Phosphite-oxazole/imidazole ligands in asymmetric intermolecular Heck reaction

Article abstract of DOI:10.1039/c0ob00656d

We describe the application of a new class of ligands -the phosphite-oxazole/imidazole (L1-L5a-g) - in asymmetric intermolecular Pd-catalyzed Heck reactions under thermal and microwave conditions. These ligands combine the advantages of the oxazole/imidaz

Full text of DOI:10.1039/c0ob00656d

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PAPER
Phosphite-oxazole/imidazole ligands in asymmetric intermolecular Heck
reaction†
Javier Mazuela,a Paivi Tolstoy,b Oscar Pa`mies,*a Pher G. Andersson*b,c and Montserrat Die´guez*a
Received 1st September 2010, Accepted 22nd October 2010
DOI: 10.1039/c0ob00656d
We describe the application of a new class of ligands –the phosphite-oxazole/imidazole (L1–L5a–g) –
in asymmetric intermolecular Pd-catalyzed Heck reactions under thermal and microwave conditions.
These ligands combine the advantages of the oxazole/imidazole moiety with those of the phosphite
moiety: they are more stable than their oxazoline counterparts, less sensitive to air and other oxidizing
agents than phosphines and phosphinites, and easy to synthesize from readily available alcohols. The
results indicate that activities, regio- and enantioselectivities, are highly influenced by the type of
nitrogen donor group (oxazole or imidazole), the oxazole and biaryl-phosphite substituents and the
axial chirality of the biaryl moiety of the ligand. By carefully selecting the ligand components, we
achieved high activities, regio- (up to 99%) and enantioselectivities (up to 99%) using several triflate
sources. Under microwave-irradiation conditions, reaction times were considerably shorter (from 24 h
to 30 min) and regio- and enantioselectivities were still excellent.
In the last decade, a group of less electron-rich phosphorus
compounds – phosphite-containing ligands – have demonstrated
The Heck reaction is one of the most versatile catalytic methods
their huge potential utility in many transition-metal catalyzed
Introduction
reactions.5 Their highly modular construction, facile synthesis
from readily available chiral alcohols and greater resistance to ox-
idation than phosphines have proved to be highly advantageous.6
Despite all these benefits, the use of phosphite-containing ligands
for the Pd-catalyzed Heck reaction has not been reported until
very recently. In this context, phosphite-oxazolines have emerged
as extremely effective ligands for improving the activity and
versatility of this process.7 Despite this success, little attention
has been paid to phosphite-containing ligands for this process
and their potential as new ligands still needs to be systematically
studied.7
To further expand the range of ligands and encouraged by
the success of biaryl phosphite-oxazoline ligands7 in this process
we report here the first application of a biaryl phosphite-
oxazole/imidazole ligand library (L1–L5a–g) in the asym-
metric intermolecular Pd-catalyzed Heck reaction (Fig. 1).
For comparative purposes, we also evaluated phosphinite-
oxazole/imidazole analogues (ligands L6 and L7, Fig. 1).
Phosphite-oxazoline/imidazole ligands combine a priori the above
mentioned advantages of introducing a phosphite moiety with
those of the oxazole/imidazole moiety. So, ligands L1–L5a–g are
more stable than their oxazoline counterparts.8 With this library
we fully investigated the effects of either an oxazole or imidazole
group in the ligand backbone, the effect of systematically varying
the electronic and steric properties of the oxazole substituents
(L1–L4) and different substituents/configurations in the biaryl
phosphite moiety (a–g). By carefully selecting these elements,
for C–C bond formation. In this process an aryl or alkenyl halide
or triflate is coupled with an alkene.1 Its applicability to highly
functionalized substrates confers upon the reaction a very wide
substrate scope, and it has been used in a number of syntheses
of complex natural products.1 During the past decade, research
in the Heck reaction has focused on the possibility of controlling
its enantioselectivity. The bulk of the reported examples involve
intramolecular reactions, which have the advantage that the alkene
regiochemistry and product geometry can be easily controlled.1
Fewer studies, however, have been conducted on the asymmetric
intermolecular version. This is mainly because regioselectivity
is also often a problem.1 Although diphosphines (such as BI-
NAP) were used early on this process,1,2 heterodonor phosphine-
oxazolines have recently emerged as more suitable ligands for the
intermolecular Heck reaction.1a–b,3,4 Two drawbacks of these latter
ligands are the long reaction times usually required to achieve full
conversion and the substrate specificity.
aDepartament de Qu´ımica F´ısica i Inorga`nica. Universitat Rovira i Virgili,
Campus Sescelades, C/Marcel·l´ı Domingo, s/n. 43007 Tarragona, Spain.
