Asymmetric catalyzed allylic substitution using a Pd/P-S catalyst library with exceptional high substrate and nucleophile versatility: DFT and Pd-π-allyl key intermediates studies

Article abstract of DOI:10.1021/acs.organomet.6b00547

A large library of furanoside phosphite/phosphinite/phosphine-thioether ligands L1-L17a-l has been applied in the Pd-catalyzed allylic substitution reactions of several substrate types using a wide range of nucleophiles. These ligands, which are prepared from inexpensive d-xylose, also incorporate the advantages of the heterodonor, the robustness of the thioether moiety, and the extra control provided by the flexibility of the chiral pocket through the presence of a biaryl phosphite group and a modular sugar backbone. By selecting the ligand components, we have been able to identify catalytic systems that can create new C-C, C-N, and C-O bonds in several substrate types (hindered and unhindered) using a wide range of nucleophiles in high yields and enantioselectivities (ee's up to >99%). Of particular note are the excellent enantioselectivities obtained in the etherification of linear and cyclic substrates, which represent the first example of successful etherification of both substrate types. The DFT computational study is in agreement with an early transition state. Further studies on the Pd-π-allyl intermediates provided a deep understanding of the effect of ligand structure in the origin of enantioselectivity.

Full text of DOI:10.1021/acs.organomet.6b00547

Article
pubs.acs.org/Organometallics
Asymmetric Catalyzed Allylic Substitution Using a Pd/P−S Catalyst
Library with Exceptional High Substrate and Nucleophile Versatility:
DFT and Pd-π-allyl Key Intermediates Studies
Jessica Margalef,† Merce Coll,† Per-Ola Norrby,*,‡,§ Oscar Pamies,*,† and Montserrat Dieguez*,†
̀
̀
̀
́
†Departament de Química Física i Inorgan
̀
ica, Universitat Rovira i Virgili, C/Marcel·lí Domingo 1, 43007 Tarragona, Spain
‡Pharmaceutical Sciences, AstraZeneca, Pepparedsleden 1, SE-431 83 Molndal, Sweden
§Department of Chemistry and Molecular Biology, University of Gothenburg, Kemigarden 4, SE-412 96 Goteborg, Sweden
̈
̊
̈
S
* Supporting Information
ABSTRACT: A large library of furanoside phosphite/
phosphinite/phosphine-thioether ligands L1−L17a−l has
been applied in the Pd-catalyzed allylic substitution reactions
of several substrate types using a wide range of nucleophiles.
These ligands, which are prepared from inexpensive D-xylose,
also incorporate the advantages of the heterodonor, the
robustness of the thioether moiety, and the extra control
provided by the flexibility of the chiral pocket through the
presence of a biaryl phosphite group and a modular sugar
backbone. By selecting the ligand components, we have been able to identify catalytic systems that can create new C−C, C−N,
and C−O bonds in several substrate types (hindered and unhindered) using a wide range of nucleophiles in high yields and
enantioselectivities (ee’s up to >99%). Of particular note are the excellent enantioselectivities obtained in the etherification of
linear and cyclic substrates, which represent the first example of successful etherification of both substrate types. The DFT
computational study is in agreement with an early transition state. Further studies on the Pd-π-allyl intermediates provided a
deep understanding of the effect of ligand structure in the origin of enantioselectivity.
the mixed P-oxazoline ligands have played a dominant role. To
a lesser extent, P-thioether ligands have also demonstrated their
potential utility in Pd-catalyzed asymmetric allylic substitution.3
The pioneering work of the groups of Pregosin4 and Evans,3a
among others, with P-thioether ligands in Pd-allylic substitution
and other relevant asymmetric processes put the focus on these
types of ligands and spur their development. Despite many P−S
ligands being developed, only a few of them were successfully
applied, and their efficiencies were limited in substrate scope
(enantioselectivities were only high in the allylic substitution of
hindered standard substrate rac-1,3-diphenyl-3-acetoxyprop-1-
ene).3 Compared to other functional groups, the thioether-
based ligands have been less used because mixtures of
diastereomeric thioether complexes are produced and because
it is difficult to control their interconversion in solution.5
Nevertheless, if the ligand scaffold can control the S-
coordination, then this feature may be extremely beneficial
because then the chirality moves closer to the metal. In this
respect, we recently identified a simple ligand backbone that
can control thioether coordination in Pd/phosphite-thioether
catalysts. Our preliminary results showed than xylofuranoside
phosphite-thioether ligands can be successfully applied in the
Pd-catalyzed allylic substitution of several substrates types using
INTRODUCTION
■
Transition-metal-based asymmetric catalysis is a reliable,
selective, and atom-economic strategy to access optically pure
compounds. Remarkable efforts have been dedicated to the
enantioselective Pd-catalyzed allylic substitution as one of the
most relevant methods for creating C−C and C−heteroatom
bonds.1 Over the last decades, a great number of ligands have
been successfully applied in this process. Most of these ligands
are equipped with strong and weak donor heteroatom pairs
(e.g., P−N, P−S, P−P′, etc.), which take advantage of the
different trans influence of the two coordinative groups.1 In this
context, our group has contributed with a new generation of
advanced ligands. We have found that biaryl π-acceptor groups
(phosphite or phosphoroamidite moieties) in the ligands have
an extremely positive effect on substrate versatility and
activity.1j,2 Despite all the remarkable advances in catalyst
design, most of the ligands still rarely tolerate a broad range of
substrates, and each type of substrate requires a particular
ligand to optimize enantiopurity. Additional efforts are also
required to widen the range of nucleophiles. Many important
nucleophiles still provide suboptimal results with known
catalysts. The discovery of more efficient catalysts, suited for
a broad range of substrate and nucleophiles, is key for achieving
the sustainable production of all the sorts of C−C and C−
heteroatom bonds required for synthesizing more complex
organic reactions in near future. Among heterodonor ligands,
Received: July 7, 2016
© XXXX American Chemical Society
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several nucleophiles.6 Despite this success, a systematic study of
the scope of P,S-ligands is still needed. Moreover, no
mechanistic studies exist about these ligands that can predict
a priori the right ligand that will provide a high
enantioselectivity. Therefore, more research is also required
to discern the role of ligand parameters in the origin of
enantioselectivity.
To investigate these possibilities, in this paper we expand the
previous study of 20146 to other furanoside phosphite-thioether
ligands (Figure 1) and also extent the study of these ligands to
substrate. Enantioselectivity is lower for unhindered substrates
than for the corresponding hindered substrates. To evaluate the
phosphite/phosphinite/phosphine-thioether ligands L1−
L17a−l in the Pd-allylic substitution of substrates with different
steric properties, we initially tested the ligands in the
substitution of the hindered substrate rac-1,3-diphenyl-3-
acetoxyprop-1-ene S1 and that of two unhindered substrates
rac-3-acetoxycyclohexene S2 and rac-1,3-dimethyl-3-acetoxy-
prop-1-ene S3 (eq 1). In all the cases, the catalysts were
generated in situ from π-allyl-palladium chloride dimer
[PdCl(η3-C3H5)]2, the corresponding ligand, and the nucleo-
phile. The results (Table 1) indicate that enantioselectivity
varies considerably depending on the position of the thioether
group in the furanoside backbone, the configuration of C3, the
thioether substituents, and the substituents/configuration in the
biaryl phosphite moiety (a−h), as well as whether the
phosphite moiety is replaced by a phosphinite (i−k) or a
phosphine (l) group.
