"This is the peer reviewed version of the following article: Synthesis, Application and Kinetic Studies of Chiral PhosphiteOxazoline Palladium Complexes as Active and Selective Catalysts in Intermolecular Heck Reactions, which has been
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Synthesis, Application and Kinetic Studies of Chiral PhosphiteOxazoline Palladium Complexes as Active and Selective
Catalysts in Intermolecular Heck Reactions
Zahra Mazloomi,a Marc Magre,a Efrem Del Valle,a Miquel A. Pericàs,b,c Oscar
Pàmies,a* P. W. N. M. van Leeuwend* and Montserrat Diégueza*
a

Universitat Rovira i Virgili, Departament de Química Física i Inorgànica, C/ Marcel·lí Domingo, 1, 43007 Tarragona,
Spain. Fax: (+34)977559563; Tel: (+34)977558780; email: oscar.pamies@urv.cat; montserrat.dieguez@urv.cat.
b
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona, Spain.
c
Departament de Química Inorgànica i Orgànica. Universitat de Barcelona. 08028 Barcelona, Spain.
d
LPCNO, Laboratoire de Physique et Chimie des Nano-Objets, INSA-Toulouse, 135, Avenue de Rangueil, F-31077
Toulouse, France; Tel: (+33)0567048857; email: vanleeuw@insa-toulouse.fr.
Abstract. This study identifies new phosphite-oxazoline be coupled with regio-, enantioselectivities and activities
ligands that have been successfully applied in the palladium- comparable to the few best ones reported. In addition, the
catalyzed intermolecular asymmetric Heck reaction. The ligands that provided the best selectivities contained an
design of the new phosphite-oxazoline ligands derives from a isopropyl oxazoline moiety instead of the tert-butyl group
previous successful generation of phosphine-oxazoline found in the related phosphine-oxazoline ligands, which is
ligands, by replacing the phosphine group with several π- made from a much more expensive precursor. In this paper
acceptor biaryl phosphite moieties. With these simple we have also carried out kinetic studies and a Hammett plot
modifications, the new phosphite-based ligands, unlike analysis to determine the rate determining step of this system
previous phosphine-oxazoline, not only present a modular in the regime of interest. We suggest a likely explanation for
design with numerous potential phosphite groups available, the fast Heck reaction of the phosphite-oxazoline catalysts.
but they are also air-stable solids, which can be made in the
same number of synthetic steps as the phosphine analogues. Keywords: Palladium; Intermolecular Heck reaction; P,NThe substitution of the phosphine by a biaryl phosphite group ligands; asymmetric catalysis; kinetic study
extended the range of substrates and triflates sources that can

Introduction
The Pd-catalyzed Heck reaction (also known as
Mizoroki–Heck reaction), i.e., the coupling of an
alkenyl or aryl (pseudo)halide to an alkene, is one of
the most powerful C–C bond forming reactions, and
Heck´s contribution was recognized with the Nobel
Prize in Chemistry in 2010, shared with Negishi and
Suzuki.[1] Its applicability to highly functionalized
substrates confers the reaction a large substrate scope
and it is widely applied in the synthesis of
pharmaceuticals, natural products, and fine
chemicals.[1] The extensive research dedicated to this
process can give the erroneous impression that Heck
chemistry is a mature area. Although the Heck reaction
has been known since the late 1960s, its asymmetric
version was not published until 1980, with most
examples dealing with intramolecular reactions, in
which the alkene regiochemistry and geometry of the
product can be easily controlled.[1] The asymmetric
intermolecular Heck reaction was not published until

1991.[2] Although since then many research groups
have devoted considerable efforts to the
intermolecular version, it is still less developed than
the intramolecular version and its synthetic utility
remains limited. This is due in part to regioselectivity
issues caused by the possible displacement of the
carbon-carbon double bond, which leads to mixtures
of products. For example, in the Heck coupling of the
model substrate 2,3-dihydrofuran (S1) with phenyl
triflate (Scheme 1), both the 2-phenyl-2,5dihydrofuran (1) and the 2-phenyl-2,3-dihydrofuran
(2) can be obtained.

Scheme 1. Model Pd-catalyzed Heck reaction of 2,3dihydrofuran (S1) with phenyl triflate

1

In the beginning, the research in the asymmetric
intermolecular reaction focused on the development of
diphosphine ligands, BINAP being the central
ligand.[1] Although Pd-diphosphine catalysts provided
high enantioselectivities, the regioselectivity and
activity were less favorable (e.g., BINAP provided
enantioselectivities up to 96% but the main product
was 2, in only 71% of regioselectivity, and the reaction
time was 9 days)[2]. This moved the research to other
types of ligands. A breakthrough was the report by
Pfaltz et al., who showed that phosphine-oxazoline
PHOX ligands (3, Figure 1) minimized the double
bond isomerization providing high regio- and
enantioselectivity to product 1, although still at low
activity with long reaction times (3–7 days to achieve
full conversion).[3] Then, the follow up work for the
intermolecular Heck reaction focused on Pd-catalysts
with modified chiral phosphine-oxazoline ligands.[4,5]
Of the many ligands developed, only a few provided
high selectivity (Figure 1) and reaction rates and
substrate specificity could not be improved
significantly either. Although microwave irradiation
considerably reduced the reaction times from weeks to
days, it affected enantioselectivity − and sometimes
regioselectivity − negatively.[6] Additionally, the most
successful phosphine-oxazoline ligands contained a
t
Bu group in the oxazoline and their synthesis required
the use of the expensive amino acid tert-leucine.
Although alternative phosphine-oxazoline ligands,
such as those incorporating geminal substituents at C4 of iPr-PHOX,[4q] were developed to solve this
limitation, they had smaller substrate scope and/or
their synthesis required more reaction steps. A final
limitation of phosphine-oxazoline ligands is that most
of them are prone to oxidation. Thus, while the PHOX
ligands were found to be extremely successful in many
reactions,[7] there remains room for improvement in the
intermolecular Heck reactions.

Figure 1. Representative privileged P-oxazoline ligands for
Pd-catalyzed asymmetric intermolecular Heck reactions.

The search for efficient ligands prepared in only a
few steps from inexpensive raw materials, easy to
handle and that induce higher rates and substrate scope
has therefore attracted the attention of many
researchers. For this purpose two main strategies have
been used for ligand design. One, developed recently

by the groups of Oestrich and Zhou, illustrates the
power of mixed phosphine-phosphine oxides which
had been discarded in the Heck reaction for decades.
Pd/phosphine-phosphine oxide systems were
successfully applied in the intermolecular Heck
reaction of several cyclic alkene substrates with
various aryl triflates and aryl halides.[8] The second
strategy was based on biaryl phosphite-oxazoline
ligands. Phosphite-containing ligands are particularly
useful for asymmetric catalysis.[9] They are modular,
easy to synthesize from available alcohols and more
resistant to oxidation than the phosphines. In this
respect, an improved generation of air stable
phosphite-oxazoline ligand libraries was developed.[10]
The application of two of these phosphite-oxazoline
libraries in the Heck reaction led to identify a
Pd/phosphite-oxazoline 7 catalyst (Figure 1) that
provided conversions of 100% at 50 °C in 24 h with
excellent regio- and enantioselectivities in the
coupling of several cyclic substrates and a variety of
aryl triflates.[11] To the best of our knowledge no other
phosphite-oxazoline ligands have been applied.
Despite the mentioned developments, the use of the
phosphite-oxazoline ligands in the intermolecular
Heck reaction has several unknowns that must be
explored to facilitate/accelerate the search for better
catalysts. For example, no mechanistic studies have
been made to discern the role of the ligand parameters
that explain in a conclusive way the high activity of
chiral phosphite-oxazoline ligands compared with
their analogues phosphine-N ligands.[12] In contrast to
other C–C bond forming reaction such as Pd TsujiTrost reactions, most of the mechanistic studies in
Heck reaction have focused on achiral systems.[13] In
this respect, efficient and accurate kinetic studies have
been reported that include the entire catalytic system.
However, no kinetic studies have been carried out for
the asymmetric version and the few mechanistic
studies for specific chiral ligands are mainly
computational.[4o,5g,14] Spectroscopic studies by NMR
and kinetic studies are hampered by the high reactivity
and multifaceted aggregation behaviour of the Pdprecursor that gives unreactive Pd black. The
experimental protocol to prevent the formation of Pd
black under reaction conditions must still be
developed.
To address these points, we report the application of
a reduced but structurally valuable library of readily
accessible phosphite-oxazoline ligands L1-L5a-e
(Figure 2). These were obtained by replacing the
phosphino group R2P- in phosphine-oxazoline ligand
5[4o] by biaryl phosphite moieties (RO)2PO- thus
increasing robustness and modularity and allowing a
better control of the flexibility of the chiral pocket.[15]
In addition, these ligands are solids and stable to air
and other oxidizing agents. In a simple two or four
step-procedure, which starts from commercially
available materials, (Scheme 2) several ligand
parameters can be easily tuned to maximize the
catalyst performance. With this ligand library we
systematically investigated the effect of changing the
oxazoline substituents (Ph, iPr and tBu) and their

