Efficient Pd0-catalyzed asymmetric activation of primary and secondary C-H bonds enabled by modular binepine ligands and carbonate bases

Article abstract of DOI:10.1021/acscatal.5b00898

New binepine ligands have been synthesized, and characterized and have been shown to induce high diastereo- and enantioselectivity in the intramolecular arylation of primary and secondary C(sp³)-H bonds, giving rise to fused cyclopentanes. The ligands were obtained as bench-stable phosphonium tetrafluoroborate salts that can be directly employed in catalysis. It was shown that a ferrocenyl P-substituent on the ligand allows achievement of high stereoselectivities in combination with potassium carbonate for the arylation of primary C-H bonds under unprecedentedly low temperature (90 °C) and catalyst loading (1-2 mol % Pd/2-3 mol % ligand). Using a base-free precatalyst, carbonate was shown to be the active base and to provide higher stereoselectivities than acetate and pivalate. The more difficult arylation of secondary C-H bonds could also be achieved and required fine-tuning of the ligand structure and the carbonate countercation. This method allowed generation of fused tricyclic products containing three adjacent stereocenters as single diastereoisomers and with moderate to high enantioselectivity. Experimental data indicated that the enantiodetermining C-H activation step involves a monoligated species. DFT (PBE0-D3) calculations were performed with a prototypical binepine ligand to understand the origin of the enantioselectivity. The preference for the major enantiomer was traced to the establishment of a more efficient network of weak attractive interactions between the phosphine ligand and the substrate.

Full text of DOI:10.1021/acscatal.5b00898

Research Article
pubs.acs.org/acscatalysis
Efficient Pd0‑Catalyzed Asymmetric Activation of Primary and
Secondary C−H Bonds Enabled by Modular Binepine Ligands and
Carbonate Bases
Philipp M. Holstein,† Maria Vogler,† Paolo Larini,† Guillaume Pilet,§ Eric Clot,*,‡ and Olivier Baudoin*,†
†Universite
Lyon, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
§Universite
de Lyon, Laboratoire des Multimateriaux et Interfaces, UMR 5615 CNRS - Universite
́
́
Claude Bernard Lyon 1, CNRS UMR 5246 − Institut de Chimie et Biochimie Molec
́
ulaires et Supramolec
Claude Bernard Lyon 1, Campus
́ ̀
Montpellier, case courier 1501, Place Eugene Bataillon, 34095 Montpellier,
́
ulaires, CPE
́
́
de la Doua, Avenue du 11 Novembre 1918, 69622 Villeurbanne, France
‡Institut Charles Gerhardt, CNRS UMR 5253, Universite
France
S
* Supporting Information
ABSTRACT: New binepine ligands have been synthesized, and
characterized and have been shown to induce high diastereo- and
enantioselectivity in the intramolecular arylation of primary and
secondary C(sp3)−H bonds, giving rise to fused cyclopentanes. The
ligands were obtained as bench-stable phosphonium tetrafluoroborate
salts that can be directly employed in catalysis. It was shown that a
ferrocenyl P-substituent on the ligand allows achievement of high
stereoselectivities in combination with potassium carbonate for the
arylation of primary C−H bonds under unprecedentedly low
temperature (90 °C) and catalyst loading (1−2 mol % Pd/2−3 mol
% ligand). Using a base-free precatalyst, carbonate was shown to be
the active base and to provide higher stereoselectivities than acetate and pivalate. The more difficult arylation of secondary C−H
bonds could also be achieved and required fine-tuning of the ligand structure and the carbonate countercation. This method
allowed generation of fused tricyclic products containing three adjacent stereocenters as single diastereoisomers and with
moderate to high enantioselectivity. Experimental data indicated that the enantiodetermining C−H activation step involves a
monoligated species. DFT (PBE0-D3) calculations were performed with a prototypical binepine ligand to understand the origin
of the enantioselectivity. The preference for the major enantiomer was traced to the establishment of a more efficient network of
weak attractive interactions between the phosphine ligand and the substrate.
KEYWORDS: asymmetric catalysis, C−C coupling, C−H activation, chiral phosphines, palladium
(Scheme 1c).6 High diastereoselectivities, albeit moderate
enantioselectivities (e.r. 76:24−90:10), were achieved.
