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

Article abstract of DOI:10.1002/adsc.200900619

We have screened a library of modular phosphite-oxazoline ligands for asymmetric allylic substitution reactions. The library is efficiently prepared from the commercially available and cheap dglucosamine. The introduction of a phosphite moiety into the ligand design is highly advantageous for the product outcome. Therefore, this ligand library affords good-to-excellent reaction rates [TOFs up to 600 mol substrate × (mol Pd × h)^-1] and enantioselectivities (ees up to 99%) and, at the same time, shows a broad scope for mono-, di-and trisubstituted linear hindered and unhindered substrates and cyclic substrates. The NMR studies on the palladium allyl intermediates provide a deeper understanding about the effect of the ligand parameters on the origin of enantioselectivity.

Full text of DOI:10.1002/adsc.200900619

FULL PAPERS
DOI: 10.1002/adsc.200900619
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
Yvette Mata,a Oscar Pꢀmies,a,* and Montserrat Diꢁgueza,*
a
Departament de Quꢂmica Fꢂsica i Inorgꢀnica, Universitat Rovira i Virgili, C/Marcel·lꢂ Domingo s/n, 43007 Tarragona,
Spain
Fax : (+34)-97-755-9563; e-mail: montserrat.dieguez@urv.catoscar.pamies@urv.cat
Received: September 6, 2009; Revised: October 14, 2009; Published online: December 10, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900619.
Abstract: We have screened a library of modular a broad scope for mono-, di- and trisubstituted linear
phosphite-oxazoline ligands for asymmetric allylic hindered and unhindered substrates and cyclic sub-
substitution reactions. The library is efficiently pre- strates. The NMR studies on the palladium allyl in-
pared from the commercially available and cheap d- termediates provide a deeper understanding about
glucosamine. The introduction of a phosphite moiety the effect of the ligand parameters on the origin of
into the ligand design is highly advantageous for the enantioselectivity.
product outcome. Therefore, this ligand library af-
fords good-to-excellent reaction rates [TOFs up to
600 mol substrateꢃ(mol Pdꢃh)À1] and enantioselec- Keywords: allylic substitution; asymmetric catalysis;
tivities (ees up to 99%) and, at the same time, shows carbohydrate ligands; P,N ligands; palladium
Introduction
tioselective Pd catalytic systems have been reported,
their activities are still very low.[1]
Palladium-catalyzed asymmetric allylic substitution is
It is therefore of great importance nowadays to
a versatile process that is widely used in organic syn- conduct research into more versatile and faster mixed
thesis for the enantioselective formation of carbon- P-N ligand systems that can be easily synthesized
carbon and carbon-heteroatom bonds.[1] Many chiral from simple starting materials. For this purpose, car-
ligands, bidentate nitrogen and phosphorus donors bohydrates are particularly advantageous because of
(both homo- and heterodonors) have been successful- their low price and easy modular constructions.[4] Al-
ly applied. Most of the chiral ligands developed are though they have been successfully used in other
mixed bidentate donor ligands (such as P-N, P-S, S-N enantioselective reactions, they have only recently
and P-P’).[1,2,3] The efficiency of this type of hard-soft shown their huge potential as a source of highly effec-
heterodonor ligand has been mainly attributed to the tive chiral ligands in this process.[4,5] Notable examples
electronic effects of the donor atoms.[1] Mixed phos- include two types of phosphorous-oxazoline li-
phorus-nitrogen ligands have played a dominant role gands.[5e,6] In this context, Uemura and co-workers
among heterodonor ligands. Nowadays several P,N li- synthesized the phosphinite-oxazoline ligands 1 (Fig-
gands have provided high enantiomeric excesses for ure 1)[5e,6b] which proved to be effective in the allylic
several types of disubstituted substrates. Nevertheless, substitution of the hindered substrate 1,3-diphenyl-3-
in general, there is still a problem of substrate specif- acetoxyprop-1-ene but which had low enantioselectiv-
icity (for example, ees are high in disubstituted linear ity for unhindered cyclic and linear substrates.[5e] On
hindered substrates and low in unhindered substrates, the basis of this structure, in this paper we have de-
and vice versa) and reaction rates. On the other hand, signed a new ligand library in which the phosphinite
monosubstituted substrates still require more active group is replaced by a phosphite group (Figure 2).
and more regio- and enantioselective Pd catalysts.[1] The advantage of incorporating a phosphite moiety
Another challenging class of substrates is that of the into the ligand is that: (i) the substrate specificity de-
trisubstituted substrates. Although a few good enan- creases because the chiral pocket created (the chiral
Adv. Synth. Catal. 2009, 351, 3217 – 3234
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Yvette Mata et al.
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their effect on catalytic performance can be deter-
mined. Therefore, with this library we fully investigat-
ed the effects of several electronic and steric proper-
ties of the oxazoline moiety (L1–L5) and several sub-
stituents/configurations in the biaryl phosphite moiet-
ies (a–i). As a result, the highly enantioselective and
active Pd-allylic substitution reactions are carried out
for several substrates.
Figure 1. Phosphinite-oxazoline ligands developed by
Uemura and co-workers.
cavity where the allyl is embedded) is flexible enough Results and Discussion
to allow the perfect coordination of hindered and un-
hindered substrates;[7,8] (ii) reaction rates increase be- Ligand Synthesis
cause of the high p-acceptor capacity of the phosphite
moiety;[7] and (iii) the regioselectivity towards the de- The synthesis of the phosphite-oxazoline ligands L1–
sired branched isomer in monosubstituted linear sub- L5a–i is straightforward (Scheme 1). They were effi-
strates increase because the p-acceptor capacity of ciently synthesized in one step by reacting the corre-
the phosphite moiety enhances the SN1 character of sponding sugar oxazoline-alcohols (3–7) with 1 equiv-
the nucleophilic attack.[9] Despite these advantages, alent of the corresponding biaryl phosphorochloridite
only one series of amino alcohol-based phosphite-oxa- [ClP(OR)2; (OR)2 =a–i] in the presence of pyridine,
zoline ligands has been extensively studied.[7b,9,10] in a parallel way (see Experimental Section for de-
Therefore, new series of phosphite-oxazoline ligands tails). Oxazoline-alcohols 3–7 are easily prepared
need to be developed and their potential studied. from inexpensive d-glucosamine 2 on a large scale.[5e]
More research needs to be done to understand the All the ligands were stable during purification on neu-
mechanistic aspects with these ligands for an a priori tral alumina under an atmosphere of argon and were
prediction of the type of ligand needed for high selec- isolated in moderate-to-good yields as white solids.
tivity.
They were stable at room temperature and very
Therefore we report here the design of a library of stable to hydrolysis. The elemental analyses were in
1
45 potential chiral phosphite-oxazoline ligands L1– agreement with the assigned structure. The H, 13C
L5a–i (Figure 2) for Pd-catalyzed allylic substitution and 31P NMR spectra were as expected for these C1 li-
reactions of several substrate types.[11] We also discuss gands. One singlet for each compound was observed
the synthesis and characterization of the Pd-p-allyl in- in the 31P NMR spectrum. Rapid ring inversions (atro-
termediates to provide greater insight into the origin poisomerization) in the biphenyl-phosphorus moieties
of the enantioselectivity. The library was synthesized (a–e) occurred on the NMR time scale because the
and screened using a series of parallel reactors, each expected diastereoisomers were not detected by low-
of which was equipped with 12 different positions. As temperature phosphorus NMR.[12]
well as containing a biaryl phosphite moiety these
new phosphite-oxazoline ligands L1–L5a–i also have
the advantage of a more flexible ligand scaffold than
ligands 1. They can be easily tuned in two different
regions (oxazoline and phosphite substituents) so that
Figure 2. Phosphite-oxazoline ligand library L1–L5a–i.
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Pyranoside Phosphite-Oxazoline Ligand Library: Highly Efficient Modular P,N Ligands
FULL PAPERS
Scheme 1. Synthesis of phosphite-oxazoline ligand library L1–L5a–i.
Allylic Substitution of Symmetrical 1,3-Disubstituted
Allylic Substrates
enantioselectivities was obtained by using dichloro-
methane as the solvent and KOAc as base (see Sup-
porting Information). Interestingly, enantioselectivi-
In this section, we report the use of the chiral phos- ties were best with a ligand-to-palladium of 0.9. This
phite-oxazoline ligand library (L1–L5a–i) in the Pd- is due to the fact that the phosphite-oxazoline ligand
catalyzed allylic substitution of linear disubstituted acts as a monodentate ligand when excess of ligand is
substrates with different steric properties [Eq. (1a)]: present (see below, Section on Origin of Enantiose-
rac-1,3-diphenyl-3-acetoxyprop-1-ene (S1) (widely lectivity. Study of the Pd-p-allyl Intermediates).
used as a model substrate) and rac-1,3-dimethyl-3-
Under the optimized conditions we tested the re-
acetoxyprop-1-ene (S2); and cyclic substrates [Eq. maining ligands. Table 1 shows the results when di-
(1b)]: rac-3-acetoxycyclohexene (S3) (widely used as methyl malonate and benzylamine were used as nu-
a model substrate) and rac-3-acetoxycycloheptene cleophiles. They indicate that catalytic performance
(S4). Two nucleophiles were used.