2

configuration, the substituents in the benzylic position
(ligands L1-L3a-e with hydrogens and ligands L4a-e
with methyl groups) and the substituents and
configuration of the biaryl phosphite moiety (a-e).
Interestingly, we found that the range of substrates and
aryl and alkyl triflates that can be successfully coupled
was larger than that for the previous phosphineoxazoline 5 counterparts, which have emerged as some
of the most successful catalysts designed for this
process. In addition, the phosphite-oxazoline ligands
that provided the best selectivities contained the iPr
substituent in the oxazoline moiety instead of the
costly tBu derivative found in the related phosphineoxazoline 5. Finally, in this paper we have also carried
out kinetics studies and a Hammett plot analysis to
determine the rate determining step. For this purpose
we have successfully developed experimental
conditions that disfavour the formation of Pd black
from Pd-intermediate species during the kinetic
experiments.

readily available starting materials.[15] Therefore,
coupling of hydroxyl-cyanide 8 with the appropriate
amino alcohol yielded the hydroxyl-oxazolines 9-12
with diverse oxazoline substituents (Scheme 2, step
i).[16] Then, compounds 9-12 readily react with the
corresponding phosphorochloridites (ClP(OR)2 (OR)2
= a-e) to yield the desired phosphite-oxazoline ligands
L1-L3a-e and L5a. For the synthesis of new
phosphite-oxazoline ligands L4, which differs from
L1-L3 in the presence of methyl groups on the
benzylic position, the commercially available 2(3H)benzofuranone 13 was converted into the
corresponding benzofuranone 14 by treatment with
methyl iodide and sodium hydride (step ii).[17]
Subsequent reaction of 14 with 3-amino-3phenylpropan-1-ol (amino alcohol) followed by
cyclization with p-TsCl afforded the desired hydroxyloxazoline 15 (steps iii and iv). Finally, condensation
of the desired in situ formed phosphorochloridites
(ClP(OR)2 (OR)2 = a-c) with hydroxyl-oxazoline 15
yielded phosphite-oxazoline ligands L4a-c, with
different biaryl phosphite groups.
All ligands were isolated as white solids in good-tohigh yields. As mentioned earlier, they can be
manipulated and stored in air. Ligands were
characterized by 31P{1H}, 1H and 13C{1H} NMR
spectra and mass spectrometry. All data were in
agreement with assigned structures (see experimental
and supporting information sections for details). The
1
H, 13C, and 31P NMR spectra showed the expected
pattern for these C1-ligands. The VT-NMR spectra in
CD2Cl2 (+35 to -85 °C) for ligands L1-L4a showed
only one isomer in solution.
Asymmetric Heck reaction of 2,3-dihydrofuran (S1)

Figure 2. Phosphite-oxazoline ligand library L1-L5a-e.

Results and Discussion
Synthesis of ligands

The sequence of the ligand synthesis is illustrated in
Scheme 2. Phosphite-oxazoline ligands L1-L3a-e and
L5c were synthesized very efficiently in a two-step
procedure as previously reported by our group from

We first applied the ligands L1-L5a-e to the Pdcatalyzed phenylation of 2,3-dihydrofuran S1. For
comparison, ligands were evaluated using the optimal
reaction conditions reported in our previous studies
with other phosphite-oxazoline ligands.[11] Reactions
were thus performed in tetrahydrofuran, at 50 °C,
using 2.5 mol% of in-situ generated catalyst, by
mixing the [Pd2(dba)3].C6H6[18] with the corresponding
chiral ligand, and iPr2NEt as base. The results are
collected in Table 1. The catalytic performance was

Scheme 2. Synthetic route for the synthesis of phosphite-oxazoline ligands L1-L5a-e. (i) amino alcohol, ZnCl2, C6H5Cl,
reflux, 16 h (yields 68-78%);[16] (ii) NaH, MeI, THF, -78 °C to rt (43% yield);[17] (iii) Aminoalcohol, NaH, MeOH, THF, 0
°C to rt, 4 h, (75% yield). (iv) p-TsCl, NEt3, DMAP, CH2Cl2, 0 °C to rt, overnight (89% yield). (v) ClP(OR)2 ((OR)2 = a-e),
Py, toluene at rt for 18 h (40-78% yields).

3

found to depend on the ligand structure, i.e., the
substituents on the oxazoline ring and on the benzylic
position and the substituents/configuration of the
biaryl phosphite moiety.
Table 1. Pd-catalyzed enantioselective phenylation of 2,3dihydrofuran S1 using ligands L1-L5a-e.a

Entry
Ligand
%Conv (1:2)b
%ee 1c
1
L1a
94 (98:2)
67 (R)
2
L1b
50 (52:48)
81 (R)
3
L1c
92 (99:1)
75 (R)
4
L2a
100 (97:3)d
90 (R)
5
L2b
42 (58:42)
47 (S)
6
L2c
97 (96:4)
71(R)
7
L2d
99 (98:2)e
92 (R)
8
L2e
88 (97:3)f
92 (R)
9
L3a
20 (44:56)
85 (R)
10
L3b
47 (43:54)
10 (S)
11
L3c
85 (96:4)
81 (R)
12
L4a
48 (20:80)
4 (R)
13
L4b
5( 45:55)
15 (R)
14
L4c
13 (43:57)
20 (R)
15
L5a
100 (96:4)g
90 (S)
16h
L2a
6 (89:11)
78 (R)
17i
L2a
100 (97:3)
85 (R)
18j
L2a
64 (87:13)
71 (R)
a
[Pd2(dba)3].benzene (1.25·10-2 mmol), S1 (2.0 mmol),
phenyl triflate (0.5 mmol), ligand (2.8·10-2 mmol), THF (3
ml), iPr2NEt (1 mmol), 50 °C, 24 h. b Conversion
percentages determined by GC. c Enantiomeric excesses
measured by GC. d 89% isolated yield. e 86% isolated yield.
f
71% isolated yield. g 87% isolated yield. h Reaction carried
out at 23 °C. i Reaction carried out at 70 °C. j Reaction
carried out in benzene.

The reactions that proceeded with the highest
activities, regio- and enantioselectivities (e.g. entries
4-6 vs 1-3 and 9-11) all have ligands containing the iPr
oxazoline group (ligands L2). This contrasts with the
oxazoline-substituent effect observed in the vast
majority of successful phosphine-oxazoline ligands
(such as the tBuPHOX 3 and the Gilberston phosphineoxazoline ligand based on ketopinic acid 4; see Figure
1) the enantioselectivities of which are higher when
tert-butyl groups are present. Interestingly, by
comparing the results with those from the analogous
Pd-phosphine-oxazoline systems 5[4o] (Figure 1, R=H)
it was found that the simple substitution of the
phosphine by biaryl phosphite groups is advantageous
since the ligands that provided the best selectivities
contained the iPr substituent in the oxazoline moiety
instead of the costly tBu derivative. As expected, the
sense of enantioselectivity is governed by the absolute
configuration of the oxazoline substituent (entry 4
ligand L2a vs entry 15 ligand L5a). Both enantiomers
of the phenylation product 1 can therefore be accessed
by simply changing the absolute configuration of the
oxazoline group.