E-mail: oscar.pamies@urv.cat, montserrat.dieguez@urv.cat
bDepartment of Biochemistry and Organic Chemistry, Uppsala University,
BOX 576, 751 23 Uppsala, Sweden. E-mail: pher.andersson@kemi.uu.se
cChemistry, University of KwaZulu-Natal (Durban), University Road,
Chiltern Hills, Westville 3629, South Africa
† Electronic supplementary information (ESI) available: Profiles of the
1
microwave experiments and H and 13C NMR of compounds L5a–c and
L7. See DOI: 10.1039/c0ob00656d
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Fig. 1 Phosphite-oxazole/imidazole ligand library L1–L5a–g and phosphinite-oxazole/imidazole ligands L6 and L7.
we achieved high selectivities (regio- and enantioselectivities) and
activities using several triflate sources.
neutral alumina under an atmosphere of argon and isolated in
moderate-to-good yields as white solids. They were stable at room
temperature and very stable to hydrolysis. The elemental analyses
were in agreement with the assigned structure. The 1H, 13C and 31
P
Results and discussion
NMR spectra were as expected for these C1 ligands. One singlet for
each compound was observed in the 31P NMR spectrum. Rapid
ring inversions (atropoisomerization) in the biphenyl-phosphorus
moieties (a–c) occurred on the NMR time scale because the
expected diastereoisomers were not detected by low-temperature
phosphorus NMR.13
Synthesis of ligands
Phosphite-oxazole ligands L1–L4a–g and phosphinite-oxazoline
ligand L6 have been synthesized from the corresponding easily
accessible ketone-oxazole as previously described.9,10 Scheme 1 il-
lustrates the sequence of synthesis for the new phosphite-imidazole
ligands L5a–c and phosphinite/imidazole ligand L7. They were
synthesized very efficiently from the easily accessible hydroxyl-
imidazole 3. This compound was prepared in a few steps from
commercially available N-methyl benzimidazole 1. In the first step
of the synthesis, 1 was acetylated via a two step one pot procedure
that involves deprotonation of 1 with LDA followed by reaction
with methyl benzoate to produce ketone 2.11 Ketone 2 was then
reduced by slow addition to a solution of (R)-Me-CBS catalyst
(10 mol%, (R)-Me-CBS = a,a-diphenyl-D-prolinolmethylboronic
acid cyclamide ester), employing BH3·SMe2 as stoichiometric
reductant in THF.12 Recrystallization from 95% ethanol of the
obtained hydroxyl-imidazole yielded enantiomerically pure 3.
Treating alcohol 3 with 1 equivalent of either the appropriate
in situ formed phosphorochloridite (ClP(OR)2; (OR)2 = a–c)
or chlorodiphenylphosphine in the presence of pyridine pro-
vided easy access to the desired phosphite-imidazole (L5a–c)
and phosphinite-imidazole (L7) ligands, respectively. All the
phosphite-imidazole ligands were stable during purification on
Asymmetric phenylation of 2,3-dihydrofuran (S1) under thermal
conditions
In a first set of experiments, we used the Pd-catalyzed phenylation
of 2,3-dihydrofuran S1 to study the potential of ligands L1–
L5a–g (eqn (1)). S1 was chosen as the substrate because the
reaction was performed with a wide range of ligands, which
enabled the efficiency of the various ligand systems to be compared
directly.1 In all cases, the catalysts were generated in situ by
mixing [Pd2(dba)3]·dba with the corresponding chiral ligand.7 The
results are summarized in Table 1. We found that the catalytic
performance was highly influenced by type of nitrogen donor
group (oxazole or imidazole), the substituents at both oxazole
and phosphite moieties and by the axial chirality of the biaryl
phosphite group. In general, high activity, regio- (up to 97%) and
enantioselectivity (up to 98%) were obtained in the phenylation
of S1.
Scheme
1
Synthesis of new phosphite/phosphinite-imidazole ligands L5a–c and L7. (a) LDA/THF then PhCOOEt (78% yield).11 (b)
(R)-Me-CBS/BH3·SMe2/THF (87% yield).12 (c) ClP(OR)2; (OR)2 = a–c/Py/toluene (Yields: 54–71%). (d) ClPPh2/Py/DMAP/THF (68% yield).
