Palladium(0)-Catalyzed Enantioselective Intramolecular Arylation of Enantiotopic Secondary C?H Bonds

Article abstract of DOI:10.1002/anie.202014605

The enantioselective functionalization of nonactivated enantiotopic secondary C?H bonds is one of the greatest challenges in transition-metal-catalyzed C?H activation proceeding by an inner-sphere mechanism. Such reactions have remained elusive within the realm of Pd⁰ catalysis. Reported here is the unique reactivity profile of the IBiox ligand family in the Pd⁰-catalyzed intramolecular arylation of such nonactivated secondary C?H bonds. Chiral C₂-symmetric IBiox ligands led to high enantioselectivities for a broad range of valuable indane products containing a tertiary stereocenter, as well as the arylation of secondary C?H bonds adjacent to amides. Depending on the amide substituents and upon control of reaction time, indanes containing labile tertiary stereocenters were also obtained with high enantioselectivities. Analysis of the steric maps of the IBiox ligands indicated that the level of enantioselectivity correlates with the difference between the two most occupied and the two less occupied space quadrants, and provided a blueprint for the design of even more efficient ligands.

Full text of DOI:10.1002/anie.202014605

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Pd0-catalyzed Enantioselective Intramolecular Arylation of
Enantiotopic Secondary C–H Bonds
Authors: Romain Melot, Marco Zuccarello, Diana Cavalli, Nadja Niggli,
Michael Devereux, Thomas Bürgi, and Olivier Baudoin
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014605
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10.1002/anie.202014605
Angewandte Chemie International Edition
RESEARCH ARTICLE
Pd0-catalyzed Enantioselective Intramolecular Arylation of
Enantiotopic Secondary C–H Bonds
Romain Melot,+ Marco Zuccarello,+ Diana Cavalli, Nadja Niggli, Michael Devereux, Thomas Bürgi, and
Olivier Baudoin*
To the memory of Kilian Muñiz.
[*]
Dr. R. Melot, M. Zuccarello, D. Cavalli, N. Niggli, Dr. M. Devereux, Prof. Dr. O. Baudoin
University of Basel, Department of Chemistry
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: olivier.baudoin@unibas.ch
Prof. Dr. T. Bürgi
University of Geneva, Department of Physical Chemistry
30 Quai Ernest-Ansermet, 1211 Geneva 4 (Switzerland)
These authors contributed equally to this work.
[+]
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: The enantioselective functionalization of nonactivated
enantiotopic secondary C–H bonds is one of the greatest challenges
in transition-metal-catalyzed C–H activation proceeding via an inner-
sphere mechanism. Notably, such reactions have remained elusive
within the realm of palladium(0)-catalysis. Here we report that N-
heterocyclic carbene ligands from the IBiox family display a unique
reactivity profile in the Pd0-catalyzed intramolecular arylation of such
nonactivated secondary C–H bonds. Chiral C2-symmetric IBiox
ligands allowed to achieve high enantioselectivities for a broad range
of valuable indane products containig a tertiary stereocenter. Similar
reaction conditions were applicable to the arylation of secondary C–H
bonds adjacent to amides. Depending on the amide substituents and
upon control of reaction time, indanes containing a labile tertiary
stereocenters were also obtained with high enantioselectivities.
Analysis of the steric maps of the IBiox ligands indicated that the level
of enantioselectivity correlates with the difference between the two
most occupied and the two less occupied space quadrants, and
provided a blueprint for the design of even more efficient ligands.
