An improved class of phosphite-oxazoline ligands for Pd-catalyzed allylic substitution reactions

Article abstract of DOI:10.1021/acscatal.9b01166

A method for generation of Pd/phosphite-oxazoline catalysts containing an alkyl backbone chain has been successfully applied to Pd-catalyzed allylic substitution reactions. By carefully selecting the substituents at both the alkyl backbone chain and the oxazoline of the ligand, as well as the configuration of the biaryl phosphite group, high activities (TOF > 8000 mol substrate × (mol Pd × h)^?1) and excellent enantioselectivities (ee's up to 99%) have been achieved for many hindered and unhindered substrates with a wide range of C-, O-, and N-nucleophiles (73 substitution products in total). Moreover, DFT and NMR studies of the key Pd-allyl complexes allowed us to better understand the origin of the excellent enantioselectivities observed experimentally. The useful application of the Pd/phosphite-oxazoline catalysts was demonstrated by the syntheses of many chiral carbobicycles, with multiples stereocenters, by simple sequential reactions involving Pd-allylic substitution and either 1,6-enyne cyclization or Pauson?Khand enyne cyclization.

Full text of DOI:10.1021/acscatal.9b01166

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Article
An improved class of phosphite-oxazoline ligands
for Pd-catalyzed allylic substitution reactions
Maria Biosca, Joan Saltó, Marc Magre, Per-Ola Norrby, Oscar Pàmies, and Montserrat Diéguez
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
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ACS Catalysis
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An improved class of phosphite-oxazoline ligands for Pd-catalyzed
allylic substitution reactions
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Maria Biosca,a Joan Saltó,a Marc Magre,a Per-Ola. Norrby,b,c,* Oscar Pàmies,a,* Montserrat Diégueza,*
a Universitat Rovira i Virgili, Departament de Química Física i Inorgànica, C/ Marcel·lí Domingo, 1, 43007 Tarragona,
Spain.
b Data Science and Modelling, Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca Gothenburg, Sweden.
c Department of Chemistry and Molecular Biology, University of Gothenburg, Kemigården 4, SE-412 96 Göteborg, Sweden.
ABSTRACT: A generation of Pd/phosphite-oxazoline catalysts containing an alkyl backbone chain has been successfully applied to
Pd-catalyzed allylic substitution reactions. By carefully selecting the substituents at both the alkyl backbone chain and the oxazoline
of the ligand, as well as the configuration of the biaryl phosphite group, high activities (TOF > 8000 mol substrate×(mol Pd×h)-1) and
excellent enantioselectivities (ee’s up to 99%) have been achieved for many hindered and unhindered substrates with a wide range of
C-, O- and N-nucleophiles (73 substitution products in total). Moreover, DFT and NMR studies of the key Pd-allyl complexes allowed
us to better understand the origin of the excellent enantioselectivities observed experimentally. The synthetic application of the
Pd/phosphite-oxazoline catalysts was demonstrated by the synthesis of many chiral carbobicyles, with multiples stereocenters, by
simple sequential reactions involving Pd-allylic substitution an either 1,6-enyne cyclization or Pauson-Khand enyne cyclization.
KEYWORDS: Palladium, asymmetric allylic substitution, DFT calculations, NMR study, mixed P,N-ligands.
change the phosphine group in privileged phosphine-oxazoline
INTRODUCTION
PHOX ligands 12e,6 by a biaryl phosphite group (Figure 1,
Many pharmaceutical, fragrance and crop protection
industries depend on chiral compounds. The finding of
synthetic methods for their preparation is a recurrent research
in chemistry1 and the Pd-catalyzed asymmetric allylic
substitution (AAS) has been proved to be one of the most
powerful approaches. AAS works with mild reaction conditions
and has a high functional group tolerance. Moreover the
substitution products can be further derivatized due to the
presence of the alkene group.1,2 Given its advantages, it is
understandable the constant aim to increase the substrate and
nucleophile scope to reach compounds with more complexity.
Its main limitation is still enantioselectivity is extremely
affected by the steric demands of the substrate.2 Each type of
substrate requires a particular ligand for optimal enantiopurity
so most of the best-performing ligands rarely tolerate many type
of substrates. Consequently, the discovery of the best
performing ligands is time consuming and expensive. This is
facilitated with the identification of ligands with a wide
substrate and nucleophile scope. Our group early found that
biaryl diphosphite-based ligands favor substrate versatility.2i,3
From a common backbone, the right combination of ligand
parameters provides ligands that are appropriated for both linear
and cyclic substrates using dimethylmalonate as nucleophile.3
The study of Pd-intermediates showed that the flexibility of the
phosphite functionalities enables the chiral pocket of the
catalyst to fit substrates with different steric hindrance. In
addition, the π-acceptor capacity of the phosphite moiety has a
positive influence on activities, providing higher TOF than the
most common ligands.2i,3,4 Encouraged by the high
enantioselectivities achieved with heterodonor-based ligands in
AAS we then started the development of heterodonor ligands
with a biaryl phosphite moiety.5 In this respect, we decided to
ligands 2).5a Whereas Pd-1 catalysts gave outstanding
enantioselectivities
with
rac-(E)-1,3-diaryl-2propenyl
substrates, moderate-to-good enantioselectivities with 1,3-
dialkyl-2-propenyl substrates and racemic results for cyclic
substrates,2e the Pd-phosphite-oxazoline counterparts 2 were
very successful in all of them.5a,7 Pd/2 emerged as an
unprecedented catalyst able to make C−C and C-X bonds with
high enantiocontrol for several hindered and unhindered
substrates using many C-, O-, and N-nucleophiles. In addition,
the improvement in activity achieved with diphosphite ligands
was maintained. Mechanistic studies established that the large
substrate scope of Pd/2 system is because the ligand is able to
adapt the size of chiral pocket to the steric demands of the
substrates.7 This adaptability of the ligand also explains the
excellent results achieved in other catalytic reactions.8
O
O
O
N
PPh2
N
O
P
iPr
tBu
2
1
O
Figure 1. PHOX-based ligand 1 and the related phosphite-
oxazoline ligands 2.
Despite the wide scope of ligands 2, there is still room for
improvement in terms of both substrate and nucleophile scope.
For instance, the efficiency disclosed for non-symmetrical
substrates has to be further enhanced and the nucleophile scope
has to be expanded to cover a wider range of amines and
alcohols. To continue the improvement of Pd-catalysts with air
stable and readily available ligands, we replaced the ortho-
phenylene tether in privileged ligands 2 by an alkyl backbone
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chain (Figure 2, ligands L1–L7a–c). With this simple
Page 2 of 17
O
(i)
(vii)
HO
L1a c
-
1
2
3
4
5
6
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8
modification, we have extended the number of ligand
parameters than can be modified to maximize the catalyst
performance. Therefore, in addition of studying different
substituents and configurations in the oxazoline and phosphite
groups we also studied the influence of a new stereogenic center
in the alkyl backbone chain and the influence of varying the
substituent in this alkyl backbone chain. In this respect, we here
report the application of ligands L1–L7a–c in the Pd-catalyzed
AAS of linear (including unsymmetrical 1,3-disubstituted and
monosubstituted substrates) and cyclic substrates with many C-,
O- and N-nucleophiles (73 substitution products in total). We
also used DFT and NMR studies of the key Pd-allyl complexes
to explain the enantioselectivities obtained experimentally.
Finally, we showed that these new Pd-catalytic systems can be
used in the synthesis of chiral carbobicyclic compounds by
simple sequential allylic substitution/1,6-enyne cyclization or
allylic substitution/Pauson-Khand reactions.
HO
COOH
CO2H
N
3
4
Ph
R1
R1
R1
OH
H
N
O
HO
(vii)
(ii-iv)
(v-vi)
*
L2 L7a c
-
-
HO
AcO
N
O
R2
R2
R1= Ph
R1= Me
R1= iPr
5
R1= Ph, R2= (S)-Ph
R1= Ph, R2= (S)-iPr
R1= Ph, R2= (S)-tBu
R1= Ph, R2= (R)-Ph
R1= Me, R2= (S)-Ph
R1= iPr, R2= (S)-Ph
R1= Ph, R2= (S)-Ph
R1= Ph, R2= (S)-iPr
R1= Ph, R2= (S)-tBu
R1= Ph, R2= (R)-Ph
R1= Me, R2= (S)-Ph
R1= iPr, R2= (S)-Ph
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Scheme 1. Synthetic route for the preparation of the phosphite-
oxazoline ligand library L1–L7a–c. (i) (S)-phenylglycinol,
xylene, reflux, 16 h;9 (ii) acetylchloride, rt, 2 h;11 (iii) SOCl2,
CH2Cl2, reflux, 3 h;11 (iv) aminoalcohol, NEt3, CH2Cl2, rt, 5 h;11
(v) DAST, K2CO3, CH2Cl2, -78 ºC to rt for 3 h;11,12 (vi) NaOH
(aq), EtOH, 0 ºC, 3 h;11,12 (vii) ClP(OR)2; (OR)2 = a–c, Py,
toluene, 16 h.
tBu
tBu
Ph
O
O
O
P
O
P
O
O
O
O
=
N
N
O
O
O
O
Allylic alkylation of disubstituted substrates S1–S2
using dimethyl malonate. The effectiveness of the phosphite-
oxazoline compounds L1–L7a–c was first studied in the Pd-
AAA of two benchmark substrates with different steric
constrains, rac-1,3-diphenyl-3-acetoxyprop-1-ene S1 and rac-
3-acetoxycyclohexene S2. For comparison, we use the same
optimal reaction conditions established in our previous study
with related Pd/PHOX-based phosphite-oxazoline catalysts 2.5a
The reactions were therefore done at 23 °C with 0.5 mol% of
catalyst and using dimethyl malonate. It should be noted, that
for cyclic S2 is more challenging to control the selectivity than
for S1 due to the presence of less bulky anti substituents.
However, by judiciously choosing the ligand parameters we
have been able to find two particular ligands L1c and L6c, that
performs exceptionally well for both substrate types, with
enantioselectivities up to 99% ee and TOF’s up to 8640 mol
substrate×(mol Pd×h)-1. The results (Table 1) indicated that
enantioselectivities are influenced by the substituents at both
the alkyl backbone chain and at the oxazoline as well as by the
biaryl phosphite groups. However, their influence on
enantioselectivity is different for both substrates. While for
substrate S1 the best enantioselectivity was achieved with L6c
(ee's up to 99%), for substrate S2 ligand L1c provided the
highest selectivity (ee's up to 99%).
R1
Ph
tBu
tBu
R1= Ph
R1= iPr
R1= tBu
L1
L2
L3
L4
a
Me3Si
R2
Ph
O
O
O
O
=
O
P
O
P
O
O
N
N
O
O
O
O
Ph
Ph
Me3Si
R2= Me
R2= iPr
b
c
(R)ax
(S)ax
L5
L6
L7
Figure 2. Phosphite-oxazoline compounds L1–L7a–c.
RESULTS AND DISCUSSION
Synthesis of ligands. Phosphite-oxazoline compounds
L1–L7a–c were synthesized through a two or five step process,
starting from commercial feedstocks (Scheme 1). Therefore,
ligands L1a–c, with two methyl groups in the alkyl backbone
chain, were synthesized in only two steps from cheap α-
hydroxyisobutyric acid 3. Condensation of 3 with (S)-
phenylglycinol afforded hydroxyl-oxazoline 4 in a multigram
scale (step i).9 Then, compound 4 react with the appropriated
phosphorochloridite (ClP(OR)2; (OR)2 = a–c; step vii) to yield
phosphite-oxazoline ligands L1a–c, with different biaryl
phosphite moieties. Phosphite-oxazolines L2–L7a–c, which
differ from previous ligands in a stereogenic center in the alkyl
backbone chain, were prepared following the procedure
previously reported in our group from commercially available
α-hydroxy acids 5–7.10 Therefore, compounds 5–7 were first
converted to amides 8–13 and subsequent reaction with
diethylaminosulfur trifluoride (DAST) followed by standard
deprotection yielded hydroxyl-oxazolines 14–19 (steps v–
vi).11,12 Finally, compounds 14–19 react with the desired
phosphorochloridite (ClP(OR)2; (OR)2 = a–c; step vii) to afford
compounds L2–L7a–c.
The results with ligands L1a–c, with an achiral alkyl
backbone chain (entries 1-3), showed that the ligand skeleton
can only control the tropoisomerization of the biphenyl
phosphite moiety (a) for substrate S1. While high
enantioselectivities are attained with L1a and L1c for substrate
S1 (96% ee, entries 1 and 3), the use of ligand L1c with an
enantiopure (S)-biaryl phosphite group is necessary to
maximize enantioselectivities for substrate S2 (99% ee, entry 3
vs 1 and 2). The same behavior is found with ligands L2–L7
that differ from L1 in that they contain a substituent at the alkyl
backbone chain that generates a new chiral center.
The results with ligands L2–L4a also indicated that
enantioselectivities are dependent on the oxazoline substituent.
Different from PHOX ligands 1, bulky substituents at the
oxazoline negatively affected enantioselectivity (see for e.g.,
entries 4, 7 and 8). Thus, the highest enantioselectivities for
both substrates were achieved using ligands L2, containing a
Advantageously, compounds L1–L7a–c were isolated as
white air-stable solids that were used and kept in air. HRMS-
ESI and H, 13C and 31P NMR spectroscopy confirmed the
1
formation of the ligands (see experimental and SI sections for
detail).
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ACS Catalysis
phenyl oxazoline substituent (entry 4). This represents an and L5b provides the opposite enantiomers than ligands L2c
1
2
3
4
5
6
7
8
advantage over the traditional phosphine-oxazoline PHOX
ligands 1 because enantiopure phenylglycinol (used for the
synthesis of L2) is much cheaper than tert-leucinol used for the
synthesis of 1.
and L5c). Both enantiomers of the products can be therefore
obtained by simple selecting the correct combination of ligand
parameters.