The introduction of methyl groups at the benzylic
position had a negative effect on both activity and
selectivity (Table 1, entries 12-14 vs 1-3). This
contrasts with the results reported for related
phosphine-oxazoline 5[4o] where the introduction of
Me substituents at the benzylic position provided the
reverse enantiomer although with somewhat lower
enantioselectivity (from 93 % (R) with a H substituent
to 81 % (S) with a Me substituent) and regioselectivity.
Finally, concerning the effect of the biaryl phosphite
group, we found that its configuration affected activity
and selectivity. In general, ligands with an Sconfiguration of the biaryl phosphite moiety provided
higher conversion, regio- and enantioselectivities than
ligands with an R-configuration (Table 1, entries 6-8
vs 5) although ligand L2a with the aquiral biaryl
phosphite group also provided high activities and
selectivities (Table 1, entry 4). This ligand maintains
the economic benefits of using an iPr oxazoline
substituent and has the added advantage that an achiral
inexpensive biaryl phosphite moiety a is used. By
comparing the results of L2a with those of the related
enantiopure biaryl ligands L2b and L2c, (entry 4 vs 5
and 6), it can be concluded that the tropoisomeric
biphenyl moiety in L2a adopts an S-configuration. The
results also show that the substituent of the biaryl
phosphite moiety has an important effect on selectivity
since ligands L2d-e provided higher selectivity than
L2c (entries 7-8 vs 6).
In an attempt to prove that the tropoisomerism of the
achiral biphenyl phosphite can be controlled by the
ligand backbone upon coordination to Pd and also to
rationalize the lower enantioselectivities with ligands
L2b and L2c than those obtained with ligands L2a,de, we investigated the coordination ability of ligands
L2a-c,e. For that purpose, the corresponding
[Pd(I)(Ph)(L)] (L=L2a-c,e) neutral complexes 16-19
were prepared. These complexes were prepared by
reaction of [Pd(I)(Ph)(TMEDA)] (TMEDA=
N,N,N,N-tetramethylethlendiamine)
with
one
equivalent of the corresponding ligands (Scheme 3).

Scheme 3. Preparation of [Pd(I)(Ph)(L)] (L=L2a-c,e)
neutral complexes. The ratio of each isomer measured by
31
P-NMR spectroscopy is also shown.

For complex 16, containing tropoisomeric ligand
L2a, only one isomer was detected by VT-NMR (30
ºC to –80 ºC) which has been assigned to the cis isomer
(Scheme 3). In contrast, for complexes containing
ligands L2b and L2c (compounds 17 and 18) the two
isomers cis and trans were observed (Scheme 3). The
minor isomer of [Pd(I)(Ph)(L2b)] and the major
isomer of [Pd(I)(Ph)(L2c)] were assigned to the cis

4

isomers. Finally, coordination of ligand L2e, led to the
formation of cis-[Pd(I)(Ph)(L2e)] (19) exclusively, as
in the case of tropoisomerically labile ligand L2a. All
these results, therefore, support the conclusion that the
flexible biphenyl phosphite moiety in ligand L2a
adopts an S-configuration upon coordination to Pd. In
addition, the presence of a mixture of isomers upon
coordination of ligands L2b and L2c (with
trimethylsilyl groups at the ortho positions of the
binaphthyl phosphite moiety), may explain the lower
enantioselectivities achieved using Pd/L2b-c, in the
phenylation of S1, than those with ligands L2a,d-e
(containing tert-butyl groups, see Table 1, entries 4, 7
and 8 vs 5 and 6).
All complexes were characterized by 1H, 13C and 31P
NMR spectroscopy and HR-mass spectrometry. The
spectral assignments were confirmed using 1H-1H, 31P1
H, 13C-1H, 1H-1H NOESY and 31P DOSY
experiments. Therefore, the 31P DOSY spectra for both
isomers of complexes with ligands L2b and L2c, show
the same diffusion coefficients. Both isomers also
show the same HR-mass spectra. All this agrees with
the presence of the two possible isomers, cis and trans.
The cis disposition of complexes with ligands L2a,
L2d and the minor isomer of [Ph(I)(Ph)(L2b)] and
major isomer of [Pd(I)(Ph)(L2c)] has been clearly
established by the small carbon-phosphorus coupling
constant observed for the Cipso of the phenyl ligand (JCP < 20 Hz). For the trans isomers the NOESY shows
NOE interactions between the isopropyl substituent of
the oxazoline group and some of the aromatic protons
of the phenyl ligand.
In summary, the highest regio- (up to 98%) and
enantioselectivities (up to 92%) were achieved with
phosphite-oxazoline ligands L2a,d-e and L5a. We
next studied the effect of the temperature with one of
the best ligands (entries 16, 17). Lowering the
temperature to 23 ºC has a negative effect on both
selectivity and activity (only 6% of conversion after
two days). High temperature (70 ºC) has also a
negative effect on enantioselectivity whereas the good
selectivity in favour of compound 1 is maintained.
Finally, we studied the effect of changing the solvent
to benzene. Most of the successful ligands reported in
the literature gave better catalytic performance using
benzene instead of THF.[3] This was not the case;
activities and selectivities were lower in benzene
(entry 18).

affected by the steric and electronic properties of the
aryl groups. Therefore, a variety of triflates with
different electronic and steric properties (1- and 2naphthyl, p-CH3-C6H4, p-NO2-C6H4, p-OMe-C6H4 and
o-OMe-C6H4) reacted with S1 in regio- and
enantioselectivities as high as or higher than those
obtained with phenyl triflate. Even the sterically
demanding 1-naphthyl and o-methoxyphenyl triflates
were cross-coupled efficiently (products 1f and 1g).
Finally, it is also worth mentioning that the addition of
cyclohexenyl triflate that usually reacted with less
regio- and enantioselectively than the coupling of
phenyl triflate proceeded with comparable high regioand enantioselectivity. All these results are among the
best that have been reported in the literature[1c,n] and
surpass the range of aryl and alkyl triflates that could
be coupled with the phosphine-oxazoline analogues
5[4o].

Other aryl and alkyl triflates. We next studied other
aryl and alkyl triflates. The results follow the same
trend, in terms of the effect of the ligand parameters,
as the phenylation of S1. Again, the best results were
obtained with L2a,d,e and L5a. As an example,
Scheme 4 shows the results using ligand L2d which
had provided one of the best results in the phenylation
of S1 (the full results are shown in the Supporting
Information). Both enantiomers of the coupling
products 1a-h were accessible with high activity,
regio- (up to 99%) and enantioselectivity (up to 98%).
Improving results reported in the literature, it was
found that the catalytic performance was hardly

The potential of L1-L5a-e ligands was further studied
by using them in the Pd-catalyzed Heck reaction of
other challenging substrates. Initially the arylation of
4,7-dihydro-1,3-dioxepin S2 with phenyl- and p-tolyl
triflates was studied (Scheme 5a). The enol ethers 20
resulting from these substrate are easily converted into
chiral β-aryl-γ-butyrolactones, which are useful
synthetic intermediates.[19] Despite its relevance,
successful examples in literature are scarce and most
of them require long reaction times for full
conversion.[20] The results are summarized in Scheme
5a and followed the same trends as for the arylation of
S1. Again, catalysts Pd/L2a,d-e and Pd/L5a provided

Scheme 4. Asymmetric Heck reaction of 2,3-dihydrofuran
S1.
Asymmetric Heck reaction of other substrates

5

both enantiomers of the arylation products 20a and
20b in high enantioselectivities (up to 95%)
comparable to the best reported so far (see Supporting
Information for complete set of results).
Dihydropyrroles are another important set of
substrates which are widely present in biological
compounds
and
have
versatile
synthetic
applications.[21] Therefore, the asymmetric Heck
reaction of N-Boc-2,3-dihydropyrrole S3 with phenyl
and p-tolyl triflates was investigated (Scheme 5b). So
far, only a few examples have been reported.[1] Again,
ligands L2a,d,e and L5a that contain the iPr
substituent in the oxazoline moiety (see the complete
results in the Supporting Information) provided the
best results with activities, regio- (up to 98%) and
enantioselectivities (up to 94%) comparable to the best
ones reported in the literature.[1]

Scheme 6. Asymmetric Heck reaction of cyclopentene S4.
(i) 2.5 mol% [Pd2(dba)3]·C6H6, 5.6 mol% L2d, iPr2NEt (2
equiv), THF, 50 °C, 48 h.

