From Prochiral N-Heterocyclic Carbenes to Optically Pure Metal Complexes: New Opportunities in Asymmetric Catalysis

Article abstract of DOI:10.1021/jacs.9b12698

Well-defined optically pure transition metal (TM) complexes bearing C₁- and C₂-symmetric N-heterocyclic carbene (NHC) ligands were prepared from prochiral NHC precursors. As predicted by DFT calculations, our strategy capitalizes on

Full text of DOI:10.1021/jacs.9b12698

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Communication
From Prochiral N-Heterocyclic Carbenes (NHCs) to Optically Pure
Metal Complexes: New Opportunities in Asymmetric Catalysis
Lingyu Kong, Jennifer Morvan, Delphine Pichon, Marion Jean, Muriel Albalat, Thomas Vives,
Sophie Colombel-Rouen, Michel Giorgi, Vincent Dorcet, Thierry Roisnel, Christophe Crévisy,
Didier Nuel, Paola Nava, Stéphane Humbel, Nicolas Vanthuyne, Marc Mauduit, and Hervé Clavier
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12698 • Publication Date (Web): 17 Dec 2019
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From Prochiral N-Heterocyclic Carbenes (NHC) to Optically Pure
Metal Complexes: New Opportunities in Asymmetric Catalysis
Lingyu Kong,§ Jennifer Morvan,† Delphine Pichon,† Marion Jean,§ Muriel Albalat,§ Thomas Vives,† So-
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†
†
†
†
⊥
phie Colombel-Rouen, Michel Giorgi, Vincent Dorcet, Thierry Roisnel, Christophe Crévisy, Didier
Nuel,§ Paola Nava,§ Stéphane Humbel,§ Nicolas Vanthuyne,§ Marc Mauduit*,† and Hervé Clavier*,§
§ Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France
† Univ Rennes, Ecole Nationale Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France
⊥ Aix Marseille Univ, CNRS, Centrale Marseille, FSCM, Marseille, France
Supporting Information Placeholder
Consequently, reducing the cost of chiral technology
remains a longstanding goal for chemists. Moreover, the
chiral relay generates a mismatch effect which might be
detrimental to chiral inductions.4 We report herein the
synthesis of many optically pure (>98% ee) well-defined
C1- and C2-symmetric NHC-TM complexes containing
an axial chirality, which may be readily synthesized
from prochiral NHC precursors (Figure 1,b).5 The chiral
resolution of resulting stable atropisomers is efficiently
achieved by HPLC on a preparative scale.6
ABSTRACT: Well-defined optically pure Transition
Metal-complexes bearing C1- and C2-symmetric N- Het-
erocyclic Carbene (NHC) ligands were prepared from
prochiral NHC precursors. As predicted by DFT calcula-
tions, our strategy capitalizes on the formation of a met-
al-carbene bond which induces an axis of chirality. Con-
figurationally stable atropisomers of various NHC con-
taining TM-complexes were isolated by preparative
HPLC on a chiral stationary phase in good yields and
excellent optical purities (up to 99.5% ee). The carbene
transfer from an optically pure Cu-complex to gold or
palladium center reveals, for the first time, a full stere-
oretentivity, supporting the hypothesis of an associative
mechanism for the transmetalation. The potential of
these new chiral TM-complexes was illustrated in
asymmetric catalysis with up to 98% ee.
(a) The chiral relay strategy for C1- and C2-symmetric chiral NHC precursors
trans
R1
R1
R1
R1
trans
trans
R2
X
X
Ar
N
N
N
N
R2
R2
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Due to their unique topology along with a highly modu-
lar steric environment around the metal, chiral N-
heterocyclic carbenes (NHCs) rapidly emerged as ste-
reo-directing ligands.1 Since the first report of a highly
enantioselective reaction in 2001,2 chiral NHCs were
intensively studied in enantioselective catalysis with
resounding breakthroughs.3 Advantageously, their versa-
tile and easy synthetic access led to the development of a
plethora of chiral NHCs containing various elements of
symmetry. Among them, chiral Transition Metal (TM)
complexes containing C2- or C1-symmetric NHC precur-
sors 1 and 2 proved to be quite efficient, thanks to the
effective chiral relay from the stereogenic substituents of
carbene backbone to the N-aryl ortho-substituent that
induces a trans-relationship (Figure 1,a).4 The resulting
chiral environment close to the metal enabled to reach
remarkable stereo-inductions (up to >99% ee) in numer-
ous asymmetric catalytic transformations.3 Despite these
notable achievements, the technology remains somewhat
costly as optically pure starting materials are required (in
both enantiomers if possible) for the synthesis of NHCs.