INTRODUCTION
■
Transition-metal catalysis has recently emerged as a powerful
tool to functionalize otherwise unreactive C(sp3)−H bonds.1 In
this context, our group2 as well as others3 have synthesized a
diverse array of fused carbocycles and heterocycles by
intramolecular palladium(0)-catalyzed arylation of unactivated
C(sp3)−H bonds from aryl halides. Recent efforts have been
directed toward the development of asymmetric versions of
Several observations can be made from these literature
precedents. First, different classes of ligands seem to be
required to achieve optimal enantioselectivites for various
classes of substrates (a−c). This indicates a strong substrate
dependency of this asymmetric reaction and suggests the
necessity to develop highly modular ligands to achieve broad
substrate scope. Second, the activity of the developed catalytic
systems clearly shows room for improvement, since little
reaction was observed at temperatures below ∼120 °C.4
However, high enantioselectivites were achieved despite the
employed high temperatures (130−160 °C), showing that the
developed chiral catalysts are robust and suggesting that these
reactions have negligible entropy variations. In this full account,
these reactions. In particular, the groups of Kundig, Kagan, and
̈
Cramer reported the synthesis of (fused) indolines (Scheme
1a) with high enantioselectivity through the activation of
methyl or methylene C−H bonds using chiral N-heterocyclic
carbene (L1) or phosphine (L2−L3) ligands.4 Shortly thereafter,
Cramer and co-workers described the enantioselective arylation
of cyclopropane C−H bonds in related nitrogenated systems
using chiral phosphoramidites (L4, Scheme 1b).5 In parallel, we
communicated our initial findings on the diastereo- and
enantioselective synthesis of fused cyclopentanes via asym-
metric C−H activation employing binepine-type ligand 1a
Received: April 30, 2015
Revised: May 31, 2015
© XXXX American Chemical Society
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a
Scheme 1. State-of-the-Art of Pd0-Catalyzed Intramolecular
Scheme 2. Synthesis of Binepine Ligands in This Study
Asymmetric C(sp3)−H Arylation
a
Route 1: R1PCl2, then BH3·THF; route 2: (i) Et2NPCl2, (ii) HCl,
b
c
(iii) R1Li, then BH3·THF. HBF4·OEt2. t-BuLi, MeI, then HBF4·
OEt2. Thermal ellipsoids at the 50% probability level, most H atoms
d
being omitted for clarity.
we report major improvements of both the enantioselectivity
and the catalyst efficiency in the activation of primary C−H
bonds giving rise to fused cyclopentanes, through the synthesis
of second-generation binepine ligands combined to carbonate
bases. In addition, the scope of the reaction was extended to the
rarer and more challenging activation of methylene C−H
bonds.
were initially isolated, but the DABCO-induced liberation of
the free phosphine was found to be tedious, especially for the
most electron-rich ligands. In addition, these free phosphines
are significantly air-sensitive. To solve these issues, the
corresponding phosphonium tetrafluoroborates 1a−k·HBF4
were directly prepared from the borane adducts upon treatment
with HBF4·OEt2 in CH2Cl2.12 These binepine·HBF4 salts are
convenient, bench-stable precursors of free binepines that can
be directly employed in the base-mediated C−H activation
reaction.13 This synthetic sequence can be performed on a
gram-scale. As a representative example, 2 g of the original
ferrocenyl-binepine14 1i·HBF4 were obtained from dilithiated
compound 6 in 51% overall yield.11 The enantiopurity of this
ligand was >99%, as determined by the HPLC analysis on a
chiral phase of the corresponding borane precursor (R)-1i·BH3
(the X-ray crystal structure of which is shown in Scheme 2)
against its racemic mixture.11 To evaluate the influence of an R2
substituent on the binepine scaffold on the enantioselectivity,
the new methylated ligand (S,S,S)-1l·HBF4 with opposite
configuration at the binaphthyl axis was prepared from the
borane adduct of (S)-1a (Scheme 2).9 Finally, ligand (S)-1m
with a phenyl group as R3 was also synthesized for comparative
purposes according to the literature procedure.10
SYNTHESIS AND PROPERTIES OF NEW BINEPINE
LIGANDS
■
Binepines are versatile chiral monodentate ligands that have
found applications in a variety of asymmetric transformations.7
They are readily available from BINOL and can be readily
modified at the R1, R2, and R3 positions (Scheme 2).
In our initial communication,6 the known t-Bu-binepine 1a8
was found to give the highest diastereo- and enantioselectivity
for the synthesis of substituted indanes (Scheme 1c). An X-ray
structure of the oxidative addition complex Pd(1a)2PhBr
revealed a short contact between the t-Bu group of 1a and
the ortho position of the Pd-bound substrate, thereby
suggesting an important role of the P-substituent. In addition,
the R1 substituent at phosphorus is easy to modify, similar to
9
R2 but unlike R3, which requires a rather long synthetic
sequence.10 On the basis of these considerations, we directed
our efforts at modifying the R1 rather than the R2 and R3
positions.