(activities and enantioselectivities) is highly affected
by the oxazoline substituents, and the axial chirality
and the substituents of the biaryl moieties. High activ-
ities [TOFs up to 600 mol S1ꢃ(mol Pdꢃh)À1] and
enantioselectivities (ees up to 99%) were obtained
with ligand L1a. Catalytic performance in the Pd-cat-
alyzed allylic amination of S1 followed the same
Allylic Substitution of rac-1,3-Diphenyl-3-acetoxy-
prop-1-ene S1 using Dimethyl Malonate and
Benzylamine as Nucleophiles [Eq. (1a)]
For an initial evaluation of the phosphite-oxazoline trend as for the allylic alkylation of S1 (Table 1). As
ligand library (L1–L5a–i), we chose the Pd-catalyzed expected, the activity was lower than in the alkylation
allylic substitution of S1 [Eq. (1a), R=Ph], which is reaction of S1. The stereoselectivity of the amination
widely used as a model substrate. We used dimethyl was the same as for the alkylation reaction, although
malonate and benzylamine as nucleophiles.
the CIP descriptor was inverted because the priority
We first determined the optimal reaction conditions of the groups had changed.
(solvent, bases and ligand-to-palladium ratio). Al-
The effect of the oxazoline substituent was studied
though toluene provided slightly higher enantioselec- with ligands L1a–L5a (Table 1, entries 1, 10–12 and
tivity than dichloromethane, its activity was lower. We 14). We found that these substituents affected both
found that the best combination of activities and activities and enantioselectivities. The results showed
Adv. Synth. Catal. 2009, 351, 3217 – 3234
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Yvette Mata et al.
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Table 1. Selected results for the Pd-catalyzed allylic substitution of S1 using phosphite-oxazoline ligand library L1–L5a–i.
[a]
H-Nu=H-CH
(COOMe)2
H-Nu=H-NHCH2Ph[b]
Entry
Ligand
% Conv. (t [min])[c]
% ee[d]
% Conv. (t [h])c
% ee[d]
1[e]
2
3
4
5
L1a
L1b
L1c
L1d
L1e
L1f
L1g
L1h
L1i
L2a
L2b
L4a
L4c
L5a
L1a
L1a
100 (30)
89 (30)
95 (30)
85 (30)
57 (30)
82 (30)
80 (30)
100 (30)
99 (30)
92 (30)
67 (30)
100 (15)
88 (15)
99 (30)
54 (300)
100 (360)
92 (S)
84 (S)
86 (S)
89 (S)
86 (S)
81 (S)
9 (S)
84 (S)
62 (S)
86 (S)
45 (S)
85 (S)
83 (S)
80 (S)
95 (S)
99 (S)
60 (24)
53 (24)
58 (24)
54 (24)
34 (24)
49 (24)
53 (24)
65 (25)
66 (24)
59 (24)
35 (24)
79 (24)
61 (24)
61 (24)
–
94 (R)
87 (R)
90 (R)
92 (R)
87 (R)
79 (R)
3 (R)
82 (R)
65 (R)
89 (R)
34 (R)
89 (R)
85 (R)
85 (R)
–
6
7
8[e]
9[e]
10
11
12[e]
13
14
15[f]
16[f,g]
–
–
[a]
All reactions were run at 238C, with 0.5 mol% [PdCl
ACHTUNGTRENNUNG
S1, 1.5 mmol BSA, 1.5 mmol dimethyl malonate, and KOAc as base.
[b]
All reactions were run at 238C with 1 mol% [PdCl
S1, and 1.5 mmol of benzylamine.
ACHTUNGTRENNUNG
[c]
[d]
[e]
[f]
Reaction time shown in parentheses.
Enantiomeric excesses. The absolute configuration appears in parentheses.
Isolated yields of 8 and 9 were >90% based on recovered starting material.
T=08C.
[g]
2 mol% Pd, toluene as solvent.
that enantioselectivity is dependent on both the elec- matched combination for ligands L1f and L1h, which
tronic and steric properties of the substituents in the contains an S-binaphthyl moiety (Table 1, entries 6
oxazoline moiety. Therefore, enantioselectivities were and 8 vs. 7 and 9). Also, by comparing the results ob-
best with ligand L1a, which contains a phenyl-oxazo- tained using ligands L1c with the related binaphthyl
line group (Table 1, entry 1).[13] However, activities ligands L1h and L1i (Table 1, entry 3 vs. 8 and 9), we
were controlled by the steric properties of the sub- can conclude that the atropoisomeric biphenyl moiety
stituents in the oxazoline groups. They were higher in ligands L1a–d adopts an S-configuration when co-
when less sterically demanding substituents were pres- ordinated in the Pd-p-allyl intermediate species.
ent (i.e., Me>PhꢀBn>i-Pr>t-Bu).
To sum up, the best result was obtained with ligand
The effects of phosphite moieties were studied L1a, which contains the optimal combination of
using ligands L1a–i (Table 1, entries 1–9). The results ligand parameters. These results clearly show the effi-
indicated that the substituents at the ortho positions ciency of highly modular scaffolds in ligand design.
of the biphenyl moiety mainly affected activities, Enantioselectivity can be improved by controlling not
while the substituents at the para positions mainly af- only the structural but also the reaction parameters.
fected enantioselectivities. Activities and enantiose- In this case, enantioselectivity was further improved
lectitivies were therefore highest when tert-butyl (ees up to 95%) with ligand L1a by lowering the reac-
groups were present at both the ortho and para posi- tion temperature to 08C (Table 1, entry 15). As ex-
tions of the biphenyl phosphite moiety (ligand L1a, pected, changing the solvent from dichloromethane to
Table 1, entry 1). With ligands L1f–L1i, which con- toluene increased enantioselectivity even further (ees
tained different enantiomerically pure binapthyl moi- up to 99%, Table 1, entry 16).[14] Interestingly, when
eties, we investigated how enantioselectivity was in- this latter result is compared with the enantioselectivi-
fluenced by the axial chirality of the biaryl moiety ties obtained with their corresponding Pd-phosphin-
(Table 1, entries 6–9). The results indicate that there ite-oxazoline 1 system (ees up to 96% at 08C), we can
is a cooperative effect between the configuration of conclude that introducing a phosphite moiety into li-
the biaryl moiety and the configurations of the ligand gands L1–L5a–i is advantageous. These results are
backbone on enantioselectivity. This leads to a among the best that have been reported.[1]
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Pyranoside Phosphite-Oxazoline Ligand Library: Highly Efficient Modular P,N Ligands
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Allylic Alkylation of rac-1,3-Dimethyl-3-acetoxy-
prop-1-ene S2 using Dimethyl Malonate as the
Nucleophile [Eq. (1a)]
considerably decreased activities and enantioselectivi-
ties (Table 2, entries 1, 10–12 and 15). Therefore, in
contrast to the alkylation of S1, both the activities
and enantioselectivities were only dependent on the
We also screened the phosphite-oxazoline ligand li- steric properties of the substituents in the oxazoline
brary L1–L5a–i in the allylic alkylation of the linear moiety and they were higher when a methyl substitu-
substrate S2 [Eq. (1a), R=Me]. This substrate is less ent was present (ligand L4a, Table 2, entry 12).
sterically demanding than substrate S1. The enantio-
As far as the effect of the phosphite moiety on cat-
selectivity for S2 is therefore more difficult to control alytic performance is concerned, bulky substituents
than with hindered substrates such as S1. If ee values need to be in the ortho position of the biphenyl moi-
are to be high, the ligand must create a small chiral eties and substituents of any group except hydrogen
pocket around the metal center, mainly because of need to be in the para positions if enantioselectivity is
the presence of less sterically demanding methyl syn to be high (Table 2, entries 1 and 2 vs. 3–5). There-
substituents.[1] There are therefore fewer successful fore, ligands L1a and L1b with bulky substituents in
catalytic systems for the Pd-catalyzed allylic substitu- the ortho positions and either tert-butyl or methoxy
tion of this substrate than for the allylic substitution groups in the para positions of the biphenyl moieties
of hindered substrate S1.[7b,15] Due to the presence of provided higher enantioselectivities than ligands L1c,
a bulky biaryl phosphite moiety in ligands L1–L5a–i, L1d and L1e. The effect of the configuration of the
which are known to be flexible and to provide large binaphthyl moiety (ligands L1f–i) is similar to the
bite angles, we expected to be able to tune the size of effect in the previous alkylation of S1 (Table 2, en-
the chiral pocket appropriately and therefore to tries 6–9). Therefore, ligands L1f and L1h with an S-
obtain high enantioselectivity for this substrate, too.
binaphthyl moiety provided higher enantioselectivities
Table 2 summarizes the results of using the phos- than ligands L1g and L1i with a R-binaphthyl group.
phite-oxazoline ligand library L1–L5a–i under the op- Interestingly, and in contrast to the substitution of S1,
timized conditions. Again, activities and enantioselec- this cooperative effect is highly advantageous. Enan-
tivities were affected by the substituents in both the tioselectivities increased from 60% to 77% ee at room
oxazoline and phosphite moiety and by the coopera- temperature (Table 2, entry 1 vs. 8).
tive effect between stereocenters. However, the effect
In summary, results were best with ligand L4h,
of these parameters on enantioselectivity was differ- which contains the optimal combination of ligand pa-
ent from their effect on the alkylation of hindered rameters (ees up to 89%, entry 18). If it is compared
substrate S1. Thus, enantioselectivity was best with with the moderate enantioselectivities obtained with
ligand L4h (ees up to 89%). This result, which again the related Pd-phosphinite-oxazoline 1 ligand systems
clearly shows the efficiency of using modular scaffolds (ees up to 57% at 08C)[5e] in the alkylation of sub-
in ligand design, is among the best that have been re- strate S2, we can again conclude that the introduction
ported for this type of unhindered linear substra- of a phosphite moiety is highly advantageous in terms
tes.[7b,15]
Regarding the effect of the oxazoline substituents,
the presence of bulky substituents in this position
of activity and enantioselectivity.
