Dual stereocontrolled alkylation of aldehydes with polystyrene-supported nickel complexes derived from α-amino amides

Article abstract of DOI:10.1039/c4ra15341c

Nickel(ii) complexes derived from α-amino amide ligands anchored to gel-type and monolithic polymers act as efficient catalysts for the enantioselective addition of dialkylzinc reagents to aldehydes. Similar to the analogous homogeneous systems, dual stereocontrol in addition products can be achieved by controlling the stoichiometry of the immobilized nickel complex. Aromatic and aliphatic aldehydes were alkylated in good yields with enantioselectivities comparable to those obtained with the homogeneous analogues. These polymer-supported catalysts offer significant advantages as no metal leaching is observed and they can be easily recovered from the reaction mixture by simple filtration and reused for subsequent experiments with consistent catalytic activity.

Full text of DOI:10.1039/c4ra15341c

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Dual stereocontrolled alkylation of aldehydes with
polystyrene-supported nickel complexes derived
from a-amino amides†
Cite this: RSC Adv., 2015, 5, 14653
Jorge Escorihuela,‡* Belen Altava, M. Isabel Burguete and Santiago V. Luis*
´
Nickel(II) complexes derived from a-amino amide ligands anchored to gel-type and monolithic polymers
act as efficient catalysts for the enantioselective addition of dialkylzinc reagents to aldehydes. Similar to
the analogous homogeneous systems, dual stereocontrol in addition products can be achieved by
controlling the stoichiometry of the immobilized nickel complex. Aromatic and aliphatic aldehydes were
alkylated in good yields with enantioselectivities comparable to those obtained with the homogeneous
analogues. These polymer-supported catalysts offer significant advantages as no metal leaching is
observed and they can be easily recovered from the reaction mixture by simple filtration and reused for
subsequent experiments with consistent catalytic activity.
Received 27th November 2014
Accepted 23rd January 2015
DOI: 10.1039/c4ra15341c
www.rsc.org/advances
6
chemical industry. The immobilization of the chiral ligand
onto an insoluble polymeric chain is still one of the best
Introduction
Asymmetric catalysis constitutes one of the most important options. Polystyrene matrices are oen selected, because of
areas in organic chemistry and thousands of chiral ligands and their well-known properties, their easy functionalization and
their transition metal complexes have been reported in the past their excellent mechanical and chemical stability.
1
several decades for different enantioselective reactions.
Carbon–carbon bond formation is the essence of organic
However, only a few examples have evolved into industrial synthesis and provides the foundation for generating complex
processes due to their high cost and the limitations related to organic compounds from simple starting materials. In this
2
the required work-up. Additionally, sometimes the nal regard, the enantioselective organozinc addition to aldehydes is
product contains high levels of metal contamination derived of long standing research interest, as the resulting optically
7
from catalyst decomplexation or degradation during the active sec-alcohols are important building blocks, and has
8
workup, which can become a serious drawback if the metal is become a benchmark reaction in asymmetric catalysis. Several
toxic, especially for application in pharmaceutical and food examples of polymer-supported chiral catalysts that have been
industries. Therefore, in order to facilitate the separation of the applied for the addition of dialkylzinc reagents to aldehydes can
chiral catalysts from the reaction mixture, different methods for be found in the literature, in particular involving chiral amino
9
anchoring homogeneous catalysts onto solid supports have alcohol structures as the ligand fragments (Fig. 1).
been developed in the last years. This immobilization facili-
3
From the different families of chiral ligands used in asym-
tates the separation of the catalyst from reagents and products, metric catalysis, nitrogen-containing ligands have received
4
simplies the recovery of the oen expensive or toxic catalysts,
and its reuse, and potentially allows the adaptation of the
immobilized catalysts to continuous ow type processes,
5
making the catalytic processes industrially applicable. More-
over, the reuse of the catalyst would reduce the amount of waste
material generated and make the process more environmentally
friendly, providing attractive their potential application in the
Departamento de Qu ´ı mica Inorg a´ nica y Org a´ nica, Universitat Jaume I, Avda. Sos
Baynat s/n, E-12071 Castell ´o n, Spain. E-mail: luiss@uji.es
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c4ra15341c
1
‡
Present address: Centro de Reconocimiento Molecular y Desarrollo Tecnol ´o gico,
Departamento de Qu ´ı mica, Universitat Polit `e cnica de Val `e ncia, Camino de Vera,
Fig. 1 Polystyrene-supported catalyst for the enantioselective addi-
tion of dialkylzinc reagents to aldehydes.
s/n, 46022 Valencia, Spain. E-mail: escorihu@uji.es.
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making any spectroscopic measurements to remove most of the
adsorbed water. Raman spectra were acquired on a JASCO
NRS-3100 dispersive spectrometer under the following condi-
tions: 785 nm laser with a single monochromator, grating 600
ꢁ
1
lines per mm, slit 0.2 mm, resolution 12.75 cm , with a center
ꢁ
1
wavenumber of 1200 cm , a laser power of 90.1 mW, and ten
accumulations of 5 s each. FTIR spectra were recorded on a
JASCO 4000 spectrometer equipped with a PIKE ATR MIRacle.
