Taming Radical Intermediates for the Construction of Enantioenriched Trifluoromethylated Quaternary Carbon Centers

Article abstract of DOI:10.1002/anie.201812793

Demonstrated herein is the construction of trifluoromethylated quaternary carbon centers by an asymmetric radical transformation. Enantioenriched trifluoromethylated oxindoles were accessed using a hypervalent iodine-based trifluoromethyl transfer reagent in combination with a magnesium Lewis acid catalyst and PyBOX-type ligands to achieve up to 99 % ee and excellent chemical yields. Mechanistic studies were performed by experimental and computational methods and suggest a single-electron transfer induced S_N2-type mechanism. This example is thereby the first report on the construction of enantioenriched trifluoromethylated carbon centers using hypervalent iodine-based reagents proceeding through such a reaction pathway.

Full text of DOI:10.1002/anie.201812793

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Accepted Article
Title: Taming Radical Intermediates for the Construction of
Enantioenriched Trifluoromethylated Quaternary Carbon Centers
Authors: Roxan Calvo, Aleix Comas-Vives, Antonio Togni, and Dmitry
Katayev
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10.1002/anie.201812793
Angewandte Chemie International Edition
COMMUNICATION
Taming Radical Intermediates for the Construction of
Enantioenriched Trifluoromethylated Quaternary Carbon Centers
Roxan Calvo, Aleix Comas-Vives,[a,b] Antonio Togni and Dmitry Katayev*[a]
Dedicated to Professor Yuri Belokon on the occasion of his 80th birthday
based reagents is thought to occur via one of two competing
reaction pathways; following suitable activation of 1 or 2, a 2-
electron reductive elimination process can occur (Scheme 1a), or
a single electron transfer (SET) induced radical process may be
favored (Scheme 1b).[2a-b,7,8] While the former inner-sphere
reductive elimination pathway is both plausible and consistent
with the expected reactivity of the 3center4electron bond
model, very little experimental evidence in support of such a
mechanism exists. Nevertheless, very little experimental
evidence in support of such a mechanism exists. In a large
majority of cases, trifluoromethylation is in fact believed to occur
via an outer-sphere radical process, whereby reduction of the
reagent by a suitable catalyst or organic substrate results in
liberation of an electrophilic CF3 radical species.
Abstract: We demonstrate the construction of trifluoromethylated
quaternary carbon centers via an asymmetric radical
transformation. Enantioenriched trifluoromethylated oxindoles
were accessed through the use of a hypervalent iodine-based
trifluoromethyl transfer reagent in combination with a magnesium
Lewis acid catalyst and PyBOX-type ligands to achieve up to 99%
ee and excellent chemical yields. Mechanistic studies were
performed by experimental and computational methods and
suggest a single electron transfer induced SN2type mechanism.
This is thereby the first report on the construction of
enantioenriched trifluoromethylated carbon centers using
hypervalent iodine-based reagents proposing such a reaction
pathway.
Nu
I
a)
F3C
A
reductive
elimination
I
O
F3C
OH
Nu-H
Taming the reactivity of radical species to favor an asymmetric
bond forming process remains a formidable challenge in modern
organic chemistry. In the field of trifluoromethylation, examples of
asymmetric radical transformations furnishing enantioenriched
perfluoroalkylated carbon centers remain exceedingly rare.[1,3,5,6]
This is a surprising fact, given the growing prevalence of the CF3
group in medicinal and agrochemistry and the concomitantly ever
growing body of literature focused on mild, selective and efficient
trifluoromethylation methodologies, often via the use of
electrophilic radical species.[2] While the first catalytic
enantioselective radical trifluoromethylation was reported in 2009
by the Macmillan group, the major drawback to the protocol was
the use of gaseous CF3I.[3] In contrast, hypervalent iodine-based
reagents 1 and 2 (Scheme 1) developed in 2006 have found
widespread use in academia as crystalline, bench stable and easy
to synthesize precursors to electrophilic CF3 radical
species.[4,2a,2b] To date, however, there exist only two examples
on the use of these reagents in asymmetric trifluoromethylation;
in follow-up work, the Macmillan group demonstrated the use of
reagent 1 with Lewis acid and enamine catalysis to generate
enantioenriched α-trifluoromethylated aldehydes.[5] Interestingly,
the authors proposed a mechanism devoid of radical species.
