Computationally guided design of a readily assembled phosphite-thioether ligand for a broad range of pd-catalyzed asymmetric allylic substitutions

Article abstract of DOI:10.1021/acscatal.7b04192

A modular approach employing indene as common starting material, has enabled the straightforward preparation in three reaction steps of P-thioether ligands for the Pd-catalyzed asymmetric allylic substitution. The analysis of a starting library of P-thioether ligands based on rational design and theoretical calculations has led to the discovery of an optimized anthracenethiol derivative with excellent behavior in the reaction of choice. Improving most approaches reported to date, this ligand presents a broad substrate and nucleophile scope. Excellent enantioselectivities have been achieved for a range of linear and cyclic allylic substrates using a large number of C-, N-, and O-nucleophiles (40 compounds in total). The species responsible for the catalytic activity have been further investigated by NMR in order to clearly establish the origin of the enantioselectivity. The resulting products have been derivatized by means of ring-closing metathesis or Pauson-Khand reactions to further prove the synthetic versatility of the methodology for preparing enantiopure complex structures.

Full text of DOI:10.1021/acscatal.7b04192

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Computationally-guided design of a readily assembled phosphite-thioether
ligand for a broad range of Pd-catalyzed asymmetric allylic substitutions
Maria Biosca, Jessica Margalef, Xisco Caldentey, Maria Besora, Carles Rodriguez-Escrich, Joan
Saltó, Xacobe C. Cambeiro, Feliu Maseras, Oscar Pàmies, Montserrat Diéguez, and Miquel A. Pericàs
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b04192 • Publication Date (Web): 21 Mar 2018
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ACS Catalysis
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Computationally-guided design of a readily assembled phosphite-
thioether ligand for a broad range of Pd-catalyzed asymmetric allylic
substitutions
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Maria Biosca,a Jèssica Margalef,a Xisco Caldentey,b Maria Besora,b,* Carles Rodríguez-Escrich,b
Joan Saltó,a Xacobe C. Cambeiro,b Feliu Maseras,b,c,* Oscar Pàmies,a,* Montserrat Diéguez,a,*
Miquel A. Pericàs,b,d,*.
a Universitat Rovira i Virgili, Departament de Química Física i Inorgànica, C/ Marcel·lí Domingo, 1, 43007 Tarrago-
na, Spain.
b Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona, Spain.
c Departament de Química. Universitat Autònoma de Barcelona. 08193 Bellaterra, Catalonia, Spain.
d Departament de Química Inorgànica i Orgànica. Universitat de Barcelona. 08028 Barcelona, Spain.
Palladium, allylic substitution, DFT study, NMR study, P,S-ligands.
ABSTRACT: A modular approach employing indene as common starting material, has enabled the straightforward prepa-
ration in three reaction steps of P-thioether ligands for the Pd-catalyzed asymmetric allylic substitution. The analysis of a
starting library of P-thioether ligands based on rational design and theoretical calculations has led to the discovery of an
optimized anthracenethiol derivative with excellent behavior in the reaction of choice. Improving most approaches re-
ported to date, this ligand presents a broad substrate and nucleophile scope. Excellent enantioselectivities have been
achieved for a range of linear and cyclic allylic substrates using a large number of C-, N- and O-nucleophiles (40 com-
pounds in total). The species responsible for the catalytic activity have been further investigated by NMR in order to
clearly establish the origin of the enantioselectivity. The resulting products have been derivatized by means of ring-
closing metathesis or Pauson-Khand reactions to further prove the synthetic versatility of the methodology for preparing
enantiopure complex structures.
several studies concerning the generation and evaluation
of myriad candidates in terms of yield, selectivity and sub-
INTRODUCTION
The future of chemical production must keep up with
the growing demand for fine chemicals while reducing
the overall waste production and energy consumption
demanded by international regulations (and common
sense). Over the last decades, this need for sustainability
has driven the shift from suboptimal non-catalyzed pro-
cesses to high-performing catalytic processes for the pro-
duction of all sorts of chemicals.1 This has been especially
noteworthy in the production of enantiopure compounds,
which play a key role in many technologically and biolog-
ically relevant applications.2 Amongst the toolkit of cata-
lytic enantioselective transformations, asymmetric Pd-
catalyzed allylic substitution stands out for its versatility
(as it creates new C-C and C-heteroatom bonds starting
from simple precursors), high functional group tolerance
and mild reaction conditions. Moreover, the resulting
products accept further derivatization thanks to the pres-
ence of an alkene functionality.3 The key role of the ligand
in the induction of chirality in this process has motivated
strate
scope.
Heterodonor
compounds
(phos-
phine/phosphinite-oxazolines being the paradigmatic
example) have proven especially advantageous because
the different trans influence of the two donor groups gen-
erates an efficient electronic differentiation between the
two allylic terminal carbon atoms. Indeed, the nucleo-
philic attack is known to take place predominantly trans
to the donor group with stronger trans influence. On the
basis of this premise, we have contributed with mixed
ligands bearing biaryl phosphite moieties,3j,4 which flexi-
ble nature allows the catalyst chiral pocket to adapt to the
steric demands of the substrate,4e resulting in a broad-
ened substrate scope.
The vast amount of Pd-catalyzed allylic substitution
studies reported in the literature have led to remarkable
advances in catalyst design; however, catalysts are still
rarely suitable for a wide range of substrates. Instead, the
most common scenario is that each allylic precursor re-
quires independent optimization to identify the optimal
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catalytic system, and a similar situation takes place with cally varying: (i) the electronic and steric properties of the
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the various nucleophiles. Consequently, the identification
of “privileged” ligands remains a central task in this type
of chemistry. In addition to giving excellent results for a
broad range of allylic precursors and nucleophiles (C-, N-
or O-based), such privileged ligands must be readily pre-
pared in both enantiomeric forms from available starting
materials and easy to handle (i.e. solid, robust and stable
in air).3
thioether (L1–L8) group, (ii) the configuration of the biar-
yl phosphite moiety (a–c), and (iii) the P-containing
group (phosphite, a–c versus phosphinite groups, d–g).
9
To this end, we recently started a research line aimed
at identifying suitable alternatives to the labile oxazoline
moiety. We were especially interested in the stable and
easy to prepare thioether group, which allowed the prepa-
ration of a Pd/phosphite-thioether furanoside-based cata-
lyst that creates C-C, C-N and C-O bonds with different
substrates and a variety of nucleophiles.5 The yields and
enantioselectivities obtained were comparable to the best
catalytic systems reported in the literature. Although the-
se furanoside ligands were prepared from inexpensive D-
xylose, their synthesis was tedious and required a large
number of steps. Other researchers have demonstrated
the utility of thioether-based P-S ligands.6 For instance,
the pioneering work in Pd-catalyzed allylic substitution
and other relevant asymmetric reactions of Pregosin7 and
Evans,6a among others, put the focus on this kind of lig-
ands and spurred their development. Despite the many
efforts devoted to develop P-S ligands, their impact has
been limited for two main reasons: (a) even in the most
successful cases, they were limited in substrate and nu-
cleophile scope: enantioselectivities were mainly high for
the allylic substitution of the standard (and hindered)
rac-1,3-diphenyl-3-acetoxyprop-1-ene S1 using dime-
thylmalonate as nucleophile,6 and (b) thioether-based
ligands are prone to producing mixtures of diastereomeric
thioether complexes, which tend to interconvert in solu-
tion.8 However, if one could design a scaffold able to con-
trol the configuration on sulfur upon coordination of the
P-S ligand, this would provide an additional chiral ele-
ment in close proximity to the metal, thus giving rise to
simpler ligands that can be prepared in fewer steps than
their oxazoline-phosphine counterparts.
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Figure 1. Phosphite/phosphinite-thioether ligand library L1–
L8a–g.
