Lanthanum-Catalyzed Enantioselective Trifluoromethylation by Using an Electrophilic Hypervalent Iodine Reagent

Article abstract of DOI:10.1002/chem.201900598

A highly enantioselective catalytic method for the synthesis of quaternary α-trifluoromethyl derivatives of 3-oxo esters is described. The reaction uses lanthanum(III) triflate and chiral PyBOX-type C₂-symmetric ligands to generate intermediate La^III complexes that incorporate an enolate moiety of the starting 3-oxo ester and the trifluoromethylation transfer reagent. The enantioselectivity of the reaction stems from the efficient blockage of one of the prochiral faces of the La^III enolate by one unit of the C₂-symmetric ligand.

Full text of DOI:10.1002/chem.201900598

A Journal of
Accepted Article
Title: Lanthanum-Catalyzed Enantioselective Trifluoromethylation using
Electrophilic Hypervalent Iodine Reagent
Authors: Fernando P. Cossío, Albert Granados, Iván Rivilla, and
Adelina Valllribera
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To be cited as: Chem. Eur. J. 10.1002/chem.201900598
Link to VoR: http://dx.doi.org/10.1002/chem.201900598
Supported by

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COMMUNICATION
Lanthanum-Catalyzed Enantioselective Trifluoromethylation
using Electrophilic Hypervalent Iodine Reagent
[
a]
[b]
[b]
[a]
Albert Granados, Iván Rivilla, Fernando P. Cossío* and Adelina Vallribera*
Abstract: A highly enantioselective catalytic method for the synthesis
ligands in the a-trifluoromethylation reaction. As a first stage, we
of quaternary α-trifluoromethyl derivatives of 3-oxo esters is described. decided to test the efficiency of the catalytic system in the model
The reaction uses lanthanum (III) triflate and chiral pybox-type C
2
-
reaction of β-keto ester 1a (Scheme 1). The selection of pentan-
3-yl derivative was done based in our previous findings; normally
increasing the size of the ester group the enantiodifferentiation is
symmetric ligands to generate intermediate La(III) complexes that
incorporate an enolate moiety of the starting 3-oxo ester and the
trifluoromethyl transfer reagent. The enantioselectivity of the reaction
stems from the efficient blockage of one of the prochiral faces of the
2
5,26
enhanced.
Keto ester 1a was achieved by treatment of methyl
analog 1b with the corresponding alcohol using catalytic amounts
2
8
La(III) enolate by one unit of the C
2
-symmetric ligand.
of ZnO in refluxing toluene in 89% yield. The pre-catalyst was
prepared mixing 10% of Ln(OTf) and 15% of py-box ligand (L) in
3
dry acetonitrile in the presence of molecular sieves overnight.
Then, the β-keto ester 1a (1 equiv.) and the trifluoromethylating
transfer agent 3a-b (1.2 equiv.) were added at room temperature.
The reaction conditions had been previously optimized for α-
Fluorinated organic compounds are extremely appealing in the
1
-5
course of pharmaceuticals and agrochemicals discovery.
Indeed, the appropriate introduction of a fluorine atom or a
fluorinated group can drastically affect the biological and physical
properties of a molecule and its physiological behavior with
25-27
amination reactions.
Initially,
by
using
5-(trifluoromethyl)dibenzothio-phenium
(Umemoto's reagent) as the
and L1, the corresponding
product 2a was obtained in 10% yield and 50% ee (table 1, entry
). Changing to Togni's reagent 3b, product 2b was afforded in
high yield (85%), although the ee did not enhance (Table 1, entry
). Screening of two other Nishiyama’s type py-box ligands (L2
6
-9
respect to the mode of action and metabolism. In this context,
tetrafluoroborate
3a
1
0-23
the trifluoromethyl motif has generated high interest.
The
trifluoromethylating reagent, La(OTf)
3
introduction of a trifluoromethyl group in an enantioselective
1
9-23
manner is one of the most challenging synthetic problems.