Table 2. Selected results for the Pd-catalyzed allylic substitution of S2 using phosphite-oxazoline ligand library L1–L5a–i.[a]
Entry
Ligand
% Conv. (min)[b]
% ee[c]
Entry
Ligand
% Conv. (min)[b]
% eec
1[d]
2
L1a
L1b
L1c
L1d
L1e
L1f
L1g
L1h
L1i
69 (30)
63 (30)
68 (30)
61 (30)
42 (30)
50 (30)
12 (30)
28 (30)
49 (30)
60 (R)
60 (R)
32 (R)
40 (R)
22 (R)
68 (R)
9 (S)
10
L2a
L3a
L4a
L4c
L4h
L5a
L1f
L1h
L4h
65 (30)
34 (30)
78 (30)
77 (30)
31 (30)
58 (30)
100 (360)
83 (600)
88 (600)
16 (R)
10 (R)
65 (R)
48 (R)
80 (R)
58 (R)
81 (R)
87 (R)
89 (R)
11
3[d]
4
12[d]
13
5
14
6[d]
7
15d
16[e]
17[e]
18[d,e]
8
9
77 (R)
9 (R)
[a]
All reactions were run at 238C with 0.5 mol% [PdClACTHNUTRGNEUNG
(h3-C3H5)]2, dichloromethane as solvent, 0.9 mol% ligand, 0.5 mmol
S2, 1.5 mmol BSA, 1.5 mmol dimethyl malonate, and KOAc as base.
Reaction time shown in parentheses.
Enantiomeric excesses. The absolute configuration appears in parentheses.
Isolated yields of 10 were >92% based on recovered starting material.
T=08C.
[b]
[c]
[d]
[e]
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Yvette Mata et al.
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Allylic Alkylation of Cyclic Substrates S3 and S4 [Eq.
(1b)]
While the effect of the oxazoline substituents on ac-
tivities is similar to the effect in the alkylation of S1
and S2, the effect of the phosphite moiety is different.
As for the unhindered substrate S2, the enantioselec- Therefore, activities were better when less sterically
tivity in cyclic substrates is difficult to control, mainly demanding oxazoline substituents were present
because of the presence of less steric anti substitu- (Table 3, entries 1 and 12 vs. 10, 11 and 14) and when
ents.[1] This section shows that the chiral phosphite-ox- bulky substituents were present at both ortho and
azoline ligand library L1–L5a–i applied above to the para positions of the biphenyl moieties (Table 3, en-
Pd-catalyzed allylic substitution of linear substrates tries 1–5).
(S1 and S2) can also be used for cyclic substrates (ees
For enantioselectivities to be high, we found that a
up to 94%). In this case, two cyclic substrates were phenyl substituent in the oxazoline moiety (Table 3,
tested [Eq. (1b)]: rac-3-acetoxycyclohexene S3 (which entries 1 vs. 10–12 and 14) and either an ortho trime-
is widely used as a model substrate) and rac-3-acet- thylsilyl-disubstituted binaphthyl moiety (Table 3 en-
A
tries 8 and 9) or an ortho and para tetrasubstituted
We initially studied the allylic alkylation of rac-3- tert-butyl biphenyl moiety (Table 3, entry 1) was
acetoxycyclohexene S3 using ligands L1–L5a–i. needed. Interestingly, in contrast to the alkylation of
Table 3 summarizes the results under the optimized S1 and S2, the cooperative effect resulted in a
conditions. Again, activities and enantioselectivities matched combination for ligand L1i, which contains
were affected by the substituents in the oxazoline an R-binapthyl phosphite group (Table 3, entries 9
moiety and the substituents/configurations of the and 16). These results show again the efficiency of
phosphite moiety. However, the effect of these pa- using a modular ligand design.
rameters was different from the effect observed in the
substitution of linear substrates S1 and S2.
This phosphite-oxazoline ligand library L1–L5a–i
was also effective (ees up to 94%) in the allylic alkyla-
tion of the seven-membered ring substrate S4
(Table 3, entries 17–19).
Table 3. Selected results for the Pd-catalyzed allylic alkyla-
tion of S3 and S4 using phosphite-oxazoline ligand library
L1–L5a–i.[a]
In summary, results were best with ligand L1i. The
enantioselectivities are among the best that have been
reported for this type of cyclic substrates.[1d,7b,15a,16]
Again the replacement of a phosphinite moiety by a
phosphite group in the ligand design leads to higher
enantioselectivities than when related ligands 1 are
used (ees up to 74% at 08C).[5e]
Entry
Ligand
Substrate
% Conv. (h)[b]
% ee[c]
1[d]
2
3
4
5
6
7
8
9
10
11
12[d]
13
14[d]
15[e]
16[e]
17[f]
18[e]
19[e]
L1a
L1b
L1c
L1d
L1e
L1f
L1g
L1h
L1i
L2a
L2b
L4a
L4c
L5a
L1a
L1i
S3
S3
S3
S3
S3
S3
S3
S3
S3
S3
S3
S3
S3
S3
S3
S3
S4
S4
S4
100 (24)
68 (24)
72 (24)
62 (24)
21 (24)
23 (24)
28 (24)
42 (24)
23 (24)
79 (24)
51 (24)
100 (24)
89 (24)
98 (24)
69 (36)
37 (36)
100 (24)
43 (36)
19 (36)
75 (R)
22 (R)
54 (R)
32 (R)
5 (R)
Allylic Substitution of Unsymmetrical 1,3,3-
Trisubstituted and Monosubstituted Allylic Substrates
28 (R)
38 (S)
73 (R)
83 (R)
43 (R)
49 (R)
34 (R)
28 (R)
13 (R)
81 (R)
85 (R)
78 (R)
92 (R)
94 (R)
In this section, we report the use of the chiral phos-
phite-oxazoline ligand library (L1–L5a–i) in the Pd-
catalyzed allylic substitution of the unsymmetrical tri-
substituted substrate [Eq. (2a)] rac-1,1,-diphenyl-1-
hepten-3-yl acetate (S5); and unsymmetrical mono-
substituted substrates [Eq. (2b)]: rac-1-(1-naph-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
L1a
L1a
L1i
Allylic Substitution of Unsymmetrical
rac-1,1,-Diphenyl-1-hepten-3-yl Acetate S5 [Eq. (2a)]
[a]
All reactions were run at 238C, with 0.5 mol% [PdClACTHNUTRGNEUNG
(h3-
C3H5)]2, dichloromethane as solvent, 0.9 mol% ligand,
0.5 mmol substrate, 1.5 mmol BSA, 1.5 mmol dimethyl
malonate, and KOAc as base.
Reaction time in hours shown in parentheses.
Enantiomeric excesses. The absolute configuration ap-
pears in parentheses.
We also screened the ligands L1–L5a–i in the allylic
substitution of rac-1,1-diphenyl-1-hepten-3-yl acetate
(S5) using dimethyl malonate as nucleophile [Eq.
(2a)]. This substrate is of synthetic interest because
the substitution product can easily be transformed
into enantiomerically enriched acid derivatives and
lactones.[17] It is more sterically demanding than the
[b]
[c]
[d]
[e]
[f]
Isolated yields of 11 were >92%.
T=À58C.
Isolated yield of 12 was 95%.
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Pyranoside Phosphite-Oxazoline Ligand Library: Highly Efficient Modular P,N Ligands
FULL PAPERS
Table 4. Selected results for the Pd-catalyzed allylic alkyla- tion of 1-(1-naphthyl)allyl acetate S6 and 1-(1-naph-
tion of S5 using phosphite-oxazoline ligand library L1–L5a–
thyl)-3-acetoxyprop-1-ene S7 with dimethyl malonate
[Eq. (2b)]. It is not only the enantioselectivity of the
process that needs to be controlled for these sub-
strates; the regioselectivity is also a problem, because
a mixture of regioisomers may be obtained. Most Pd
catalysts developed to date favor the formation of
achiral linear product 15 rather than the desired
branched isomer 14.[19] Therefore, the development of
highly regio- and enantioselective Pd catalysts is still
a challenge.[7b,9,10c,20] Because the p-acceptor capacity
of the biaryl phosphite moiety in ligands L1–L5a–i is
high, we expected to enhance the SN1 character of the
nucleophilic attack, which would favor the formation
of the branched isomer 14.[9]
i.[a]
Entry
Ligand
% Conv. (h)[b]
% ee[c]
1
2
3
4
5
6
7
8
9
L1a
L1b
L1c
L1d
L1e
L1f
L2a
L3a
L4a
L5a
80 (24)
66 (24)
82 (24)
64 (24)
49 (24)
73 (24)
65 (24)
25 (24)
95 (24)
75 (24)
91 (S)
84 (S)
85 (S)
84 (S)
62 (S)
78 (S)
76 (S)
34 (S)
84 (S)
78 (S)
10
[a]
All reactions were run at 238C, with 1 mol% [PdClACTHNUTRGNEUNG
(h3-
Table 5 summarizes the results obtained with the
phosphite-oxazoline ligand library L1–L5a–i. High ac-
C3H5)]2, dichloromethane as solvent, and 1.8 mol%
ligand.
Conversion measured by H NMR. Reaction time shown
in parentheses.
Enantiomeric excesses measured by HPLC. Absolute
configuration shown in parentheses.
