Copper-Catalyzed Enantioselective Formation of C?CF3 Centers from β-CF3-Substituted Acrylates and Acrylonitriles

Article abstract of DOI:10.1002/chem.201904192

The catalytic asymmetric synthesis of β-trifluoromethylated esters or nitriles is reported. The use of an in situ formed chiral Cu?H complex allowed the enantioselective reduction of β-trifluoromethylated acrylates or acrylonitriles. The reaction proceeds

Full text of DOI:10.1002/chem.201904192

A Journal of
Accepted Article
Title: Copper-Catalyzed Enantioselective Formation of C-CF3 Centers
from β-CF3-Substituted Acrylates and Acrylonitriles.
Authors: Pauline Poutrel, Maria V Ivanova, Xavier Pannecoucke,
Philippe Jubault, and Thomas Poisson
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To be cited as: Chem. Eur. J. 10.1002/chem.201904192
Link to VoR: http://dx.doi.org/10.1002/chem.201904192
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COMMUNICATION
Copper-Catalyzed Enantioselective Formation of C-CF3 Centers
b
from -CF3-Substituted Acrylates and Acrylonitriles.
Pauline Poutrel, Maria V. Ivanova, Xavier Pannecoucke, Philippe Jubault, and Thomas Poisson*
Abstract:
The
catalytic
asymmetric
synthesis
of
b-
center and would tackle the limitations of the existing methods.
As part of our research program aiming at offering new Cu-
based transformations,[11] we envisioned the catalytic
asymmetric reduction of the readily available b-CF3-substituted
Michael acceptors using an in situ formed chiral CuH species.
Indeed, CuH-based reductions are well recognized to operate
under mild reaction conditions, with a large functional group
tolerance and using inexpensive silane as reductive species.[12]
Hence, such a transformation would offer a powerful manifold to
build up high added value molecules containing C-CF3 chiral
center.
trifluoromethylated esters or nitriles is reported. The use of an in situ
formed chiral Cu-H complex allowed the enantioselective reduction
of b-trifluoromethylated acrylates or acrylonitriles. The reaction
proceeds smoothly affording the corresponding enantioenriched
products in good to excellent yields and outstanding
enantioselectivities (up to 98% ee). The mechanism of the reaction
was studied and a plausible reaction pathway was suggested
accordingly. Finally, the versatility of the products was highlighted
through functional group manipulations.
Nowadays, organofluorine chemistry is attracting a lot of interest
from the organic chemist community. Indeed, the molecules
bearing
a fluorine atom or a fluorinated group have a
Previous work:
tremendous impact in the discovery of bioactive molecules.[1] For
instance, among the 29 small molecules approved by the FDA in
2017, 10 are having at least one fluorine atom on their
backbone.[2] As part of the commonly used fluorinated motifs in
medicinal chemistry, the trifluoromethyl unit (CF3) is probably the
most popular one and is present on the structure of several
blockbusters (eg. Januvia®, Tasigna® and Xtandi®).[3] Although,
the construction of non-stereogenic C-CF3 center has been
widely studied over the last two decades,[4] the catalytic
asymmetric construction of chiral C-CF3 centers remains less
explored. Among the existing methods, the 1,2-addition
reactions on carbonyl derivatives or surrogates are the most
popular methods.[5] In contrast, the formation of stereogenic C-
CF3 centers a- to a carbonyl derivative has been scarcely
studied,[6] while the catalytic asymmetric formation of a remote
C-CF3 stereogenic center remains an unknown transformation.