To obtain precise information on the electronic and steric
properties of the synthesized ligands, the corresponding
31P−77Se coupling constants were measured,15 and the percent
buried volumes16 were calculated from the DFT-optimized
oxidative addition complexes (phosphine)PdPhBr (Table 1; see
also Figures S6−S10).11 The electronic and steric parameters of
P(t-Bu)3, PCy3, and PPh3 are also reported for comparison
The known binepines (R)-1a−d as well as seven new
binepines (R)-1e−k were synthesized from the dilithiated
precursor (R)-6 (obtained from (R)-BINOL in three steps),
either upon reaction with R1PCl2 or via the chlorophosphine
intermediate.11 The phosphine−borane complexes 1a−k·BH3
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Table 1. Electronic and Steric Parameters of Binepine
Ligands
EFFECT OF BINEPINES IN ASYMMETRIC C(SP3)−H
■
ARYLATION
The synthesized binepine·HBF4 salts were evaluated on the
asymmetric C−H arylation of aryl bromide 2a under previously
optimized conditions (Table 2).6 Consistent with previous
% Vbur for Pd−P length
b
at
a
entry
ligand
1JP−Se (Hz)
2.00 Å
2.28 Å
1
2
P(t-Bu)3
PCy3
PPh3
1a
685
42.7
37.3
33.7
35.0
33.9
31.5
31.8
31.9
31.5
33.3
34.2
34.5
39.8
37.3
38.6
34.5
37.0
32.3
28.8
30.0
28.9
26.6
26.9
27.1
26.7
28.3
29.2
29.5
34.6
32.3
33.3
29.9
c
Table 2. Effect of the Structure of Binepines on the
673
a
Asymmetric C(sp3)−H Arylation
c
3
729
4
706
709
728
731
756
729
705
707
726
724
707
718
726
5
1b
6
1c
7
1d
8
1e
9
1f
b
b
c
entry
ligand
GC yield (%)
d.r.
e.r.
10
11
12
13
14
15
16
1g
1
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1f
(R)-1g
(R)-1h
(R)-1i
(R)-1j
(R)-1k
(S)-1l
73
19:1
21:1
24:1
42:1
13:1
19:1
14:1
28:1
55:1
12:1
77:23
77:23
85:15
86:14
73:27
86:14
82:18
85:15
93:7
1h
2
83
1i
3
85 (82)
1j
4
63
1k
5
56
1l
6
79
1m
7
99
a
31P−77Se coupling constant measured from the 31P NMR spectrum of
8
28
the phosphine selenides. Percent buried volumes calculated by DFT11
b
c
9
69 (67)
for (phosphine)PdPhBr complexes. From ref 17.
10
11
12
13
69
3
85:15
95
75
19:1
7:1
60:40
19:81
(S)-1m
(entries 1−3). The percent Vbur values of P(t-Bu)3, PCy3, and
PPh3 obtained with this method are very close ( 1.5%) to
those reported for the corresponding (phosphine)AuCl
complexes.16
a
The absolute configuration of the shown major stereoisomer of 3a
b
was ascribed as described in Scheme 3. Determined by GC/MS using
tetradecane as the internal standard. Yield of the isolated product in
parentheses. Determined by HPLC using a chiral phase.
c
The P−Se coupling constants obtained for binepines 1a−m
indicate that all these ligands are significantly less electron-rich
than P(t-Bu)3 and PCy3.17 Except for binepines with R1 = t-Bu,
Cy, o-Tol, 1-Napth, and o-Biph (entries 4, 5, 10, 11, 14), which
have 1JP−Se values between P(t-Bu)3 and PPh3, and 1e, which is
significantly less basic than PPh3 (entry 8), all synthesized
phosphepines are actually in the same range as PPh3. This is
somewhat surprising because binepines have been often
regarded as chiral analogues of trialkylphosphines, but the
current data indicate that this perception is somewhat
erroneous and that at least aryl-substituted binepines should
be considered as chiral analogues of PPh3.