[b]
[c]
1
Table 5. Selected results for the Pd-catalyzed allylic alkyla-
tion of monosubstituted substrate S6 and S7 using the ligand
library L1–L5a–i under standard conditions.[a]
Entry Ligand Substrate % Conv.[b] (min) 14/15[c] % ee[d]
previously used substrate S1,[1] and it is therefore
more difficult to achieve excellent enantioselectivities
with it than with S1.[17,18] Interestingly, with this phos-
phite-oxazoline ligand library, we obtained high enan-
tiomeric excesses (ees up to 91%) under standard re-
action conditions. Although, as expected, the activi-
ties were lower than in the alkylation reaction of S1,
they were much higher than those obtained with
other successful ligands under similar reaction condi-
tions.[18] The results, summarized in Table 4, followed
a trend similar to that of the more hindered substrate
S1. Thus, ligand L1a provided the best enantioselec-
tivity (ees up to 91%). These results are among the
best reported for this class of substrate.[18]
1
2
3
4
L1a
L1b
L1c
L1d
L1e
L1f
L1i
L2a
L3a
L4a
L4c
L5a
L1c
S6
S6
S6
S6
S6
S6
S6
S6
S6
S6
S6
S6
S7
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
100 (60)
65/35 83 (S)
55/45 90 (S)
80/20 90 (S)
65/35 63 (S)
55/45 42 (S)
50/50 96 (S)
85/15 88 (S)
55/45 32 (S)
55/45 32 (S)
50/50 78 (S)
75/25 80 (S)
60/40 72 (S)
80/20 91 (S)
5
6
7[e]
8
9
10
11
12
13
[a]
All reactions were run at 238C, with 1 mol% [PdClACHTUNGTRENNUNG
(h3-
C3H5)]2, dichloromethane as solvent, 1.8 mol% ligand,
0.5 mmol substrate, 1.5 mmol BSA, 1.5 mmol dimethyl
malonate, and KOAc as base.
Reaction time in minutes shown in parentheses.
Percentage of branched (14) and linear (15) isomers
Enantiomeric excesses. The absolute configuration ap-
pears in parentheses.
Allylic Substitution of Monosubstituted Linear
Substrates S6 and S7 [Eq. (2b)]
[b]
[c]
[d]
To further study the potential of these ligands, we ex-
amined the regio- and stereoselective allylic alkyla-
[e]
Isolated yield of 14 was 83%.
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tivities and enantioselectivities (ees up to 96%) com-
bined with regioselectivities up to 85% in favor of the
branched product 14 were obtained, under standard
reaction conditions. The results indicated that the
combination between regio- and enantioselectivities
was best for ligands that contain a phenyl substituent
in the oxazoline moiety and trimethylsilyl substituents
at the ortho positions of the biaryl group. Therefore,
ligands L1c and L1i produced the desired branched
isomer 14 as the major product with high enantiose-
lectivity (Table 5, entries 3 and 7). Again, these results
are among the best reported for this type of sub-
Scheme 3. Drawings of the Pd-p-allyl intermediates contain-
ing ligand (a) L1h and (b) L1i. H atoms are omitted for
clarity.
ACHTUNGTRENNUNG
best (up to 96%) with ligand L1h, but selectivity to-
wards the formation of the desired branched isomer
14 was only moderate (Table 5, entry 6). However,
the related ligand L1i, with the opposite configuration
of the binaphthyl phosphite moiety, affords product
14 in high amount (Table 5, entry 7). This can be ex-
plained by the different spatial arrangement of the
biaryl phosphite group around the metal center,
which is determined by the configuration of the bi-
naphthyl group. Therefore, assuming that the nucleo-
philic attack takes place trans to the phosphite moiety
(the best p-acceptor group) (vide infra) and taking
into account that the nucleophilic attack by an SN2
type process should take place preferentially at the
less substituted allyl terminus (Scheme 2, species B),[9]
Scheme 4. Preparation of [Pd
16–25.
(h3-allyl)(L)]BF4 complexes
ACHTUNGTRENNUNG
the study of the models[21] (Scheme 3) indicates that Origin of Enantioselectivity. Study of the Pd-p-allyl
the Pd-p-allyl isomer containing ligand L1i, with an Intermediates
R-binaphthyl, produced a steric repulsion between
the phosphite moiety and the naphthyl of the sub- In order to provide further insight into how ligand pa-
strate [Scheme 3 (b)] that shifted the equilibrium to rameters affect catalytic performance, we studied the
species A and favored the formation of the desired Pd-p-allyl compounds 16–25, [PdACHTUNGTRNEUNG
(h3-allyl)(L)]BF4
regioisomer 14 (Scheme 2). In contrast, ligand L1h (L=phosphite-oxazoline ligands), since they are key
has an S-binaphthyl moiety and a different spatial ori- intermediates in the allylic substitution reactions stud-
entation of the biaryl phosphite moiety, which reduces ied.[1] These ionic palladium complexes, which contain
the steric repulsion between the phosphite and the 1,3-diphenyl, 1,3-dimethyl- or cyclohexenyl-allyl
substrate S6 [Scheme 3 (a)], thus favoring the forma- groups, were prepared using the methodology previ-
tion of the B isomer, which is responsible for the ously described from the corresponding Pd-allyl
linear product.
dimer and the appropriate ligand in the presence of
silver tetrafluoroborate (Scheme 4).[22] The complexes
were characterized by elemental analysis and by in
1
situ H, 13C and 31P NMR spectroscopy. The spectral
assignments (see Supporting Information) were based
1
on information from H-1H, 31P-1H and 13C-1H corre-
lation measurements in combination with 1H-1H
NOESY experiments.
Palladium 1,3-Diphenylallyl Complexes
When the phosphite-oxazoline ligand library L1–L5a–
i was used in the allylic substitution of disubstituted
hindered substrate S1, the catalytic results indicated
that enantioselectivity is highly affected by the ligand
Scheme 2. Nucleophilic attack in the Pd-catalyzed allylic al-
kylation of substrate S6 with ligand L1i.
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Pyranoside Phosphite-Oxazoline Ligand Library: Highly Efficient Modular P,N Ligands
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Scheme 5. Diastereoisomer Pd-allyl intermediates 16 for S1 with ligand L1a. The relative amounts of each isomer are given
in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are shown.
Figure 3. Relevant NOE contacts from NOESY experiment of syn/syn isomers 16A and 16B and syn/anti isomer 16C.
parameters. A phenyl substituent in the oxazoline (Scheme 5). In isomers A and B, the NOE indicates
group and a biphenyl phosphite moiety with bulky interactions between both terminal protons of the
substituents in ortho and para positions are therefore allyl group and also between the central allyl proton
required if enantioselectivity is to be high. In addi- with ortho hydrogens of both phenyl groups of the
tion, the ligand-to-palladium ratio was found to have allyl ligand, which clearly indicates a syn/syn disposi-
an important effect on enantioselectivity. To under- tion (Figure 3). However, for compound C the central
stand this catalytic behavior, we decided to study the allyl proton shows a NOE interaction with only one
Pd-p-allyl complexes 16–19 which contain ligands of the phenyl substituents and only one of the termi-
L1a, L1f, L1b and L3a, respectively, at a ligand-to- nal allyl protons, thus suggesting a syn/anti conforma-
t’
palladium ratio of 0.9 and 2. Although ligand L1a tion. Moreover, the terminal allyl proton HB of the
with a phenyl substituent in the oxazoline moiety and isomer B shows an NOE interaction with the ortho
a
tetrasubstituted tert-butyl biphenyl phosphite hydrogen of the phenyl-oxazoline substituent, while
moiety provided high enantioselectivity (ees up to in A isomer there is an interaction between the termi-
t
92% at room temperature), ligand L1b, with methoxy nal allyl proton HA and the tert-butyl substituents at
substituents at the para position of the biphenyl phos- the biaryl phosphite moiety. Such interactions can be
phite moiety, and ligand L3a, with a bulky tert-butyl explained by assuming a syn/syn endo arrangement
group in the oxazoline group, were less enantioselec- for isomer A and a syn/syn exo arrangement for
tive (ees up to 84% and 45%, respectively, at room isomer B (Figure 3). In addition, exchange signals be-
temperature).
tween syn/syn isomer A and syn/anti isomer C were
The VT-NMR (308C to À858C) study of Pd-allyl observed in the NOESY spectra (see Supporting In-
intermediate 16, which contains ligand L1a, per- formation). This agrees with an equilibrium between
t’
formed at a ligand-to-palladium ratio of 0.9 had a isomers A and C. Exchange between HA at 6.69 ppm
t’
mixture of three isomers in equilibrium in a ratio of of the A isomer and HC at 5.15 ppm of the C isomer
3.3:2.6:1 (see Supporting Information). The three iso- confirms h3–h1–h3 movement for the exchange be-
mers were unambiguously assigned by NMR to the tween isomers A and C.[23] In addition, the fact that
two syn/syn endo A and exo B isomers, while com- no other Hanti–Hsyn exchange is observed indicates
pound
C was assigned to the syn/anti isomer that the exchange mechanism takes place by the se-
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Scheme 6. Drawings of the Pd-allyl intermediates 16A, 16A’ and 16C for S1 with ligand L1a. H atoms are omitted for clarity.
À
lective opening of one of the terminal Pd C bond.
Accordingly, the study of the models[21 indicated that
the change in configuration of the biphenyl phosphite
moiety (atropoisomerism) in the major A intermedi-
ate increases the steric repulsion between the biaryl
phosphite group and one of the phenyl substituents in
S1 (Scheme 6, species A’). The formation of the syn/
anti isomer C minimizes this new steric interaction.