Finally, the influence of the substituent at the alkyl chain was
examined using compounds L1, L2, L6 and L7. The best
enantioselectivities were achieved with ligands L1 (for S2) and
L6 (for S1) containing two or one methyl group at the alkyl
backbone chain, respectively.
Table 1. Pd-catalyzed AAA of substrates S1 and S2 with
ligands L1–L7a–c a
O
O
MeO
O
MeO
Ph
OMe
O
In summary, the enantioselectivities with Pd/L1c and Pd/L6c
are excellent and similar to those with previous Pd/PHOX-
based phosphite-oxazoline catalysts 2 that have recently
become one of the most effective catalysts for Pd-AAS, with
the added advantage that the activity with Pd/L1c and Pd/L6c
is much higher13.
9
*
Ph 20
OMe
*
21
10
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12
13
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Entry
1
L
% Convb
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
72
%eec
96 (S)
86 (S)
96 (S)
93 (S)
40 (S)
90 (S)
92 (S)
73 (S)
90 (R)
94 (R)
55 (R)
97 (S)
89 (S)
99 (S)
84 (S)
91 (S)
90 (S)
99 (S)
% Convd
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
41
%eee
L1a
L1b
L1c
L2a
L2b
L2c
L3a
L4a
L5a
L5b
L5c
L6a
L6b
L6c
L7a
L7b
L7c
L6c
60 (S)
78 (R)
99 (S)
40 (S)
74 (R)
90 (S)
7 (S)
2
Allylic substitution of disubstituted linear and cyclic
substrates with several C-, O- and N-nucleophiles. We
further studied the performance of L1–L7a–c in the AAS of
other linear substrates, including unsymmetrical 1,3-
disubstituted ones and cyclic disubstituted substrates with
different steric and electronic properties. The range of
nucleophiles was also extended with special attention to some
more puzzling and appealing from a synthetic point of view,
3
4
5
6
7
8
4 (S)
namely
functionalized
malonates,
β-diketones,
2-
9
20 (R)
81 (R)
77 (S)
44 (S)
65 (R)
96 (S)
33 (S)
60 (R)
97 (S)
96 (S)
cyanoacetates, amines, pyrroles and aliphatic alcohols.
10
11
12
13
14
15
16
17
18f
Initially, the nucleophile scope for the Pd-AAS of S1 was
examined with ligand L6c that gave the best ees in the AAA of
S1 using dimethyl malonate. The results showed that many C-,
N- and O-nucleophiles could be efficiently used for this
transformation (Figure 3).
In this respect, a broad range of malonates, containing allyl-,
butenyl, pentenyl- and propargyl- groups, alkylated S1 to give
compounds 22–28 in excellent yields and enantioselectivities
(ee’s ≥99%). These results are relevant since the resulting
products (22–28) are crucial intermediates for preparing more
complex chiral compounds (for some of their applications see
synthetic applications section, vide infra).14 The use of
malononitrile (compound 29) and acetylacetone (compound 31)
also gave the desired alkylated products in excellent
enantioselectivities (>99% ee). Similarly to previous reports,
the use of isopropyl cyanoacetate as nucleophile (compound 30)
produced two diastereoisomers,15 albeit both diastereoisomers
were obtained almost enantiopure (ee’s up to 99%).
a
0.5 mol% [PdCl(η3-C3H5)]2, ligand (0.011 mmol), substrate (1
mmol), BSA (3 equiv), dimethyl malonate (3 equiv), KOAc (3
b
mol%), CH2Cl2 (2 mL) at 23 °C.
Conversion percentage
determined by 1H-NMR after 10 min. Enantiomeric excesses
c
determined by HPLC. Absolute configuration drawn in
d
parentheses. Conversion percentage calculated by GC after 30
e
min.
Enantiomeric excesses calculated by GC. Absolute
configuration drawn in parentheses. f Reactions performed with 0.1
mol% of catalyst precursor for 5 min.
The nucleophile scope was expanded to use pyrroles as C-
nucleophiles (Figure 3, compounds 32–35). Pyrroles are present
in many relevant compounds with biological and synthetic
applications.16 Despite their relevance only two successful
examples can be found in the literature17 and one of them
required -20 °C to attain high enantioselectivities17a. The
difficulty of using pyrroles as C-nucleophiles is also manifested
by the fact that two of the most successful ligands for Pd allylic
alkylation (PHOX 1 and Trost diphosphine) did not perform
well using pyrroles.17a By improving the Pd/2 catalysts, we were
pleased to see that we could reach for substituted pyrroles high
ee's (up to 99%) and yields working at 23 °C.
The results comparing the use of diasteriomeric ligands
L2b–c and L5b–c indicated the presence of a cooperative effect
between the configurations of both, the biaryl phosphite group
and the oxazoline substituent. The right combination of
configurations occurred in ligands L2c and L5b (entries 6 and
10). In addition, while the configuration of the oxazoline
substituent controls the sense of enantioselectivity for linear
substrate S1 (ligands L2 provide the opposite enantiomer of
alkylated products than ligands L5; entries 4–6 vs 9–11), it is
the configuration of the biaryl phosphite who controls the sense
of enantioselectivity for the cyclic substrate S2 (ligands L2b
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Page 4 of 17
* Carbon nucleophile scope
1
2
3
4
5
6
O
O
O
O
CO2Me
CO2Me
CO2Et
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
EtO
Ph
OEt
BnO
OBn
Ph
28
Ph
Ph
Ph
Ph
Ph
23
Ph
Ph
24
Ph
Ph
25
Ph
Ph
26
Ph
22
94% yield
>99% (S) ee
93% yield
>99% (S) ee
94% yield
>99% (R) ee
92% yield
99% (R) ee
89% yield
>99% (R) ee
89% yield
>99% (R) ee
27
90% yield
>99% (R) ee
Et
Et
7
8
9
O
O
O
N
N
N
NH
NH
Ph
NH
Ph
NH
Ph
OiPr
Ph
*
*
10
11
12
13
14
15
16
17
18
19
20
21
22
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60
Ph
Ph
Ph
30
Ph
Ph
Ph
Ph
Ph
Ph
Ph
91% yielda
95% (R) ee
89% yielda
99% (R) ee
54% yielda,b
62% (R) ee
91% yielda
92% (R) ee
29
31
32
33
34
35
90% yield
>99% (S) ee
91% yield
d.r. = 55/45
99% ee / 96% ee
91% yield
>99% (S) ee
* Nitrogen nucleophile scope
O
NH
NH
NH
NH
NH
NH
F3C
MeO
41
71% yield
38
83% yield
>99% (R) ee
36
39
92% yield
85% yield
>99% (R) ee
37
40
76% yield
81% yield
99% (R) ee
98% (R) ee
99% (R) ee
97% (R) ee
O
Ph
Ts
Ph
NH
N
NH
N
NH
NH
47
83% yield
44
80% yield
92% (R) ee
42
45
84% yield
83% yield
93% (R) ee
43
46
91% yield
75% yield
96% (R) ee
>99% (R) ee
93% (R) ee
98% (R) ee
* Oxygen nucleophile scope
Ph3Si
O
O
O
O
O
O
O
F3C
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
91% yieldc
Ph
Ph
90% yieldc
Ph
Ph
Ph
Ph
95% yieldc
72% (S) ee
91% yieldc
97% (-) ee
79% yieldc
99% (-) ee
87% yieldc
99% (R) ee
89% yieldc
60% (-) ee
52
48
51
49
53
54
50
99% (R) ee
99% (-) ee
Figure 3. Allylic substitution of S1 with other several C-, N- and O-nucleophiles with Pd/L6c catalytic system. Reaction conditions: 0.5
mol% [PdCl(η3-C3H5)]2, L6c (0.011 mmol), S1 (1 mmol), BSA (3 equiv), nucleophile (3 equiv), KOAc (3 mol%), CH2Cl2 (2 mL) at 23 °C.
Full conversions were attained in 2 h. a Reactions carried out using K2CO3 (3 equiv). b Reaction performed at -20 °C for 48 h. c Reactions
performed with 2 mol % [PdCl(η3-C3H5)]2, 4 mol% ligand, and Cs2CO3 (3 equiv). Full conversions were attained after 18 h.
The reaction also performed well when using amines as
nucleophiles. High yields and enantioselectivities in products
36–47, comparable to those achieved with C-nucleophiles, were
obtained with many primary and secondary amines (aryl-,
alkyl-, allyl- and propargyl-substituted amines). Among them,
several benzylic amines, including furfurylamine, afforded the
substitution products 36–39 in excellent enantioselectivities
(>99% ee). Enantiocontrol was also excellent in the addition of
alkyl primary amines (products 42–43) and cyclic secondary
amines (products 44–45). Gratifyingly, Pd/L6c was also
successfully applied when using sulfonamide and aromatic
amines (compounds 46 and 47, ee’s up to >99%). Finally,
enantioselectivities up to 98% ee with high yields were also
found with allyl- and propargyl-substituted amines (compounds
40 and 41, respectively). These results represent a significant
improvement compared to those obtained with the Pd/2
catalytic system, for which a high enantioselectivity has been
only reported for benzylamine.5a
The excellent enantioselectivities also extend to the addition
of O-nucleophiles (Figure 3, compounds 48–54) with
enantioselectivities as high as those attained with dimethyl
malonate. Aliphatic alcohols are another relevant set of
nucleophiles whose resulting chiral ethers are found in
biologically active targets.18 Despite the fact that addition of
aliphatic alcohols has been well examined, there are few
effective examples reported.19 In addition, the type of aliphatic
alcohol highly influences the enantioselectivity, whose value
largely depends on the electronic characteristics of the alcohol.
In this context, for previous Pd/phosphite-oxazoline PHOX
systems 2 the highest enantioselectivity was only obtained
when the benzylic alcohol had a para-CF3 substituent (ee's up
to 97%), and the selectivity decreased with electron-rich para
substitutents.20 Improving these previous results with Pd/L6c
catalyst, high enantioselectivity was achieved for the addition
of a broader range of benzylic alcohols (compounds 48–51, ee's
up to 99%). The only exception was compound 50 with a para-
CF3 substituent that provided lower enantioselectivity.
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Similarly, the use of butanol gave the corresponding product 52 propargyl malonate as nucleophile for which high
1
2
3
in 72% ee. Enantioselectivities up to 99% ee were also attained
for the addition of the much less studied allylic alcohol
(compound 53) and the triphenylsilanol (compound 54).21
enantioselectivity has only been obtained with a few Pd-
catalysts.2
We further extended our work to a more challenging class of
linear disubstituted substrates, the unsymmetrical 1,3-
disubstituted ones. For this substrate class not only
regioselectivity has to be controlled, but also most of the
catalytic systems tend to proceed via kinetic resolution, which
limits the maximum yield to 50%.22 There are, however, few
successful examples in which the catalyst is able to epimerize
the Pd-allyl intermediates under reaction conditions and
therefore they are able to overcome the 50% maximum yield
limitation via a dynamic kinetic asymmetric transformation
(DYKAT).23 Due to the relevance of chiral organofluorine
molecules we focused on the Pd-catalyzed allylic alkylation of
the CF3-group-substituted linear substrate S9 with several C-
nucleophiles (Table 2). For this substrate only one catalytic
system, the Pd/(S)-tol-BINAP, has been successfully applied
but it required a high catalyst loading (10 mol% Pd), a
temperature of 60 °C and used dioxane as solvent.23h
Interestingly, Pd/L6c catalytic system is able to promote a
DYKAT process of rac-S9 under mild reaction conditions (see
Supporting Information for details). Thus, excellent
regioselectivities and promising enantioselectivities (up to 80%
ee) were achieved with our Pd/L6c system using several C-
nucleophiles (Table 2, compounds 65–69). The results obtained
using propargyl malonate as nucleophile is of special interest
because the alkylated compound 69 can be used in the
preparation of molecules of more complexity such as a chiral
bicyclopentenone derivative by a Pauson-Khand reaction (vide
infra).
4
5
6
7
8
9
We then used the Pd/L6c catalytic system to study other
symmetrical disubstituted linear substrates S3–S8 (Table 2) that
have different electronic and steric properties than substrate S1.
The results indicated that Pd/L6c can also be used for the
alkylation of substrates S3–S5 (compounds 55–60), with
different aryl substitution patterns, even with highly interesting
substituted malonates containing allyl, pentenyl and propargyl
groups, with yields and enantioselectivities comparable to those
of S1 (compounds 55–60, ee’s ≥99%).
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 2. Pd-AAS of S3-S9 with different C-nucleophiles
with Pd/L6c.a
[PdCl(3-C3H5)]2 (0.5 mol%)
CO2R3
CO2R3
R1
R2
OAc
R2
CO2R3
CO2R3
L6c
(1.1 mol%)
+
H
R1
CH2Cl2 (0.25 M), 23 o
C
R
R
(rac)
S3-S9
*
BSA (3 equiv); KOAc (3 mol%)
O
O
CO2Me
CO2Me
CO2Et
CO2Et
MeO
OMe
55
S3
56
S3
57
S3
(from )
(from
91% yield
>99% (S) ee
)
(from
92% yield
>99% (R) ee
)
88% yield
>99% (R) ee
O
O
O
O
CO2Me
CO2Me
MeO
OMe
MeO
OMe
MeO
Br
OMe
Br
58
S3
)
(from
90% yield
99% (R) ee
59
S4
60
S5
)
(from
)
(from
89% yield
>99% (S) ee
86% yield
>99% (S) ee
Based on the successful results described above for the cyclic
substrate S2, we expanded the substrate scope to other 5-, 6-
and 7-membered cyclic substrates (S2, S10 and S11) and with
nucleophiles other than the dimethyl malonate (Table 3). These
studies were carried out with ligand L1c that had shown the best
enantioselectivities in the Pd-AAS of S2 (see Table 1 above).