desymmetrization of two enantiotopic alkyl groups, leading to the
generation of a stereogenic center remote to the activated C–H
bond (Scheme 1a).4,5 If the activation site is secondary (R ≠ H),
then the two hydrogen atoms at this site are also diastereotopic
and two adjacent stereocenters are generated.4a–c,5a,b As an
extension, parallel kinetic resolution may occur when the two alkyl
groups are different, thereby leading to the formation of two
enantioenriched regioisomeric products.6 2. Type II: the
desymmetrization of enantiotopic hydrogen atoms on secondary
carbons, creating a stereogenic center at the activated site
(Scheme 1b).7 To date, type I reactions, which are enabled by a
variety of chiral ancillary ligands or chiral anions,4,5 are by far the
most developed. An application in natural product synthesis was
recently reported by our group.8 The prevalence of type I
reactions over type II can be explained by the high density of C–
H bonds (4 for methylenes and 6 for methyl groups) on substrates
bearing two alkyl groups, that strongly favors the C–H activation
step. In contrast, despite the conceptual simplicity and the
potentially greater applicability of type II reactions, only one
example was reported so far, i. e. the synthesis of b-lactams from
a-chloroamides by Cramer and co-workers (Scheme 1b), using
chiral phosphoramidite ligands.7 However, this transformation is
so far limited to activated secondary C–H bonds on benzylic
positions. Nonetheless, it should be noted that in contrast to Pd0
catalysis, the PdII-catalyzed enantioselective intermolecular
functionalization of nonbenzylic enantiotopic secondary C–H
bonds (type II reactions) has been recently reported using a
directing group strategy.9 However, such reactions are less suited
to the construction of scalemic carbo- and heterocycles.
Introduction
Enantioselective organometallic C–H activation is a current
topic of great interest, providing a straightforward access to high
value-added scalemic intermediates from easily accessible
precursors.1 Indeed, the replacement of a hydrogen atom by a
carbon or heteroatom on a C(sp3) center is arguably one of the
simplest ways to construct stereogenic centers. Of course, this is
far from trivial to achieve in practice, due to the lack of reactivity
of C(sp3)–H bonds towards cleavage by transition-metals.2 To
tackle this challenge, a variety of directing group- and oxidative
addition-based strategies have been deployed to render the C–H
activation step intramolecular and hence kinetically more
accessible. In particular, Pd0-catalyzed C(sp3)–H activation
induced by C(sp2)–X oxidative addition has proven a general and
effective method to construct a variety of cyclic systems.3 In the
past decade, enantioselective versions have been developed,4
which can be classified in two main categories: 1. Type I: the
The development of enantioselective reactions of type II
(Scheme 1b) faces a number of obstacles, including the lower
reactivity of secondary C–H bonds compared to primary ones, the
low density of C–H bonds as already noted above, and the
competitive β-H elimination leading to olefins instead of reductive
elimination products.10 Herein, we report that IBiox-type chiral
NHCs show both an exceptional reactivity towards unbiased
secondary C–H bonds and a high enantioselectivity for the
formation of enantioenriched indanes (Scheme 1b, bottom).
1
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10.1002/anie.202014605
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RESEARCH ARTICLE
a) type I: desymmetrization of enantiotopic alkyl groups
CO2Me
CO2Me
Pd source, ligand
CO2Me
H
H
stereogenic center
Pd0/L*
Z
Z
R
CO2Me
R
CsOPiv, Cs2CO3
mesitylene, 160 °C
F
Br
1a
F
R
H
Br
H
2a
R
C–H activation site
second stereogenic center
(if R ≠ H)
• enantiotopic alkyl groups
• diastereotopic H atoms (if R ≠ H)
O
O
N
N
b) type II: desymmetrization of enantiotopic hydrogen atoms
Ad
Ad
N
N
N
N
R
R
H
H
R
R
IAd
Pd0/L*
Y
Y
IBioxMe4: R = Me
IBiox6: R,R = (CH2)5
Z
R
Z
C–H activation site &
stereogenic center
IPr
X
H
R
Ar1
enantiotopic H atoms
single precedent:
R
Ar1
Ar1
N
N
MeO
MeO
O
Ar2
P
Fc
P
O
R
Pd0/L*
O
N
Ar
O
L* = chiral
N
Ar1
phosphoramidite
H
H
Cl
this work:
Ar
e.r. up to 99.5:0.5
L1
L2
L3
H
H
Pd0/L*
Z
R
L* = chiral IBiox
Z
Z
Z
Br
H
R
R ≠ Ar
Scheme 1. Enantioselective Pd0-catalyzed C(sp3)–H activation.