Elemental analyses were performed on an Elemental Carlo Erba
Fig.
2 Structures of a-amino amide 1 and polymer-supported
a-amino amide ligand 2.
ꢁ
1
10
1108 apparatus. DSC curves were obtained at 10 K min under
nitrogen atmosphere. Diffuse reectance UV-Visible (DR
UV-Vis) spectra were recorded on a Shimadzu UV-2450 spec-
trometer equipped with an integrating sphere unit (ISR-2200).
Thermal analyses were carried out using a TG-STDA Mettler
Toledo model TGA/SDTA851e/LF/1600 analyzer under a ow of
. The temperature range for TGA was 30–400 C at 10
min . TEM and XDS experiments were carried out with a JEOL
100 instrument. Access to the above equipment was provided
important attention over the last years. In this regard, simple
a-amino amides 1, having an amino group and an easily ion-
isable N–H amide subunit, can be compared to amino alcohols
and structures of this class have been recently reported as good
ligands for different transformations, such as the Ru(II)-cata-
11
lyzed asymmetric transfer hydrogenation of acetophenone,
epoxidation of chromenes and the conjugate addition of dia-
ꢀ
ꢀ
12
N
2
C
ꢁ
1
13
lkylzinc to chalcones. In previous contributions from our
group, Ni(II) complexes of amino amides were shown to be able
to efficiently catalyse the addition of dialkylzincs to aldehydes,
achieving an excellent dual stereocontrol just by a proper
adjustment of the stoichiometry of those Ni complexes. In this
regard, we showed that 1 : 1 Ni : ligand complexes provided the
2
by the SCIC (Servei Central d'Instrumentaci ´o Cient ´ı ca) of the
Universidad Jaume I.
14
Synthesis of resins 2
S enantiomer for the addition product (up to 97% ee) while the The general synthesis and characterization of a-amino amide
1
: 2 Ni complexes afforded the R enantiomer (up to 95% ee). functionalized resins 2 has been described elsewhere in our
15
Both catalytic systems were demonstrated to be very active, the previous work.
corresponding 1 : 1 complexes providing faster reactions than
their related 1 : 2 complexes.
General procedure for the preparation of nickel complexes
Recently, it has been shown that the Zn complexes of this kind with 1 : 1 metal : ligand stoichiometry (3)
of homogenous ligands (1), which are inactive for the considered
A solution of nickel(II) acetate (1 equiv.) in methanol was added
to a suspension of 2 (1.2 equiv.) in methanol. Aer stirring the
mixture for 20 min at room temperature, KOH (3 equiv.) in
2 2
CH Cl : methanol (1 : 1) was added and the solution was
reaction, can be transformed, upon immobilization of the ligand
onto a polystyrene–divinylbenzene polymer (2), into an active,
15
highly selective and enantioselective catalytic system (Fig. 2).
In the past years, the possibility of obtaining both enantio-
mers using a single chiral source by changing the reaction
reuxed overnight. The resulting resin was ltered and washed
with diethylether (3 ꢂ 10 mL), methanol (3 ꢂ 10 mL), water (3 ꢂ
16
conditions has received special attention. This dual stereo-
control can be achieved in different ways, such as using different
metals coordinated to the chiral ligand, by modication of the
solvent system or by introducing structural features that modify
the catalytic mechanism or the structure of the catalytic site.
Although, most examples focus on homogeneous systems, a few
1
1
0 mL), a diluted KOH solution (3 ꢂ 10 mL), methanol (3 ꢂ
ꢀ
0 mL) and CH
2
Cl
2
(3 ꢂ 10 mL) and vacuum dried at 50 C
overnight to give the polymer-supported nickel complex 3. IR:
ꢁ1
n
max ¼ 3023, 2921, 2848, 1663, 1600, 1499, 1442, 752, 690 cm
;
elemental analysis (N, theoretical values given in parentheses)
for 3a, 1.70% N (1.93% N); 3b, 1.82% N (2.15% N); 3c, 2.58% N
17
examples have been reported using immobilized catalysts.
(2.94% N); 3d, 3.01% N (3.15% N); 3e, 3.22% N (3.35% N); 3f,
Herein, as a continuation of our catalytic studies with
polymer-supported a-amino amides, we report the preparation
and study of novel heterogeneous chiral Ni(II) complexes
derived from a-amino amides supported on Merrield resins.
Supported complexes with 1 : 1 and 1 : 2 stoichiometries have
been prepared, and their application in the enantioselective
addition of dialkylzinc reagents to aldehydes has allowed an
efficient dual stereocontrol in the catalytic reactions. Besides,
they provide additional features as green catalysts.
1
.67% N (1.90% N); 3g, 2.55% N (2.71% N); 3h, 2.76% N (2.94%
N); 3i, 3.08% N (3.23% N).