For the Pd-AAA of S2, high yields and excellent
enantioselectivities (ee’s to >99%) were attained with many C-
nucleophiles (compounds 70–75), including the propargyl-
substituted malonate (compound 74) whose alkylation gave a
O
O
O
O
O
O
MeO
OMe
MeO
OMe
Me
MeO
Me
OMe
Me
Me
Me
Me
S7
61
S6
)
62
63
S8
)
(from
(from
)
(from
87% yield
>99% (S) ee
86% yield
>95% (S) ee
86% yield
82% (S) ee
O
O
O
O
CO2Me
CO2Me
MeO
F3C
OMe
BnO
F3C
OBn
)
Me
Me
lower
enantioselectivity
with
Pd/2.
Excellent
64
S8
)
65b
S9
)
66b
S9
(from
(from
(from
87% yield
72% yield
62% yield
enantioselectivities were also obtained for substrate S11 using
dimethyl and propargyl malonates (ee's up to >99%;
compounds 81–82). The good results were also expanded to the
more challenging five-membered cyclic substrate S10
(compounds 79–80). Note that the resulting propargylated
compounds 74, 80 and 82 are crucial intermediates for the
construction of more complex molecules such as chiral
carbobicycles by a subsequent simple 1,6-enyne cyclization
reaction (vide infra).
83% (S) ee
76% (R) ee
78% (R) ee
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
F3C
F3C
68b,c
F3C
69b,c
67b,c
S9
)
S9
)
S9
)
(from
(from
(from
59% yield
80% (S) ee
60% yield
77% (S) ee
62% yield
73% (S) ee
a Full conversions were attained after 2 h (except for reactions using
substrates S6 and S7 that were run for 12 h; and for S9 that were
run for 18 h). b Complete regioselectivity towards the nucleophilic
The allylic amination of cyclic substrates turned to be more
challenging than the amination of linear substrates described
above.2c,m,5k,24 The reactions with cyclic substrates are less
studied and in general provide low enantioselectivity.
Improving on Pd/2 catalysts, Pd/L1c were also found to be well
suited for the allylic amination of S2 (Table 3, compounds 76–
78), albeit the enantioselectivities where somewhat lower than
in the allylic alkylation. The results also showed that the
enantioselectivity is hardly influenced by the electronic
properties of the group at the para position of the phenyl group.
c
attack at carbon next to the aryl group was obtained. Reactions
carried out at 40 °C.
The scope of Pd/L6c was also studied with substrates S6–S8
that have different steric constrains, and are typically alkylated
with lower enantioselectivity than the benchmark substrate S1.2
Thus, comparable high enantioselectivities were still attained in
the alkylation of those more sterically demanding substrates
(compounds 61 and 62). Pd/L6c could also successfully adapt
its chiral pocket in the alkylation of the much less sterically
demanding substrate S8 (compounds 63 and 64), even using
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Table 3. Pd-AAS of cyclic substrates S2, S10 and S11 with
Table 4. Regio- and enantioselective Pd-AAA of
different C- and N-nucleophiles with Pd/L1c.a
monosubstituted substrate S12.a
1
2
3
4
5
6
7
8
9
CH(COOMe)2
[PdCl(3-C3H5)]2 (0.5 mol%)
OAc
Nu
L1c
(1.1 mol%)
CH2Cl2 (0.25 M), 23 o
BSA (3 equiv); KOAc (3 mol%)
OAc
*
+
H
Nu
O
CH2(COOMe)2 / BSA
*
83a
C
n
(rac)
[PdCl(3-C3H5)]2 / L
n
+
S2, S10 S11
-
S12
CH(COOMe)2
EtO
O
BnO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C
O
O
83b
OEt
S2
OBn
S2
Entry Ligand % Convb (% yield)
% branchedc
% eed
64 (S)
37 (S)
88 (S)
64 (S)
34 (S)
91 (S)
45 (R)
87 (R)
45 (R)
93 (S)
98 (S)
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
70
71
72
S2
)
73
S2
)
74
S2
)
(from
82% yield
)
(from
89% yield
98% (S) ee
)
(from
(from
(from
80% yield
>99% (S) ee
86% yield
79% yield
1
2
L1a
L1b
L1c
L2a
L2b
L2c
L5a
L5b
L5c
L6c
L7c
100 (88)
100 (89)
100 (88)
100 (91)
100 (89)
100 (90)
100 (89)
100 (88)
100 (91)
100 (90)
100 (91)
80
80
75
75
80
75
80
85
70
70
90
99% (S) ee
99% (+) ee
95% (-) ee
O
OMe
CF3
H
N
H
H
O
N
N
3
4
77b
S2
)
76b
S2
(from
78b
S2
(from
)
(from
)
75
S2
)
76% yield
99% (-) ee
(from
81% yield
95% yield
5
90% yield
79% (S) ee
81% (S) ee
83% (S) ee
6
MeO
O
MeO
O
CO2Me
MeO2C
CO2Me
MeO2C
7
O
O
OMe
8
OMe
S10
79
80
S10
)
(from
)
(from
89% yield
93% (S) ee
9
81
S11
82
S11
)
93% yield
>99% (S) ee
(from
87% yield
>99% (S) ee
)
(from
81% yield
91% (-) ee
10
11
a
b
Full conversions were attained after 2 h. Reactions performed
with cyclohex-2-en-1-yl ethyl carbonate as substrate and [PdCl(η3-
a 1 mol% [Pd(η3-C3H5)Cl]2, 2.2 mol% ligand, benzene as solvent,
b
C3H5)]2 (1 mol%) for 18 h.
BSA/KOAc as base, 0 °C. % Conversion measured after 1 h.
Isolated yield shown in parenthesis. c Regioselectivity determined
by 1H NMR. d Enantiomeric excesses measured by chiral HPLC.
Allylic alkylation of monosubstituted substrates S12–
S18. We tested whether the good catalytic performance
obtained in the allylic alkylation of 1,3-disubstituted substrates
could be retained for the monosubstituted ones. In these
substrates the catalyst must control not only the
enantioselectivity but also the regioselectivity and most Pd-
catalysts tend to produce the undesired achiral linear product.
For monosubstituted substrates, the discovery of Pd-catalyst
able to provide high regio- and enantioselectivities is still quite
an unsolved issue.25
With the optimal ligand L7c, we next studied the Pd-AAS of
other challenging monosubstituted substrates that have different
electronic and steric parameters, using dimethyl malonate as
nucleophile (Table 5). In previous studies with Pd/2, it has been
observed that the enantioselectivity and the regioselectivity to
the desired branched isomer were reduced when the 1-naphthyl
group was replaced by a phenyl (S13).7 This effect was also
observed with the Pd/1 catalyst. In addition, the decrease in
regioselectivity was more pronounced or reversed to the achiral
linear product 83b for substrates with electron-withdrawing
substitutents on the aryl group.25a This was overcome with
ligand Pd/L7c. Thus, enantioselectivities and regioselectivities
(Table 5) were quite independent on the substitution pattern of
the substituent of the aryl group, and high enantioselectivities
(up to 96%) and regioselectivities up to 84% were obtained for
substrates 84a–89a with different electronic properties on the
aromatic ring. Finally, we studied the use of other nucleophiles.
Although the good performance in terms of regioselectivity was
not retained, promising high enantioselectivities were achieved
(compounds 90a–92a).
Table 4 collects the results in the allylic alkylation of
benchmark monosubstituted subtrate S12 under the optimized
reaction conditions found with related Pd/2. Pd/L7c provided
the desired branched product in high regioselectivity (up to
90%) with an enantioselectivity (up to 98% ee) that was
somewhat higher than those obtained with the Pd/2 systems. It
was also found that the ligand structure hardly affected
regioselectivity but did affect enantioselectivity substantially.
More precisely, while the configuration/substituent at both the
oxazoline and the biaryl phosphite groups affected the
enantioselectivity like in the alkylation of disubstituted S1, the
influence of the type of substituent at the alkyl backbone chain
was different. Thus, Pd/L7c catalyst, which contains an
isopropyl group at the alkyl backbone chain, provided the
highest enantioselectivities (ee’s up to 98%; entry 11). Like for
S1, the sense of enantioselectivity was dictated by the
configuration of the oxazoline substituent (entries 4–6 vs 7–9)
while its value depended on the configurations at both the biaryl
phosphite group and at the oxazoline substituent (compare e.g.,
ligand L2c, entry 6 and ligand L5b, entry 8). The control on the
ligand structure allowed us to reach both configurations of the
alkylated compound in enantioselectivities as high as 98% ee.
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ACS Catalysis
lower than with L1c, which agrees with the higher
Table 5. Pd-AAA of monosubstituted substrates S13–S18
with ligand L7c.a
enantioselectivities obtained with L1c (Table 1; for S1, 96% (S)
ee for L1c vs. 86% (S) ee for L1b and for S2, 99% (S) ee for
L1c vs. 78% (R) ee for L1b). With S2 the calculations also
properly predict the production of the reverse product
enantiomers with L1b and L1c.
1
2
3
4
5
6
7
8
9
[PdCl(3-C3H5)]2 (0.5 mol%)
L7c
OAc
+
Nu
(1.1 mol%)
+
H
Nu
R
Nu
R
R
Benzene (0.25 M)
BSA (3 equiv); KOAc (3 mol%)
0 oC, 2 h
(rac)
81-89a
81-89b
S13-S18
Table 6. Calculated energies for the most stable TSs with S1
and S2 and NH3.a
O
O
O
O
O
O
MeO
OMe
MeO
OMe
(from
93% yield
83% regio
94% (S) ee
MeO
OMe
(from
Structure
L1b
L1c
L6c
86a
S15
)
(from
84a
S13
85a
S14
)
)
MeO
85% yield
82% regio
93% (S) ee
N
Pd P
91% yield
78% regio
95% (S) ee
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
Ph
H3N
16.6b
21
14.2
O
O
O
O
O
O
Ph
TS(R) endo
MeO
OMe
MeO
OMe
MeO
OMe
MeO
89a
S18
)
N
Pd P
(from
87a
S16
88a
S17
(from )
(from
)
F3C
87% yield
81% regio
96% (S) ee
92% yield
75% regio
92% (S) ee
89% yield
81% regio
96% (S) ee
Ph
5.4b
0
0
0
0
H3N
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
TS(S) exo
N
92a
S13
)
(from
90a
S13
91a
S13
(from )
(from
)
P
Pd
84% yield
55% regio
89% (R) ee
81% yield
60% regio
86% (R) ee
79% yield
50% regio
88% (R) ee
5c
H3N
TS(S) endo
a
Regioselectivities calculated by 1H NMR and enantiomeric
excesses determined by HPLC.
N
P
Pd
H3N
Origin of enantioselectivity
4c
15.6
13.6
DFT computational studies. Previous mechanistic studies
TS(R) exo
with related Pd/phosphite-oxazoline
2 showed that the
nucleophilic attack, that is the step that determines
enantioselectivity, occurs by an early transition state (TS).7
Thus, the electrophilicity of the allylic carbon atoms governs
the stereochemistry of the reaction. In accordance with the
higher trans influence of the P, the allylic carbon trans to P is
more reactive than the allylic carbon trans to the oxazoline
group.26 With the aim of identifying what properties of ligands
L1–L7a–c are responsible for the catalytic performance, we
carried a DFT study of the early TSs involved in the
enantiocontrol of the hindered substrate S1 and the unhindered
substrate S2 with ligands L1b, L1c and L6c.27 With these
ligands we studied the effect on enantioselectivity of varying
the configuration of the phosphite functionality (ligands L1b
and L1c) as well as the effect of having a chiral center in the
alkyl backbone chain (ligand L6c). To accelerate DFT
calculations, we used NH3 as the nucleophile rather than
dimethyl malonate.28,29 Moreover, and in agreement with that
already described in the literature, only the two syn-syn Pd-allyl
compounds were considered (TSendo and TSexo), neglecting the
involvement of the anti-anti and syn-anti allylic species of
higher energy.2d
a Relative energies in kJ/mol. b Energies relative to that of TS(R) exo-
L1c. c Energies relative to that of TS(S) endo-L1c.
Of all the TSs evaluated in reactions of S1 and S2 with
ligands L1b and L1c, Figure 4 shows the two most stable for
each substrate. The analysis of these structures allows us to
explain the impact of the configuration of the phosphite group
on enantioselectivity. Interestingly, for both catalytic systems
(Pd/L1b–c) with substrate S1 the endo TSs are destabilized
through a steric repulsion generated between one of the phenyl
substituents of S1 and the oxazoline substituent. This repulsion
is not observed for substrate S2. Accordingly, this unfavorable
interaction causes a larger dihedral angle  (C1-N-C2-C3) in exo
TSs than in endo TSs of S1. In the endo TSs of S1 this
unfavorable interaction shoves the oxazoline moiety away
which causes a lower dihedral angle. These destabilized
interactions justify that for both ligands the same configuration
of the resulting product was achieved.
In S1, it is also interesting to note that for Pd/L1c the exo
TS(S) presents a CH/π interaction between one of the phenyl
rings of S1 and the biaryl phosphite group (see the non-covalent
interaction (NCI) plots in Figure 5(b)) that further stabilize this
TS. This increases the energy gap between the endo and exo
TSs and could explain the preference for one of the pathways
and, consequently, the higher enantiomeric excess achieved
with Pd/L1c compared with Pd/L1b. In the Pd/L1b catalyst,
there is also a CH/π interaction but in this case in the endo TS(R).
Therefore the energy of the two TSs are more similar among
them than for the Pd/L1c (see NCI plot in Figure 5(a)).
Table 6 collects the calculated energies for the most stable
TSs, producing both enantiomers of the product (TS(S) and
TS(R)), with the three ligands (see Supporting Information for
the full set of calculated coordinates and energies of all TSs).