The results indicate a cooperative effect between the position
of the thioether group and the configuration of carbon atom C3
of the furanoside backbone (Table 1, entries 1, 12, 31, 34, 39,
43, and 44). While for substrates S1 and S2 the matched
combination is achieved with 5-deoxy-xylofuranoside derived
ligands L1−L9 (which have the thioether at C5 of the
furanoside backbone and whose carbon atom C3 has an S
configuration), for substrate S3 the matched combination is
achieved with 5-deoxy-ribofuranoside derived ligands L10−
L13. It should be pointed out when the thioether group was
attached to C3 (ligands L14−L17; entries 39−44) the
enantioselectivity was lower than when the thioether moiety
was attached to C5. This suggests that the furanoside backbone
controls better the thioether inversion when the thioether
group is attached to C5 (flexible primary carbon) rather to the
stereogenic secondary carbon C3. This unexpected behavior
proves the relevance of using highly modular scaffold to make
new ligands.
The effects of the phosphite moiety were studied with the 5-
deoxy-xylofuranoside ligands L1a−h (Table 1, entries 1−8).
We found that enantioselectivity increased with bulky
substituents at the ortho positions of the biaryl phosphite
moieties (i.e., entries 1−3 vs 4) but was hardly changed by the
nature of the substituents at the para positions of the biaryl
phosphite group (entries 1−3). The results also show a
cooperative effect between the configuration of the bulky
biphenyl moiety and the configurations of the ligand backbone.
This led to a matched combination for ligand L1f, which
contains an S-biaryl moiety (entry 6). Nevertheless, the
cooperative effect using 5-deoxy-ribofuranoside ligands L13e,f
led to a matched combination for ligand L13e, containing an R-
biaryl moiety (entry 37). The results also indicated that to
obtain high enantioselectivities an S configuration of the biaryl
phosphite moiety must be adopted for substrates S1 and S2
(entries 6, 21, and 29) while an R configuration is needed for
substrate S3 (entries 32 and 37).
Figure 1. Phosphite/phosphinite/phosphine-thioether ligand library
L1−L17a−l.
other substrates and nucleophiles. To do so, we have taken
advantage of the high modularity of these sugar-based ligands
and have synthesized and screened a library of potential 204
furanoside phosphorus-thioether ligands starting from the same
underlying structure (Figure 1). We have therefore added two
new ligand backbones (ligands L14−L15 and L16−L17) to the
Pd−P,S catalyst library, thus completing a two-level two-factor
design with the four diastereomers that can be obtained by
varying the configuration of C3 and the position of the
thioether groups at either C5 and C3 of the furanoside
backbone. This design allowed a comparative study of the
effects of these configurations and of the position of the
thioether group, as well as to discover any cooperative effects
between them.
We have also enlarged the whole catalyst library by adding
new substituents in the thioether and biaryl phosphite group.
Finally, we also compare the effectiveness of these phosphite-
thioether ligands with the related phosphinite-thioethers (L1−
L17i−k) and phosphine-thioethers (L1−L17l). By varying
these ligand parameters, we achieved high enantioselectivities
and activities in a large number of hindered and unhindered
substrates using a wide range of C-, N-, and O-nucleophiles. We
have also extended the use of these new catalytic systems in
propylene carbonate as alternative environmentally friendly
solvent. In this paper we have also carried out DFT calculations
and the synthesis of the Pd-π-allyl intermediates in order to
explain the origin of enantioselectivity.
RESULTS AND DISCUSSION
■
Allylic Substitution of Disubstituted Substrates S1−
S3 Using Dimethyl Malonate as Nucleophile. As
mentioned previously, asymmetric Pd-catalyzed allylic sub-
stitution is highly dependent on the steric demands of the
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a
Table 1. Pd-Catalyzed Allylic Alkylation of S1−S3 with Dimethyl Malonate Using the Ligand Library L1−L17a−l
a
0.5 mol % [PdCl(η3-C3H5)]2, ligand (0.011 mmol), S1−S3 (1 mmol), CH2Cl2 (2 mL), BSA (3 equiv), dimethyl malonate (3 equiv), KOAc (5 mol
b
c
%), rt. Conversion percentage determined by 1H NMR (for S1) or GC (for S2 and S3). Enantiomeric excesses determined by HPLC (for S1) and
GC (for S2−S3). Absolute configuration drawn in parentheses. Isolated yields ≥92%.
d
The effect of the phosphinite moiety was studied with ligands
L1i−k. The results indicated that enantioselectivity was
negatively affected by the steric bulk of the phosphinite
group (entries 9−11). Thus, in general, ligands containing a
mesityl phosphinite group provided the lowest enantioselecti-
vites of the phosphinite series. Moreover, when we compared
these results with those achieved with the phosphite (L1a−h)
and phosphine (L7l; entry 22) counterparts, we observed that
the best enantioselectivities were obtained with ligands
containing a bulky S-biaryl phosphite moiety (ligand L1f).
C
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The effect of the thioether substituent was studied with
ligands L1−L9 (Table 1). Results showed that an aryl thioether
substituent is needed for high enantioselectivity. Thus, in
general the highest enantioselectivities were achieved using a
phenyl (ligands L1), 2,6-dimethylphenyl (ligands L7), or a 1-
naphthyl (ligands L9) thioether groups.
best results with Pd-(R,R)-FerroNPS11c and Pd-CycloN2P2-
Phos11d catalytic systems specifically designed for this purpose.
We also found that the biaryl phosphite group in Pd-L9f and
Pd-L13e can adapt its chiral pocket and successfully catalyze
other linear substrates S3−S8 with different steric and
electronic requirements (Table 2, entries 17−25). Advanta-
geously, we found that the catalytic performance was not
affected by either the introduction of ortho- and meta-
substituents at the phenyl groups of the substrate S1 or the
introduction of electron-withdrawing and -donating groups
(compounds 20 and 23−25). The use of C-nucleophiles other
than dimethyl malonate provides comparable excellent
enantioselectivities. In the alkylation of the unhindered
substrate S3 using Pd-L13e catalytic system as observed
using dimethyl malonate as nucleophile (Table 1), the use of
other C-nucleophiles led to a lower but still remarkable
enantioselectivity (ee’s up to 90%, compounds 26 and 27) for
this challenging substrate. There are fewer successful catalysts
for the Pd-catalyzed allylic substitution of S3 than the allylic
substitution of hindered S1 due to the presence of less sterically
demanding methyl syn substituents. Also, the Pd-allylic
alkylation of substrate S8, which is more sterically demanding
and is usually substituted much less enantioselectively than S1,
also proceeded with high enantioselectivity (>95% ee;
compound 28, entry 25). These results are among the best in
the literature for these substrates, even with synthetically useful
nucleophiles other than dimethyl malonate, for which only very
few catalytic systems have provided high enantioselectivities.
We completed the study by applying Pd-L9f in the allylic
substitution of cyclic substrates with different ring size (S2, S9,
and S10) with a range of C-, N-, and O-nucleophiles (Table 2,
entries 27−35). Due to the presence of less bulky anti-
substituents, the enantioselectivity for cyclic substrates is more
difficult to control than for S1. The results show that
enantioselectivities in the allylic alkylation of S2 were as high
as those obtained using dimethyl malonate (ee’s up to 98%),
except when the nucleophile was dimethyl methylmalonate,
which led to a slightly lower enantioselectivity (compound 29;
87% ee). Excellent ee’s were therefore obtained using
challenging allyl- and propargyl-substituted nucleophiles
(compounds 30 and 31), acetylacetone (compound 32), and
benzylamine (compound 33). Even more remarkable are the
high yields and enantioselectivities achieved in the etherification
of S2 (compound 34). Pd-L9f is the first catalytic system that
can etherificate both linear substrates S1 (Table 2, compounds
15−19) and cyclic substrates S2 with high ee’s (compound 34,
entry 31).11a
In summary, the optimization of the ligand structure lead us
to identify Pd/L9f and Pd/L13e as two of the very few Pd-
catalysts that can provide excellent enantiocontrol for the
substrates with different steric demands that we tested (ee’s up
to >99% for S1 and S2 with Pd/5-deoxy-xylofuranoside based
ligand L9f, entry 29, and up to 96% for S3 with Pd/using 5-
deoxy-ribofuranoside ligand L13e, entry 37). These results
compare favorably with the best ones reported in the literature.
