Conformational Preferences of a Tropos Biphenyl Phosphinooxazoline-a Ligand with Wide Substrate Scope

Article abstract of DOI:10.1021/acscatal.5b02766

Excellent enantioselectivities are observed in palladium-catalyzed allylic substitutions of a wide range of substrate types and nucleophiles using a bidentate ligand composed of oxazoline and chirally flexible biaryl phosphite elements. This unusually wid

Full text of DOI:10.1021/acscatal.5b02766

Research Article
pubs.acs.org/acscatalysis
Conformational Preferences of a Tropos Biphenyl
Phosphinooxazoline−a Ligand with Wide Substrate Scope
Rosalba Bellini,†,⊥ Marc Magre,‡,⊥ Maria Biosca,‡ Per-Ola Norrby,*,§,∥ Oscar Pamies,*,‡
̀
Montserrat Dieguez,*,‡ and Christina Moberg*,†
́
†KTH Royal Institute of Technology, Department of Chemistry, Organic Chemistry, SE 10044 Stockholm, Sweden
‡
́
́
̀
Universitat Rovira i Virgili, Departament de Quımica Fısica i Inorganica, C/Marcel.lí Domingo s/n., ES 43007 Tarragona, Spain
§Department of Chemistry and Molecular Biology, University of Gothenburg, Kemigarden 4, SE 41296 Gothenburg, Sweden
̊
∥Pharmaceutical Technology & Development, AstraZeneca, Pepparedsleden 1, SE-43183 Molndal, Sweden
̈
S
* Supporting Information
ABSTRACT: Excellent enantioselectivities are observed in
palladium-catalyzed allylic substitutions of a wide range of
substrate types and nucleophiles using a bidentate ligand
composed of oxazoline and chirally flexible biaryl phosphite
elements. This unusually wide substrate scope is shown by
experimental and theoretical studies of its η3-allyl and η2-olefin
complexes not to be a result of configurational interconversion of
the biaryl unit, since the ligand in all reactions adopts an Sa,S
configuration on coordination to palladium, but rather the ability
of the ligand to adapt the size of the substrate-binding pocket to the reacting substrate. This ability also serves as an explanation
to its excellent performance in other types of catalytic processes.
KEYWORDS: palladium, allylic substitution, tropos P,N-ligands, NMR study, DFT study
INTRODUCTION
■
Enantioselective metal-catalyzed synthetic processes are ubiq-
uitous for the construction of nonracemic chiral organic
compounds.1 The stereodirecting power of a catalyst usually
relies on the choice of chiral ligand bound to the metal. Ligands
with broad substrate scope are desirable in order to limit time-
consuming ligand design and preparation. The identification of
privileged ligands2 useful for a wide range of substrates and for
different types of reactions is therefore an important issue.
Conformationally flexible ligands are viable candidates for the
design of catalysts with wide substrate scope. Mikami and co-
workers3 have demonstrated that stereochemically dynamic
tropos3d,4 ligands are capable of adapting their sense of chirality
to a proximal chiral motif bound to the same metal center and
consequently are able to replace rigid analogues with either
Figure 1. (a) Conformationally flexible phosphephine and azepine
ligands 1 and 2. (b) Palladium olefin complexes 3 and 4.
absolute configuration. In a similar manner, adaptable ligand
but also by the substrate undergoing reaction. In this particular
catalytic process different ligands are usually required for
different types of substrates in order to obtain products with
high enantiopurity.7 By using bis-azepine ligands with two
flexible biaryl moieties, we were able to demonstrate that in
palladium olefin complexes 3 and 4, aimed at mimicing the
product olefin complexes from the reaction of bulky linear
(“broad”) and small cyclic (“narrow”) substrates, respectively,
systems composed of a stereochemically flexible part covalently
bound to a group with a rigid stereogenic element have been
successfully employed in asymmetric catalysis.5 In order to
further exploit self-adaptable ligands in asymmetric catalysis,
studies of their conformational preferences under different
reaction conditions are desirable.
We have previously studied the conformational behavior of
phosphepine and azepine ligands, such as 1 and 2 (Figure 1a).6
By using palladium-catalyzed asymmetric allylic alkylation as an
illustrative model process to probe the conformational issues,
we found that the conformation of these flexible ligands may be
influenced not only by structural units present in the catalyst
Received: December 7, 2015
Revised: January 27, 2016
© XXXX American Chemical Society
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Figure 2. Phosphite-oxazoline ligands (S)-5a, (Sa,S)-5b, and (Ra,S)-5c.
an R*,R* (C2) configuration was preferred in the complex
containing the trans olefin, whereas R*,S* (Cs) was preferred in
the complex with the cis olefin (Figure 1b).8 In contrast, an
R*,S* configuration of the ligand was observed in η3-allyl
palladium complexes derived from (E)-1,3-diphenyl-2-propenyl
acetate as well as from 3-cyclohexenyl acetate (not shown).
Although tropoisomerization in azepine derivatives occurs
while the ligand is coordinated to the metal center,9
conformational change in ligands 1 and 2 was slow in
comparison to nucleophilic attack, and the flexible ligands
therefore behaved essentially as a mixture of the analogous rigid
ligands and thus proved to be less general than desired.
Scheme 1. Preparation of Ligand (Sa,S)-5b
Ligands that tolerate a wide range of substrates are indeed
rare. In this context, some of us were able to show that
substrate versatility in Pd-catalyzed allylic substitutions can
benefit from the introduction of a conformationally flexible
biaryl phosphite element.10 Thus, phosphite-oxazoline (S)-5a
(Figure 2) constitutes one of the few examples of ligands that
have provided high ee values in the Pd-catalyzed allylic
alkylation of both the hindered model compound rac-(E)-1,3-
diphenyl-2-propenyl acetate (S1) and unhindered cyclic
substrate rac-3-cyclohexenyl acetate (S2).11 This ligand has
also been successfully applied in enantioselective palladium-
catalyzed Heck reactions,12 rhodium-catalyzed hydrosilylation
of ketones,13 and iridium-catalyzed hydroboration of 1,1-
disubstituted olefins.14 Since the barrier to inversion in
phosphite ligands is known to be lower than that in
phosphepine and azepine ligands,15 we assumed that the
broad substrate tolerance of (S)-5a may originate in its ability
to adapt the conformation to the substrate undergoing reaction.
In order to test if this was the case, we decided to study the
conformational preferences of ligand (S)-5a in palladium
complexes with relevance for asymmetric allylic alkylation.
Toward this aim, we needed access to rigid analogues of (S)-5a.