For both substrates, the calculated TSs energies agree with the
experimental results. They correctly identify the Pd/L1c and
Pd/L6c catalytic systems as more enantioselective than Pd/L1b.
Similarly, in the reaction of both substrates with ligands L1b
and L1c, the energy difference between the TSs with L1b is
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1
2
3
4
5
6
7
8
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
Figure 4. Most stable calculated TSs (TS(R) endo and TS(S) exo) from S1 using ligands (a) L1b and (b) L1c; and from S2 using ligands (c)
L1b and (d) L1c. All hydrogens atoms are not shown for clarity. Relative free energies in solution and in kJ/mol respect to the corresponding
lowest energy transition state.
(whose phosphite group has the opposite configuration) this is
found in endo TS(S) responsible of the S-product. This explains
the formation of opposite enantiomers when using both ligands.
Moreover, these weak attractive interactions are larger in the
endo TS(S) of ligand L1c than in exo TS(R) of ligand L1b, which
agrees with the highest enantioselectivity obtained with ligand
L1c.
Figure 5. NCI plots of the most stable calculated TSs (TS(R) endo
and TS(S) exo) from S1 using ligands (a) L1b and (b) L1c. Strong
and attractive interactions are blue, weak interactions are green and
strong and repulsive interactions are red.
For substrate S2 the NCI plots of the two most stable TSs of
ligands L1b and L1c showed weak stabilizing attractive
interactions between the substrate and one of the aryls of
Figure 6. NCI plots of the most stable calculated TSs (TS(R) endo
and TS(S) exo) from S2 using ligands (a) L1b and (b) L1c. Strong
phosphite moiety (Figure 6). However, while with ligand L1b
with an R- phosphite group this favorable interaction is found
in the exo TS(R) leading to the R-product, with ligand L1c
and attractive interactions are blue, weak interactions are green and
strong and repulsive interactions are red.
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In summary, the DFT calculations showed that while for
isomers. The NOE interactions also confirmed an exo and endo
dispositions for the major and minor isomers, respectively
(NOE details can be found in the Supporting Information). The
carbon chemical shifts of compounds 93 and 94 showed that the
most electrophilic allylic terminal carbons are trans to the P in
the major exo isomers. Since the nucleophilic attack occurs at
the more electron deficient allylic carbon terminus and the fact
that the diastereomeric excesses of the intermediates vary from
the enantiomeric excesses found experimentally, the major
isomers should react faster than the minor ones. If we take into
account that the electronic differentiation between the more
electrophilic allylic terminus carbon atoms of both isomers 93
(13C) ≈ 12.4 ppm) is higher than for 94 (13C) ≈ 8 ppm),
then the major isomer of 93 should react faster than the major
isomer of 94. However, the reactivity, by in situ NMR, of
complexes 93 and 94 with sodium dimethyl malonate, at low
temperature, indicated that both isomers react with comparable
rates: the major isomer of 93 reacts 8 times faster than the minor
isomer while the relative reaction rate of 94 is of 7.5 times faster
than the minor isomer (see Figure S20 in the Supporting
Information). Since the speeds are similar, the higher
enantioselectivity with Pd/L6c is explained by the much higher
relative population of the faster reacting isomer in Pd/L6c
catalytic system than that of Pd/L2c. This indicates that the
ability of Pd/L6c to effectively control both the population and
the relative electrophilicity in the Pd-allyl intermediates is
crucial for achieving excellent enantiocontrol.
1
cyclic substrates the enantioselectivity is mostly controlled by
the biaryl phosphite groups, for linear substrates the oxazoline
substituent also has a crucial role.
2
3
4
5
6
7
8
9
Preparation and NMR study of Pd-allyl intermediates. DFT
calculations pointed out that enantiocontrol occurs during the
nucleophilic attack through an early transition state.
Consequently, the study of the Pd-allyl complexes and their
reactivity with the nucleophile will provide additional
information about the influence of the ligand components on
catalytic performance. For this purpose, we prepared the Pd-π-
1,3-diphenyl/cyclohexenyl based allyl compounds 93–96
[Pd(η3-allyl)(L)]BF4 (L= L2c and L6c) (Scheme 2).30 Ligands
L2c and L6c were chosen to complete the study of the influence
on enantioselectivity of different groups in the alkyl backbone
chain.31
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11
12
13
14
15
16
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28
29
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49
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59
60
AgBF4
[PdCl(3-allyl)]2
+
2 L
2 [Pd(3-allyl)(L)]BF4 + 2 AgCl
93
94
95
96
L2c
L6c
L2c
L6c
allyl = 1,3-Ph2-C3H3; L=
allyl = 1,3-Ph2-C3H3; L=
allyl = cyclo-C6H9; L=
allyl = cyclo-C6H9; L=
Scheme 2. Preparation of [Pd(3-allyl)(L)]BF4 complexes
93–96.
The variable temperature NMR study (30 oC to -80 oC) of Pd-
1,3-diphenyl allyl complexes 93 and 94 displayed a mixture of
two isomers in equilibrium at 3:1 and 10:1 ratios respectively
(Scheme 3). No changes in the signals have been observed
during these VT-experiments, which agree with a fast
equilibrium between both isomers even at low temperature. The
NOE shows interaction between the two terminal protons of the
allyl group which agrees with a syn/syn disposition for these
The VT-NMR study (30 oC to -80 oC) of the Pd-1,3-
cyclohexenyl allyl complex 95 displayed a mixture of two
isomers in fast equilibrium in a 15:1 ratio, while for
intermediate 96 only one isomer was detected (Scheme 4).
P
P
P
P
Ph
68.3
Ph
67.9
Ph
68.4
Ph
74.1
N
N
N
N
Pd
Pd
Pd
Pd
98.8
Ph
94
95.9
Ph
93
Nu-
Nu-
Ph
Ph
Nu-
endo
Minor (1)
Nu-
endo
Minor (1)
106.8
94
108.1
93
exo
Major (10)
exo
Major (3)
kexo/kendo = 7.5
kexo/kendo = 8
CH(CO2Me)2
Ph
CH(CO2Me)2
Ph
CH(CO2Me)2
Ph
CH(CO2Me)2
Ph
(R)
(S)
(R)
(S)
Ph
Ph
Ph
Ph
Scheme 3. Diastereoisomeric Pd-allyl intermediates for S1 with ligands L2c (isomers 93) and L6c (isomers 94). The relative amounts
of each isomer are shown in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are also shown.
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Page 10 of 17
1
2
3
4
5
6
P
P
P
P
67.9
Nu-
68.5
N
N
N
68.5
N
Pd
Pd
Pd
Pd
104.0
96
102.8
Nu-
104.4
Nu-
endo
95
95
endo
96
exo
exo
Major (15)
not detected
Minor (1)
7
8
9
CH(CO2Me)2
CH(CO2Me)2
CH(CO2Me)2
10
11
12
13
14
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)
(S)
(R)
Scheme 4. Diastereoisomeric Pd-allyl intermediates for S2 with ligands L2c (isomers 95) and L6c (isomers 96). The relative amounts
of each isomer are shown in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are also shown.
OAc
n
The major isomers of intermediates 95 and 96 were
characterized by NOE as endo isomers (see Supporting
Information for NOE details). Again the most electrophilic
allylic carbon is trans to the P. Since for intermediate 95, the
electrophilicity of the allylic carbon trans to the P is very similar
in endo and exo isomers (13C) ≈ 1.6 ppm), both isomers
should react at a similar rate. Therefore, we can conclude that
changing the substituent in the alkyl backbone chain modify the
percentage of the species that let to both enantiomers. The
enantioselectivity is therefore mostly governed by the relative
ratio of the endo and exo isomers. The higher enantioselectivity
provided by Pd/L6c can be due that only the endo isomer is
detected.
MeO2C
CO2Me
+
MeO2C
MeO2C
L1c
Pd/
OMe
n
Overall
yield
n
MeO2C
MeO2C
a)
H
% ee
MeO
97
98
99
/
0
1
2
9 %
60 %
46 %
99 (R,S,S)
93 (R,S,S)
>99 (R,S,S)
l 2
PtC
RuC
n
74 80 82
b)
MeO2C
MeO2C
l
3
,
,
/
MeOH
Overall
yield
n
Synthetic applications of the allylic alkylated
compounds. Construction of chiral carbobicycles. In this
section we show a further application of the propargylated
compounds 28, 69, 74, 80, 82 and 92, prepared in previous
section by Pd-AAS, to produce a range of chiral carbobicycles
(97-104) with multiple stereocentres. These carbobicycles have
been synthesized by simple sequential reactions involving the
Pd-AAS and either 1,6-enyne cyclization (Scheme 5) or a
Pauson−Khand enyne cyclization (Scheme 6).
n
% ee
100
101
1
2
61 %
70 %
>99 (R,S)
>99 (R,S)
Scheme 5. Preparation of chiral carbobicycles compounds 97–
101.
The second derivatization consisted of a Pauson-Khand
reaction of three linear alkylated derivatives 28, 69 and 92,
which differ in the substituents of the allylic substrate (Scheme
6). In the three cases the corresponding bicyclopentenones 102–
104 were attained in good yields and maintaining the ee’s
achieved in the Pd-AAS. This derivatization was not affected
by the substituents of the substrate (102–104).
The first studied derivatization was a 1,6-enyne cyclization
of the propargylated derivatives 74, 80 and 82, with different
cycloalkane ring sizes (Scheme 5). By changing the catalyst
source we were able to prepare two types of carbobicycles:
PtCl2/MeOH lead to bicycles with insertion of methanol into the
double bond (Scheme 5a),32 and RuCl3/MeOH gave unsaturated
bicycles maintaining the endocyclic double bond (Scheme
5b)33. With these strategies, the alkylated derivatives 74, 80 and
82, undergo the cyclization with no loss of enantioselectivity,
providing carbobicycles 97–101 in good yields, except for the
most sterically constrained compound 97, and excellent-to-high
enantioselectivities (Scheme 5).
1) [PdCl(3-C3H3)]2 / L
MeO2C
MeO2C
MeO2C
MeO2C
OAc
O
Ph
R
2) Co2(CO)8
H
Ph
R
Overall
yield
% ee
R
L
102
103 CF3 L6c
104 H L7c
L6c
Ph
62 % 99 (R,R,S)
39 % 73 (R,R,R)
41 %
89 (R,S)
Scheme 6. Preparation of chiral bicyclopentenone compounds
102–104.
CONCLUSIONS
We report a new generation of air stable and readily available
Pd/phosphite-oxazoline complexes for the Pd-AAS of several
linear substrates (including unsymmetrical di- and
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monosubstituted) and cyclic substrates with different electronic was used for all elements except palladium for which SDD basis
1
2
3
4
5
6
7
8
and steric properties, with many C-, N- and O- nucleophiles. A
total of 73 combinations of substrate-nucleophile have been
studied. These catalysts derive from the successful Pd/2
catalysts by replacing the ortho-phenylene tether by an alkyl
backbone chain. With this simple modification, we have
increased the number of ligand components than can be
modified to increase activities and enantioselectivities for a
major number of substrates and nucleophiles. We have been
able to identify three ligands with high enantioselectivities for
a broad range of linear disubstituted substrates (ligand L6c) and
monosubstituted substrates (ligand L7c) and cyclic substrates
(ligand L1c), with many nucleophiles (73 compounds in total).
The three ligands have in common a chiral biaryl phosphite
moiety with an S-configuration, the same substituent and
configuration at the oxazoline moiety but differ on the alkyl
backbone chain substituent; whereas L6c has a methyl, L7c has
isopropyl and L1c has two methyl groups. In comparison with
Pd/2 the new Pd-catalysts provided better activities for a
broader substrate and nucleophile scope.
set was employed. All energies reported are Gibbs free energies
at 298.15 K and calculated as Greported = G6-31G* + (E6-311+G** - E6-
31G*).
We used the NCI method43 to study the non-covalent
interactions. The method, which is based on electron density
and its gradient, is able of mapping real-space regions where
NCI are relevant. The resulting NCI plots information is mainly
qualitative. To perform these calculations, we used promolecular
approximation using xyz files.
9
Typical methodology for the preparation of phosphite-
oxazoline ligands. A solution of the desired alcohol-oxazoline
(1.0 mmol) and pyridine (0.16 mL, 2.0 mmol) in toluene (6 mL)
was added dropwise at -78 °C to a solution of phosphochloridite
(1.1 mmol) and pyridine (0.16 mL, 2.0 mmol) in toluene (6
mL). The mixture was left to warm to room temperature and
stirred overnight at this temperature. The precipitate formed
was filtered under argon and the solvent was evaporated under
vacuum. The residue was purified by flash chromatography
(under argon, using neutral alumina and dry toluene as eluent
system) to afford the corresponding phosphite-oxazoline L1–
L7a–c as white solids.
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59
60
Mechanistic studies based on DFT calculations and NMR
spectroscopy let us find the species responsible for the catalytic
performance and the impact of the ligand components on the
origin of enantioselectivity. Thus, these studies confirm that the
ratio of the Pd-allyl intermediates that provide both enantiomers
is influenced by the ligand parameters. The enantioselectivity is
therefore mostly governed by the relative ratio of the endo and
exo isomers. However, while the ratios of endo and exo isomers
for cyclic substrates is mainly controlled by the configuration
of the phosphite moiety and the substituent in the alkyl
backbone chain, for linear substrates the oxazoline substituent
also has a crucial role.