Gade and co-workers later reported the copper catalyzed
enantioselective trifluoromethylation of βketoesters using
pincer-type ligands and reagent 1.[6] No mechanistic work was
conducted and the involvement of radical intermediates was not
discussed. Generally, trifluoromethylation by hypervalent iodine-
A = Brønsted acid,
non-reducing Lewis
acid
R
R
Nu CF3
R
R
1 (R = Me)
2 (2R = O)
Nu
I
b)
F3C
A
SET induced
radical
fragmentation
H
I
O
F3C
O
Nu-H
A = transition metal,
photoredox catalyst,
organic substrate
R
R
R
R
CF3
Nu
1 (R = Me)
2 (2R = O)
c) This work:
Nu*
H
R
CF3
F3C
I
O
F3C
I
O
SET induced SN2
Nu-H
*
O
R'
N
R''
1
Scheme 1. Generally accepted mechanisms of CF3 transfer from hypervalent
iodine-based reagents 1 and 2 to nucleophilic substrates. [a] Reductive
elimination pathway. [b] Radical pathway. [c] Our work on the enantioselective
radical trifluoromethylation of oxindoles via a SET induced SN2-type pathway.
Previously, our group have demonstrated the successful
trifluoromethylation of a wide range of enolate intermediates by
reagents 1 and 2 to generate α-trifluoromethylated carbonyl
compounds and in selected examples, mechanistic work
indicated the involvement of radical intermediates.[8] We
postulated that the generation of a chiral environment around the
nucleophilic enolate center could open the door to the
development of an enantioselective radical trifluoromethylation
(Scheme 1c). Preliminary investigations revealed that up to
88% enantiomeric excess (ee) could be induced in the
magnesium catalyzed trifluoromethylation of oxindoles through
employing the commercially available chiral PyBOX ligand L1
(Table 1).[8d] Oxindoles form the core of an extensive range of
natural products and bioactive compounds, many of which have
been studied as potential therapeutic agents, and therefore act as
useful templates for further reaction development.[9] Herein, we
present our development of the asymmetric trifluoromethylation of
substituted oxindoles using a combination of MgBr2•Et2O with
[a]
R. Calvo, Dr. A. Comas-Vives, Prof. Dr. A. Togni, Dr. D. Katayev
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology, ETH Zürich
Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland 1
E-mail: katayev@inorg.chem.ethz.ch
[b]
Dr. A. Comas-Vives
Department of Chemistry
Universitat Autònoma de Barcelona
Cerdanyla del Vallès 08193, Catalonia, Spain.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201812793
Angewandte Chemie International Edition
COMMUNICATION
1 "RF" (1.5 eq.)
MgBr2•Et2O (10 mol%)
L4 or L12 (11-14 mol%)
PyBOX-type ligands. Furthermore, we present experimental
evidence in combination with comprehensive density functional
theory (DFT) investigations in support of a radical-based
mechanism.
R
R
CF3
*
O
O
R'
R'
N
R''
N
DCM, -78 °C to rt, 19 h
R''
We commenced our investigations using N-Boc protected 3a as
a model substrate and applied reaction conditions determined in
our previous work (Table 1).[8d] An extensive screening revealed
that the introduction of aromatic substituents at the C4 position
provided higher enantioselectivities in almost all cases when
compared to alkyl substituted ligands (L2-L3). We were pleased
to observe that introduction of an electron-rich methoxy group at
the para position of the phenyl ring (L4) improved both the
enantioselectivity and yield relative to L1, while introduction of
methoxy groups at the meta positions (L5-L6) proved unfavorable.
Substituents at the C5 positions (L10) did not improve
enantiocontrol relative to L1 and likewise, L11 and L12 also
provided low enantioselectivities.
3
4
CF3
CF3
O
CF3
O
CF3
O
O
N
N
N
N
Boc
CO2Me
Cbz
CO2iBu
4a,a 91%, 95% ee 4b,a 90%, 95% ee
4c,a 94%, 98% ee
4d,a 90%, 91% ee
Br
CF3
CF3
CF3
CF3
F3CO
O
N
Cbz
O
O
O
N
Fmoc
N
Cbz
N
CO2CH2Ad
4g,a 95%, 94% ee 4h,a 99%, 91% ee
4e,a 88%, 91% ee 4f,a 84%, 95% ee
CF3
CF3
CF3
CF3
F
Cl
Br
Table 1. Ligand screening for the enantioselective trifluoromethylation of 3a.a
1 "CF3" (1.5 eq.)