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Table 1 Selected results for the Pd-catalyzed enantioselective phenylation
of 2,3-dihydrofuran S1 using ligands L1–L5a–ga
Table 2 Selected results for Pd-catalysed enantioselective arylation of
2,3-dihydrofuran S1 using ligands L1–L5a–ga
Entry
Ligand
% Conv (4 : 5)b
% ee 4c
Entry
L
R
% Conv (4 : 5)b % Yield 4 % ee 4c
1
2
3
4
5
6
7
8
L1a
L1b
L1c
L1d
L1e
L1f
L1g
L2a
L3a
L4a
L5a
L5b
L5c
L6
77 (97 : 3)e
27 (97 : 3)
21 (94 : 6)
17 (96 : 4)
7 (92 : 8)
<5
98 (R)
97 (R)
91 (R)
96 (R)
89 (R)
ndd
1
2
3
4
5
6
7
8
L1a 4-CH3-C6H4
L1b 4-CH3-C6H4
L1c 4-CH3-C6H4
L1d 4-CH3-C6H4
L1e 4-CH3-C6H4
L4a 4-CH3-C6H4
L5a 4-CH3-C6H4
L1a 4-NO2-C6H4
L1b 4-NO2-C6H4
L1c 4-NO2-C6H4
L4a 4-NO2-C6H4
L5a 4-NO2-C6H4
L1a 1-Naphthyl
69 (92 : 8)
23 (92 : 8)
24 (90 : 10)
23 (92 : 8)
19 (89 : 11)
<5
21 (84 : 16)
99 (>99:<1)
37 (99 : 1)
31 (96 : 4)
<5
60
18
17
16
15
ndd
15
97
34
28
ndd
21
93
90
ndd
9
99 (R)
99 (R)
92 (R)
98 (R)
87 (R)
ndd
73 (R)
99 (R)
99 (R)
97 (R)
ndd
<5
ndd
74 (97 : 3)
54 (96 : 4)
<5
24 (85 : 15)
7 (83 : 17)
8 (84 : 16)
9 (81 : 19)
6 (78 : 22)
98 (R)
96 (R)
ndd
75 (R)
73 (R)
64 (R)
56 (R)
21 (R)
9
9
10
11
12
13
14f
15f
10
11
12
13
14
15
16
26 (88 : 12)
98 (95 : 5)
72 (R)
>99 (R)
69 (R)
ndd
L1a 1-Cyclohexenyl 92 (99 : 1)
L4a 1-Cyclohexenyl <5
L5a 1-Cyclohexenyl 15 (80 : 20)
L7
54 (R)
a [Pd2(dba)3]·dba (1.25 ¥ 10-2 mmol), S1 (2.0 mmol), phenyl triflate
(0.5 mmol), Ligand (2.8 ¥ 10-2 mmol), THF (3 mL), Pr2NEt (1 mmol),
a [Pd2(dba)3]·dba (2.5 ¥ 10-2 mmol), S1 (4.0 mmol), triflate (1 mmol),
i
T = 50 ◦C, t = 24 h. b Conversion percentages determined by GC.
c Enantiomeric excesses measured by GC. d Not determined. e % isolated
yield of 4. f t = 48 h.
Ligand (5.6 ¥ 10-2 mmol), THF (6 mL), Pr2NEt (2 mmol), T = 50 ◦C,
i
t = 24 h. b Conversion percentages determined by GC or 1H-NMR (see
Experimental section). c Enantiomeric excesses measured by GC or HPLC
(see Experimental section). d Not determined.
an imidazole donor group has a negative effect on activity, regio-
and enantioselectivity (Table 1, entries 11–13 vs. 1–3).
To sum up, the best activities, regio- (up to 97%) and enan-
tioselectivities (up to 98%) were obtained with ligand L1a, which
contains the optimal combination of substituents in the oxazole
and in the biaryl phosphite moiety. Interestingly, when this
latter result is compared with the enantioselectivities obtained
with their corresponding Pd-phosphinite-oxazole/imidazole (Pd-
L6/L7) catalytic systems (Table 1, entries 14 and 15), we can con-
clude that introducing a phosphite moiety into the ligand design
is advantageous. These results also clearly show the efficiency of
using highly modular scaffolds in the ligand design and are among
the best that have been reported in the literature.3a,b,e,k,l,7b,c
(1)
Regarding the effect of the oxazole substituents, we found that
these groups affected mainly activities (Table 1, entries 1 and
8–10). Bulky substituents at this position dramatically decreased
activities (Table 1, entry 1 vs. 10). This contrasts with the oxazoline-
substituent effect observed for the vast majority of successful
phosphine-oxazoline ligands, for which better results are obtained
when bulky tert-butyl groups are present.3 In addition, we also
found that the presence of electron-withdrawing substituents also
has a negative effect on activity, but almost no effect on the regio-
and enantioselectivity of the process (Table 1, entries 1, 8 and 9).