À
Therefore, the open Pd C bond belongs to the less
electrophilic carbon atom with the substituent that
undergoes the biggest steric hindrance with the biaryl
phosphite fragment. Together with the NOE interac-
tion between the terminal syn proton and the ortho
hydrogen of the phenyl-oxazoline substituent, this
agrees with the syn/anti arrangement depicted in
Figure 3 for isomer C. The study of the models also
indicates that in isomer A there is a stabilizing p-
stacking interaction between the phenyl oxazoline
group and one of the phenyl substituents in S1
(Scheme 6). This explains why syn/syn isomer A is
preferentially formed to syn/syn isomer B. For all iso-
mers, the carbon NMR chemical shifts indicate that
the most electrophilic allyl carbon terminus is trans to
the phosphite moiety. Assuming that the nucleophilic
Figure 4. 31P{1H NMR spectra of [Pd(h3-1,3-diphenylallyl)-
(L1a)]BF4 (16) in CD2Cl2 at À708C (a) before the addition
of sodium malonate and (b) after the addition of sodium
attack takes place at the most electrophilic terminal
carbon atom, the attack at the syn/syn isomer A and
syn/anti isomer C will lead to the formation of (S)-8
AHCTUNGTRENNUNG
while the attack at the syn/syn isomer B will lead to malonate.
the formation of the opposite enantiomer of the alky-
lation product 8. The fact that the enantiomeric
excess of alkylation product 8 [ees up to 92% (S) at moiety of the major A Pd intermediate. This is also
room temperature] is higher than the diastereoisomer- consistent with the fact that for all isomers, the most
ic excesses of the Pd intermediates (de=72%) indi- electrophilic allylic terminal carbon atom is the one
cated that isomer A must react faster than com- trans to the phosphite in the major A isomer.
pounds B and C. To prove this we used in situ NMR
We next performed an NMR study of Pd-allyl inter-
to study the reactivity of the Pd intermediates with mediate 16 at a ligand-to-palladium ratio of 2. The
sodium malonate at low temperature (Figure 4). Our 31P NMR indicated that the major species was a new
results show that isomer A reacts around 10 times one with a signal at 137.4 ppm (40%) (Scheme 7).
faster than isomer B, while C reacts much slower. If This species was attributed to Pd-allyl complex 26
we take into account the relative reaction rates and {[PdACHTNUGRTENNUG AHCTUNGTREN(NUGN L1a)2]BF4} in which two phosphite-oxa-
(h3-allyl)
the abundance of the reacting isomers (A and B), the zoline L1a ligands are coordinated in a monodentate
calculated ee should be 94% (S), which matches the fashion through the phosphite moiety. This type of
ee obtained experimentally. We can therefore con- complex is known to be faster and less enantioselec-
clude that the nucleophilic attack takes place prefer- tive than its bidentate counterpart because it has
entially at the allyl terminus trans to the phosphite more degrees of freedom.[10a,24] This explains the drop
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ratio of 6:1 but no syn/anti isomer C (Scheme 8). No
changes were observed at temperatures as low as
À858C. For both isomers, the carbon NMR chemical
shifts indicate that the most electrophilic allyl carbon
terminus is trans to the phosphite moiety. On the
basis of the observed stereochemical outcome of the
reaction, 81% (S) in product 8, and the fact that the
enantiomeric excess of alkylation product 8 is higher
than the diastereoisomeric excesses of the Pd inter-
mediates, the A isomer must again react faster than
the B isomer. This was confirmed by an in situ NMR
Scheme 7. Pd-intermediate with two phosphite-oxazoline
L1a ligands coordinated as monodentates through the phos-
phite moiety.
in enantioselectivity observed at ligand-to-palladium study of the reactivity of the Pd intermediates with
ratios higher than 0.9 when the Pd/L1a catalyst sodium malonate at low temperature (the A isomer
system was used (see Supporting Information).
reacts around three times faster than the B isomer).
We next studied the Pd-allyl intermediate 18 (at a
To provide further evidence that the syn-anti iso-
merism observed in complex 16 is caused by the atro- ligand-to-palladium ratio of 0.9) containing ligand
poisomerism of the biphenyl moieties, we studied the L1b. This complex has the same substituent in the ox-
palladium allyl intermediate [Pd(h3-1,3-diphenylallyl)- azoline moiety but differs from ligand L1a in the
ACHTUNGTRENNUNG(L1f)]BF4 (17), which contains enantiopure S-bi- para-substituents in the biaryl phosphite moiety. The
naphthyl ligand L1f. As expected, and in contrast to VT-NMR study showed a mixture of three isomers in
complex 16, the VT-NMR study performed at a equilibrium at a ratio of 2:1:1.3 (see Supporting Infor-
ligand-to-palladium ratio of 0.9 showed a mixture of mation). The major A and the minor B isomers were
the two syn/syn endo (A) and exo (B) isomers in a assigned to the two syn/syn endo and exo isomers,
while isomer C was assigned to the syn/anti isomer
(Scheme 9). As for complex 16, the NOESY showed
exchange signals between syn/syn isomer A and syn/
anti isomer C. Again, this syn/syn–syn/anti equilibri-
um is due to the atropoisomerism of the biphenyl
phosphite moiety (vide supra). As for complex 16, it
should be noted that, for all isomers, the most electro-
philic allyl carbon terminus is trans to the phosphite
moiety and isomer A reacts faster than the other iso-
mers. However, the lower enantioselectivity with this
system than with the previous Pd/L1a catalytic system
can mainly be attributed to the decrease in the ratio
between the species that provide the S-enantiomer (A
and C) with respect to the species that provides R-8
(B), compared with the population of the isomers
(A–C) for complex 16.
Finally, we studied the Pd-allyl intermediate 19 (at
a ligand-to-palladium ratio of 0.9) containing ligand
Scheme 8. Diastereoisomeric Pd-allyl intermediates 17 for
S1 with ligand L1f. The relative amounts of each isomer are
given in parentheses. The chemical shifts (in ppm) of the al-
lylic terminal carbons are shown.
Scheme 9. Diastereoisomeric Pd-allyl intermediates 18 for S1 with ligand L1b. The relative amounts of each isomer are
given in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are shown.
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L3a, which has a different substituent in the oxazoline tions of the biphenyl moieties were substituted with a
moiety and provides much lower enantioselectivity group other than hydrogen. The ligand-to-palladium
(ees up to 45%) than the previously studied Pd/L1a ratio was also found to have an effect on enantiose-
catalyst. In contrast to complexes 16–18 studied lectivity. To understand this catalytic behavior, we
above, the VT-NMR spectra showed that species with studied the [PdACHTNUTGRNEUNG
(h3-allyl)(L)]BF4 complexes 20–22
two phosphite-oxazoline ligands coordinated in a which contain ligands L1a, L3a and L1c, at a ligand-
monodentate fashion are the major ones (70%). We to-palladium ratio of 0.9 and 2. Thus, while ligand
believe that this is due to the increase in the steric L1a, which contains bulky tert-butyl groups at the
bulk of the oxazoline moiety because a phenyl (li- ortho and para positions of the biaryl moiety, provid-
gands L1a–b and L1f) was replaced with a tert-butyl ed good enantioselectivities, ligand L1c, without sub-
group (L3a). The presence of this species fully ac- stituents in the para positions of the biphenyl moiety,
counts for the low enantioselectivity observed for this and ligand L3a, with a bulky tert-butyl group in the
catalyst.
oxazoline group, were less enantioselective.
The VT-NMR (308C to À858C) study of Pd-1,3-di-
methyl allyl intermediate 20 at a ligand-to-palladium
ratio of 0.9, which contains ligand L1a, indicated the
presence of a mixture of three isomers in equilibrium
Palladium 1,3-Dimethylallyl Complexes
When the phosphite-oxazoline ligand library L1–L5a– at a ratio of 5:4:1 (see Supporting Information). The
i was used in the allylic substitution of unhindered major A and the minor B isomers were assigned by
linear S2 substrate, the catalytic results revealed a dif- NOE to the two syn/syn exo and endo isomers respec-
ferent trend with regard to the effect of the ligand pa- tively, while isomer C was assigned to the syn/anti
rameters than with the hindered substrate S1. Bulky isomer (Scheme 10 and Figure 5). In contrast to com-
substituents in the oxazoline group decreased enantio- plex 16, the major syn/syn isomer 20A adopts a W
selectivities. On the other hand, enantioselectivities (exo) spatial arrangement. This is due to the absence
were high when bulky substituents were in the ortho of the favorable p-stacking interaction observed in re-
position of the biphenyl moieties and the para posi- lated complex 16. The formation of isomer C was at-
Scheme 10. Diastereoisomeric Pd-allyl intermediates 20 for S2 with ligand L1a. The relative amounts of each isomer are
given in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are shown.