With respect to steric bulk, it is interesting to note that t-Bu,
Cy, and Ph-substituted binepines 1a−c (entries 4−6) have
significantly smaller buried volumes than P(t-Bu)3, PCy3, and
PPh3 (entries 1−3), respectively. In addition to 1c, aryl-
substituted binepines 1d−i display buried volumes that are
smaller or in the same range as PPh3, (entries 7−12), including
ligands 1g−i. Even ligands 1j−k bearing bulky 9-methylfluor-
enyl18 or o-biphenyl19 groups do not have much larger buried
volumes (entries 13−14). Finally, ligands 1l and 1m containing
Me or Ph groups as R2 or R3 are, as expected, significantly more
bulky than the corresponding unsubstituted ligands 1a and 1c
(entries 15−16). Of note, the buried volume model permits a
rough steric comparison within the binepine family of ligands,
but obviously it cannot be employed to predict the effects
induced by R1 and R3 substituents on the enantioselectivity of
the studied C−H activation reaction because the latter is
affected by remote substrate−ligand interactions that are not
taken into account in the model.
results, t-Bu and Cy binepines 1a−b furnished indane 3a in
good diastereoselectivity and 77:23 e.r. (entries 1−2). Under
the same conditions, we were surprised to find that Ph-
substituted binepine 1c gave a higher d.r. and e.r. (entry 3).
Other P-substituted binepines gave variable results (entries 4−
11). The most interesting stereoselectivities were obtained with
ferrocenylbinepine 1i (entry 9), which furnished 3a in good
yield, high diastereoselectivity (d.r. 55:1) and enantioselectivity
(93:7). Of note, ligand 1l with the opposite (S) axial
configuration and R2 = Me provided the same major
enantiomer of 3a, but with a low e.r. (entry 12). Finally, ligand
(S)-1m with R3 = Ph induced the same sense of
enantioselectivity, but the e.r. was not improved compared
with the parent ligand 1c with R3 = H (entry 13). These results
somewhat validate our initial choice to focus our efforts on the
modification of the phosphorus substituent.
In parallel, we reexamined the effect of the basic system in
this reaction. Indeed, our initial optimized conditions involved
Pd(OAc)2 as the palladium source and K2CO3 as the base
(Table 2). However, in a polar solvent such as DMSO, both
acetate and carbonate are able to act as the active base in the
C−H activation step that proceeds through the concerted
metalation−deprotonation mechanism.20,21 To lift this ambi-
guity, different bases were tested in combination with Pd2dba3
as the Pd source and 1c as the chiral ligand (Table 3). In the
presence of KOAc as the sole base, a marked decrease of both
the d.r. and the e.r. was observed (entry 2) compared with the
Pd(OAc)2/K2CO3 combination (entry 1). In contrast, with
K2CO3 alone, slightly higher d.r. and e.r. were observed
compared with the Pd(OAc)2/K2CO3 mixture (entry 3). These
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on the stereoselectivity in the current reaction. Finally, the well-
defined Buchwald-Tudge-type22 precatalyst 7, which was
readily synthesized from (R)-1c·HBF4 and which should
generate the corresponding monoligated Pd0−L complex
under the current basic reaction conditions, gave results similar
to the Pd2dba3/1c in situ combination (entry 10).
This major effect of the base being clarified, the reaction
conditions were refined (Table 4). Gratifyingly, the combina-
Table 4. Final Optimization of the Asymmetric C(sp3)−H
Arylation
Table 3. Effect of the Base on the Asymmetric C(sp3)−H
Arylation
mol %
Pd2(dba)3
mol %
1i
temp
(°C)
a
b
c
entry
yield (%)
d.r.
e.r.
1
2
3
4
5
6
2.5
2.5
2.5
1
10
7.5
7.5
3
140
90
75
87
48
96
65:1
≥99:1
≥99:1
89:1
94:6
96:4
95:5
96:4
95:5
a
b
c
entry
Pd source
base
d.r.
e.r.
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
7
K2CO3
KOAc
24:1
9:1
85:15
75:25
87:13
80:20
87:13
89:11
84:16
72:28
58:42
90:10
80
90
K2CO3
Na2CO3
Rb2CO3
Cs2CO3
K3PO4
KOPiv
KOPiv
K2CO3
34:1
23:1
42:1
51:1
36:1
6:1
0.5
d
1.5
d
90
88
80:1
e
90
b
10 (67)
18:1
a
Yield of the isolated product. Determined by GC/MS using
tetradecane as the internal standard. Determined by HPLC using a
chiral phase. Reaction performed with Pd(PPh3)4 (5 mol %) as the
catalyst. Reaction performed at 140 °C.
c
d
e
d
9
4:1
e
10
47:1
tion of binepine 1i with Pd2dba3 and K2CO3 under acetate-free
conditions allowed achievement of high diastereo- and
enantioselectivity (entry 1). Remarkably, the temperature
could be reduced to 90 °C with a slight increase in
stereoselectivity (entry 2), but the reactivity dropped below
this temperature (entry 3). Moreover, we were able to reduce
the catalyst loading to 1 mol % Pd and 1.5 mol % ligand
(entries 4−5), while retaining similar levels of stereoselectivity.