N
N
N
N
N
N
O
Ph
S
[M]
[M]
[M]
M= Ru, Cu, Pd,…
O
O
Excellent enantio-inductions in various catalytic transformations
Require optically pure diamines
Dedrimental mismatch effect
(b) New access to chiral TM-complexes from prochiral NHCs (This work) :
Optically pure NHC-TM complexes
free
rotation
X
Me
Me
restricted
rotation
Me
Me
Me
Me
1) Base, [M]
N
N
Ar
N
N
N
N
Ar
Ar
2) Chiral
Resolution
(HPLC)
R
R
[M]
[M]
(Sa)-[M] (>99.5% ee)
R
Prochiral NHC
precursor
(Ra)-[M] (>99.5% ee)
Me
Me
Me
Me
[M] = CuCl
N
N
N
N
R = iPr; Ar = DIPP
Au
Cl
[Pd(Allyl)Cl]2
Pd
AuCl·SMe2
Cl
1st stereoretentive
transmetalation
(Ra)-Au-3 (>99% ee)
(Ra)-Pd-3 (98% ee)
Wide library of optically pure
C1- and C2-symmetric TM-complexes
up to 98% ee in
asymmetric catalysis
Both enantiomers
available
Figure 1. Design of chiral NHC-TM catalysts
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These new C1- and C2-symmetric chiral Cu- and Pd-
Page 2 of 7
and G≠
= 123.1 kJ∙mol-1). In order to assess experi-
(BB)
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complexes display excellent performances in asymmet-
ric catalysis (up to 98% ee). Importantly, and for the first
time, we demonstrate that the carbene transfer from an
optically pure Cu-complex to gold or palladium center
occurred with a full stereoretentivity giving experi-
mental insights to the NHC transmetalation mechanism.
Our study began with the design of prochiral NHC
precursors, i.e. imidazolium salts 3∙Cl (Figure 2). Given
the infinite substitution patterns that could be considered
either on the carbene backbone or on N-aryl substituents,
prior theoretical calculations appeared useful to deter-
mine with accuracy the expected rotational barriers of
the N-aryl bond after coordination to copper(I) chloride
(>93 kJ∙mol-1; t1/2 >1000 s at 25 °C to observe atropiso-
mers, but ideally >110 kJ∙mol-1; t1/2 >12 days at 25 °C).7
With a bulky isopropyl group on ortho position of N-aryl
substituents (Cu-3a), the rotation barrier values are too
mentally these data obtained from theoretical calcula-
tions, Cu-3b complex was synthesized from the prochi-
ral imidazolium salt 3b∙Cl (Scheme 1, see Supporting
Information; SI).9 The deprotonation of the latter by
K2CO3 in the presence of CuCl afforded the desired
complex Cu-3b in 57% yield after silica gel purifica-
tion.10 The HPLC analysis on chiral stationary phase
confirmed clearly that stable atropisomers were formed
in a racemic mixture (Scheme 1).
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Scheme 1. Synthesis of optically pure copper-complexes
Cu-3b from prochiral imidazolium 3b∙Cl
Me
Me
N
N
3b·Cl
K2CO3
Cu
Cl
1st eluted
CuCl
Acetone
(Ra)-(–)-Cu-3b (42.5% yield)a
60 °C, 24 h
>99% eeb
Chiral
(rac)-Cu-3b HPLC
low to obtain stable atropisomers (Figure 2,a; G≠
51.0 kJ∙mol-1 and G≠(BB) = 42.6 kJ∙mol-1).8
=
(Cu)
Me
Me
(57% yield)a
(80 mg
scale)
N
N
(Ra)
(Sa)
X-Ray of (Sa)-(+)-Cu-3b
Cu
Cl
2nd eluted
(Sa)-(+)-Cu-3b (41% yield)a
>99.5% eeb
Time [min.]
b
aIsolated yields. Determined by chiral-stationary phase HPLC analy-
sis.