O
O
O
O
N
N
N
N
CF3
MgBr2•Et2O (10 mol%)
Cbz
4i,a 97%, 95% ee
CF3
Cbz
Cbz
Cbz
Ligand (11 mol%)
*
O
O
4j,a 92%, 93% ee
4k,a 91%, 97% ee
4l,a 95%, 97% ee
N
Boc
3a
N
Boc
DCM, -78 °C to rt, 19 h
CF3
CF3
CF3
MeO
4a
O
N
Boc
O
O
N
Cbz
O
N
Cbz
N
Cbz
Cl
O
O
O
O
F
N
N
4m,a 96%, 97% ee 4n,a 94%, 97% ee
4o,a 89%, 91% ee 4p,a 96%, 96% ee
N
N
*
N
N
*
R
TMS
R
O
CF3
CF3
CF3
88% ee (69%)
38% ee (75%)
38% ee (73%)
95% ee (91%)
L11: 16% ee (81%)
L1: R = (R)-Ph
L2: R = (R)-iPr
L3: R = (S)-tBu
CF3
O
O
O
O
N
N
N
N
L4: R = (R)-4-(OMe)-C6H4
Cbz
Cbz
Cbz
Boc
O
O
N
L5: R = (R)-3,5-(OMe)2-C6H3 88% ee (85%)
4q,a 93%, 96% ee 4r,a 85%, 92% ee 4s,a 89%, 93% ee
4t,a 81%, 90% ee
N
N
L6: R = (R)-3,4,5-(OMe)3-C6H2
L7: R = (R)-1-napthyl
5% ee (89%)
38% ee (96%)
90% ee (92%)
90% ee (88%)
84% ee (56%)
CN
L8: R = (R)-4-(OMe)-1-napthyl
L9: R = (R)-2-napthyl
L10: R = (S)-Phb
CF3
C3F7
O
C2F5
O
CF3
L12: 55% ee (81%)
O
O
N
N
N
N
Boc
Boc
Cbz
Cbz
[a] Reactions were conducted on a 0.16 mmol scale, 0.08 M in DCM. Yields are
shown in brackets and were determined by 19F NMR spectroscopy using
trifluorotoluene as internal standard. The ee values were determined by chiral
HPLC analysis. See Supporting Information (SI) for the complete list of ligands
tested. [b] C5 positions are di-substituted with phenyl groups.
4u,a 83%, 90% ee 4v,a 93%, 96% ee
4w,a 95%, 96% ee 4x,b 94%, 91% ee
F
O
F
CF3
CF3
O
CF3
CF3
O
O
O
N
Boc
N
Boc
N
N
Boc
4ab,b 87%, 94% ee
With L4 providing the highest level of stereocontrol, we turned to
investigating the scope of the transformation. Our study
commenced by varying the N-protecting group, whereby we
observed the Cbz group afforded the highest enantioselectivity
and reactivity (Scheme 2). We subsequently explored the
influence of electronic perturbations on the aromatic core of the
oxindole, while retaining the Cbz protected nitrogen. Both
enantioinduction and reactivity were maintained upon the
introduction of electron withdrawing groups at the C4 (4g), C5
(4h-k) and C6 (4n) positions, and upon introduction of electron
rich groups (4l-m). Only in the case of the C7 fluorinated 4o did
the Cbz group prove difficult to install, and a slight decrease to
91% ee was observed. Moreover, longer perfluoroalkyl chains
were introduced with excellent enantioselectivity and reactivity
from the corresponding hypervalent iodine reagents (4v-4w).
Following deprotection of 4k [see (SI)], the absolute configuration
of 5 was determined to be R by single crystal X-ray structure
analysis, when the (R,R)-L4 configured ligand was used [see (SI)].
We were pleased to observe that the reaction proved amenable
to various C3 substitutions including progressively larger alkyl
groups (4p-s), as well as alkyne (4t) and nitrile (4u) groups.
Boc
4aa,b 97%, 99% ee
4y,b 97%, 99% ee 4z,b 96%, 97% ee
O
O
S
CF3
CF3
CF3
CF3
O
O
O
O
N
Boc
N
N
N
Boc
Boc
Boc
4ac,b 85%, 96% ee 4ad,b 93%, 95% ee 4ae,b 91%, 97% ee
4af,b 92%, 92% ee
Scheme 2. Reaction scope of the enantioselective trifluoromethylation of
oxindoles. Reactions were conducted on a 0.16 mmol scale, 0.08 M in DCM.