General procedure for the preparation of nickel complexes
with 1 : 2 metal : ligand stoichiometry (4)
A solution of a-amino amide 1 (1 equiv.) in methanol was added
to a suspension of 3 (1 equiv.) in CH
stirring the mixture for 20 min at room temperature, KOH
3 equiv.) in CH Cl : methanol (1 : 1) was added and the solu-
2 2
Cl : methanol (1 : 1). Aer
(
2
2
tion was reuxed overnight. The resulting resin was ltered and
washed with diethylether (3 ꢂ 10 mL), methanol (3 ꢂ 10 mL),
water (3 ꢂ 10 mL), a diluted KOH solution (3 ꢂ 10 mL), meth-
anol (3 ꢂ 10 mL) and CH Cl (3 ꢂ 10 mL) and vacuum dried at
Experimental
Materials
2
2
ꢀ
All reagents were used as received, without any further puri- 50 C overnight to give the polymer-supported nickel complex 4.
ꢀ
cation. All samples were vacuum-dried at 60 C for 24 h before IR: nmax ¼ 3028, 2921, 2845, 1668, 1601, 1500, 1444, 754,
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ꢁ
1
6
92 cm ; elemental analysis (N, theoretical values given in
parentheses) for 4a, 3.12% N (3.31% N); 4b, 3.61% N (3.83% N);
c, 4.88% N (5.04% N); 4d, 5.19% N (5.33% N); 4e, 4.79% N
5.02% N); 4f, 3.18% N (3.43% N); 4g, 4.34% N (4.70% N); 4h,
.68% N (5.02% N); 4i, 5.12% N (5.44% N).
4
(
4
General procedure for the asymmetric addition of diethylzinc
to aldehydes catalysed by Polystyrene-Supported (PS) catalysts
Scheme 1 Synthesis of polymer-supported Ni(II) complexes with 1 : 1
and 1 : 2 metal : ligand stoichiometries.
To a stirred suspension of the polymer-supported catalyst
(
(
10 mol%) in toluene (1 mL) was added a solution of diethylzinc
1.1 M in toluene) at 0 C, and the stirring was continued at 0 C
considered for the preparation of the corresponding supported
Ni(II) complexes with 1 : 1 and 1 : 2 stoichiometries. The prep-
aration of the 1 : 1 complex follows a strategy very similar to that
used for the preparation of the catalytic zinc complexes, but
involved the preparation and isolation of the metal complex
prior to its application in the catalytic process. For the prepa-
ration of the 1 : 2 complex, however, a different approach was
used involving the incorporation of a second non-supported
ligand moiety to the preformed 1 : 1 supported complex.
According to previous studies in the eld of polymer-
supported catalysts, the morphology and loading of the poly-
meric support can have a signicant inuence on the nature of
the complexes formed and on the nal catalytic results. Thus, a
detailed study of this aspect was required in this case for a
ꢀ
ꢀ
for 10 min. Next, an aldehyde solution in toluene was slowly
added under an argon atmosphere. Aer the addition was
complete, the reaction mixture was stirred at 0 C during 36 h,
and was then quenched with 1 M HCl (4 mL). The resulting
mixture was ltered and the ltrate was extracted with CH Cl
(
anhydrous MgSO and concentrated under reduced pressure.
Purication of the residue by ash chromatography (PE/AcOEt
ꢀ
2
2
3 ꢂ 10 mL). The combined organic layers were dried with
4
1
5 : 1) afforded the desired alcohol. Conversions and selectiv-
1
ities were determined by H NMR before column purication.
The enantiomeric excess and the absolute conguration of the
resulting alcohols were determined by HPLC and optical rota-
tion. The catalyst was collected by ltration, washed with dry
CH Cl , vacuum dried and used for a new run. For regeneration,
18
proper understanding of the experimental results. For this
purpose, both, gel-type commercially available Merrield resins
2
2
the polymer was stirred with 1 M HCl–THF (1 : 2 mL) for 1 h,
and then washed successively with CH
(
for the preparation of catalysts 3a–e and 4a–e) and monolithic
macroporous resins (for the preparation of catalysts 3f–i and
f–i) were used as the starting polymers. They provided polymer
2
Cl
2
(3 ꢂ 15 mL), THF
ꢀ
(
2 ꢂ 15 mL) and MeOH (2 ꢂ 15 mL). Aer vacuum dried at 50 C
4
for 5 h, the resin could be reused in the successive catalytic
reactions. When performing the recycling studies, the catalyst
supported amino amides 2 with different loadings as shown in
Table 2. Monolithic chloromethylated resins with appropriate
properties, in particular regarding morphology and porosity,
were previously prepared by polymerization of a mixture of
styrene, divinylbenzene and chloromethylstyrene under radical
was separated by ltration, under a N
quenching and washed with CH Cl , being quantitatively
reused as such for subsequent runs.
2
atmosphere, before
2
2
19
conditions following reported procedures. Under the studied
conditions, polymerizations proceed, in general, in quantitative
Conditions for the analysis of chiral secondary alcohols
Chiral Capillary GC column VF-5 ms; 30 m ꢂ 0.25 mm, 0.25 mm. yields. The crosslinking degrees for the polymers used in this
ꢁ
1
ꢀ
Carrier gas : H
3
2
(5 mL min ). Injector 230 C, detector (FID) work were 1% for gel-type resins and 20% for the monoliths.