For this reason, (Sa,S)-5b and (Ra,S)-5c were prepared (Figure
2), their behavior in the catalytic reactions was investigated, and
the structures of the corresponding olefin complexes were
studied by NMR spectroscopy and DFT calculations.
chlorophosphite (S)-9 with (S)-2-(4-isopropyl-4,5-dihydroox-
azol-2-yl)phenol18 afforded in good yield the final product
(Sa,S)-5b. Ligand (Ra,S)-5c was prepared analogously starting
from (R)-binol. The flexible ligand (S)-5a was prepared as
previously described.11
The rigid ligands gave rise to single signals in the 31P NMR
spectra: (Sa,S)-5b at 127.9 ppm and (Ra,S)-5c at 129.3 ppm. A
single 31P resonance was also observed from compound (S)-5a,
at 136.6 ppm. Interestingly, upon gradual cooling this signal
first broadened and at around −20 °C split into two signals
originating from the Sa and Ra conformers, as a result of
tropoisomerization being slow on the NMR time scale. The
original spectrum, containing a single 31P resonance, was
1
restored by warming the sample to 25 °C. In the H NMR
spectrum several signals were split upon cooling (see the
Supporting Information).
Catalytic Reactions. Palladium-catalyzed allylic alkylations
of rac-(E)-1,3-diphenyl-2-propenyl acetate (S1) and rac-3-
cyclohexenyl acetate (S2), with dimethyl malonate as
nucleophile and [Pd(η3-C3H3)Cl]2 as palladium source, were
studied with the three ligands (Scheme 2, eq 1, and Table 1). In
reactions with S1 as substrate, use of the catalyst containing
flexible ligand (S)-5a resulted in full conversion to the product
(10) with S absolute configuration with >99% ee within 10 min
We have also extended the previous work on dimethyl
malonate and benzylamine to other C-nucleophiles and to O-
nucleophiles, among which are the rarely studied α-substituted
malonates, β-diketones, alkyl alcohols, silanols, and fluorobis-
(phenylsulfonyl)methane, and to alkylations of other substrates,
thereby further underlining the versatility of ligand 5a.
Scheme 2. Allylic Alkylations of rac-(E)-1,3-Diphenyl-2-
propenyl Acetate (S1) and rac-3-Cyclohexenyl Acetate (S2)
RESULTS AND DISCUSSION
■
Preparation of Ligands. Ligand (Sa,S)-5b was prepared
starting from (S)-binol (6), as shown in Scheme 1. Catalytic
hydrogenation following a published procedure gave (S)-7,16
which was reacted with tert-butyl chloride in the presence of
chloropentacarbonylrhenium(I)17 to yield (S)-8. Reaction with
phosphorus trichloride gave compound (S)-9. Condensation of
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Table 1. Palladium-Catalyzed Allylic Alkylations of S1 and
S2 with Ligands (S)-5a, (Sa,S)-5b, and (Ra,S)-5c
Scheme 3. Preparation of Pd(0) Olefin Complexes 12−17
a
a
Conditions: 0.5 mol % [Pd(η3-C3H5)Cl]2, 1.1 mol % ligand, CH2Cl2
b
1
as solvent, BSA/KOAc as base, room temperature. Measured by H
NMR after 10 min. Determined by HPLC. Determined by GC after
30 min. Determined by GC.
c
d
e
(Table 1, entry 1). Whereas use of (Sa,S)-5b also gave
essentially enantiopure product with S absolute configuration
(entry 2), a catalyst containing (Ra,S)-5c gave the opposite
product enantiomer with merely 20% ee (entry 3). By
employing a mixture of (Sa,S)-5b and (Ra,S)-5c, the S
enantiomer was obtained with 90% ee (entry 4). This
demonstrates that the catalyst containing the former ligand
forms a considerably more reactive catalyst. These experiments
also demonstrate that the flexible ligand thus behaved
essentially in the same way as ligand (Sa,S)-5b.
Also with S2 as substrate the flexible ligand (S)-5a gave the
same product enantiomer, (S)-11, as (Sa,S)-5b (Table 1, entries
1 and 2), but with somewhat lower selectivity (94% as
compared to 99% ee). Reaction in the presence of ligand
(Ra,S)-5c resulted in the formation of the opposite enantiomer
with lower enantioselectivity also in reactions with this
substrate, although the difference was considerably smaller
than for S1 (entry 3). The higher reactivity of (Sa,S)-5b was
again shown from the results of an experiment where a mixture
of the two rigid ligands was used (entry 4). The absolute
configurations of the products obtained demonstrate that the
binaphthyl part of the ligand is mainly responsible for chirality
transfer and that the conformation of (S)-5a in the selectivity-
determining complex resembles that of (Sa,S)-5b.
Preparation and NMR Studies of Palladium Olefin
Complexes. Nucleophilic attack on the allyl group in
palladium-catalyzed allylic alkylations has been argued to
occur via a late, i.e. productlike, transition state, and the
stereochemistry is accordingly governed by formation of the
most stable olefin complex.19 With the aim of gaining a deeper
insight into the conformation of flexible ligand (S)-5a in the
selectivity-determining step, palladium(0) olefin complexes
with the three ligands were prepared in order to mimic the
product olefin complexes from allylic alkylations. Dimethyl
fumarate and diethyl maleate were selected as olefins in order
to form complexes with sufficient stability to allow isolation and
studies by NMR spectroscopy. The complexes were obtained
by stirring equimolar amounts of ligand and olefin with 1 equiv
of Pd2(dba)3·CHCl3 in deuterated dichloromethane (Scheme
3). Complex formation with dimethyl fumarate was achieved
within 30 min at ambient temperature, whereas 16 h was
required to obtain the desired complexes from diethyl maleate.
As a result of the symmetry of the olefins employed, a
maximum of two olefin complexes can form with each ligand,
those from dimethyl fumarate depicted as A and B in Figure 3
and those from diethyl maleate as C and D. Attempts were first
made to determine the configuration of flexible ligand (S)-5a in
Figure 3. Possible isomers of palladium(0) olefin complexes.
complexes with the two types of olefins by comparison of the
spectra of 12 and 15 with those of the complexes with rigid
ligands, i.e. 13, 14 and 16, 17, respectively.