In summary, the replacement of the phosphine by a
phosphite group in the phosphine-oxazoline ligands 5
provided air stable ligands which in addition extended
the range of substrates and aryl and alkyl triflates that
could be successfully coupled with regio-,
enantioselectivities and activities that were among the
few best reported so far.[1] In addition, the ligands that
provided the best enantioselectivities contained the iPr
substituent in the oxazoline moiety instead of the tBu
substituent leading to a cost reduction.
Asymmetric Heck reaction of 2,3-dihydrofuran with aryl halides

Scheme 5. Asymmetric Heck reaction of (a) 4,7-dihydro1,3-dioxepin S2 and (b) N-Boc-2,3-dihydropyrrole S3.

Finally the attention was turned to the asymmetric
alkenylation of cyclopentene S4 (Scheme 6). Due to
extensive double-bond displacement, the selectivity is
more difficult to control in this substrate than in
functionalized alkenes, such as S1 and S3.[1] Most of
the catalysts fail to control the regioselectivivity and,
in addition to the desired product 23, the
corresponding achiral regioisomers 24 and 25 can be
obtained.[1] Catalytic systems Pd/L2a,d-e and Pd/L5a
turned out to be efficient in the alkenylation of S4
using four aryl triflates with different electronic and
steric proprieties (Scheme 5 and Supporting
Information for full set of results). In all cases high
activities, regio- and enantioselectivities in both
enantiomers of the arylation products 23a-d were
achieved without the formation of the undesired
achiral product 25.

Carbon electrophiles in the asymmetric intermolecular
Heck reaction have been mostly restricted to aryl or
vinyl triflates. To date, only a few successful examples
using aryldiazonium salts,[5h,22] arylboronic acids[23]
and benzylic electrophiles[24] and one using aryl
halides[8d] have been reported. With aryl halides, mixed
phosphine-phosphine oxide ligands were found to be
the best choice whilst BINAP and tBu-PHOX provided
very low activities (< 10%) and BINAP also extremely
low enantioselectivity (<5% ee).[8d] The success of this
transformation also required the addition of 1 equiv. of
additive (mainly p-NO2PhCO2H although silver salts
such as AgOTf were also used) and ethylene glycol or
methanol as solvents (the more common toluene, ether
and 1,4 dioxane led to poor results). In addition, most
of the electrophiles were aryl bromides and only a few
were ArCl. Aryl iodides gave not only lower
enantioselectivity but also a shift to the preferential
formation of regiosomer 2 (i.e., the phenylation of S1
afforded 1 and 2 at a 1:2 ratio).[8d] Under these reaction
conditions, we tested whether ligands L1-L5a-e could
do the desired coupling (Scheme 7). The reaction of S1
with phenyl bromide provided the desired regioisomer
1 as a major product in high enantioselectivity (87%
ee), albeit with low conversion. The use of phenyl
iodide led to similar levels of enantioselectivities
although the formation of isomer 2 is favored.

6

Scheme 7. Asymmetric Heck reaction of S1 with aryl
halides. (i) 2.5 mol% [Pd2(dba)3]·C6H6, 3 mol% L2a,
i
Pr2NEt (3 equiv), AgOTf (1.5 equiv), ethylene glycol, 80
°C, 24 h.
Kinetic studies and Hammett plot analysis

There are no mechanistic studies that give a conclusive
reason why the chiral phosphite-oxazoline ligands
give a higher activity than most of the phosphineoxazolines.[11] Old studies (<2000) on achiral systems
mostly containing an excess of PPh3 or dba reported
evidence for the oxidative addition as the rate-limiting
step in this chemistry, which in the present case would
have led to a faster reaction of the phosphine
analogues.[25] Since then kinetic studies using achiral
monophosphite ligands[13a,e] and studies using
metallocyclic phosphine and imine precursors[13b,c]
showed that the rate determining step in those systems
is the alkene coordination or the migratory insertion of
the alkene, the migratory insertion being the most
plausible choice as tentatively suggested by further
electronic alkene effects.[13a,e]
We decided to perform a brief kinetic study under
practical conditions to determine the rate determining
step in the reactions of the Pd/phosphite-oxazoline
catalysts reported in this manuscript. To achieve this
goal first a viable catalyst precursor was synthesized
and new reactions conditions were developed to
prevent the formation of Pd black. Scheme 8 presents
the generally accepted mechanism for the Heck
coupling reaction that served as the basis for the
kinetic study (all steps shown as reversible). The
catalytic cycle is initiated by the oxidative addition of
phenyl triflate to the Pd(0)-PN* complex resulting in
the four coordinate aryl-Pd(II) complex which then
reacts with the olefin to form the p-complex. Insertion
of the olefin into the Pd-Ph bond leads to a Pd-alkyl
species which undergoes b-hydride elimination,
followed by dissociation to the product and a Pdhydride complex. The catalytic cycle is completed by
base-assisted reductive elimination of HOTf
regenerating the catalytically active Pd(0)complex.

Scheme 8. Accepted mechanism for the asymmetric Pdcatalyzed Heck reaction of S1.

[Pd(Ph)(OTf)(L2a)] 26 was used as a viable catalyst
precursor for the kinetic study. The use of
Pd2(dba)3/L2a or its [Pd(dba)(L2a)] analogues was
discarded because the active species form too slowly
under the employed conditions.[26] Complex 26 was
synthesized from the corresponding compound
[Pd(I)(Ph) L2a)] (16) by iodine abstraction with
AgOTf (Scheme 9). Complex 26 was characterized by
31
P, 1H and 13C NMR spectroscopy. The VT-NMR
experiments (–78 to 30 °C) indicated the formation of
a single stereoisomer. This is in agreement with the
atropoisomerism of the biphenyl phosphite moiety
being controlled by the ligand backbone upon
coordination to the Pd-centre observed in Table 1 (vide
supra).[27] The NMR data also indicated that, as
previously observed for other P,N-containing
complexes, the phenyl ligand is located cis to the
phosphite moiety.[5a] To prove the viability of 26 as a
catalyst precursor, we first performed the
stoichiometric reaction by adding 2 equivalents of S1
and an excess of base. The regio- and
enantioselectivity achieved were similar to those
achieved using the catalytic conditions (95%
regioselectivity and 88% ee), which clearly indicated
that [Pd(Ph)(OTf)(L2a)] is a viable intermediate.

Scheme 9. Preparation of [Pd(Ph)(OTf)(L2a)] (26). (i)
AgOTf, THF (90% yield).

Prior to the kinetic studies we performed a control
experiment to study the stability of compound 26
under catalytic conditions monitoring the reaction
during 24 h. Unfortunately, deactivation of the
molecular system was observed after 10–15 minutes,
due to the formation of an inactive black precipitate.

7

This contrasts with the stability observed in the
catalytic runs using [Pd2(dba)3]/L1–L5a–e catalytic
precursors (see vide supra) and this suggests that the
presence of dba (although it does not participate in the
catalytic cycle) and/or the excess of ligand are
necessary to stabilize the molecular Pd(0) species thus
preventing the formation of the inactive Pd precipitate.
It was found that the addition of 12 mol% of excess of
ligand prevents the deactivation of the molecular
system. Thus, the precipitation of Pd was not observed
during the first 12 hours.
With the appropriate reaction conditions in hand the
kinetic studies were performed using a simple
approach[28], in which the concentration of each of the
reagents involved was varied and the reaction rate
measured after 1 h (TOFini).[29] Rates were plotted
versus the concentrations (Figure 3). The rate of the
reaction between S1 and phenyl triflate catalyzed by
Pd-complex 26 was independent of the concentration
of N,N-diisopropylethylamine (0.16–2.7 M; Figure
3a) and phenyl triflate (0.16–2 M; Figure 3b). The zero
order dependence in phenyl triflate agrees with a rapid
oxidative addition. The independence of the reaction
rate
on
the
concentration
of
N,Ndiisopropylethylamine agrees with the fact that the
elimination/reduction steps, that are base-assisted, are
also fast. The effect of the Pd loading (2–16 mM) on
the activity (Figure 3c) indicates a first orderdependency, because the rate of product formation is
proportional to the Pd concentration. This is in contrast
with the involvement of dimeric species reported for
monodentate ligands (including phosphites).[13a-e]