Concerning the effect of the phosphite moiety on the catalytic
performance, we found that bulky tert-butyl substituents at both
the ortho and para positions are necessary for high activity and
regio- and enantioselectivity (Table 1, entry 1 vs. 2 and 3). To
further investigate how enantioselectivity was influenced by the
axial chirality of the biaryl moiety, ligands L1d and L1e, con-
taining different enantiomerically pure trimethylsilyl-substituted
binaphthyl moieties, were also tested (Table 1, entries 4 and 5).
The results indicate that there is a cooperative effect between the
configuration of the biaryl moiety and the configuration of the
ligand backbone on enantioselectivity that results in a matched
combination for ligand L1d, which contains an S-binaphthyl
moiety (Table 1, entry 4). In addition, by comparing the results
obtained using ligand L1c with those of the related binaphthyl
ligands L1d and L1e (Table 2, entries 3–5), we can conclude that:
a) atropoisomerization in the biphenyl moiety can be controlled if
substituents at the para position are present, and b) the biphenyl
phosphite moieties in ligands L1a and L1b adopt S-configurations
upon complexation to palladium.14
Asymmetric Heck reaction of 2,3-dihydrofuran (S1) using other
triflate sources under thermal conditions
To further study the potential of these readily available ligands,
we also examined L1–L5a–g in the Pd-catalyzed Heck reaction of
S1 with several aryl triflates. Therefore the effects of the electronic
and steric properties of the aryl triflate source on the product
outcome were systematically evaluated (eqn (2), R = p-CH3-C6H4,
p-NO2-C6H4, 1-naphthyl).
(2)
The most noteworthy results are shown in Table 2 (entries 1–13).
They followed the same trends as for the phenylation of S1. Again,
the arylated products 4 were accessible in high activities, and high
regio- (up to >99%) and enantioselectivities (ee’s up to >99%)
with Pd/L1a catalytic system. The results indicate that both the
steric and electronic parameters of the triflate affected mainly
regioselectivity, whereas their effect on enantioselectivity was less
Finally, after comparing these results with those from
phosphite-imidazole ligands L5, we found that the presence of
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Table 3 Selected results for the microwave-assisted Pd-catalyzed enan-
tioselective Heck reaction of 2,3-dihydrofuran S1 using ligands L1–L5c–ga
Encouraged by these excellent results, we also studied the
cyclohexenylation of S1, which provided moderate enantiose-
lectivity under thermal conditions (Table 2, entry 12). After
the reaction parameters had been optimized, we found that the
optimal temperature was 80 ◦C. By using microwave irradiation,
enantioselectivity increased up to 89% with a regioselectivity of
92% (Table 3, entry 12).
Entry
L
R
T/◦C t/min % Conv (4 : 5)b % ee 4c
1
2
3
4
5
6
7
8
L1a C6H5
50
70
70
70
70
70
70
70
70
70
70
30
10
30
30
30
30
30
30
30
30
30
360
<5
ndd
L1a C6H5
48 (98 : 2)
100 (98 : 2)
32 (94 : 6)
96 (98 : 2)
85 (96 : 4)
<5
69 (89 : 11)
92 (99 : 1)
96 (98 : 2)
92 (97 : 3)
89 (92 : 8)
99 (R)
99 (R)
92 (R)
98 (R)
96 (R)
ndd
76 (R)
99 (R)
98 (R)
99 (R)
89 (R)
L1a C6H5
L1c C6H5
L2a C6H5
L3a C6H5
Conclusions
L4a C6H5
L5a C6H5
We have described the first application of phosphite-
oxazole/imidazole ligands in asymmetric intermolecular Pd-
catalyzed Heck reactions under thermal and microwave con-
ditions. These ligands are more stable than their oxazoline
counterparts, less sensitive to air and other oxidizing agents
than phosphines and phosphinites, and easy to synthesize from
readily available alcohols. In addition, they can be easily tuned
in the oxazole and biaryl phosphite moieties, so that their effect
on catalytic performance can be explored. We found that regio-
and enantioselectivities and activities are highly influenced by the
ligand components. By carefully selecting them, excellent activities
(up to 100% conversion in 30 min) and regio- (up to >99%) and
enantioselectivities (up to 99% ee) were obtained using several tri-
flate sources. The use of microwave irradiation conditions allowed
considerably shorter reaction times maintaining excellent regio-
and enantioselectivities. In addition, the efficiency of this ligand
design is also corroborated by the fact that these Pd-phosphite-
oxazole/imidazole catalysts provided higher enantioselectivity
than their phosphinite analogues. These results open up a new
class of robust phosphite-oxazole ligands for the highly active and
enantioselective Pd-catalyzed Heck reaction, which will be of great
practical interest.