Allylic Substitution of Disubstituted Substrates Using
Several Nucleophiles: Scope and Limitations. We also
studied the scope of the best catalytic systems (Pd-L9f for
hindered linear substrate S1 and unhindered cyclic substrate
S2; Pd-L13e for unhindered linear substrate S3) considering
other C-, N-, and O-nucleophiles and more substrates (Figure
2).
Figure 2. Substrates S1−S10 used in this study.
We first studied the allylic substitution of S1 with Pd-L9f
catalyst using a variety of C-, N-, and O-nucleophiles (Table 2).
Several malonates, including those substituted with allyl,
butenyl, pentenyl, and propargyl groups, reacted efficiently
with S1 to afford products 4−10 in high yields and
enantioselectivities (ee’s up to 99%, entries 1−7) comparable
to those obtained with dimethyl malonate. These results are
highly relevant because compounds 7−10 are key intermediates
for synthesizing more complex chiral molecules.7 The reaction
also worked well when the nucleophiles were acetylacetone
(compound 11, entry 8) and benzylamine (compound 14,
entry 11) (ee’s up to >99%). The excellent enantiocontrol also
extends to the use of malononitrile and isopropyl cyanoacetate
(compounds 12 and 13; ee’s up to 99%, entries 9 and 10). The
use of the isopropyl cyanoacetate resulted in the formation of
two diastereoisomers in excellent ee’s, albeit with low
diastereoselectivity, like in previous reports.8
Aliphatic alcohols are other relevant nucleophiles that are
receiving much attention. The allylic substitution with this type
of O-nucleophiles opens up a path for obtaining aliphatic chiral
ethers which are important for the synthesis of biologically
active targets.9 However, in contrast to the use of phenols as
nucleophiles,10 aliphatic alcohols have been less stud-
ied.2g,3a,7c,11 Moreover, the results of the aliphatic alcohols to
a larger extent depend on the type of alcohol, and simple
modifications in its electronic properties can lead to important
differences in enantioselectivity.2g,3a,7c,11 Improving previous
results, we found that Pd-L9f is quite robust to varying
electronic properties of the nucleophile (Table 2, entries 12−
16). A broad range of aliphatic alcohols reacted efficiently with
S1 to afford compounds 15−19 with excellent yields and
enantioselectivities (ee’s up to >99%). Our results surpass the
Advantageously, Pd-L9f could also provide excellent yields
and enantioselectivities, comparable to the best ones reported
in the literature with other cyclic substrates with a different ring
size (entries 32−25). Pd-L9f also successfully catalyzed the
allylic substitution of rac-3-acetoxycyclopentene (compounds
35 and 36), which is usually substituted less enantioselectively
than the 6-membered cyclic substrate S2 thanks to the ability of
the biaryl phosphite group to adapt its chiral pocket.
Encouraged by the excellent results, we went one step further
and studied the Pd-catalyzed allylic substitution using 1,2-
propylene carbonate (PC). PC has emerged as a sustainable
“green” alternative to standard organic solvents because of its
high boiling point, low toxicity, and environmentally friendly
synthesis.12 We repeated, using PC as solvent, the allylic
substitution of substrates S1−S10 with the ligands that
provided the best enantioselectivities for each substrate and
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a
Table 2. Pd-Catalyzed Allylic Alkylation of S1−S10
a
0.5 mol % [PdCl(η3-C3H5)]2, L9f (0.011 mmol), substrate (1 mmol), CH2Cl2 (2 mL), BSA (3 equiv), nucleophile (3 equiv), KOAc (5 mol %), 3 h,
b
c
rt. Enantiomeric excesses determined by HPLC or GC. Absolute configuration drawn in parentheses. Reactions carried out using 2 mol %
d
[PdCl(η3-C3H5)]2, 4 mol % ligand, Cs2CO3 (3 equiv) for 18 h. Reactions carried out using L13e at 0 °C.
with various C- and N-nucleophiles. The results are collected in
Table 3. We were pleased to see that the enantioselectivities
with PC remained as high as those observed with dichloro-
methane for a wide range of nucleophiles and substrates types.
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either early or late depending on the nucleophile, ligands, and
reaction conditions. In an early TS, the interactions leading to
stereochemical differentiation can be understood from the
structure of the Pd-allyl intermediate,13 whereas the late TS is
more reminiscent of the Pd-alkene product complex.14 For the
early TS case, stereochemistry is governed by both the
population of the Pd-η3-allyl intermediates and the relative
electrophilicity of the allylic carbon atoms. When the TS is late,
the formation of the most stable Pd-olefin complex controls
enantioselectivity. Previous experience has shown that
ammonia can be used as a good model nucleophile,15 avoiding
the problems related to charge separation in conjunction with a
continuum solvent model. Note that the use of ammonia as
nucleophile instead of dimethyl malonate results in the
inversion of the CIP descriptor in the 1,3-diphenylallyl case,
due to the change in priority of the groups, although the sense
of stereoselectivity is maintained.
Table 3. Pd-Catalyzed Allylic Alkylation of S1−S10 Using
a
Propylene Carbonate (PC) as Solvent
b
entry substrate
Nu−H (product)
% yield
% ee
1
S1
S1
S1
S1
S1
S1
S1
S1
S2
S2
S2
S3
S4
S4
S5
S6
S7
S8
S9
S10
S10
H−CH(COOMe)2 (1)
H−CMe(COOMe)2 (6)
H−Callyl(COOMe)2 (7)
H−Cbutenyl(COOMe)2 (8)
H−Cpentenyl(COOMe)2 (9)
H−Cpropargyl(COOMe)2 (10)
H−CH(COMe)2 (11)
87
88
90
86
87
84
90
87
87
78
80
81
87
85
81
83
86
82
73
83
81
98 (S)
97 (R)
92 (R)
97 (R)
94 (R)
98 (R)
98 (S)
99 (R)
95 (S)
98 (S)
95 (S)
94 (S)
98 (S)
98 (R)
97 (S)
97 (S)
99 (S)
>95 (S)
>95 (S)
98 (S)
99 (S)
2
3
4
5
6
7
8
H−NHBn (14)
9
H−CH(COOMe)2 (2)
H−Cpropargyl(COOMe)2 (31)
H−CH(COMe)2 (32)
10
11
12
13
14
15
16
17
18
19
20
21
c
H−CH(COOMe)2 (3)
H−CH(COOMe)2 (20)
H−Callyl(COOMe)2 (21)
H−CH(COOMe)2 (23)
H−CH(COOMe)2 (24)
H−CH(COOMe)2 (25)
H−CH(COOMe)2 (28)
H−CH(COOMe)2 (35)
H−CH(COOMe)2 (37)
H−Cpropargyl(COOMe)2 (38)
We calculated the relative stability of the transition states
TSendo and TSexo using NH3 as nucleophile and the Pd-olefin
intermediates (Pd-olefinendo and Pd-olefinexo). Only the two
syn−syn allyl complexes were calculated. The contribution of
the other allylic species of higher energy (anti−anti and syn−
anti) was neglected. In this study we have taken into account
the configuration of the thioether, the rotation of the thioether
substituent, and the attack of the nucleophile trans to P and S
atoms. In contrast to P,N-ligands, the trans effect between the
thioether and the phosphite are more similar. Recent studies by
Norrby et al. have shown that small changes in sterics can shift
the trans preference in P,S-ligands.16 The results of the most
stable transition states leading to the formation of both product
enantiomers are shown in Table 4 (the results of the full set of
calculated TS can be found in the Supporting Information).