Finally, the kinetic study shows a linear dependence of
the initial turn-over frequency (TOFini) on alkene
concentration (Figure 3d). The first-order rate
dependence on the alkene concentration clearly shows
that the substrate is involved in the turn-over limiting
step, either directly or in a pre-equilibrium. According
to Scheme 8 this implies that either the alkene
coordination to Pd or the subsequent insertion into the
Pd–Ph bond must be the turn-over limiting step. These
two steps cannot be distinguished from the kinetic
results described so far. To analyse this in more detail,
we next determined the initial reaction rates with
several para-substituted phenyl triflates (p-RC6H4OTf; R= OMe, Me, H, NO2) using Pd-complex
26 under the same reaction conditions. The Hammett
plot (Figure 4) shows a linear correlation between the
Hammett s value and the relative reaction rates,[30]
with a negative r value (r = –0.89). Thus, the use of
electron-withdrawing aryl triflates led to lower
reaction rates, exhibiting the order p-NO2<p-H<pMe<p-OMe. Both rate and equilibrium constant of the
alkene coordination are only slightly affected by the
electron donicity of the aryl group as it is in a cis
position; besides the reverse order would have been
expected. Thus the Hammett plot is not in line with a
rate-limiting alkene coordination step. Migration of
the aryl group, however, is known to be enhanced by
increasing electron density on the migrating group,[31]
which is in agreement with the observed Hammett
relation. Thus, we conclude that the migratory
insertion is the rate-limiting step.

Figure 3. Kinetic measurements. Plots of TOFini versus (a) [NiPr2Et], (b) [PhOTf], (c) [Pd] and (d) [S1] for the reaction of
S1 with PhOTf in THF at 50 °C catalyzed by complex [Pd(Ph)(OTf)(L2a)]. TOFini measured after 1 h (conversions typically
of 5-10%).

8

Conclusion

Figure 4. Hammet plot showing the effect of substituents
on the Heck reaction using catalytic system Pd/L2a.

We return to the question why phosphite-oxazolines
give faster catalysts than phosphine-oxazolines.
Assuming that in the two related ligand groups the
mechanism remains the same, the electronwithdrawing phosphites will raise the alkene-Pd
adduct concentration (27a in Scheme 10 and species
4-o´clock in Scheme 8) and thus this will increase the
rate of reaction, other things being equal. However,
migratory insertion in palladium complexes
containing non-symmetric bidentates is a complicated
process.[32] As shown in Scheme 10 a slow migratory
insertion may take place in the alkene adduct 27a
(Schemes 8 and 10) or this intermediate may first
isomerize to the more reactive isomer 27b, as found
before for a small number of examples[33]. In the
absence of more data we refrain from speculations on
these details and propose that the higher rate for
phosphite catalysts is caused by the higher population
of alkene adducts 27a–b as stated above and
depictured in Scheme 10.

A new series of robust phosphite-oxazoline ligands has
been successfully applied in the Pd-catalyzed
enantioselective intermolecular Heck reaction. These
ligands are based on one of the most successful
phosphine-oxazoline ligand family 5 for this process,
in which the phosphine moiety has been replaced by
several biaryl phosphite groups. With these simple
modifications, the phosphite-based ligands not only
present, unlike 5, a modular design with numerous
potential phosphite groups available, but they are also
air-stable solids made in the same number of synthetic
steps as the phosphine analogs. With a careful
selection of the ligand components, (oxazoline
substituent and its configuration, the substituents in the
benzylic position and the substituents and
configurations of the biaryl phosphite moiety) the new
ligands were superior to the privileged phosphineoxazolines 5, extending the range of substrates and
triflates sources than can be coupled with high regio-,
enantioselectivities and activities. In addition, the
phosphite-oxazoline ligands that provided the best
selectivities contained the iPr substituent in the
oxazoline moiety instead of the expensive tBu
substituent found in the related phosphine-oxazoline 5.
Interestingly, ligand L2a with the achiral biphenyl
phosphite group provided activities and selectivities as
high as those achieved using ligands containing chiral
biaryl phosphite moieties. Studies of the coordination
chemistry of the Pd-aryl intermediates have shown that
the chirality of the oxazoline ligand backbone is able
to control the tropoisomerism of the achiral biphenyl
phosphite moiety in L2a, thus making the use of chiral
phosphites superfluous. Preliminary kinetic studies in
a practical regime indicated that migratory insertion of
the alkene is rate-limiting and that most likely the more
favourable formation of alkene adducts makes the
phosphite based catalysts more active than the
phosphine based ones.

Experimental Section
General information

All syntheses were performed with standard Schlenk
techniques under argon atmosphere. The kinetic studies
were performed using a glove box. Solvents were purified
by standard procedures. All reagents were used as
commercially available. Compounds 9-12,[16] 14,[17]
phosphochloridites,[34]
ligands
L1-L3a-e[15]
and
[Pd(Ph)(I)(TMEDA)][35] were prepared as previously
reported. 1H, 13C{1H} and 31P{1H} NMR spectra were
recorded on a Varian Gemini 400 MHz spectrometer. The
chemical shifts are referenced to tetramethylsilane (1H and
13
C) as internal standard or H3PO4 (31P) as external standard.
The 1H and 13C{1H} NMR spectral assignments were
determined by 1H-1H and 1H-13C correlation spectra.

Scheme 10. Olefin coordination and migratory insertion
pathways leading to the products.

General procedure for the preparation of phosphite-oxazoline
ligands

To a solution of in situ generated phosphochloridite (1.1
mmol) in dry toluene (6 mL), pyridine (0.16 mL, 2.0 mmol)
was added. Then, this solution was placed in a -78 ºC bath.

9

After 2 min at that temperature, a solution of the
corresponding alcohol-oxazoline (1.0 mmol) and pyridine
(0.16 mL, 2.0 mmol) in toluene (6 mL) was added drop wise
at -78 °C. 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 as white solids.

hydroxy-1-phenylethyl)-2-(2-hydroxyphenyl)-2methylpropanamide as a white solid. Yield: 1.17 g (75%).
1
H NMR (400 MHz, C6D6): δ = 1.59 (s, 3H, CH3), 1.63 (s,
3H, CH3), 3.72 (dd, 1H, CH2-O, 2JH-H = 11.4 Hz, 3JH-H = 7.2
Hz), 3.90 (dd, 1H, CH2-O, 2JH-H = 11.4 Hz, 3JH-H = 4.0 Hz),
5.11 (m, 1H, CH), 6.12 (d, 1H, NH, 3JH-H = 7.6 Hz), 6.92
(m, 2H, CH=), 7.18 (m, 3H, CH=), 7.29 (m, 4H, CH=). 13C
(100.6 MHz, C6D6): δ= 25.2 (CH3), 25.9 (CH3), 45.3 (C,
CMe2), 55.6 (CH-N), 66.05 (CH2-O), 117-155 (aromatic
carbons).

(S)-4-Phenyl-2-(2-(2-((2,4,8,10-tetra-tertbutyldibenzo[d,f][1,3,2]dioxaphosphepin-6yl)oxy)phenyl)propan-2-yl)-4,5-dihydrooxazole (L4a):
Yield: 261.5 mg (40%); 31P NMR (161.9 MHz, C6D6): δ =
137.0 ppm (s). 1H NMR (400 MHz, C6D6): δ = 1.22 (s, 9H,
CH3, tBu), 1.24 (s, 9H, CH3, tBu), 1.42 (s, 9H, CH3, tBu),
1.45 (s, 9H, CH3, tBu), 1.78 (s, 3H, CH3), 1.80 (s, 3H, CH3),
3.71 (m, 1H, CH2-O), 3.98 (dd, 1H, CH2-O, 2JH-H = 10.0 Hz,
3
JH-H = 7.6 Hz), 4.92 (dd, 1H, CH-N, 3JH-H = 9.6 Hz, 3JH-H =
7.6 Hz), 6.83 (m, 1H, CH=), 6.90 (m, 1H, CH=), 7.01 (m,
2H, CH=), 7.09 (m, 3H, CH=), 7.21 (s, 1H, CH=), 7.23 (s,
1H, CH=), 7.03 (d, 1H, 3JH-H = 2.0 Hz), 7.35 (d, 1H, 3JH-H =
2.4 Hz), 7.54 (m, 2H, CH=). 13C (100.6 MHz, C6D6): δ=
27.0 (CH3), 27.9 (CH3), 30.9 (CH3, tBu), 31.2 (CH3, tBu),
34.3 (C, tBu), 35.3 (C, tBu), 35.4 (C, tBu), 39.7 (C, CMe2),
69.6 (CH-N), 74.5 (CH2-O), 120.6-150.3 (aromatic
carbons), 173.1 (C=N).