Yields are isolated yields, ee values were determined by chiral HPLC analysis.
[a] Employing L4, 11 mol%. [b] Employing L12, 14 mol%.
Upon introduction of a benzyl group a dramatic decrease to
40% ee was observed, and ligand screening had to be
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10.1002/anie.201812793
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"CF3" (1.5 eq.)
MgBr2•Et2O (10 mol%)
L1 (11 mol%)
recommenced [see (SI)]. We were pleased to discover that the
tetralin containing L12 provided a satisfactory 91% ee in
combination with a Boc protecting group (4x). Moreover, this is to
the best of our knowledge the first report on the application of L12
in asymmetric catalysis. With these modified conditions in hand,
3y-ae containing substituted benzyl groups were successfully
trifluoromethylated in excellent enantioselectivity and yield, as
well as the thienyl methyl containing 3af.
CF3
O
N
Boc
O
N
Boc
3a
DCM, -78 °C to rt, 19 h
4a
F3C
I
O
F3C
I
O
F3C
I
O
F3C
I
O
With the transformation proving versatile, we aimed to determine
the plausibility of our initial hypothesis and probe whether the
reaction was indeed proceeding through a radical pathway in
combination with a chiral nucleophilic species. We commenced
by investigating the role of the magnesium in the transformation
and postulated that it acts as the catalytic center, coordinating
both the ligand and oxindole substrate. Separate stoichiometric
experiments revealed 1H NMR chemical shifts consistent with the
formation of a Mg-L1 complex, and also provided evidence for the
coordination of this complex to the substrate 4a [see (SI) for NMR
spectra and full experimental details).[10a] Additional 19F NMR
experiments demonstrated the potential of magnesium to activate
reagent 1 [see (SI)].[10b] Nevertheless, whether the reaction
proceeds via activation of 1 by the magnesium catalyst, or via
activation through a proton transfer from the oxindole substrate
remained unclear.
We subsequently focused our attention on the mechanism of CF3
transfer. Conducting the asymmetric trifluoromethylation of 3a
using L1 in the presence of an excess of radical scavengers
styrene or 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) led to
complete inhibition of the reaction in both cases (see [SI] for full
details).[11] The radical reaction pathway indicated by these results
is in line with the known propensity of reagents 1 and 2 to
generate CF3 radicals. However, given the notorious difficulty in
controlling the reactivity and selectivity of such radical reactions,
we postulated that additional interactions must be at play. In
particular, we were curious about the role of the reagent scaffold
1
6
7
8
88% ee (68%)
76% ee (78%)
48% ee (74%)
32% ee (72%)
Scheme 3. Enantioselective trifluoromethylation fo 3a by hypervalent iodine
reagents 6-8 using L1. Yields of 4a shown in brackets and determined by 19F
NMR spectroscopy with trifluorotoluene as internal standard. The ee values
were determined by chiral HPLC analysis.
Furthermore, a few key elements were drawn from careful
observation of the geometry of TS 4-OS pro-R (Figure 2a). C-C
distances equal to 3.412 and 3.628 Å between 3b’s aromatic core
and L4’s phenyl group suggests a  stacking interaction, and
could account for the favourable effect of the electron donating p-
OMe substituent on enantioselectivity. More notable however, is
the planar arrangement of the CF3 radical between 1 and the
substrate. This is a stark contrast to the generally observed
pyramidal geometry of the CF3 radical, and its associated high
barrier to inversion of about 25 kcal mol-1.[14] The CF3 transfer
appears to be proceeding via an assisted inversion; at a distance
of 3.28 Å, it appears that the radical maintains a weak interaction
with the iodine, while concomitantly interacting with 3b, located at
a distance of 2.917 Å. This TS thereby corroborates well with our
experimentally observed effect of the reagent scaffold on the level
of enantioinduction (Scheme 3). With this structure resembling an
SN2 transition state and due to its open-shell character, our DFT
calculations supported by experimental evidence suggest that the
reaction occurs via a SET induced SN2-type pathway (Figure 2b).