The energy differences of the calculated TS’s using S1 and S2
agree with the catalytic results. The energy difference between
a
0.5 mol % [PdCl(η3-C3H5)]2, L9f (0.011 mmol), substrate (1 mmol),
CH2Cl2 (2 mL), BSA (3 equiv), nucleophile (3 equiv), KOAc (5 mol
b
%), 40 °C, 3 h. Enantiomeric excesses determined by HPLC or GC.
c
Absolute configuration drawn in parentheses. Reaction carried out
using L13e.
Origin of Enantioselectivity. DFT Computational Stud-
ies. We performed a DFT computational study of the key
intermediates and transition states involved in the enantiocon-
trol of the Pd-catalyzed allylic substitution of hindered substrate
S1 and unhindered substrate S2, using ligands L9e and L9f as
models. These ligands contain two different biaryl phosphite
groups that will help us understand the reason why bulky chiral
biaryl phosphite moieties enhance enantioselectivity. The
mechanistic studies found in the literature have shown that
enantioselectivity is controlled in the effectively irreversible
nucleophilic attack, but transition state (TS) for this step can be
the TS’s using S1 with ligand L9f (ΔG# = 18.7 kJ mol−1; eecalc
>
=
99(S)) is higher than that of L9e (ΔG# = 2.9 kJ mol−1; eecalc
52% (R)). This is in good agreement with the higher
enantioselectivities achieved using L9f (Table 1, > 99% ee for
L9f vs 33% ee for L9e). In addition, the formation of the
opposite enantiomers of the substituted product is predicted
when L9e and L9f are used. Similarly, in the reaction of S2 with
Table 4. Calculated Energies for the Most Stable TS’s and Pd−Olefin Complexes Using S1 and S2 and NH3 as Nucleophile
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Figure 3. Representation of the calculated most-stable transition states from (a) S1 and (b) S2 using ligands L9e and L9f.
L9f, the TS leading to the product observed experimentally is
the most stable one. However, the energy difference between
the TS’s (ΔG# = 4.1 kJ mol−1) is lower than that for substrate
S1 (ΔG# = 18.7 kJ mol−1), which agrees with the lower
enantioselectivity achieved with S2. It should be pointed out
that with S2 and ligand L9f both enantiomers of the
substitution product arise from TS’s with endo coordination
of the substrate with the nucleophile attack trans to P (for the
major enantiomer) and trans to S (for the minor enantiomer).
Figure 3 shows the calculated transition states using ligands L9e
and L9f. We can see that the most stable TS’s, which for both
substrates contain ligand L9f (Pd-L9f TSexo for S1 and Pd-L9f
TSendo for S2), show a different ligand disposition around the
metal center than the less stable TS’s. As a consequence, the
biaryl phosphite moiety in ligand L9f has the sufficient
flexibility to generate a suitable chiral pocket that can effectively
accommodate both types of substrates, thereby yielding high
enantioselectivities for both substrates.
However, the calculated energies of the Pd-olefin inter-
mediates do not correlate well with the experimental results.
For instance, although the calculated results of the Pd-olefin
complexes of S1 correctly predict the formation of opposite
enantiomers of the substitution products with L9e and L9f; the
calculated energy differences between both Pd-olefin complexes
are very similar for both ligands (for ligand L9e, ΔG# = 10.1 kJ
mol−1; eecalc = 97% (R); for ligand L9f, ΔG# = 12.3 kJ mol−1;
eecalc = 99% (S)). This indicates that if the reaction proceeds via
a late TS then both ligands should provide similar levels of
enantioselectivity which does not agree with the experimental
results.
understand their catalytic behavior. For this purpose, we next
studied the Pd-π-allyl compounds 39−43 [Pd(η3-allyl)(L)]BF4
(L = L1a, L9e,f and L13e). Pd-complexes 39−43 containing
1,3-diphenyl, 1,3-dimethyl, or cyclohexenyl allyl groups were
prepared as previously reported from the corresponding Pd-
allyl dimer and the appropriate ligand in the presence of silver
tetrafluoroborate (Scheme 1).17 We have used 1H, 13C, and 31
P
Scheme 1. Preparation of [Pd(η3-allyl)(L)]BF4 Complexes
39−43
NMR spectroscopy to characterize them. The NMR assign-
ments have been performed using the information from
1H−1H, 31P−1H, and 13C−1H correlation measurements in
combination with 1H−1H NOESY experiments. Unfortunately,
we were unable to achieve crystal of sufficient quality to make
X-ray diffraction measurements.
The VT-NMR study (30 °C to −80 °C) of Pd-1,3-diphenyl
allyl intermediate 39, which contains the ligand that has
provided the highest enantioselectivity in the allylic substitution
of S1 (Table 1), showed a 1:4 mixture of two isomers in
equilibrium (Scheme 2).
Both isomers were unambiguously assigned by NMR to the
two syn/syn Pd-η3-endo and exo isomers. In both isomers, the
NOE indicated interactions between the two terminal protons
of the allyl group, which clearly indicates a syn/syn disposition.
In addition, for the major isomer, one of the tert-butyl
substituents of the phosphite moiety (the one that shows NOE
interaction with the hydrogen attached to C3) showed NOE-
Preparation and NMR Study of Pd-Allyl Intermediates.
DFT studies have shown that enantioselectivity is determined
during the nucleophilic attack. Consequently, the structural
elucidation of the Pd-allyl intermediates and the determination
of their relative reactivity toward the nucleophile are crucial to
G
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We also studied Pd-1,3-diphenyl allyl intermediate 40. This
contains ligand L1a which differs from previous ligand L9f in
the presence of an achiral biaryl phosphite moiety and provided
low enantioselectivity in the substitution of S1 (Table 1). As for
intermediate 39, a 1:4 mixture of two isomers in equilibrium
was observed (Scheme 3). However, an important difference is
Scheme 2. Diastereoisomer Pd-allyl Intermediates for S1
with Ligand L9f (Isomers 39)
a
Scheme 3. Diastereoisomer Pd-allyl Intermediates for S1
a
with Ligands L1a (Isomers 40)
a
The relative amounts of each isomer are shown in parentheses. The
chemical shifts (in ppm) of the allylic terminal carbons are also shown.
interaction with the terminal allyl proton trans to the thioether
group, while for the minor isomer this interaction appears with
the central allyl proton (Figure 4). These interactions can be
a
The relative amounts of each isomer are shown in parentheses. The
chemical shifts (in ppm) of the allylic terminal carbons are also shown.
that the electrophilicities of the allylic terminal carbon atom
trans to the phosphite are rather similar in both complexes
(Δδ(13C) ≈ 0.3 ppm), which makes both species react at
similar rate. This agrees with the low enantioselectivity
obtained with Pd-L1a.
We next studied Pd π-allyl complex [Pd(η3-1,3-dimethyl-
allyl)(L13e)]BF4 (41) with unhindered linear substrate S3 and
the ligand that had provided the highest enantioselectivity. The
VT-NMR study (30 °C to −80 °C) showed a 1:3 mixture of
two isomers in equilibrium, which were assigned by NMR to
the two syn/syn Pd-η3-endo and exo isomers (Scheme 4). In
Figure 4. Main NOE contacts for Pd-allyl intermediates 39.
explained by assuming a syn/syn Pd-exo disposition for the
major isomer and an endo disposition for the minor isomer.