The 31P as well as 1H NMR spectra of the complexes
containing rigid ligands (13, 14 and 16, 17) suggested that
essentially single isomers were obtained in each case. For
instance, the proton-coupled 31P NMR spectrum of complex
13, containing (Sa,S)-5b and dimethyl fumarate, showed a
doublet of doublets at δ 152.6 (JPH = 15.9 and 4.7 Hz), along
with a small signal at 151.7 (ratio ca. 50:1), while the fumarate
complex with (Ra,S)-5c (14) showed a doublet of doublet at δ
154.0 (JPH = 15.1 and 5.5 Hz) and a minor signal at 145.6 ppm
(ratio ca. 12:1), as well as a signal at 151.1 ppm, probably
originating from a complex with dba. Diethyl maleate complex
16 showed a 31P NMR signal at 153.2 ppm, which slowly
replaced an initially observed signal at 149.3 ppm and that of 17
a signal at 155.1 ppm (minor signal at 147.7 ppm and a signal at
152.5 ppm originating from a complex with dba). In the 31P
NMR spectra of complexes 12 and 15, with the flexible ligand
(S)-5a, signals at 153.6 and 155.8 ppm, respectively, were
observed together with minor signals (155.7 ppm in 12 and at
156.6 ppm in 15) originating from minor isomers (ratio ca.
11:1 in both cases). No separation of signals in the 31P or H
1
NMR spectra occurred upon cooling to −70 °C, thus
demonstrating that the spectra observed at ambient temper-
ature are not a result of rapid equilibration of isomers (see the
1
Supporting Information). Characteristic H and 31P signals are
shown in Table 2.
Although the NMR spectra of the three complexes 12−14
have many features in common (Table 2 and the Supporting
Information), that of 12, with flexible ligand (S)-5a, resembles
more that of the complex with rigid ligand (Sa,S)-5b than that
with (Ra,S)-5c, as judged by the chemical shifts and coupling
constants of the oxazoline ring protons (see the Supporting
Information) and the olefinic protons as well as by the chemical
shift difference of the tert-butyl protons ortho to the phosphite
function (Δδ ca. 0.2 ppm in 12 and 13 and 0.01 ppm in 14),
which is influenced by the proximity of the coordinated olefin
and thereby by the conformation of the ligand. These spectral
features suggest that the ligand in complex 12 adopts an Sa,S
1
configuration. Complete assignment of the H NMR spectrum
of 16 was hampered as a result of overlapping signals, but due
to the similarity of the spectra 15 and 16, in particular the
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Table 2. Characteristic NMR Data for Olefin Protons Ha and Hb for Complexes 12−17
δ(Ha) (ppm)
δ(Hb) (ppm)
δ(P) (ppm)
JH H (Hz)
JH P (Hz)
JH P (Hz)
δ(Meligand) (ppm)
δ(Meolefin) (ppm)
δ(tBu) (ppm)
a
b
a
b
compd
12
13
14
15
3.72
3.72
3.86
3.76
3.57
3.55
3.51
3.42
153.6
152.6
154.0
155.8
153.2
155.1
10.2
10
4.6
4.7
5.5
5.1
15
16
15
12
0.94, 1.01
0.88, 1.01
0.69, 0.95
0.93, 1.04
0.90, 1.04
0.72, 1.00
3.42, 2.93
3.07, 3.41
2.97, 3.37
0.65, 1.04
0.83, 1.03
0.78, 1.38
1.10, 1.3
1.07, 1.32
1.26, 1.29
1.10, 1.3
1.08, 1.31
1.28, 1.29
10
10
a
16
17
3.88
3.49
10
5.5
15
a
Assignments hampered due to overlapping signals.
chemical shifts of the oxazoline ring protons (see the
Supporting Information) and the tert-butyl protons ortho to
the phosphite moiety, it was assumed that 15 and 16 have the
same absolute configuration. Although the NMR study thus
suggests that the flexible ligand adopts an Sa,S configuration in
complexes with both types of olefins, the spectra do not allow
definite conclusions about the configuration of the flexible
ligand in the two complexes. For this reason DFT calculations
were performed (see below).
Knowing that the catalyst with (Sa,S)-5b leads to the S
product enantiomer and that with (Ra,S)-5c to the opposite
enantiomer, each olefin was expected to coordinate with
different faces to palladium in complexes with the two ligands.
Nucleophilic attack trans to phosphorus rather than trans to
nitrogen is expected as a result of the stronger trans influence of
phosphorus.20 Due to the analogy of the product olefin
complexes and our model complexes, those containing the
(Sa,S)-5b ligand were thus expected to be A and C, and those
with the diastereomeric (Ra,S)-5c ligand B and D (Figure 3).
However, NOESY experiments of the three palladium fumarate
complexes 12−14 showed NOE interactions between the
olefinic proton located trans to the phosphite moiety (Hb) and
the proton of the isopropyl oxazoline substituent (Figure 4).
This suggests that, in contrast to expectations, all fumarate
complexes coordinate as in A, regardless of the configuration of
the biaryl phosphite moiety.
Figure 5. Calculated relative energies for palladium complexes A and
B containing olefin 10 using ligands (a) (Sa,S)-5b and (b) (Ra,S)-5c.
For use of A and B, compare Figure 3.
Figure 4. Relevant NOE contacts of Pd complexes 12−14.
Theoretical Studies. In order to determine the config-
uration of the flexible ligand in reactions with the two
substrates as well as whether the olefins coordinate via the
same face in complexes with the two rigid ligands although
products with different absolute configuration were obtained,
DFT calculations were performed. The relative stabilities of the
product olefin complexes were initially calculated, using the
olefin complexes obtained from nucleophilic addition of
dimethyl malonate to allyl complexes derived from the two
substrates (Figures 5 and 6).
In agreement with the results of the NMR study, it was found
that complexes containing product olefins with S absolute
configuration were more stable than those with R configuration
for both ligands and for both olefins (Figures 5 and 6); large
energy differences were indeed found for the two complexes
(Sa,S)-S (A) and (Sa,S)-R (B) with linear olefin 10 (Figure 5a)
Figure 6. Calculated relative energies for palladium complexes C and
D containing olefin 11 using ligands (a) (Sa,S)-5b and (b) (Ra,S)-5c.
For use of C and D, compare Figure 3.
as well as for (Ra,S)-S (C) and (Ra,S)-R (D), containing cyclic
olefin 11 (Figure 6a).
A smaller energy difference between the two olefin
complexes (Ra,S)-S (A) and (Ra,S)-R (B) was observed,
although the configuration of the product 10 predicted by
the calculations is opposite to that observed experimentally
(Figure 5b). The opposite isomer is also predicted for reaction
with 3-cyclohexenyl acetate using (Ra,S)-5c (Figure 6b). The
explanation for the formation of products with opposite
absolute configuration from catalytic reactions using complexes
containing (Sa,S)-5b and (Ra,S)-5c should therefore be sought
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in the relative stabilities of the transition states leading to the
different products. Transition state (TS) calculations were
therefore performed. In order to simplify the calculations, NH3
was used as the nucleophile.