1
Thus, the non-asymmetric electrophilic α-trifluoromethylation of β-
keto esters has been extensively studied, whereas the
asymmetric examples are scarcely documented. In particular,
MacMillan and co-workers reported that combining chiral
organocatalysis and Lewis acid catalysis and Togni’s reagent (3b)
3
and L3) revealed the greater effectiveness of indanyl-py-box
ligand (L3) in obtaining an optimum reactivity and
enantioselectivity that could be improved up to 91% performing
as a CF
3
-transfer highly enantioenriched α-trifluoromethylated
o
the reaction at -35 C (Table 3, entry 6). Eu(OTf)
3
gave less ee and
2
0
aldehydes could be obtained. We were stimulated by the
yield, showing the dependence of the reaction with the ionic radio
of the Lewis acid and selected py-box.
2
3
impressive work of Gade and co-workers in 2012. They
developed boxmi chiral pincer ligands which combined with
copper proved to be excellent catalysts for the enantioselective
trifluoromethylation of β-keto esters by using commercial
electrophilic trifluoromethylating agents.
In our own research, we have extensively used py-box ligands
and lanthanides for the enantioselective α-amination of β-keto
2
4-27
esters.
The versatility offered by lanthanides and their
increased coordination numbers suggested us that we should test
their combination with cheap commercially available py-box chiral
[
a]
b]
Dr. A. Granados, Prof. A. Vallribera
Department of Chemistry and Centro de Innovación en Química
Avanzada (ORFEO-CINQA)
Universitat Autònoma de Barcelona
08193-Cerdanyola del Vallès, Barcelona, Spain
E-mail: adelina.vallribera@uab.es
Scheme 1. Trifluoromethylation of ester 1a with La(OTf)
the presence of chiral ligands L1-3.
and reagents 3a,b in
3
[
Dr. I. Rivilla and Prof. Fernando P. Cossío
Departamento de Química Orgánica I and Centro de Innovación en
Química Avanzada (ORFEO-CINQA)
Universidad del País Vasco and Donostia International Physics
Center (DIPC)
Then, a broad range of cyclic β-keto esters was examined using
Pº Manuel Lardizabal, 3. 20018 Donostia - San Sebastián, Spain
E-mail: fp.cossio@ehu.es
the optimized pre-catalyst combination and reaction conditions.
28,29,30
Keto esters 1 were prepared as previously described
(see
Supporting information for this article is given via a link at the end of
the document.
SI). First, we noticed that the size of the ester group had a strong
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Chemistry - A European Journal
10.1002/chem.201900598
COMMUNICATION
influence on the enantiocontrol. Bulky tert-butyl and 2,4-
dimethylpentan-3-yl esters gave lower ee’s (82
substituent in this six-position of the aromatic ring. Large tert-butyl
and trifluoromethyl substituents gave higher enantioselectivities
(
3
98-99%) compared with H, F and O-CH (88-92%). Unexpectedly,
a tert-butyl group placed in five-position rendered 2j in a slightly
lower 87% ee. Moreover, the α-trifluoromethylation reaction of β-
keto ester 1i gave an excellent 91% ee. Fortunately, the method
can be successfully employed in the presence of substituents in
other aromatic positions of the substrate. Excellent results were
obtained in terms of enantioselectivity for 2k and 2l (91 and 99%
ee respectively). The more flexible cyclic six-membered ring b-
keto ester gave the trifluoromethylated product 2m with a
significant decrease in enantioselectivity (65%) under the same
conditions. We also tested the formation of 2n as an example of
a substrate lacking the fused aromatic ring. A low 53% ee was
obtained suggesting the existence of a positive p-stacking
interaction between the enolate-1 and the indanyl-py-box at the
TS can enhance the ee.
Table 1. Trifluoromethylation of β-keto ester 1a with lanthanide(III) triflates
3
Ln(OTf) and reagents 3a,b in the presence of chiral basic ligands L1-3.
[
a]
[b]
Entry
3
Ln
La
La
La
La
La
La
Eu
T (ºC)
Yield (%)
ee (%)
50
1
2
3
4
5
6
7
3a
3a
3b
3b
3b
3b
3b
L1
10
85
85
82
87
71
65
[
c]
L1
15
L1
L2
L3
L3
L3
55
58
78
91
The assignment of the absolute configuration of 2a as R was
based on the comparison of the positive specific rotation
80
2
2
described for (S)-2a in the literature. Cahard also described a
positive Cotton effect for the n-p transition at about 320 nm in the
case of (S)-2a. As expected, this latter compound presented a
[
a] Yields of isolated pure product 2a. [b] Enantiomeric excesses determined
by HPLC and calculated as ee=100 x ([R]-[S]) / ([R]+[S]). [c] DIPEA was
used as a base.