Although the population of the Pd-allyl intermediates obtained
by DFT calculations is different than those found by NMR, the
general trend is reproduced well (see Table S1). Thus, the
major isomer is Pd-η3-exo. The carbon chemical shifts of
compound 39 indicate that the most electrophilic allylic
terminal carbon is located trans to the phosphite moiety in
the major isomer (Δδ(13C) ≈ 5.4 ppm). Assuming that the
nucleophilic attack takes place at the more electrophilic allyl
carbon terminus and in line with the DFT calculations, the
stereochemical outcome of the reaction is not fully controlled
by the population of the Pd-allyl intermediates (note that the
diastereomeric excesses differ from the enantiomeric excesses),
so the relative electrophilicity of the terminal allylic carbons of
each isomer plays an important role and has to be taken into
account. The excellent enantioselectivities obtained with Pd-9f
catalytic system can be therefore explained by the fact that the
major isomer is also the fast-reacting one. To prove this, we
studied the reactivity of Pd-1,3-diphenyl allyl intermediate 39
with sodium malonate at low temperature (−80 °C) by in situ
NMR (see Supporting Information). Our results showed that
the major exo isomer reacts around 8 times faster than the endo
isomer, affording the alkylation product in 96% (S) ee. If we
take into account the relative reaction rates and the abundance
of both isomers, then the calculated ee should be 94% (S),
which is in a good accordance with the ee obtained
experimentally.
Scheme 4. Diastereoisomer Pd-allyl Intermediates for S3
a
with Ligands L13e (Isomers 41)
a
The relative amounts of each isomer are shown in parentheses. The
chemical shifts (in ppm) of the allylic terminal carbons are also shown.
both isomers, the NOE indicated interactions between the
central allyl proton and the two methyl substituents, which
clearly indicates a syn/syn disposition. In addition, for the minor
endo isomer, there is a NOE interaction between the central
allyl proton and the tert-butyl substituent of the phosphite
moiety that shows NOE with the hydrogen attached to C4
(Figure 5). For the major exo isomer, there is a NOE
interaction between one of the methyl substituents of the
H
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Figure 6. Main NOE contacts for the major isomer of Pd-allyl
intermediates 42 and 43.
Figure 5. Main NOE contacts for Pd-allyl intermediates 41.
therefore be attributed to the fact that only one Pd-allyl
intermediate is detected.
substrate (the one trans to the thioether) and one of the tert-
butyl substituents of the phosphite group (the one that does
not show NOE with the hydrogen attached to C4 of the
furanoside backbone; Figure 5). The carbon chemical shifts
show that the most electrophilic allylic terminal carbon is
located trans to the phosphite in the major isomer (Δδ(13C) ≈
4.7 ppm). The high enantioselectivity obtained with Pd/L13e
system can be therefore attributed to the fact that the major
isomer is also the fastest-reacting one.
CONCLUSIONS
■
A large library of furanoside phosphite/phosphinite/phosphine-
thioether ligands L1−L17a−l has been applied in the Pd-
catalyzed allylic substitution of several substrates using a wide
range of nucleophiles. These ligands, which are prepared from
inexpensive D-xylose, have the advantages of the robustness of
the thioether moiety and the extra control provided by the
flexibility of the chiral pocket through the presence of a biaryl
phosphite group and a modular sugar backbone. Other
advantages are that they are stable to air and other oxidizing
agents and can be manipulated/stored in air. The structural
variety of this library allowed us to investigate the effect on
catalytic performance of systematically varying the position of
the thioether group at either C5 or C3 of the furanoside
backbone and the effect of the configuration at C3 of the
furanoside backbone. We also studied the effects of the
substituents in the thioether group, the configuration of the
biaryl phosphite moiety and of their substituents, and the
replacement of the phosphite moiety by either a phosphinite
group or a phosphine group. By choosing the ligand
components, we have identified catalytic systems that create
C−C, C−N, and C−O bonds in hindered and unhindered
substrates for a wide range of nucleophiles in high
enantioselectivities (ee’s up to >99%) and yields. We note
the excellent enantioselectivities achieved in the etherification
of linear and cyclic substrates, which represent the first
successful etherification of both hindered and unhindered
substrates. The results presented here compete very well with a
few other ligands that also provide high ee in several substrate
types using C-, N-, and O-nucleophiles. Moreover, the process
Finally, in an attempt to learn more how the configuration of
the biaryl phosphite group affects the enantioselectivity
observed in the allylic substitution of the unhindered cyclic
substrate S3, we studied Pd-1,3-cyclohexenyl-allyl intermediate
42, which contains L9e, and compared it with its related
counterpart Pd/L9f (compound 43). The VT-NMR study (30
°C to −80 °C) of Pd-1,3-cyclohexenyl allyl intermediates 42
and 43 showed a mixture of two isomers in equilibrium at a
ratio of 3:2 and >20:1, respectively (Scheme 5). The major
isomers were unambiguously assigned by NOE to Pd-η3-endo
isomers. Thus, NOE interactions were found between one of
the tert-butyl substituents of the phosphite moiety (the one that
shows NOE interaction with the hydrogen attached to C3) and
the central allyl proton and the allyl proton trans to the
thioether group (Figure 6). The same population of the Pd-allyl
intermediates was predicted by DFT (see Table S1). The
carbon NMR chemical shifts indicated that the most electro-
philic allylic terminus carbon is trans to the phosphite moiety.
For complex 42, the fact that the electrophilicity of the allylic
terminal carbon atom trans to the phosphite is rather similar in
both complexes (Δδ(13C) ≈ 1.1 ppm) suggests that both
isomers react at a similar rate, so the enantioselectivity is mainly
affected by the population of the endo and exo isomers. The
much higher enantioselectivity obtained using Pd-L9f can
a
Scheme 5. Diastereoisomer Pd-allyl Intermediates for S2 with Ligands L9e (Isomers 42) and L9f (Isomer 43)
a
The relative amounts of each isomer are shown in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are also shown.
I
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(262 μL, 3 mmol) was 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. The solvent was removed,
conversions were measured by 1H NMR, and enantiomeric excesses of
compounds were determined by HPLC.
can be carried out in propylene carbonate as alternative
environmentally friendly solvent with no loss of enantiose-
lectivity. A DFT computational study of the key intermediates
and transition states involved in the enantiocontrol is in
agreement with an early transition state. Further studies on the
Pd π-allyl intermediates improved our understanding of the
effect of the ligand parameters on the origin of the
enantioselectivity. Therefore, for enantioselectivities to be
high, the ligand parameters need to be correctly combined so
that either the Pd-intermediate that has the fastest reaction with
the nucleophile is predominantly formed (for linear hindered
S1 and unhindered S3 type substrates) and/or that one of the
isomers is predominantly formed (for unhindered cyclic S2).
These results open up the enantioselective Pd-allylic sub-
stitution of several substrate types with a large variety of
nucleophiles to the potential effective use of readily available,
easy to handle, and highly modular phosphite-thioether ligands.
Typical Procedure for the Allylic Etherification. A degassed
solution of [PdCl(η3-C3H5)]2 (0.9 mg, 0.0025 mmol) and the
corresponding ligand (0.0055 mmol) in dichloromethane (0.5 mL)
was stirred for 30 min. Subsequently, a solution of the corresponding
substrate (31.5 mg, 0.125 mmol) in dichloromethane (1.5 mL) was
added. After 10 min, Cs2CO3 (122 mg, 0.375 mmol) and benzyl
alcohol (40 μL, 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 dried over MgSO4. The solvent was removed,
1
conversions were measured by H NMR, and enantiomeric excesses
were determined by HPLC.
Preparation of Pd-Allyl Intermediates. The corresponding
ligand (0.05 mmol) and the complex [Pd(μ-Cl)(η3-1,3-allyl)]2 (0.025
mmol) were dissolved in CD2Cl2 (1.5 mL) at room temperature
under argon. AgBF4 (9.8 mg, 0.05 mmol) was added after 30 min and
the mixture was stirred for 30 min. The mixture was then filtered over
Celite under argon and the resulting solutions were analyzed by NMR.
After the NMR analysis, the complexes were precipitated as pale
yellow solids by adding hexane.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out using
standard Schlenk techniques under an argon atmosphere. Commercial
chemicals were used as received. Solvents were dried by means of
standard procedures and stored under argon. 1H, 13C{1H}, and
31P{1H} NMR spectra were recorded using a Varian Mercury 400
MHz spectrometer. Chemical shifts are relative to that of SiMe4 (1H
and 13C{1H}) as an internal standard. Racemic substrates S1−S10
were prepared as previously reported.18 Ligands L1−L17a−l were
prepared as previously described.19
Computational Details. Geometries of all transition states and
intermediates were optimized using the Gaussian 09 program,20
employing the B3LYP21 density functional and the LANL2DZ22 basis
set for palladium and the 6-31G*23 basis set for all other elements.