Figure 5. Relevant NOE contacts from NOESY experiment of syn/syn isomers 20A and 20B and syn/anti isomer 20C
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Scheme 11. Drawings of the Pd-allyl intermediates 20A, 20A’ and 20C for S2 with ligand L1a. H atoms are omitted for clari-
ty.
tributed to the atropoisomerism of the biphenyl phos- ligands are coordinated in a monodentate fashion
phite in isomer A as it was in the related Pd-1,3-di- through the phosphite moiety {[Pd(1,3-dimethylallyl)-
phenylallyl complexes 16 and 18. However, the study
of the models indicates that the change in configura- nylallyl intermediate 16, the amount of this {[Pd(1,3-
tion of the biphenyl phosphite moiety results in a dimethylallyl)(L1a)2]BF4} species is lower. This is
ACHTUNGTRENN(NUG L1a)2]BF4}. Interestingly, in contrast to Pd-1,3-diphe-
AHCTUNGTRENNUNG
steric interaction between the oxazoline phenyl group probably due to the presence of less sterically hin-
and one of the methyl substituents in S2 (isomer A’, dered 1,3-dimethylallyl and explains why the enantio-
Scheme 11). The formation of syn/anti isomer C mini- selectivity observed ligand-to-palladium ratios higher
mizes this steric interaction (Scheme 11). Therefore, than 0.9 in the alkylation of S2 decreased less than in
À
the open Pd C bond belongs to the more electrophil- the alkylation of S1.
ic carbon atom containing the substituent that under-
The VT-NMR study of Pd-1,3-dimethylallyl inter-
goes the biggest steric hindrance with the phenyl oxa- mediate 21, which contains ligand L3a with a bulky
zoline fragment. Again, the most electrophilic allyl tert-butyl group at the oxazoline, indicated the pres-
carbon terminus is trans to the phosphite moiety in ence of a mixture of four isomers in equilibrium in a
syn/syn isomer A and syn/syn isomer B, and the allylic ratio of 4:2:1:0.4 at a ligand-to-palladium ratio of 0.9
terminus carbon in isomer C is far less electrophilic (see Supporting Information). Isomers A, B and C
[D
ACHTUNGTRENNUNG
dance of isomers A and B, the calculated diastereo- endo and syn/anti isomers, respectively, while isomer
meric excess matches the enantiomeric excess ob- D was attributed to the isomer that contains two li-
tained experimentally for product 10 [ee=60% (R)].
gands coordinated in
a
monodentate fashion
We also performed the VT-NMR study of Pd-allyl (Scheme 12). As for complex 20, the most electrophil-
intermediate 20 at a ligand-to-palladium ratio of 2. ic allyl carbon terminus was trans to the phosphite
The 31P NMR indicated the presence of a new species moiety in syn/syn isomers A and B, and the allylic
(10%, d=136.9 ppm) which was attributed to the Pd- carbon terminus in isomer C was less electrophilic
allyl complex in which two phosphite-oxazoline L1a [D
ACHTUNGTRENNUNG
Scheme 12. Diastereoisomeric Pd-allyl intermediates 21 for S2 with ligand L3a. The relative amounts of each isomer are
given in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are shown.
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Scheme 13. Diastereoisomeric Pd-allyl intermediates 22 for S2 with ligand L3a. The relative amounts of each isomer are
given in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are shown.
tioselectivity with the Pd/L3a catalyst system is lower good enantioselectivities, ligand L1b, with a methoxy
than with the Pd/L1a catalyst system may be due to substituent in the para positions of the biphenyl
the presence of the less enantioselective isomer D moiety, and ligand L4a, with a methyl substituent in
and the decrease in the relative amount of isomers A the oxazoline group, were less enantioselective.
and B (5:1 ratio for complex 20 and 4:1 ratio for com-
plex 21).
The VT-NMR (308C to À858C) study of Pd-1,3-cy-
clohexenylallyl intermediate 23, which contains ligand
We next studied Pd-allyl intermediate 22 (at a L1a, showed a mixture of two isomers in equilibrium
ligand-to-palladium ratio of 0.9) containing ligand at a ratio of 10:1.2 and at a ligand-to-palladium ratio
L1c. This complex has the same substituent in the ox- of 0.9 (see Supporting Information). Both isomers
azoline moiety as complex 20 but differs from ligand were assigned by NOE to the two syn/syn isomers
L1a in the substituents of the biphenyl phosphite (Scheme 14 and Figure 6). For both isomers, the
moiety. The VT-NMR study showed a mixture of carbon NMR chemical shifts indicated that the most
three isomers in equilibrium at a ratio of 1:1:2 (see electrophilic allylic terminus carbon is trans to the
Supporting Information) (Scheme 13). As for complex phosphite moiety. On the basis of the relative abun-
20, these were assigned to the two syn/syn exo (A) dance of isomers A and B, the calculated diastereo-
and endo (B) isomers and to the syn/anti isomer (C). meric excess matched the enantiomeric excess ob-
Again, the most electrophilic allyl carbon terminus is tained experimentally for product 11 [ee=75% (R)].
found in species A and B. However, in contrast to
The VT-NMR study of Pd-1,3-cyclohexenylallyl in-
complex 20, the allylic carbon atoms trans to the termediates 24 and 25, which contain ligands L1b and
phosphite moiety in isomer A is much more electro- L4a, showed a mixture of two isomers in a ratio of
philic than the one in isomer B [DACHTNUGTRENNUNG
Therefore, isomer A should react faster than isomer
B. Despite this, the fact that B is the major isomer
may explain why the enantioselectivity with this cata-
lytic system is lower than with Pd/L1a.
Palladium 1,3-Cyclohexenylallyl Complexes
When the phosphite-oxazoline ligand library L1–5a–i
was used in the allylic substitution of cyclic substrate
S3, the catalytic results revealed that bulky tert-butyl
substituents in ortho and para positions of the biphen-
yl phosphite moiety and a phenyl substituent in the
oxazoline group are needed if enantioselectivity is to
be high. To understand this catalytic behavior we
studied the Pd-p-allyl complexes 23–25 which contain
ligands L1a, L4a and L1b. Thus, while ligand L1a,
which contains bulky tert-butyl groups at the ortho
Scheme 14. Diastereoisomeric Pd-allyl intermediates 23 for
S3 with ligand L1a. The relative amounts of each isomer are
given in parentheses. The chemical shifts (in ppm) of the al-
and para positions of the biaryl moiety, provided lylic terminal carbons are shown.
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Pyranoside Phosphite-Oxazoline Ligand Library: Highly Efficient Modular P,N Ligands
FULL PAPERS
Figure 6. Relevant NOE contacts from NOESY experiment of isomers 23A and 23B.
Scheme 15. Diastereoisomeric Pd-allyl intermediates (a) 24 for S3 with ligand L1b and (b) 25 for S3 with ligand L4a. The
relative amounts of each isomer are given in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are
shown.
ratio of 0.9, see Supporting Information). All the spe- stitution reactions of several substrates with different
cies were assigned by NOE to the two syn/syn isomers electronic and steric properties. These series of li-
possible for each Pd-allyl complex (Scheme 15). For gands have four main advantages: (1) they can be ef-
all isomers, the carbon NMR chemical shifts indicated ficiently prepared from readily available d-glucos-
that the most electrophilic allylic terminus carbon is
ACHTUNGTRENaNGNU mine; (2) the p-acceptor character of the phosphite
trans to the phosphite moiety. However, in contrast to moiety increases reaction rates; (3) the flexibility cre-
complex 23, the nucleophilic attack at the major B ated by the biaryl phosphite moiety increases versatil-
isomers will lead to the formation of the (S)-11 prod- ity and (4) their modular nature enables the substitu-
uct. Therefore, the difference between the diastereo- ents in the oxazoline moiety and the substituents/con-
isomeric ratio and enantioselectivity observed in the figurations in the biaryl phosphite moiety to be easily
alkylation of S3 [de=80% (S) vs. ee=22% (R) for and systematically varied, so activities and enantiose-
Pd/L1b; de=40% (S) vs. ee=34% (R) for Pd/L1b] in- lectivities can be maximized for each substrate as re-
dicates that the nucleophile reacts faster with the quired. The results indicate that catalytic performance
minor isomer A. This was confirmed by an in situ is mainly affected by the substituents in both the oxa-
NMR study of the reactivity of the Pd intermediates zoline and the phosphite moieties and the cooperative
of both Pd-cyclohexenylallyl complexes 24 and 25 effect between stereocenters. However, the effect of
with sodium malonate at low temperature.[25]
these parameters depends on each substrate class. By
carefully selecting the ligand components, high enan-
tioselectivities (ees up to 99%) and good activities
have been achieved in a broad range of mono-, di-
and trisubstituted hindered and unhindered linear and
Conclusions
A library of phosphite-oxazoline ligands L1–L5a–i cyclic substrates. These results are among the best
has been synthesized for the Pd-catalyzed allylic sub- that have been reported. Particular note should be
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FULL PAPERS
was stirred overnight at 808C, 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 correspond-
ing ligand as a white solid. For yields and analytical data of
the new ligands see the Supporting Information.
taken of the high enantio- and regioselectivities (up
to 96% ee and 85%, respectively) combined with the
high activities obtained for mono- and trisubstituted
substrates. In addition, the efficiency of this ligand
design is also corroborated by the fact that these Pd-
phosphite-oxazoline catalysts provided higher enan-
tioselectivity than their phosphinite-oxazoline ana-
logues in several substrate types. These results open
up the allylic alkylation of a wide range of substrates
to the potential effective use of readily available and
highly modular sugar-based phosphite-oxazoline li-
gands.