Thanks to the robustness of copper-NHC complexes
toward silica gel, the chiral resolution of (rac)-Cu-3b by
HPLC on a preparative scale (80 mg, flow-rate = 5
mL.min.-1; see SI) enabled to isolate both atropisomers
(+)-Cu-3b and (–)-Cu-3b in excellent yields and re-
markable >99% optical purities. Moreover, the Electron-
ic Circular Dichroism (ECD), affording chiroptical
properties of the copper complex, showed expected
mirror-image spectra for both enantiomers (see SI, Fig-
ure S4). X-ray diffraction analysis of the second eluted
atropisomers (+)-Cu-3b confirmed its structure but also
enabled to determine its absolute configuration (Sa,
Scheme 1). Furthermore, kinetic of enantiomerization of
(Sa)-(+)-Cu-3b in 1,2-dichloroethane at 83.5 °C gave
access to the experimental rotation barrier value (G≠ =
117.2 kJ∙mol-1) which fits with the predicted lowest
value (G≠
= 116.5 kJ∙mol-1, see Figure 2,b). This
(Cu)
Figure 2. DFT calculations of rotational barriers for NHC-
copper complexes Cu-3a,-3b,-3c. G≠ and G≠
are
validates the use of theoretical calculations as a reliable
tool to design the NHC structures.
(Cu)
(BB)
the values of rotation barriers on backbone (BB) and
copper (Cu) sides, respectively.
We next turned our attention to the synthesis of other
optically pure atropisomeric NHC transition metal com-
plexes. On this concern, the transmetalation represents a
fundamental organometallic reaction as numerous transi-
tion-metal complexes were and are synthesized via this
process.11 Furthermore, the elucidation of its mechanism,
notably when coinage NHC-TM complexes are in-
volved, remains a longstanding goal for organometallic
chemists. The stable optically pure atropisomers of cop-
per-NHC complexes, in which the axis of chirality is
induced by the metal-carbene bond, represents an oppor-
Nevertheless, the backbone substitution with methyl
groups (Cu-3b) leads to a substantial increase of the
rotation barriers values up to expect configurationally
stable enantiomers (Figure 2,b, G≠
= 116.4 kJ∙mol-1
(Cu)
and G≠
= 144.1 kJ∙mol-1). Of note, despite the me-
(BB)
thyl groups on the backbone, a methyl substituent in
ortho position of the aryl group (Cu-3c) could not pre-
vent the aryl rotation (Figure 2,c, G≠(Cu) = 94.4 kJ∙mol-1
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tunity to generate other TM-complexes and to gain valu-
order to shorten the reaction time, the media was heated
up to 80 °C. Satisfactory, similar isolated yields could be
reached with a duration dropping to 2 h. However, a
slight erosion of the optical purity was observed from
95% ee at 40 °C to 81% ee at 80 °C. This behavior could
be relied to a racemization of the starting copper com-
plex occurring at this temperature.14 Indeed, the rotation
barriers of Pd-3b obtained from DFT calculations
1
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4
5
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able insights about the mechanistic route of transmeta-
lation (vide infra).12 In that respect, the optically pure
(Sa)-(+)-Cu-3b complex (>99.5% ee) was treated with
AuCl∙SMe2 complex in dichloromethane at 40 °C over 2
h (Scheme 2, a).13 To our delight, the corresponding gold
complex Au-3b was isolated in quantitative yield. HPLC
analysis confirmed the high enantiopurity of the newly
formed gold complex (>99.5% ee) attesting that no rac-
emization occurred during the transmetalation.
(G≠ = 133.4 kJ∙mol-1 and G≠
= 159.4 kJ∙mol-1)
(Pd)
(BB)
9
and experimentally (G≠ = 131.5 kJ∙mol-1 at 132 °C in
chlorobenzene) are higher than for Cu-3b. (Ra)-(–)-Cu-
3b is quite stable at 40 °C with a half-life time of 22
days, but at higher temperatures, the enantiomerization
occurs rapidly (t1/2 = 3 h at 80 °C). Regarding palladium
and gold counterparts, they show greatly higher stabili-
ties, even at 80 °C, with half-life times up to 15 days and
2 years respectively.14 Considering the aforementioned
experimental results, a hypothetic reaction pathway for
the transmetalation process is depicted in Figure 3. First,
the observed stereoretentivity supports that an associa-
tive pathway could occur for the transmetalation of
coinage NHC-TM complexes (Figure 3, A).