This level of efficiency and stereoselectivity at such a mild
temperature is unprecedented in this type of reactions.4−6 In
addition, a control experiment with Pd(PPh3)4 as catalyst
showed the superior activity of the binepine-based catalyst that
promotes the reaction at 90 °C, whereas the former is active
only at higher temperatures (entry 6).
a
20 mol % ligand were used with Pd(OAc)2 and 10 mol % with
b
Pd2dba3. Determined by GC/MS using tetradecane as the internal
standard. Determined by HPLC using a chiral phase. With
mesitylene instead of DMSO as the solvent. With precatalyst 7
instead of Pd2dba3/(R)-1c·HBF4 and 100 °C instead of 140 °C.
c
d
e
observations show not only that carbonate is the active base in
this reaction performed in a polar solvent such as DMSO, but
also that carbonate furnishes higher stereoselectivities than
acetate. Thus, the catalytic amount of acetate introduced when
Pd(OAc)2 is employed as the Pd source can be only
detrimental to the stereoselectivity. Another clear advantage
of using Pd2dba3 instead of Pd(OAc)2 is the fact that the latter
requires sacrificing 1 equiv of precious chiral ligand to generate
the active Pd0 catalyst.
Other carbonate bases were then tested in combination with
Pd2dba3 (entries 4−6). The highest stereoselectivities were
obtained with Cs2CO3 (entry 6). However, the difference
between Cs2CO3 and K2CO3 was less pronounced under the
final optimized conditions (vide infra), and thus, the cheaper
K2CO3 was chosen for scope studies. Interestingly, potassium
phosphate was also found to be a competent base for this
reaction (entry 7). Pivalate, which is widely employed as the
active base in C(sp3)−H activation reactions,2−4 behaved
similarly to acetate and was less selective than carbonate (entry
8). This effect was even more pronounced when mesitylene was
used instead of DMSO as the solvent (entry 9), thereby
showing the dramatic impact of the base/solvent combination
SCOPE EXTENSION
■
The scope of the methyl activation/intramolecular arylation
was next examined employing 1 mol % Pd2dba3 and 3 mol %
ligand (Scheme 3). Good yields, diastereo-, and enantiosectiv-
ities were achieved for indanes 3a−e bearing various types of
substituents on the benzene ring and for fused thiophene−
cyclopentane 3f, with an e.r. in the range 92:8−96:4 and
excellent diastereoselectivities. Importantly, the reaction of 2a
was performed with equal efficiency and selectivity on gram
scale, thereby demonstrating the robustness of this method. For
compounds 3c, 3d, and 3f, the reaction had to be conducted at
140 °C to reach full conversion. The reaction of bromopyridine
2g was found to be less selective with 1i as the ligand, but
gratifyingly, the use of 9-methylfluorenyl analogue 1j (see
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other derivatization methods for the determination of absolute
configuration.23 The same configuration was ascribed to
analogues 3b−g based on this assignment.24
Next, we turned our attention to the activation of secondary
C−H bonds by examining the reaction of substrates 4a−e
bearing enantiotopic cycloalkanes (Scheme 4). This is a
Scheme 3. Scope of the Asymmetric Arylation of Primary
C−H Bonds
a
a
Scheme 4. Asymmetric Arylation of Secondary C−H Bonds
a
a
Yields refer to the isolated product; d.r. determined by GC/MS using
Yields refer to the isolated product; d.r. determined by GC/MS using
tetradecane as the internal standard; e.r. determined by HPLC using a
chiral phase. The corresponding racemic products were obtained using
P(Cyp)3 as the ligand.11 The absolute configurations of the shown
tetradecane as the internal standard; e.r. determined by HPLC using a
chiral phase. The corresponding racemic products were obtained using
Pd(PPh3)4 as catalyst.11 The absolute configuration of the shown
major enantiomers was ascribed by analogy with that of 3a, and their
relative configuration was deduced from the shown X-ray structures.
Relative structure of the enantioenriched (5a) or racemic (5e)
compound, with thermal ellipsoids at the 50% probability level, most
H atoms being omitted for clarity.
b
major stereoisomers were deduced from that of 3a. Reaction
c
performed on 1.9 g of substrate 2a. Reaction performed at 140 °C.
d
e
b
Reaction performed at 120 °C. Reaction performed with 1j·HBF4
f
instead of 1i·HBF4. Thermal ellipsoids at the 50% probability level,
most H atoms being omitted for clarity.