General Procedure for the Preparation of [Pd
allyl)(L)]BF4 Complexes 16–25
(h3-
ACHTUNGTRENNUNG
The desired amount of the corresponding ligand
(0.045 mmol for a L/Pd=0.9; 0.1 mmol for a L/Pd=2) and
the complex [PdACTHNUTRGNEUNG
(m-Cl)(h3-1,3-allyl)]2 (0.025 mmol) were dis-
solved in CD2Cl2 (1.5 mL) at room temperature under
argon. AgBF4 (9.8 mg, 0.5 mmol) was added after 30 min
and the mixture was stirred for 30 min. The mixture was
then filtered over celite under argon and the resulting solu-
tions were analyzed by NMR. After the NMR analysis, the
complexes were precipitated by adding hexane. The com-
plexes were filtered off and washed with cold hexane to
afford 16–25 as pale yellow solids. For analytical data of
complexes 16–25 see the Supporting Information
The study of the Pd-1,3-diphenyl, 1,3-dimethyl and
1,3-cyclohexenyl allyl intermediates by NMR spec-
troscopy makes it possible to understand the catalytic
behavior observed. Therefore, it indicates that for
enantioselectivities to be high, the substituents in the
biaryl phosphite moiety and the electronic and steric
properties at the oxazoline substituents need to be
correctly combined in order to form predominantly
the isomer that reacts faster with the nucleophile and
also to avoid the formation of species with ligands co-
ordinated in a monodentated fashion. This study also
indicates that the nucleophilic attack takes place pre-
dominantly at the allylic terminal carbon atom locat-
ed trans to the phosphite moiety.
Study of the Reactivity of the {Pd
with Sodium Malonate by in situ NMR[36]
[(h3-allyl)(L)]}BF4
ACHTUNGTRENNUNG
A solution of in situ prepared [PdACHTUNGTRNEUNG
(h3-allyl)(L)]BF4 (L=
phosphite-oxazoline, 0.05 mmol) in CD2Cl2 (1 mL) was
cooled in the NMR at À708C. At this temperature, a solu-
tion of cooled sodium malonate (0.1 mmol) was added. The
reaction was then followed by 31P NMR. The relative reac-
tion rates were calculated using a capillary containing a so-
lution of triphenylphosphine in CD2Cl2 as external standard.
Experimental Section
General Considerations
All reactions were carried out using standard Schlenk tech-
niques under an atmosphere of argon. Solvents were puri-
fied and dried by standard procedures. Phosphorochloridites
are easily prepared in one step from the corresponding bi-
Typical Procedure for Allylic Alkylation of Substrates
S1–S7
(h3-C3H5)]2 (0.0025 mmol for
A degassed solution of [PdClACHTNUGRTNEUNG
S1–S2; 0.005 mmol for S3–S4 and S6–S7; 0.01 mmol for S5)
and the corresponding phosphite-nitrogen (0.0045 mmol for
S1–S2; 0.009 mmol for S3–S4 and S6–S7; 0.018 mmol for S5)
in dichloromethane (0.5 mL) was stirred for 30 min. Subse-
ACHTUNGTRENNUNG
aryls.[26] Ligands L1a–i, L2a, L3a and L4a,c were prepared
as previously described.[11,27,28] Racemic substrates S1–S7
were prepared as previously reported.[29,30,31,32] [Pd(h3-1,3-
[34]
Ph2-C3H3)
G
E
and
[35]
[Pd(h3-cyclohexenyl)
(m-Cl)]2 were prepared as previously
quently,
(0.5 mmol) in dichloromethane (1.5 mL), dimethyl malonate
(171 mL, 1.5 mmol), N,O-bis(trimethylsilyl)-acetamide
a
solution of the corresponding substrate
described. H, 13C{1H}, and 31P{1H} NMR spectra were re-
corded using a 400 MHz spectrometer. Chemical shifts are
relative to that of SiMe4 (1H and 13C) as internal standard or
H3PO4 (31P) as external standard. 1H, 13C and 31P assign-
(370 mL, 1.5 mmol) and KOAc (1 mg) were added. The reac-
tion mixture was stirred at room temperature. After the de-
sired reaction time the reaction mixture was diluted with
Et2O (5 mL) and saturated aqueous NH4Cl (25 mL) was
added. The mixture was extracted with Et2O (3ꢃ10 mL)
and the extract dried over MgSO4. For substrate S1, solvent
ments were done based on H-1H gCOSY, H-13C gHSQC
and H-31P gHMBC experiments. All catalytic experiments
1
were performed three times.
1
was removed and conversion was measured by H NMR. To
General Procedure for the Preparation of Ligands
L1–L5a–i
determine the ee by HPLC (Chiralcel OD, 0.5% 2-propanol/
hexane, flow 0.5 mLminÀ1), a sample was filtered over basic
alumina using dichloromethane as the eluent.[37] For sub-
strates S2–S4 conversion and enantiomeric excess was deter-
mined by GC.[23] For substrates S5–S7, solvent was removed
and conversion and regioselectivity were measured by
1H NMR. To determine the ee by HPLC (Chiralcel OJ, 13%
2-propanol/hexane, flow 0.7 mLminÀ1), a sample was filtered
over basic alumina using dichloromethane as the
eluent.[18c,38]
The corresponding phosphorochloridite (3.0 mmol) pro-
duced in situ was dissolved in toluene (12.5 mL) and pyri-
dine (1.14 mL, 14 mmol) was added. The corresponding hy-
droxyoxazoline compound (2.8 mmol) was azeotropically
dried with toluene (3ꢃ2 mL) and then dissolved in toluene
(12.5 mL) to which pyridine (1.14 mL, 14 mmol) was added.
The oxazoline solution was transferred slowly at 08C to the
solution of the phosphorochloridite. The reaction mixture
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Pyranoside Phosphite-Oxazoline Ligand Library: Highly Efficient Modular P,N Ligands
FULL PAPERS
try 2005, 16, 959; e) K. Yonehara, T. Jashizume, K.
Mori, K. Ohe, S. Uemura, J. Org. Chem. 1999, 64,
9374; f) K. Boog-Wick, P. S. Pregosin, C. Trabesinger,
Organometallics 1998, 17, 3254; g) M. Diꢁguez, S.
Jansat, M. Gomez, A. Ruiz, G. Muller, C. Claver,
Chem. Commun. 2001, 1132; h) E. Raluy, O. Pꢀmies,
M. Diꢁguez, J. Org. Chem. 2007, 72, 2842.
Typical Procedure for Allylic Amination of rac-1,3-
Diphenyl-3-acetoxyprop-1-ene S1
A
degassed solution of [PdClACTHGNUTERNNUG
(h3-C3H5)]2 (1.8 mg,
0.005 mmol) and the corresponding phosphite-oxazoline
(0.009 mmol) in dichloromethane (0.5 mL) was stirred for
30 min. Subsequently, a solution of S1 (126 mg, 0.5 mmol) in
dichloromethane (1.5 mL) and benzylamine (131 mL,
1.5 mmol) were added. The reaction mixture was stirred at
room temperature. After 24 h the reaction mixture was di-
luted with Et2O (5 mL) and saturated aqueous NH4Cl
(25 mL) was added. The mixture was extracted with Et2O
(3ꢃ10 mL) and the extract dried over MgSO4. Solvent was
[6] a) B. Glꢆser, H. Kunz, Synlett 1998, 53; b) K. Yonehara,
T. Hashizume, K. Mori, K. Ohe, S. Uemura, Chem.
Commun. 1999, 415.
[7] Bulky biphenyl phosphites are known to provide larger
bite angles than phosphinites. The opening of the bite
angle is necessary for high chiral recognition in the Pd-
catalyzed alkylation reactions. See for example:
a) B. M. Trost, D. L. van Vranken, C. Bingel, J. Am.
Chem. Soc. 1992, 114, 9327; b) P. W. N. M. van Leeu-
wen, P. C. J. Kamer, J. N. H. Reek, P. Dierkes, Chem.
Rev. 2000, 100, 2741.
1
removed and conversion was measured by H NMR. To de-
termine the ee by HPLC (Chiralcel OJ, 13% 2-propanol/
hexane, flow 0.5 mLminÀ1), a sample was filtered over silica
using 10% Et2O/hexane mixture as the eluent.[37]
[8] The flexibility offered by the biphenyl moiety can be
used to fine-tune the chiral pocket formed upon com-
plexation. Phosphite ligands have therefore proven to
be highly versatile and active in Pd-catalyzed asymmet-
ric substitution reactions, See for example a) M. Diꢁ-
guez, O. Pꢀmies, C. Claver, J. Org. Chem. 2005, 70,
3363; b) O. Pꢀmies, M. Diꢁguez, C. Claver, J. Am.
Chem. Soc. 2005, 127, 3646; c) M. Diꢁguez, O. Pꢀmies,
C. Claver, Adv. Synth. Catal. 2005, 347, 1257.
Acknowledgements
We are indebted to Prof. P. W. N. M. van Leeuwen, University
of Amsterdam, for his comments and suggestions. We thank
the Spanish Government (Consolider Ingenio CSD2006-
0003, CTQ2007-62288/BQU, 2008PGIR/07 to O.P. and
2008PGIR/08 to M.D) and the Catalan Government
(2005SGR007777 and Distinction to M.D.) for financial sup-
port.
[9] R. Prꢁtꢇt, A. Pfaltz, Angew. Chem. 1998, 110, 337;
Angew. Chem. Int. Ed. 1998, 37, 323.
[10] a) M. Diꢁguez, O. Pꢀmies, Chem. Eur. J. 2008, 14, 3653;
b) K. N. Gavrilov, V. N. Tsarev, S. V. Zheglov, S. E. Lyu-
bimov, A. A. Shyryaev, P. V. Petrovskii, V. A. Davan-
kov, Mendeleev Commun. 2004, 260; c) R. Hilgraf, A.
Pfaltz, Adv. Synth. Catal. 2005, 347, 61.
[11] The preliminary results were partly reported in the
communication: Y. Mata, O. Pꢀmies, M. Diꢁguez, C.