L1b: Yield: 398.3 mg (60%); 31P NMR (161.9 MHz, C6D6):
δ = 153.9 (s); 1H NMR (400 MHz, C6D6): δ = 0.52 (s, 9H, CH3,
SiMe3), 0.57 (s, 9H, CH3, SiMe3), 1.57 (s, 3H, CH3), 1.74 (s,
3H, CH3), 3.76 (pt, 1H, CH-O, JH-H= 8.4 Hz), 4.07 (dd, 1H, CH-
O, 2JH-H= 10.0 Hz; 3JH-H= 8.4 Hz), 4.92 (dd, 1H, CH-N, 2JH-H
=
10.0 Hz, 3JH-H= 8.4 Hz ), 6.82 (m, 2H, CH=), 6.96-7.13 (m, 7H,
CH=), 7.26 (d, 1H, CH=, 3JH-H= 8.4 Hz), 7.27 (d, 1H, CH=, 3JH-
H= 8.4 Hz), 7.66 (m, 2H, CH=), 8.09 (s, 1H, CH=), 8.15 (s, 1H,
CH=). 13C (100.6 MHz, C6D6): δ = -0.3 (d, CH3, SiMe3, JC-P
=
4.5 Hz), 0.4 (CH3, SiMe3), 28.2 (d, CH3, 3JC-P= 3.8 Hz), 28.7 (d,
Finally, to evaluate the potential impact of this new
generation of Pd-catalysts in synthesis, some alkylated products
have been applied in subsequent sequential derivatizations,
such as Pauson-Khand or 1,6-enyne cyclizations, to produce a
range of chiral carbobicycles with multiple stereocentres with
excellent transmission of the enantioselectivity.
3
CH3, JC-P= 7.7 Hz), 69.8 (CH-N), 74.9 (CH2-O), 76.2 (d, C,
3
CMe2, JC-P= 5.3 Hz), 122.6-152.4 (aromatic carbons), 169.1
(C=N). TOF-MS (ESI+): m/z
= 686.2285, calcd. for
C38H42NNaO4PSi2 [M+Na]+: 686.2282.
L1c: Yield: 331.9 mg (50%); 31P NMR (161.9 MHz, C6D6):
δ = 153.6 (s); 1H NMR (400 MHz, C6D6): δ = 0.53 (s, 9H, CH3,
SiMe3), 0.59 (s, 9H, CH3, SiMe3), 1.62 (s, 3H, CH3), 1.77 (s,
3H, CH3), 3.55 (pt, 1H, CH-O, JH-H = 8.0 Hz), 4.06 (dd, 1H,
CH-O, 2JH-H= 10.8 Hz, 3JH-H= 8.8 Hz), 4.92 (dd, 1H, CH-N, 2JH-
H= 10.0 Hz, 3JH-H= 8.0 Hz), 6.81 (m, 2H, CH=), 6.95-7.11 (m,
7H, CH=), 7.26 (m, 2H, CH=), 7.67 (m, 2H, CH=), 8.11 (s, 1H,
CH=), 8.15 (s, 1H, CH=). 13C (100.6 MHz, C6D6): δ = -0.3 (d,
CH3, SiMe3, JC-P= 4.6 Hz), 0.4 (CH3, SiMe3), 28.0 (d, CH3, 3JC-
EXPERIMENTAL SECTION
General considerations. All reactions were performed
with standard Schlenk techniques using argon. Commercial
chemicals were used as received. Solvents were dried by means
1
of standard procedures and stored under inert atmosphere. H,
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}) or H3PO4 (31P{1H})
as internal standard. Racemic substrates S1–S1234 and S13–
3
P= 3.9 Hz), 28.7 (d, CH3, JC-P= 6.9 Hz), 69.5 (CH-N), 74.8
3
(CH2-O), 75.9 (d, C, CMe2, JC-P= 5.3 Hz), 122.5-152.4
(aromatic carbons), 169.0 (C=N). TOF-MS (ESI+): m/z =
S1835,
compounds
4,9
8–137,11
and
14–197,11
,
686.2280, calcd. for C38H42NNaO4PSi2 [M+Na]+: 686.2282.
phosphorochloridites36 and ligands L1a8a and L2–L7a–c7 were
General methodology for the preparation of [Pd(η3-
allyl)(P-N)]BF4 complexes 93–96. Compound [Pd(µ-Cl)(η3-
1,3-allyl)]2 (0.025 mmol) and the corresponding ligand (0.05
mmol) were dissolved in CD2Cl2 (1.5 mL) at room temperature
under argon. After 30 minutes, AgBF4 (9.8 mg, 0.05 mmol) was
added and the mixture was stirred for 30 minutes. Silver salts
were then removed by filtration over celite under argon and the
resulting solutions were analyzed by NMR. After the NMR
analysis, the [Pd(η3-allyl)(P-N)]BF4 complexes were
precipitated by adding hexane as pale yellow solids.
synthesized following already reported procedures.
Computational details. The geometries of all
intermediates were optimized using the Gaussian 09 program,37
employing the B3LYP-D338 density functional and the
LANL2DZ39 basis set for palladium and the 6-31G* basis set
for all other elements.40 Solvation correction was applied in the
course of the optimizations using the PCM model with the
default parameters for dichloromethane.41 The complexes were
treated with charge +1 and in the singlet state. No symmetry
constraints were applied. The energies were further refined by
performing single point calculations using the above-mentioned
parameters, with the exception that the 6-311+G**42 basis set
[Pd(η3-1,3-diphenylallyl)(L2c)]BF4 (93): Major isomer
(75%): 31P NMR (161.9 MHz, CD2Cl2): δ= 139.5 (s). 1H NMR
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(400 MHz, CD2Cl2): δ= 0.30 (s, 9H, CH3, SiMe3), 0.54 (s, 9H,
Page 12 of 17
[Pd(η3-1,3-cyclohexenyl)(L6c)]BF4 (96): 31P NMR (161.9
MHz, CD2Cl2): δ= 143.7 (s). 1H NMR (400 MHz, CD2Cl2): δ=
0.11 (m, 1H, CH2), 0.47 (s, 9H, CH3, SiMe3), 0.54 (s, 9H, CH3,
SiMe3), 0.68 (m, 1H, CH2), 1.0-1.3 (m, 4H, CH2), 1.89 (d, 1H,
1
2
3
4
5
6
7
8
CH3, SiMe3), 4.38 (m, 1H, CH2), 4.47 (m, 1H, CH= trans to N),
5.01 (m, 2H, CH2, CH-N), 5.96 (m, 1H, CHc=), 6.15 (m, 2H,
CH-O, CH= trans to P), 7.10-8.21 (m, 30H, CH=). 13C (100.6
MHz, CD2Cl2): δ= -0.1 (CH3, SiMe3), 0.6 (CH3, SiMe3), 67.7
(CH-N), 67.9 (d, CH= trans to N, JC-P= 10.7 Hz), 76.3 (CH-OP),
78.0 (CH2), 108.1 (d, CH= trans to P, JC-P= 29.8 Hz), 112.6 (d,
CHc=, JC-P= 9.9 Hz), 120.0-150.0 (aromatic carbons), 169.5
(C=N). Minor isomer (25%): 31P NMR (161.9 MHz, CD2Cl2):
δ= 140.2 (s). 1H NMR (400 MHz, CD2Cl2): δ= 0.20 (s, 9H, CH3,
SiMe3), 0.39 (s, 9H, CH3, SiMe3), 4.35 (m, 1H, CH2), 4.74 (m,
1H, CH-N), 5.01 (m, 1H, CH2), 5.23 (m, 1H, CH= trans to N),
5.27 (m, 1H, CH= trans to P), 5.60 (m, 1H, CHc=), 6.15 (m, 1H,
CH-OP), 7.1-8.2 (m, 25H, CH=). 13C (100.6 MHz, CD2Cl2): δ=
-0.5 (CH3, SiMe3), -0.2 (CH3, SiMe3), 68.9 (CH-N), 74.1 (d,
CH= trans to N, JC-P= 10.7 Hz), 75.9 (CH-OP), 77.6 (CH2), 95.9
(d, CH= trans to P, JC-P= 42 Hz), 109.2 (d, CHc=, JC-P= 13.0
Hz), 120.0-150.0 (aromatic carbons), 170.2 (C=N).
3
CH3, JH-H= 6.8 Hz), 4.04 (b, 1H, CH= trans to N), 4.51 (dd,
1H, CH2, 2JH-H= 9.2 Hz, 3JH-H= 8 Hz), 5.15 (dd, 1H, CH2, 2JH-H
=
9.2 Hz, 3JH-H= 10.8 Hz), 5.33 (m, 1H, CHc=), 5.36 (q, 1H, CH,
3JH-H= 6.8 Hz), 5.71 (dd, 1H, CH-N, 3JH-H= 8.0 Hz, 3JH-H= 10.8
Hz), 5.95 (m, 1H, CH= trans to P), 6.99 (d, 1H, CH=, 3JH-H= 8.8
Hz), 7.12 (d, 1H, CH=, 3JH-H= 8.8 Hz), 7.28 (m, 2H, CH=), 7.41-
7.50 (m, 7H, CH=), 8.02 (t, 1H, CH=, 3JH-H= 8.8 Hz), 8.23 (d,
9
1H, CH=, JH-H= 7.2 Hz). 13C (100.6 MHz, CD2Cl2): δ= -0.1
3
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(CH3, SiMe3), 0.0 (CH3, SiMe3), 19.5 (CH2), 22.9 (d, CH3, JC-
P= 4.5 Hz), 27.1 (b, CH2), 67.9 (d, CH= trans to N, JC-P= 9.2
Hz), 71.6 (CH-OP), 74.3 (CH-N), 78.2 (CH2), 104.0 (d, CH=
trans to P, JC-P= 40 Hz), 111.7 (d, CHc=, JC-P= 10.7 Hz), 121.0-
151.0 (aromatic carbons), 171.8 (C=N).
Typical methodology for the allylic alkylation of linear
(S1, S3–S9, S12–S18) and cyclic (S2, S10 and S11)
substrates. A solution of the desired phosphite-oxazoline
ligand (0.011 mmol) and [PdCl(η3-C3H5)]2 (1.8 mg, 0.005
mmol) in CH2Cl2 (0.5 mL) was stirred. After 30 min a solution
of substrate (1 mmol) in CH2Cl2 (1.5 mL), nucleophile (3
mmol), N,O-bis(trimethylsilyl)-acetamide (730 µL, 3 mmol)
and KOAc (3 mg, 0.03 mmol) were subsequently added. After
the desired reaction time the reaction mixture was diluted with
Et2O (5 mL). Saturated NH4Cl (aq) (25 mL) was then added
and the mixture was extracted with Et2O (3 x 10 mL) and the
extract dried over MgSO4. For compounds 20, 22–35, 55–61,
64–69, 72–73 and 82–92, the solvent was evaporated,
conversions were measured by 1H NMR and ees were
calculated by HPLC. For compounds 21, 63, 70–71, 74–75 and
80–81, conversion and ees were determined by GC.5g For
[Pd(η3-1,3-diphenylallyl)(L6c)]BF4 (94): Major isomer
(91%): 31P NMR (161.9 MHz, CD2Cl2): δ= 140.3 (s). 1H NMR
(400 MHz, CD2Cl2): δ= 0.46 (s, 9H, CH3, SiMe3), 0.74 (s, 9H,
3
CH3, SiMe3), 1.96 (d, 3H, CH3, JH-H= 6.8 Hz), 4.33 (dd, 1H,
CH2, 2JH-H= 8.8 Hz, 3JH-H= 4.8 Hz), 4.51 (m, 1H, CH= trans to
N), 4.88 (m, 1H, CH-N), 5.00 (m, 1H, CH2), 5.12 (m, 1H, CH-
OP), 6.02 (m, 2H, CHc=, CH= trans to P), 6.3-8.4 (m, 25H,
CH=). 13C (100.6 MHz, CD2Cl2): δ= -0.1 (CH3, SiMe3), 0.8
(CH3, SiMe3), 22.6 (b, CH3), 67.3 (CH-N), 68.3 (d, CH= trans
to N, JC-P= 9.9 Hz), 71.5 (CH-OP), 78.2 (CH2), 106.8 (d, CH=
trans to P, JC-P= 30.4 Hz), 112.2 (d, CHc=, JC-P= 9.8 Hz), 121.0-
150.0 (aromatic carbons), 172.1 (C=N). Minor isomer (9%): 31
P
NMR (161.9 MHz, CD2Cl2): δ= 142.9 (s). 1H NMR (400 MHz,
CD2Cl2): δ= 0.41 (s, 9H, CH3, SiMe3), 0.62 (s, 9H, CH3, SiMe3),
1.75 (d, 3H, CH3, 3JH-H= 6.8 Hz), 4.39 (dd, 1H, CH2, 2JH-H= 8.8
Hz, 3JH-H= 4.4 Hz), 4.53 (m, 1H, CH= trans to N), 4.71 (m, 1H,
CH2), 4.88 (m, 1H, CH-N), 5.12 (m, 1H, CH-OP), 5.98 (m, 1H,
CH= trans to P), 6.09 (m, 1H, CHc=), 6.3-8.4 (m, 25H, CH=).
13C (100.6 MHz, CD2Cl2): δ= 0.1 (CH3, SiMe3), 0.3 (CH3,
SiMe3), 22.4 (b, CH3), 68.1 (CH-N), 68.4 (d, CH= trans to N,
JC-P= 9.2 Hz), 70.9 (CH-OP), 78.0 (CH2), 98.8 (d, CH= trans to
P, JC-P= 32.4 Hz), 112.7 (d, CHc=, JC-P= 9.2 Hz), 121.0-150.0
(aromatic carbons), 172.3 (C=N).
1
compounds 62 and 79, conversion was measured by H NMR
1
and ees were determined by H NMR using [Eu(hfc)3]. See
Supporting Information for characterization and enantiomeric
excess determination details.
Typical methodology for the allylic amination of S1
and S2. A solution of the desired phosphite-oxazoline ligand
(0.011 mmol) and [PdCl(η3-C3H5)]2 (1.8 mg, 0.005 mmol) in
CH2Cl2 (0.5 mL) was stirred. After 30 min, a solution of
substrate (1 mmol) in CH2Cl2 (1.5 mL) and the corresponding
amine (3 mmol) were subsequently added. After the desired
reaction time the reaction mixture was diluted with Et2O (5
mL). Saturated NH4Cl (aq) (25 mL) was then added and the
mixture was extracted with Et2O (3 x 10 mL) and the extract
dried over MgSO4. Conversions were determined by 1H NMR.