As the catalytic asymmetric 1,4-addition of the CF3 group
remains an elusive goal,[7] alternative methods were elaborated
to access chiral b-C-CF3 centers. The catalytic asymmetric 1,4-
addition on b-CF3-substituted Michael acceptors found a broad
range of applications for the introduction of various nucleophiles
(Figure 1, eq.1).[8] On the other hand, the chemistry of chiral N-
heterocyclic carbene catalysts offered new entries toward the
formation of these chiral trifluoromethylated molecules from b-
CF3 enals (themselves synthesized from the corresponding
esters) (eq. 2).[9] Finally, the catalytic asymmetric reduction of b-
CF3-substituted acrylic acids has been developed using a Rh-
catalyst under 20 atm of dihydrogen gas with outstanding
enantioselectivities and high yields (eq.3).[10] Complementary to
these methods, we thought that the development of a practical
catalytic enantioselective method using an inexpensive catalyst
along with an excellent functional group tolerance would offer a
straightforward access to molecules containing a chiral C-CF3
Chiral Catalyst
NuH
CF3
O
CF3 O
*
Nu
R1
(eq. 1)
(eq. 2)
R1
R2
H
R2
Chiral NHC
NuH
CF3
O
CF3
O
H
R1
*
R1
CF3
Nu
87-92% ee
Rh(I), L*
O
CF3 O
*
OH
90-99% ee
H
R1
(eq. 3)
R1
H2, 20 atm
OH
This work:
CF3
*
CF3
H
R1
EWG
CuH
EWG
R1
P Inexpensive copper salt
P PMHS as a green reductant
P Good functional group tolerance (halogens, allyl, heteroaryles…)
Figure 1. State of the art and present work.
At the outset of the study we chose (E)-b-CF3 ethyl cinnamate
1a as a model substrate and we evaluated its reduction in the
presence of catalytic amount of a Cu salt, a chiral ligand (L) and
a silane (R3SiH) as the reductive species (Table 1).
After a careful examination of all reaction parameters we found
that 5 mol% of Cu(OAc)2, chiral ligand L1 (Josiphos SL-J007-1)
and tBuONa in the presence of 2 equiv of PMHS and tBuOH in
toluene at – 20 °C gave the expected product 2a in 71% isolated
yield and an excellent 97% ee (Table 1, entry 1). Note that the
reaction performed at RT afforded 2a in lower yield and ee
(entry 2). Chiral ligand L1 prove to be the most efficient from the
Josiphos family (entry 3).[13] During the optimization of the
reaction, we found that chiral biaryl diphosphine ligands were
less efficient as demonstrated with L3, L4 and L5. PMHS proved
to be the most efficient silane for this transformation, as showed
in entry 7. A decrease of the amount of tBuOH from 2 to 1 equiv
had a significant impact on the reaction outcome (entry 8). To
our delight, we observed that the loading of Cu(OAc)2 and L1
could be decrease to 2.5 mol% without an alteration of the
reaction efficiency (entry 9).
[*]
P. Poutrel, Dr. M. V. Ivanova, Prof. Dr. X. Pannecoucke, Prof. Dr. P.
Jubault and Prof. Dr. T. Poisson.
Normandie Univ., INSA Rouen, UNIROUEN, CNRS, COBRA (UMR
6014), 76000 Rouen, France.
E-mail: thomas.poisson@insa-rouen.fr
Prof. Dr. T. Poisson.
Institut Universitaire de France, 1 rue Descartes, 75231 Paris, France.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201904192
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COMMUNICATION
of the method. Then meta-substituted aromatic derivatives were
evaluated and the desired products 2f and 2g were obtained in
87% and 76% yields, respectively. Note that in both cases an
excellent level of enantioselectivity was obtained (95% and
97%). Note that, the ortho-methyl and the mesitylene derivatives
were reluctant in our hands, affording the corresponding
products in very low yield (<10%), probably due to steric
hindrance. Acrylate 1h, bearing a 2-naphtyl substituent gave the
corresponding product 2h in moderate yield and excellent ee
after an extension of the reaction time to 48 h and an increase of
the amount of tBuOH to 4 equiv. An allyl ester was tolerated and
the product 2i was obtained in a moderate 50% NMR yield and
94% ee. Aromatic derivatives bearing a halogen (1j and 1k)
were also converted into the enantioenriched products 2j and 2k
in good yields with high enantioselectivities, at the cost of an
extension of the reaction time to 48 h. Note that the absolute
configuration of 2k was unambiguously determined as S, after
X-Ray crystallographic analysis. Trifluoromethyl group, as well
as a methyl ester substituents were suitable. The reaction with
1l and 1m proved to be highly enantioselective and the products
2l and 2m in 97 and 96% ee, respectively, with very good yields.
Unfortunately, the aliphatic derivative 1n was not reactive under
out standard conditions and no reduced product was observed.