2
2
negative Cotton Effect. We assigned the absolute configuration
R to all compounds 2 showing negative specific rotation and
negative Cotton effect (see Supporting Information).
The mechanism of the reaction was first investigated by ESI-MS.
We conducted an ESI mass spectrometry study to detect short-
lived reaction intermediates present in the solution. Our
investigation was based on the reaction of 1b with 3b using the
3
combination of La(OTf) and L3 as a pre-catalytic system in
acetonitrile at room temperature. First of all, individual
components of the reaction were analyzed, as well as mixtures of
two or more components and finally the ongoing reaction in its
initial state and after 10 and 75 minutes, respectively (see
Supporting Information). We first analyzed the binary mixtures.
The ESI-MS spectrum of a stoichiometric mixture of L3 and
La(OTf)
3
showed one peak m/z = 829.9587 corresponding to a
complex (denoted as INT1 in Figure 1, vide infra) of lanthanum
+
with one pybox ligand [(L3)La(OTf)
2
]
and another peak m/z =
1
223.1038 corresponding to a complex of lanthanum with two
+
2 2 3
pybox ligands [(L3) La(OTf) ] . For the mixture of 1b with La(OTf)
we identified two peaks m/z = 626.8734 corresponding to
+
+
[
2 2 2
(1b)La(OTf) ] and m/z = 816.9357 identified as [(1b) La(OTf) ] .
No binary species could be identified from the ESI-MS spectrum
of a stoichiometric mixture of Togni’s reagent 3b and La(OTf)3.
Scheme 2. Synthesis of chiral esters 2a-n with La(OTf)
of chiral ligand L3.
3
and 3b in the presence
Then we studied ternary mixtures. From the mixture La(OTf)
and 1b (0.4:0.4:1), we identified two important species
corresponding to peaks at m/z 870.0622 ([(enolate-
b)(L3)La(OTf)] , denoted as INT2 in Figure 1, vide infra) and m/z
3
, L3
=
+
1
+
and 71% ee respectively). In contrast, indanone-derived methyl
β-keto ester (1b) yielded the corresponding product 2b in high
enantioselectivity (89% ee) comparable with the pentan-3-yl
derivative. This is a remarkable point since it allows applying this
chemistry to simple methyl β-keto esters. Next, we studied the
influence of aromatic substituents at the six-position of the
aromatic part. No clear electronic effects were observed. Thus, in
the presence of either electron–donating tert-butyl or electron–
withdrawing trifluoromethyl groups excellent enantioselectivities
were obtained. However, the ee’s depend on the size of the
= 1263.2087 ([(enolate-1b)(L3) La(OTf)] ). These results indicate
2
that in the presence of pybox ligands the β-keto ester is in its
enolate form. In the case of La(OTf) , L3 and 3b (0.4:0.4:1), no
3
ternary specie was identified. In our last set of experiments, we
performed the reaction with all the components using 25% molar
of the catalyst (L3/La(OTf) ). Samples were taken at different
3
intervals. The ESI-MS spectra afforded the signals already
observed in the ternary mixtures. Surprisingly the peak
corresponding to the trifluoromethylated product 2b could not be
observed under these conditions.
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COMMUNICATION
The absence of species with Togni’s reagent, 3b, coordinated
with lanthanide in MS-ESI studies probably indicate that very
active species are formed during the reaction. The activating
cyclohexadien-1-ylidene)-p-tolyloxy]. After 48 hours, the reaction
with TEMPO gave only trace amounts of product 2b, but
nevertheless racemic 4 was isolated in high yield (85%). The
same yield was obtained directly mixing 1b and TEMPO,
suggesting that the radical reaction takes places in the absence
of Togni’s reagent and therefore does not provide any information
about the mechanism of trifluoromethylation. However, the
experiment adding galvinoxyl free radical gave exclusively the
1
9
mode of Togni’s reagent was studied by F NMR mixing La(OTf)
and reagent 3b (1:1) in CD CN. After several minutes 3b was
converted to a new species with a shift of the CF from δ = -44.6
ppm to δ = -33.7 ppm. We propose the formation of the reactive
3
3
3
1
9
cationic iodonium species a1 (eq. 1). Moreover, F NMR-based
titration furnished a Job plot indicating a 1:1 complexation of 3b
corresponding CF
3
adduct 5 (45%). The total amount of unaltered
3
1
with La(OTf)
activation in the presence of other Lewis acids as MgBr
Furthermore, the appearance of a broad signal at the same δ = -
3
(see SI). Other authors have proposed a similar
1b could be recovered. Compound 5 was first identified by a
3
2
12
19
2
or CuI . unique single signal in F NMR at -60.1 ppm characteristic of a
O-CF unit, and by the ESI-MS fragmentation analysis which
3
evidenced the loss of the O-CF group (M -85, see SI).
