Recycling of allylic alkylation Pd catalysts containing phosphine-imidazoline ligands in ionic liquids

Article abstract of DOI:10.1039/c2gc35732a

An efficient catalytic system to perform allylic alkylation in ionic liquids based on a Pd/phosphine imidazoline system has been designed. This system affords very good results (ee's up to 95%) when used with the appropriate ionic liquid as well as under microwave conditions. Recycling experiments were conducted showing very promising results.

Full text of DOI:10.1039/c2gc35732a

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COMMUNICATION
Recycling of allylic alkylation Pd catalysts containing phosphine-imidazoline
ligands in ionic liquids†
Verónica de la Fuente,a Nicolas Fleury-Brégeot,a Sergio Castillón*b and Carmen Claver*a
Received 13th May 2012, Accepted 15th August 2012
DOI: 10.1039/c2gc35732a
allylic substitution reaction using a pyrrolidinium-based ionic
liquid achieving enantioselectivities up to 95%.4j The glucose
based ligand naplephos developed by Ruffo et al. has also been
tested in this reaction with very limited success.4k Oxyphos-
phanes have also been investigated and while providing good
catalytic activity, the asymmetric induction was found to be very
low.4l
An efficient catalytic system to perform allylic alkylation in
ionic liquids based on a Pd/phosphine-imidazoline system
has been designed. This system affords very good results
(ee’s up to 95%) when used with the appropriate ionic liquid
as well as under microwave conditions. Recycling experi-
ments were conducted showing very promising results.
Phosphine-imidazoline (PHIM) ligands5,6 are interesting ana-
logues of the well known phosphine-oxazolines, where the
second nitrogen atom represents an additional source of mole-
cular diversity, allowing the programmed modification of the
electronic properties of the coordinating nitrogen atom. In the
past few years, these ligands have provided good results in
various metal-catalyzed reactions such as asymmetric hydrogen-
ation,7 the Heck reaction8 and allylic substitution.9,10
The importance of ionic liquids in the field of organic synthesis
is increasing due to their unique features such as low vapor
pressure, low toxicity, immiscibility with some organic solvents,
along with the fact that they readily dissolve metal catalysts and
organic compounds. These characteristics combined with the
possibility of catalyst recycling make them very attractive
alternatives to the usual organic solvents in the context of envir-
onmentally-friendly processes.1
Therefore in the last few years, many research groups, both
academic and industrial, have studied how to replace convention-
al organic solvents in catalytic reactions, mainly metal-catalyzed
reactions, by ionic liquids.2 Among the C–C bond forming reac-
tions, Pd-catalyzed allylic alkylation is a very well known reac-
tion that has been intensively studied in the last twenty years
with outstanding developments being achieved.3 The earliest
example of use of an ionic liquid (1-butyl-3-methylimidazolium
tetrafluoroborate ([bmim][BF4])) in this reaction was reported by
Xiao et al. in 1999.4a Since then, only a few works concerning
the use of ionic liquids have been reported.4 Particularly, as far
as we know, there are only six precedents in the literature con-
cerning asymmetric versions. In 2000 and 2002, Toma et al.
described the alkylation of 1,3-diphenyl-3-acetoxy propene with
dimethyl malonate in [bmim][PF6] using ferrocene-based chiral
ligands, achieving 92% ee and very low conversions. No
efficient recycling was possible under those conditions, and it
was observed that the ee decreased with the reaction time.4g,h
Recently, Pd/bis(oxazoline)-phosphorus ligands were found to
be active catalysts in this reaction although the recycling of the
catalysts failed.4i Chiral carbohydrate-based diphosphite ligands
have also been efficiently applied and reused in the Pd-catalyzed
In the context of a project devoted to evaluate the potentiality
of the phosphine-imidazoline ligands in metal-catalyzed asym-
metric catalysis, we report here their application in Pd-catalyzed
allylic alkylation in ILs. Both high conversions and enantio-
selectivities, together with an efficient recovery of the catalysts,
in the Pd/PHIM-catalyzed allylic alkylation of rac-1,3-diphenyl-
prop-2-en-1-yl acetate (SI) with dimethyl malonate can be
achieved by choosing appropriately the ionic liquid used as the
solvent for this chemical reaction.