9
L1a 4-CH3-C6H4
L1a 4-NO2-C6H4
L1a 1-Naphthyl
10
11
12
L1a 1-Cyclohexenyl 80
a [Pd2(dba)3]·dba (1.25 ¥ 10-2 mmol), S1 (2.0 mmol), triflate (0.5 mmol),
i
ligand (2.8 ¥ 10-2 mmol), THF (3 mL), Pr2NEt (1 mmol). b Conversion
1
percentages determined by GC or H-NMR (see Experimental section).
c Enantiomeric excesses measured by GC or HPLC (see Experimental
section). d Not determined.
important (Table 2, entries 1, 8 and 13). Thus, regioselectivities are
best with the electron-deficient para-nitrophenyl triflate. Again,
these results are among the best that have been reported in the
literature.3f,k,l,7b
We next evaluated the ligand library in the Heck reaction of S1
with cyclohexenyl triflate (eqn (2), R = 1-cyclohexenyl; Table 2,
entries 14–16). Although the Pd-catalyst precursors containing
ligand L1a again provided the alkenylated product 4 in high
activity and regioselectivity (up to 99%), enantioselectivity was
only moderate (up to 69% ee).
Microwave-assisted asymmetric Heck reactions
Experimental section
The benefits of microwave irradiation, including reduction of
reaction times and electricity costs, have already been reported
in several C–C coupling reactions.15 In this context we have
recently shown that, when microwaves are used as the source
of heat, the reaction proceeds much faster and retains excellent
enantioselectivity, allowing for a highly selective intermolecular
Heck reaction.7b,16 Therefore, we decided to use ligands L1–L5a–g
to take advantage of microwave irradiation in asymmetric Pd-
catalyzed Heck reactions.
We first studied how temperature affected the Pd-catalyzed
asymmetric Heck reaction of substrate S1 using phenyl triflate
with ligand L1a (Table 3). We found that the optimal temperature
was 70 ◦C. At a lower temperature, activities decreased consid-
erably (Table 3, entries 1 vs. 2 and 3). Under these optimized
conditions, we evaluated the complete series of ligands. The most
noteworthy results are shown in Table 3 (entries 3–8). Catalytic
performance in the Pd-catalyzed phenylation of S1 under mi-
crowave conditions followed the same trend as for the phenylation
under thermal conditions. As expected, however, using controlled
microwave dielectric heating considerably improved activities
(from 24 h to 30 min), while maintaining the excellent regio- (up to
98%) and enantioselectivities (up to 99% ee). These observations
are also true for other aryl triflate sources, so activities, and regio-
(up to 99%) and enantioselectivities (up to 99% ee) are excellent
(Table 3, entries 9–11).
General considerations
All syntheses were performed with standard Schlenk techniques
under argon atmosphere. Solvents were purified by standard
procedures. Ligands L1–L4a–g and L6 were synthesized as previ-
ously described.9,10 All other reagents were used as commercially
1
1
1
available. H, 13C{ H} and 31P{ H} NMR spectra were recorded
on a 400 MHz spectrometer. The chemical shifts are referenced
to tetramethylsilane (1H and 13C) as internal standard or H3PO4
(31P) as external standard. The 1H and 13C NMR spectral
assignments were determined by H-1H and H-13C correlation
spectra. Microwave experiments were carried out using a CEM
Explorer, in which the temperature is controlled by a non-contact
infrared sensor that is located beneath the cavity floor and “looks”
up to the bottom of the vessel.
1
1
General procedure for the preparation of ligands L5a–c
The corresponding phosphorochloridite (1.5 mmol) produced in
situ was dissolved in toluene (6 mL) and pyridine (0.57 mL,
12 mmol) was added. Hydroxyl-imidazole 312 (333.6 mg, 1.4 mmol)
was azeotropically dried with toluene (3 ¥ 2 mL) and then dissolved
in toluene (6 mL) to which pyridine (0.57 mL, 12 mmol◦) was
added. The imidazole solution was transferred slowly at 0 C to
the solution of phosphorochloridite. The reaction mixture was
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stirred overnight at 80 ◦C, and the pyridine salts were removed
by filtration. Evaporation of the solvent gave a white foam, which
was purified by flash chromatography in alumina (toluene/NEt3 =
100/1) to produce the corresponding ligand as a white solid.