Results and Discussion
We started to explore the reactivity of aryl bromide 1a with
ligands that were previously employed in both enantioselective
and non-enantioselective Pd0-catalyzed C(sp3)–H activation
reactions (Figure 1A).4-7 Compound 1a was chosen both for its
accessibility and because the gem-diesters should favor the
challenging C–H activation step via the Thorpe-Ingold effect.
However, electronically diverse ligands, from the electron-poor
phosphonite L1,5e to increasingly s-donor phosphines PPh3,5d
Binepine L2,5b PCy3,11 PAd2(n-Bu)],5e and N-heterocyclic
carbenes IPr and IAd, furnished only marginal amounts of product
2a even at a high temperature, while proto-debromination and
decarboxylation were observed as main side-reactions.12 In
addition, the chiral NHC L3, which was successfully employed in
a range of desymmetrization reactions (Scheme 1a),4a,5a,6,8 did not
Figure 1. Initial ligand screen. Standard conditions: Pd2dba3 (phosphorus
ligands) or [Pd(p-cinnamyl)Cl]2 (NHCs) (5 mol%), ligand (10 mol%), CsOPiv (1.0
equiv), Cs2CO3 (1.5 equiv), mesitylene, 160 °C, 18 h. Ar1 = 3,5-di-CF3Ph, Ar2
=
3,5-di-t-Bu-4-OMePh, Fc = ferrocene. Conversions were determined by 19F
NMR.
Then, we prepared and tested a number of C2-symmetric
chiral IBiox ligands17 and analyzed the conversion and
enantioselectivity (Figure 2). The results are shown with
optimized conditions employing 5 mol% [Pd(p-allyl)Cl]2 as the Pd
source, 10 mol% ligand, 30 mol% CsOPiv and 1 equiv Cs2CO3 in
PhCF3 at 140 °C.12 The most sterically demanding chiral IBiox
NHCs provided again the highest conversions, and the best
enantioselectivities were achieved with ligands containing tertiary
stereogenic centers equipped with bulky alkyl groups. In particular,
IBioxtBu and the new IBioxAd furnished both high conversions (ca.
90%) and enantiomeric ratios (e.r. 98:2). The very bulky menthyl-
derived ligand IBioxMenth17b provided a high conversion but a
lower enantioselectivity (e.r. 86:14) whereas the aminoindanol-
derived IBioxInd provided a poor conversion. Kündig’s ligand L3
(see Figure 1) was re-tested under these optimized conditions
and little conversion was again observed, hence further
illustrating the unique behavior of IBiox-type ligands for this
challenging transformation. Interestingly, control experiments with
stoichiometric cesium pivalate and cesium carbonate alone did
not furnish any product, which indicates that the C–H activation
step could involve both bases, presumably as a cluster.18
furnish
a reactive catalyst in the current case. The first
breakthrough was achieved when IBioxMe4, designed by Glorius
and co-workers,13 was employed, providing a 30% conversion.
Moreover, the spirocyclic analogue IBiox614 furnished an
improved conversion of 73%, hence establishing IBiox-type NHCs
as uniquely reactive ligands for this transformation. Although the
reasons behind this unique reactivity are not clear yet, it was
previously argued that these ligands possess “flexible steric bulk”
favoring difficult catalytic elementary steps and hemilabile
interactions such as agostic bonds,15 which might be crucial for
the current challenging C–H activation step occurring through the
concerted metalation-deprotonation (CMD) mechanism.11,16
2
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10.1002/anie.202014605
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RESEARCH ARTICLE
CO2Me
[Pd(π-allyl)Cl]2 (5 mol%)
NHC•HOTf (10 mol%)
methyl with ethyl (2k) or isopropyl (2l) esters did not affect the
enantioselectivity, although the latter was isolated with a much
CO2Me
CO2Me
CO2Me
CsOPiv, Cs2CO3
PhCF3, 140 °C
F
Br
1a
reduced yield due to
a
difficult separation from the
F
protodehalogenated product.
2a
Next, we probed the influence of substituents on the aromatic
ring. Electron-withdrawing substituents in meta or para position to
the initial bromine atom were well tolerated (2a, 2m-2q) and gave
O
O
O
O
O
O
N
N
N
N
N
N
R
R
consistently good results.