Claver, Adv. Synth. Catal. 2005, 347, 1943.
References
[1] For recent reviews, see: a) B. M. Trost, D. L. van V-
ranken, Chem. Rev. 1996, 96, 395; b) M. Johannsen,
K. A. Jorgensen, Chem. Rev. 1998, 98, 1689; c) A.
Pfaltz, M. Lautens, in: Comprehensive Asymmetric Cat-
alysis, (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer-Verlag, Berlin, 1999, Vol. 2, Chapter 24; d) G.
Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336;
e) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103,
2921; f) Z. Lu, S. Ma, Angew. Chem. 2008, 120, 264;
Angew. Chem. Int. Ed. 2008, 47, 258.
[12] O. Pꢀmies, M. Diꢁguez, G. Net, A. Ruiz, C. Claver, Or-
ganometallics 2000, 19, 1488.
[13] This behavior contrasts with the effect of the oxazo-
line-substituent observed for related phosphinite-oxa-
zoline ligands 1, for which enantioselectivities were
higher when a methyl substituent was present. See
ref.[5e].
[2] a) A. M. Masdeu-Bultꢅ, M. Diꢁguez, E. Martin, M.
Gꢅmez, Coord. Chem. Rev. 2003, 242, 159; b) E.
Martꢂn, M. Diꢁguez, C. R. Chemie 2007, 10, 188.
[14] Changing the Pd catalyst concentration from 2 mol%
down to 0.5 mol% has no affect on enantioselectivity.
[15] For some successful applications, see: a) P. Dierkes, S.
Randechul, L. Barloy, D. De Cian, J. Fischer, P. C. J.
Kamer, P. W. N. M. van Leeuwen, J. A. Osborn, Angew.
Chem. 1998, 110, 3299; Angew. Chem. Int. Ed. 1998, 37,
3116; b) B. M. Trost, A. C. Krueger, R. C. Bunt, J.
Zambrano, J. Am. Chem. Soc. 1996, 118, 6520; c) B.
Wiene, G. Helmchen, Tetrahedron Lett. 1998, 39, 5727.
[16] For some successful applications, see: a) B. M. Trost,
R. C. Bunt, J. Am. Chem. Soc. 1994, 116, 4089; b) G.
Helmchen, S. Kudis, P. Sennhenn, H. Steinhagen, Pure
Appl. Chem. 1997, 69, 513.
[3] See for instance: a) E. Raluy, C. Claver, O. Pꢀmies, M.
Diꢁguez, Org. Lett. 2007, 9, 49; b) M. Diꢁguez, O.
Pꢀmies, C. Claver, Adv. Synth. Catal. 2007, 349, 836;
c) O. Pꢀmies, M. Diꢁguez, Chem. Eur. J. 2008, 14, 944.
[4] For recent reviews, see for example: a) M. Diꢁguez, O.
Pꢀmies, C. Claver, Chem. Rev. 2004, 104, 3189; b) M.
Diꢁguez, O. Pꢀmies, A. Ruiz, Y. Dꢂaz, S. Castillꢅn, C.
Claver, Coord. Chem. Rev. 2004, 248, 2165; c) M. Diꢁ-
guez, A. Ruiz, C. Claver, Dalton Trans. 2003, 2957;
d) M. Diꢁguez, C. Claver, O. Pꢀmies, Eur. J. Org.
Chem. 2007, 4621.
[17] See, for instance: a) A. Sudo, K. Saigo, J. Org. Chem.
1997, 62, 5508; b) G. J. Dawson, J. M. J. Williams, S. J.
Coote, Tetrahedron: Asymmetry 1995, 6, 2535; c) C. J.
Martin, D. J. Rawson, J. M. J. Williams, Tetrahedron:
Asymmetry 1998, 9, 3723.
[5] See for example: a) Y. Y. Yan, T. V. RajanBabu, Org.
Lett. 2000, 2, 199; b) D. Liu, W. Li, X. Zhang, Org.
Lett. 2002, 4, 4471; c) A. Albinati, P. S. Pregosin, K.
Wick, Organometallics 1996, 15, 2419; d) E. Guimet,
M. Diꢁguez, A. Ruiz, C. Claver, Tetrahedron: Asymme-
Adv. Synth. Catal. 2009, 351, 3217 – 3234
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3233

Yvette Mata et al.
FULL PAPERS
[18] For successful applications, see also: a) G. J. Dawson,
J. M. J. Williams, S. J. Coote, Tetrahedron Lett. 1995, 36,
461; b) D. A. Evans, K. R. Campos, J. S. Tedrow, F. E.
Michael, M. R. Gagnꢁ, J. Am. Chem. Soc. 2000, 122,
7905; c) D. Popa, C. Puigjaner, M. Gomez, J. Bene
tBuchholz, A. Vidal-Ferran, M. A. Pericas, Adv. Synth.
Catal. 2007, 349, 2265.
[19] In contrast to Pd-catalytic systems, Ir, Ru, W and Mo
catalysts provide very high selectivity in order for the
attack at the non-terminal carbon to give the chiral
product. See, for instance: a) C. Bruneau, J. L. Renaud,
B. Demersemen, Chem. Eur. J. 2006, 12, 5178; b) A. V.
[24] A. M. Porte, J. Reinbenspies, K. Burgess, J. Am. Chem.
Soc. 1998, 120, 9180.
[25] The in situ NMR studies indicate that isomers 24A and
25A react 15 and 5 times faster than isomers 24B and
25B, respectively.
[26] G. J. H. Buisman, P. C. J. Kamer, P. W. N. M. van Leeu-
wen, Tetrahedron: Asymmetry 1993, 4, 1625.
[27] Y. Mata, O. Pꢀmies, M. Diꢁguez, Chem. Eur. J. 2007,
13, 3296.
[28] M. Diꢁguez, J. Mazuela, O. Pꢀmies, J. J. Verendel, P. G.
Andersson, J. Am. Chem. Soc. 2008, 130, 7208.
[29] P. R. Auburn, P. B. Mackenzie, B. Bosnich, J. Am.
Chem. Soc. 1985, 107, 2033.
´
Malkov, L. Gouriou, G. C. Lloyd-Jones, I. Stary, V.
[30] C. Jia, P. Mꢈller, H. Mimoun, J. Mol. Cat. A: Chem.
ˇ
´
Langer, P. Spoor, V. Vinader, P. Kocovsky, Chem. Eur.
J. 2006, 12, 6910; c) B. M. Trost, S. Hildbrand, K.
Dogra, J. Am. Chem. Soc. 1999, 121, 10416; d) A. Alex-
akis, D. Polet, Org. Lett. 2004, 6, 3529; e) B. M. Trost,
M. H. Hung, J. Am. Chem. Soc. 1983, 105, 7757;
f) G. C. Lloyd-Jones, A. Pfaltz, Angew. Chem. 1995,
107, 534; Angew. Chem. Int. Ed. Engl.Angew. Chem.
Int. Ed. 1995, 34, 462.
1995, 101, 127.
[31] J. Lehman, G. C. Lloyd-Jones, Tetrahedron 1995, 51,
8863.
[32] T. Hayashi, A. Yamamoto, Y. Ito, E. Nishioka, H.
Miura, K. Yanagi, J. Am. Chem. Soc. 1989, 111, 6301.
[33] P. von Matt, G. C. Lloyd-Jones, A. B. E Minidis, A.
Pfaltz, L. Macko, M. Neuburger, M. Zehnder, H. Rueg-
ger, P. S. Pregosin, Helv. Chim. Acta 1995, 78, 265.
[34] M. Kollmar, B. Goldfuss, M. Reggelin, F. Rominger, G.
Helmchen, Chem. Eur. J. 2001, 7, 4913.
[20] For recent successful applications of Pd-catalysts, see:
a) S.-L. You, X.-Z. Zhu, Y.-M. Luo, X.-L. Hou, L.-X.
Dai, J. Am. Chem. Soc. 2001, 123, 7471; b) R. Hilgraf,
A. Pfaltz, Synlett 1999, 1814.
[21] The study of the models has been performed using mo-
lecular mechanics calculations using the universal force
field (UFF).
[22] S. Deerenberg, H. S. Schrekker, G. P. F. van Strijdonck,
P. C. J. Kamer, P. W. N. M. van Leeuwen, J. Fraanje, K.
Goubitz, J. Org. Chem. 2000, 65, 4810.
[23] M. A. Pericꢀs, C. Puigjaner, A. Riera, A. Vidal-Ferran,
M. Gꢅmez, F. Jimꢁnez, G. Muller, M. Rocamora,
Chem. Eur. J. 2002, 8, 4164.
[35] B. M. Trost, P. E. Strege, L. Weber, J. Am. Chem. Soc.
1978, 100, 3407.
[36] R. J. van Haaren, P. H. Keeven, L. A. van der Veen, K.
Goubitz, G. P. F. van Strijdonck, H. Oevering, J. N. H.
Reek, P. C. J. Kamer, P. W. N. M. van Leeuwen, Inorg.
Chim. Acta 2002, 327, 108.
[37] O. Pꢀmies, G. P. F. van Strijdonck, M. Diꢁguez, S. Deer-
enberg, G. Net, A. Ruiz, C. Claver, P. C. J. Kamer,
P. W. N. M. van Leeuwen, J. Org. Chem. 2001, 66, 8867.
[38] J. P. Janssen, G. Helmchen, Tetrahedron Lett. 1997, 38,
8025.
3234
asc.wiley-vch.de
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 3217 – 3234