(S)-5a as ligand are also reflected in the energy difference
calculated for the endo and exo structures with this ligand.
Analogous calculations were performed for complexes from
3-cyclohexenyl acetate (Figure 8). The calculated TS energy
Neglecting anti,anti and anti,syn complexes, which constitute
minor isomers, two syn,syn Pd η3-allyl, exo and endo,
complexes derived from 1,3-diphenyl-2-propenyl acetate are
possible from each ligand, as illustrated for (Sa,S)-5b, (Ra,S)-5c,
and (S)-5a in Figure 7. Assuming that nucleophilic attack on
Figure 8. Pd η3-allyl exo and endo complexes from 3-cyclohexenyl
acetate (S2).
differences between the exo and endo complexes (Table 3) are
in agreement with the high enantiomeric excesses observed
using (Sa,S)-5b as ligand, and also with the observation of
opposite enantiomers of alkylated product 11 using the two
diastereoisomeric ligands (Sa,S)-5b and (Ra,S)-5c (99% S using
(Sa,S)-5b vs 92% R for (Ra,S)-5c; Table 1, entry 2 vs entry 3).
Again, the energy of the TS for the reaction catalyzed by (Ra,S)-
5c is higher than that of the reaction catalyzed by (Sa,S)-5b,
which is in agreement with the higher reactivity observed for
Pd/(Sa,S)-5b in comparison to Pd/(Ra,S)-5c catalyst.
Figure 7. Pd η3-allyl exo and endo complexes from 1,3-diphenyl-2-
propenyl acetate (S1).
the allyl complex to form the product olefin complex proceeds
by a least-motion reaction path,21 allyl complexes (Sa,S)-exo and
(Ra,S)-endo are those which lead to the observed products, with
S and R configuration, respectively.
The calculated energies of the transition states leading to the
observed product and the enantiomers are shown in Table 3. A
The conclusion of the calculations is thus that in the reaction
of (E)-1,3-diphenyl-2-propenyl acetate with (Sa,S)-5b the TS
leading to the product with S configuration, which is the
product observed experimentally, is lowest in energy, and the
olefin complex of this product is that which is most stable. In
contrast, for (Ra,S)-5c, the TS leading to the product with R
configuration, which is the product observed experimentally, is
lowest in energy, whereas the olefin complex of the product
with S configuration is lowest in energy.
In the reaction of 3-cyclohexenyl acetate with (Sa,S,)-5b, the
TS leading to the product with S configuration, which is the
product observed experimentally, is lowest in energy, and the
olefin complex of this product is that which is most stable. In
contrast, for (Ra,S)-5c, the TS leading to the product with R
configuration, which is the product observed experimentally, is
lowest in energy, whereas the olefin complex of the product
with S configuration is lowest in energy. Thus, in reactions with
both types of substrates where (Ra,S)-5c is used as ligand, the
lowest energy transition state complexes lead to product olefin
complexes which are higher in energy than those from olefins
with opposite absolute configuration. The calculations thus
provide an explanation why the model olefins coordinate to
Table 3. Calculated Relative Energies (in kcal/mol) for the
TSs from Exo and Endo Pd η3-Allyl Intermediates, Using S1
and S2 and NH3 as Nucleophile
S1
S2
ligand
exo
endo
4
exo
endo
0
(Sa,S)-5b
(Ra,S)-5c
(S)-5a
0
2
a
a
b
b
2.6
0
2.5
2.2
1
2.8
4.3
0
a
b
Energies relative to that of exo-(Sa,S)-5b. Energies relative to that of
endo-(Sa,S)-5b.
larger energy difference was found between the two TSs leading
to opposite enantiomers in reactions with ligand (Sa,S)-5b in
comparison to those with (Ra,S)-5c, which is in accordance
with the experimental results (>99% (S) vs 20% (R); Table 1,
entries 2 vs 3). In addition, the TSs for (Ra,S)-5c are higher in
energy than the most stable TS for (Sa,S)-5b, which fully
accounts for the lower reactivity observed for the Pd/(Ra,S)-5c
catalytic system. The high ee values observed in reactions using
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a
Table 4. Pd-Catalyzed Allylic Substitution of Disubstituted Linear Substrates Using Ligand (S)-5a
a
b
Conditions: 0.5 mol % [Pd(η3-C3H5)Cl]2, 1.1 mol % ligand, CH2Cl2 as solvent, BSA/KOAc as base, room temperature. Percent conversion
c
d
measured after 10 min. Isolated yields are shown in parentheses. Enantiomeric excesses determined by chiral HPLC or GC. Conversions and yields
e
f
measured after 18 h. Measured after desilylation to the corresponding alcohol. Measured after transformation to the corresponding RCM adduct.
g
h
1
Reactions carried out at 0 °C for 18 h. Enantiomeric excesses measured by H NMR using [Eu(hfc)3].
palladium via the same face in complexes with the two rigid
ligands, although they lead to products with opposite absolute
configuration in the catalytic reactions.
the allylic substitution of substrate S1 (Table 4, entries 1−18).
We were pleased to note that Pd/(S)-5a is very tolerant to
variation of the steric properties of the ester moiety and the
substituents of the malonate nucleophiles (entries 2−8). A
broad range of malonates provided products 18−24 in high
yields and with excellent enantioselectivities, comparable to
those obtained with dimetyl malonate (ee values up to >99%).
Of particular interest are the high enantioselectivities achieved
with allyl-, butenyl-, pentenyl-, and propargyl-substituted
malonates, whose products are key intermediates in the
synthesis of more complex chiral products.22 The addition of
acetylacetone (compound 25) also proceeded with similar high
enantioselectivities (ee values up to 98%, entry 9). Interestingly,
we could also reach ee values up to 99% and high yield in the
allylic fluorobis(phenylsulfonyl)methylation of S1 using Pd/
Other Substrates and Nucleophiles. Scope and
Limitations. To further study the behavior of ligand (S)-5a
and its rigid analogues (Sa,S)-5b and (Ra,S)-5c, and to
investigate whether the similar behavior of the two best ligands
(S)-5a and (Sa,S)-5b is general, we extended the previous work
to O-nucleophiles and C-nucleophiles other than dimethyl
malonate as well as to the alkylation of other substrates (Tables
4−7).