ꢀ
ꢀ
ꢀ
ꢁ1
00 C, oven 60–130 C, 10 C min . Chiral HPLC : Chiralcel
Treatment of these chloromethylated polymers with potas-
OD columm; 254 nm UV detector. The racemic alcohols prod- sium phthalimide and subsequent reaction with hydrazine
ucts were obtained by addition of Et Zn and Me
Zn to alde- hydrate provided the corresponding aminomethyl polystyrene
hydes. The conditions of analysis and retention times of the R resins in high yields. The complete conversion of the chlor-
2
2
and S isomers are described in the ESI.†
omethyl groups into amine groups was assessed by means of
FTIR, Raman spectroscopy, and the 4-(4-nitrobenzyl)pyridine
20
(NBP) test. The conversion of the aminomethyl resins into
Results and discussion
Catalyst preparation and characterization
amino amide functionalized polymers was carried out by reac-
tion with N-Cbz-(S)-phenylalanine succinimide ester and nal
Taking into consideration our previous results showing the deprotection of the amine groups with 33% HBr/HOAc treat-
excellent reactivity and enantioselectivity obtained in the addi- ment, following a similar protocol to that used for the prepa-
1
4,15,21
tion of organozinc reagents to aldehydes displayed by polymer- ration of related compounds in solution.
The nal
14
supported chiral amino amides (2), as well as the ability of the functionalized resins showed the complete absence of the Cbz
ꢁ
1
Ni(II) complexes of homogeneous amides 1 to achieve a dual band at 1716 cm in their IR spectra.
stereocontrol for this reaction through different metal : ligand
Thus, by using this methodology, two different families of
stoichiometries, we envisaged the potential of the related functionalized PS–DVB resins, with nal loadings ranging from
15
ꢁ
1
nickel complexes as green catalyst systems for the addition of 0.8 to 2.0 mmol g , according to their elemental analysis, were
organozinc reagents to aldehydes with efficient dual stereo- obtained. The rst group (2a–e) were microporous resins (1%
ꢁ1
control. In this regard, the approach shown in Scheme 1 was crosslinked, 0.8 to 2.0 mmol g ); whereas the second (2f–i)
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Fig. 4 TEM images of the PS–Ni catalyst 3b.
3
3
Fig. 3 FTIR spectra for polymers 2b, 3b and 4b; 3b and 4b prepared
from 2b containing 1 mmol of a-amino amide per g of resin.
assigned to two spin-allowed transitions A2g(F) / T1g(F) and
3
3
23
A
2g(F) /
T1g(P). According to this, additional solvent
molecules must be coordinated to the metal center to provide
this octahedral coordination sphere. For the 1 : 2 immobilized
Ni(II) complex (4b), the UV-Vis spectra displayed a band at
consisted of macroporous resins (20% crosslinked, 0.9 to
ꢁ1
2.0 mmol g ). In general, for the synthesis of the different
1
3
4
40 nm, assigned to the LMCT transitions ( A / A ), which
1g 2g
polymer-supported chiral a-amino amides, excellent yields
could be achieved for all the considered transformations.
Next, polymer-supported nickel complexes with 1 : 1 and
clearly revealed the existence of a complex with square planar
geometry.
Finally, the thermal stability of the complexes was investi-
1
: 2 metal : ligand stoichiometries, namely resins 3 and 4,
ꢀ
ꢁ1
gated using TGA–DTA at a heating rate of 10 C min in air over
respectively were prepared (Scheme 1). The formation of the
corresponding 1 : 1 active complexes (3) was carried out in
methanol containing KOH and was accompanied by deproto-
nation of the amide (NH) group. In all cases, the vibrational
band corresponding to the C]O stretching (Fig. 3), was shied
ꢀ
a temperature range of 50–500 C. The TGA curves for the
polymer-supported ligand 2b and the corresponding metal
complexes 3b and 4b are shown in Fig. 6. It can be seen that the
presence of the Ni(II) complexes is accompanied by a slight
increase in the thermal stability of the polymers 3b and 4b as
compared with 2b. A similar effect is reected in the DTA
curves.
ꢁ
1
to lower wavenumbers (from 1670 to 1553 cm ) indicating the
participation of the deprotonated amide group in the coordi-
22
nation to the nickel atom, as observed in related systems. As
nickel(II) acetate in basic methanol is used for the preparation
of these complexes, the R groups in 3 can be either acetate or
Catalysis with immobilized nickel complexes
methoxy groups or solvent molecules. Addition of an additional The catalytic efficiency of the functionalized resins 3 and 4 was
equivalent of the homogeneous ligand 1 to the supported 1 : 1 initially tested for the asymmetric addition of Et Zn to benzal-
complexes 3 afforded the corresponding heterogeneized 1 : 2 dehyde (5) leading to the formation of 1-phenylpropanol (6), as
2
complexes 4.
the model reaction (Scheme 2) and the results were compared
In addition, transmission electron microscopy (TEM) of
these immobilized catalysts was carried out to characterize the
catalytic complexes. As inferred from the TEM images (Fig. 4),
PS–Ni catalysts (3b and 4b) showed a uniform distribution of
the metal species in the polymeric matrix. Energy-dispersive X-
ray analyses (EDX analysis) of the metallic complexes 3b and 4b
conrmed the presence of the metal complexes in the polymeric
matrix as shown in Fig. S4 and S5 (ESI†).