3
1
9
+
3
3.7 ppm in the F NMR spectrum of a mixture of all the
components of the reaction, namely 1a, L3, 3b and La(OTf)
1:0.4:1:0.4) show the coordination of 3b to lanthanide probably
3
3
3
Consequently, competition of trifluoromethyl radicals in the
alkylation process cannot be discarded.
(
given mixtures of binary and tertiary complexes.
HO
OTf
F3C
I
O
F3C
I
O
La
I
F3C
I
O
OTf
TfO
(1)
+
La(OTf)3
3
b
3’b
O
O
3b
a1
CO2Me
2
CO Me
CF3
rxn
H
ΔE = −75.6
rxn
1
Detailed diffusion H NMR experiments were carried out. The self-
ΔG298 = −74.7
2b
1
b
diffusion coefficient of 3b was consistent with its relatively small
-
9
2
La(OTf)3 + L3
volume (D = 2.23 x 10 m /s; r = 2.87 Å). The addition of La(OTf)
to a solution of 3b (1:1) induced important changes showing the
3
TfO
-
9
2
presence of only one species (a1, D = 2.00 x 10 m /s; r = 3.19
Å). Then, an experiment with a mixture of 1b, L3, 3b and La(OTf)
L3
N
1b + L3
3
L3 + 3’b + 2b
N
N
(
1:0.12:1:0.1) showed the formation of a unique ternary metal
La
(
+23.1)
[−6.1]
(−13.9)
[+2.4]
-
9
TfO
OTf
complex which revealed a diffusion coefficient of D = 1.48 x 10
INT1
(0.0)
0.0]
2
m /s that was consistent with a larger volume (r = 4.33 Å). Thus,
the formation of a ternary complex, denoted as INT3 in Figure 1,
was confirmed by diffusion measurements.
[
L3
L3
N
N
N
N
N
N
OTf
L3·HOTf
La
La
O
O
OTf
O
I
TEMPO (1 equiv.)
O
3
La(OTf) (10 mol%)
O
O
F
3
C
I
O
O
O
O
O
L
3
(12 mol%)
Me
OMe
O
CF3 OMe
+
INT2
O
N
CH
3
CN, 4Å MS
85%
Me
INT4
1
b
4
(−52.0)
[−54.0]
(−32.8)
[−16.9]
L3
N
3
b
N
N
OTf
O
TS
O
N
3b
O
O
La
CH
3
CN, 4Å MS
5%
+
O
O
8
Me
O
I
1
b
F3C OMe
Galvinoxyl (1 equiv.)
La(OTf) (10 mol%)
INT3
tBu
tBu
O
O
F3C
I
O
3
L
3
(12 mol%)
O
Figure 1. Proposed catalytic cycle for the formation of quaternary 2-
trifluoromethyl ester (R)-2b from (±)-1b in the presence of La(OTf) , Togni’s
reagent 3b and chiral ligand L3. Numbers in parentheses and in square
brackets (in blue) correspond to the relative (with respect to INT1) total and
Gibbs energies, respectively, in kcal/mol. These energies were calculated at the
B3LYP-D3(PCM, solvent=acetonitrile)/6-31G*&LanL2DZ level of theory. The
+
O
CH
3
CN, 4Å MS
3
1
b
O
Me
CF
tBu
5
tBu
3
4
5%
3
b
Scheme 3. Reaction of β-keto ester 1b with radical scavengers TEMPO and
rxn
ꢄꢅꢆ
total (DE ) and free (∆ꢀꢁꢂꢃ ) reaction energies, in kcal/mol, associated with the
b+3bà2b+3’b transformation, are also given.