Table 4 shows the results of the use of Pd/(S)-5a in the
allylic substitution of several symmetrically disubstituted linear
substrates, with different steric and electronic properties, using
a wide range of C- and O-nucleophiles. We initially considered
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(S)-5a (compound 26, entry 10). The efficient allylic
substitution with this type of nucleophile opens up a path for
obtaining highly appealing chiral monofluoromethylated
compounds, which are attracting significant attention in the
field of medicinal chemistry.23 Despite this, only one catalytic
system has previously been successfully applied, although it
resulted in lower enantioselectivity (ee values up to 96%) than
the present system and also required lower temperature (0 °C)
than our Pd/(S)-5a catalyst.24
Table 5. Pd-Catalyzed Allylic Substitution of Cyclic
Substrates Using Ligand (Sa,S)-5b
a
We then considered the allylic substitution of S1 using
several O-nucleophiles (Table 4, entries 11−18). Asymmetric
Pd-catalyzed allylic etherification has recently attracted the
attention of many researchers because the resulting chiral
ethers and related derivatives are important intermediates in the
synthesis of biologically active compounds.25 Despite its
importance, few successful examples exist and most of them
use phenols as O-nucleophiles,26 aliphatic ethers27 and
silanols27d being much less studied. The application of Pd/
(S)-5a to several aliphatic alcohols provided the desired
products in excellent yields. For benzylic alcohols, the
enantioselectivity was affected by the electronic nature of the
nucleophile. The best enantioselectivity (97% ee, entry 13) was
achieved with an electron-withdrawing group in the para
position of the aryl group. Even more interesting are the almost
perfect enantioselectivities (ee values up to 99%) and high
yields achieved in the etherification of S1 with silanols (entries
17 and 18). The results surpass those of the only Pd/
CycloN2P2-Phos catalytic type system that has provided high
enantioselectivities (up to 94%)27d so far. Therefore, Pd/(S)-5a
can be used for preparing chiral silyl ethers that can be easily
transformed into high-value compounds such as chiral aromatic
allylic alcohols.
The scope of Pd/(S)-5a was further investigated by using
other symmetrical linear substrates with steric and electronic
requirements (S3−S8) different from those of S1. The Pd/(S)-
5a catalytic system can also be used for the alkylation of
substrates S3−S6, with different substituents in the aryl groups,
with various carbon nucleophiles in excellent enantioselectiv-
ities and yields, comparable to those of S1 (Table 4, entries
19−24). We also found that the biaryl phosphite group in Pd/
(S)-5a can adapt its chiral pocket and successfully catalyze the
alkylation of S7 (entries 25−31). This substrate is less sterically
demanding, and therefore enantioselectivities tend to be lower
than those with model substrate S1. The present results are
among the best in the literature for this substrate,7 even using
highly appealing nucleophiles such as those α-substituted with
methyl, allyl, and butenyl groups, for which only very few
catalytic systems have provided high enantioselectivities.22
Interestingly, Pd/(S)-5a can also successfully be used for the
alkylation of S8 (ee values up to >95%, entry 32). This
substrate is more sterically demanding, and it usually reacts
with catalytic performance inferior to that of S1 and S3−S4.
We then focused our attention on the allylic substitution of
cyclic substrate S2 with nucleophiles more challenging than
dimethyl malonate and on the alkylation of other cyclic
substrates with different ring sizes (S9 and S10). Table 5 shows
that a wide range of C-nucleophiles, including the less studied
α-substituted malonates and acetylacetone, can efficiently react
with S2 to provide the corresponding compounds (49−54)
with high yields and enantioselectivities (ee values up to
>99%), comparable to those obtained with dimethyl malonate
(11). The exception was propargyl-substituted malonate, which
led to somewhat lower enantioselectivity (compound 53, ee
a
Conditions: 0.5 mol % [Pd(η3-C3H5)Cl]2, 1.1 mol % ligand, CH2Cl2
b
as solvent, BSA/KOAc as base, room temperature. Percent
conversion measured after 30 min. Isolated yields are shown in
parentheses. Enantiomeric excesses determined by chiral HPLC or
GC. Enantiomeric excesses measured by H NMR using [Eu(hfc)3].
c
d
1
values up to 92%), but was still good for this challenging C-
nucleophile. Remarkably, Pd/(Sa,S)-5b also efficiently catalyzes
the alkylation of cyclic substrates S9 and S10 (Table 5, entries
8−11, compounds 55−58). Excellent to high enantioselectiv-
ities (ee values between 96% and >99%) were obtained in both
cases, even with S10, which usually provides products with
enantioselectivities much lower than those with cyclic S2.7
We next studied if the rigid analogues of (S)-5a (ligands
(Sa,S)-5b and (Ra,S)-5c) follow the same trend in the allylic
substitution of unsymmetrical monosubstituted substrates S11
and S12 (eq 2) as in reactions with disubstituted substrates.
The challenge in these substrates is that both the
enantioselectivity and regioselectivity need to be controlled,
and most palladium catalysts favor the formation of the usually
undesired achiral linear product.7,28,29 In our previous work we
found that alkylation of S11 and S12 catalyzed by Pd/(S)-5a
proceeded with regio- and enantioselectivities comparable to
those of the best values reported.11 As observed with the
previously studied linear disubstituted substrates, Pd/(SaS)-5b
gave the best results and provided the desired branched isomers
(compounds 59 and 61), with enantioselectivities that were as
high as those obtained with Pd/(S)-5a, as major products
(Table 6).
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variety of catalytic processes phosphite ligand (S)-5 has
properties similar to those of phosphine ligands 65.33 However,
whereas (4S)-2-(2′-diphenylphosphino)phenyl-4-isopropyl-4,5-
dihydrooxazole (65; Figure 9) gives excellent results in
Table 6. Pd-Catalyzed Allylic Substitution of
Monosubstituted Substrates S11 and S12
a
b
conv (%)
branched
c
d
entry substrate
ligand
(S)-5a
(yield (%))
(%)
ee (%)
1
2
3
4
S11
S11
S11
S11
100 (91)
100 (90)
100 (90)
100 (91)
68
65
15
50
86 (S)
85 (S)
42 (R)
79 (S)
(Sa,S)-5b
(Ra,S)-5c
(Sa,S)-5b +
(Ra,S)-5c
5
6
7
8
S12
S12
S12
S12
(S)-5a
100 (92)
100 (89)
100 (90)
100 (91)
> 99
95
92 (S)
90 (S)
41 (R)
61 (S)
(Sa,S)-5b
(Ra,S)-5c
Figure 9. Phosphinooxazoline ligand 65.