Scheme 2) allowed restoration of high levels of stereoselectivity
for the formation of 3g at 120 °C. Interestingly, the reaction
turned out to be very sensitive to the nature of the R1
substituent at the benzylic position. For instance, the reaction
of compound 2h bearing a CH2N(Ts)Me group instead of CN
gave rise to olefin 3h,2a,b not to the corresponding indane
product. This olefin was obtained in low but significant (e.r.
63:37) enantioselectivity. This promising result opens the way
for the enantioselective synthesis of olefins adjacent to a
quaternary carbon after further optimization.
Of note, the R,R absolute configuration of 3a was deduced
from the X-ray diffraction analysis of its derivative 3i, obtained
through reduction of the nitrile group and amide formation
with ferrocenecarboxylic acid. The latter introduces a ferrocene
moiety in the structure that both improves the crystallization
properties and allows determination of the absolute config-
uration with high precision (Flack parameter x = 0.006(12)),
and we believe that this system represents a useful alternative to
somewhat more challenging case because secondary C−H
bonds are supposed to be less reactive than primary ones with
regard to the base-mediated C−H activation mechanism.2d
Indeed, only a few cases of noncyclopropane, nonbenzylic
methylene C−H activation under palladium(0) catalysis have
been reported in the literature.2a,b,3d,4a,c,d,f,25 In contrast to
methyl activation, ferrocenyl ligand 1i furnished disappointing
results in the reaction of dicyclohexyl substrate 4a (46% yield,
e.r. 88:12). Fortunately, we found that o-tolyl-substituted ligand
1g (see Scheme 2) restored both reactivity (80% yield) and
high enantioselectivity (e.r. 98:2) at 90 °C. Remarkably,
although the corresponding fused tricyclic product 5a now
contains three contiguous stereocenters, only one diaster-
eoisomer was observed in this case, as well as for related
products 5b−e. The relative configuration of 5a was ascribed by
X-ray crystallographic analysis (Scheme 4), and the shown
absolute configuration was ascribed in analogy to that of 3a.
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Compounds 4b−c bearing heterocyclic six-membered rings
provided similarly satisfying results with binepine 1g as the
ligand.
the corresponding in situ Pd/ligand mixture (Table 3, entry
10).
On the basis of these elements, it seems reasonable to
propose that the enantiodetermining C−H activation step
involves a monoligated Pd species in the present case, as well.
Only a handful of studies have dealt with catalytic
enantioselective C(sp3)−H activation processes from a
computational perspective.4f,g In previous studies, we have
shown that the geometry imposed by the C−Br oxidative
addition of the substrate to the palladium center induces a
preferential geometry for the coordination of the base.2c,d,20
The newly formed Pd−C(sp2) bond is trans to the phosphine
ligand and the base is coordinated trans to a C(sp3)−H agostic
interaction (Scheme 5). In the transition state of the C−H
The reactions of the higher (4d) and lower (4e) homologues
of 4a were found to be more challenging. Indeed, the reaction
of 4d was sluggish with binepine 1g (incomplete conversion,
20% yield), even at a higher temperature (140 °C). The use of
ferrocenylbinepine 1i restored reactivity (76% yield), but the
enantioselectivity was lower (e.r. = 80:20) than with 1g (e.r. =
92:8). In the case of dicyclopentyl substrate 4e, all bulky
ligands, such as 1g and 1i failed to give useful conversions, and
only the smaller Ph-substituted binepine 1c gave significant,
albeit moderate, results (e.r. = 78:22). These and previous
observations point to the high sensitivity of this reaction to
substrate modifications close to the activated C−H bond.
Fortunately, the high modularity of binepine ligands allowed us
to achieve high stereoselectivity in most cases by simply testing
a small number of analogues. The relative configuration of 5e
was found to be identical to that of 5a by X-ray diffraction
analysis (Scheme 4). Interestingly, 5e displays the unusual,
contrathermodynamic trans-5,5 ring junction.26
Scheme 5. Computed Base-Assisted C−H Activation
MECHANISTIC CONSIDERATIONS
■
All previous theoretical studies on Pd0-catalyzed C(sp3)−H
activation reactions were performed considering a monoligated
(PdL) species in the C−H activation step;2c,d,i,3c,e,4f,g,20,27
however, we were puzzled by the reported reactivity and
enantioselectivity of the bidentate phosphines Me-Duphos4b
and Josiphos6 in similar transformations, raising the possibility
of an alternative C−H activation mode from a bis-ligated
(PdL2) species, in line with a previous study on Pd0-catalyzed
C(sp2)−H activation.28,29 In addition, binepines are not
particularly bulky, as shown above with their calculated buried
volumes, and they commonly adopt ML2 coordination modes
in other catalytic reactions.7 To get more insight on the nature
of the active species formed with binepines in the current
reaction, we studied the linearity of the ee of indane 3a vs the
ee of ferrocenylbinepine 1i (Figure 1). A linear correlation was
found, which is indicative of the monoligated nature of the Pd
complex involved in the enantiodetermining C−H activation
step.30,31 This would also be consistent with the experiment
performed with precatalyst 7, which showed results similar to
activation, the O−Pd−C(sp3) angle is reduced to ∼120° for a
noncoordinated oxygen atom to abstract the hydrogen atom in
an AMLA(6) process,32 thereby putting the carbonate ligand
above the initial coordination plane.