HPLC was employed to calculate enantiomeric excesses of
compounds 36–47 and 76–78. See Supporting Information for
characterization and enantiomeric excess determination details.
[Pd(η3-1,3-cyclohexenyl)(L2c)]BF4 (95): Major isomer
(95%): 31P NMR (161.9 MHz, CD2Cl2): δ= 143.3 (s). 1H NMR
(400 MHz, CD2Cl2): δ= 0.03 (s, 9H, CH3, SiMe3), 0.10 (m, 1H,
CH2), 0.61 (s, 9H, CH3, SiMe3), 0.81 (m, 1H, CH2), 1.0-1.3 (m,
4H, CH2), 4.05 (b, 1H, CH= trans to N), 4.53 (m, 1H, CH2),
5.18 (m, 1H, CH2), 5.33 (m, 1H, CHc=), 5.95 (m, 1H, CH-N),
6.09 (m, 1H, CH= trans to P) 6.36 (d, 1H, CH-OP, JC-P= 26.0
Hz), 7.10 (d, 1H, CH=, 3JH-H= 8.8 Hz) , 7.11-7.30 (m, 2H, CH=),
3
7.42-7.60 (m, 14H, CH=), 8.02 (d, 2H, CH=, JH-H= 8.4 Hz),
8.24 (s, 1H, CH=). 13C (100.6 MHz, CD2Cl2): δ= -0.4 (CH3,
SiMe3), 0.0 (CH3, SiMe3), 19.9 (CH2), 27.0 (b, CH2), 68.5 (d,
CH= trans to N, JC-P= 9.1 Hz), 74.5 (CH-OP), 76.4 (CH-N),
78.2 (CH2), 104.4 (d, CH= trans to P, JC-P= 39.5 Hz), 111.6 (d,
CHc=, JC-P= 10.7 Hz), 122.7-151.0 (aromatic carbons), 169.4
(C=N). Minor isomer (5%): 31P NMR (161.9 MHz, CD2Cl2): δ=
Typical methodology for the allylic etherification and
silylation of S1. A solution of the desired phosphite-oxazoline
ligand (0.011 mmol) and [PdCl(η3-C3H5)]2 (1.8 mg, 0.005
mmol) in CH2Cl2 (0.5 mL) was stirred. After 30 min, a solution
of S1 (31.5 mg, 0.125 mmol) in CH2Cl2 (1.5 mL) was added.
After 10 min, Cs2CO3 (122 mg, 0.375 mmol) and the
corresponding alkyl alcohol or silanol (0.375 mmol) were
added. . After the desired reaction time, the reaction mixture
was diluted with Et2O (5 mL). Saturated NH4Cl (aq) (25 mL)
was then added and the mixture was extracted with Et2O (3 x
10 mL) and the extract dried over MgSO4. Conversions were
1
139.5 (s). H NMR (400 MHz, CD2Cl2): δ= 0.08 (s, 9H, CH3,
SiMe3), 0.10 (m, 1H, CH2), 0.61 (s, 9H, CH3, SiMe3), 0.81 (m,
1H, CH2), 1.0-1.3 (m, 4H, CH2), 3.94 (b, 1H, CH= trans to N),
4.53 (m, 1H, CH2), 5.21 (m, 2H, CH2, CHc=), 5.95 (m, 2H, CH=
trans to P, CH-N), 6.34 (d, 1H, CH-OP, JC-P= 21.0 Hz), 7.0-8.2
(m, 20H, CH=).
1
determined by H NMR. HPLC was employed to calculate
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ACS Catalysis
Johannsen, M.; Jorgensen, K. A. Allylic Amination. Chem. Rev. 1998,
enantiomeric excesses of substrates 48–54. See Supporting
98, 1689–1708; (d) Pfaltz, A.; Lautens, M. In Comprehensive
Asymmetric Catalysis, Vol. 2; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: Berlin, 1999, Chapter 24, pp 833–884; (e)
Helmchen, G.; Pfaltz, A. Phosphinooxazolines – A New Class of
Versatile, Modular P,N-Ligands for Asymmetric Catalysis. Acc. Chem.
Res. 2000, 33, 336–345; (f) Trost, B. M.; Crawley, M. L. Asymmetric
Transition-Metal-Catalyzed Allylic Alkylations:ꢀ Applications in Total
Synthesis. Chem. Rev. 2003, 103, 2921–2944; (g) Martin, E.; Diéguez,
M. Thioether Containing Ligands for Asymmetric Allylic Substitution
Reactions. C. R. Chim. 2007, 10, 188–205; (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.
New Efficient Adaptative Ligands for Pd-Catalyzed Asymmetric
Allylic Substitution 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. Mo-Catalyzed Asymmetric Allylic Alkylation. Org. Process 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.
(3) See for instance: (a) Diéguez, M.; Ruiz, A.; Müller, G.; Claver,
C.; Jansat, S.; Gómez, M. Diphosphites as a Promising New Class of
Ligands in Pd-catalysed Asymmetric Allylic Alkylation. Chem.
Commun. 2001, 1132–1133; (b) Diéguez, M.; Pàmies, O.; Claver, C.
Modular Furanoside Diphosphite Ligands for Pd-Catalyzed
Asymmetric Allylic Substitution Reactions: Scope and Limitations.
Adv. Synth. Catal. 2005, 347, 1257–1266; (c) Diéguez, M.: Pàmies, O.;
Claver, C. Palladium-Diphosphite Catalysts for the Asymmetric Allylic
Substitution Reactions. J. Org. Chem. 2005, 70, 3363–3368. For
reviews, see: (d) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Claver,
C.; Pàmies, O.; Diéguez, M. Phosphite-Containing Ligands for
Asymmetric Catalysis. Chem. Rev. 2011, 111, 2077–2118; (e) 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.
1
2
3
4
5
6
7
8
Information for characterization and enantiomeric excess
determination details.
Typical methodology for the preparation of
carbobicycles 97–101. A mixture of the enyne (1 mmol) and
PdCl2 or RuCl3 (0.05 mmol) in MeOH (5 mL) was heated at
reflux for 24 h. Then, the solution was cooled down, the solvent
was removed in vacuo and the residue was purified by column
chromatography (hexane: EtOAc mixtures) to give the desired
carbobicycle. See Supporting Information for characterization
and enantiomeric excess determination details.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
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36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Typical methodology for the preparation of
bicyclopentenones 102–104. Under an atmosphere of argon
a solution of the enyne (1.0 mmol.) and Co2(CO)8 (359 mg, 1.05
mmol) in dry CH2Cl2 (0.06 M) was stirred at room temperature
until TLC monitoring indicated full conversion. Then
Me3NO·2H2O (3–10 mmol) was added in one portion. Stirring
was continued until TLC monitoring showed complete
consumption of the cobalt-alkyne complex. The solvent was
then evaporated under reduced pressure, and the residue was
purified by column chromatography (petroleum ether/ethyl
acetate) to give the desired bicyclopentenone. See Supporting
Information for characterization and enantiomeric excess
determination details.
AUTHOR INFORMATION
Corresponding Author
* E-mail for P.-O. N.: Per-Ola.Norrby@astrazeneca.com
* E-mail for O.P.: oscar.pamies@urv.cat.
* E-mail for M.D.: montserrat.dieguez@urv.cat.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Copies of NMR spectra of the new ligands L1b–c and Pd-allyl
intermediates 93–96. Reactivity studies of Pd-intermediates. NMR
and ee determination details of substitution products and chiral
functionalized bicyclic compounds.
Calculated energies and coordinates for all computational
structures.
(4) (a) Balanta, A.; Favier, I.; Teuma, E.; Castillón, S.; Godard, C.;
Aghmiz, A.; Claver, C.; Gómez, M. An Outstanding Palladium System
Containing a C2-symmetrical Phosphite Ligand for Enantioselective
Allylic Substitution Processes. Chem. Commun. 2008, 6197–6199; (b)
Gual, A.; Castillón, S.; Pàmies, O.; Diéguez, M.; Claver, C. C1-
Symmetric Carbohydrate Diphosphite Ligands for Asymmetric Pd-
Allylic Alkylation Reactions. Study of the key Pd-allyl intermediates.
Dalton Trans. 2011, 40, 2852–2860.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Spanish
Ministry of Economy and Competitiveness (CTQ2016-74878-P),
European Regional Development Fund (AEI/FEDER, UE), the
Catalan Government (2017SGR1472), and the ICREA Foundation
(ICREA Academia award to M.D).
(5) For examples of heterodonor P,N ligands, see: (a) Pàmies, O.;
Diéguez, M.; Claver, C. New Phosphite−Oxazoline Ligands for
Efficient Pd-Catalyzed Substitution Reactions. J. Am. Chem. Soc.
2005, 127, 3646–3647; (b) Mata, Y.; Diéguez, M.; Pàmies, O.; Claver,
C. New Carbohydrate-Based Phosphite-Oxazoline Ligands as Highly
Versatile Ligands for Palladium-Catalyzed Allylic Substitution
Reactions. Adv. Synth. Catal. 2005, 347, 1943–1947; (c) Diéguez, M.;
Pàmies, O. Modular Phosphite–Oxazoline/Oxazine Ligand Library for
Asymmetric Pd‐Catalyzed Allylic Substitution Reactions: Scope and
Limitations–Origin of Enantioselectivity. Chem. Eur. J. 2008, 14,
3653–3669; (d) 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; (e) 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 Intermediates. Chem. Eur. J. 2013, 19, 2416–2432; (f) Magre,
M.; Biosca, M.; Norrby, P.-O.; Pàmies, O.; Diéguez, M. Theoretical
and Experimental Optimization of a New Amino Phosphite Ligand
Library for Asymmetric Palladium‐Catalyzed Allylic Substitution.
REFERENCES
(1) (a) Asymmetric Catalysis in Industrial Scale: Challenges,
Approaches and Solutions, Blaser, H. U, Schmidt, E., Eds.; Wiley-
VCH: Weinheim, 2003; (b) Comprehensive Asymmetric Catalysis,
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; (c) Asymmetric Catalysis in Organic Synthesis, Noyori, R., Ed.;
Wiley: New York, 1994; (d) Applied Homogeneous Catalysis with
Organometallics Compounds, 2nd ed.; Cornils, B., Hermann, W. A.,
Eds.; WileyVCH: Weinheim, 2002; (e) Catalytic Asymmetric
Synthesis, Ojima, I., Ed.; Wiley: Hobocken, 2010.
(2) For reviews, see: (a) Tsuji, J. In Palladium Reagents and
Catalysis: Innovations in Organic Synthesis; Wiley: New York, 1995;
(b) Trost, B. M.; van Vranken, D. L. Asymmetric Transition Metal-
Catalyzed Allylic Alkylations. Chem. Rev. 1996, 96, 395–422; (c)
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ACS Catalysis
Page 14 of 17
ChemCatChem 2015, 7, 4091–4107; (g) Borràs, C.; Elías-Rodríguez,
(12) Li, Z.-T.; Li, X.-S.; Li, L.-C.; Xu, D.-C. Convenient Synthesis
P.; Carmona, A. T.; Robina, I.; Pàmies, O.; Diéguez, M. Amino-P
Ligands from Iminosugars: New Readily Available and Modular
Ligands for Enantioselective Pd-Catalyzed Allylic Substitutions.
Organometallics 2018, 37, 1682–1694. For examples on heterodonor
P-P’ ligands, see: (h) Raluy, E.; Claver, C.; Pàmies, O.; Diéguez, M.
First Chiral Phosphoroamidite-phosphite Ligands for Highly
Enantioselective and Versatile Pd-Catalyzed Asymmetric Allylic
Substitution Reactions. Org. Lett. 2007, 9, 49–52; (i) Pàmies, O.;
Diéguez, M. Screening of a Phosphite–Phosphoramidite Ligand
Library for Palladium‐Catalysed Asymmetric Allylic Substitution
Reactions: The Origin of Enantioselectivity. Chem. Eur. J. 2008, 14,
944–960; (j) Raluy, E.; Pàmies, O.; Diéguez, M. Modular Furanoside
Phosphite‐Phosphoroamidites, a Readily Available Ligand Library for
Asymmetric Palladium‐Catalyzed Allylic Substitution Reactions.
Origin of Enantioselectivity. Adv. Synth. Catal. 2009, 351, 1648–1670.
For examples on heterodonor P,S-ligands, see: (k) 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; (l) Margalef,
J.; Coll, M.; Norrby, P.-O.; Pàmies, O.; Diéguez, M. 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. Organometallics 2016, 35, 3323–
3335.
(6) (a) von Matt, P.; Pfaltz, A. Chiral Phosphinoaryldihydrooxazoles
as Ligands in Asymmetric Catalysis: Pd‐Catalyzed Allylic
Substitution. Angew. Chem. Int. Ed. 1993, 32, 566–568; (b) Sprinz, J.;
Helmchen, G. Phosphinoaryl- and Phosphinoalkyloxazolines as New
Chiral Ligands for Enantioselective Catalysis: Very High
Enantioselectivity in Palladium Catalyzed Allylic Substitutions.
Tetrahedron Lett. 1993, 34, 1769–1772; (c) Dawson, G. J.; Frost, C.
G.; Williams,J. M. J.; Coote, S. J. Asymmetric Palladium Catalysed
Allylic Substitution Using Phosphorus Containing Oxazoline Ligands.
Tetrahedron Lett. 1993, 34, 3149–3150.
of a New Class of Chiral Hydroxymethyldihydrooxazole Ligands and
Their Application in Asymmetric Addition of Diethylzinc to Aromatic
Aldehydes. Russ. J. Organ. Chem. 2006, 42, 545–549.