An additional advantage of this set of ligands is the fact
that their simplified backbone renders very simple NMR
spectra, thus reducing signal overlap, as well as facilitat-
ing the identification of relevant intermediates and accel-
erating the DFT calculations performed to rationalize the
behavior of the system. By combining theoretical studies
and NMR spectroscopy, we have been able to rationally
fine-tune the ligands, improve enantioselectivity and
identify the species responsible for the catalytic perfor-
mance. This optimized ligand has proven active in the Pd-
catalyzed allylic substitution of both linear and cyclic sub-
strates with a broad range of C-, N-, and O-nucleophiles
(26 examples in total), even with the environmentally
friendly propylene carbonate as solvent. Finally, the ap-
plicability of the new Pd/P-thioether catalysts has been
further demonstrated in the practical synthesis of chiral
(poly)carbo– and heterocyclic compounds using straight-
forward sequences of allylic substitution/ring-closing me-
tathesis or allylic alkylation/Pauson-Khand reactions.
RESULTS AND DISCUSSION
Synthesis of the first generation ligand library
L1–L7a–g. Phosphite/phosphinite-thioether ligands L1–
L7a–g can be efficiently prepared in three steps as illus-
trated in Scheme 1. In the first step, epoxidation of inex-
pensive indene 1 with bleach using Jacobsen's catalyst,
followed by low-temperature crystallization, yielded in-
dene oxide with 99% ee.10 Next, the regio- and stereospe-
cific ring opening of 2 with the corresponding thiol was
carried out with sodium hydroxide in a dioxane/water
mixture.11 In order to ensure chemical diversity, seven
thiols with markedly different steric and electronic prop-
erties were used at this stage. Finally, we took advantage
of the hydroxy group in 3–9 to establish a representative
set of phosphite and phosphinite moieties following
standard procedures.6f,12 The resulting enantiopure lig-
ands were isolated in good yields as white solids (phos-
phite-thioether ligands L1–L7a–c) or colorless oils (phos-
phinite-thioether ligands L1–L7d–g). Phosphite-thioether
ligands were found to be stable in air and resistant to hy-
drolysis, whereas the phosphinite analogues proved less
stable, slowly decomposing even when stored at low tem-
perature.
Herein, we give a new push to the study of the catalytic
potential of P,S-ligands by screening novel, readily acces-
sible thioether-containing compounds, including a de-
tailed study of the species responsible for the catalytic
performance. For this purpose, we designed a small but
structurally diverse library of P-thioether ligands L1–L8a–
g (Figure 1) that was tested in the Pd-catalyzed allylic sub-
stitution of a broad range of substrates and nucleophiles.
These new P,S-ligands are synthesized in only three steps
from inexpensive indene (ca. 20 USD/kg in bulk) and,
since the corresponding enantiopure epoxide is prepared
through Jacobsen epoxidation, both enantiomeric series
are equally available. This modular approach9 greatly ex-
pedites the evaluation of several thioether and phos-
phite/phosphinite moieties, which is deemed crucial for
the iterative optimization of the most promising candi-
dates. Consequently, the catalytic performance of the lig-
ands depicted in Figure 1 has been studied by systemati-
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3
L1c
L1d
100 (0.5)
100 (0.5)
75 (S)
100 (2)
100 (2)
61 (S)
28 (S)
1
2
3
4
5
6
7
8
4
50
(R)
5
L1e
L1f
100 (0.5)
5 (0.5)
25
(R)
100 (2)
10 (2)
11 (S)
6
32
(R)
28 (S)
14 (R)
7
L1g
100 (0.5)
100 (0.5)
4 (R)
100 (2)
100 (2)
9
8
L2b
90
62
10
11
12
13
14
(R)
(R)
9
L3b
L3e
L4b
L5b
L5c
L5d
L5e
L6b
L7b
L5b
100 (0.5)
100 (0.5)
84
(R)
100 (2)
100 (2)
100 (2)
100 (2)
100 (2)
100 (2)
100 (2)
100 (2)
100 (2)
100 (4)
60
(R)
10
63
(R)
77 (S)
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Scheme
1.
Three-step
synthesis
of
phos-
11
100 (0.5)d 97
85
(R)
phite/phosphinite-thioether ligands L1–L7a–g from in-
dene. (i) (R,R)-Mn-salen catalyst, 4-PPNO, aq. NaClO,
CH2Cl2;10 (ii) RSH, NaOH, dioxane/H2O (10:1);11 (iii)
ClP(OR1R2)2; (OR1R2)2= a–c, Py, toluene and (iv) ClPR32;
R3= d–g, NEt3, toluene.
(R)
12
13
14
15
16
17
18e
100 (0.5)
100 (0.5)
100 (0.5)
100 (0.5)
100 (0.5)
100 (0.5)
100 (1)
96
(R)
86
(R)
80
(S)
84
(S)
All ligands were characterized by P{1H}, H and 13C{1H}
NMR spectroscopy and HRMS. All data were in agree-
ment with assigned structures.13 See experimental section
for purification and characterization details.
31
1
28
(R)
13 (S)
40
(R)
11 (S)
Evaluation of the first generation ligand library
in the allylic substitution of symmetrical 1,3-
disubstituted allylic substrates. As already men-
tioned, the catalyst’s ability to adjust to the steric de-
mands of the substrate is a key factor in transferring the
chiral information to the product. To assess the potential
of this ligand library in the allylic substitution, we first
tested L1–L7a–g in the Pd-catalyzed allylic substitution of
two substrates with different steric requirements: the
benchmark substrate S1 and the more challenging cyclic
S2 (Table 1). Excellent yields were almost invariably ob-
tained under mild reaction conditions (i.e. 1 mol% Pd,
ligand-to-palladium ratio of 1.1 at room temperature) with
TOF as high as 2000 mol (mol h)–1. As for the enantiose-
lectivities, up to 97% ee for S1 and 88% ee for S2 could be
achieved by using ligands that combine an aryl thioether
group with a chiral biaryl phosphite moiety.
96
(R)
88
(R)
97
(R)
87
(R)
96
(R)
85
(R)
a 0.5 mol% [PdCl(η3-C3H5)]2, ligand (0.011 mmol), substrate (1
mmol), CH2Cl2 (2 mL), BSA (3 equiv), nucleophile (3 equiv),
b
1
c
KOAc (pinch) at rt. Conversion measured by H NMR.
Enantiomeric excesses measured by HPLC for dimethyl 2-
(1,3-diphenylallyl)malonate (10) and by GC for dimethyl 2-
(1,3-cyclohexanylallyl)malonate (11). d TOF= 2000 mol (mol
h)-1 calculated after 5 min from catalysis performed at 0.25
mol% of Pd. e Reactions carried out using PC as solvent at 40
°C.
In an effort to measure the contribution of the different
P-donor groups, we analyzed the results of ligands L1a–g
(entries 1–7). The trend was clearly pointing out to a supe-
rior performance of phosphite- over phosphinite-based
structures (i.e. entry 2 vs. 4–7), even with very bulky ones.
We wondered whether the ligand chirality might be able
to control the conformation around a biphenyl moiety
devoid of chiral axis. However, this possibility was ruled
out by comparing entries 1-3, where the superior perfor-
mance of ligands bearing a phosphite with axial chirality
was evident (entries 2–3). Actually, the chiral axis seems
to be the major factor in controlling the enantioselectivi-
ty. Indeed, ligands differing only in the configuration of
this chiral axis (but otherwise having the same stereocen-
ters) give rise to products with opposite absolute configu-
ration (entries 2–3). Considering the substrates inde-
Table 1. Pd-catalyzed allylic alkylation of S1–S2 with
dimethyl malonate as nucleophile using ligands L1–
L7a–g.a
Entry
L
%
Conv %eec
%
Conv %eec
(h)b
(h)b
1
L1a
L1b
100 (0.5)
100 (0.5)
17 (R)
100 (2)
100 (2)
15 (S)
2
90
66
(R)
(R)
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pendently, with S1 a remarkable cooperative effect be- using the model substrate S1 and dimethyl malonate as
1
2
3
4
5
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7
8
tween the configuration of the biaryl phosphite moiety
and the ligand backbone is observed, which results in a
matched combination with ligand L1b, that bears an (R)
chiral axis (entry 2 vs 3). This cooperative effect is less
pronounced for cyclic substrate S2, and both enantiomers
of the alkylated products are therefore easily accessible
with similar levels of enantioselectivity by simply setting
the configuration of the biaryl phosphite moiety (entry 2
vs 3).
