertiary R-fluorinated ketones.
Table 1. Reaction Optimization for the Allylation of 4a
with at least one fluorine atom has increased dramatically over the
past years.2 However, a structural evaluation of fluorinated drugs
reveals that only a small number possess a stereogenic (sp3-
hybridized) carbon atom bearing fluorine.3 The limited number of
methods allowing the asymmetric synthesis of fluorinated com-
pounds is likely to be a reason for this lack of diversity,4 and the
development of novel methodologies is therefore highly desirable.5
R-Fluorocarbonyl compounds, in particular tertiary R-fluorinated
ketones (2, Figure 1), is a class of fluorinated compounds that has
received much attention recently.5 Two main strategies for the
enantioselective preparation of tertiary R-fluorinated ketones (2)
have been investigated so far (Figure 1).4
The best results obtained thus far using these strategies necessitate
the use of â-ketoester derivatives as starting substrate. In the first
case (1 f 2), Togni,6 Sodeoka,7 and others4,8 have shown that 2
could be produced from 1 (R ) carbonyl) by using chiral metal
complexes (Ti, Pd, Cu, etc.) along with an achiral electrophilic
source of fluorine. While promising results have been obtained with
this strategy, the requisite use of 1,3-dicarbonyls or â-ketophos-
phonates limits its general applicability.9 More recently, Nakamura
and Stoltz independently showed that 2 could be obtained from 3
(R ) allyl ester) via a catalytic, enantioselective decarboxylation
of racemic R-fluoro-â-keto esters.10
Pd catalyst
(mol %)
T
yield
(%)b
ee
entrya
ligand
solvent
(
°
C)
(%)c
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
5
2.5
1.25
1.25
1.25
6
7
8
9
9
9
9
9
9
9
9
9
THF
THF
THF
THF
CH2Cl2
Et2O
benzene
toluene
toluene
toluene
toluene
toluene
20
20
20
20
20
20
20
20
20
20
20
40
traces
0
n.d.
33
37
50
62
76
73
53
47
65
85
10
91
26
93
92
93
93
93
93
92
10
11d
12d
a Reaction time ) 4 h. b Isolated yield. c Determined by chiral HPLC
(see Supporting Information for details); n.d. ) not determined. d Reaction
time ) 17 h.
In the course of our study on the development of novel synthetic
approaches to organofluorine compounds, we became interested
in the chemistry of fluorinated silyl enol ethers.11 We envisioned
that their use as nucleophiles in the palladium-catalyzed allylic
alkylation reaction12,13 could provide facile access to compounds
such as 2. We envisaged that this reaction would offer the promise
of a general solution to the synthesis of fluorinated stereogenic
centers with the significant advantages over previously documented
procedures since it will not be limited to substrates containing
dicarbonyl compounds. We therefore describe herein the application
of this new approach to the development of the first enantioselective
Pd-catalyzed allylation reaction of fluorinated silyl enol ethers.14,15
Initial studies were performed using the fluorinated silyl enol
ether derived from R-tetralone (4)16 as substrate along with allyl
ethyl carbonate (1.1 equiv) as the allyl source, 35 mol % of
tetrabutylammonium triphenyldifluorosilicate (TBAT) to activate
the silyl enol ether in situ,17 and [Pd(C3H5)Cl]2 as the Pd catalyst.
Different ligands were then examined using a 4 h reaction period
using THF as the solvent (Table 1). No product was isolated using
either the Trost ligand or Josiphos while BINAP furnished 518 in
33% yield but with a disappointing 10% ee. The use of t-Bu-
PHOX19 dramatically improved the enantiomeric excess resulting
in the isolation of the desired product in 91% ee. A solvent
screening was then performed using the PHOX ligand. While the
use of CH2Cl2 resulted in a marked decrease in enantiomeric excess
(26% ee), the use of Et2O resulted in an improved yield (62%)
while maintaining the enantiomeric excess (93% ee). Finally, both
benzene and toluene afforded the desired product in good yield
and excellent ee, and toluene was chosen for further optimization.20
The effect of catalyst loading was next examined, and reducing
the amount of catalyst from 5 to 1.25 mol % for a reaction time of
4 h caused a significant drop in yield (73% to 47%), however
without any influence on the enantiomeric excess (entries 8-10).
Finally, a longer reaction time (17 h) and gentle heating at 40 °C
allowed the desired product to be isolated in excellent yield with
92% ee (entry 12).
With the optimal conditions in hand, a variety of substrates were
examined (Table 2).18 A variety of allyl sources could be used,
ethyl allyl carbonate (entries 1, 4, 5, 7, 9, and 11) could be
9
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J. AM. CHEM. SOC. 2007, 129, 1034-1035
10.1021/ja067501q CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction of Various Cyclic Fluorinated Silyl Enol Ethersa
In summary, we have developed the first enantioselective Pd-
catalyzed allylation reaction of fluorinated silyl enol ethers. This
reactions allows the efficient and stereoselective synthesis of
allylated tertiary R-fluoroketones from achiral fluorinated precur-
sors. Extension of this methodology to other classes of substrates
is currently underway and will be reported in due course.