For the rest of the compounds, conversion and selectivity were
determined by GC.3e
Acknowledgements
L5a. Yield: 0.67 g, 71%. 31P NMR (400 MHz, C6D6), d: 143.0
(s). 1H NMR (400 MHz, C6D6), d: 1.25 (br, 36H, CH3, tBu), 2.97
(s, 3H, CH3-N), 6.86 (d, 1H, CH-O, J = 9.2 Hz), 6.76–7.92 (m,
13H, CH ). 13C NMR (400 MHz, C6D6), d: 30.7 (CH3-N), 31.8
(CH3, tBu), 32.5 (CH3, tBu), 35.6 (C, tBu), 36.3 (C, tBu), 75.3 (d,
C-O, JC–P = 8.4 Hz), 110–155 (aromatic carbons). Anal. Calc (%)
for C43H53N2O3P: C 76.30, H 7.89, N 4.14; found C 76.35, H 7.92,
N 4.11.
We thank the Spanish Government (Consolider-Ingenio
CSD2006-0003, CTQ2010-15835/BQU, 2008PGIR/07 to O.
Pa`mies and 2008PGIR/08 to M. Die´guez and ICREA
Academia award to M. Die´guez) and the Catalan Government
(2009SGR116), COST D40, Vetenskapsra˚det (VR), and Astra
Zeneca for support. Knut and Alice Wallenbergs Stiftelse are also
gratefully acknowledged for generous financial support.
L5b. Yield: 0.47 g, 54%. 31P NMR (400 MHz, C6D6), d: 143.1
(s). 1H NMR (400 MHz, C6D6), d: 1.23 (s, 9H, CH3, tBu), 1.25 (s,
9H, CH3, tBu), 3.09 (s, 3H, CH3-N), 3.32 (s, 3H, CH3-O), 3.34 (s,
3H, CH3-O), 6.80 (d, 1H, CH-O, J = 7.2 Hz), 6.72–7.98 (m, 13H,
CH ). 13C NMR (400 MHz, C6D6), d: 30.3 (CH3-N), 31.1 (CH3,
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N. Feiken, R. W. Kunz, P. S. Pregosin and M. Tschoerner, J. Am.
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Albinati, Organometallics, 1999, 18, 670; (d) L. F. Tietze, K. Thede and
F. Sannicolo`, Chem. Commun., 1999, 1811; (e) N. G. Andersen, M.
Parvez and B. A. Keay, Org. Lett., 2000, 2, 2817.
t
tBu), 35.7 (C, Bu), 55.5 (CH3-O), 74.9 (d, C-O, JC–P = 13 Hz),
110–155 (aromatic carbons). Anal. Calc (%) for C37H41N2O5P: C
71.14, H 6.62, N 4.48; found C 71.21, H 6.68, N 4.43.
L5c. Yield: 0.53 g, 63%. 31P NMR (400 MHz, C6D6), d: 143.7
1
(s). H NMR (400 MHz, C6D6), d: 0.16 (s, 9H, CH3-Si), 0.19 (s,
9H, CH3-Si), 3.00 (s, 3H, CH3-N), 6.89 (d, 1H, CH-O, J = 9.2 Hz),
6.84–8.00 (m, 15H, CH ). 13C NMR (400 MHz, C6D6), d: 0.0
(CH3-Si), 0.1 (CH3-Si), 30.1 (CH3-N), 74.2 (d, C-O, JC–P = 3.8 Hz),
110–155 (aromatic carbons). Anal. Calc (%) for C33H37N2O3PSi2:
C 66.41, H 6.25, N 4.69; found C 66.38, H 6.21, N 4.71.
Procedure for the preparation of ligand L7
A solution of chlorodiphenylphosphine (0.14 mL, 0.77 mmol) in
THF (3 mL) was slowly added at 0 ◦C to a solution of 3 (166.8 mg,
0.7 mmol) and 18.3 mg (0.15 mmol) of DMAP in pyridine (1 mL).
The reaction mixture was stirred overnight at room temperature.