Galvinoxyl.
1
Next, the reaction of 1b under the conditions described in Scheme
Computational
studies
at
the
B3LYP-D3(SCRF,
1
was carried out in the presence of one equivalent of two different
radical scavengers (Scheme 3) such as 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO) and galvinoxyl free
radical [2,6-di-tert-butyl-α-(3,5-di-tert-butyl-4-oxo-2,5-
3
4-38
solvent=acetonitrile)/6-31G*&LanL2DZ level of theory
were
carried out in order to get a better understanding of the
experimental results. Although biradical species were searched
along the catalytic cycle at the UB3LYP level, all the wave
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Chemistry - A European Journal
10.1002/chem.201900598
COMMUNICATION
functions of the intermediate species converged to closed-shell
RB3LYP solutions. From the information obtained in the ESI-MS
and 2D-DOSY experiments (vide supra), we assumed the
formation, among other intermediates, of INT1 from the reaction
extended to other C-CF
quaternary centers.
3
bond forming reactions leading to chiral
3
between La(OTf) and chiral ligand L3 (Figure 1). This cationic
intermediate can react with ester 1b and with an additional
equivalent of L3, which acts as a base, to yield the enolate
intermediate INT2, also detected by ESI-MS (vide supra),
together with a L3·HOTf complex. This process shows a negative
relative energy with respect to INT1, although the step is almost
isoenergetic in terms of relative Gibbs energies at 298 K. Cationic
intermediate INT2 can incorporate one molecule of Togni’s
reagent 3b to yield formally heptacoordinated La(III) cation INT3.
This step is strongly exothermic and is compatible with the
detection of a bulky intermediate by 2D-DOSY experiments (vide
supra).
L3
La
8
9.9
Re
attack
2.89
2.20
I
2
.89
9
9.1
TS
ΔE ‡‡ = 28.4
ΔG298 = 28.7
L3
As far as the origin of the enantiocontrol in the formation of
quaternary ester 2b is concerned, the role of pybox ligand L3 is
readily assessed by inspection of the chief features of INT3
INT3
L3
I
2
.19
La
2.67
(
Figure 2). Thus, the coordination pattern of this cationic complex
1
.54
reveals an efficient blockage of the prochiral Si face of the La(III)
110.1
[
39]
enolate of 1b. In addition, the Natural Bond Orbital Analysis
of
2.43
La
2
b
2
.37
a single-point calculation on TS using Al(III) instead of La(III)
revealed a p-stacking interaction between the phenyl group of the
substrate 1b and the closest phenyl group of L3, with an
associated second-order stabilizing energy of ca. 0.75 kcal/mol.
The hindrance of the Si face of the substrate results in an efficient
I
2.16
INT4
rxn
2
.27
ΔE = −52.0
ΔG298 = −54.0
3
b
rxn
1
b
Blockage of
the Si face
S
N
2-like saddle point TS, which consists of a Re attack of the C
atom of the enolate moiety on the CF group of 3b, with
concomitant departure of the iodine-aryl group. This linear
arrangement of the C ···CF ···I-Ar system is associated with
a
Figure 2. Fully optimized geometries of cationic intermediates INT3 and INT4,
connected by saddle point TS. Bond distances and angles are given in Å and
deg., respectively. See Figure 1 caption for additional details. The origin of the
3
3
enantioselective formation of the C*···CF bond by blockage of one of the
a
3
prochiral faces of the La(III)-enolate of 1b is highlighted.