For an achiral phosphine such as PPh3, the two enantiomeric
transition states in Scheme 6 have the same energy, and racemic
Scheme 6. Enantiomeric Transition States for C−H
Activation
mixtures are obtained for any distribution of the R1-R4
substituents. However, the energy of the six-membered
palladacycle that is formed in the transition state is strongly
influenced by the actual nature of the R1-R4 substituents. This
leads to the selective formation of one diastereoisomer, as
shown previously (Table 4, entry 6).2b,d The indane
diastereoisomer with the Me group cis to the CN group is
favored over the diastereoisomer with Me cis to i-Pr by a ratio
of 18:1, roughly identical to the d.r. observed when binepine
(R)-1a is used as the phosphine ligand (Table 2, entry 1).
With a chiral phosphine, the two transition states in Scheme
6 are diastereoisomeric, and therefore, they do not have the
same energy. This induces selective formation of one
enantiomer; however, the energy penalty imposed on one
enantiomer by the chiral phosphine is expected to be lower
than the penalty imposed by the relative position of the various
substituents on the six-membered palladacycle. With four
different substituents, R1−R4, a total of eight different transition
states should be considered for the C−H activation catalyzed
by Pd[(R)-1a]. Indeed, the respective positions of the four
substituents generate four different palladacycles, and the
carbonate base can promote the C−H activation either from
Figure 1. Linearity of the enantiomeric excess of product 3a vs that of
ligand 1i. Experiments were conducted under conditions described in
Scheme 3.11
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Research Article
the top of the forming palladacycle (as shown in Scheme 6) or
from the bottom.
Geometry optimizations have been carried out in the gas
phase for the eight possible transition states in the case of
binepine (R)-1a,33 using the hybrid PBE0 functional34 and the
D3(bj) correction as implemented by Grimme.35 The influence
of the solvent (DMSO) was taken into consideration through
single-point calculations on the gas-phase optimized geometry
within the SMD model.36 The various transition state structures
are labeled according to the configuration of the corresponding
indane product (first R or S label for the carbon substituted by
CN) and according to the geometry of the attack by the base
(up or down, the representation in Scheme 5 defining up).
Table 5 collects the relative Gibbs free energies of the various
Table 5. Relative Gibbs Free Energies (kcal mol−1, 413 K) of
the Various Transition States for C−H Activation
ΔΔG‡
ΔΔG‡
R-R-up
0.0
1.0
3.8
7.5
R-R-down
S-S-up
16.0
14.3
9.1
S-S-down
R-S-up
R-S-down
S-R-up
S-R-down
11.0
transition states computed in DMSO at 413 K (the geometries
of the various TS are available in a single .xyz file in the
Supporting Information).11
From Table 5, there appear to be two groups of values for
the relative energies of the transition states. The highest values
are all associated with transition state structures in which the
cyano group is in an axial position in the forming six-membered
palladacycle, facing the carbonate base. In these structures, the
isopropyl group experiences a gauche interaction with the
vicinal methyl group, as well as allylic strain with the aromatic
ring, thus leading to significant steric repulsion.
Figure 2. Optimized geometry of the two lowest transition state
structures, R-R-up and S-S-down, showing selected short contacts.
carbonate. These short contacts are to be compared with the
O···H bond distance of 1.415 Å between the oxygen atom and
the abstracted hydrogen atom. In this orientation of the
phosphine, one naphthyl group is located below the substrate,
and the shortest C···C contact between this naphthyl group and
the aromatic ring of the substrate is 3.509 Å. In addition, the
nonactivated methyl group of the isopropyl group undergoing
C−H activation presents a C−H···π interaction with the
naphthyl group, as illustrated by the distance of 2.890 Å
between the proximal hydrogen atom and the centroid of one
aromatic ring of the naphthyl (Figure 2). All these contacts are
associated with weakly stabilizing nonbonding interactions, as
illustrated by the noncovalent interaction (NCI) maps between
the phosphine ligand and the base + substrate ensemble shown
in Figure 3.11
In S-S-down, the situation is significantly different. The
binepine ligand does not display the same kind of stabilizing
network of short contacts as observed in R-R-up (Figure 2).
