Highly enantioselective copper-catalyzed electrophilic trifluoromethylation of β-ketoesters

Article abstract of DOI:10.1021/ja3039773

Enantioselective Cu-catalyzed trifluoromethylation of β-ketoesters using commercially available trifluoromethylating reagents is reported. A number of α-CF₃ β-ketoesters are obtained with up to 99% ee. The trifluoromethylated products were then transformed diastereoselectively to α-CF₃ β-hydroxyesters with two adjacent quaternary stereocenters via a Grignard reaction.

Full text of DOI:10.1021/ja3039773

Communication
pubs.acs.org/JACS
Highly Enantioselective Copper-Catalyzed Electrophilic
Trifluoromethylation of β-Ketoesters
Qing-Hai Deng, Hubert Wadepohl, and Lutz H. Gade*
Anorganisch-Chemisches Institut, Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
̈
S
* Supporting Information
Table 1. Optimization of Reaction Conditions for the
Trifluoromethylation of 5a
ABSTRACT: Enantioselective Cu-catalyzed trifluorome-
thylation of β-ketoesters using commercially available
trifluoromethylating reagents is reported. A number of α-
CF3 β-ketoesters are obtained with up to 99% ee. The
trifluoromethylated products were then transformed
diastereoselectively to α-CF3 β-hydroxyesters with two
adjacent quaternary stereocenters via a Grignard reaction.
t
yield
a
ee
b
entry
[Cu]
Lig
1
n
(h)
(%)
(%)
c
1
Cu(OTf)2
2d
2d
2d
2d
2d
2d
2d
2a
2b
2c
2e
3
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
2
48
48
15
15
15
15
15
15
15
15
15
19
24
16
18
24
82
95
−
d
2
Cu(OTf)2
2
NR
3
Cu(OTf)2
2
92
90
89
91
91
91
92
90
89
89
90
91
92
89
95
89
94
94
92
93
73
62
95
he physical, chemical, and biological properties of organic
4
Cu(OAc)2·H2O
Cu(ClO4)2·6H2O
Cu(OTf)·0.5tol.
Cu(BF4)·4MeCN
Cu(OTf)2
2
T
molecules may be significantly modified in the presence of
trifluoromethyl groups.1 Thus, great efforts have been made to
develop reactions to generate trifluoromethylated compounds
during the past decades.2−4 In particular, the stereoselective
introduction of trifluoromethyl groups to generate chiral
centers has been of growing interest.5 While there is an ever
growing number of catalytic enantioselective nucleophilic
trifluoromethylations,5,6 the corresponding electrophilic variant
remains comparatively rare.5 To date, the only catalytic
enantioselective electrophilic trifluoromethylation has been
reported by MacMillan and co-workers in 2010, combining
chiral organocatalysis and Lewis acid catalysis and using Togni’s
reagent (1c)7 as a CF3-transfer reagent to obtain enantioen-
riched α-trifluoromethylated aldehydes.8
5
2
6
2
7
2
8
2
9
Cu(OTf)2
2
10
11
12
13
14
15
16
Cu(OTf)2
2
Cu(OTf)2
2
Cu(OTf)2
2
−49
0
Cu(OTf)2
4
2
Cu(OTf)2
2d
2d
2d
1.5
1.2
1.1
95
95
93
Cu(OTf)2
Cu(OTf)2
a
b
c
Isolated yields. Determined by HPLC analysis. Adding 2 equiv of
d
iPr2NEt as base. No reaction.
Enantiopure α-CF3 β-ketoesters are attractive targets because
they possess both a chiral CF3-containing quaternary stereo-
center and an easily derivatized carbonyl group. The non-
asymmetric trifluoromethylation has been studied exten-
sively;7,9 but surprisingly, only two stoichiometric asymmetric
examples have been documented, giving rise to moderate
enantioselectivities (up to 71% ee).10−12 Therefore, the
development of an efficient enantioselective catalytic electro-
philic trifluoromethylation of β-ketoesters remains a challenge
in organic synthesis.
ligands in Cu-catalyzed enantioselective alkylations of β-
ketoesters and their subsequent cyclization.13 Employing such
chiral Cu-pincer systems we now report the highly
enantioselective catalytic trifluoromethylation of β-ketoesters
under mild conditions by using commercial electrophilic
trifluoromethylating agents.