C···C and C···I distances of ca. 2.9 Å, which corresponds to a
bipyramidal geometry (see the ca. 90 deg. bond angles in the
structure of TS gathered in Figure 2) in which the trifluoromethyl
group has a planar cationic character with a significant radical
component, as revealed by its Mulliken charge of +0.58 e. This
partial biradicaloid singlet character of this reaction step is
compatible with the competition of radical scavengers with the
trifluoromethylation process (vide supra). The activation energy
associated with the C-C bond forming step was calculated to be
of ca. 28 kcal/mol, a noticeable value despite the strong
exergonicity of this step (Figure 2). Once intermediate INT4 is
formed, our calculations predict the release of trifluoromethyl
ester 2b, together with 2-(2-iodoohenyl)propan-2-ol 3’b and one
equivalent of L3 via proton transfer from the L3·HOTf complex
Acknowledgements
Financial support for this work was provided by the Spanish
Ministerio de Ciencia, Innovación
y Universidades (Grants
CTQ2016-80375-P, CTQ2014-53662-P and 2016-81797-REDC),
by the Gobierno Vasco/Eusko Jaurlaritza (Grant IT673-13) and by
Generalitat de Catalunya (2017 SGR 00465). I. R. thanks the
DIPC for his postdoctoral contract. I. R. and F. P. C. also thank
the SGI/IZO-SGIker of the UPV/EHU and the DIPC for generous
allocation of computational resources.
Keywords: trifluoromethylation • catalysis • lanthanum • DFT •
(
see Figure 1). It is interesting to note that the Gibbs energy
pybox
associated with this last step is the responsible for the completion
of the catalytic cycle. In addition, the energy balance of the whole
process is calculated to be highly exergonic (see Figure 1)
because of the energy release associated with conversion of
Togni’s reagent 3b into 3’b, which is produced during the
formation of INT4.
[1]
[2]
F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27-33.
C. Isanbor, D. O’Hagan,. J. Fluorine Chem. 2006, 127, 303-319.
a) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881-1886; b) D.
O’Hagan, J. Fluorine Chem. 2010, 131, 1071-1081.
[
[
[
3]
4]
5]
E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem. 2014, 57, 2832-
2
842.
In summary, in this communication an efficient method for the
enantioselective α-trifluoromethylation of β-oxo esters is
described. The reaction can proceed with high chemical yields
and ee’s and the origins of the enantiocontrol has been
rationalized by experimental and computational methods. We
think that the methods and models shown in this paper can be
J. Wang, M. Sanchez-Roselló, J. L. Aceña, C. del Pozo, C. A. E.
Sorochinsky, V.A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432-
2
506.
[6]
[7]
B. E. Smart, J. Fluorine Chem. 2001, 109, 3-11.
S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2
008, 37, 320-330.
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Chemistry - A European Journal
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COMMUNICATION
[
8]
Fluorine in medicinal chemistry and chemical biology, I. Ojima, Ed.;
Wiley-Blackwell: Hobpken, NY 2009.
[25] A. Pericas, A. Shafir, A. Vallribera, Org. Lett. 2013, 15, 1448-1451;
Highlighted in Synfacts 2013, 9, 700.
[
9]
B. K. Park, N. R. Kitteringham, P. M. O’Neil, Annu. Res. Pharmacol.
Toxicol. 2001, 41, 443-470.
[26] A. Pericas, R. Jiménez, A. Granados, A. Shafir, A. Vallribera, A. Roglans,
E. Molins, ChemistrySelect 2016, 1, 4305-4312.
[
[
10] J.-A. Ma, D. Cahard, D. J. Fluorine Chem. 2007, 128, 975-996.
[27] A. Granados, A. del Olmo, F. Peccati, T. Billard, M. Sodupe, A. Vallribera,
J. Org. Chem. 2018, 83, 303-313.
11] N. Shibata, A. Matsnev, D. Cahard, Beilstein J. Org. Chem. 2010, 6, 1-
1
9.
12] S. Barata-Vallejo, B. Lantaño, A. Postigo, Chem. Eur. J. 2014, 20, 16806-
6829.
[28] A. Pericas, A. Shafir, A. Vallribera, Tetrahedron 2008, 64, 9258-9263.
Highlighted in Synfacts, 2009, 1, 81.
[
1
[29] A. A. Cordi, J.-M. Lacoste, J.-J. Descombes, C. Courchay, P. M.
Vanhoutte, M. Laubie, T. J. Verbeuren, J. Med. Chem. 1995, 38, 4056-
4069.
[
[
[
13] J. Miró, C. del Pozo, Chem Rev. 2016, 116, 11924-11966.
14] J.-A. Ma, D. Cahard, J. Org. Chem. 2003, 68, 8726-8729.
15] I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. Int. Ed. 2007, 46,
[30] B. Ma, X. Lin, L. Lin, X. Feng, X. Liu, J. Org. Chem. 2017, 82, 701-708.