Solvation correction was applied in the course of the optimizations
using the PCM model with the default parameters for dichloro-
methane.24 The complexes were treated with charge +1 and in the
singlet state. No symmetry constraints were applied. Normal mode
analysis of all transition states revealed a single imaginary mode
corresponding to the expected nucleophilic attack of ammonia to one
of the two allylic termini. The energies were further refined by
performing single-point calculations using the above-mentioned
parameters, with the exception that the 6-311+G**25 basis set was
used for all elements except for palladium, and by applying dispersion
correction using the DFT-D326 model. All energies reported are Gibbs
[Pd(η3-1,3-diphenylallyl)(L9f)]BF4 (39). Isomer endo (20%): 31P
NMR (161 MHz, CD2Cl2, δ) 137.1 (s). 1H NMR (400 MHz, CD2Cl2,
δ) 1.19 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.58 (s, 9H, CH3, t-Bu), 1.67
(s, 9H, CH3, t-Bu), 1.72 (s, 3H, CH3), 1.76 (s, 3H, CH3), 2.31 (s, 3H,
CH3), 2.37 (s, 3H, CH3), 3.21 (m, 1H, H5′), 3.56 (dd, 1H, H5, 2J5−5′
3
= 12.4 Hz, J5−4 = 4.8 Hz), 4.42 (m, 2H, H4, CHallyl trans to S),
3
4.63 (d, 1H, H2, J2−1 = 3.6 Hz), 4.97 (b, 1H, H3), 5.03 (m, 1H,
CHallyl trans to P), 5.71 (d, 1H, H1, 3J1−2 = 3.6 Hz), 6.42 (m, 1H,
CHallyl central), 6.5−8.4 (m, 17H, CH). 13C NMR (100 MHz,
CD2Cl2, δ) 16.8 (CH3), 17.1 (CH3), 20.6 (CH3), 20.7 (CH3), 26.4
(CH3), 27.0 (CH3), 32.2 (CH3, t-Bu), 32.3 (CH3, t-Bu), 35.2 (C, t-
Bu), 35.7 (C, t-Bu), 41.8 (C5), 77.0 (C4), 78.7 (b, CHallyl trans to
S), 81.7 (b, C3), 84.4 (C2), 100.9 (d, CHallyl trans to P, JC−P = 33.2
Hz), 105.5 (C1), 112.2 (d, CHallyl central, JC−P = 9.2 Hz), 113.5
(CMe2), 124.1−143.9 (aromatic carbons). Isomer exo (80%): 31P
NMR (161 MHz, CD2Cl2, δ) 138.0 (s). 1H NMR (400 MHz, CD2Cl2,
δ) 1.22 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.38 (s, 9H, CH3, t-Bu), 1.74
(s, 3H, CH3), 1.78 (s, 3H, CH3), 1.81 (s, 9H, CH3, t-Bu), 2.25 (s, 3H,
CH3), 2.47 (s, 3H, CH3), 3.39 (m, 2H, H5′, H5), 4.21 (d, 1H, H2,
3J2−1 = 3.6 Hz), 4.32 (m, 1H, H4), 4.97 (m, 1H, CHallyl trans to S),
5.00 (b, 1H, H3), 5.52 (m, 1H, CHallyl trans to P), 5.64 (d, 1H, H1,
3J1−2 = 3.6 Hz), 6.24 (m, 1H, CHallyl central), 6.5−8.4 (m, 17H,
CH). 13C NMR (100 MHz, CD2Cl2, δ) 16.9 (CH3), 17.3 (CH3),
20.6 (CH3), 20.8 (CH3), 26.5 (CH3), 26.8 (CH3), 32.0 (CH3, t-Bu),
32.7 (CH3, t-Bu), 35.2 (C, t-Bu), 35.8 (C, t-Bu), 39.6 (C5), 76.4 (C4),
78.1 (b, CHallyl trans to S), 81.7 (b, C3), 84.6 (C2), 105.1 (C1),
106.3 (d, CHallyl trans to P, JC−P = 32.4 Hz), 110.9 (d, CHallyl
central, JC−P = 9.5 Hz), 113.3 (CMe2), 124.1−143.9 (aromatic
carbons). MS HR-ESI [found 1013.3187, C57H64O6PPdS (M − BF4)+
requires 1013.3191].
free energies at 298.15 K and calculated as Greported = G6‑31G*
E6‑311+G** − E6‑31G* + EDFT‑D3
+
.
Typical Procedure for the Allylic Alkylation. A degassed
solution of [PdCl(η3-C3H5)]2 (1.8 mg, 0.005 mmol) and the
corresponding ligand (0.011 mmol) in dichloromethane (0.5 mL)
was stirred for 30 min. Subsequently, a solution of the corresponding
substrate (1 mmol) in dichloromethane (1.5 mL), nucleophile (3
mmol), N,O-bis(trimethylsilyl)-acetamide (740 μL, 3 mmol), and the
corresponding base (5 mol %) 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 1, 4−26,
29, 30, 33, and 34, the solvent was removed, conversions were
measured by 1H NMR, and enantiomeric excesses were determined by
HPLC. For compounds 2, 3, 27, 31, 32 and 36−38, conversion and
enantiomeric excesses were determined by GC. For compounds 28
and 35, conversion were measured by 1H NMR, and ee’s were
[Pd(η3-1,3-diphenylallyl)(L1a)]BF4 (40). Isomer exo (80%): 31P
NMR (161 MHz, CD2Cl2, δ) 143.6 (s). 1H NMR (400 MHz, CD2Cl2,
δ) 1.25 (s, 3H, CH3), 1.28 (s, 3H, CH3), 1.36 (s, 9H, CH3, t-Bu), 1.45
(s, 9H, CH3, t-Bu), 1.59 (s, 9H, CH33, t-Bu), 1.63 (s, 9H, CH3, t-Bu),
2
3.00 (dd, 1H, H5′, J5′−5 = 13.6 Hz, J5′−4 = 11.6 Hz), 3.56 (dd, 1H,
2
3
H5, J5−5′ = 13.6 Hz, J5−4 = 4.0 Hz), 4.09 (m, 1H, H4), 4.53 (d, 1H,
1
3
determined by H NMR using [Eu(hfc)3].