Initially, by using 5-(trifluoromethyl)dibenzothiophenium
tetrafluoroborate (Umemoto’s reagent,9b 1a) as the trifluor-
omethylating agent, the trifluoromethylation of β-ketoester 5a
was performed in CH2Cl2 at room temperature with the
catalyst generated in situ from 10 mol % of Cu(OTf)2 and 12
mol % of 2d in the presence of molecular sieves, under reaction
conditions which had been previously optimized for
enantioselective alkylations.13b The corresponding product 6a
was obtained in 82% yield with 95% ee (Table 1, entry 1).
Screening two types of Togni’s reagents revealed that while 1b
was ineffective for this system reagent 1c gave the product in
higher yield with the same enantioselectivity and in a
We recently developed a class of chiral pincer ligands, boxmi
(2), which proved to be highly efficient as stereodirecting
Received: April 25, 2012
Published: June 13, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
considerably shorter reaction time (entries 2 and 3). Various
copper catalyst precursors were tested in the reaction, and
Cu(OTf)2 was found to be optimal in terms of yield and
enantioselectivity (entries 3−7). In contrast to the ligand 2d,
other boxmi derivatives containing different substituents gave
lower enantioselectivities or yields (entries 8−11).
differently functionalized tert-butyl esters of cyclopentenone
were converted to the corresponding products in high yields
with excellent enantioselectivities (6m−6o), providing another
valuable class of building blocks.16 Finally, a cyclopentanone-
derived benzyl β-ketoester was also successfully employed in
the process to generate 6p with 92% ee.
The absolute configuration of the optically active 6d was
established to be R by single crystal X-ray structure analysis
(Figure 1). Based on the absolute configuration of the product
Two other bisoxazoline ligands, (R, R)-Ph-Box 314 and
Nishiyama’s (R, R)-Ph-Pybox 4,15 were also compared under
identical reaction conditions. The product was obtained with
only −49% and 0% ee respectively (entries 12 and 13), which
indicated the greater effectiveness of the boxmi system in
obtaining optimum enantioselectivity in the Cu-catalyzed
trifluoromethylation of β-ketoesters. Finally, we found that a
1.2 equiv amount of the trifluoromethylating reagent was
sufficient for this reaction (entries 14−16).
A broad range of cyclic five-membered ring β-ketoesters was
examined with the optimized catalyst and reaction conditions
(Scheme 1). Indanone-derived tert-butyl β-ketoesters generated
Scheme 1. Enantioselective Trifluoromethylation of Five-
a
Membered Ring β-Ketoesters
Figure 1. Molecular structure of trifluoromethylated product 6d;
hydrogen atoms omitted for clarity.
formed, we assume that the key reaction intermediate is similar
to the one we have proposed previously for the catalytic cycle
of the asymmetric alkylation reaction.13b
In contrast to the substrates depicted in Scheme 1, the more
easily enolizable cyclic six-membered ring β-ketoester 7a was
trifluoromethylated with a significant decrease in enantiose-
lectivity (63% ee) under the conditions described above (Table
2, entry 1). However, upon using the combination of reagent
Table 2. Optimization of Reaction Conditions for the
Trifluoromethylation of 7a
a
b
entry
1
base
T (°C)
t (h)
yield (%)
ee (%)
1
2
3
4
1c
1a
1a
1a
−
rt
12
20
36
48
88
90
90
63
84
95
iPr2NEt
iPr2NEt
iPr2NEt
rt
0
c
−20
11
ND
a
b
c
Isolated yields. Determined by HPLC analysis. Not determined.
1a and diisopropyl ethylamine instead of 1c, the ee value
increased to 84% (entry 2) and the enantioselectivity was
further enhanced to 95% ee when the reaction was carried out
at 0 °C (entry 3).
a
Yields refer to isolated products; ee’s were determined by HPLC
With these optimized reaction conditions we explored the
generality of the protocol for six-membered ring β-ketoesters
(Scheme 2). Tetralone-derived tert-butyl β-ketoesters generated
the trifluoromethylated products with excellent enantioselectiv-
ities (8a−8e). Cyclohexenone-derived tert-butyl ester also
generated the corresponding prouduct with high ee (8f).