1
2
3
4
5
6
7
8
(13) Previous Pd/PHOX-based phosphite-oxazoline catalysts 2
provided TOF’s up to >2400 mol substrate×(mol Pd×h)-1, see ref. 5a.
(14) See for example: (a) Dugal-Tessier, J.; Dake, G. R.; Gates, D.
P. Chiral Phosphaalkene−Oxazoline Ligands for the Palladium-
Catalyzed Asymmetric Allylic Alkylation. Org. Lett. 2010, 12, 4667–
4669; (b) Nakai, Y.; Uozumi, Y. Cycloisomerization of 1,6-Enynes:ꢀ
Asymmetric Multistep Preparation of a Hydrindane Framework in
Water with Polymeric Catalysts. Org. Lett. 2005, 7, 291–293; (c) Son,
S. U.; Park, K. H.; Seo, H.; Chung, Y. K.; Lee, S.-G. Catalytic
Asymmetric Synthesis of Cyclopentenones from Propargyl Malonates
and Allylic Acetate by Successive Action of Homogeneous
Palladium(II) and Cobalt on Charcoal Catalysts in a One-pot Reaction.
Chem. Commun. 2001, 2440–2441; (d) Farwick, A.; Engelhart, J. U.;
Tverskoy, O.; Welter, C.; Umlauf, Q. E.; Rominger, F.; WillKerr, W.
J.; Helmchen, G. Bicyclic Cyclopentenones via the Combination of an
Iridium‐ Catalyzed Allylic Substitution with a Diastereoselective
Intramolecular Pauson–Khand Reaction. Adv. Synth. Catal. 2011, 353,
349–370.
(15) (a) Kmentová, I.; Gotov, B.; Solcániová, E.; Toma, Š. Study of
Ligand and Base Effects on Enantioselective Allylation Catalyzed by
Pd(0) Phosphine Complexes in [bmim][PF6] Ionic Liquid. Green
Chem. 2002, 4, 103–106; (b) Liu, J.; Chen, G.; Xing, J.; Liao, J. tert-
Butanesulfinylthioether Ligands: Synthesis and Application in
Palladium-catalyzed Asymmetric Allylic Alkylation. Tetrahedron:
Asymmetry 2011, 22, 575–579; (c) Jin, Y.; Du, D. M. The Synthesis of
Phosphine Oxide-linked Bis(oxazoline) Ligands and Their Application
in Asymmetric Allylic Alkylation. Tetrahedron 2012, 68, 3633–6340;
(d) Martin, C. J.; Rawson, D. J.; Williams, J. M. J. The Preparation of
Enantiomerically Enriched γ-Amino Acids (GABAs) Using Palladium
Catalysed Allylic Substitution. Tetrahedron: Asymmetry 1998, 9,
3723–3730. (e) Deng, W. H.; Ye, F.; Bai, X. F.; Zheng, Z. J.; Cui, Y.
M.; Xu, L. W. Multistereogenic Phosphine Ligand‐promoted
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
(7) Bellini, R.; Magre, M.; Biosca, M.; Norrby, P.-O.; Pàmies, O.;
Diéguez, M.; Moberg, C. Conformational Preferences of a Tropos
Biphenyl Phosphinooxazoline–a Ligand with Wide Substrate Scope.
ACS Catal. 2016, 6, 1701–1712.
Palladium‐Catalyzed
Allylic
Alkylation
of
Cyanoesters.
ChemCatChem 2015, 7, 75–79.
(16) For a recent review, see: d’Ischia, M.; Napolitano, A.; Pezzella,
A. In Comprehensive Heterocyclic Chemistry III: Pyrroles and their
Benzo Derivatives: Applications; Katritzky, A. R., Ramsden, C. A.,
Scriven, E. F. V., TaylorE. J. K., Eds.; Elsevier: Amsterdam, 2008; Vol.
3, pp 353–388.
(17) (a) Liu, Y.; Cao, Z.; Du, H. Asymmetric Allylic Alkylation of
Pyrroles and 4,7-Dihydroindoles with Alkene–Phosphine Ligands. J.
Org. Chem. 2012, 77, 4479–4483; (b) Biosca, M.; Margalef, J.;
Caldentey, X.; Besora, M.; Rodríguez-Escrich, C.; Saltó, J.; Cambeiro,
X. C.; Maseras, F.; Pàmies, O.; Diéguez, M.; Pericàs, M. A.
Computationally Guided Design of a Readily Assembled Phosphite–
Thioether Ligand for a Broad Range of Pd-Catalyzed Asymmetric
Allylic Substitutions. ACS Catal. 2018, 8, 3587–3601.
(8) See for example: (a) Mazuela, J.; Pàmies, O.; Diéguez, M. Biaryl
Phosphite–Oxazoline Ligands from the Chiral Pool: Highly Efficient
Modular Ligands for the Asymmetric Pd‐Catalyzed Heck Reaction.
Chem. Eur. J. 2010, 16, 3434−3440 (asymmetric Heck reaction); (b)
Magre, M.; Biosca, M.; Pàmies, O.; Diéguez, M. Filling the Gaps in the
Challenging Asymmetric Hydroboration of 1,1‐Disubstituted Alkenes
with Simple Phosphite‐Based Phosphinooxazoline Iridium Catalysts.
ChemCatChem 2015, 7, 114−120 (asymmetric hydroboration); (c)
Biosca, M.; Magre, M.; Coll, M.; Pàmies, O.; Diéguez, M. Alternatives
to Phosphinooxazoline (t‐BuPHOX) Ligands in the Metal‐Catalyzed
Hydrogenation of Minimally Functionalized Olefins and Cyclic
β‐Enamides. Adv. Synth. Catal. 2017, 359, 2801–2814 (asymmetric
hydrogenation).
(9) Allen, J. V.; Williams, J. M. J. Enantiomerically Pure Oxazolines
Tethered to Alcohols. Preparation and Use in Asymmetric Catalysis.
Tetrahedron: Asymmetry 1994, 5, 277–282.
(10) Biosca, M.; Magre, M.; Pàmies, O.; Diéguez, M. Asymmetric
Hydrogenation of Disubstituted, Trisubstituted, and Tetrasubstituted
Minimally Functionalized Olefins and Cyclic β-Enamides with Easily
Accessible Ir–P,Oxazoline Catalysts. ACS Catal. 2018, 8, 10316–
10320.
(11) (a) Bolm, V.; Zani, L.; Rudolph, J.; Schiffers, I. New Chiral
Ligands Derived from Mandelic Acid: Synthesis and Application in the
Asymmetric Phenyl Transfer Reaction to an Aromatic Aldehyde.
Synthesis 2004, 13, 2173–2180; (b) Buisson, D.; Azerad, R.
Preparation and Use of (S)-O-Acetyllactyl Chloride (Mosandl's
Reagent) as a Chiral Derivatizing Agent. Tetrahedron: Asymmetry
1999, 10, 2997–3002; (c) Kardassi, G.; Brungs, P.; Nothelfer, C.;
Eberhard, S. Electrogenerated Chiral Cationic Glycine Equivalents —
Part 2: Chiral 3-Methoxy-2,5-morpholinediones from (S)-α-Hydroxy
Acids and Dimethyl Aminomalonate. Tetrahedron 1998, 54, 3479–
3488.
(18) (a) Dictionary of Natural Products; Buckingham, J, Ed.;
Cambridge University Press.: Cambridge, 1994; (b) Lumbroso, A.;
Cooke, M. L.; Breit, B. Catalytic Asymmetric Synthesis of Allylic
Alcohols and Derivatives and their Applications in Organic Synthesis.
Angew. Chem. Int., Ed. 2013, 52, 1890–1893.
(19) The use of aliphatic alcohols has been much less studied than
those using phenols. See: (a) Iourtchenko, A.; Sinou, D. Asymmetric
Palladium(0)-Catalyzed Synthesis of Allylic Ethers. J. Mol. Catal. A
1997, 122, 91–93; (b) Haight, A. R.; Stoner, E. J.; Peterson, M. J.;
Grover, V. K. General Method for the Palladium-Catalyzed Allylation
of Aliphatic Alcohols. J. Org. Chem. 2003, 68, 8092–8096; (c) Lam, F.
L.; Au-Yeung, T. T. L.; Kwong, F. Y.; Zhou, Z.; Wong, K. Y.; Chan,
A. S. C. Palladium–(S,pR)‐FerroNPS‐Catalyzed Asymmetric Allylic
Etherification: Electronic Effect of Nonconjugated Substituents on
Benzylic Alcohols on Enantioselectivity. Angew. Chem. Int. Ed. 2008,
47, 1280–1283; (d) Ye, F.; Zheng, Z.-J.; Li, L.; Yang, K.-F.; Xia, C.-
G.; Xu, L.-W. Development of a Novel Multifunctional N,P Ligand for
Highly Enantioselective Palladium‐Catalyzed Asymmetric Allylic
Etherification of Alcohols and Silanols. Chem. Eur. J. 2013, 19,
15452–15457; (e) Caldentey, X.; Pericàs, M. A. Modular P,S-Ligands
ACS Paragon Plus Environment

Page 15 of 17
ACS Catalysis
for Pd-Catalyzed Asymmetric Allylic Substitutions. J. Org. Chem.
16, 2442–2445; (h) Ikeda, K.; Futamura, T.; Hanakawa, T.; Minakawa,
M.; Kawatsura, M. Palladium-catalyzed Enantioselective Allylic
Alkylation of Trifluoromethyl Group Substituted Racemic and Acyclic
Unsymmetrical 1,3-Disubstituted Allylic Esters with Malonate Anions.
Org. Biomol. Chem. 2016, 14, 3501–3505.
(24) (a) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.;
Gagné, M. R. Chiral Mixed Phosphorus/Sulfur Ligands for Palladium-
Catalyzed Allylic Alkylations and Aminations. J. Org. Chem. 1999, 64,
2994–2995; (b) Zhao, D.; Ding, K. A New Type of C2-Symmetric
2010, 75, 2628–2644; (f) Liu, Z.; Du, H. Development of Chiral
Terminal-Alkene−Phosphine Hybrid Ligands for Palladium-Catalyzed
Asymmetric Allylic Substitutions. Org. Lett. 2010, 12, 3054–3057; (g)
Kato, M.; Nakamura, T.; Ogata, K.; Fukuzawa, S.-I. Synthesis of Novel
Ferrocenyl‐Based P,S Ligands (ThioClickFerrophos) and Their Use in
Pd‐Catalyzed Asymmetric Allylic Substitutions. Eur. J. Org. Chem.
2009, 5232–5238; (h) Feng, B.; Cheng, H.-G.; Chen, J.-R.; Deng, Q.-
R.; Lu, L.-Q.; Xiao, W.-J. Palladium/Sulfoxide–Phosphine-Catalyzed
Highly Enantioselective Allylic Etherification and Amination. Chem.
Commun. 2014, 50, 9550–9553.
1
2
3
4
5
6
7
8
Bisphospine Ligands with
a Cyclobutane Backbone:ꢀ Practical
Synthesis and Application. Org. Lett. 2003, 5, 1349–1351; c) Zhao, D.;
Sun, J.; Ding, K. New Types of Soluble Polymer‐Supported
Bisphosphine Ligands with a Cyclobutane Backbone for Pd‐Catalyzed
Enantioselective Allylic Substitution Reactions. Chem. Eur. J. 2004,
10, 5952–5963.
9
(20) While low enantioselectivities were achieved for compounds
48-49 and 51 (ee’s ranging from 25% to 37% ee), high ee’s were
achieved for compound 50 (97% ee) using Pd/2 catalytic systems. See
ref. 7.
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(21) Silanols have been less studied than other type of nucleophile
and there are only few catalytic systems that has provided high levels
of enantioselectivity, see: (a) ref. 19d; (b) ref. 7.
(25) For successful applications of Pd-catalysts, see: (a) Prétôt, R.;
Pfaltz, A. New Ligands for Regio‐ and Enantiocontrol in Pd‐Catalyzed
Allylic Alkylations. Angew. Chem. Int. Ed. 1998, 37, 323–325; (b)
Hilgraf, R.; Pfaltz, A. Chiral Bis(N-tosylamino)phosphine- and
TADDOL-Phosphite-Oxazolines as Ligands in Asymmetric Catalysis.
Synlett 1999, 1814–1816. (c) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou,
X.-L.; Dai, L.-X. Highly Regio- and Enantioselective Pd-Catalyzed
Allylic Alkylation and Amination of Monosubstituted Allylic Acetates
with Novel Ferrocene P,N-Ligands. J. Am. Chem. Soc. 2001, 123,
7471–7472; (d) Hilgraf, R.; Pfaltz, A. Chiral Bis(N-
(22) The isomerization of the Pd-allyl intermediates between the
enantiomeric manifolds is usually very slow. For examples of
successful kinetic resolutions, see: (a) Ramdeehul, S.; Dierkes, P.;
Aguado, R.; Kamer, P. C. J.; van Leeuwen, P. W. N,. M.; Osborn, J. A.
Mechanistic Implications of the Observation of Kinetic Resolution in a
Palladium-Catalyzed Enantioselective Allylic Alkylation. Angew.
Chem., Int. Ed. 1998, 37, 3118–3121; (b) Dominguez, B.; Hodnett, N.
S.; Lloyd-Jones, G. C. Testing Racemic Chiral Catalysts for Kinetic
Resolution Potential. Angew. Chem., Int. Ed. 2001, 40, 4289–4291; (c)
Lüssemand, B. J.; Gais, H.-J. Palladium-Catalyzed Deracemization of
Allylic Carbonates in Water with Formation of Allylic Alcohols:ꢀ
Hydrogen Carbonate Ion as Nucleophile in the Palladium-Catalyzed
Allylic Substitution and Kinetic Resolution. J. Am. Chem. Soc.