The functionalized resins were also characterized by UV-Vis
spectroscopy in the diffuse reectance mode (DR UV-Vis) to
elucidate the coordination environment of the metallic cation
in the polymeric network. Some of the recorded spectra are
displayed in Fig. 5. As it can be seen, the spectra showed the
2
+
8
bands mainly associated with the d–d transitions of Ni (d ). In
the case of the catalysts derived from 2b, the UV-Vis spectrum
for 3b displayed two peaks at 390 nm and at 640 nm, which
2
+
corresponds to Ni
in octahedral coordination and are
Fig. 5 DR-UV-Vis spectra for PS–Ni catalysts 3b and 4b.
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2
Scheme 2 Asymmetric addition of Et Zn to benzaldehyde.
the stoichiometry of the corresponding Ni complexes (1 : 1 or
1
: 2 metal : ligand ratio).
The effect of the temperature on the reaction was then
investigated. It must be noted that the addition of dialkylzinc to
aldehydes usually reaches a maximum ee value at a certain
25
temperature, which is called the isoinversion temperature. As
ꢀ
described above, initial experiments were carried out at 0 C. A
Fig. 6 Thermal analysis of the polymeric ligand 2b, and the polymeric
complexes 3b and 4b.
ꢀ
further decrease in the reaction temperature to ꢁ25 C did not
provide a signicant variation of the enantioselectivity, but, on
the contrary much lower reaction rates were observed (entry 6,
Table 1). On the other hand, when the reaction was carried out
at room temperature, the enantioselectivity decreased to 59% in
the case of 3b. A similar trend was observed when performing
the addition reaction in the presence of the PS-catalyst 4b.
According to the former results, all subsequent reactions were
with those previously obtained with the homogeneous
systems.
14a,14b
Catalysts 3b and 4b were used for the optimization studies.
For the initial study, diethylzinc (1.2 equiv.) was added dropwise
ꢀ
to a suspension of the polymeric catalyst (5 mol%) at 0 C over
ꢀ
carried out in toluene at 0 C.
ca. 10 min, and then a solution of benzaldehyde (1 equiv.) was
slowly added. Aer stirring for 36 h at the same temperature,
the liquid phase was separated from the polymer by simple
In order to determine the optimal amount of the polymer-
supported catalyst, experiments using variable quantities of
resins 3b and 4b were also carried out. In these studies, the
concentrations of benzaldehyde and diethylzinc were kept
constant at 1.0 and 1.2 mM, respectively, and the reaction was

ltration and the solution was quenched (1 M HCl), to afford,
aer the corresponding work-up, the expected chiral secondary
alcohol.
ꢀ
conducted at 0 C in toluene. When the reaction was carried out
The solvent is known to inuence the activity and the
using a 1 mol% loading of catalyst 3b lower yields (below 90%)
and ee (below 50%) were observed (ESI†). When the loading of
the catalyst was increased to 3 mol%, the yield and ee slightly
increased. Optimum results, in terms of yield and enantiose-
lectivity were achieved when 5 mol% of 3b were used. A further
increase of the catalyst to 10 mol% did not signicantly improve
the results. Similar trends were observed when using resin 4b.
Thus, for all subsequent reactions, loadings of the functional-
ized resins were kept at 5 mol%. Most likely, this indicates that
for low catalyst loadings, for which an important reduction in
the rate of the catalysed reaction takes place, the non-catalysed
addition starts to provide a relatively signicant contribution to
24
enantioselectivity of a catalytic reaction. Therefore, various
solvents frequently used for this type of reaction were screened.
The results, gathered in Table 1 for the supported catalysts 3b
and 4b, showed a remarkable effect of the solvent on the
enantioselectivity and the yield. Non-coordinating solvents such
as hexane and toluene gave higher enantioselectivities than
coordinating solvents such as THF (entries 1 and 2 vs. entry 4).