Diethyl ether was then added and the pyridine salts were removed
by filtration. The residue was purified by flash chromatography
(eluent: toluene/NEt3 100/1, Rf 0.9) to produce 0.10 g (34%) of
a colorless oil. 31P-NMR (400 MHz, C6D6), d: 99.8 (s). 1H-NMR
(400 MHz, C6D6), d: 2.94 (s, 3H, CH3-N), 6.43 (m, 1H, CH-
O), 6.7–8.0 (m, 19H, CH ). 13C NMR (400 MHz, C6D6), d: 30.3
(CH3-N), 69.8 (b, CH-O), 110–155 (aromatic carbons). Anal. Calc
(%) for C27H23N2OP: C 76.76, H 5.49, N 6.63; found C 76.75, H
5.51, N 6.61.
3 For phosphine-oxazoline ligands, see for instance: (a) O. Loiseleur, P.
Meier and A Pfaltz, Angew. Chem., Int. Ed. Engl., 1996, 35, 200; (b) O.
Loiseleur, M. Hayashi, N. Schmees and A. Pfaltz, Synthesis, 1997, 1338;
(c) T. Tu, X. L. Hou and L. X. Dai, Org. Lett., 2003, 5, 3651; (d) S. R.
Gilbertson, D. Xie and Z. Fu, J. Org. Chem., 2001, 66, 7240; (e) S. R.
Gilbertson and Z. Fu, Org. Lett., 2001, 3, 161; (f) T. Tu, W. P. Deng,
X. L. Hou, L. X. Dai and X. C. Dong, Chem.–Eur. J., 2003, 9, 3073;
(g) S. R. Gilbertson, D. G. Genov and A. L. Rheingold, Org. Lett.,
2000, 2, 2885; (h) Y. Hashimoto, Y. Horie, M. Hayashi and K. Saigo,
Tetrahedron: Asymmetry, 2000, 11, 2205; (i) X. L. Hou, D. X. Dong
and K. Yuan, Tetrahedron: Asymmetry, 2004, 15, 2189; (j) D. Liu, Q.
Dai and X. Zhang, Tetrahedron, 2005, 61, 6460; (k) W.-Q. Wu, Q. Peng,
D.-X. Dong, X.-L. Hou and Y.-D. Wu, J. Am. Chem. Soc., 2008, 130,
9717; (l) M. Rubina, W. M. Sherrill and M. Rubin, Organometallics,
2008, 27, 6393; (m) M. O. Fitzpatrick, H. Mu¨ller-Bunz and P. J. Guiry,
Eur. J. Org. Chem., 2009, 1889; (n) T. G. Kilroy, A. J. Hennessy, D. J.
Connolly, Y. M. Malone, A. Farrell and P. J. Guiry, J. Mol. Catal. A:
Chem., 2003, 196, 65; (o) M. Ogasawara, K. Yoshida, H. Kamei, K.
Kato, Y. Uozumi and T. Hayashi, Tetrahedron: Asymmetry, 1998, 9,
1779; (p) A. J. Hennessy, Y. M. Malone and P. J. Guiry, Tetrahedron
Lett., 1999, 40, 9163; (q) A. J. Hennessy, D. J. Connolly, Y. M. Malone
and P. J. Guiry, Tetrahedron Lett., 2000, 41, 7757; (r) S. R. Gilbertson,
D. Xie and Z. Fu, Tetrahedron Lett., 2001, 42, 365; (s) T. G. Kilroy,
P.-G. Cozzi, N. End and P. J. Guiry, Synlett, 2004, 106; (t) T. G. Kilroy,
P.-G. Cozzi, N. End and P. J. Guiry, Synthesis, 2004, 1879.
4 For other successful types of P,N-ligands such as phosphinite-
oxazoline, phosphine-pyridine derivatives, phosphine-thiazole and
phosphine-imidazole ligands, see: (a) K. Yonehara, K. Mori, T.
Hashizume, K. G. Chung, K. Ohe and S. Uemura, J. Organomet. Chem.,
2000, 603, 40; (b) W. J. Drury III, N. Zimmermann, M. Keenan, M.
Hayashi, S. Kaiser, R. Goddard and A. Pfaltz, Angew. Chem., Int. Ed.,
2004, 43, 70; (c) S. T. Henriksen, P. O. Norrby, P. Kaukoranta and P.
G. Andersson, J. Am. Chem. Soc., 2008, 130, 10414; (d) C. A. Busacca,
D. Grossbach, R. C. So, E. M. O’Brien and E. M. Spinelli, Org. Lett.,
2003, 5, 595.