nucleophile with ligands L5b–c. The goal was to evaluate
the effect of the chiral axis of the biaryl phosphite moiety,
as these ligands differ only in the configuration of this
biaryl (see Table 1, entry 12 vs 13). Only the two syn-syn
allyl complexes were calculated, neglecting the contribu-
tion of other allylic species of higher energy (anti-anti and
syn-anti).3d In this study, we have taken into account the
configuration of the thioether and the attack of the nu-
cleophile trans to P and S atoms. In contrast to P-N lig-
ands, the trans effect exerted by the thioether and the
phosphite are of a similar magnitude; indeed, previous
studies have shown that small changes in the ligand can
shift the trans preference in P,S-ligands.5b,17 The results of
the most stable transition states (TS(R) and TS(S)) and Pd-
olefin intermediates (Pd-olefin(R) and Pd-olefin(S)) leading
to the formation of both product enantiomers are shown
in Table 2 (the full set of calculated TSs and Pd-olefin
intermediates can be found in the Supporting Infor-
mation). The energy differences of the calculated TSs
match the results obtained in the catalytic process, the
value for L5b (ΔΔG#= 28 kJmol-1; eecalc > 99% (R)) being
therefore higher than that of L5c (ΔΔG#= 10.8 kJmol-1; ee-
calc = 96% (S)). This is in agreement with the higher enan-
tioselectivities achieved using L5b than L5c (96% (R) ee
for L5b vs 80% (S) ee for L5c; Table 1, entries 12 and 13). It
must be mentioned here that the calculated ee values
were obtained by using the eight different transition
states for each ligand reported in the Supporting Infor-
mation. If we had only used the two reported in Table 2,
the values for L5b and L5c would have been 99% (R) and
98% (S), respectively.
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Finally, by further comparing ligands L1–L7b, we found
that the electronic and steric properties of the thioether
substituent have a small but important effect on the en-
antioselectivities: ligands with aryl-thioether groups led
to higher ee’s (especially with cyclic substrate S2; i.e. entry
11 vs 2, 8 and 9) than their counterparts with alkyl thi-
oether moieties, even for the bulky tert-butyl thiol deriva-
tive. In summary, the best enantioselectivities for S1 (ee's
up to 97%) were obtained with ligands L4–L7b, built from
a combination of any aryl thioether group with an R-
biaryl phosphite group: the above mentioned matched
combination (entries 11, 12, 16 and 17). On the other hand,
the best enantioselectivities recorded for substrate S2
(ee's up to 88%), in both enantiomers of the alkylated
product, were obtained with ligands L4–L7b–c, contain-
ing either an R- or S-biaryl phosphite group with an aryl
thioether moiety (i.e. entries 11–13 and 16–17).
With the aim of improving the sustainability profile of
the process, we studied the reactions in 1,2-propylene
carbonate (PC), an environmentally friendly alternative to
standard organic solvents because of its high boiling
point, low toxicity, and "green" synthesis.14 In spite of the-
se environmental advantages, this solvent has been
scarcely used in asymmetric Pd-catalyzed allylic substitu-
tion and mainly limited to the standard S1 substrate and
dimethyl malonate as nucleophile.4d,14b,15 Thus, we repeat-
ed the allylic substitution of substrates S1 and S2 in PC
(Table 1, entry 18; see also Table S1 in the Supporting In-
formation for the use of PC for the allylic substitution of
other substrates and nucleophiles). Gratifyingly, the en-
antioselectivities remained as high as those observed
when dichloromethane was used.
Moreover, DFT correctly predicts the formation of the
opposite product enantiomers when L5b and L5c are ap-
plied. It should be noted that, in contrast to what was
observed with ligand L5b, both enantiomers of the substi-
tution product obtained with ligand L5c arise from TSs
with exo coordination of the substrate, with the nucleo-
philic attack trans to P (for the major enantiomer) and
trans to S (for the minor enantiomer). Finally, the calcu-
lated energies of the Pd-olefin intermediates do not corre-
late well with the experimental results (Table 2). For both
ligands, the most stable olefin complex corresponds to
the R-enantiomer in more than 99% ee.
Optimization of ligand parameters. DFT compu-
tational studies guiding to fine-tuned phosphite-
thioether ligands L8. With the ultimate goal of fine-
tuning the ligands to increase enantioselectivity, we car-
ried out DFT calculations of the transition states and key
Pd-olefin intermediates involved in the enantiodetermin-
ing step. Previous mechanistic studies on Pd-catalyzed
allylic alkylation have established the irreversible nucleo-
philic attack as the enantiodetermining step, although the
corresponding transition state (TS) can be either early or
late, depending on the nucleophile, ligands, and reaction
conditions.16 In the latter case, if the transition states are
very similar to products the enantioselectivity of the pro-
cess could also be described by the Pd-olefin complexes.
Identification of the origin of enantioselectivity from
direct inspection of the structures for the two most stable
transition states (TSs) with ligands L5b and L5c (shown in
Figure S1 in the Supporting Information) is not trivial. We
tried to apply a distortion/interaction analysis, also in the
SI, but the results were inconclusive. The differences be-
tween the two systems were in the distortion part, but
their analysis was difficult. A quadrant analysis (see Sec-
tion SI.23) was on the contrary more indicative. The key
to selectivity is in the steric repulsion between one of the
phenyl substituents of the substrate and the biaryl phos-
phite moiety. The modifications between the L5b and L5c
ligands places the steric bulk associated to the biaryl
phosphite in a different quadrant, thus favoring different
enantiomers. Interestingly, the steric bulk on the "sulphur
Therefore, we started by calculating the relative stabil-
ity of the transition states and the Pd-olefin intermediates
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bulkier than the 2,6-dimethylphenyl moiety, while main-
side" of the catalyst is also important, as it pushes the
1
2
3
4
5
6
7
sterically active regions of substrate and catalyst closer to
each other, thus enhancing selectivity.
taining the aryl group (that has been shown to perform
better than its alkylic counterparts). For this purpose, we
ran analogous TS calculations for S2 with ligand L5b
(bearing the 2,6-dimethylphenyl thioether group) and
with other ligands containing instead the bulkier 2,6-
diisopropylphenyl or anthryl moieties. To accelerate the
DFT calcu
Based on the previous findings, we investigated wheth-
er the lower enantiomeric excesses recorded with the cy-
clic substrate S2 (ee’s up to 88%) could be improved by
increasing the steric hindrance of the ligand. A simple
way to do this is to introduce a thioether group that is
8
9
Table 2. Schematic representation and relative free energies in solution of the most stable R- and S- transition
states in kJ/mol (left) and of the most stable R- and S- Pd-π-olefin complexes (right) for the substrate S1 with
dimethyl malonate and L5b and L5c ligands. Computational and experimental enantiomeric excesses are also
presented.
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22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Transition states (TSs)
TS(S)
Pd-olefin complexes
Pd-olefin(S)
TS(R)
Lig-
and
% eecalc
%
eeexp
Pd-olefin(R)
% eecalc
%
eeexp
L5b
>99 (R) 96 (R)
>99 (R) 96 (R)
L5c
96 (S)
80 (S)
>99 (R) 80 (S)
E= CO2Me
lations we used ammonia as model nucleophile.18 The
results show that the enantioselectivity is affected by the
steric effects of the thioether group (Table 3), increasing
from 9% (R) for ligand L5b (with a 2,6-dimethylphenyl
thioether group) to 35% (R) with a 2,6-diisopropylphenyl
thioether, and to 74% (R) with an anthryl thioether moie-
ty. The results of these calculations prompted us to pre-
pare two new ligands containing an anthryl thioether
group (L8b and L8c; Figure 1)19 and test them in the Pd-
catalyzed alkylation of S2. To our delight, the introduc-
tion of this bulky aromatic moiety did affect positively the
enantioselectivity, which increased from 86% ee to 94%
ee (Table 3), as predicted by the theoretical calculations.20
This result is comparable to the best one reported in the
literature for this challenging substrate.3 Interestingly,
ligand L8b also provided the highest enantioselectivity in
the alkylation of linear substrate S1 (ee’s up to 99% (R),
compared to previous best value 97% with ligand L7b,
under the same reaction conditions).