Interestingly, when changing the solvent from hexane to
toluene (entries 1 and 2), the enantioselectivity signicantly
increased from 44 to 64% for 3b and the yield was almost
quantitative. In the case of 4b the change from hexane to
toluene produced a clear improvement in the yield, but the
enantioselectivity was less affected, as excellent enantiose-
lectivities were observed in both cases (up to 91% for toluene).
a
In the case of CH
2
Cl
2
and CH
3
CN (entries 3 and 5), yields were Table 1 Solvent effects on the addition of Et
2
Zn to benzaldehyde
around 90% for 3b, but signicantly lower enantioselectivities
were observed. Similar trends were observed for 4b, although
these solvent effects were less pronounced. Since toluene gave Entry
the best yield and enantioselectivity for both supported cata-
Catalyst 3b
Catalyst 4b
b
c
b
c
Solvent
Yield (%)
ee (%)
Yield (%)
ee (%)
1
Hexane
Toluene
74
91
87
48
89
69
44 (S)
64 (S)
57 (S)
27 (S)
52 (S)
65 (S)
75
98
71
72
87
70
88 (R)
91 (R)
83 (R)
67 (R)
72 (R)
92 (R)
lysts, this solvent was selected for the rest of the study.
As previously reported for the related homogeneous cata-
lysts, the immobilized 1 : 1 complex afforded (S)-1-phenyl-
2
3
4
CH Cl
2 2
THF
propanol as the major enantiomer whilst the complex prepared
with a 1 : 2 metal : ligand ratio produced (R)-1-phenylpropanol
as the predominant product. Thus, an effective chirality
switching is achieved with this simple ligand just by adjusting
5
6
CH CN
3
d
Toluene
a
b
ꢀ
Performed at 0 C using polymeric catalysts 3b or 4b (5 mol%).
Isolated yield aer column chromatography. Determined by HPLC
c
d
ꢀ
(Chiralcel OD). Performed at ꢁ25 C.
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enanatioselectivity was observed for the 1 : 1 supported catalyst.
However, for 1 : 2 complexes, enantioselectivities were similar
to those obtained with the homogeneous analogue. This
suggests that the uniform formation of 1 : 2 complexes is easily
achieved in the heterogeneous catalyst 4b, while the formation
of these 1 : 2 complexes cannot be completely avoided when the
preparation of the corresponding polymer-supported 1 : 1 Ni
complexes is attempted.
Taking this into consideration, the morphology and loading
of the polymers could have a key inuence on the catalytic
properties of the resulting supported Ni complexes, in partic-
ular in the case of catalysts 3. Accordingly, aer achieving
optimum reaction parameters, the effect of the resin
morphology and loading was studied. For this, the asymmetric
Zn addition of diethylzinc to benzaldehyde was assayed using
several gel-type and monolithic polymer-supported catalysts
with different crosslinking degrees and loadings. The results
obtained are presented in Table 2. As can be seen in this table,
Fig. 7 Kinetic analysis of the reaction of benzaldehyde with Et
using catalysts 3b and 4b at 0 C in toluene. Selectivity > 99%.
2
ꢀ
the process. In the same way, the selectivity also decreases for catalysts 3a–e derived from gel-type resins with low crosslinking
low catalyst loadings, as the non-catalysed side reaction leading degrees gave better results in terms of enantioselectivity than
to the formation of benzyl alcohol also increases.
the monolithic analogues 3f–i. However, yields were not
Finally, a kinetic study was performed under the optimized signicantly affected in most cases. This seems surprising as
ꢀ
conditions (5 mol% catalyst, toluene, 0 C) and the yield, gel-type resins with low crosslinking degrees provide a higher
conversion and selectivity (>99%) of the formed product was degree of exibility to the polymeric chains, and accordingly to
1
determined by performing H NMR spectroscopy on periodi- the functional sites, which could favor the formation of the
cally collected samples (ESI†). The corresponding ee values were more stable 1 : 2 complexes. Thus, the observed results suggest
determined by chiral HPLC. As shown in Fig. 7, the formation of that, in the case of the monoliths, the polymerization of the
1-phenylpropanol increased almost linearly during the rst monomeric mixture, under the described conditions, does not
reaction period of 8 h. Then, the conversion slowed down and provide a uniform distribution of the functional groups through
the product yield reached a plateau at a period of 24 and 34 h, the polymer, thus the catalytic sites are not concentrated on the
for the 1 : 1 and the 1 : 2 polymer-supported nickel complexes, accessible surfaces. On the other hand, no signicant differ-
respectively. In comparison with the homogeneous systems, ences were observed for PS-catalysts 4a–i, which suggests that
longer reaction times were required to complete the studied formation of 1 : 2 complexes involves one covalently polymer-
reaction, being the catalyst 3b slightly more active than 4b.
linked ligand unit and a second non-polymeric ligand frag-
From results shown in Table 1 and Fig. 7, it is clear that ment, as depicted in Scheme 1. This is more favourable than
enantioselectivities obtained from catalyst 4b are always formation of 1 : 2 intrapolymeric complexes involving two
signicantly higher than those observed with catalyst 3b, which covalently supported ligand moieties.