A small library of phosphine-imidazoline ligands 3, 4, 9 and
10 was synthesized from the dithioester 1 following a known
procedure previously reported in the literature (Scheme 1).7a,9
The catalytic system Pd/3 was first tested in the alkylation of
rac-1,3-diphenylprop-2-en-1-yl acetate by dimethyl malonate.
When the previously reported ionic liquids [bmim][PF6] (12)
and [bmim][BF4] (13) were used, the obtained conversions and
enantioselectivities were low, and more importantly not reprodu-
cible. Ionic liquid 13 ([bmim][BF4])4c led to a conversion range
of 54–64% with enantiomeric excesses of 25–64% (entry 2,
Table 1). The same behaviour was observed when the counterion
−
was PF6 (IL 12), with a conversion range of 22–52% and
enantioselectivities ranging between 56 and 61% (entry 1).
Other ionic liquids were then investigated in this reaction.
When the reaction was carried out in 2,3-dimethyl-1-butylimida-
zolium hexafluorophosphate ([2,3-dmbim][PF6]) (15), complete
conversion was observed, but the enantioselectivity was low
(entry 4). The use of ionic liquid 16 allowed us to obtain full
conversion with excellent enantioselectivity up to 90% (entry 5).
Interestingly, in both latter cases, the results were found to be
reproducible.
aDepartament de Química Física i Inorgànica, Universitat Rovira
i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarragona, Spain.
E-mail: carmen.claver@urv.cat; Fax: (+34)977 559563
bDepartament de Química Analítica i Orgànica, Universitat Rovira
i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarragona, Spain.
E-mail: sergio.castillon@urv.cat; Fax: (+34)977 558446
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc35732a
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Fig. 1 Complexes formed in the presence of a palladium precursor,
ligand 3, ionic liquid 7 and KOAc.
However, heating at 120 °C was shown to be detrimental to the
reaction (entry 7). The use of a Pd(0) source did not provide a
positive effect either (entries 8 and 9).
The difference between ionic liquids 12, 13 and 15, 16 is the
presence in the former of an acidic proton in position 2, which in
the presence of a base can lead to the formation of different
species, in particular carbenes, as previously reported,12 which
would hamper the catalytic results.
In order to investigate further such behaviour, ionic liquid 13
was placed in the basic conditions of the allylic alkylation in the
presence of the Pd/3 catalytic system and the formation of new
Scheme 1 Synthesis of phosphine-imidazoline ligands 3, 4, 9 and 10.
1
species was studied by 31P and H NMR as well as mass spec-
Table 1 Pd-allylic alkylation of rac-1,3-diphenylprop-2-en-1-yl acetate
trometry. When the palladium precursor was tested alone, the
formation of complex 17 was observed, while when Pd/3 was
used, the formation of carbene complexes 17, 19 together with
the expected catalyst 18 was detected (Fig. 1).13,14
in different ILsa
The catalytic behaviour of complex 17 in the Pd-catalyzed
allylic alkylation was verified,15 and therefore it can be respon-
sible for the non-reproducibility of the results and low ee’s
observed while performing the reaction in ILs 12 and 13.16
A
similar behaviour is expected for complex 19. These obser-
vations emphasize that the choice of the ionic liquid is essential
for the success of the reaction.17
Surprisingly, IL 14, which presents a structure similar to 12 or
13 bearing (2-methoxy-ethoxy)ethyl sulfate as a counterion,
gave reproducible results and an excellent asymmetric induction
(94% ee), although with a modest conversion (44%) (Table 1,
entry 3). No trace of formation of carbene complexes was
noticed when this ionic liquid was in the presence of [Pd(η3-
C3H5)Cl]2 and potassium acetate. In the present case, this could
be explained by a different strength in the ion pair between the
imidazolium cation and the different anions.18 According to
several research groups, there is hydrogen bonding between the
acidic protons of the imidazolium ring and the anion.19 It is
likely that this hydrogen bonding is stronger in the case of the
sulfate anion than in the case of tetrafluoroborate, thus creating a
stronger network of cations and anions that would avoid the
abstraction of this acidic proton by the base. The use of this
specific counter ion leads solely to the chiral palladium catalyst
resulting in excellent enantioselectivity. All these results clearly
illustrate the importance of the nature of the counter ion in deter-
mining the chemical properties of the ionic liquids.