We then thought to extend this transformation to b-CF3-
acrylonitrile derivatives 3 to provide the first general access to
chiral b-CF3-substituted nitrile derivatives 4.[15] To our delight,
after a slight optimization of the reaction conditions, we found
that the replacement of L1 by L6 (Walphos SL-W001-1) and a
slight increase of the reaction temperature from -20 °C to -15 °C
allowed the formation of 4a in high yield (82%) and excellent
enantioselectivity (96%) (Scheme 1B).[12] The scope of this
transformation was then studied. The presence of a methyl,
methoxy or a tertbutyl group at the para-position as well as the
meta-methoxy substituted aromatic ring did not alter the
enantioselectivity of the process (91%, 96% and 98% ee) and
afforded the products 4b, 4c, 4d and 4e in moderate to good
isolated yields. The b-trifluoromethylated derivatives 3f and 3g,
having a halogen (F and Br) at the para or meta position of the
aromatic ring, were readily converted into the corresponding
products 4f and 4g in good yields and excellent ee. Finally, the
reaction was applied to the thiophene derivative 3h, giving 4h in
59% yield and 90% ee. Unfortunately, other b-
trifluoromethylated Michael acceptor as sulfone and nitro
derivatives 5 and 6 were either not reactive or gave poor results
in terms of yield and enantioselectivity (Scheme 1C).[16]
Table 1. Optimization of the catalytic enantioselective reduction of 1a.[a]
Cu(OAc)2 (5 mol%), L1 (5 mol%)
CF3
CF3
tBuONa (5 mol%)
CO2Et
(S)
PMHS (2 equiv), tBuOH (2 equiv)
CO2Et
toluene, - 20 °C
1a
2a
Entry
Variation from standard conditions
Yield (%)[b] ee (%)[c]
1
2
None
71
60
97
89
73
44
72
64
93
88
97
at RT
L2 instead of L1 at RT
L3 instead of L1 at RT
L4 instead of L1 at RT
L5 instead of L1 at RT
(EtO)3SiH instead of PMHS
1 equiv of tBuOH at RT
2.5 mol% of Cu(OAc)2 and L1
48
3
41
4
55
5
36
6
88[d]
51
7
8
85
9
Enantiomer of L1 was used
77
98[e]
10
[a] 1a (0.33 mmol), Cu(OAc)2 (5 mol%), L1 (5 mol%), tBuONa (5 mol%), tBuOH
(2 equiv), PMHS (2 equiv), toluene (0.25 M), - 20 °C, Ar.
Enantiomeric excess determined by HPLC on a chiral stationary phase. 2a
was contaminated with silane. [e] (R)-2a was obtained.
[b]
[c]
Isolated yield.
[d]
R1
R2
O
O
R3
P
MeO
MeO
PPh2
PPh2
PAr2
PAr2
PAr2
PAr2
R1
R1
P
R3
Fe
O
O
Me
R2
R1
L1, R1 = Me, R2 = OMe, R3 = C6H11
L2, R1 = R2 = H, R3 = C6H11
L3
L4, Ar = 3,5-Me2C6H3 L5, Ar = 3,5-Me2C6H3
Finally, we demonstrated that the use of the enantiomer of L1
led to the conversion of 1a into the opposite enantiomer of 2a, in
similar yield and level of enantioselectivity (entry 10). It is worth
to notice that, we did not observe the dehydrodefluorination of
the CF3 group of 2a into the corresponding a,a-difluoroalkene as
observed by Hoveyda during the development of Cu-catalyzed
enantioselective hydroboration[14a] and Zhou in the course of the
development of the NiH catalyzed reduction of b,b-disubstituted
acrylates.[14b]
With these optimization conditions, we then sought to broaden
the scope of the transformation to various b-CF3-cinnamate
derivatives (Scheme 1A). First, we demonstrated that the
reaction with 1a could be performed on a larger scale (3.3 mmol)
without loss of efficiency as the desired product 2a was isolated
in a quantitative yield with a similar ee (97%). Then, para-
methyl, para-tertbutyl and para-methoxy b-CF3 cinnamate
derivatives 1b, 1c and 1d were readily converted into the
corresponding enantioenriched compounds 2b, 2c and 2d in
good yields with excellent enantioselectivities (96% - 97%).