L5b 1.2 kJ/mol
9 (R)
86 (R)
6.3 kJ/mol
-
2.1 kJ/mol 35 (R)
-
-
L8b 6.8 kJ/mol 74 (R)
94 (R)b 8.6 kJ/mol
Reaction conditions: 0.5 mol% [PdCl(η3-C3H5)]2, ligand
(0.011 mmol), substrate (1 mmol), CH2Cl2 (2 mL), BSA (3
equiv), nucleophile (3 equiv), KOAc (pinch) at rt for 2 hours.
b Ligand L8c provided the alkylated product 11 in 93% ee (S).
a
Allylic substitution of linear substrate S1 with
several nucleophiles. Scope and limitations. We
initially considered the allylic substitution of substrate S1
with an extensive range of C-, N- and O-nucleophiles.
Table 4 shows the results using ligand L8b, which had
provided the best results in the allylic alkylation of S1
Table 3. Comparison between theoretical and exper-
imental results in the Pd-catalyzed allylic substitu-
tion of S2.
a
L
ΔΔG#
%
%
ΔΔG#
exp
calc
a
eecalc
eeexp
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with dimethyl malonate as benchmark nucleophile. A 29; entry 17), while allylamine proceeded with comparably
1
2
3
4
5
6
7
8
variety of malonates, including the allyl-, butenyl-, pen-
tenyl- and propargyl-substituted ones, reacted with S1 to
provide products 13–19 in high yields and enantioselectivi-
ties (up to 99% ee, entries 1–7). These substituted malo-
nates are known to be more challenging nucleophiles for
Pd-catalyzed allylic substitution, but they give rise to
more interesting products from a synthetic point of view
(see section 2.6 below). The addition of acetylacetone also
proceeded with high enantiocontrol (entry 8, ee's up to
98%). High yields and enantioselectivities were also
found in the addition of malononitrile and isopropyl cy-
anoacetate (products 21 and 22; ee's up to 99%, entries 9
and 10) albeit the diastereoselectivity of the latter was
low, as expected for such an acidic stereocentre.21
high enantioselectivity (97% ee; entry 18). This is especial-
ly interesting given the fact that the amination product 30
is a key intermediate in the synthesis of complex mole-
cules. For example, the Boc protected derivative of 30 can
be further applied in metathesis reactions for the con-
struction of a dihydropyrrole derivative (see section 2.6
below).
The exquisite enantiocontrol observed for C- and N-
nucleophiles can also be extended to aliphatic alcohols
(compounds 31–35, ee's up to 99%; entries 19–23). The
effective allylic substitution with this type of O-
nucleophiles opens up new synthetic avenues towards
chiral ethers, which are important for the synthesis of
biologically active molecules.24 Despite the potential of
the resulting products, a general catalytic solution for the
Pd-catalyzed allylic etherification has remained elusive
and most of the few successful examples reported to date
deal with phenols,25 while aliphatic alcohols have been
less studied.4e,6a,f,26 Moreover, the enantioselectivities re-
ported so far largely depend on the type of aliphatic alco-
hol and small modifications of their electronic proper-
ties4e,6a,f,26 can have a large impact on this parameter. Us-
ing our streamlined ligand L8b, we found that benzylic
alcohols gave excellent results regardless of the steric and
electronic properties of the aryl group (entries 19–22).
Allyl alcohol also furnished the desired product in high
yield and ee (entry 23). Even more outstanding are the
almost perfect enantioselectivities (ee's up to 99%) and
high yields achieved in the etherification of S1 with tri-
phenylsilanol (entry 24), a rather unusual nucleophile
that gives rise to a protected chiral alcohol.26e Remarka-
bly, enantioselectivities recorded with O-nucleophiles
(entries 19–24) were, at the very least, as high as those
obtained with dimethyl malonate.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pyrroles, which are electron-rich N-containing hetero-
cycles interesting from a synthetic and biological point of
view,22 also performed well as nucleophiles in this reac-
tion. Despite their importance, as far as we know only one
catalytic system has been reported to be successful in the
Pd-catalyzed allylic alkylation of S1 type substrates with
pyrroles, the reaction involving inconvenient low temper-
ature (–20 ºC).23 The difficulty of the transformation is
more evident if we consider that, even two of the most
successful ligands developed for this process (Trost di-
phosphine and phosphine-oxazoline PHOX), did not
work with pyrroles.23 Thus, we were pleased to find that
using the Pd/L8b system we could reach ee's up to 99%
and high yields working at room temperature (entries 11
and 12).
Chiral allylic amines are also ubiquitous in biologically
active compounds,3n so we next studied the use of amine
derivatives as nucleophiles. Benzylamine provided the
substitution product 25 in high yield and enantioselectivi-
ty (99% ee; entry 13). To test the scope of allylic amina-
tion, the reaction of S1 was evaluated using other N-
nucleophilic compounds (entries 14–18). The combination
Pd/L8b also proved highly efficient in the addition of p-
methoxy- and p-trifluoromethylbenzylamines (com-
pounds 26 and 27) and the furfurylamine 28 (entries 14–
16), enantiocontrol being always excellent. The addition
of morpholine, a cyclic secondary amine, also gave the
expected product with high enantioselectivity (product
Allylic substitution of several linear and cyclic
substrates S2–S9 using several C-nucleophiles.
Scope and limitations. After the broad scope of nucle-
ophiles displayed by the catalytic system with S1, we
turned our attention to the use of five additional linear
substrates (S3–S7) with electronic and steric requirements
different from S1 (Table 5, entries 1–6). Advantageously,
we found
Table 4. Pd-catalyzed allylic substitution of linear substrate S1 with different types of C-, N- and O-nucleophiles
using Pd/L8b catalytic system.a
Entry
1
Product
% Yieldb
94
% eec
Entry
13
Product
% Yieldb
88
% eec
99 (R)
99 (S)
2
92
98 (R)
14
81
99 (S)
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ACS Catalysis
1
2
3
4
5
6
7
8
3
92
93
97 (S)
98 (S)
15
78
83
99 (S)
97 (S)
4
16
17
5
89
98 (S)
87
98 (S)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
7
8
91
90
88
95(S)
99 (S)
98 (R)
18
19e
20e
79
92
90
97 (S)
99 (S)
99 (S)
9
84
99 (R)
21e
91
98 (S)
98 (S)
10
82 (60:40
dr)
98/97d
22e
93
11d
87
85
96 (S)
23e
24e
83
78
96 (S)
99 (R)
12d
>99 (S)
a 0.5 mol% [PdCl(η3-C3H5)]2, 1.1 mol% ligand, CH2Cl2 (2 mL), BSA (3 equiv), nucleophile (3 equiv), KOAc (pinch) at rt for 30 min.
Isolated yield. Enantiomeric excesses measured by HPLC or GC. 2 mol% [PdCl(η3-C3H5)]2, 4.4 mol% ligand CH2Cl2 (2 mL),
b
c
d
K2CO3 (2 equiv) at rt for 18 h. e 2 mol% [PdCl(η3-C3H5)]2, 4.4 mol% ligand CH2Cl2 (2 mL), Cs2CO3 (3 equiv) at rt for 18 h.
that the catalytic performance was neither affected by
the introduction of electron-withdrawing, electron-
donating groups (entries 1–3), nor by the presence of or-
tho- and metha-substituents at the phenyl groups of the
substrate (entries 4–5). A remarkable enantioselectivity
(entry 6) was still achieved in the Pd-catalyzed allylic al-
kylation of S7, a challenging substrate that typically gives
rise to the corresponding substitution products in much
lower enantioselectivities than S1 in otherwise identical
conditions.
(ee's up to 97%, entries 7–11). The only exception was
acetylacetone that led to somewhat lower enantioselectiv-
ity (entry 12). High enantioselectivities in both enantio-
mers of the substitution products were thus obtained us-
ing methyl-, allyl- and propargyl-substituted malonates
(compounds 45–47; Table 5; entries 9–11 and Table S2).
Furthermore, the biaryl phosphite group in Pd/L8b and
Pd/L8c can adapt its chiral pocket to efficiently mediate
the substitution of other cyclic substrates (entries 13–16).