To a cold (0 °C) solution of (S)-N-(2-hydroxy-1phenylethyl)-2-(2-hydroxyphenyl)-2-methylpropanamide
(1.25 g, 4.18 mmol) in CH2Cl2 (10 mL) was sequentially
added triethylamine (2.91 mL, 20.88 mmol), DMAP (76
mg, 0.63 mmol) and methanesulfonyl chloride (0.36 mL,
4.59 mmol). The resultant mixture was warmed to room
temperature and stirred overnight. The excess
methanesulfonyl chloride was hydrolyzed by adding water
(10 mL) and heating to reflux for 30 min. Another portion
of water (25 mL) was added, and the mixture was extracted
with CH2Cl2 (3 x 25 mL). The combined organic phases
were washed with saturated NaCl solution and dried over
Na2SO4. After filtration and removal of the solvent under
vacuum, the product was purified by flash chromatography,
5 % methanol in dichloromethane. Yield: 705 mg (60%). 1H
NMR (400 MHz, C6D6): δ = 1.69 (b, 6H, CH3), 4.08 (b, 1H,
CH2), 4.63 (b, 1H, CH), 4.5.17 (b, 1H, CH2), 6.8-7.4 (m, 9H,
CH=). MS HR-ESI [found 281.1416, C18H19NO2 requires
281.1417].

(4S)-2-(2-(2-(((11bR)-2,6Bis(trimethylsilyl)dinaphtho[2,1-d:1',2'f][1,3,2]dioxaphosphepin-4-yl)oxy)phenyl)propan-2-yl)4-phenyl-4,5-dihydrooxazole (L4b). Yield: 261.5 mg
(40%); 31P NMR (161.9 MHz, C6D6): δ = 142.1 ppm (s). 1H
NMR (400 MHz, C6D6): δ = 0.37 (s, 9H, CH3-Si), 0.41 (s,
9H, CH3-Si), 1.61 (s, 3H, CH3), 1.67 (s, 3H, CH3), 3.51 (t,
1H, CH2-O, 3JH-H = 2JH-H = 10.0 Hz), 3.86 (dd, 1H, CH2-O,
2
JH-H = 10.0 Hz, 3JH-H = 8.0 Hz), 4.60 (dd, 1H, CH-N, 3JH-H
= 10.0 Hz, 3JH-H = 8.0 Hz), 6.79 (m, 4H, CH=), 6.96 (m, 2H,
CH=), 7.07 (m, 4H, CH=), 7.24 (m, 4H, CH=), 7.65 (m, 3H,
CH=), 8.07 (s, 1H, CH=), 8.14 (s, 1H, CH=). 13C (100.6
MHz, C6D6): δ= -0.2 (d, CH3-Si, JC-P= 4.5 Hz), 0.0 (CH3Si), 27.0 (CH3), 27.9 (CH3), 40.0 (C, CMe2), 69.0 (CH-N),
74.1 (CH2-O), 119.6-152.4 (aromatic carbons), 172.8
(C=N).

General procedure for the synthesis of [Pd(I)(Ph)(L)]
complexes 16-19

A solution of [Ph(I)(Ph)(TMEDA)] (25 mg, 0.058 mmol)
and the corresponding ligand (0.058 mmol) in dry degassed
benzene (3 ml) was stirred under Ar atmosphere at r.t. for
48 h. The reaction was monitored by 31P{1H} NMR during
this time. The organic solvent was removed under reduced
pressure. Purification by column chromatography (neutral
Al2O3; toluene/CH2Cl2 gradient 1:0 to 0:1) yielded the
desired products as pale-yellow solids.

Synthesis of (S)-2-(2-(4-phenyl-4,5-dihydrooxazol-2-yl)propan2-yl)phenol (15)

(Iodo)[(S)-4-isopropyl-2-(2-((2,4,8,10-tetra-tertbutyldibenzo[d,f][1,3,2]dioxaphosphepin-6yl)oxy)benzyl)-4,5-dihydrooxazole](phenyl)palladium
[Pd(I)(Ph)(L2a)] (16). Yield: 37 mg (66 %). MS HR-ESI
[found 840.3371, C47H61NO4PPd+ requires 840.3368].31P
NMR (162 MHz, CD2Cl2) δ 96.7. 1H NMR (400 MHz,
C6D6), δ: 7.56 (d, 2H, J = 2.3 Hz, CH=), 7.46 (d, 1H, J =
2.3 Hz, CH=), 7.13 (d, 1H, 3JH-H = 7.5 Hz, CH=), 7.02 (d,
1H, 3JH-H = 6.9 Hz, CH=), 6.85-6.80 (m, 4H, CH=), 6.77 –
6.68 (m, 2H, CH=), 6.63 – 6.54 (m, 2H, CH=), 5.94 (d, 1H,
3
JH-H = 7.3 Hz, CH˗N), 4.67 (d, 1H, 2JH-H = 14.5 Hz, CH2),
3.72 – 3.60 (m, 2H, CH˗O), 3.10 (d, 1H, 2JH-H = 14.6 Hz,
CH2), 2.94 (m, 1H, CH, iPr), 1.58 (s, 18 H, CH3, tBu), 1.19
(s, 9 H, CH3, tBu), 1.13 (s, 9 H, CH3, tBu), 0.97 (d, 3H, 3JHi
3
i
H = 6.8 Hz, CH3, Pr), 0.87 (d, 3H, JH-H = 6.9 Hz, CH3, Pr).
13
C NMR (100 MHz, C6D6), δ: 166.3 (C=N), 152.7 (d, Cipso,
JC-P= 15.8 Hz), 148.4 (d, C-O, JC-P= 16.1 Hz), 147.3 (d, CO, JC-P= 6.2 Hz), 148.445.6 (d, C-O, JC-P= 11.2 Hz),138.7121.3 (aromatic carbons), 72.3 (CH˗O), 69.8 (CH-N), 36.2
(CH2), 34.6 (C), 31.7 (CH3, tBu), 31.5 (CH3, tBu), 31.4
(CH3, tBu), 31.3 (CH3, tBu), 31.0 (C, iPr), 19.3 (CH3, iPr),
16.2 (CH3, iPr).

MeOH (7.21 ml, 0.29 mmol) was added to a solution of NaH
(60% in mineral oil, 244.16 mg, 6.10 mmol) in THF (5.1 ml)
at 0°C under argon and string for 1 h. The solution of 3,3dimethylbenzofuran-2(3H)-one 14 (700 mg, 5.55 mmol) in
THF (5.1 ml) was added at 0 °C. The resultant mixture was
warmed to room temperature during 1 h. A solution of (S)(+)-2-phenylglycinol (837.34 mg, 6.10 mmol) in THF (5.1
ml) was added dropwise. The mixture was stirred for 2 h.
The mixture was suspended in CH2Cl2 (30 mL) and washed
with NaOH solution (2 × 50 mL), then with 2 M HCl
solution to reach to pH = 2. After drying over MgSO4,
solvent was evaporated to obtain intermediate (S)-N-(2-

(Iodo)(phenyl)[(4S)-2-(2-(((11bR)-2,6bis(trimethylsilyl)dinaphtho[2,1-d:1',2'f][1,3,2]dioxaphosphepin-4-yl)oxy)benzyl)-4-isopropyl4,5-dihydrooxazole]palladium [Pd(I)(Ph)(L2b)] (17).
Yield: 6 mg (12%). MS HR-ESI [found 860.1959,
C45H49NO4PPdSi2+ requires 860.1967]. Major isomer: 31P
NMR (162 MHz, CD2Cl2) δ 112.3 (b, 1P). 1H NMR (400
MHz, CD2Cl2), δ: 0.62 (s, 18H, SiMe3), 0.96 (d, 6H, 3JH-H=
5.6 Hz, CH3, iPr), 2.61 (m, 1H, CH, iPr), 4.27 (m, 1H, CH2),
4.30 (m, 2H, CH2-O), 4.40 (m, 1H, CH2), 4.70 (m, 1H, CHN), 6.10 (m, 1H, CH=), 6.7-7.9 (m, 17H, CH=), 8.20 (s, 1H,
CH=). Minor isomer: 31P NMR (162 MHz, CD2Cl2) δ 104.6