Interestingly, the O-allyl derivative 2e was obtained in a decent
42% yield and 96% ee and no reduction of the olefin part was
observed. This example highlights the functional group tolerance
Then, the mechanism of the reaction was studied (Scheme 1).
First, a linear dependence of the enantiomeric excess of the
product and the enantiomeric excess of the catalyst was
observed (Scheme 1D). This result suggested the involvement
of a monomeric catalytically active species.[17] Finally, the
reaction was carried out with the opposite stereoisomer of the
Michael acceptor, the (Z)-acrylates 1j and 1k and the (Z)-
acrylonitrile 3b (Scheme 1E). Interestingly, when L1 was used
the opposite enantiomer was obtained in all cases, with
somehow lower enantioselectivities (ca. 10% less), as already
described by Buchwald and Lipshutz, independently.[18] These
results demonstrated that the control of the enantioselectivity
seems to be dependent on the geometry of the starting Michael
acceptor. Unexpectedly, when the catalytic enantioselective
reduction of (Z)-2k was carried out with the enantiomer of L1
(Josiphos SL-J007-2), the product having a similar absolute
configuration as the one obtained with L1 (Josiphos SL-J007-1)
was obtained, albeit with a moderate 58% ee. Unfortunately, we
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have not been able, so far, to find any clue to explain this
reversed
enantioselectivity.
Me
F3C
Fe
CF3
MeO
Cu(OAc)2 (5 mol%), L1 or L6 (5 mol%)
tBuONa (5 mol%)
CF3
CF3
Ph2P
P
Me
Me
P
P
CF3
EWG
Fe
Me
R
R
Me
PMHS (2 equiv), tBuOH (2 equiv)
toluene, - 20 or - 15 °C, 24 h
EWG
MeO
CF3
Me
L1 (JosiPhos SL-J007-1)
L6 (Walphos SL-W001-1)
1, EWG = CO2R
3, EWG = CN
2, EWG = CO2R
4, EWG = CN
A. EWG = CO2R with L1 at - 20°C
CF3
CF3
CF3
CF3
CF3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
MeO
2d, 90%, ee = 96%
O
Me
tBu
2a, 85%,[a] ee = 97%
2e, 42%, ee = 96%
2b, 83%, ee = 97%
2c, 80%, ee = 97%
99%,[b] ee = 97%
CF3
CF3
CF3
CF3
CF3 O
CO2Et
Me
CO2Et MeO
CO2Et
CO2Et
O
F
2h, 65%,[c],[d] ee = 93%
2i, 50%,[e],[g] ee = 94%
2g, 76%, ee = 97%
2j, 77%,[d] ee = 97%
2f, 87%, ee = 95%
CF3
CF3
CF3
C. Reluctant substrates
CF3
CO2Et
CO2Et
CO2Et
F3C
MeO2C
Br
CO2Et
Ar
2k, 64%, ee = 97%
2l, 89%,[d] ee = 97%
2m, 79%,[d],[e],[f] ee = 96%
CCDC 1900064
Ar = 2,4,6-Me3C6H2, NR
Ar = 2-Me-C6H4, NR
B. EWG = CN with L6 at - 15 °C
CF3
CF3
CF3
CF3
CF3
Ph
CO2Et
CN
CN
CN
CN
NR
CF3
Me
MeO
tBu
4a, 82%, ee = 96%
4b, 59% (100%)[e]
4c, 83%, ee = 98%
4d, 52% (100%)[e]
Ph
ee = 98%
ee = 96%
SO2Ph
CF3
CF3
CF3
CF3
5, NR
CF3
CN
MeO
CN
Br
CN
CN
NO2
S
F
Ph
6, 23%,[e] ee = 50%
4g, 75%,[e],[i] ee = 91%
4f, 71%,[h] ee = 93%
4e, 63%, ee = 91%
4h, 59%, ee = 90%
F. [D]-labelling
E. Substrate geometry's influence
D. Linear effect
CF3
CF3
standard
conditions
standard
EWG
EWG
*
[D]-2a, 71%
ee = 99%
1a
conditions
R
R
tBuOD was used
EWG
R
Yield (%) ee (%)
(E) or (Z) 1j, 1k and 3k
(S)-2j CO2Et
(S)-2k CO2Et
(R)-4b CN
F
Br
Me
77
64
59
97
97
98
CF3
0% D
H
From (E)-olefin
CO2Et
Hb
Ha
(R)-2j CO2Et
(R)-2k CO2Et
(S)-4b CN
F
Br
Me
66
75
91
83
84
84
Monomeric catalytically
active species
75% D
10% D
From (Z)-olefin
Diastereoselective protonation
of the transient Cu-enolate
with the enantiomer of L1
(R)-2k CO2Et
Br
87
58[a]