[31] J. Charpentier, N. Fru, A. Togni, Chem.Rev. 2015, 115, 650−682.
[32] a) D. Katayev, H. Katija, A. Togni, Chem. Eur. J. 2017, 23, 8353-8357;
b) N. Santschi, A. Togni, Chimia 2014, 68, 419-424.
7
54-757.
[
[
[
16] S. Noritake, N. Shibata, S. Nakamura, T. Toru, M. Shiro, Eur. J. Org.
Chem. 2008, 3465-3468.
17] A. Matsnev, S. Noritake, Y. Nomura, E. Tokunaga, S. Nakamura, N.
Shibata, Angew. Chem. Int. Ed. 2010, 49, 572-576.
[33] R. Calvo, A. Comas-Vives, A. Togni, D. Katayev, Angew. Chem. Int. Ed.
2019, 58, 1447-1452.
18] Y. Ohtsuka, D. Uraguchi, K. Yamamoto, T. Yamakawa, T. Tetrahedron
[34] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648−5652; b) C. Lee, W. Yang,
R. G. Parr, Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37,
785−789.
2
012, 68, 2636-2649.
[
[
19] T. Umemoto, K. Adachi, J. Org. Chem. 1994, 59, 5692-5699.
20] A. E. Allen, D. W. C. MacMillan, J. Am. Chem. Soc. 2010, 132, 4986-
[35] S. Grimme, J. Antony, S. Ehrlich, S. Krieg, J. Chem. Phys. 2010, 132,
154104−154104.
4
987.
21] D. A. Nagib, M. E. Scott, D. W. C. MacMillan, J. Am. Chem. Soc. 2009,
31, 10875-10877.
[
[
[36] a) R. Cammi, B. Mennucci, J. Tomasi, J. Phys. Chem. A. 2000, 104,
5631−5637; b) J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005,
105, 2999−3094.
1
22] For enantioselective α-trifluorometilation of β-keto esters see: S. Noritake,
N. Shibata, Y. Nomura, Y. Huang, A. Matnev, S. Nakamura, T. Toru, D.
Cahard, Org. Biomol. Chem. 2009, 7, 3599-3604.
[37] W. R. Wadt, P. J. Hay, J. Chem. Phys. 1985, 82, 284-299.
[38] M. J. Frisch, et al. Gaussian 09, revision D.01; Gaussian, Inc.:
Wallingford, CT, 2009 (full reference in the Supporting Information).
[39] a) F. Weinhold, J. Comput. Chem. 2012, 33, 2363-2379; b) F. Weinhold,
C. R. Landis, Valency and Bonding: A Natural Bond Orbital Donosr-
Acceptor Perspective, Cambridge UK Press: Cambridge, UK, 2005.
[
[
23] Q.-H. Deng, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2012, 134,
1
0769-10772.
24] J. Comelles, A. Pericas, M. Moreno-Mañas, A. Vallribera, G. Drudis-Solé,
A. Lledós, T. Parella, A. Roglans, S. García-Granda, L. Roces-
Fernández, J. Org. Chem. 2007, 72, 2077-2087.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201900598
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
[
a]
[b]
Albert Granados, Iván Rivilla,
L3
La La Ligand: Oxoesters possessing
Fernando P. Cossío* and Adelina
Vallribera*
O
O
quaternary trifluoromethyl groups can be
N
N
N
3
generated by means of La(OTf) and
L3
PyBox chiral ligands as catalysts and
Togni’s reagent as trifluoromethyl transfer
reactant. The reaction takes place with
excellent ee’s and good chemical yields.
The origins of the observed selectivity lie
in the blockage of one prochiral face of
La
O
I
Page No. – Page No.
1
4 examples
up to 98 % yield
up to 99 % ee
3b
CF
3
1
b
Lanthanum-Catalyzed
3
Ln(OTf) , Ligand
Enantioselective Trifluoromethylation
using Electrophilic Hypervalent Iodine
Reagent
O
X-CF3
3a,b
O
R
i
R
i
CF3
CO
2a-n
CO
a-n
2
R
2
R
the lanthanum enolate by the C
chiral ligand.
2
-symetric
1
This article is protected by copyright. All rights reserved.