([bmim] = 1-butyl-3-methylimidazolium, [2,3-dmbim] = 2,3-dimethyl-
butylimidazolium)
Entry
Precursor
IL
T (°C)
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
[Pd(η3-C3H5)Cl]2
[Pd(η3-C3H5)Cl]2
[Pd(η3-C3H5)Cl]2
[Pd(η3-C3H5)Cl]2
[Pd(η3-C3H5)Cl]2
[Pd(η3-C3H5)Cl]2
[Pd(η3-C3H5)Cl]2
Pd2(dba)3
12
13
14
15
16
16
16
16
16
45
45
45
45
45
Rt
120
Rt
45
22–52d
54–64d
44
>95
>95e
>95
93
56–61d
25–64d
94
55
90
61
41
48
68
54
>95
Pd2(dba)3
a Reaction conditions: [Pd(η3-C3H5)Cl]2 (5 μmol); ligand 3 (11 μmol),
substrate (250 μmol); dimethyl malonate (750 μmol); BSA (750 μmol),
KOAc (5 μmol) in the corresponding ionic liquid, at 45 °C, 24 h.
b Conversion determined by NMR. c The product has an R configuration.
Enantiomeric excess determined by HPLC on a Chiracel-OD-H column.
d Range of results obtained in 5 different runs. e Isolated yield 82%.
Microwave irradiation has scarcely been used in the asym-
metric allylic alkylation reaction in ionic liquids.20 Usually,
microwave irradiation allows us to shorten the reaction time by
providing better heating of the reaction vessel. In our study, re-
cycling experiments were first performed under microwave
irradiation (P = 8 watts, Table 2, entry 1). Thus, we were pleased
to observe complete conversion and 87% enantioselectivity in
Other parameters of the reaction such as palladium precursors
and reaction temperatures were investigated by performing the
reaction in ionic liquid 16. Despite the fact that catalytic activity
is observed at rt, heating seemed to be required in order to obtain
high enantioselectivity, probably by facilitating the isomerization
between allylpalladium intermediates (entries 5 and 6).11
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Table 2 Recycling in the Pd-allylic alkylation of rac-1,3-
diphenylprop-2-en-1-yl acetate in ionic liquid 16a
Table 4 Recycling and microwave irradiation in the Pd-allylic
alkylation of rac-1,3-diphenylprop-2-en-1-yl acetate with Pd/9 in ionic
liquid 16a
Entry
Cycle
Reaction time
Conv.b (%)
eec (%)
Entry
Cycle
Conv.b (%)
eec (%)
1
2
3
4
5
1
1
2
3
4
3 h
1 h
1 h
1 h
1 h
>95
94
93
90
68
87
90
89
88
77
1
2
3
4
1
2
3
4
96
93
81
66
95
96
78
74
a Reaction conditions: [Pd(η3-C3H5)Cl]2 (5 μmol); ligand 3 (11 μmol),
substrate (250 μmol); dimethyl malonate (750 μmol); BSA (750 μmol),
KOAc (5 μmol) in ionic liquid 16 under microwave irradiation P = 8
watts. b Conversion determined by 1H NMR analysis. c Enantiomeric
excess determined by HPLC on a Chiracel-OD-H column.
a Reaction conditions: [Pd(η3-C3H5)Cl]2 (5 μmol); ligand 9 (11 μmol),
substrate (250 μmol); dimethyl malonate (750 μmol); BSA (750 μmol),
KOAc (5 μmol) in ionic liquid 16 under microwave irradiation P = 8
watts,
1
h. b Conversion determined by 1H NMR analysis.
c Enantiomeric excess determined by HPLC on a Chiracel-OD-H
column.
though the Pd/9 system is the most enantioselective catalyst, it
may be less robust than Pd/3.