Excellent yields and enantioselectivities, comparable to
the best reported in the literature, were obtained in the
allylic alkylation of a 7-membered cyclic substrate with
different C-nucleophiles (products 51 and 52; entries 15
and 16). Even more interesting is that the good perfor-
mance could be also extended to the allylic alkylation of a
more challenging 5-membered cyclic substrate (com-
Finally, we wanted to see if the high enantioselectivities
achieved in the allylic substitution of linear substrates
were retained for their notoriously difficult cyclic ana-
logues. To this end, a number of cyclic substrates with
different ring sizes were tested using ligand L8b (Table 5,
entries 7–16; for the results using the Pd/L8c catalytic
system see Table S2 in the Supporting Information). For
the cyclohexenyl derivative S2, a range of C-nucleophiles
proved to give yields and enantioselectivities as high, if
not higher, as those recorded with dimethyl malonate
pounds
49
and
50;
entries
13
and
14).
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lowed by either ring-closing metathesis (Scheme 2) or
1
2
3
4
5
6
7
8
Pauson-Khand enyne cyclization (Scheme 3).
Synthetic applications of the allylic substitution
compounds. Preparation of chiral functionalized
(poly)carbocyclic and heterocyclic compounds 53–
61. To illustrate the synthetic versatility of the com-
pounds obtained from the enantioselective Pd-catalyzed
allylic substitution, we have prepared a range of chiral
functionalized carbocycles (53–56), heterocycles (57–58)
and polycarbocycles (59–61) from the enantioenriched
allylic substitution products. These compounds have been
synthesized by straightforward reaction sequences involv-
ing allylic substitution of the appropriate substrates fol-
According to this strategy, the alkylated compounds
16–18 (see Table 4 above) and 38 (see Table 5 above) un-
dergo clean ring-closing metathesis with no loss of enan-
tiopurity, furnishing a number of 5, 6 and 7-membered
carbocyles, in high yields and enantioselectivities (ee’s
ranging from 95–98%; Scheme 2). In an analogous man-
ner, the O-heterocycle (S)-57 is achieved by sequential
allylic etherification of S1 with allylic alcohol and ring-
closing metathesis reacti-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Pd-catalyzed allylic substitution of substrates S2–S9 with several C-nucleophiles using Pd/L8b catalytic
system.a
Entry Substrate
Product
%
% eec
Entry Substrate
Product
%
% eec
Yieldb
Yieldb
1
S3
98
98 (R)
9
S2
87
91 (R)
2
3
S3
S4
87
89
97 (R)
96 (R)
10
11
S2
S2
84
86
94 (R)
97 (R)
4
5
6
S5
S6
S7
91
87
91
97 (R)
99 (R)
>95 (R)
12
13
14
S2
S8
S8
82
80
83
80 (-)
84 (-)
85 (-)
7
S2
S2
87
84
95 (R)
95 (R)
15
16
S9
S9
90
92
96 (R)
96 (R)
8
a 0.5 mol% [PdCl(η3ꢀC3H5)]2, 1.1 mol% ligand, CH2Cl2 (2 mL), BSA (3 equiv), nucleophile (3 equiv), KOAc (pinch) at rt for 2 h. b Isolat-
ed yield. c Enantiomeric excesses measured by HPLC, GC or 1H-NMR using [Eu(hfc)3].
tion (Scheme 2); the corresponding N-heterocycle 58 per-
forms similarly, albeit it requires protection of the amine
with Boc prior to the ring-closing metathesis reaction,
presumably owing to the azophilicity of ruthenium.
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ACS Catalysis
the enantiodetermining step (see section 2.3, vide supra).
1
2
3
4
5
6
7
8
With the aim of better understanding the catalytic pro-
cess, we decided to prepare and characterize the Pd-allyl
intermediates and determine their relative reactivity to-
wards the nucleophile. Consequently, we studied the Pd-
π-allyl compounds 62–65 [Pd(η3-allyl)(P-S)]BF4 (P-S =
L5b–c) by NMR and DFT studies. These Pd-intermediates
containing cyclohexenyl and 1,3-diphenyl allyl groups
were synthesized as previously reported (Scheme 4).28 All
1
complexes were characterized by H, 13C and 31P NMR
9
spectroscopy29 and mass spectrometry. Unfortunately, we
were unable to obtain crystals of sufficient quality to per-
form X-ray diffraction measurements. The ESI-HR-MS
showed the heaviest ions at m/z corresponding to the
cation.
10
11
12
13
14
15
Scheme 2. Preparation of chiral functionalized carbo-
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
and heterocyclic compounds 53–58.
The second derivatization we tackled was the Pauson-
Khand reaction of the propargylated derivatives 47, 50
and 52 (see Table 5 above), which differ only in the size of
the cycloalkene ring. Formation of the complex with
Co2(CO)8, followed by thermal decomposition, gave rise
to the [2+2+1] cycloadducts 59–61, which feature an archi-
tecturally complex tricyclic system (Scheme 3).
Scheme 4. Preparation of [Pd(η3-allyl)(P-S)]BF4 (P-S =
L5b–c) complexes 62–65.
To understand why the configuration of the enantio-
mer of the alkylated product changes with the configura-
tion of the biaryl phosphite group in the substitution of
cyclic substrate S2, we compared the Pd-1,3-cyclohexenyl-
allyl intermediate 62, which contains ligand L5b with its
counterpart Pd/L5c intermediate (63). The VT-NMR
study (30 ºC to –80 ºC) showed the presence of essentially
single isomers (ratio ca. 20:1; Scheme 5) for both interme-
diates (62 and 63). The major isomers were unambiguous-
ly assigned by NMR to be the exo isomer for 62 and the
endo isomer for 63 (see Supporting Information for NOE
details). In both cases, the thioether group had an S-
configuration. The assignments are in agreement with the
DFT calculations of the Pd-η3-cyclohexenyl complexes
(see Supporting Information for the results of the full set
of calculated Pd-η3-allyl intermediates). Thus, for Pd/L5b
the major Pd-η3-exo isomer is 9.5 kJ/mol more stable than
the most stable endo isomer, while for Pd/L5c the Pd-η3-
endo isomer energy is 7.3 kJ/mol lower than the most sta-
ble exo isomer. The 13C NMR chemical shifts indicate that
for both major isomers the most electron-deficient allylic
terminal carbon is trans to the phosphite group. Assum-
ing that the nucleophilic attack takes place at the more
electron-deficient allyl carbon terminus, the fact that the
observed stereochemical outcome of the reaction (86% ee
(R) for Pd/L5b and 84% ee (S) for Pd/L5c) is similar to the
diastereoisomeric excess (de 90%) of the Pd-
intermediates indicates that both major and minor spe-
cies react at a similar rate. In summary, the study of Pd-
allyl intermediates shows that changes in the configura-
tion of the phosphite moiety lead to changes in the ratio
of the species that provide both enantiomers of the alkyl-
ated product. The enantioselectivity is therefore mainly
Scheme 3. Preparation of chiral functionalized polycar-
bocyclic compounds 59–61. X-ray structure of compound
61 is also included.
Remarkably, the chiral information on the allylic sub-
stitution products was reliably conveyed to the final
products, which were isolated as single diastereomers and
with ee’s replicating those of the starting materials. The
relative configuration of ketone 61 was assigned to be
trans–cis on the basis of a single crystal X-ray diffraction
image. In contrast, 59 and 60 are assigned as the cis–cis
diastereomer according to literature precedents.27
Study of the Pd-π-allyl intermediates. Our DFT
calculations have established the nucleophilic attack as
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Page 10 of 17
controlled by the population of the Pd-allyl intermedi- allyl endo intermediate, being the pathway through the
1
2
3
4
5
6
7
8
ates.
exo TS higher in energy (ΔΔG#= 28 kJ/mol; Table 2). All
these evidences further support the DFT calculations that
suggest that for intermediates 64 the major isomer has an
exo disposition, while the minor isomer has an endo spa-
tial arrangement. In contrast, the reactivity study of the
Pd-allyl complex 65 indicates that the major exo isomer is
the isomer that reacts faster with a nucleophile (Figure S3
of the SI; kexo/kendo ≈ 3.5). Again, this finding is in agree-
ment with the DFT calculations (vide supra, ΔΔG#= 10.8
kJ/mol, Table 2) and corroborates the DFT isomer as-
signment of the Pd-allyl intermediates observed in solu-
tion, having the major isomer an exo arrangement.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It should be pointed out that, albeit for the Pd/L5c cat-
alytic system the relative population of the faster reacting
isomer is much higher than that of Pd/L5b, the latter pro-
vides higher enantioselectivity (96% ee for Pd/L5b vs 80%
ee for Pd/L5c). Hence, in the case of S1 the enantioselec-
tivity seems to be controlled by the different reactivity of
the allyl intermediates towards the nucleophile (rather
than their population, as was the case for S2). These re-
sults are in line with the previous DFT calculations (see
section 2.3, Table 2) and therefore further corroborate
that the energy gap between the most stable TSs leading
to each of the product enantiomers is higher for the
Pd/L5b catalytic system than for Pd/L5c.