represents a remarkable deviation from the behaviour observed
To further investigate the scope of the catalytic systems, the
with the related homogeneous catalysts. In the latter case, when addition of diethylzinc to a wide variety of aldehydes was
comparing to the homogeneous system, a 33% decrease in
a
Table 2 Effect of resin morphology on the addition of Et
2
Zn to benzaldehyde
Catalyst 3b
Catalyst 4b
b
c
d
c
d
Entry
Resin
Crosslinking degree (%)
Loading found
Yield (%)
ee (%)
Yield (%)
ee (%)
e
1
2
3
4
5
6
7
8
9
a
1
1
1
1
1
20
20
20
20
0.8
1.0
1.6
1.8
2.0
0.9
1.5
1.7
2.0
95
91
94
92
94
95
87
85
90
61 (S)
64 (S)
62 (S)
58 (S)
60 (S)
55 (S)
40 (S)
35 (S)
32 (S)
94
98
98
98
98
98
98
98
98
90 (R)
91 (R)
89 (R)
88 (R)
90 (R)
90 (R)
89 (R)
90 (R)
89 (R)
e
b
e
c
e
d
e
e
f
f
f
g
f
h
f
i
a
ꢀ
b
Performed at 0 C using polymeric catalysts 3b or 4b (5 mol%). Loading of a-amino amide groups in resins 2 calculated by N elemental analysis
c
d
e
f
(mmol functional group per g resin). Isolated yield aer column chromatography. Gel type. Determined by by HPLC (Chiralcel OD). Monolith.
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Table 3 Enantioselective addition of diethylzinc to aldehydes in the give the major (R) enantiomer. Thus, with 4b, aromatic alde-
a
presence of polymer-supported Ni(II) complexes
hydes gave excellent yields and ee values, especially for alde-
hydes with strong electron-donating groups, with
enantioselectivities reaching up to 92% (entry 2). On the
ee (%) contrary, the presence of an electron-withdrawing group seems
to produce a decrease in the ee value (78% for Cl, entry 4). Even
Catalyst 3b
Catalyst 4b
b
c
b
c
Entry
RCHO (R)
Yield (%)
ee (%)
Yield (%)
1
2
3
4
5
6
7
8
9
C
6
H
5
91
95
90
91
76
94
88
84
59
64 (S)
69 (S)
59 (S)
56 (S)
51 (S)
52 (S)
53 (S)
52 (S)
44 (S)
98
98
89
86
82
98
89
89
87
91 (R)
94 (R)
88 (R)
82 (R)
86 (R)
94 (R)
84 (R)
77 (R)
76 (R)
bulky aromatic aldehydes, such as 2-naphthaldehyde, afforded
good enantioselectivies (82%, entry 5). Also, aliphatic aldehydes
p-CH
p-CH
3
OC
6
H
4
3
6
C H
4
p-ClC
6
H
4
(entries 6 and 7) provided good results when catalyst 4b was
used, although the corresponding enantiomeric excesses were
somehow lower than those for aromatic aldehydes. As previ-
ously reported by different authors, the steric bulk around the
chiral carbon atom or the nitrogen atom in chiral b-amino
alcohol ligands generally enhances the enantioselectivity of the
o-CH
m-CH
3
OC
OC
6
H
4
3
6 4
H
2-Naphtyl
Cyclohexyl
n-C
5
H
11
a
All reactions were performed using polymeric catalysts 3b or 4b
5 mol%) at 0 C. Isolated yield aer column chromatography.
Determined by HPLC (Chiralcel OD).
27
ꢀ
b
2
Et Zn addition to benzaldehyde. Accordingly, the polymer-
(
c
supported 1 : 1 and 1 : 2 nickel complexes prepared from
a-amino amides derived from different amino acids were
assayed as catalysts in the asymmetric addition of diethylzinc to
benzaldehyde under the optimized reaction conditions (5 mol%
examined and several trends emerged from these experiments
Table 3). In general, using both catalysts 3b and 4b good yields
ꢀ
catalyst, 0 C, toluene, 36 h). According to the above considered
(
results, the polymeric support used in this case was identical to
the one employed in the case of the catalysts 3b and 4b. The
main results obtained are gathered in Table 5 and conrms the
expected trends. All polymer-supported catalysts provided the
chiral alcohol with yields higher than 90%. Again, better ee
were obtained (>75%), although in all cases better enantiose-
lectivities were obtained when catalyst 4b was used. The pres-
ence of electron-donating or electron-withdrawing substituents
on the aromatic ring is also compatible with these reaction
conditions, although, in general, aromatic aldehydes with
electron-donating groups were ethylated with higher enantio-
selectivities. When catalyst 4b was used, aromatic substrates
Table 4 Enantioselective addition of dimethylzinc to aldehydes in the
including
2-naphthaldehyde,
benzaldehyde,
4-methox-
a
presence of polymer-supported Ni(II) complexes
ybenzaldehyde and 4-chlorobenzaldehyde reacted with dieth-
ylzinc to afford the corresponding (R)-alcohol in 82–94% ee. The
observed substituent effect was most pronounced at the ortho
position, most likely due to the increased steric effects that
these groups exert in this position. Interestingly, aliphatic
aldehydes were also ethylated, although the enantioselectivity,
and in some cases the yields were reduced in comparison with
aromatic aldehydes (entries 8 and 9).