Scheme 1. Catalytic asymmetric reduction of b-CF3-acrylates 1 and b-CF3-acrylonitrile derivatives 3. Reaction conditions: 1 or 3 (0.5 mmol), Cu(OAc)2 (5 mol%),
L1 or L6 (5 mol%), tBuONa (5 mol%), tBuOH (2 equiv), PMHS (2 equiv), toluene (0.25 M), - 20 °C, Ar. Isolated yields were reported unless otherwise stated. The
enantiomeric excess (ee) was determined by HPLC on a chiral stationary phase. [a] 2.5 mol% of Cu(OAc)2 and L1 were used. [b] Reaction was performed on a
3.3 mmol scale (ca. 1g). [c] 4 Equiv of tBuOH were used. [d] 48 h reaction time. [e] Determined by 19F NMR analysis on the crude reaction mixture. [f] 7.5 mol% of
Cu(OAc)2 and L1 were used. [g] L6 was used and the reaction was carried out – 15 °C. [h] Reaction was carried at 0 °C. [i] 64 h reaction time.
Finally, the use of tBuOH d-10 with PMHS under the standard
reaction conditions demonstrated that the hydride came from the
silane (PMHS), while the protonation of the transient copper
enolate is performed by the alcohol (Scheme 1F). Moreover, the
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was determined by HPLC on a chiral stationary phase. [a] determined by 19F
NMR.
isotopic distribution on [D]-2a, resulting from this experiment,
revealed that the deuteration reaction on the transient chiral
copper enolate is rather diastereoselective. Note that no D
incorporation at the b-position was detected, probably due to the
low catalyst loading as well as the low reaction temperature.[19]
With these experimental observations, we suggested the
following mechanism, in agreement with the literature (Scheme
2).[12]
First, the ester 2a was readily reduced into the corresponding
alcohol 7 using LiBH4 in good yield without alteration of the
enantiomeric excess. Using LiOH in THF, the ester 2a was
converted into the acid 8 in good yield and no erosion of the
optical purity of the product was detected. We demonstrated that
ester 2a can react with MeMgBr to give access to the tertiary
alcohol 9, in good yield (75%) and a similar ee as 2a. In the
same vein, 2a was smoothly converted into the corresponding
Weinreb amide 10 in 70% without decrease of the enantiomeric
excess. On the other hand, the nitrile 4a was easily reduced into
the corresponding amine and converted into the N-Boc
protected derivative 11 in 95% NMR yield. We transformed 4a
into the amide 12 in 77% yield. Note that in both case no
alteration of the ee was detected.
In conclusion, we developed an efficient and practical catalytic
asymmetric method to build-up chiral C-CF3 centers using
Cu(OAc)2 and L1 or L6 in the presence of PMHS. The reaction
was applied to a,b-unsaturated esters and nitriles. The
corresponding chiral trifluoromethyl compounds were obtained in
good yields (42-90%) and excellent enantioselectivities (up to
98% ee). The mechanism of the reaction was studied and
demonstrated that the selectivity of the reaction was dependent
on the geometry of the starting Michael acceptor. A plausible
mechanism and a transition state to explain the stereochemical
outcome of the reaction with b-CF3-acrylates were suggested.
Cu(OAc)2 + PMHS + L*
1 or 3
L*CuH
A
R3SiOtBu
CF3 OCuL*
CF3
H
H
R1
N
or
CuL*
R1
OR2
B
C
tBuOH
PMHS
L*CuOtBu
D
2 or 4
Scheme 2. Suggested mechanism for the formation of the enantioenriched
products 2 and 4.