Scheme 5. Diastereoisomeric Pd-η3-allyl intermediates for
S2 with ligands L5b and L5c. The relative amounts of each
isomer are shown in parentheses. The chemical shifts (in
ppm) of the allylic terminal carbons and the computed
relative free energies in solution between the endo and
exo Pd-allyl intermediates are also shown for compounds
62 and 63, in kJ/mol.
Finally, to assess the impact of the phosphite chiral axis
configuration on the enantioselectivity obtained for S1,
we compared the corresponding Pd allylic intermediates
with ligands L5b and L5c (64 and 65, respectively). In this
case, L5b provided high enantioselectivity whereas L5c
proved less selective, which is in contrast to the observa-
tion made for the alkylation of the cyclic substrate S2. The
VT-NMR study (30 ºC to –80 ºC) of intermediates 64 and
65 showed a mixture of two isomers in equilibrium with
ratios 1.3:1 and 2.3:1, respectively (Scheme 6). All isomers
were assigned to be syn/syn, according to the NOE inter-
action between the two terminal protons of the allyl
group. Unfortunately, the NOE contacts are not conclu-
sive enough to unambiguously assign the 3D structure of
these isomers. The final assignment of these Pd-allyl in-
termediates was performed by DFT studies (see Support-
ing Information) and further assessed by studying the
reactivity of the Pd-intermediates with sodium dimethyl
malonate at low temperature by in situ NMR studies (Fig-
ure S3 of the SI). The DFT-calculated population of the
different Pd-allyl species (i.e. ratio of 1.4:1 for complex 64)
is in good agreement with the population obtained exper-
imentally (i.e. ratio of 1.3:1 for 64). Calculations indicate
that for both systems, the most stable Pd-allyl intermedi-
ate is the exo isomer, the endo isomer being higher in
energy (0.8 kJ/mol for Pd/L5b and 5.5 kJ/mol for Pd/L5c).
On the other hand, the reactivity study of the Pd-
intermediate 64 with sodium dimethyl malonate at low
temperature reveals that the minor endo isomer reacts
faster than the major isomer (Figure S3 of the SI; kendo/kexo
>20). This reactivity pattern is in agreement with the pre-
viously presented TS calculations (see Section 2.2), which
indicate that the most favourable (lowest in energy) tran-
sition state arises from the nucleophilic attack to the Pd-
Scheme 6. Diastereoisomer Pd-η3-allyl intermediates for
S1 with ligands L5b and L5c. The relative amounts of each
isomer are shown in parentheses. The chemical shifts (in
ppm) of the allylic terminal carbons and the computed
relative free energies in solution between the endo and
exo Pd-allyl intermediates are also shown for compounds
64 and 65, in kJ/mol.
CONCLUSIONS
A new and small library of P-thioether ligands has been
tested in the Pd-catalyzed allylic substitution reaction.
The modular architecture of the ligands has allowed the
iterative optimization of the ligand parameters in order to
fine control the chiral cavity in which the allyl system is
embedded. The robustness of the thioether group adds
another advantage to these ligands. Compared to previ-
ously reported larger furanoside derived P-S ligand li-
brary, the new library is easier to synthesize, in only three
steps, from inexpensive indene. The simpler backbone of
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ACS Catalysis
tion mixture is capped and stirred at 55 °C until the epox-
these new ligands gives rise to neat NMR spectra with less
1
2
3
4
5
6
7
8
signal overlap, which facilitates the identification of rele-
vant intermediates and accelerates the DFT calculations
in the search for better catalysts. The combination of ex-
perimental and theoretical studies has therefore lead us
to the rational design of an optimal, solid, air-stable P-S
ligand for the Pd-catalyzed enantioselective allylic substi-
tution. This ligand consistently gave excellent enantiose-
lectivities for 40 compounds involving linear and cyclic
substrates and a broad range C-, N-, and O-nucleophiles.
The results were maintained using the propylene car-
bonate as green solvent. In comparison with previous
furanoside-based P-S ligands, which have emerged as
some of the most successful catalyst for this process, the
new P-S ligand also provided a better activity and a wider
nucleophile scope (i.e. including the addition of pyrroles
and a broader range of amines). The species responsible
for the catalytic performance were also identified by
mechanistic studies based on NMR spectroscopy, thus
rationalizing the origin of the enantioselectivity. For en-
antioselectivities to be high, the ligand parameters there-
fore need to be correctly chosen to either increase the
difference in population of the possible Pd-allyl interme-
diates (for cyclic substrates) or to increase the relative
rates of the nucleophilic attack for each of the possible
Pd-allyl complexes (linear substrates). Finally, to assess
the potential impact of this catalytic system in synthesis,
the products have been employed in ring-closing metath-
esis or Pauson-Khand reactions, giving rise to a set of chi-
ral (poly)carbo- and heterocyclic compounds with faithful
transmission of the chiral information. The results pre-
sented here compete very well with a few other ligands
that also provide high catalytic performance in several
substrate and nucleophiles.
ide is consumed according to TLC analysis (ca. 45-60
min). After this, the mixture is cooled to room tempera-
ture, diluted with water and extracted with CH2Cl2 (3 x 20
mL). The combined organic layers are dried over Na2SO4
and concentrated to give a residue that is purified by flash
chromatography on silica gel (eluent specified in each
case) to give the desired thioether-alcohol (see Support-
ing Information for characterization details).
9
General procedure for the preparation of phos-
phite-thioether ligands L1–L8a–c. The corresponding
phosphorochloridite (1.1 mmol) produced in situ was dis-
solved in toluene (5 mL), and pyridine (0.3 mL, 3.9 mmol)
was added. The corresponding thioether-hydroxyl com-
pound (1 mmol) was azeotropically dried with toluene (3 x
2 mL) and then dissolved in toluene (5 mL) to which pyr-
idine (0.3 mL, 3.9 mmol) was added. The alcohol solution
was transferred slowly to a solution of phosphorochlorid-
ite. The reaction mixture was stirred at 80 ºC for 90 min,
after which the pyridine salts were removed by filtration.
Evaporation of the solvent gave a white foam, which was
purified by flash chromatography in silica (Hex-
ane/Toluene/NEt3 = 7/3/1) to produce the corresponding
ligand as a white solid (see Supporting Information for
characterization details).
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General procedure for the preparation of phos-
phinite-thioether ligands L1–L8d–g. The correspond-
ing thioether-hydroxyl compound (0.5 mmol) and DMAP
(6.7 mg, 0.055 mmol) were dissolved in toluene (1 ml),
and triethylamine was added (0.09 ml, 0.65 mmol) at rt,
followed by the addition of the corresponding chloro-
phosphine (0.55 mmol) via syringe. The reaction was
stirred for 20 min at room temperature. The solvent was
removed in vacuo, and the product was purified by flash
chromatography on alumina (toluene/NEt3 = 100/1) to
produce the corresponding ligand as an oil (see Support-
ing Information for characterization details).