40
(Sa,S)-5b +
(Ra,S)-5c
70
asymmetric allylic alkylations with rac-(E)-1,3-diphenyl-2-
propenyl as substrate (98% ee), modest to good results are
obtained with 1,3-dialkyl-2-propenyl substrates and racemic
products are obtained with the 3-cyclohexenyl derivatives. In
contrast, 5a provides excellent results with all of these types of
substrates. The chiral PHOX ligands interact with the substrate
mainly at its wings. As a consequence, allylic systems with bulky
substituents show high exo:endo ratios and high enantiose-
lectivities, whereas narrow systems give low selectivity.33 In
contrast, ligands (S)-5a and (Sa,S)-5b are more flexible and can
accommodate a wider range of substrates, thereby yielding
excellent enantioselectivities for both “broad” and “narrow”
substrates. In fact, by replacing the phosphine moiety by a
biaryl phosphite in the PHOX ligand, we were able to identify
unprecedented catalytic systems (Pd/(S)-5a and Pd/(Sa,S)-5b)
that with high enantiocontrol generate C−C, C−N, and C−O
bonds for a number of hindered and unhindered mono-, di-,
and trisubstituted substrates using a wide range of C-, N-, and
O-nucleophiles.
The enantioselectivity of the catalytic reactions is reflected by
the energy difference between the exo- and endo-like transition
states, provided that nucleophilic attack occurs only trans to
phosphorus. In the reaction of (E)-1,3-diphenyl-2-propenyl
acetate (S1) in the presence of (Sa,S)-5b (with NH3 as
nucleophile) this difference was calculated as 4 kcal/mol, in
good agreement with the selectivity observed experimentally
(>99% ee). The selectivity observed experimentally in the
reaction with the cyclic substrate S2 was slightly lower, 99% ee,
corresponding well to the computed energy difference between
the two transition states, 2 kcal/mol. For reactions of the two
substrates in the presence of PHOX ligand 65 (Figure 9) the
corresponding values were calculated to be 2.2 and 0 kcal/mol,
respectively, thus reflecting the somewhat lower selectivity
obtained from S1 in comparison to that obtained using (Sa,S)-
5b and the formation of racemic product from S2.21
Contrary to expectations, the absolute configuration of the
products could not be entirely predicted from the structure of
the most stable olefin complex, implying that, at least for
reactions employing (Ra,S)-5c as ligand, the transition states
resemble the palladium allyl complexes rather than the olefin
complexes. For (S)-5a and (Sa,S)-5b exo complexes are more
stable than endo complexes, in analogy to complexes with
PHOX ligands, whereas for (Ra,S)-5c the endo complex has
slightly higher stability than the exo complex.
While the previously studied semiflexible ligands 1 and 2
(Figure 1) adopt different configurations in product olefin
complexes obtained in reactions with the two types of
substrates, (S)-5a prefers a Sa,S configuration with both
“broad” and “narrow” substrates. The ability of this ligand to
adapt the size of the substrate-binding pocket to the reacting
a
Conditions: 1 mol % [Pd(η3-C3H5)Cl]2, 2.2 mol % ligand, benzene as
b
solvent, BSA/KOAc as base, 0 °C. Percent conversion measured after
2 h. Isolated yields are shown in parentheses. Regioselectivity
measured by H NMR. Enantiomeric excesses determined by chiral
HPLC.
c
d
1
Finally, the good performance of Pd/(S)-5a and Pd/(Sa,S)-
5b also extended to the allylic substitution of unsymmetrical
1,3,3-trisubstituted allylic substrates (S13 and S14, Table 7).
Table 7. Pd-Catalyzed Allylic Substitution of Trisubstituted
Substrates S13 and S14
a
b
c
entry
substrate
ligand
conv (%) (yield (%))
ee (%)
1
2
3
4
5
6
S13
S13
S13
S14
S14
S14
(S)-5a
87 (84)
84 (79)
65 (62)
98 (95)
95 (90)
71 (65)
>99 (R)
99 (R)
41 (S)
(Sa,S)-5b
(Ra,S)-5c
(S)-5a
>99 (R)
99 (R)
24 (S)
(Sa,S)-5b
(Ra,S)-5c
a
Conditions: 2 mol % [Pd(η3-C3H5)Cl]2, 4.4 mol % ligand, CH2Cl2 as
b
solvent, BSA/KOAc as base, room temperature. Percent conversion
measured after 24 h. Isolated yields are shown in parentheses.
c
Enantiomeric excesses determined by chiral HPLC.
These reactions have attracted great interest because the
substitution products can easily be transformed into chiral acid
derivatives and lactones.30 These substrates have been less
studied and less successfully alkylated than disubstituted
substrates because they are more sterically demanding than
model substrate S1.31 The results shown in Table 7 show the
same trend as for the allylic substitution of S1. The Pd catalysts
containing ligands (S)-5a and (Sa,S)-5b provided the best
enantioselectivities (ee values up to >99% for both substrates).
Again the flexibility conferred by the biaryl phosphite moiety
was enough to adequately control the size of the chiral pocket
in order to achieve enantioselectivities comparable to the best
value reported.31 In line with the literature results, and as
observed for S8, the activities were lower than in the alkylation
reaction of S1.
Comparison of PHOX Ligands and Their Phosphite
Analogues 5. High enantiocontrol is achieved in a variety of
processes employing metal complexes with phosphinooxazoline
ligands (PHOX, e.g., 65) as catalysts,32 and for this reason
phosphinooxazolines are classified as privileged ligands.2 In a
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substrate is therefore a result of the high flexibility of the biaryl
phosphite group.
(m, 2H), 1.65 (m, 4H), 1.59 (m, 4H), 1.33 (s, 18H); 13C NMR
(126 MHz): 150.1 (C), 134.5 (C), 133.8 (C), 129.1 (C), 128.3
(C), 119.5 (C), 34.5 (CH), 29.6 (CH3), 29.5 (CH2), 26.8
(CH2), 23.2 (CH2).
CONCLUSIONS
■
Synthesis of Compound (S)-9.44 In a flame-dried Schlenk,
distilled PCl3 (0.21 mL, 2.46 mmol) and Et3N (0.70 mL, 4.92
mmol) were dissolved in dry toluene (22 mL). The solution
was cooled to −78 °C, and a solution of (S)-8 (500 mg, 1.23
mmol) and DMAP (10 mol %) in toluene (3 mL) was added
dropwise over 10 min. The mixture was warmed to room
temperature overnight. After this time the formation of product
was checked by 31P NMR. The solvent and the residual PCl3
were removed under vacuum. The resulting solid was used for
the next step without any further purification.
In contrast with previously studied flexible ligands, (S)-5a
adopts an Sa,S configuration in complexes mimicking product
olefin complexes obtained in palladium-catalyzed allylic
alkylations of both “broad” and “narrow” allylic substrates.
Although the olefins coordinate with the same face to palladium
in diastereomeric rigid ligands with Sa,S and Ra,S configurations,
products with opposite absolute configuration are obtained.