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Scheme 2. Stereoretentive transmetalation affording opti-
cally pure gold and palladium complexes
Me
Me
Me
Me
AuCl·SMe2
N
N
N
N
a)
CH2Cl2, 40 °C, 2 h
>99% yielda
Cu
Cl
Au
Cl
(Sa)-(+)-Cu-3b >99.5% eea
(Sa)-(+)-Au-3b >99.5% eea
X-ray of (Sa)-(+)-Au-3b
Me
Me
Me
Me
N
N
N
N
AuCl·SMe2
b)
CH2Cl2, 40 °C, 2 h
Au
Cl
Cu
Cl
>99% yielda
(Ra)-(–)-Cu-3b >99% eea
(Ra)-(–)-Au-3b >99% eea
Me
Me
Me
Me
[Pd(Allyl)Cl]2
N
N
N
N
c)
CH2Cl2, temp., time
Pd
Cu
Cl
Cl
(Ra)-(–)-Cu-3b
>99% eea
(Ra)-(+)-Pd-3b
@ 20 °C, 24 h : 86% yielda, 98% eea
@ 40 °C, 20 h : 83% yielda, 95% eea
@ 60 °Cb, 5 h : 86% yielda, 92% eea
@ 80 °Cb, 2h : 86% yielda, 81% eea
X-ray of (Ra)-(+)-Pd-3b
aDetermined by chiral-stationary phase HPLC analysis. bReaction
performed in dichloroethane.
Figure 3. Proposed associative (A) vs dissociative (B)
transmetalation pathway.
Moreover, X-ray diffraction analysis allowed us to con-
firm the complex structure and determine its absolute
configuration (Sa, Scheme 2). Similarly, the transmeta-
lation starting from (Ra)-(–)-Cu-3b afforded the corre-
sponding gold enantiomer (Ra)-(–)-Au-3b in quantitative
yield and full optical purity, indicating unambiguously
the stereoretentivity of the transmetalation (Scheme 2,
b). Importantly the rotation barriers of Au-3b were as-
Indeed, a dissociative pathway (Figure 3, B) that would
involve a transient free carbene seems incompatible with
stereoretention as partial to full racemization could hap-
pen due to the free rotation around the N-Aryl bond,15 as
demonstrated by DFT calculations with low values for
rotational barriers on free NHC (G≠
= 60.9
(Carbene)
kJ∙mol-1; t1/2 = 0.8 ms at 40 °C). Second, considering the
steric hindrance within the metal coordination sphere, a
four–center transition state is suspected for the associa-
tive pathway, probably in the less sterically hindered
pocket in opposite side to that of iPr-aryl substituents
(Figure 3, A). DFT calculations related to the formation
of Au-3b from Cu-3b are currently underway to provide
useful information regarding the transmetalation path-
way. Of note, Au-3b and Pd-3b could be also prepared
as heterochiral complexes from the corresponding imid-
azolium and then efficiently separated by chiral HPLC
on preparative scale.
sessed both by DFT calculations (G≠
= 145.5
(Au)
kJ∙mol-1 and G≠
= 158.5 kJ∙mol-1) and experimen-
(BB)
tally (G≠ = 142.4 kJ∙mol-1 at 132 °C in chlorobenzene),
showing their enhancement over the analogous Cu-
complex. The transmetalation process was then success-
fully extended to -allyl palladium chloride (Scheme 2,
c).13 Nevertheless, a prolonged reaction time (24 h) was
required to reach a good 86% isolated yield. The optical
purity of the newly formed Pd-complex (98% ee) was
confirmed by HPLC analysis attesting again that no
racemization occurred during the transmetalation. In
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Page 4 of 7
Scheme 4. Library of optically pure C2-symmetric
NHC-copper and -palladium complexes
Following the aforementioned protocol depicted in
scheme 1, various optically pure C1-symmetric Cu-
complexes were synthesized from NHC precursors 3b,d-
h featuring bulky ortho-substituents (Scheme 3). In all
cases, stable atropisomeric complexes were formed and
each enantiomer was isolated in moderate to excellent
yields and high optical purities. Moreover, the absolute
configuration of each complex was assigned via X-ray
diffraction analysis.16 The methodology was then ex-
tended to synthesis of C2-symmetric NHC complexes
from symmetric NHC precursors 4a-c (Scheme 4). Nev-
ertheless, the formation of meso complexes could com-
plicate the cHPLC resolution in addition to lower the
quantity of expected chiral complexes. Indeed, with
imidazolium 4a∙Cl and 4a∙BF4, meso and heterochiral
complexes Cu-4a and Pd-4a were respectively isolated
with ratios of 1:1.8 and 2.2:1 (Scheme 4). Fortunately,
the preparative cHPLC allowed their efficient separa-
tions and the expected C2-symmetric homochiral Pd-4a
and Cu-4a complexes were isolated in moderate to good
yields (27-34%) and remarkable optical purities
(>99.5% ee), highlighting the versatility of the concept.