First, the Cu(II) precatalyst (Cu(OAc)2) is reduced onto the chiral
CuH complex A,[20] in the presence of PMHS and tBuONa. This
chiral complex reacts with 1 or 3 to provide, after reduction of
the substrate, the chiral Cu-enolate B or nitrile anion C, which is
finally protonated with tBuOH to deliver the product 2 or 4,
respectively, along with the formation of the chiral CuOtBu
complex D. The latter reacts with PMHS to regenerate the chiral
catalyst A (L*CuH).
Acknowledgements
This work was supported by INSA Rouen, Rouen University,
CNRS, EFRD, Labex SynOrg (ANR-11-LABX-0029) and Région
Normandie (Crunch Network). P.P. thanks the Région
Normandie for a doctoral fellowship. M.V.I. thanks the MESR for
a doctoral fellowship. T.P. thanks the Institut Universitaire de
France (IUF) for support. E. Roger is gratefully acknowledge for
the preparation of some starting materials. L. Bailly and E. Petit
are gratefully acknowledged for their help with the HLPC
analysis.
Finally, the versatility of the products was then highlighted
(Scheme 3).
CF3
CF3
a)
b)
CO2H
OH
CF3
7, 81%, ee = 96%
CF3 OH
8, 90%, ee = 97%
CO2Et
Keywords: Trifluoromethyl Group • Copper • Asymmetric
Catalysis • Reduction • Copper Hydride
CF3
O
2a, ee = 97%
c) d)
OMe
N
[1]
a) E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem. 2014, 57,
2832–2842; b) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo,
A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev.
2014, 114, 2432–2506; c) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320–330; d) E. P. Gillis, K. J.
Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem.
2015, 58, 8315–8359; e) N. A. Meanwell, J. Med. Chem. 2018, 61,
5822–5880.
9, 75%, ee = 97%
10, 70%, ee = 97%
CF3
NHBoc
e)
f)
CF3
11, 95%,[a] ee = 99%
CN
[2]
[3]
[4]
L.M. Jarvis, C&EN news, A banner year for new drugs 96 (4) (January
22, 2018) 26.
CF3
CONH2
E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem. 2014, 57, 2832–
2842.
4a, ee = 97%
For selected reviews, see: a) T. Furuya, A. S. Kamlet, T. Ritter, Nature
2011, 473, 470–477; b) X.-F. Wu, H. Neumann, M. Beller, Chem. Asian
J. 2012, 7, 1744–1754; c) T. Liang, C. N. Neumann, T. Ritter, Angew.
Chem. Int. Ed. 2013, 52, 8214–8264; d) X. Liu, C. Xu, M. Wang, Q. Liu,
Chem. Rev. 2015, 115, 683–730; e) P. A. Champagne, J. Desroches,
J.-D. Hamel, M. Vandamme, J.-F. Paquin, Chem. Rev. 2015, 115,
9073–9174; f) J. Charpentier, N. Früh, A. Togni, Chem. Rev. 2015, 115,
650–682; g) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111,
12, 77%, ee = 97%
Scheme 3. Synthetically useful transformations of the products 2a and 4a. a)
LiBH4 (4 equiv), THF, 0 °C to RT. b) LiOH.H2O (3.9 equiv),THF:H2O (4:1), 0 °C
to RT. c) MeMgBr (2.5 equiv), THF, - 78 °C to RT. d) MeO(Me)NH.HCl (1.55
equiv), iPrMgCl (3 equiv), THF, 0 °C to RT. e) i. LiAlH4 (2 equiv), THF, 0 °C to
RT; ii. Boc2O (3 equiv), DMAP (10 mol%), Et3N (3 equiv), DCM, 35 °C. f)
Cu(OAc)2 (2 mol%), Et2NOH (3 equiv), H2O, 35 °C. The enantiomeric excess
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4475–4521; h) T. Besset, T. Poisson, X. Pannecoucke, Chem. Eur. J.
2014, 20, 16830–16845.