The explanation is found in the different energies of the
transition state complexes.
The origin of the exceptionally broad substrate scope of the
ligand as well as its ability to control the stereochemistry in a
variety of catalytic processes is connected to its defined
stereochemical structure combined with the high flexibility of
the tropos unit. The unique ability of the ligand to modify its
chiral pocket would justify its addition to the family of
privileged ligands.
Synthesis of Compound (Sa,S)-5b. To a solution of
compound (S)-9 in dry toluene (7 mL) in a flame-dried
Schlenk was added a solution of (S)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)phenol (252.4 mg, 1.23 mmol), Et3N
(0.51 mL, 3.69 mmol), and DMAP (10 mol %) in toluene (3
mL) dropwise at −78 °C. The mixture was warmed to room
temperature and stirred overnight at this temperature. The
precipitate that formed was filtered over a pad of Celite, and the
solvent was evaporated under vacuum. The residue was purified
by flash chromatography (silica gel, hexane/Et2O 10/1 to 3/1)
and then crystallized from hexane/Et2O 5/1 to afford (Sa,S)-5b
EXPERIMENTAL SECTION
■
General Procedures. Unless stated otherwise, reactions
were carried out under an atmosphere of nitrogen using
standard Schlenk techniques. NMR spectra (1H, 13C, and 31P)
were measured on Bruker DRX 400 MHz and Bruker DRX 500
MHz instruments; CDCl3 was used as a solvent, if not further
specified.
1
(75 mg, 10% over two steps) as white crystals. H NMR (500
MHz, CD2Cl2): δ 7.64 (m, 1H), 7.12 (d, J = 10.1 Hz, 1H), 6.98
(m, 1H), 6.93 (s, 1H), 6.92 (s, 1H), 5.58 (m, 1H), 4.29 (dd, J =
17.8, 9.6 Hz, 1H), 4.02 (dd, J = 17.1, 7.7 Hz, 1H), 3.95 (dd, J =
18.1, 8.3 Hz, 1H), 2.84−2.74 (m, 2H), 2.67 (m, 2H), 2.25 (m,
2H), 1.94−1.77 (m, 2H), 1.71 (m, 4H), 1.57 (m, 4H), 1.46 (m,
1H), 1.40 (d, J = 10.1 Hz, 9H), 1.21 (d, J = 10.1 Hz, 9H), 0.97
Materials. With exception of the compounds given below,
all reagents were purchased from commercial suppliers and
used without further purification. The following compounds
were synthesized according to published procedures: (S)-
5,6,7,8,5,6,7,8-octahydro-(1,1′-binaphthalene)-2,2′-diol ((S)-
7),16 (R)-5,6,7,8,5,6,7,8-octahydro-(1,1′-binaphthalene)-2,2′-
diol ((R)-7),16 and (S)-2-(4-isopropyl-4,5-dihydrooxazol-2-
yl)phenol.18 Racemic substrates S1−S14,34 diethyl 2-(3-
butenyl)malonate,35 and diethyl 2-(4-penten-1-yl)malonate36
were prepared as previously reported.
Computational Details. The geometries of all intermedi-
ates were optimized using the Gaussian 09 program,37
employing the B3LYP38 density functional and the
LANL2DZ39 basis set for iridium and the 6-31G* basis set
for all other elements.40 Solvation correction was applied in the
course of the optimizations using the PCM model with the
default parameters for dichloromethane.41 The complexes were
treated with charge +1 and in the single state. No symmetry
constraints were applied. The energies were further refined by
performing single-point calculations using the aformentioned
parameters, with the exception that the 6-311+G**42 basis set
was used for all elements except iridium, and by applying
dispersion correction using the DFT-D343 model. All energies
reported are Gibbs free energies at 298.15 K and calculated as
(dd, J = 10.0, 6.7 Hz, 3H), 0.86 (dd, J = 10.0, 6.8 Hz, 3H). 13
C
NMR (126 MHz): δ 160.9 (CH), 151.7 (C), 151.0 (C), 145.4
(C), 138.8 (C), 138.3 (CH), 135.7 (CH), 135.5 (CH), 133.6
(CH), 133.0 (CH), 131.5 (C), 130.2 (CH), 127.8 (CH), 127.6
(CH), 124.1 (CH), 123.7 (C), 73.5 (CH2), 70.2 (CH2), 34.9
(CH), 34.7 (CH), 33.6 (CH2), 31.2 (CH3), 30.7 (CH2), 29.9
(CH2), 27.7 (CH2), 27.4 (CH2), 23.6 (CH2), 23.5 (CH2),
23.38 (CH2), 23.35 (CH2), 19.3 (CH3), 18.8 (CH3). 31P NMR
(202 MHz): δ 129.0. MS HR-ESI: found 662.3377,
C40H50NO4P (M − Na)+ requires 662.3375.
Synthesis of Compound (R)-8.17 In a Schlenk were
placed (R)-7 (1.0 g, 3.4 mmol), tert-butyl chloride (9.2 mL, 85
mmol), and chloropentacarbonylrhenium(I) (10 mol %). The
reaction mixture was heated at reflux for 18 h under a stream of
nitrogen. The mixture was cooled to room temperature and
concentrated. The residue was purified by flash chromatog-
raphy (silica gel, hexane/CH2Cl2 3/1) to afford (R)-7 (1.0 g,
1
yield 72%) as a white foam. H NMR (500 MHz, CDCl3): δ
6.99 (s, 2H), 4.78 (s, 2H), 2.66 (m, 4H), 2.11 (m, 2H), 2.02
(m, 2H), 1.65 (m, 4H), 1.59 (m, 4H), 1.33 (s, 18H). 13C NMR
(126 MHz): 150.1 (C), 134.5 (C), 133.8 (C), 129.1 (C), 128.3
(C), 119.5 (C), 34.5 (CH), 29.6 (CH3), 29.5 (CH2), 26.8
(CH2), 23.2 (CH2).
Greported = G6‑31G* + (E6‑311+G** − E6‑31G*) + EDFT‑D3
.