Acknowledgment. We gratefully acknowledge the Universite´
Laval for financial support of this work. J.-F.P. thanks the Canada
Research Chair Program for a Tier 2 CRC in Organic and Medicinal
Chemistry. OmegaChem Inc. is thanked for a generous gift of L-tert-
leucine.
Supporting Information Available: Experimental procedures and
characterization data for all the new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Hiyama, T. In Organofluorine Compounds; Chemistry and Applica-
tions; Yamamoto, H., Ed.; Springer: New York, 2000; p 1-23; 137-
182.
(2) Thayer, A. M. Chem. Eng. News 2006, 84, 15.
(3) Myers, A. G.; Barbay, J. K.; Zhong, B. J. Am. Chem. Soc. 2001, 123,
7207.
(4) Review: Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104, 6119.
(5) (a) Prakash, G. K. S.; Beier, P. Angew. Chem., Int. Ed. 2006, 45, 2172.
(b) Pihko, P. M. Angew. Chem., Int. Ed. 2006, 45, 544.
(6) Review: Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147.
(7) Hamashima, Y.; Sodeoka, M. Synlett 2006, 1467 and references therein.
(8) (a) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2004, 125, 1357. (b) Shibata,
N.; Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004, 1703.
(9) For an exception using oxindole derivatives, see: Hamashima, Y.; Suzuki,
T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127,
10164.
(10) (a) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2005, 44, 6924. (b) Nakamura, M.; Hajra, A.; Endo, K.;
Nakamura, E. Angew. Chem., Int. Ed. 2005, 44, 7248.
(11) There are limited reports on the use of fluorinated silyl enol ethers as
fluorinated synthons, see for example: (a) Chanteau, F.; Didier, B.; Dondy,
B.; Doussot, P.; Plantier-Royon, R.; Portella, C. Eur. J. Org. Chem. 2004,
1444. (b) Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67, 3479.
(c) Hata, H.; Kobayashi, T.; Amii, H.; Uneyama, K.; Welch, J. T.
Tetrahedron Lett. 2002, 43, 6099. (d) Prakash, G. K. S.; Hu, J.; Olah, G.
A. J. Fluorine Chem. 2001, 112, 355. (e) Iseki, K.; Kuroki, Y.; Asada,
D.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y. Tetrahedron 1997, 53,
10271.
(12) For reviews on the asymmetric allylic alkylation reaction, see: (a) Paquin,
J.-F.; Lautens, M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer-Verlag: Berlin, 2004; (Suppl.
2), pp 73-95 and references therein. (b) Pfaltz, A.; Lautens, M. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 2, pp 833-884
and references therein.
(13) For a recent review on the use of preformed enolates in the Pd-catalyzed
allylic alkylation reaction, see: Braun, M.; Meier, T. Synlett 2006, 661
and references therein.
(14) (a) Trost, B. M; Keinan, E. Tetrahedron Lett. 1980, 21, 2591. (b) Tsuji,
J.; Minami, I.; Shimizu, I. Chem. Lett. 1983, 1325.
a Reaction conditions: [Pd(C3H5)Cl]2 (1.25 mol %), (S)-t-Bu-PHOX (3.1
mol %), allyl ethyl carbonate or ethyl 2-methylallyl carbonate (1.1 equiv),
TBAT (35 mol %), toluene (0.1 M), 40 °C, 14-18 h. b Isolated yields.
c Determined by chiral HPLC (see Supporting Information for details).
d Diallylcarbonate was used instead of allyl ethyl carbonate. e The reaction
was performed using [Pd(C3H5)Cl]2 (2.5 mol %) and (S)-t-Bu-PHOX (6.25
mol %). f The lower yields are due to product loss because of its low boiling
point.
(15) For the first example of enantioselective allylation of silyl enol ether with
Pd, see: Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044. With Ir, see: Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005,
127, 17192.
(16) Silyl enol ether 4 was easily prepared in two steps from R-tetralone. See
Supporting Information for details.
substituted by diallyl carbonate (entry 2) with similar results while
the use of ethyl 2-methylallyl carbonate resulted in the desired
2-methylallylated products in good yield and excellent ee (entries
3, 6, 8, 10, and 12). Interestingly, the more stable TES silyl enol
ether was equally effective in this transformation (entry 4). This
reaction was examined in a range of five-, six-, and seven-membered
ketones, and in all cases, good to excellent yields of the R-fluo-
roketones were obtained with excellent enantioselectivities. While
this reaction can also be applied to acyclic fluorinated silyl enol
ethers, the selectivity obtained is so far moderate.10b,21
(17) While using less TBAT reduced the yield, an increased amount had no
significant effect. Another fluoride source such as CsF was ineffective.
(18) The absolute configurations were assigned by comparison of the [R]D
values of known compounds or assigned, for the new compounds prepared,
based on the established stereochemical outcome of the reaction. See
Supporting Information for details.
(19) (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. (b) Williams,
J. M. J. Synlett 1996, 705.
(20) No product formation was observed with other solvents such as dioxane,
MTBE, hexane, and CH3CN.
(21) For example, the reaction of the (Z)-triethylsilyl enol ether of 2-fluoro-
propiophenone furnished the desired product with ca. 40% ee.
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