H2, J2−1 = 4.0 Hz), 5.66 (m, 2H, H3, CHallyl trans to S), 5.73 (d,
1H, H1, 3J1−2 = 4.0 Hz), 5.83 (m, 1H, CHallyl trans to P), 6.56 (m,
1H, CHallyl central), 6.7−7.7 (m, 19H, CH). 13C NMR (100
MHz, CD2Cl2, δ) 26.5 (CH3), 26.6 (CH3), 31.6 (CH3, t-Bu), 31.7
(CH3, t-Bu), 32.0 (CH3, t-Bu), 32.3 (CH3, t-Bu), 35.1 (C, t-Bu), 35.2
(C, t-Bu), 35.8 (C, t-Bu), 36.5 (C, t-Bu), 37.3 (b, C5), 76.2 (C4), 78.8
Typical Procedure for the Allylic Amination. A degassed
solution of [PdCl(η3-C3H5)]2 (1.8 mg, 0.005 mmol) and the
corresponding ligand (0.011 mmol) in dichloromethane (0.5 mL)
was stirred for 30 min. Subsequently, a solution of the corresponding
substrate (1 mmol) in dichloromethane (1.5 mL) and benzylamine
J
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(d, C3, JC−P = 10.7 Hz), 85.1 (d, C2, JC−P = 8.4 Hz), 90.0 (b, CH
allyl trans to S), 99.9 (d, CHallyl trans to P, JC−P = 32.4 Hz), 104.9
(C1), 113.0 (CMe2), 114.4 (d, CHallyl central, JC−P = 10.1 Hz),
125.4−149.4 (aromatic carbons). Isomer endo (20%): 31P NMR (161
MHz, CD2Cl2, δ) 140.6 (s). 1H NMR (400 MHz, CD2Cl2, δ) 1.15 (s,
3H, CH3), 1.18 (s, 3H, CH3), 1.37 (s, 9H, CH3, t-Bu), 1.47 (s, 9H,
CH3, t-Bu), 1.59 (s, 9H, CH3, t-Bu), 1.72 (s, 9H, CH3, t-Bu), 3.29 (m,
1H, H5′), 3.64 (dd, 1H, H5, 2J5−5′ = 13.6 Hz, 3J5−4 = 4.8 Hz), 3.92 (m,
1H, H4), 4.28 (d, 1H, H2, 3J2−1 = 3.6 Hz), 4.92 (m, 1H, H3), 5.30 (m,
1H, CHallyl trans to S), 5.44 (m, 1H, CHallyl trans to P), 5.71
(d, 1H, H1, 3J1−2 = 3.6 Hz), 6.81 (m, 1H, CHallyl central), 6.7−7.7
(m, 19H, CH). 13C NMR (100 MHz, CD2Cl2, δ) 26.2 (CH3), 26.4
(CH3), 31.6 (CH3, t-Bu), 31.7 (CH3, t-Bu), 32.0 (CH3, t-Bu), 32.3
(CH3, t-Bu), 35.2 (C, t-Bu), 35.3 (C, t-Bu), 35.8 (C, t-Bu), 36.2 (C, t-
Bu), 38.1 (b, C5), 76.2 (C4), 78.8 (d, C3, JC−P = 10.7 Hz), 84.6 (d,
C2, JC−P = 7.8 Hz), 91.2 (b, CHallyl trans to S), 99.6 (d, CHallyl
trans to P, JC−P = 33.4 Hz), 104.9 (C1), 109.8 (d, CHallyl central,
JC−P = 9.8 Hz), 113.0 (CMe2), 125.4−149.4 (aromatic carbons). MS
HR-ESI [found 1019.3656, C57H70O6PPdS (M − BF4)+ requires
1019.3660].
0.87−1.09 (m, 2H, CH2), 1.11 (s, 3H, CH3), 1.28−1.40 (m, 2H,
CH2), 1.28 (s, 3H, CH3), 1.50 (s, 9H, CH3, t-Bu), 1.54 (s, 9H, CH3, t-
Bu), 1.80−2.10 (m, 2H, CH2), 1.85 (s, 3H, CH3), 1.99 (s, 3H, CH3),
2.33 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.62 (m, 1H, H4), 3.77 (m, 1H,
3
H5′), 3.93 (m, 1H, H5), 4.55 (d, 1H, H2, J2−1 = 3.6 Hz), 4.61 (m,
1H, CHallyl trans to S), 5.24 (m, 2H, H3, CHallyl trans to P),
3
5.87 (d, 1H, H1, J1−2 = 3.6 Hz), 5.95 (m, 1H, CHallyl central),
7.31 (d, 1H, CH, J = 6 Hz), 7.6−7.8 (m, 4H, CH), 8.0−8.2 (m,
2H, CH), 8.38 (d, 1H, CH, J = 8.4 Hz). 13C NMR (100 MHz,
CD2Cl2, δ) 16.0 (CH3), 16.8 (CH3), 19.3 (CH2), 20.0 (CH3), 20.1
(CH3), 25.7 (CH3), 26.1 (CH3), 29.3 (b, CH2), 29.6 (CH2), 31.7
(CH3, t-Bu), 32.2 (CH3, t-Bu), 34.9 (C, t-Bu), 35.2 (C, t-Bu), 38.5 (b,
C5), 76.4 (C4), 78.0 (d, C3, JC−P = 7.5 Hz), 83.5 (d, CHallyl trans
to S, JC−P = 6.9 Hz), 84.5 (d, C2, JC−P = 7.6 Hz), 100.3 (d, CHallyl
trans to P, JC−P = 34.0 Hz), 104.2 (C1), 112.8 (CMe2), 113.6 (d,
CHallyl central, JC−P = 9.9 Hz), 123.5−144.9 (aromatic carbons).
MS HR-ESI [found 901.2872, C48H60O6PPdS (M − BF4)+ requires
901.2878].
[Pd(η3-1,3-cyclohexenylallyl)(L9f)]BF4 (43). 31P NMR (161 MHz,
1
CD2Cl2, δ) 138.5 (s). H NMR (400 MHz, CD2Cl2, δ) 0.95 (m, 1H,
[Pd(η3-1,3-dimethylallyl)(L13e)]BF4 (41). Isomer endo (25%): 31P
CH2), 1.27 (s, 3H, CH3), 1.40 (m, 1H, CH2), 1.42 (b, 2H, CH2), 1.43
(s, 3H, CH3), 1.48 (s, 9H, CH3, t-Bu), 1.57 (s, 9H, CH3, t-Bu), 1.79 (s,
3H, CH3), 1.93 (m, 1H, CH2), 1.94 (s, 3H, CH3), 2.32 (s, 3H, CH3),
NMR (161 MHz, CD2Cl2, δ) 137.4 (s). 1H NMR (400 MHz, CD2Cl2,
3
3
δ) 0.59 (d, 3H, CH3, JH−H = 5.6 Hz), 1.14 (d, 3H, CH3, JH−H = 6.0
Hz), 1.16 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.44 (s, 9H, CH3, t-Bu),
1.55 (s, 9H, CH3, t-Bu), 1.78 (s, 3H, CH3), 1.85 (s, 3H, CH3), 2.29 (s,
3H, CH3), 2.34 (s, 3H, CH3), 3.41 (m, 1H, CH trans to S), 3.46 (m,
1H, H5), 3.58 (m, 1H, CH trans to P), 3.91 (m, 1H, H5′), 4.48 (m,
1H, H3), 4.54 (m, 1H, H2), 4.86 (m, 1H, H4), 5.00 (m, 1H, CH
2
3
2.38 (s, 3H, CH3), 3.80 (dd, 1H, H5′, J5′−5 = 11.6 Hz, J5′−4 = 4.8
Hz), 3.91 (b, 2H, H5, CHallyl trans to S), 4.54 (m, 1H, H4), 4.71
(d, 1H, H2, 3J2−1 = 3.6 Hz), 4.95 (dd, 1H, H3, 3J3−P = 15.6 Hz, 3J3−4
=
2.4 Hz), 5.03 (m, 1H, CHallyl trans to P), 5.21 (m, 1H, CHallyl
3
central), 5.85 (d, 1H, H1, J1−2 = 3.6 Hz), 7.44 (d, 2H, CH, J = 6
3
central), 5.75 (d, 1H, H1, J1−2 = 4.0 Hz), 7.1−8.6 (m, 9H, CH).
Hz), 7.62 (m, 1H, CH), 7.71 (m, 1H, CH), 7.78 (m, 2H, CH),
8.06 (m, 2H, CH), 8.32 (d, 1H, CH, J = 8.4 Hz). 13C NMR (100
MHz, CD2Cl2, δ) 16.3 (CH3), 16.4 (CH3), 19.7 (CH2), 20.0 (CH3),
20.3 (CH3), 25.9 (CH3), 26.3 (CH3), 26.5 (b, CH2), 27.5 (CH2), 31.3
(CH3, t-Bu), 31.4 (CH3, t-Bu), 34.9 (C, t-Bu), 35.0 (C, t-Bu), 37.6
(C5), 76.5 (d, C4, JC−P = 2.3 Hz), 76.7 (d, C3, JC−P = 3.8 Hz), 82.4 (d,
CHallyl trans to S, JC−P = 6.9 Hz), 83.8 (d, C2, JC−P = 3.8 Hz),
103.4 (d, CHallyl trans to P, JC−P = 35.9 Hz), 104.6 (C1), 111.9 (d,
CHallyl central, JC−P = 9.9 Hz), 113.1 (CMe2), 123.5−144.9
(aromatic carbons). MS HR-ESI [found, 901.2869, C48H60O6PPdS (M
− BF4)+ requires 901.2878].