The short contacts between the carbonate and the hydrogen
atoms on the phosphine ligand are distributed on the t-Bu
group (2.124 Å), a bridging methylene (2.360 Å), and a
naphthyl group (2.088 Å). In addition, the isopropyl group of
the substrate also shows a short C−H···O contact of 2.182 Å. In
S-S-down, the forming O···H bond (1.321 Å) is much more
advanced than in R-R-up. This network of contacts sets the
global positioning of the phosphine ligand and prevents the
establishment of any significant C−H···π or stacking interaction
between the substrate and the naphthyl groups of the ligand, as
illustrated by the longer contact (3.06 Å) between a C−H bond
For the four other cases, in which the isopropyl group
occupies the axial position facing the carbonate, the stereo-
isomers with Me cis to CN, that is, R-R-up and S-S-down, are
computed to be significantly favored over the stereoisomers
with Me trans to CN, that is, R-S-up and S-R-down, as
observed experimentally. The ΔΔG‡ value of 3.8 kcal mol−1
translates to a kinetic preference for the formation of R-R-up
with respect to R-S-up of ∼100:1, in qualitative agreement with
the experimental observations. The calculations do reproduce
the kinetic preference to form a specific couple of enantiomers.
In addition, the ΔΔG‡ value of 1.0 kcal mol−1 computed
between the transition states R-R-up and S-S-down translates
into an e.r. of 77:23 at 413 K, in excellent agreement with
experiment (Table 2).37 Of note, the activation barrier between
the lowest transition state, R-R-up, and the corresponding
agostic complex was computed to be ΔG‡ = 15.7 kcal mol−1 (at
413 K), which is a significantly lower value than those
computed for similar reactions (typically around 25 kcal
mol−1).2d,3e,4f This is in qualitative agreement with the fact that
the current ligand/base/solvent system allows one to perform
the reaction at a lower temperature (363 K).
The main difference between the two transition state
geometries, R-R-up and S-S-down, is the orientation of the
phosphine ligand with respect to the base + substrate ensemble
(Figure 2). In R-R-up, the t-Bu group on the phosphine is
facing the carbonate, and two C−H···O short contacts are
present (2.189 and 2.341 Å). There is also a short C−H···O
contact of 2.328 Å between the axial isopropyl group and the
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Research Article
the ligand structure and the carbonate countercation. This
allowed us to generate polycyclic products containing three
adjacent stereocenters as single diastereoisomers and with
moderate to high enantioselectivity. Experimental data
indicated that the enantiodetermining C−H activation step
involves a monoligated species. DFT (PBE0-D3) calculations
performed with binepine (R)-1a reproduced well the
experimental enantiomeric ratio. The preferred formation of
the (R,R) indane enantiomer was attributed to the establish-
ment of a more efficient network of stabilizing weak
interactions between the phosphine and the base + substrate
ensemble in the transition state.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b00898.
■
S
Full characterization of all new compounds, detailed
experimental procedures, Cartesian coordinates, elec-
tronic and Gibbs free energies for the systems computed
(PDF)
NMR spectra and HPLC analyses for target molecules
(PDF)
Rotatable structure images of the various TS (XYZ)
X-ray crystallographic (CIF) data (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: clot@univ-montp2.fr.
*E-mail: olivier.baudoin@univ-lyon1.fr.
■
Figure 3. NCI maps of weak interactions between the phosphine
ligand and the base + substrate ensemble.11 Only intermolecular maps
using promolecular densities are shown, and the blue regions are
associated with slightly attractive weak interactions, whereas the red
regions are associated with repulsive interactions.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
of the activated methyl group and the centroid of the proximal
aromatic ring of the ligand. Contrary to what is observed on the
NCI maps for R-R-up, in the case of S-S-down, a significant
region of slightly repulsive interactions is developing between
the phosphine ligand and the base + substrate ensemble. Even
though these NCI plots present only qualitative behavior, they
clearly show that significantly different networks of interactions
between the reactive center and the phosphine ligand are
operating in the two transition states. It is interesting to note
that the favored transition state features mostly stabilizing
interactions, albeit weak in magnitude.
We thank the Minister
̀
e de l’Enseignement Super
́
ieur et de la
Recherche and Institut Universitaire de France for financial
́
support, and CCIR-ICBMS (Universite Claude Bernard Lyon
1) for the allocation of computational resources.
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