To demonstrate the utility of the enantioenriched
trifluoromethylated oxindoles as valuable synthetic intermediates,
we subjected three of our products to various conditions (Scheme
4). Pyrroloindoline 9 was accessed following reductive cyclization
of 4u with LiAlH4. Treatment of 4o with a catalytic amount of
MeONa caused a ring opening, thereby providing direct access to
enantioenriched α-trifluoromethylated ester 10. To our surprise,
subjecting 4n to the same reaction conditions led to deprotection
of the Cbz group in an unprecedented fashion.
as
a potential contributing factor to the high level of
enantioinduction. To this end, we synthesized molecularly edited
hypervalent iodine-based reagents 6-8 containing sterically
demanding alkyl substituents and employed these in the
asymmetric trifluoromethylation of 3a (Scheme 3). To our surprise,
a
drastic decrease in enantioinduction was observed
accompanying the larger alkyl substituents.
To acquire a deeper understanding of the factors affecting
enantioinduction and to fully understand the interaction of the Mg-
oxindole complex with the reagent, we turned to computational
methods.[12] Ligand L4 and substrate 3b were selected to perform
the theoretical analysis, and [MgBr2L4] was taken as the initial
catalytic species. Coordination of 3b to the magnesium center
was found to be the rate determining step of the transformation
[see (SI) for full Gibbs relative free energy profile]. Activation of
the reagent was then found to occur through proton transfer from
the substrate, generating the enolate intermediate (Int 3) (Figure
2a). The magnesium catalyst was not found to contribute to the
activation of 1 due to the corresponding minimum not being stable.
At this point, minima corresponding to both closed and open-shell
species (Int 3’ and Int 3’-OS, respectively) were found. The
energetically more favourable path was found to proceed from Int
3’-OS pro-R to the TS 4-OS pro-R. After the highly exergonic
enantiodetermining CF3 transfer step occurs, the catalytic cycle
closes with de-coordination of the product and regeneration of the
[MgBr2L4] species. With these results confirming our initial
hypothesis of a radical pathway, we postulated that the reaction
proceeds via reduction of 1 by the [MgBr2L4] complex, followed
by liberation of the CF3 radical (Figure 2b). Indeed, following the
evolution of the spin as a function of the reaction coordinate of the
CF3 transfer, the spin density was found to reach a maximum prior
to the transition state optimized geometry (TS 4-OS), before
decaying and leading to the trifluoromethylated product (see [SI]
for plot).[13]
R
CF3
R'
O
N
R''
a
b
c
F3C
R
CF3
O
CF3
OMe
NH
O
N
N
H
Cl
H
H
NHBoc
F
11, 98%, 97% ee
9, 90%, 90% ee
10, 71%, 91% ee
Scheme 4. Derivitization of enantioenriched trifluoromethylated oxindoles.
Yields are isolated. [a] Starting material 4u, LiAlH4, THF, reflux, 5 h. [b] Starting
material 4o, MeONa 5 mol%, MeOH, 0 °C, 1 h. [c] Starting material 4n, MeONa
5 mol%, MeOH, 0 °C, 1 h.
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10.1002/anie.201812793
Angewandte Chemie International Edition
COMMUNICATION
3.628
3.412
2.917
3.280
Geometry of TS4-OS pro-R
[b]
O
O
O
I
I
H
I
H
H
F3C
F3C
F3C
O
SN2-type
SET
Br
Br
MgL*
Br
O
O
O
O
CF3 transfer
N
MgL*
N
N
MgL*
O
MeO
MeO
MeO
[a] Gibbs relative free energy profile of the enantioselective trifluoromethylation of 3b using L4 and 1. All energies presented are relative Gibbs
free energies in solution in kcal mol-1. See (SI) for full computational details and for complete catalytic cycle. The relative Gibbs free energy of Int 4
is not to scale. An inset of the TS4-OS pro-R geometry is shown; hydrogens have been omitted for clarity and structural distances are shown in Å.
[b] The mechanism of the SET-induced SN2-type pathway initiated by reduction of the reagent by [oxindole-Mg-L] complex.
Figure 1. Energy profile of the enantioselective trifluoromethylation of oxindoles by DFT analysis and experimental methods. Gibbs energies in solution (SMD
method) calculated at PW6B95-D3 level using the def2-TZVPP basis set.[15] b) The geometry was optimized at B97-D2 level.
In conclusion we have demonstrated the enantioselective
trifluoromethylation of oxindoles using a hypervalent iodine-based
reagent in combination with magnesium Lewis acid catalysis and
chiral PyBOX-type ligands. The reaction is tolerant towards a
broad range of variously substituted oxindole substrates and
provides C3 trifluoromethylated oxindoles in excellent
enantiomeric excess and yield. In addition, the synthetic utility of
the enantioenriched products was demonstrated through further
simple derivitization. Moreover, mechanistic studies via both
experimental and computational methods led us to propose a SET
induced SN2-type mechanism. With this being the first proposal of
such a reaction pathway in the context of trifluoromethylation via
hypervalent iodine-based reagents, we anticipate that this new
understanding of the underlying mechanism of CF3 transfer will
help guide future reaction developments towards asymmetric
perfluoralkylation.