General procedure for Pd-catalyzed enantioselective Heck
reactions
A mixture of [Pd2(dba)3]dba (12 mg, 1.25 ¥ 10-2 mmol) and the
appropriate chiral ligand (2.8 ¥ 10-2 mmol) in dry degassed THF
(3.0 mL) was stirred under argon at room temperature for 15 min.
The olefin (2.0 mmol), triflate (0.50 mmol) and base (1.0 mmol)
were added to the catalyst solution. The solution was stirred at
the desired temperature under argon. After the desired reaction
time, the mixture was diluted with additional diethyl ether and
washed with water, dried over MgSO4, and evaporated. For com-
pounds 2-(1-naphthyl)-2,5-dihydrofuran and 2-(4-nitrophenyl)-
2,5-dihydrofuran, conversion and regioselectivity were measured
1
by H-NMR and enantioselectivity was measured by HPLC.3b
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5 For representative examples, see: hydrogenation: (a) M. T. Reetz and
G. Mehler, Angew. Chem., Int. Ed., 2000, 39, 3889; (b) I. Ojima, M.
Takai and T. Takahashi, PCT Int. Appl., 2004 WO 2004078766 A1;
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G. Andersson, O. Pa`mies and M. Die´guez, J. Am. Chem. Soc., 2009,
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Buisman, L. A. van der Veen, A. Klootwijk, W. G. J. de Lange, P. C. J.
Kamer, P. W. N. M. van Leeuwen and D. Vogt, Organometallics, 1997,
16, 2929; (f) M. Die´guez, O. Pa`mies and C. Claver, Chem. Commun.,
2005, 1221 Conjugated addition: (g) M. Yan, Z.-Y. Zhou and A. S.
C. Chan, Chem. Commun., 2000, 115; (h) M. Die´guez, A. Ruiz and
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Benhaim, S. Rosset and M. Humam, J. Am. Chem. Soc., 2002, 124,
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Res., 2010, 43, 312.
6 For some representative reviews, see: (a) C. Claver, O. Pa`mies and M.
Die´guez, Chiral Diphosphinites, Diphosphonites, Diphosphites and
Mixed PO-Ligands, in Phosphorous Ligands in Asymmetric Catalysis;
Ed. A. Bo¨rner, WileysVCH, Weinheim, 2008, Chapter 3, vol. 2; (b) M.
Die´guez, O. Pa`mies, A. Ruiz, C. Claver in Methodologies in Asymmetric
Cata´lisis; Ed. S. V. Malhotra, ACS, Washington, 2004, pp. 161.
7 (a) Y. Mata, O. Pa`mies and M. Die´guez, Org. Lett., 2005, 7, 5597;
(b) Y. Mata, O. Pa`mies and M. Die´guez, Chem.–Eur. J., 2007, 13, 3296;
(c) J. Mazuela, O. Pa`mies and M. Die´guez, Chem.–Eur. J., 2010, 16,
3434.
8 J. A. Joule and K. Mills Heterocyclic Chemistry; Fourth Edition,
Blackwell Science Ltd, Oxford, 2000.
9 J. Mazuela, A. Paptchikhine, P. Tolstoy, O. Pa`mies, M. Die´guez and P.
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10 K. Ka¨llstro¨m, C. Hedberg, P. Brandt, A. Bayer and P. G. Andersson,
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11 K. Asakawa, J. J. Dannenberg, K. J. Fitch, S. S. Hall, C. Kadowaki, S.
Karady, S. Kii, K. Maeda, B. F. Marcune, T. Mase, R. A. Miller, R. A.
Reamera and D. M. Tschaen, Tetrahedron Lett., 2005, 46, 5081.
12 A. Torrens, J. A. Castrillo, A. Claparols and J. Redondo, Synlett, 1999,
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13 O. Pa`mies, M. Die´guez, G. Net, A. Ruiz and C. Claver, Organometallics,
2000, 19, 1488.
14 The rapid ring inversion (atropoisomerization) in the biaryl phosphite
moiety is usually stopped upon coordination to the metal center. See
for example: (a) M. Die´guez and O Pa`mies, Chem.–Eur. J., 2008, 14,
3653; (b) O. Pa`mies and M. Die´guez, Chem.–Eur. J., 2008, 14, 944.
15 See for instance: Microwave Assisted Organic Synthesis. J. P. Tierney, P.
Lidstro¨m, ed. Blackwell Publishing Ltd., Oxford, 2005 and references
therein.
16 P. Kaukoranta, K. Ka¨llstro¨m and P. G. Andersson, Adv. Synth. Catal.,
2007, 349, 2595.
946 | Org. Biomol. Chem., 2011, 9, 941–946
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