However, with the corresponding methyl β-ketoester and
cyclohexanone-derived benzyl β-ketoester the ee values were
reduced to 82% and 80%, respectively (8g and 8h).
Unfortunately, acyclic ketoesters proved to be unreactive
under these reaction conditions.17
analysis.
the corresponding products in high yields with excellent
enantioselectivities (92−99% ee) regardless of the nature and
the position of the substituents of the β-ketoesters derivatives
(Scheme 1, 6a−6j). In the presence of either electron-
withdrawing or -donating groups, and even methylthio units
in the aromatic ring, excellent enantioselectivities were
obtained. Methyl and benzyl β-ketoesters also yielded the
corresponding products with excellent enantioselectivities (6k
and 6l), showing that the size of the ester group only has a
slight influence on the enantiocontrol. Furthermore, three
To highlight the utility of the enantioselective trifluorome-
thylation developed in this work, we undertook further
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Journal of the American Chemical Society
Communication
Scheme 2. Enantioselective Trifluoromethylation of Six-
a
Membered Ring β-Ketoesters
Figure 2. Molecular structure of trifluoromethylated product rac-9b;
hydrogen atoms omitted for clarity.
a
a
Scheme 4. Lactonization of α-CF3 β-Hydroxyester 9b
Yields refer to isolated products; ee’s were determined by HPLC
analysis.
transformations of the trifluoromethylated products. The
trifluoromethylated β-ketoesters reacted with Grignard reagents
(methyl-, 2-methylallyl-, or allylmagnesium bromide) in Et2O at
0 °C to give the α-CF3 β-hydroxyesters 9a−9c in high yields
with excellent diastereoselectivities (Scheme 3). The relative
a
Yields refer to isolated products; ee’s were determined by HPLC
analysis.
Scheme 3. Highly Diastereoselective Grignard Reaction of α-
CF3 β-Ketoesters
reaction constructed two adjacent quaternary stereocenters
with a well-defined absolute configuration to give stereochemi-
cally pure α-CF3 β-hydroxyesters.
a
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectral data for all compounds, and
■
S
crystallographic results (for 6d and 9b) in cif format. The
1
details of NMR data and H−19F NOE experiments (for 9a).
This material is available free of charge via the Internet at
http://pubs.acs.org.
a
Yields refer to isolated products; ee’s were determined by HPLC
AUTHOR INFORMATION
Corresponding Author
lutz.gade@uni-hd.de
■
analysis. Determined by H and 19F NMR.
b
1
stereochemistry of products 9 was assigned by comparison of
NMR data and 1H−19F NOE experiments17 which showed that
the methyl group and CF3 group have a relative trans
orientation in 9a. The X-ray structure analysis of rac-9b also
confirmed that the hydroxyl group and CF3 group are cis
oriented relative to each other (Figure 2). This stereochemistry
might arise from the formation of a Mg2+ chelate with the keto
and the ester carbonyl groups, which is attacked by the
nucleophile from the less hindered face, that is, opposite to the
CF3 group.18
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Q.-H.D. acknowledges support by the Alexander von
Humboldt Foundation. Funding was also provided by the
Deutsche Forschungsgemeinschaft (SFB 623, TP B6). We
thank Prof. Markus Enders (Heidelberg University) for
performing the H−19F NOE experiments.
1
Furthermore, in the presence of 5 mol % of Cu(OTf)2 and 3
equiv of BF3·Et2O,13b lactonization and dehydration of α-CF3
β-hydroxyester 9b readily occurred in dichloromethane at 0 °C
yielding a substituted 9,9a-dihydroindeno[2,1-c]pyran-1(3H)-
one 10 with comparable enantioselectivity (Scheme 4).
In conclusion, we have developed an efficient protocol for
enantioselective trifluoromethylation of cyclic β-ketoesters
using commercially available reagents via Cu-boxmi catalysis.
Both five- and six-membered ring β-ketoesters were converted
to the corresponding products in high yields with up to 99% ee
under mild conditions. Furthermore, the subsequent Grignard
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