Heterochiral salts could easily be separated from the
meso stereoisomers and used to prepare complexes Pd-
4b and Pd-4c, which were isolated free of meso isomers,
and very efficiently resolved on preparative cHPLC. For
instance, both enantiomers of Pd-4b were separated with
91% yield on 580 mg-scale in only 3 hours. DFT calcu-
lations confirmed that an additional ortho-substituent,
even a fluorine, is sufficient to restrict the aryl rotation
along the N-C bond which leads to configurationally
stable NHC precursors (lowest rotation barriers: for
1
2
3
4
5
6
7
8
Me
Me
R1
R1
N
N
R2
R2
Cu-4a (62% yield)
meso/C2 : 1/1.8
Ph
Ph
Ph
Ph
MLn
Ph
Ph
Me
Me
R1
meso complex
Me
Me
R1
Pd-4a (90% yield)
meso/C2 : 2.2/1a
1) K2CO3, MLn
+
N
N
acetone, 60 °C
Pd-4b (79% yield)
only C2
R2
R2
Ph
Ph
X
R1
Ph
N
N
Ph
Pd-4c (72% yield)
only C2
R2
R2
Ph
R1
(X = Cl or BF4)
MLn
Ph
4a·X: R1 = R2 = H
4b·X: R1 = R2 = Me
4c·X: R1 = F, R2 = Me
9
C2-symmetric complexes (rac)
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Chiral HPLC
Me
Me
Me
Me
Ph
Ph
Ph
Ph
R1
R1
N
N
N
N
R2
R2
R2
R2
R1
R1
Ph
Ph
Ph
Ph
MLn
MLn
(Sa,Sa)-complex: (yield)b eec
(Ra,Ra)-complex: (yield)b eec
X-ray of (Sa,Sa)-(–)-Cu-4a
(Sa,Sa)-(–)-Cu-4a (28% yield)d >99.5% ee
(Ra,Ra)-(+)-Cu-4a (27% yield)d >99.5% ee
(Sa,Sa)-(–)-Pd-4a (34% yield) >99.5% ee
(Ra,Ra)-(+)-Pd-4a (34% yield) >99.5% ee
(Sa,Sa)-(–)-Pd-4b (47% yield) >99.5% ee
(Ra,Ra)-(+)-Pd-4b (44% yield) >99.5% ee
(Ra,Ra)-(–)-Pd-4c (45% yield) >99% ee
(Sa,Sa)-(+)-Pd-4c (44% yield) >99% ee
X-ray of (Ra,Ra)-(+)-Pd-4b
b
aDiastereomers were separated by SiO2 chromatography. Isolated yields
c
d
after preparative chiral resolution. Determined by cHPLC analysis. 34%
of meso Cu-4a was also isolated.
X-ray diffraction analysis of homochiral complexes
confirmed their structure and enabled to determine their
related absolute configurations (Scheme 4).16 Having
these new C1- and C2-symmetric NHC TM-complexes in
hands, we next investigated their catalytic performances
in asymmetric catalysis. First, the copper-catalyzed
asymmetric allylic alkylation18 of diethylzinc to allyl
phosphates 8 was explored (Scheme 5,a).