25, 3262-3266; b) M. V. Ivanova, A. Bayle, T. Besset, X. Pannecoucke,
T. Poisson, Chem. Eur. J. 2017, 23, 17318–17338; c) M. V. Ivanova, A.
Bayle, T. Besset, X. Pannecoucke, T. Poisson, Angew. Chem. Int. Ed.
2016, 55, 14141–14145; d) M. V. Ivanova, A. Bayle, T. Besset, T.
Poisson, X. Pannecoucke, Angew. Chem. Int. Ed. 2015, 54, 13406–
13410; e) M.-C. Belhomme, A. Bayle, T. Poisson, X. Pannecoucke,
Eur. J. Org. Chem. 2015, 1719–1726; f) M.-C. Belhomme, T. Poisson,
X. Pannecoucke, J. Org. Chem. 2014, 79, 7205–7211; g) M.-C.
Belhomme, T. Poisson, X. Pannecoucke, Org. Lett. 2013, 15, 3428–
3431.
[5]
For reviews, see: a) N. Shibata, S. Mizuta, H. Kawai, Tetrahedron:
Asymmetry 2008, 19, 2633–2644; b) J.-A. Ma, D. Cahard, Chem. Rev.
2008, 108, PR1–PR43; c) X. Yang, T. Wu, R. J. Phipps, F. D. Toste,
Chem. Rev. 2015, 115, 826–870.
[6]
a) D. A. Nagib, M. E. Scott, D. W. C. MacMillan, J. Am. Chem. Soc.
2009, 131, 10875–10877; b) A. E. Allen, D. W. C. MacMillan, J. Am.
Chem. Soc. 2010, 132, 4986–4987; c) T. Furukawa, T. Nishimine, E.
Tokunaga, K. Hasegawa, M. Shiro, N. Shibata, Org. Lett. 2011, 13,
3972–3975; d) Y. Li, F. Liang, Q. Li, Y.-C. Xu, Q.-R. Wang, L. Jiang,
Org. Lett. 2011, 13, 6082–6085; e) Q.-H. Deng, H. Wadepohl, L. H.
Gade, J. Am. Chem. Soc. 2012, 134, 10769–10772; f) Ł. Woźniak, J. J.
Murphy, P. Melchiorre, J. Am. Chem. Soc. 2015, 137, 5678–5681; g) F.
Gelat, A. Patra, X. Pannecoucke, A. T. Biju, T. Poisson, T. Besset, Org.
Lett. 2018, 20, 3897–3901.
[12] a) C. Deutsch, N. Krause, B. H. Lipshutz, Chem. Rev. 2008, 108,
2916–2927; b) S. Rendler, M. Oestreich, Angew. Chem. Int. Ed. 2007,
46, 498–504; c) A. J. Jordan, G. Lalic, J. P. Sadighi, Chem. Rev. 2016,
116, 8318–8372.
[13] See supporting information for details.
[14] a) R. Corberán, N. W. Mszar, A. H. Hoveyda, Angew. Chem. Int. Ed.
2011, 50, 7079–7082; b) S. Guo, P. Yang, J. S. Zhou, Chem. Commun.
2015, 51, 12115–12117; c) During the preparation of this manuscript,
Baker and coworkers described the hydrodefluorination reaction using
CuH, see: N. O. Andrella, N. Xu, B. M. Gabidullin, C. Ehm, R. T. Baker,
J. Am. Chem. Soc. 2019, DOI 10.1021/jacs.9b03101.
[7]
[8]
T. Besset, T. Poisson, X. Pannecoucke, J. Fluorine Chem. 2015, 178,
225–240.
For a review, see: a) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem.
Rev. 2011, 111, 455–529; b) X.-H. He, Y.-L. Ji, C. Peng, B. Han, Adv.
Synth. Catal. 2019, 361, 1923-1957; for selected examples, see: c) W.-
F. Hu, J.-Q. Zhao, Y.-Z. Chen, X.-M. Zhang, X.-Y. Xu, W.-C. Yuan, J.
Org. Chem. 2018, 83, 5771–5777; d) B. Huang, C. Li, H. Wang, C.