Table 3 Ligand effect on the Pd-allylic alkylation of rac-1,3-
diphenylprop-2-en-1-yl acetate in ionic liquid 16 under microwave
irradiationa
Entry
Ligand
Conv.b (%)
eec (%)
Conclusions
1
2
3
4
3
4
9
10
99d
99
99
87
90
53
95
73
In conclusion, we have demonstrated that ILs can be an efficient
solvent for the Pd-catalyzed allylic alkylation using Pd/phos-
phine-imidazoline catalytic systems, reaching enantioselectivity
up to 95%. The choice of the ionic liquid is important as side-
reactions might occur due to the formation of other catalytic
species. The designed catalytic system using IL 16 is stable and
allows efficient recycling as well as the use of microwave con-
ditions providing a high level of conversion and enantioselectiv-
ity. Further studies are ongoing in our laboratory to expand the
scope of this family of ligands in this reaction as well as in other
organometallic reactions in ionic liquids and will be reported in
due course.
a Reaction conditions: [Pd(η3-C3H5)Cl]2 (5 μmol); ligand (11 μmol),
substrate (250 μmol); dimethyl malonate (750 μmol); BSA (750 μmol),
KOAc (5 μmol) in ionic liquid 16 under microwave irradiation P = 8
watts, 1 h. b Conversion determined by NMR. c The product has an
R configuration. Enantiomeric excess determined by HPLC on a Chiracel-
OD-H column. d Isolated yield 78%.
3 h. Further experiments proved that within 1 h, more than 90%
conversion and 90% enantioselectivity were achieved.
After each run, the ionic liquid was extracted with dry
degassed toluene (3 times) and kept under vacuum for at least
3 h. The next run was then started by simply adding the rac-1,3-
diphenylprop-2-en-1-yl acetate, dimethyl malonate, BSA and
potassium acetate. Interestingly, after the second run, the conver-
sion and the enantioselectivity remained excellent and as high as
in the first experiment with 93% conversion and 89% of enan-
tioselectivity. After 4 cycles, using the same ionic liquid solu-
tion, the conversion was still around 70% and the
enantioselectivity good at 77% demonstrating the robustness of
the system.21
Next, the ligands 4, 9 and 10 were tested in the palladium-
catalyzed allylic alkylation reaction under microwave irradiation
(Table 3). The results can be summarized as follows: (a) the
incorporation of a cyclohexyl group on the imidazoline ring pro-
duces a negative effect on the enantioselectivity as previously
observed (entry 1 vs. 2, Table 3); (b) the introduction of a triazo-
lyl substituent on the nitrogen atom of the imidazoline ring has a
beneficial effect on the enantioselectivity (entries 1 and 2 vs. 3
and 4, Table 3). Ligands 4, 9 and 10 were also tested under
thermal conditions; 24 h were required in order to achieve com-
parable results with those obtained under microwave irradiation.
Finally, a set of recycling experiments with ligand 9 was per-
formed (Table 4). It was observed that after the third run the con-
version and the enantioselectivity dramatically decreased. Even
Experimental section
Typical reaction procedure: in an inerted Schlenk tube are intro-
duced [Pd(η3-C3H5)Cl]2 (1.84 mg, 5 μmol, 2 mol%) and the
phosphine-imidazoline ligand (0.011 mmol) in [2,3-dmbim]-
[BF4] (2 mL). The resulting mixture is heated at 85 °C for
20 min, under nitrogen to obtain the Pd complex. After cooling
to rt, rac-1,3-diphenylprop-2-en-1-yl acetate (62.5 mg,
250 μmol), dimethyl malonate (750 μmol), BSA (185 μL,
750 μmol) and KOAc (0.5 mg, 2 mol%) are successively intro-
duced. The resulting solution is then put under microwave
irradiation (P = 8 watts) for 1 h. After cooling to rt, the products
are extracted from the ionic liquid using dry degassed toluene
(3 × 5 mL), filtered over celite and the solvent removed. The
ionic liquid is kept under vacuum for 3 h under stirring to
remove traces of organic solvent, and reused for another batch
reaction by simply adding rac-1,3-diphenylprop-2-en-1-yl
acetate (62.5 mg, 250 μmol, 1 equiv.), dimethyl malonate
(86 μL, 750 μmol, 3 equiv.), BSA (185 μL, 750 μmol, 3 equiv.)
and KOAc (0.5 mg, 2 mol%).
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