(4S)-2-(2-(2-(((11bS)-2,6Bis(trimethylsilyl)dinaphtho[2,1-d:1',2'f][1,3,2]dioxaphosphepin-4-yl)oxy)phenyl)propan-2-yl)4-phenyl-4,5-dihydrooxazole (L4c). Yield: 261.5 mg
(40%); 31P NMR (161.9 MHz, C6D6): δ = 142.3 ppm (s). 1H
NMR (400 MHz, C6D6): δ = 0.38 (s, 9H, CH3-Si), 0.40 (s,
9H, CH3-Si), 1.62 (s, 3H, CH3), 1.76 (s, 3H, CH3), 3.48 (m,
1H, CH2-O), 3.68 (dd, 1H, CH2-O, 2JH-H = 10.4 Hz, 3JH-H =
8.0 Hz), 4.25 (dd, 1H, CH-N, 3JH-H = 10.0 Hz, 3JH-H = 8.0
Hz), 6.80 (m, 5H, CH=), 6.88 (m, 1H, CH=), 6.9-7.1 (m, 5H,
CH=), 7.23 (m, 4H, CH=), 7.63 (m, 1H, CH=), 7.66 (m, 1H,
CH=), 8.08 (s, 1H, CH=), 8.09 (s, 1H, CH=). 13C (100.6
MHz, C6D6): δ= -0.2 (d, CH3-Si, JC-P= 4.5 Hz), 0.0 (CH3Si), 26.8 (CH3), 28.4 (CH3), 39.7 (C, CMe2), 69.0 (CH-N),
74.4 (CH2-O), 119.9-152.3 (aromatic carbons), 172.5
(C=N).

10

(b, 1P). 1H NMR (400 MHz, CD2Cl2), δ: 0.45 (s, 18H,
SiMe3), 0.91 (d, 3H, 3JH-H= 5.6 Hz, CH3, iPr), 0.93 (d, 3H,
3
JH-H= 5.6 Hz, CH3, iPr), 2.61 (m, 1H, CH, iPr), 4.24 (m, 1H,
CH2), 4.31 (m, 2H, CH2-O), 4.40 (m, 1H, CH2), 4.73 (m,
1H, CH-N), 5.94 (m, 1H, CH=), 6.7-7.9 (m, 17H, CH=),
8.25 (s, 1H, CH=).
(Iodo)(phenyl)[(4S)-2-(2-(((11bS)-2,6bis(trimethylsilyl)dinaphtho[2,1-d:1',2'f][1,3,2]dioxaphosphepin-4-yl)oxy)benzyl)-4-isopropyl4,5-dihydrooxazole]palladium [Pd(I)(Ph)(L2c)] (18).
Yield: 36 mg (73%). MS HR-ESI [found 860.1961,
C45H49NO4PPdSi2+ requires 860.1967]. Major isomer: 31P
NMR (162 MHz, CD2Cl2) δ 101.2. 1H NMR (400 MHz,
CD2Cl2), δ: 0.62 (s, 9H, SiMe3), 0.65 (s, 9H, SiMe3), 1.02
(d, 3H, 3JH-H= 5.8 Hz, CH3, iPr), 1.10 (d, 3H, 3JH-H= 5.6 Hz,
CH3, iPr), 2.74 (m, 1H, CH, iPr), 3.57 (d, 1H, 2JH-H= 11.0 Hz,
CH2), 4.27 (m, 1H, CH2-O), 4.41 (dd, 1H, 2JH-H= 8.4 Hz, 3JH2
H= 7.2 Hz, CH2-O), 4.60 (d, 1H, JH-H= 11.0 Hz, CH2), 5.15
(m, 1H, CH-N), 5.84 (d, 1H, 3JH-H= 6.6 Hz, CH=), 5.97 (m,
1H, CH=), 6.26 (m, 1H, CH=), 6.71 (m, 2H, CH=), 6.84 (m,
1H, CH=), 7.03 (m, 1H, CH=), 7.12 (m, 3H, CH=), 7.26 (m,
1H, CH=), 7.44 (m, 3H, CH=), 7.95 (m, 3H, CH=), 8.14 (s,
1H, CH=), 8.25 (s, 1H, CH=). 13C NMR (100 MHz,
CD2Cl2), δ: 0.3 (CH3-Si), 0.46 (CH3-Si), 16.1 (CH3, iPr),
19.6 (CH3, iPr), 30.6 (CH, iPr), 34.7 (CH2), 70.0 (CH2-O),
71.9 (CH-N), 113.7-138.2 (aromatic carbons), 150.3 (d, CO, JC-P= 11 Hz), 151.5 (d, C-O, JC-P= 6.4 Hz), 151.6 (d, Cipso,
JC-P= 18.6 Hz), 151.7 (d, C-O, JC-P= 3.2 Hz), 166.5 (d, C=N,
JC-P= 3.0 Hz). Minor isomer: 31P NMR (162 MHz, CD2Cl2)
δ 110.8. 1H NMR (400 MHz, CD2Cl2), δ: 0.63 (s, 9H,
SiMe3), 0.66 (s, 9H, SiMe3), 1.02 (d, 3H, 3JH-H= 5.8 Hz, CH3,
i
Pr), 1.09 (d, 3H, 3JH-H= 5.6 Hz, CH3, iPr), 2.74 (m, 1H, CH,
i
Pr), 3.59 (d, 1H, 2JH-H= 11.0 Hz, CH2), 4.27 (m, 1H, CH2O), 4.46 (dd, 1H, 2JH-H= 8.2 Hz, 3JH-H= 7.2 Hz, CH2-O), 4.61
(d, 1H, 2JH-H= 11.4 Hz, CH2), 4.95 (m, 1H, CH-N), 5.80 (d,
1H, 3JH-H= 6.6 Hz, CH=), 6.13 (m, 1H, CH=), 6.71 (m, 2H,
CH=), 6.84 (m, 1H, CH=), 6.90 (m, 1H, CH=), 7.03 (m, 1H,
CH=), 7.12 (m, 3H, CH=), 7.26 (m, 1H, CH=), 7.44 (m, 3H,
CH=), 7.95 (m, 3H, CH=), 8.11 (s, 1H, CH=), 8.26 (s, 1H,
CH=). 13C NMR (100 MHz, CD2Cl2), δ: 0.2 (CH3-Si), 0.3
(CH3-Si), 16.1 (CH3, iPr), 19.5 (CH3, iPr), 30.7 (CH, iPr),
34.7 (CH2), 69.4 (CH-N), 69.9 (CH2-O), 113.7-138.2
(aromatic carbons), 150.4 (d, C-O, JC-P= 10 Hz), 151.4 (d,
C-O, JC-P= 6.4 Hz), 151.7 (d, C-O, JC-P= 3.0 Hz), 166.4 (d,
C=N, JC-P= 2.6 Hz).
[(4S)-2-(2-(((11aS)-4,8-di-tert-butyl-1,2,10,11tetramethyldibenzo[d,f][1,3,2]dioxaphosphepin-6yl)oxy)benzyl)-4-isopropyl-4,5dihydrooxazole](iodo)(phenyl)palladium
[Pd(I)(Ph)(L2e)] (19). Yield: 32 mg (71%). MS HR-ESI
[found 784.2739, C43H53NO4PPd+ requires 784.2742]. 31P
NMR (162 MHz, CD2Cl2) δ 91.3 (s). 1H NMR (400 MHz,
CD2Cl2), δ: 0.99 (s, 6H, CH3, iPr), 1.50 (s, 9H, CH3, tBu),
1.56 (s, 9H, CH3, tBu), 2.20 (s, 3H, CH3), 2.23 (s, 6H, CH3)
2.30 (s, 3H, CH3), 2.73 (m, 1H, CH, iPr), 3.53 (d, 1H, 2JH-H=
14.0 Hz, CH2), 4.22 (m, 1H, CH2-O), 4.34 (m, 1H, CH2-O),
4.56 (d, 1H, 2JH-H= 14.0 Hz, CH2), 5.05 (m, 1H, CH-N), 5.84
(d, 1H, 3JH-H= 7.6 Hz, CH=), 6.51 (m, 2H, CH=), 6.7-7.3 (m,
7H, CH=), 7.35 (s, 1H, CH=). 13C NMR (100 MHz,
CD2Cl2), δ: 15.6 (CH3, iPr), 15.7 (CH3, iPr), 19.1 (CH3), 19.7
(CH3), 20.0 (CH3), 30.8 (CH, iPr), 31.1 (CH3, tBu), 31.5
(CH3, tBu), 34.1 (C, tBu), 34.3 (C, tBu), 34.7 (CH2), 69.7
(CH2-O), 71.9 (CH-N), 121.0-143.7 (aromatic carbons),
145.3 (d, Cipso, JC-P= 16.4 Hz), 166.5 (C=N).
Synthesis of (iodo)[(S)-4-isopropyl-2-(2-((2,4,8,10-tetra-tertbutyldibenzo[d,f][1,3,2]dioxaphosphepin-6-yl)oxy)benzyl)-4,5dihydrooxazole](trifluoromethanesulphonate)palladium
[Pd(Ph)(OTf)(L2a)] (26)