A more moderate yield but a
comparable enantioselectivity was observed with substrate 1r
bearing an electron-donating 1,3-dioxolane motif. It is noteworthy
that very similar results were obtained for 2a with the well-defined
complex [Pd(IBioxAd)(p-allyl)Cl)],12 thus showing that the in situ
deprotonation and coordination of the imidazolium NHC precursor
to form the active Pd–NHC complex do not have a significant
impact on the reactivity. Finally, the double C–H activation product
2s was obtained in high enantioselectivity (e.r. >20:1) upon
doubling the catalyst loading. The meso diastereoisomer was
probably formed in small quantities but could not be isolated.
IBioxiPr: R = i-Pr
IBioxCy: R = Cya
IBioxtBu: R = t-Bu
IBioxAd: R = Ad
IBioxMenth
IBioxInd
[Pd(π-allyl)Cl]2 (5 mol%)
IBioxAd•HOTf (10 mol%)
Z
Z
Z
Z
R2
R2
CsOPiv, Cs2CO3
PhCF3, 5 Å MS, 140 °C, 18 h
R1
X
R1
1a-q
2a-q
CO2Me
CO2Me
CO2Me
CO2Me
R
Et
2b, R = Me: 74%, e.r. 96:4
2d, R = n-Bu: 61%, e.r. 99:1
2e, R = i-Bu: 61%, e.r. 98:2
2c, X = Br: 72%, e.r. 98:2
X = Cl: 92%, e.r. 98:2
Figure 2. Identification of the optimal chiral ligand. Optimized conditions: [Pd(p-
allyl)Cl]2 (5 mol%), NHC•HOTf (10 mol%), CsOPiv (30 mol%), Cs2CO3 (1.0
equiv), PhCF3, 5 Å MS, 140 °C, 18 h. Conversions were determined by 19F NMR
CO2Me
CO2Me
CO2Me
CO2Me
and ee values by HPLC using
a chiral stationary phase. The absolute
configuration of 2a was ascribed by analogy to 2c, 2t and 2ja. aThe opposite
( )3
TBSO
( )2
enantiomer of this ligand was used, hence resulting in the other enantiomer of
2a.
R
2f, R = F: 91%, e.r. 98:2
2i: 77%, e.r. 98:2
2g, R = CO2Me: 48%, e.r. 98:2
2h, R = OPMP: 59%, e.r. >99:1a (99:1)b
Having established IBioxAd as the ligand of choice and the
optimal reaction conditions, we investigated the scope of the
reaction (Scheme 2). First, different unfunctionalized alkyl chains
underwent selective C–H activation at the proximal methylene
group, hence leading to the corresponding indane products in
good yields and excellent enantioselectivities (2b-2e). Of note,
indane 2c was obtained in good yield and enantioselectivity from
both the aryl bromide and aryl chloride precursors, thereby
establishing the latter as competent substrates. Other products
thereafter were also obtained from chlorides (2o, 2p, 2q).
Moreover, alkyl chains bearing a terminal fluorine atom (2f) and a
range of functional groups such an ester (2g), protected alcohols
(2h-i) and a protected amine (2j) worked well, which opens the
possibility for further synthetic transformations. In some cases,
recrystallization allowed further enantioenrichment (2h, 2j). To
test the robustness of this method, substrate 1j was engaged in a
CO2Me
CO2R
CO2R
CO2Me
F
( )2
Et
PhthN
2j: 82%, e.r. 98:2a (97:3)b
2k, R = Et: 71%, e.r. 98:2
2l, R = i-Pr: 34%, e.r. 98:2
63%,c e.r. >99:1a (95:5)b
R
CO2Me
CO2Me
CO2Me
CO2Me
R
Et
Et
2a, R = F: 86%, e.r. 98:2 (84%, e.r. 98:2)d
2p, R = CO2Me, X = Cl: 89%, e.r. 96:4
2q, R = SO2Me, X = Cl: 64%, e.r. 97:3
2m, R = F: 72%, e.r. 98:2
2n, R = NO2: 61%, e.r. 94:6
2o, R = CF3, X = Cl: 92%, e.r. 99:1
O
O
Et
CO2Me
CO2Me
MeO2C
MeO2C
CO2Me
CO2Me
Et
2r: 51%, e.r. 98:2
Et
2s: 55%, e.r. >99:1e
gram scale reaction. Although
a
slight decrease in
enantioselectivity (e.r. 95:5) was observed for the crude mixture,
product 2j was isolated in 63% yield as a single observable
enantiomer after recrystallization. The gem-diester groups
adjacent to the activated methylene, which allow an easy access
to the reaction substrates by standard alkylation procedures, were
also essential for the reaction to proceed, presumably because
they induce a strong Thorpe-Ingold effect.19 In addition, these
esters could enhance the reactivity of the C–H bonds at the b
position through inductive effects. However, exchanging the
Scheme 2. Reaction scope. aAfter recrystallization. bE.r. of the crude mixture.