[1]
[2]
a) X. Yang, T. Wu, R. Philipps, F. Toste, Chem. Rev. 2015, 115, 826.
For relevant reviews see; a) J. Charpentier, N. Früh, A. Togni, Chem.
Rev. 2015, 115, 650; b) N. Früh, J. Charpentier, A. Togni, Top. Curr.
Chem. 2015, 373, 167; c) A. Prieto, O. Baudoin, D. Bouyssi, N. Monteiro,
Chem. Commun. 2016, 52, 869; d) N. Shibata, A. Matsnev, D. Cahard,
Beilstein J. Org. Chem. 2010, 6, 1; e) S. Barata-Vallejo, B. Lantaço, A.
Postigo, Chem. Eur. J. 2014, 20, 16806; f) X. Pan, H. Xia, J. Wu, Org.
Chem. Front. 2016, 3, 1163; g) T. Furuya, A. Kamlet, T. Ritter, Nature,
2011, 473, 470; h) T. Liang, C. Neumann, T. Ritter, Angew. Chem. Int.
Ed. 2013, 52, 8214; Angew. Chem. 2013, 125, 8372; i) Li. G, Zhang. C,
Song. C, Ma. Y, Beilstein J. Org. Chem. 2018, 14, 155.
[3]
[4]
a) D. Nagib, M. Scott, D. MacMillan, J. Am. Chem. Soc. 2009, 131, 10875.
a) P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 2006, 12, 2579;
b) I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. Int. Ed. 2007, 46,
754; Angew. Chem. 2007, 119, 768.
[5]
[6]
A. Allen, D. MacMillan, J. Am. Chem. Soc. 2010, 132, 4986.
a) Q. Deng, H. Wadepohl, L. Gade, J. Am. Chem. Soc. 2012, 133, 10769;
Acknowledgements
for an example of a diastereoselective trifluoromethylation using
hypervalent iodine reagents see b) V. Matoušek, A. Togni, V. Bizet, D.
Cahard, Org. Lett. 2011, 13, 5762; for further examples of
diastereoselective radical trifluoromethylations see c) A. T. Herrmann, L.
L. Smith, A. Zakarian, J. Am. Chem. Soc. 2012, 134, 6976; d) K. Iseki, T.
Nagai, Y. Kobayashi, Tetrahedron Lett. 1993, 34, 2169; e) K. Iseki, T.
Nagai, Y. Kobayashi, Tetrahedron: Asymmetry, 1994, 5, 961.
We gratefully acknowledge the financial support from the ETH
Zürich and the Swiss National Science Foundation (SNSF). A.C-
V. acknowledges the financial support from the Holcim
Foundation and the Spanish MEC and the European Social Grant
(Ramon y Cajal contract, RYC-2016-19930).
[7]
For discussions of inner vs outer sphere mechanisms of CF3 transfer
from 1 and 2 and discussions on their trifluoromethyl radical donor
abilities see a) D. Katayev, B. Jelier, A. Togni, Halogenation and
Perfluoralkylation Chemistry Using Hypervalent Halogen Compounds in
PATAI’s Chemistry of Functional Groups, John Wiley & Sons Ltd. 2018
pp1-52; b) O. Sala, H. Lüthi, A. Togni, M. Iannuzzi, J. Hutter, J. Comput.
Keywords: asymmetric catalysis • radical • trifluoromethylation •
chiral ligand • magnesium • hypervalent iodine
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10.1002/anie.201812793
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Entry for the Table of Contents
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R. Calvo, A. Comas-Vives, A. Togni, D.
Katayev.*
Page No. – Page No.
Taming Radical Intermediates for the
Construction of Enantioenriched
Trifluoromethylated Quaternary
Carbon Centers
Taming the CF3 radical: A unique SET-induced SN2-type reaction enables the
construction of enantioenriched trifluoromethylated oxindoles using a hypervalent
iodine based trifluoromethyl transfer reagent. A combination of magnesium Lewis
acid catalysis and PyBOX-type ligands successfully tames the highly reactive CF3
radical to achieve excellent enantioselectivities.
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