4a∙BF4: G≠ = 69.7 kJ∙mol-1; for 4b∙BF4: G≠
=
(H)
(H)
Scheme 5. Catalytic performances of optically pure
NHC Cu- and Pd-complexes in asymmetric catalysis
155.9 kJ∙mol-1; for 4c∙BF4: G≠(H) = 108.7 kJ∙mol-1).17
Scheme 3. Library of optically pure C1-symmetric
NHC-copper complexes
Me
Me
Me
R3
Me
Cu-3d (70% yield)
Cu-3e (53% yield)
Cu-3f (75% yield)
Cu-3g (55% yield)
Cu-3h (60% yield)
R3
K2CO3, CuCl
N
N
N
N
acetone, 60 °C
R2
R1
R2
Cl
20 h
Cu
R1
Cl
3d·Cl: R1 = t-Bu, R2 = R3 = H
3e·Cl: R1 = CF3, R2 = R3 = ;
3f·Cl: R1 = CHPh2, R2 = R3 = H
3g·Cl: R1 = CHPh2, R2 = R3 = Me
3h·Cl: R1 = CHPh2, R2 = Me, R3 = F
C1-symmetric complexes
(rac)
Chiral HPLC
Me
R3
Me
Me
N
Me
R3
N
N
N
R2 R2
R1
R1
Cu
Cu
Cl
(Ra)-complex: (yield)a eeb
Cl
(Sa)-complex: (yield)a eeb
X-ray of (Sa)-(–)-Cu-3e
(Ra)-(–)-Cu-3d: (45% yield) >99% ee
(Sa)-(+)-Cu-3d: (47% yield) >97% ee
(Ra)-(+)-Cu-3e: (39% yield) >99.5% ee
(Sa)-(–)-Cu-3e: (38% yield) >99.5% ee
(Sa)-(–)-Cu-3f: (32% yield) >98% ee
(Ra)-(+)-Cu-3f: (34% yield) >98% ee
(Sa)-(–)-Cu-3g: (18% yield) >99.5% ee
(Ra)-(+)-Cu-3g: (14% yield) >98% ee
(Ra)-(–)-Cu-3h: (30% yield) >99.5% ee
(Sa)-(+)-Cu-3h: (39% yield) >99.5% ee
X-ray of (Sa)-(+)-Cu-3h
aMolar ratio of  adduct were monitored by 1H NMR spectroscopy
analysis. bIsolated yields after SiO2 chromatography. cDetermined by
chiral-phase GC analysis. dDetermined by chiral-phase HPLC analysis.
b
aIsolated yields after preparative chiral resolution. Determined by chiral-
stationary phase HPLC analysis.
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From the copper-catalysts library19, optically pure C1-
symmetric (Sa)-(+)-Cu-3h and C2-symmetric (Ra,Ra)-(+)-
Cu-4a featuring respectively ortho-F/CHPh2 and ortho-
H/CHPh2 substituents were found to be the best cata-
lysts. The desired -adducts 9a,b were produced with
complete regioselectivity and up to 90% ee, and isolated
in excellent yields.20 Advantageously, by using opposite
enantiomers of Cu-complexes, the -adducts (ent)-9b
could also be produced with similar efficiencies. The
second asymmetric transformation investigated was the
asymmetric intramolecular -arylation21 of amides 10
(Scheme 5,b). Among C2-symmetric Pd-complexes22,
the homochiral (Sa,Sa)-(–)-Pd-4b afforded the highest
enantioselectivity. Resulting adducts (R)-11a,b were
isolated in good to excellent yields and remarkable chi-
ral inductions (95 to 98% ee). Of note, (S)-11a was also
obtained in similar good yield and ee using (Ra,Ra)-(+)-
Pd-4b.
Vincent Dorcet: 0000-0001-9423-995X
1
2
3
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6
7
8
Thierry Roisnel: 0000-0002-6088-4472
Christophe Crévisy: 0000-0001-5145-1600
Didier Nuel: 0000-0002-5055-0583
Paola Nava: 0000-0002-8909-8002
Stéphane Humbel : 0000-0001-5405-1848
Nicolas Vanthuyne: 0000-0003-2598-7940
Marc Mauduit : 0000-0002-7080-9708
Hervé Clavier: 0000-0002-2458-3015
Notes
9
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
We are grateful to the CNRS, Aix-Marseille Université, the
ECM and the ENSCR. L.K. thanks the China Scholarship
Council for a Ph.D. grant. This work was supported by the
Region Bretagne (ARED 2018 “Biometa” N° 601, grant to
J.M.). M.M and D.P. thank the Agence Nationale de la
Recherche (ANR-16-CE07-0019 Hel-NHC). Umicore AG
& Co is acknowledged for a generous gift of complexes.