Wang, L. Liu, J. Zhang, Org. Lett. 2017, 19, 5102–5105; e) L.-Y. Zhang,
J.-H. Zhou, Y.-H. Xu, T.-P. Loh, Chem. Asian J. 2015, 10, 844–848; f)
P. Kwiatkowski, A. Cholewiak, A. Kasztelan, Org. Lett. 2014, 16, 5930–
5933; g) L. Li, J.-Y. Guo, X.-G. Liu, S. Chen, Y. Wang, B. Tan, X.-Y.
Liu, Org. Lett. 2014, 16, 6032–6035; h) W. Chen, Z. Jing, K. F. Chin, B.
Qiao, Y. Zhao, L. Yan, C.-H. Tan, Z. Jiang, Adv. Synth. Catal. 2014,
356, 1292–1300; i) L. Wen, L. Yin, Q. Shen, L. Lu, ACS Catal. 2013, 3,
502–506; j) X.-Q. Dong, X. Fang, C.-J. Wang, Org. Lett. 2011, 13,
4426–4429; k) G. Blay, I. Fernández, M. C. Muñoz, J. R. Pedro, C. Vila,
Chem. Eur. J. 2010, 16, 9117–9122; l) Y. Huang, E. Tokunaga, S.
Suzuki, M. Shiro, N. Shibata, Org. Lett. 2010, 12, 1136–1138.
a) J. Chen, P. Yuan, L. Wang, Y. Huang, J. Am. Chem. Soc. 2017, 139,
7045–7051; b) P. Yuan, J. Chen, J. Zhao, Y. Huang, Angew. Chem. Int.
Ed. 2018, 57, 8503–8507.
[15] A single example of asymmetric reduction of b-trifluoromethylated
acrylonitrile has been reported to date, see: Z. C. Litman, Y. Wang, H.
Zhao, J. F. Hartwig, Nature 2018, 560, 355–359.
[16] The reduction of b-CF3-nitrostyrene derivatives was already reported
using a thiourea based organocatalyst along with a Hantzch ester, see:
a) E. Massolo, M. Benaglia, M. Orlandi, S. Rossi, G. Celentano, Chem.
Eur. J. 2015, 21, 3589–3595; b) E. Martinelli, A. C. Vicini, M. Mancinelli,
A. Mazzanti, P. Zani, L. Bernardi, M. Fochi, Chem. Commun. 2015, 51,
658–660.
[17] a) T. Satyanarayana, S. Abraham, H. B. Kagan, Angew. Chem. Int. Ed.
2009, 48, 456–494; b) M. Kalek, G. C. Fu, J. Am. Chem. Soc. 2017,
139, 4225–4229.
[18] a) D. H. Appella, Y. Moritani, R. Shintani, E. M. Ferreira, S. L.
Buchwald, J. Am. Chem. Soc. 1999, 121, 9473–9474; b) B. H. Lipshutz,
J. M. Servesko, B. R. Taft, J. Am. Chem. Soc. 2004, 126, 8352–8353.
[19] B. H. Lipshutz, J. M. Servesko, B. R. Taft, J. Am. Chem. Soc. 2004,
126, 8352–8353.
[9]
[10] K. Dong, Y. Li, Z. Wang, K. Ding, Angew. Chem. Int. Ed. 2013, 52,
14191–14195.
[20] D.-W. Lee, J. Yun, Tetrahedron Lett. 2005, 46, 2037–2039.
[11] a) A. Nitelet, D. Thevenet, B. Schiavi, C. Hardouin, J. Fournier, R.
Tamion, X. Pannecoucke, P. Jubault, T. Poisson, Chem. Eur. J. 2019,
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10.1002/chem.201904192
Chemistry - A European Journal
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Pauline Poutrel, Maria V. Ivanova, Xavier
Pannecoucke, Philippe Jubault and
Thomas Poisson*
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Copper-Catalyzed Enantioselective
Formation of C-CF3 Centers from
CF3-Substituted Acrylates and
Acrylonitriles.
b
-
CF3
CF3
CuH
Chiral ligand
PMHS
CF3
CF3
or
or
R1
CO2R2
R1
CN
R1
R1
*
*
CO2R2
CN
P 21 examples
P Inexpensive copper salt
P High yields (up to 90%)
P High ee (93-97%)
P PMHS as a green reductant
P Good functional group tolerance
This article is protected by copyright. All rights reserved.