Silver triflate (16 mg, 0.062 mmol) was added to a
vigorously stirred solution of the complex [Pd(I)(Ph)(L2a)]
(30 mg, 0.031 mmol) in dry degassed THF (4 ml) under Ar
atmosphere at r.t.. Stirring was continued for 1h, during
which period a pale grey precipitate was formed. The
reaction mixture then filtered over celite, and all volatiles

were removed under reduced pressure to yield the final
product as a pale brown solid (55 mg, 90 %). 31P NMR (162
MHz, CD2Cl2), δ: 96.99. 1H NMR (401 MHz, CD2Cl2), δ:
7.59 (d, 1H, 3JH-H = 2.3 Hz, CH=), 7.47 (d, 1H, 3JH-H = 2.1
Hz, CH=), 7.34 – 7.27 (m, 3H, CH=), 7.09 (t, 1H, 3JH-H = 7.5
Hz, CH=), 7.01 (dd, 1H, 3JH-H = 7.9, 1.3 Hz, CH=), 6.99 –
6.88 (m, 5H, CH=), 5.84 (d, 1H, 3JH-H = 8.1 Hz, CH=), 4.57
(d, 1H, 2JH-H = 14.6 Hz, CH2), 4.48 (d, 1H, 3JH-H = 8.3 Hz,
CH2˗O), 4.38 (m, 1H, CH-N), 4.29 (m, 1H, CH2˗O), 3.71 (d,
1H, 2JH-H = 14.5 Hz, CH2), 2.52 (m, 1H, CH, iPr), 1.60 (s,
9H, CH3, tBu), 1.54 (s, 9H, CH3, tBu), 1.34 (s, 9H, CH3, tBu),
1.30 (s, 9H, CH3, tBu), 1.07 (d, 3H, iPr, 3JH-H = 6.9 Hz), 1.03
(d, 3H, iPr, 3JH-H = 6.7 Hz).13C NMR (101 MHz, CD2Cl2), δ:
169.2 (C=N), 151.7˗121.3 (aromatic carbons), 70.9 (CH˗O),
69.8 (CH-N), 34.5 (CH2), 34.1 (C), 33.9 (C), 31.9 (CH3,
t
Bu), 31.6 (CH3, tBu), 31.4 (CH3, tBu), 31.0 (CH3, tBu), 30.0
(C, iPr), 19.1 (CH3, iPr), 16.4 (CH3, iPr). 19F NMR (377
MHz, CD2Cl2), δ: -78.01. MS HR-ESI [found 840.3372,
C47H61NO4PPd+ requires 840.3368].
General procedure for Pd-catalyzed enantioselective Heck
reactions with several triflates

A mixture of [Pd2(dba)3]·C6H6 (12 mg, 1.25 × 10-2 mmol)
and the corresponding chiral ligand (2.3 equiv) in dry
degassed solvent (3.0 mL) was stirred at room temperature
for 20 min. The corresponding olefin (2.0 mmol), triflate
(0.50 mmol) and N-diisopropylethylamine (1.0 mmol) were
added to the catalyst solution. The vial was sealed and
brought out and the solution was vigorously stirred at the
desired temperature. After the desired reaction time, the
reaction mixture was cooled to ambient temperature and
internal standard (undecane, 0.5 mmol) was added. The
mixture was diluted with additional diethyl ether and after
agitation, the mixture was filtered through a short silica gel
plug and analyzed by 1H-NMR or GC to determine the
conversion and regioselectivity. The crude was subjected to
flash chromatography (pentane/Et2O) to give the purified
product. Enantioselectivities were determined using chiral
HPLC or GC (see Supporting Information for details).
Pd-catalyzed enantioselective Heck reactions of 2,3dihydrofuran with aryl halides

[Pd(dba)2]·C6H6 (8.5 mg, 0.013 mmol) and ligand (0.015
mmol) in degassed ethylene glycol (1.0 mL) were stirred at
room temperature for 20 min. Aryl halide (0.50 mmol), Ndiisopropylethylamine (255 μL, 1.5 mmol, 3 equiv), silver
triflate (192.7 mg, 0.75 mmol, 1.5 equiv) and 2,3dihydrofuran (75 μL, 1.0 mmol, 2 equiv) were added to the
catalyst solution. The vial was sealed and brought out and
the mixture was vigorously stirred in an oil bath at 80 oC,
for 24h. The reaction mixture was cooled to ambient
temperature and internal standard (undecane, 0.5 mmol) was
added. The mixture was diluted with additional diethyl ether
and after agitation, the mixture was filtered through a short
silica gel plug and analyzed by 1H-NMR or GC to determine
the conversion and regioselectivity. The crude was
subjected to flash chromatography (pentane/Et2O) to give
the purified product. Enantioselectivities were determined
using chiral HPLC or GC (see Supporting Information for
details).

Acknowledgements
Financial support from the Spanish Ministry of Economy and
Competitiveness
(CTQ2016-74878-P,
CTQ2015-69136-R,
CTQ2016-81293-REDC/AEI)
and
European
Regional
Development Fund (AEI/FEDER, UE), the Catalan Government
(2014SGR670, 2014SGR827 and 2017SGR1472), ICIQ (the
Institute of Chemical Research of Catalonia) (Ph.D fellowship to
Z. M.), the CNRS (GDRI Toulousse/Catalonia-HC3A) and the
ICREA Foundation (ICREA Academia award to M.D), the
Université Fédérale Toulouse Midi-Pyrénées (IDEX Chair to
P.v.L.) is gratefully acknowledged.

11

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influences of the two donors, which for phosphiteoxazolines is smaller than the difference in phosphineoxazoline complexes. See: a) G. P. C. M. Dekker, C. J.
Elsevier, K. Vrieze, P. W. N. M. van Leeuwen, C. F.
Roobeek, J. Organomet. Chem. 1992, 430, 357–372; b)

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G. P. C. M. Dekker, A. Buijs, C. J. Elsevier, K. Vrieze,
P. W. N. M. van Leeuwen, W. J. J. Smeets, A. L. Spek,
Y. F. Wang, C. H. Stam, Organometallics 1992, 11,
1937–1948.
[33] P. W. N. M. van Leeuwen, C. F. Roobeek, H. van der
Heijden, J. Am. Chem. Soc. 1994, 116, 12117–12118.

[34] G. J. H. Buisman, P. C. J. Kamer, P. W. N. M. van
Leeuwen, Tetrahedron: Asymmetry 1993, 4, 1625–1634.
[35] J. C. Holder, L. Zou, A. N. Marziale, P. Liu, Y. Lan,
M. Gatti, K. Kikushima, K. N. Houk, B. M. Stoltz, J.
Am. Chem. Soc. 2013, 135, 14996–15007.

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FULL PAPER
Synthesis, Application and Kinetic studies of
Chiral Phosphite-Oxazoline Palladium Complexes
as Highly Active and Selective Catalysts in
Intermolecular Heck Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Zahra Mazloomi, Marc Magre, Efrem Del Valle,
Miquel A. Pericàs, Oscar Pàmies,* Piet. W. N. M.
van Leeuwen* and Montserrat Diéguez*

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