In summary, a novel access to chiral C1- and C2-
symmetric NHC-TM complexes from readily accessible
prochiral NHC precursors was developed. As predicted
by DFT calculations, the appropriate choice of the N-
aryl ortho-substituents and the NHC backbone substitu-
ents induced an axis of chirality which is constrained by
the carbene-metal coordination. Resulting configura-
tionally stable atropisomers of TM-complexes were
successfully separated by preparative chiral HPLC in
good yields and up to >99.5% ee. For the first time, an
REFERENCES
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Vanthuyne, N.; Williams, J. A. G.; Lescop, C.; Roussel, C.; Autsch-
bach, J.; Crassous, J.; R. Réau, R. Metallahelicenes: Easily Accessible
Helicene Derivatives with Large and Tunable Chiroptical Properties.
Angew. Chem. Int. Ed. 2010, 49, 99–102; (b) Hellou, N.; Jahier-
Diallo, C.; Baslé, O.; Srebro-Hooper, M.; Toupet, L.; Roisnel, T.;
Caytan, E.; Roussel, C.; Vanthuyne, N.; Autschbach, J.; Mauduit, M.;
Crassous, J. Electronic and Chiroptical Properties of Chiral Cycloirid-
iated Complexes Bearing Helicenic NHC Ligands. Chem. Commun.
2016, 52, 9243−9246; (c) Hellou, N.; Srebro-Hooper, M.; Favereau,
L.; Zinna, F.; Caytan, E.; Toupet, L.; Dorcet, V.; Jean, M.; Vanthu-
yne, N.; Williams, J. A. G.; Di Bari, L.; Autschbach, J.; Crassous, J.
Enantiopure Cycloiridiated Complexes Bearing a Pentahelicenic N-
optically
pure
Cu-complex
was
successfully
transmetaled to gold and palladium counterparts in ex-
cellent yields with a full stereoretentivity (>99.5% ee).
Valuable insights to the transmetalation pathway were
therefore obtained, supporting the hypothesis of an asso-
ciative mechanism. The catalytic performances of these
Cu- and Pd-complexes were illustrated in Cu-AAA and
Pd-AIA with up to 98% ee.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
NMR spectra of products, HPLC traces, experimental procedures
and single crystal X-ray diffraction (PDF)
X-ray crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Authors
* E-mail: herve.clavier@univ.amu.fr
* E-mail: marc.mauduit@ensc-rennes.fr
ORCID
Lingyu Kong: 0000-0002-7125-680X
Jennifer Morvan: 0000-0003-1210-7975
Delphine Pichon: 0000-0002-2307-6388
Marion Jean: 0000-0003-0524-8825
Muriel Albalat: 0000-0002-0215-0999
Thomas Vives: 0000-0001-6533-0703
Sophie Colombel-Rouen: 0000-0003-2603-2783
Michel Giorgi: 0000-0002-4367-1985
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Heterocyclic Carbene and Displaying Long-Lived Circularly Polar-
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H.), Hoboken, NJ, John Wiley & Sons, 1983, pp. 1-82; (b) Ibon, A.;
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ny, J.; Ehrlich, S.; Krieg, H. A Consistent and Accurate Ab Initio
Parametrization of Density Functional Dispersion Correction (DFT-
D) for the 94 Elements H-Pu. J. Chem. Phys. 2010, 132, 154104–
154104; (d) Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J.
E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
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B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford
CT, 2013.
(9) Imidazolium salts were prepared in moderate yields by adapting
protocols from the literature, see: (a) Zhang, J.; Fu, J.; Su, X.; Wang,
X.; Song, S.; Shi, M. Synthesis of Various Saturated and Unsaturated
N-Heterocyclic Carbene Precursors by Triflic Anhydride Mediated
Intramolecular Cyclization. Chem. Asian J. 2013, 8, 552–555;
(10) For the synthesis of Cu-NHC complexes, see for instance:
Lazreg, F.; Cazin, C. S. J. NHC-copper complexes and their applica-
tions in N-Heterocyclic Carbenes – Effective Tools for Organometal-
lic Synthesis; Nolan, S. P. Ed.; Wiley-VCH, Mannheim, 2014, 199-
242.