Synthesis of Compound (S)-8.17 In a Schlenk were placed
(S)-7 (1.0 g, 3.4 mmol), tert-butyl chloride (9.2 mL, 85 mmol),
and chloropentacarbonylrhenium(I) (10 mol %). The reaction
mixture was heated at reflux for 18 h under a stream of
nitrogen. The mixture was cooled to room temperature and
concentrated. The residue was purified by flash chromatog-
raphy (silica gel, hexane/CH2Cl2 3/1) to afford (S)-8 (1.34 g,
Synthesis of Compound (R)-9.44 In a flame-dried
Schlenk, distilled PCl3 (0.21 mL, 2.46 mmol) and Et3N (0.70
mL, 4.92 mmol) were dissolved in dry toluene (22 mL). The
solution was cooled to −78 °C, and a solution of (R)-8 (500
mg, 1.23 mmol) and DMAP (10 mol %) in toluene (3 mL) was
added dropwise over 10 min. The mixture was warmed to room
temperature overnight. After this time the formation of product
was checked by 31P NMR. The solvent and the residual PCl3
1
yield 97%) as a white foam. H NMR (500 MHz, CDCl3): δ
6.99 (s, 2H), 4.78 (s, 2H), 2.66 (m, 4H), 2.11 (m, 2H), 2.02
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were removed under vacuum. The resulting solid was used for
the next step without any further purification.
0.125 mmol) in dichloromethane (1.5 mL) was added. After 10
min, Cs2CO3 (122 mg, 0.375 mmol) and the corresponding
alkyl alcohol or silanol (0.375 mmol) were added. The reaction
mixture was stirred at room temperature. After the desired
reaction time, the reaction mixture was diluted with Et2O (5
mL) and saturated NH4Cl(aq) (25 mL) was added. The
mixture was extracted with Et2O (3 × 10 mL) and the extract
Synthesis of Compound (Ra,S)-5c. To a solution of
compound (R)-9 in dry toluene (7 mL) in a flame-dried
Schlenk was added a solution of (S)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)phenol (252.4 mg, 1.23 mmol), Et3N
(0.51 mL, 3.69 mmol), and DMAP (10 mol %) in toluene (3
mL) dropwise at −78 °C. The mixture was warmed to room
temperature and stirred overnight at this temperature. The
precipitate that formed was filtered over a pad of Celite, and the
solvent was evaporated under vacuum. The residue was purified
by flash chromatography (silica gel, hexane/Et2O 10/1) to
afford (Ra,S)-5c (69 mg, 9% over two steps) as a white foam.
1H NMR (400 MHz, CD2Cl2): δ 7.71 (m, 1H), 7.09 (m, 1H),
6.98 (m, 2H), 6.12 (m, 1H), 4.28 (m, 1H), 3.94 (m, 2H), 2.77
(m, 2H), 2.70 (m, 2H), 2.30 (m, 2H), 1.92 (m, 2H), 1.66 (m,
8H), 1.47 (s, 2H), 1.38 (m, 9H), 1.34 (m, 1H), 1.21 (m, 10H),
0.96 (d, J = 8.0 Hz, 3H), 0.82 (d, J = 8.0 Hz, 3H). 13C NMR
(101 MHz): δ 161.7 (CH), 150.8 (C), 145.3 (C), 144.9 (C),
139.0 (C), 138.6 (CH), 135.45 (CH), 135.47 (CH), 133.9
(CH), 133.2 (CH), 131.8 (C), 130.0 (CH), 128.1 (CH), 127.8
(CH), 124.2 (CH), 121.7 (C), 73.6 (CH2), 70.7 (CH2), 35.07
(CH), 35.05 (CH), 33.6 (CH2), 31.5 (CH3), 31.3 (CH2), 30.2
(CH2), 27.9 (CH2), 23.51 (CH2), 23.48 (CH2), 23.47 (CH2),
23.38 (CH2), 23.35 (CH2), 19.6 (CH3), 18.7 (CH3). 31P NMR
(162 MHz):L δ 129.33. MS HR-ESI: found 662.3379,
C40H50NO4P (M − Na)+ requires 662.3375.
General Procedure for the Preparation of the Pd(0)
Olefin Complexes for NMR Studies. A solution of ligand
(0.015 mmol), olefin (dimethyl fumarate or diethyl maleate)
(0.015 mmol), and [Pd2(dba)3·CHCl3] (0.0075 mmol) in
CD2Cl2 (15 mM) was stirred for 30 min when dimethyl
fumarate was used and for 16 h when diethyl maleate was used.
After this time the mixture was transferred into a 5 mm NMR
tube and the spectra were recorded. For NMR data, see Table 3
and the Supporting Information.
Typical Procedure for the Allylic Alkylation of Linear
(S1, S3−S8, S11, and S12) and Cyclic (S2, S9, and S10)
Substrates. A degassed solution of [PdCl(η3-C3H5)]2 (1.8 mg,
0.005 mmol) and the desired phosphite-oxazoline ligand 5
(0.011 mmol) in dichloromethane (0.5 mL) was stirred for 30
min. After this time, a solution of substrate (0.5 mmol) in
dichloromethane (1.5 mL), nucleophile (1.5 mmol), N,O-
bis(trimethylsilyl)acetamide (1.5 mmol) and KOAc (3 mg, 0.03
mmol) were added. The reaction mixture was stirred at room
temperature. After the desired reaction time the reaction
mixture was diluted with Et2O (5 mL) and saturated
NH4Cl(aq) (25 mL) was added. The mixture was extracted
with Et2O (3 × 10 mL) and the extract dried over MgSO4. For
compounds 10, 18−26, 35−40, 42, 45−47, 49−52, 56, 59, 61,
63, and 64, the solvent was removed, conversions were
measured by 1H NMR, and enantiomeric excesses were
determined by HPLC. For compounds 11, 41, 43, 44, 53−
55, and 58, conversions and enantiomeric excesses were
determined by GC. For compounds 48 and 57, conversions
were measured by 1H NMR and ee values were determined by
1H NMR using [Eu(hfc)3]. For characterization and ee
determination details see the Supporting Information.
1
dried over MgSO4. Conversion was measured by H NMR.
HPLC was used to determine enantiomeric excesses of
substrates 27−34. For characterization and ee determination
details see the Supporting Information.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b02766.
1H and 13C NMR spectra of (S)-8 and (R)-8, H, 13C,
1
and 31P NMR spectra of 5b,c, H and 31P NMR spectra
1
of 12−17, and computed structures and energies of Pd
olefin complexes and transition states (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail for P.-O.N.: Per-Ola.Norrby@astrazeneca.com.
*E-mail for O.P.: oscar.pamies@urv.cat.
*E-mail for M.D.: montserrat.dieguez@urv.cat.
*E-mail for C.M.: kimo@kth.se.
Author Contributions
⊥These authors contributed equally to this study.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Swedish Research Council (Grant
621-2012-3391), the Spanish Government (CTQ2013-
40568P), the Catalan Government (2014SGR670), and the
ICREA Foundation (ICREA Academia awards to M.D. and
O.P.) is gratefully acknowledged.
REFERENCES
■
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