13C NMR (100 MHz, CD2Cl2, δ) 16.2−17.1 (CH3 allyl), 16.7 (b,
CH3), 20.3 (CH3), 26.0 (CH3), 26.1 (CH3), 31.0−31.9 (CH3, t-Bu),
34.9−35.2 (C, t-Bu), 37.6 (C5), 75.9−76.5 (C4, C3), 80.2 (b, CH
trans to S), 83.7 (C2), 102.7 (d, CHtrans to P, JC−P = 35.2 Hz),
104.5 (C1), 112.8 (CMe2), 116.5 (d, CH central, JC−P = 12.1 Hz),
122−146 (aromatic carbons). Isomer exo (75%): 31P NMR (161 MHz,
1
CD2Cl2, δ) 138.2 (s). H NMR (400 MHz, CD2Cl2, δ) 0.77 (d, 3H,
CH3, 3JH−H = 6.4 Hz), 0.92 (d, 3H, CH3, 3JH−H = 6.4 Hz), 1.21 (s, 3H,
CH3), 1.39 (s, 9H, CH3, t-Bu), 1.44 (s, 3H, CH3), 1.52 (s, 9H, CH3, t-
Bu), 1.74 (s, 3H, CH3), 1.92 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.27 (s,
3H, CH3), 3.32 (m, 1H, CH trans to S), 3.46 (m, 1H, H5), 3.5 (m,
1H, CH trans to P), 3.99 (m, 1H, H5′), 4.58 (m, 1H, H3), 4.72 (m,
1H, H2), 4.86 (m, 1H, H4), 4.93 (m, 1H, CH central), 5.78 (d, 1H,
Study of the Reactivity of the [Pd(η3-allyl)(L))]BF4 with
Sodium Malonate by in Situ NMR.27 A solution of in situ prepared
[Pd(η3-allyl)(L)]BF4 (L = phosphite-thioether, 0.05 mmol) in CD2Cl2
(1 mL) was cooled in the NMR at −80 °C. At this temperature, a
solution of cooled sodium malonate (0.1 mmol) was added. The
reaction was then followed by 31P NMR. The relative reaction rates
were calculated using a capillary containing a solution of
triphenylphosphine in CD2Cl2 as external standard.
3
H1, J1−2 = 4.0 Hz), 7.1−8.6 (m, 9H, CH). 13C NMR (100 MHz,
CD2Cl2, δ) 16.2−17.1 (CH3 allyl), 16.7 (b, CH3), 20.4 (CH3), 20.6
(CH3), 26.1 (CH3), 26.2 (CH3), 31.0−31.9 (CH3, t-Bu), 34.9−35.2
(C, t-Bu), 39.2 (C5), 75.9−76.5 (C4, C3), 79.0 (b, CH trans to S),
83.6 (C2), 104.5 (C1), 107.4 (d, CHtrans to P, JC−P = 36.6 Hz),
113.1 (CMe2), 116.8 (d, CH central, JC−P = 10.9 Hz), 122−146
(aromatic carbons). MS HR-ESI [found 867.3028, C45H62O6PPdS (M
− BF4)+ requires 867.3034].
ASSOCIATED CONTENT
* Supporting Information
■
S
[Pd(η3-1,3-cyclohexenylallyl)(L9e)]BF4 (42). Isomer endo (60%):
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00547.
1
31P NMR (161 MHz, CD2Cl2, δ) 139.5 (s). H NMR (400 MHz,
CD2Cl2, δ) 0.87−1.09 (m, 2H, CH2), 1.20 (s, 3H, CH3), 1.28−1.40
(m, 2H, CH2), 1.32 (s, 3H, CH3), 1.53 (s, 9H, CH3, t-Bu), 1.62 (s, 9H,
CH3, t-Bu), 1.80−2.10 (m, 2H, CH2), 1.83 (s, 3H, CH3), 1.86 (s, 3H,
CH3), 2.32 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.21 (m, 1H, H4), 3.77
Copies of 31P{1H} and 1H and 13C{1H} NMR spectra of
Pd-intermediates 39−43, reactivity study of Pd-inter-
mediate 39 with sodium malonate. NMR and ee
determination details of substitution products 1−38
(PDF). (PDF)
Calculated energies and coordinates for all computational
structures (PDF)
Computed Cartesian coordinates of all of the molecules
reported in this study (XYZ)
3
(m, 1H, H5′), 3.93 (m, 1H, H5), 4.46 (d, 1H, H2, J2−1 = 3.6 Hz),
4.69 (m, 1H, CHallyl trans to S), 5.13 (dd, 1H, H3, 3J3−P = 13.2 Hz,
3J3−4 = 2.0 Hz), 5.72 (d, 1H, H1, 3J1−2 = 3.6 Hz), 5.93 ((m, 1H, CH
allyl trans to P), 6.17 (m, 1H, CHallyl central), 7.29 (d, 1H, CH,
J = 6 Hz), 7.6−7.8 (m, 4H, CH), 8.0−8.2 (m, 2H, CH), 8.50 (d,
1H, CH, J = 8.4 Hz). 13C NMR (100 MHz, CD2Cl2, δ) 16.3 (CH3),
16.4 (CH3), 19.3 (CH2), 20.0 (CH3), 20.1 (CH3), 25.8 (CH3), 25.9
(CH3), 28.1 (CH2), 29.0 (CH2), 31.3 (CH3, t-Bu), 31.4 (CH3, t-Bu),
34.7 (C, t-Bu), 35.0 (C, t-Bu), 38.5 (b, C5), 75.8 (C4), 78.2 (d, C3,
JC−P = 10.7 Hz), 84.2 (d, C2, JC−P = 9.1 Hz), 89.1 (d, CHallyl trans
to S, JC−P = 6.8 Hz), 101.4 (d, CHallyl trans to P, JC−P = 34.2 Hz),
104.1 (C1), 112.4 (CMe2), 114.6 (d, CHallyl central, JC−P = 9.9
Hz), 123.5−144.9 (aromatic carbons). Isomer exo (40%): 31P NMR
AUTHOR INFORMATION
Corresponding Authors
*E-mail: Per-Ola.Norrby@astrazeneca.com.
*E-mail: oscar.pamies@urv.cat.
■
1
(161 MHz, CD2Cl2, δ) 139.2 (s). H NMR (400 MHz, CD2Cl2, δ)
K
DOI: 10.1021/acs.organomet.6b00547
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(9) (a) Buckingham, J., Ed. Dictionary of Natural Products; Cambridge
University Press: Cambridge, U.K., 1994. (b) Lumbroso, A.; Cooke,
M. L.; Breit, B. Angew. Chem., Int. Ed. 2013, 52, 1890−1932.
*E-mail: montserrat.dieguez@urv.cat.
Notes
The authors declare no competing financial interest.
(10) For successful examples of Pd-catalysts, see (a) Trost, B. M.;
Shen, H. C.; Dong, L.; Surivet, J.-P. J. Am. Chem. Soc. 2003, 125,
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catalysts with phenols, see (g) Shu, C.; Hartwig, J. F. Angew. Chem., Int.
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ACKNOWLEDGMENTS
■
Financial support from 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.
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DOI: 10.1021/acs.organomet.6b00547
Organometallics XXXX, XXX, XXX−XXX