cPerformed on a gram scale. dUsing the well-defined complex [Pd(IBioxAd)(p-
allyl)Cl)] (10 mol%). eUsing 10 mol% [Pd(p-allyl)Cl)]2, 20 mol% IBioxAd•HOTf,
60 mol% CsOPiv and 2 equiv Cs2CO3. Reactions were performed from aryl
bromides (X = Br) and on a 0.2 mmol scale unless otherwise stated. E.r. values
were determined by HPLC using
a chiral stationary phase. Absolute
configurations were ascribed by analogy to 2c, 2t and 2ja. PMP = p-
methoxyphenyl, TBS = tert-butyldimethylsilyl, Phth = Phthalimide.
3
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10.1002/anie.202014605
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[Pd(IBioxtBu)(π-allyl)Cl]
(10 mol%)
CsOPiv, Cs2CO3
Motivated by the above results, we turned our interest to the
intramolecular arylation of secondary C–H bonds adjacent to a
carbonyl group. This is a very challenging case since the tertiary
stereocenter of the corresponding indane product is both benzylic
and adjacent to the carbonyl group and is therefore prone to
epimerization. However, we surmised that the current basic
conditions, i. e. the combination of Cs2CO3 and CsOPiv in an
apolar solvent, could be mild enough to escape racemization. The
reaction would again proceed through the CMD mechanism,
rather than an enolate arylation mechanism.20 To test this
hypothesis, we prepared various substrates containing the least
a-acidic amide group and subjected them to catalysis (Table 1).
Gratifyingly, the dimethylamide 1t gave good results under the
standard conditions, with a high yield and enantioselectivity (entry
1). However, in the cases of morpholine (1u) and Weinreb (1v)
amides, a significant drop in enantioselectivity was observed
(entries 2, 4). This problem was solved by reducing the reaction
time to 8 and 4 h, respectively, indicating that racemization is
slower than the reaction and occurs after full conversion (entries
3, 5). The corresponding amide products 2u-v were obtained in
good yields (75-95%) and high enantioselectivities (e.r. 97:3-98:2).
In contrast, little enantioselectivity was observed in the reaction of
the more acidic methyl ester 1w, even at short times (entry 6). In
this case racemization occurred faster than the reaction. Although
currently limited to amides, these results represent, to the best of
our knowledge, the first enantioselective Pd-catalyzed a-arylation
of carbonyl groups to generate epimerizable tertiary
stereocenters without the preformation of a silicon or tin enolate.21
CO2Me
CO2Me
CO2Me
CO2Me
R2
R
PhCF3, 5Å MS, 140 °C
F
F
Br
R1
(parallel experiments)
2x: R1 = H, R2 = CH3
2y: R1 = D, R2 = CD3
1x: R = CH2CH3
1y: R = CD2CD3
Figure 3. Formation kinetics of protiated (2x, filled circles) and deuterated (2y,
empty circles) products.