EXPERIMENTAL SECTION
General considerations. All reactions were carried
out using standard Schlenk techniques under an atmos-
phere of argon. Solvents were purified and dried by
standard procedures. Phosphorochloridites were easily
prepared in one step from the corresponding biaryls.30
Enantiopure (–)-indene oxide 210 and phosphinite-
thioether ligands L1d12a and L5d12a were prepared as previ-
ously described. Racemic substrates S1-S931 and Pd-allyl
complexes [Pd(η3-1,3-Ph2-C3H3)(μ-Cl)]232 and [Pd(η3-
Typical procedure for the allylic alkylation of
disubstituted linear (S1 and S3–S7) and cyclic (S2
and S8–S9) substrates. 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 corre-
sponding substrate (0.5 mmol) in dichloromethane (1.5
mL), nucleophile (1.5 mmol), N,O-bis(trimethylsilyl)-
acetamide (370 μL, 1.5 mmol) and a pinch of KOAc were
added. The reaction mixture was stirred at room tempera-
ture. 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 x 10 mL) and the extract dried over MgSO4. Conver-
33
cyclohexenyl)(μ-Cl)]2 were prepared as previously re-
ported. 1H, 13C{1H}, and 31P{1H} NMR spectra were recorded
using a 400 MHz spectrometer. Chemical shifts are rela-
tive to that of SiMe4 (1H and 13C) as internal standard or
1
H3PO4 (31P) as external standard. H, 13C and 31P assign-
1
1
ments were made on the basis of H-1H gCOSY, H-13C
gHSQC and 1H-31P gHMBC experiments.
1
sions were measured by H NMR and enantiomeric ex-
General procedure for the regio- and stereospe-
cific ring opening of 2. Preparation of thioether-
alcohols 3-9 and 12. A solution of (–)-indene oxide 2 (2
mmol, 264 mg) in dioxane (4.5 mL/mmol of indene oxide)
is treated with the corresponding thiol (3 mmol). Then, a
solution of NaOH (3 mmol, 120 mg) in water (0.45
mL/mmol of indene oxide) is added dropwise. The reac-
cesses were determined either by HPLC (compounds 10,
13–22, 37–41 and 43–46) or by GC (compounds 11, 47–48
and 50–52) or by 1H NMR using [Eu(hfc)3] (compounds 42
and 49). For characterization and ee determination de-
tails see Supporting Information.
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Page 12 of 17
Typical procedure for the allylic alkylation of
disubstituted linear substrate S1 using pyrroles.
Typical procedure for the preparation of chiral
tricyclic compounds 59–61. A solution of the starting
1
2
3
4
5
6
7
8
A
degassed solution of [PdCl(η3-C3H5)]2 (1.8 mg, 0.005
mmol) and the corresponding phosphite/phosphinite-
thioether (0.011 mmol) in dichloromethane (0.5 mL) was
stirred for 30 min. Subsequently, a solution of the corre-
sponding substrate (0.5 mmol) in dichloromethane (1.5
mL), the corresponding pyrrole (0.4 mmol) and K2CO3
(110 mg, 0.8 mmol) were added. The reaction mixture was
stirred at room temperature. After 18 h, the reaction mix-
ture was diluted with Et2O (5 mL) and saturated NH4Cl
(aq) (25 mL) was added. The mixture was extracted with
Et2O (3 x 10 mL) and the extract dried over MgSO4. Con-
enyne (0.187 mmol) in 1 mL of tert-butylbenzene was add-
ed to a solution of Co2(CO)8 (83 mg, 0.243 mmmol) in 0.5
mL of tert-butylbenzene under air. The flask was rinsed
with 0.5 mL more of the same solvent. The resulting mix-
ture was stirred at room temperature for 1 h, until full
consumption of the starting material was observed by
TLC. After that, the system was heated at 170 °C for a fur-
ther hour. Then, it was cooled to room temperature, fil-
tered on Celite with CH2Cl2 and concentrated in vacuo.
The crude mixture was purified by flash column chroma-
tography on silica gel eluting with cyclohexane/EtOAc
(gradient form 90:10 to 70:30) to furnish the desired tricy-
clic compound as a white solid. For characterization and
ee determination details see Supporting Information.
General procedure for the preparation of [Pd(η3-
allyl)(L)]BF4 complexes 62–65. The corresponding lig-
and (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 minutes and the mixture was stirred for 30
minutes. 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 (see Supporting
Information for characterization details).
Study of the reactivity of the [Pd(η3-allyl)(L))]BF4
with sodium dimethyl malonate by in situ NMR.34
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 solu-
tion of cooled sodium dimethyl 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.
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1
versions were measured by H NMR and enantiomeric
excesses were determined by HPLC. For characterization
and ee determination details see Supporting Information.
Typical procedure for the allylic amination of
disubstituted linear substrate S1. A degassed solution
of [PdCl(η3-C3H5)]2 (0.9 mg, 0.0025 mmol) and the corre-
sponding ligand (0.0055 mmol) in dichloromethane (0.5
mL) was stirred for 30 min. Subsequently, a solution of
rac-1,3-diphenyl-3-acetoxyprop-1-ene (S1) (0.5 mmol) in
dichloromethane (1.5 mL), the corresponding amine (1.5
mmol), N,O-bis(trimethylsilyl)-acetamide (370 μL, 1.5
mmol) and a pinch of KOAc were added. The reaction
mixture was stirred at room temperature. After 2 hours,
the reaction mixture was diluted with Et2O (5 mL) and
saturated NH4Cl (aq) (25 mL) was added. The mixture
was extracted with Et2O (3 x 10 mL) and the extract dried
1
over MgSO4. Conversions were measured by H NMR and
enantiomeric excesses were determined by HPLC. For
characterization and ee determination details see Sup-
porting Information.
Typical procedure for the allylic etherification
and silylation of disubstituted linear substrate S1.
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. Subse-
quently, a solution of rac-1,3-diphenyl-3-acetoxyprop-1-
ene (S1) (31.5 mg, 0.125 mmol) in dichloromethane (1.5
mL) was added. After 10 minutes, Cs2CO3 (122 mg, 0.375
mmol) and the corresponding alcohol or silanol (0.375
mmol) were added. The reaction mixture was stirred at
room temperature. After 18 h, the reaction mixture was
diluted with Et2O (5 mL) and saturated NH4Cl (aq) (25
mL) was added. The mixture was extracted with Et2O (3 x
10 mL) and the extract dried over MgSO4. Conversions
Computational details. All calculations were per-
formed using the Gaussian 09 program.35 Optimizations
of minima and transition states were performed employ-
ing the B3LYP36 density functional and the 6-31G(d) basis
set for all elements except for Pd for which the
LANL2DZ37 was used.38 All energies presented correspond
to single point calculations with the B3LYP-D3 function-
al39 and the larger 6-311+G(d,p)40 basis set for all elements
except Pd. Solvation was taken into account along opti-
mization and single points through the use of the PCM
continuum model with the default parameters for di-
chloromethane.41 No symmetry constraints were applied.
The validity of the model was confirmed by a series of
geometry optimizations at the B3LYP-D3 level on the four
key transition states. The qualitative trends were un-
changed: ligand L5b favored the R product (corrected ee
of 64 vs uncorrected ee of 99.99) and ligand L5c favored
the S product (corrected ee of 99.6 vs uncorrected ee of
97.5). Normal mode analysis of all transition states re-
vealed a single imaginary mode corresponding to the ex-
pected nucleophilic attack of the nucleophile to one of
1
were measured by H NMR and enantiomeric excesses
were determined by HPLC. For characterization and ee
determination details see Supporting Information.
Typical procedure for the preparation of chiral
carbo- and heterocyclic compounds 53–58. A solu-
tion of Grubbs II catalyst (5 mg, 0.006 mmol) and the
corresponding alkylated product (0.12 mmol) in CH2Cl2 (3
mL) was stirred for 16 h. The solution was directly puri-
fied by flash chromatography (Hex/EtOAc 95:5) to ob-
tained the desired compounds. For characterization and
ee determination details see Supporting Information.
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ACS Catalysis
(c) Johannsen, M.; Jorgensen, K. A. Allylic Amination. Chem. Rev.
the two allylic termini carbons. All energies reported are
1998, 98, 1689–1708. (d) Pfaltz, A.; Lautens, M. in Comprehensive
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds.; Springer-Verlag: Berlin, 1999; Vol. 2, Chapter 24. (e) Helm-
chen, G.; Pfaltz, A. Phosphinooxazolines – A New Class of Versa-
tile, Modular P,N-Ligands for Asymmetric Catalysis. Acc. Chem.
Res. 2000, 33, 336–345. (f) Martin, E.; Diéguez, M. Thioether
Containing Ligands for Asymmetric Allylic Substitution Reac-
tions. C. R. Chim. 2007, 10, 188–205. (g) Trost, B. M.; Crawley, M.
L. Asymmetric Transition-Metal-Catalyzed Allylic Alkylations:ꢁ
Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921–2944.