Catalyst 3b
Catalyst 4b
b
c
b
c
Entry
RCHO (R)
Yield (%)
ee (%)
Yield (%)
ee (%)
1
2
3
4
5
6
7
C
6
H
5
86
84
87
92
86
60
63
62 (S)
58 (S)
60 (S)
67 (S)
51 (S)
33 (S)
32 (S)
85
97
84
85
88
74
71
91 (R)
92 (R)
83 (R)
78 (R)
82 (R)
72 (R)
67 (R)
p-CH
p-CH C H
4
3 6 4
OC H
3
6
p-ClC
2-Naphtyl
n-C
6 4
H
Enantioselective addition of dimethylzinc to aldehydes has
attracted much less attention than diethylzinc additions
5
H
11
Cyclohexyl
26
because of its lower reactivity. However, the development of an
efficient method for the asymmetric addition of dimethylzinc is
still a highly desirable goal in asymmetric catalysis. The related
process for the addition of dimethylzinc to aldehydes was then
evaluated with the same supported catalysts. Thus, in the
a
ꢀ
Performed at 0 C using polymeric catalysts 3b or 4b (5 mol%).
b
c
Isolated yield aer column chromatography. Determined by GC.
presence of 5 mol% of the Ni(II) catalyst 4b, the reaction with
Table 5 Effect of the amino acid side chain in the addition of dieth-
ꢀ
a
benzaldehyde was complete aer 24 h at 0 C with a 91% ee. At ylzinc to benzaldehyde
ꢀ
2
5 C the reaction afforded the desired product in 83% yield
1
: 1 Catalyst
1 : 2 Catalyst
with 81% ee. At room temperature, a further increase in the
catalyst loading to 10 mol% did not benet the enantiose-
lectivity and the yield of the product was maintained. Thus,
b
c
b
c
Entry
Amino acid
Yield (%)
ee (%)
Yield (%)
ee (%)
ꢀ
5
mol% of catalyst loading and 0 C was selected as the best
1
2
3
4
5
Phe
Val
Leu
Ala
95
94
94
91
90
65 (S)
51 (S)
33 (S)
29 (S)
68 (S)
96
95
92
93
91
91 (R)
61 (R)
79 (R)
59 (R)
92 (R)
reaction conditions in toluene.
In the asymmetric addition of dimethylzinc to aldehydes the
supported catalysts 3b and 4b gave moderate to excellent yields
PhGly
(
3
Table 4). The enantioselectivities were moderate when catalyst
b was used, affording the major (S) enantiomer. While much
a
ꢀ
Performed at 0 C using polymeric catalysts derived from different
b
amino acids related to 3b or 4b (5 mol%). Isolated yield aer
c
higher ee values were obtained when the catalyst 4b was used to column chromatography. Determined by HPLC (Chiralcel OD).
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aromatic and aliphatic aldehydes. The preparation of 1 : 2
complexes, obtained by reaction of the supported 1 : 1
complexes with an additional equivalent of the homogeneous
ligand, illustrates the potential of this novel approach, in which
the metal is anchored rst and then a chiral ligand is bound
from the solution to metal. The results obtained clearly
demonstrate the capacity of these heterogeneous catalysts for
the production of both enantiomers, which may be produced by
fully green catalytic processes. Although the enantiomeric
excesses were slightly lower than those obtained with homo-
geneous catalysts in the case of 1 : 1 complexes, the enantio-
selectivity was identical in the case of 1 : 2 complexes, and both
heterogeneous systems (1 : 1 and 1 : 2 metal : ligand
complexes) had the advantage of their simple and efficient
recyclability. Further investigation on the applications of these
nickel complexes for other asymmetric reactions as well as the
use in continuous ow systems is ongoing in our laboratory.
Fig. 8 Reuse of polymer supported catalysts 3b and 4b.
values were obtained when 1 : 2 metal : ligand catalysts were
used to give the (R)-alcohol as the major enantiomer. Catalysts
containing ligands derived from phenylalanine and phenyl-
glycine provided the highest ee values for the ethylation of
benzaldehyde (91–92% ee). The enantioselectivity observed for
catalysts derived from ligands containing aliphatic side chains
was signicantly affected by the presence of a and b-branching.
In this regard, the enantioselectivity was higher for the Val
derivative than for the Leu derivative for the corresponding 1 : 1
complexes, while the reverse was observed for the 1 : 2
complexes. As expected, the Ala derivatives, having the less
sterically demanding side chain gave lower enantioselectivities.
One of the purposes for designing heterogeneous catalysts is
to reuse the catalyst in subsequent reactions. Thus, the poten-
tial reuse of the functionalized resins was examined for the
Acknowledgements
This research was nancially supported by Ministerio de
Econom ´ı a y Competitividad (CTQ2011-28903-C02-01), General-
itat
Valenciana
(PROMETEO/2012/020)
and
PPI-UJI
(P1-1B-2013-38).
Notes and references
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enantioselective addition of Et
completion of the reaction as monitored by TLC analysis, the
catalyst was separated by ltration under N atmosphere and
washed with dry CH Cl . Importantly, the presence of neither
2
Zn to benzaldehyde. Aer
2
2
3
2
2
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