Furthermore,
in
an
attempt
to
rationalize
the
enantioselectivities achieved with the C2-symmetric chiral IBiox
ligands, the steric maps and buried volumes of their DFT-
optimized [PdL(p-allyl)Cl] complexes were computed using the
SambVca 2.1 application developed by Cavallo and co-workers
(Figure 4).12,22 As shown with the comparison of IBioxMenth with
other ligands, there is no correlation between the buried volumes
(%VBur) and the measured e.r. values. However, the four space
quadrants of the steric map of IBioxMenth are occupied, whereas
ligands bearing tertiary stereogenic centers display two more
occupied and two less occupied quadrants. The mean occupation
difference between the two sets of opposite quadrants on such
C2-symmetric ligands can be quantified as %VBur(QD), deduced
from the %VBur calculated in each quadrant. These values better
correlate to the observed e.r. than the global buried volumes, with
Table 1. Enantioselective a-arylation of amides to generate labile tertiary
stereocenters.
CO2Me
[Pd(π-allyl)Cl]2 (5 mol%)
IBioxAd•HOTf (10 mol%)
CO2Me
CO2Me
CO2Me
O
CsOPiv, Cs2CO3
PhCF3,
Br
5
Å
MS, 140 °C, t (h)
O
R
R
1t-w
2t-w
Entry
Product
2t
R
t (h)
18
18
8
Yield (%)[a]
e.r.
1
2
3
4
5
6
NMe2
94
95:5
68:32
97:3
70:30
98:2
55:45
higher
%VBur(QD)
values
corresponding
to
higher
2u
NC4H8O
NC4H8O
87
enantioselectivities (Figures S2-S3).
2u
95
2v
N(Me)OMe
N(Me)OMe
OMe
18
4
80
2v
75
2w
2
n.d. [b]
[a] Yield of isolated product. [b] Product not isolated. n.d. = not determined. E.r.
values were determined by HPLC using a chiral stationary phase. Absolute
configurations were ascribed by analogy to 2c, 2t and 2ja.
IBioxMenth
%VBur 43.5
%VBur(QD) 1.4
e.r. 6.1
IBioxiPr
%VBur 30.1
%VBur(QD) 14.0
e.r. 5.7
IBioxCy
%VBur 30.1
%VBur(QD) 14.1
e.r. 13.3
To get an insight on the turnover-limiting step of the reaction,
parallel kinetic experiments were conducted from protiated (1x)
and deuterated (1y) isotopomers using the well-defined complex
[Pd(IBioxtBu)(p-allyl)Cl] (Figure 3).12 Despite the presence of an
induction period, presumably corresponding to the generation of
the active Pd0(NHC) complex and preventing the determination of
a precise kH/kD value, a clear primary kinetic isotope effect was
observed, indicating that the C–H activation step is turnover-
limiting (see Figure S1 for a proposed catalytic cycle).
IBioxtBu
%VBur 34.2
%VBur(QD) 22.2
e.r. 49.0
IBioxAd
%VBur 34.5
%VBur(QD) 22.2
e.r. 49.0
IBioxtBuMe4
%VBur 34.7
%VBur(QD) 23.0
e.r. 165.7
4
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10.1002/anie.202014605
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RESEARCH ARTICLE
Figure 4. Steric maps and buried volumes of IBiox ligands (L) in [PdL(p-allyl)Cl]
Of note, it proved challenging to ascribe the absolute
configurations of the indane products generated in this study. In
particular, despite extensive efforts, it was difficult to obtain
crystals of these products or derivatives thereof suitable for Xray
diffraction analysis, and the obtained diffraction data did not show
sufficiently precise Flack parameters for an unambiguous
assignment. Based on a similar experience with indane products,8
we could solve this issue via vibrational circular dichroism
(VCD),27 by comparing calculated and experimental VCD spectra
of three different types of indane products, 2c, 2t and 2ja, which
provided similar results (Figures S4-S18). The configurations of
other indane products were assigned by analogy.
complexes. The Quadrant Difference Buried Volume is defined as: %VBur(QD)
[%VBur(NE quadrant) + %VBur(SW quadrant) ‒ %VBur(NW quadrant) ‒ %VBur(SE quadrant)]/2.