(h) Lu, Z.; Ma, S. Metal-Catalyzed Enantioselective Allylation in
Asymmetric Synthesis. Angew. Chem. Int. Ed. 2008, 47, 258–297.
(i) Diéguez, M.; Pàmies, O. Biaryl Phosphites: New Efficient Ad-
aptative Ligands for Pd-Catalyzed Asymmetric Allylic Substitu-
tion Reactions. Acc. Chem. Res. 2010, 43, 312–322. (j) Trost, B. M.;
Zhang, T.; Sieber, J. D. Catalytic Asymmetric Allylic Alkylation
Employing Heteroatom Nucleophiles: a Powerful Method for C–
X Bond Formation. Chem. Sci. 2010, 1, 427–440. (k) Trost, B. M.
Pd- and Mo-Catalyzed Asymmetric Allylic Alkylation. Org. Pro-
cess Res. Dev. 2012, 16, 185–194. (l) Butt, N.; Zhang, W. Transition
Metal-Catalyzed Allylic Substitution Reactions with Unactivated
Allylic Substrates. Chem. Soc. Rev. 2015, 44, 7929−7967. (m)
Grange, R. L.; Clizbe, E. A.; Evans, P. A. Recent Developments in
Asymmetric Allylic Amination Reactions. Synthesis 2016, 48,
2911–2968. (n) Butt, N.; Yang, G.; Zhang, W. Allylic Alkylations
with Enamine Nucleophiles. Chem. Rec. 2016, 16, 2683−2692.
(4) For recent selected publications, see: (a) Mata, Y.; Pàmies,
O.; Diéguez, M. Pyranoside Phosphite-Oxazoline Ligand Library:
Highly Efficient Modular P,N Ligands for Palladium-Catalyzed
Allylic Substitution Reactions. A Study of the Key Palladium
Allyl Intermediates. Adv. Synth. Catal. 2009, 351, 3217–3234. (b)
Mazuela, J.; Pàmies, O.; Diéguez, M. A New Modular Phosphite-
Pyridine Ligand Library for Asymmetric Pd-Catalyzed Allylic
Substitution Reactions: A Study of the Key Pd-π-Allyl Intermedi-
ates. Chem. Eur. J. 2013, 19, 2416–2432. (c) Bellini, R.;, Magre, M.;
Biosca, M.; Norrby, P.-O.; Pàmies, O.; Diéguez, M.; Moberg, C.
1
2
3
4
5
6
7
8
Gibbs free energies in solution at 298.15 K and calculated
as ∆Greported = ∆GB3LYP/6-31G(d) + (∆EB3LYP-D3/6-311+G(d,p) - ∆EB3LYP/6-
31G(d)). A data set collection of the computational results is
available in the ioChem-BD repository.42
ASSOCIATED CONTENT
Characterization details and copies of NMR spectra of the
new ligands L1–L8a–g, ligand intermediates 3–9 and 12, and
Pd-allyl intermediates 62–65. NOE experiments and reactivi-
ty studies of Pd-intermediates. NMR and ee determination
details of substitution products and chiral functionalized
(poly)carbocyclic and heterocyclic compounds.
Full sets of results for the allylic substitution of S1–S9 in pro-
pylene carbonate as solvent and of cyclic substrates using
Pd/L8c catalytic system.
Crystal data and structure refinement of compound 61.
Calculated energies and coordinates for all computational
structures.
Deformation and interaction energies for the TS containing
ligands L5b–c.
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AUTHOR INFORMATION
Corresponding Author
* E-mail for M.B.: mbesora@iciq.es.
* E-mail for F.M.: fmaseras@iciq.es.
* E-mail for O.P.: oscar.pamies@urv.cat.
* E-mail for M.D.: montserrat.dieguez@urv.cat.
* E-mail for M.A.P.: mapericas@iciq.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Conformational
Preferences
of
a
Tropos
Biphenyl
We all acknowledge MINECO for the INTECAT network
CTQ2016-81293-REDC/AEI. The URV members gratefully
acknowledge financial support from the Spanish Ministry of
Economy and Competitiveness (CTQ2016-74878-P) and Eu-
ropean Regional Development Fund (AEI/FEDER, UE), the
Catalan Government (2014SGR670), and the ICREA Founda-
tion (ICREA Academia award to M.D). The ICIQ members
gratefully acknowledge financial support from CERCA Pro-
gramme/Generalitat de Catalunya, the Spanish Ministry of
Phosphinooxazoline–a Ligand with Wide Substrate Scope. ACS
Catalysis 2016, 6, 1701–1712. (d) Pàmies, O.; Diéguez, M.
Adaptable P-X Biaryl Phosphite/Phosphoroamidite-Containing
Ligands for Asymmetric Hydrogenation and C-X Bond-Forming
Reactions: Ligand Libraries with Exceptionally Wide Substrate
Scope. Chem. Rec. 2016, 16, 2460–2481.
(5) (a) Coll, M.; Pàmies, O.; Diéguez, M. Highly Versatile Pd–
Thioether–Phosphite Catalytic Systems for Asymmetric Allylic
Alkylation, Amination, and Etherification Reactions. Org. Lett.
2014, 16, 1892–1895. (b) Margalef, J.; Coll, M.; Norrby, P.-O.;
Pàmies, O.; Diéguez, M. Asymmetric Catalyzed Allylic Substitu-
tion Using a Pd/P–S Catalyst Library with Exceptional High Sub-
strate and Nucleophile Versatility: DFT and Pd-π-allyl Key In-
termediates Studies. Organometallics 2016, 35, 3323–3335.
(6) For successful applications, see: (a) Evans, D. A.; Campos,
K. R.; Tedrow, J. S.; Michael, F. E.; Gagné, M. R. Application of
Chiral Mixed Phosphorus/Sulfur Ligands to Palladium-Catalyzed
Allylic Substitutions. J. Am. Chem. Soc. 2000, 122, 7905–7920 (up
to 98% and 90% ee at -20 °C for S1 and S2, respectively). (b)
Nakano, H.; Okuyama, Y.; Hongo, H. New Chiral Phosphinooxa-
thiane Ligands for Palladium-Catalyzed Asymmetric Allylic Sub-
stitution Reactions. Tetrahedron Lett. 2000, 41, 4615–4618 (up to
94% ee at -30 °C for S1). (c) García Mancheño, O.; Priego, J.;
Cabrera, S.; Gómez Arrayás, R.; Llamas, T.; Carretero, J. C. 1-
Phosphino-2-sulfenylferrocenes as Planar Chiral Ligands in En-
antioselective Palladium-Catalyzed Allylic Substitutions. J. Org.
Chem. 2003, 68, 3679–3686 (up to 97% ee at -20 °C for S1). (d)
Enders, D.; Peters, R.; Runsink, J.; Bats, J. W. Novel Ferrocenyl
Ligands with Planar and Central Chirality in Pd-Catalyzed Allylic
Economy and Competitiveness
(CTQ2015-69136-R,
CTQ2017-87792-R, AEI/MINECO/FEDER, UE and Severo
Ochoa Excellence Accreditation 2014–2018, SEV-2013-0319)
and DEC Generalitat de Catalunya (Grant 2014SGR827). The
CELLEX Foundation is also acknowledged for financing the
High Throughput Experimentation (HTE) laboratory.
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(19) Ligands L8b and L8c were prepared from (1S,2S)-1-(9-
anthrylthio)-2,3-dihydro-1H-inden-2-ol (12) as described in
Scheme 1. See experimental section for purification and charac-
terization details.
(20) If we compare the calculated and experimental values
(Table 3), we can see that, despite the fact that the calculated
free energy differences are systematically lower than the experi-
mental values, the general trend is reproduced well. The robust-
ness of the theoretical model is demonstrated with the predic-
tion of the new improved ligands L8b,c containing an anthryl
moiety.
(13) The spectra assignments were supported by the infor-
1
1
mation obtained from H–1H and H–13C correlation measure-
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1
pected pattern for the C1–ligands. The VT-NMR in CD2Cl2 (+35 to
–85 °C) spectra of the ligands L1–L7a showed only one isomer in
solution. In all cases, one singlet in the 31P{1H} NMR spectra was
observed.
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