2003,125, 6066–6067; (d) Lei, B.-L.; Ding, C.-H.; Yang, X.-F.; Wan,
X.-L.; Hou, X.-L. Kinetic Resolution of 2,3-Dihydro-2-substituted 4-
Quinolones by Palladium-Catalyzed Asymmetric Allylic Alkylation. J.
Am. Chem. Soc. 2009, 131, 18250–18251; (e) Cheung, H. Y.; Yu, W.-
Y.; Au-Yeung, T. T. L.; Zhou, Z. A. S. C. Chan, Effective Chiral
Ferrocenyl Phosphine‐Thioether Ligands in Enantioselective
Palladium‐Catalyzed Allylic Alkylations. Adv. Synth. Catal. 2009, 351,
1412–1422; (f) Hirakawa, T.; Ikeda, K.; Ikeda, D.; Tanaka, T.; Ogasa,
H.; Kawatsura, M.; Itoh, T. Regioselective Synthesis of
Trifluoromethyl Group Containing Allylic Amines by Palladium-
catalyzed Allylic Amination and Sequential Isomerization.
Tetrahedron 2011, 67, 8238–8247; (g) Mao, B.; Ji, Y.; Fañanás-
Mastral, M.; Caroli, G.; Meetsma, A.; Feringa, B. L. Highly
Enantioselective Synthesis of 3‐Substituted Furanones by
Palladium‐Catalyzed Kinetic Resolution of Unsymmetrical Allyl
Acetates. Angew. Chem., Int. Ed. 2012, 51, 3168–3173.
sulfonylamino)phosphine-
and
TADDOL-Phosphite-Oxazoline
Ligands: Synthesis and Application in Asymmetric Catalysis. Adv.
Synth. Catal. 2005, 347, 61–77; (e) Chen, J.-P.; Ding, C.-H.; Liu, W.;
Hou, X.-L.; Dai, L.-X. Palladium-Catalyzed Regio-, Diastereo-, and
Enantioselective Allylic Alkylation of Acylsilanes with
Monosubstituted Allyl Substrates. J. Am. Chem. Soc. 2010, 132,
15493–15495.
(26) (a) Oslob, J. D.; Åkermark, B.; Helquist, P.; Norrby, P.-O.
Steric Influences on the Selectivity in Palladium-Catalyzed Allylation.
Organometallics 1997, 16, 3015–3021; (b) Hagelin, H.; Åkermark, B.;
Norrby, P.-O. New Molecular Mechanics (MM3*) Force Field
Parameters for Calculations on (η3-Allyl)palladium Complexes with
Nitrogen and Phosphorus Ligands. Organometallics 1999, 18, 2884–
2895.
(27) Considering the possibility of a late transition state the relative
stability of the Pd-olefin intermediates (Pd-olefinendo and Pd-olefinexo
)
after the addition of the nucleophile has also been calculated (the full
set of calculation can be found in the Supporting Information, section).
According to expectations the calculated energy of these Pd-olefin
intermediates do not correlate well with the experimental results (see
section 5 in the Supporting Information). For examples of late
transition transition states, see: (a) Hagelin, H.; Svensson, M.;
Äkermark, B.; Norrby, P.-O. Molecular Mechanics (MM3*) Force
Field Parameters for Calculations on Palladium Olefin Complexes with
Phosphorus Ligands. Organometallics 1999, 18, 4574–4583; (b)
Moberg, C.; Bremberg, U.; Hallman, K.; Svensson, M.; Norrby, P.-O.;
Hallberg, A.; Larhed, M.; Csçregh, I. Selectivity and Reactivity in
Asymmetric Allylic Alkylation. Pure Appl. Chem. 1999, 71, 1477–
1483.
(28) Note that using ammonia 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.
(29) The use of ammonia as nucleophile circumvents the issues
associated to charge separation along with a continuum solvent model
when using malonates as nucleophiles. (a) Butts, C. P.; Filali, E.;
Lloyd-Jones, G. C.; Norrby, P.-O.; Sale, D. A.; Schramm, Y. Structure-
Based Rationale for Selectivity in the Asymmetric Allylic Alkylation
of Cycloalkenyl Esters Employing the Trost ‘Standard Ligand’ (TSL):
Isolation, Analysis and Alkylation of the Monomeric form of the
Cationic η3-Cyclohexenyl Complex [(η3-c-C6H9)Pd(TSL)]+. J. Am.
Chem. Soc. 2009, 131, 9945–9957; (b) Fristrup, P.; Ahlquist, M.;
Tanner, D.; Norrby, P.-O. On the Nature of the Intermediates and the
Role of Chloride Ions in Pd-Catalyzed Allylic Alkylations: Added
Insight from Density Functional Theory. J. Phys. Chem. 2008, 112,
12862–12867.
(23) See for example: (a) Trost, B. M.; Toste, F. D. Regio- and
Enantioselective Allylic Alkylation of an Unsymmetrical Substrate:ꢀ A
Working Model. J. Am. Chem. Soc. 1999, 121, 4545–4554; (b) Trost,
B. M.; Toste, F. D. Palladium Catalyzed Kinetic and Dynamic Kinetic
Asymmetric
Transformations
of
γ-Acyloxybutenolides.
Enantioselective Total Synthesis of (+)-Aflatoxin B1 and B2a. J. Am.
Chem. Soc. 2003, 125, 3090–3100; (c) Dong, Y.; Teesdale-Spittle, P.;
Hoberg, J. O. Regioselective Palladium-catalyzed Allylic Alkylations.
Tetrahedron Lett. 2005, 46, 353–355; (d) Gais, H.-J.; Bondarev, O.;
Hetzer, R. Palladium-catalyzed Asymmetric Synthesis of Allylic
Alcohols from Unsymmetrical and Symmetrical Racemic Alylic
Carbonates Featuring C–O-Bond Formation and Dynamic Kinetic
Resolution. Tetrahedron Lett. 2005, 46, 6279–6283; (e) Kukkadapu, K.
K.; Ouach, A.; Lozano, P.; Vaultier, M.; Pucheault, M. Achieving
Chemo-, Regio-, and Stereoselectivity in Palladium-Catalyzed
Reaction of γ-Borylated Allylic Acetates. Org. Lett. 2011, 13, 4132–
4135; (f) Du, L.; Cao, P.; Xing, J.; Lou, Y.; Jiang, L.; Li, L.; Liao, J.
Hydrogen‐Bond‐Promoted Palladium Catalysis: Allylic Alkylation of
Indoles with Unsymmetrical 1,3‐Disubstituted Allyl Acetates Using
Chiral Bis(sulfoxide) Phosphine Ligands. Angew. Chem. Int. Ed. 2013,
52, 4207–4211; (g) Kawatsura, M.; Terasaki, S.; Minakawa, M.;
Hirakawa, T.; Ikeda, K.; Itoh, T. Enantioselective Allylic Amination of
Trifluoromethyl Group Substituted Racemic and Unsymmetrical 1,3-
Disubstituted Allylic Esters by Palladium Catalysts. Org. Lett. 2014,
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(30) (a) Deerenberg, S.; Schrekker, H. S.; van Strijdonck, G. P. F.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Fraanje, J.; Goubitz, K.
New Chiral Phosphine−Phosphite Ligands in the Enantioselective
Palladium-Catalyzed Allylic Alkylation. J. Org. Chem. 2000, 65,
4810–4817. (b) Fernández, F.; Gómez, M.; Jansat, S.; Muller, G.;
Martín, E.; Flores Santos, L.; García, P. X.; Acosta, A.; Aghmiz, A.;
Jiménez-Pedrós, M.; Masdeu-Bultó, A. M.; Diéguez, M.; Claver, C.;
Maestro, M. A. Allylic Alkylations Catalyzed by Palladium Systems
Containing Modular Chiral Dithioethers. A Structural Study of the
Allylic Intermediates. Organometallics 2005, 24, 3946–3956.
(31) Complexes 93–96 were characterized by 1H, 13C and 31P NMR
spectroscopy and HRMS. The structural assignments were supported
by 1H-1H, 31P-1H, 13C-1H and 1H-1H NOESY experiments.
(32) Méndez, M.; Muñoz, M. P.; Echavarren, A. M. Platinum-
Catalyzed Alkoxy- and Hydroxycyclization of Enynes. J. Am. Chem.
Soc. 2000, 122, 11549–11550.
(33) Sole, D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A.
Intramolecular Nitrogen Assistance in the Nickel-Promoted Tandem
Cyclization-Capture of Amino-Tethered Vinyl Bromides and Alkenes.
J. Am. Chem. Soc. 1994, 116, 12133–12134
(34) (a) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. Asymmetric
Synthesis. Asymmetric Catalytic Allylation Using Palladium Chiral
Phosphine Complexes. J. Am. Chem. Soc. 1985, 107, 2033–2046; (b)
Jia, C.; Müller, P.; Mimoun, H. Palladium-catalyzed Allylic
Acetoxylation of Olefins Using Hydrogen Peroxide as Oxidant. J. Mol.
Cat. A: Chem. 1995, 101, 127–136; (c) Lehman, J.; Lloyd-Jones, G. C.
Regiocontrol and Stereoselectivity in Tungsten-Bipyridine Catalysed
Allylic Alkylation. Tetrahedron 1995, 51, 8863–8874; (d) Hayashi, T.;
Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K.
Asymmetric Synthesis Catalyzed by Chiral Ferrocenylphosphine -
Transition-metal Complexes. 8. Palladium-catalyzed Asymmetric
Allylic Amination. J. Am. Chem. Soc. 1989, 111, 6301–6311; (e) Le,
D.; Peng, C.; Jian, L. Bifunctional Ligand Promoted Pd-Catalyzed
Asymmetric Allylic Etherification/Amination. Acta Chim. Sinica 2013,
71, 1239–1242; (f) Jayakumar, S.; Kumarswamyreddy, N.; Prakash,
M.; Kesavan, V. Palladium Catalyzed Asymmetric Allylation of 3-
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.;
Peralta, J. E., Jr.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;
Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J.
B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.
E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Revision
A.02 ed; Gaussian: Wallingford, CT, 2009.
(38) (a) Lee, C.; Yang,W.; Parr, R. G. Development of the Colle-
Salvetti Correlation-Energy Formula into a Functional of the Electron
Density. Phys. Rev. B 1988, 37, 785–789. (b) Becke, A. D.
Density‐Functional Thermochemistry. III. The Role of Exact
Exchange. J. Chem. Phys. 1993, 98, 5648–5652.
1
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46
47
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49
50
51
52
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54
55
56
57
58
59
60
(39) Hay, P. J.; Wadt, W. R. Ab initio Effective Core Potentials for
Molecular Calculations. Potentials for K to Au Including the Outermost
Core Orbitals. J. Chem. Phys. 1985, 82, 299–310.
(40) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. Self—Consistent
Molecular Orbital Methods. XII. Further Extensions of Gaussian—
Type Basis Sets for Use in Molecular Orbital Studies of Organic
Molecules. J. Chem. Phys. 1972, 56, 2257–2261. (b) Hariharan, P. C.;
Pople, J. A. The Influence of Polarization Functions on Molecular
Orbital Hydrogenation Energies. Theor. Chim. Acta 1973, 28, 213–
222. (c) Francl, M. M.; Pietro,W. J.; Hehre,W. J.; Binkley, J. S.;
Gordon, M. S.; Defrees, D. J.; Pople, J. A. Self‐Consistent Molecular
Orbital Methods. XXIII. A Polarization‐type Basis Set for Second-row
Elements. J. Chem. Phys. 1982, 77, 3654–3665.
(41) (a) Miertus, S.; Tomasi, J. Approximate Evaluations of the
Electrostatic Free Energy and Internal Energy Changes in Solution
Processes. Chem. Phys. 1982, 65, 239–245. (b) Mennucci, B.; Tomasi,
J. Continuum Solvation Models: A New Approach to the Problem of
Solute’s Charge Distribution and Cavity Boundaries. J. Chem. Phys.
1997, 106, 5151–5158. (c) Cossi, M.; Barone, V.; Menucci, B.; Tomasi,
J. Ab initio Study of Ionic Solutions by a Polarizable Continuum
Dielectric Model Chem. Phys. Lett. 1998, 286, 253–260.
(42) (a) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A.
Self‐Consistent Molecular Orbital Methods. XX. A Basis Set for
Correlated Wave Functions. J. Chem. Phys. 1980, 72, 650–654. (b)
McLean, A. D.; Chandler, G. S. Contracted Gaussian Basis Sets for
Molecular Calculations. I. Second Row Atoms, Z=11–18. J. Chem.
Phys. 1980, 72, 5639–5648.
(43) (a) Johnson, E.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.;
Cohen, A.; Yang, W. J. Am. Chem. Soc. 2010, 132, 6498–6506; (b)
Contreras-García, J.; Johnson, E.; Keinan, S.; Chaudret, R.; Piquemal,
J.; Beratan, D.; Yang, W. J. Chem. Theory Comput. 2011, 7, 625–632;
(c) Contreras-García, J.; Yang, W.; Johnson, E. J. Phys. Chem. A 2011,
115, 12983–12990.
OBoc-Oxindoles:
An
Efficient
Synthesis
of
3-Allyl-3-
hydroxyoxindoles. Org. Lett. 2015, 17, 1066–1069; (g) Ref. 22f.
(35) Ward, Y. D.; Villanueva, L. A.; Allred, G. D.; Payne, C. C.;
Semones, M. A.; Liebeskind, L. S. Synthesis, Characterization, and
Configurational Lability of (.eta.3-Allyl)dicarbonyl[hydrotris(1-
pyrazolyl)borato]molybdenum Complexes Bearing Substituents at the
Termini: Thermodynamic Preference for the Anti Stereoisomer.
Organometallics 1995, 14, 4132–4156.
(36) Buisman, G. J. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Rhodium Catalysed Asymmetric Hydroformylation with Chiral
Diphosphite Ligands. Tetrahedron: Asymmetry 1993, 4, 1625–1634.
(37) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
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