=
Following up on this model and inspired by work in the
bis(oxazoline) and phosphinooxazoline family of ligands,23 we
synthesized a new IBiox ligand containing gem-dimethyl groups
on the oxazoline rings, named IBioxtBuMe4 (Scheme 3). These
substituents should further restrict the rotation of the t-butyl
groups and increase their influence on the coordination sphere.
The calculated %VBur(QD) for this ligand (Figure 4, bottom right)
was indeed found to be higher (23.0) than that of the parent
unsubstituted ligand, IBioxtBu (22.2). This higher value correlated
with an increased enantioselectivity in the reaction of aryl bromide
1a (Scheme 3). Indeed, indane 2a was obtained in 78% yield with
a very high enantioselectivity (e.r. 99.4:0.6). Moreover, nitro-
substituted substrate 1n, which previously gave the lowest e.r.
value (94:6) among all substrates with IBioxAd (see Scheme 2),
led to indane 2n with an improved e.r. of 98.5:1.5 with
IBioxtBuMe4 (Scheme 3).
Conclusion
In conclusion, the enantioselective intramolecular arylation of
enantiotopic secondary C–H bonds via Pd0-catalysis was
developed. The IBiox family of NHC ligands displayed a unique
reactivity among all ligand classes tested for the arylation of
nonactivated C–H bonds. Chiral C2-symmetric IBiox ligands
possessing the greatest difference between the two most
occupied and the two less occupied space quadrants furnished
the highest enantioselectivity. The reaction showed high
enantioselectivities across a broad range of indanes. Moreover,
the arylation of secondary C–H bonds adjacent to amides
provided indanes with a sensitive tertiary stereocenter upon
careful control of the reaction time. The current method should
streamline the access to complex molecules containing a chiral
indane motif.
CO2Me
R1
R2
R1
R2
Pd/IBioxtBuMe4 cat.
std. cond.a
CO2Me
CO2Me
CO2Me
Br
Me
Me
Me
Me
O
O
1a (R1 = H, R2 = F)
1n (R1 = NO2, R2 = H)
2a: 78%, e.r. 99.4:0.6
2n: 72%, e.r. 98.5:1.5
N
N
t-Bu
t-Bu
IBioxtBuMe4
Scheme 3. Performance of a newly designed IBiox ligand. a[Pd(p-allyl)Cl]2 (5
mol%), IBioxtBuMe4•HOTf (10 mol%), CsOPiv (30 mol%), Cs2CO3 (1.0 equiv),
PhCF3, 5 Å MS, 140 °C, 18 h.
Acknowledgements
Chiral indanes are widespread structural motifs found in
natural products and bioactive molecules,24 and hence
enantioselective methods to access these systems are of high
interest.25 To demonstrate the application potential of the current
method, we derivatized indane 2j, which was synthesized in
enantiopure form on a gram scale (see Scheme 2). Cleavage of
the phthalimide group under standard conditions employing
hydrazine was accompanied by lactamization, thus providing the
tricyclic product 2ja in high yield as a single cis diastereoisomer.
In addition, the valuable spirocyclic barbiturate26 2jb was
synthesized upon cyclocondensation with urea and methylation.
This work was financially supported by the Swiss National
Science Foundation (grant # 200021_184608) and the University
of Basel. We thank Dr. D. Häussinger for NMR experiments, S.
Mittelheisser and Dr. M. Pfeffer for MS analyses.
Keywords: asymmetric catalysis • C–H activation • indanes • N-
heterocyclic carbenes • palladium
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6
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RESEARCH ARTICLE
Entry for the Table of Contents
Z
Pd/IBioxAd cat.
Z
Z
Z
R2
R2
CsOPiv, Cs2CO3
R1
X
R1
O
O
• 22 examples, e.r. ≥94:6
• nonactivated 2° C–H bonds
• no racemization with R1 = amide
N
N
Ad
Ad
IBioxAd
Chiral IBiox ligands show an exceptional reactivity and a high enantioselectivity in the Pd0-catalyzed enantioselective arylation of
enantiotopic secondary C–H bonds. This reaction leads to a variety of scalemic indane products containing a tertiary stereocenter
from easily accessible precursors.
7
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