(11) Wendt, O. F. Transmetalation Reactions Involving Group 10
Metals. Curr. Org. Chem. 2007, 11, 1417−1433;
(12) For previous works on transmetalation with copper-
complexes, see: (a) Santoro, O.; Lazreg, F.; Cordes, D. B.; Slawin, A.
M. Z.; Cazin, C. S. J. Homoleptic and Heteroleptic Bis-NHC Cu(I)
(19) See Supporting Information, Table S22.
(20) It is noteworthy that the chiral induction reached here is one of
the best reported so far regarding the class of C1-symmetric monoden-
tate NHCs, see ref. 3.
(21) For a selected example of successful Pd-AIA promoted by chi-
ral NHC ligands, see: Kündig, E. P.; Seidel, T.M.; Jia, Y.-X.; Ber-
nardinelli, G. Bulky Chiral Carbene Ligands and Their Application in
the Palladium‐Catalyzed Asymmetric Intramolecular α‐Arylation of
Amides. Angew. Chem. Int. Ed. 2007, 46, 8484−8487. See also ref. 4.
(22) See Supporting Information, Table S24.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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Complexes
as
Carbene
Transfer
Reagents.
Dalton
Trans. 2016, 45, 4970−4973; (b) Nahra, F.; Gomez-Herrera, A.;
Cazin, C. S. J. Copper(I)–NHC Complexes as NHC Transfer Agents.
Dalton Trans. 2017, 46, 628−631.
(13) For selected recent examples of synthesis of Pd- and Au-NHC
complexes, see: (a) Vanden Broeck, S. M. P.; Nahra, F.; Cazin, C. S.
J. Bulky-yet-flexible Carbene Ligands and Their Use in Palladium
Cross-coupling. Inorganics, 2019, 7, 78; (b) Zinser, C. M.; Nahra, F.;
Falivene, L.; Brill, M.; Cordes, D. B.; Slawin, A. M. Z.; Cavallo, L.;
Cazin, C. S. J.; Nolan, S. P. Synthesis and Reactivity of [Au(NHC)
(Bpin)] Complexes. Chem. Commun. 2019, 55, 6799−6802.
(14) See Supporting Information, Table S1, entry 5.
(15) These values are in line with those determined both by DFT
calculations and experimentally in previous reports, see: (a) Luan, X.;
Mariz, R.; Gatti, M.; Costabile, C.; Poater, A.; Cavallo, L.; Linden,
A.; Dorta, R. Identification and Characterization of a New Family of
Catalytically Highly Active Imidazolin-2-ylidenes. J. Am. Chem. Soc.
2008, 130, 6848−6858; (b) Laidlaw, G.; Wood, S. H.; Kennedy, A.
R.; Nelson, D. J. An N-Heterocyclic Carbene with a Saturated Back-
bone and Spatially-Defined Steric Impact. Z. Anorg. Allg. Chem.
2019, 645, 105−112.
(16) See Supporting Information, Schemes S1 and S2.
(17) See Supporting Information, Scheme S11.
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1
2
free
rotation
Me
Me
restricted
rotation
Me
Me
Me
Me
3
4
5
6
1) Base, [M]
N
N
Ar
N
N
N
N
Ar
Ar
2) Chiral
Resolution
(HPLC)
R
R
X
R
[M]
[M]
(Sa)-[M] (>99.5% ee)
Me
Prochiral NHC
precursor
(Ra)-[M] (>99.5% ee)
Me
Me
Me
7
8
9
[M] = CuCl
N
N
N
N
R = iPr; Ar = DIPP
Au
Cl
Pd
[Pd(Allyl)Cl]2
1st stereoretentive
transmetalation
AuCl·SMe2
Cl
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(Ra)-Au (>99% ee)
(Ra)-Pd (98% ee)
Wide library of optically pure
C1- and C2-symmetric TM-complexes
up to 98% ee in
asymmetric catalysis
Both enantiomers
available
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