Polymer-supported chiral α-amino amides for the asymmetric addition of diethylzinc to aldehydes: Transforming an inactive homogeneous system into an efficient catalyst

Article abstract of DOI:10.1016/j.apcata.2013.04.030

A series of polymer-supported α-amino amides derived from natural amino acids have been easily synthesized and fully characterized. Their chiral Zn (II) complexes catalyzed the enantioselective addition of diethylzinc to aldehydes to form chiral secondary alcohols in high yields and enantioselectivities up to 95% were obtained. The results showed that the immobilization of this chiral ligand onto a polymeric matrix transforms the inactive homogeneous system into an efficient catalyst. Moreover, the supported catalyst could be re-used at least five times without any significant loss of catalytic activity.

Full text of DOI:10.1016/j.apcata.2013.04.030

Accepted Manuscript
Title: Polymer-supported chiral ␣-amino amides for the
asymmetric addition of diethylzinc to aldehydes:
Transforming an inactive homogeneous system into an
efficient catalyst
´
´
Authors: Jorge Escorihuela Laura Gonzalez Belen Altava M.
Isabel Burguete Santiago V. Luis
PII:
S0926-860X(13)00234-2
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2013.04.030
APCATA 14199
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
7-1-2013
25-3-2013
16-4-2013
´
Please cite this article as: J. Escorihuela, L. Gonzalez, B. Altava, M.I. Burguete,
S.V. Luis, Polymer-supported chiral ␣-amino amides for the asymmetric
addition of diethylzinc to aldehydes: Transforming an inactive homogeneous
system into an efficient catalyst, Applied Catalysis A, General (2013),
http://dx.doi.org/10.1016/j.apcata.2013.04.030
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Polymer-supported chiral -amino amides for the asymmetric addition
of diethylzinc to aldehydes: Transforming an inactive homogeneous
system into an efficient catalyst
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Jorge Escorihuela,† Laura González, Belén Altava, M. Isabel Burguete, Santiago V.
Luis*
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Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat s/n, E-12071
Castellón (Spain), Fax: (+34) 964728214, e-mail: luiss@qio.uji.es
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Abstract
A series of polymer-supported -amino amides derived from natural amino acids have
been easily synthesized and fully characterized. Their chiral Zn (II) complexes
catalyzed the enantioselective addition of diethylzinc to aldehydes to form chiral
secondary alcohols in high yields and enantioselectivities up to 95% were obtained. The
results showed that the immobilization of this chiral ligand onto a polymeric matrix
transforms the inactive homogeneous system into an efficient catalyst. Moreover, the
supported catalyst could be re-used at least five times without any significant loss of
catalytic activity.
Keywords: asymmetric catalysis, polymer-supported catalysts, diethylzinc, N-
containing ligands, enantioselective addition
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†
Current address: Centro de Reconocimiento Molecular y Desarrollo Tecnológico, Departamento de Química, Universitat
Politècnica de València, Camino de Vera, s/n, 46022 Valencia (Spain)
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1. Introduction
The use of polymer-supported catalysts in asymmetric reactions is a vigorously pursued
area of research.[1-4] Besides simplification of separation and recycling, immobilized
catalysts offer additional benefits including easier handling of toxic reagents, improved
stability of labile systems in the polymeric matrix and convenient operation in
continuous flow reactors, making the catalytic processes more environmentally friendly
and industrially applicable.[5] Thus, the industrial applications of even expensive and
complex chiral catalysts can be achieved in an economical and environmentally benign
way. Carbon-carbon bond formation is the essence of organic synthesis and provides the
foundation for generating more complicated organic compounds from the simpler ones.
In this regard, the enantioselective organozinc addition to aldehydes is of long standing
research interest as the resulting optically active sec-alcohols are important building
blocks,[6] and has become a benchmark reaction in enantioselective catalysis.[7-8] This
process is efficiently catalyzed by homogeneous catalysts derived from a variety of
chiral ligands such as amino alcohols (N, O ligands),[9-11] diamines (N, N
ligands),[12-13] or diols (O, O ligands).[14-15]. Some drawbacks of the homogeneous
catalytic systems are the difficulties involved in separation of catalyst from the reaction
media, purification of the products and the reuse of the catalyst, normally requiring
tedious procedures. Thus, it is not surprising that, since the seminal work by Soai,
Itsuno and Frechet,[16-17] different research groups have been involved in the
preparation of polymer-supported chiral ligands, being able to efficiently mediate this
transformation.[18-23] Most efforts are directed towards the preparation of supported
systems being able to act in a comparable way to that of the homogeneous counterparts
by reducing the potential interferences of the polymeric matrix.[24-27] This has been
based on the consideration that the micro heterogeneities provided by the presence of
the matrix produce a reduction in the performance of the polymer-supported system. An
alternative approach is to take advantage of the properties of the polymeric matrix and
the immobilization process to develop supported catalytic systems with higher activities
and selectivities than their homogeneous counterparts.[28-30]
From the several families of chiral ligands used in asymmetric catalysis, nitrogen-
containing ligands have received an important attention over the last years.[31] In this
regard, simple -amino amides 1 and bis(amino amides) 2, having an amino group and
an easily ionisable N-H amide subunit, can be compared to amino alcohols and
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structures of this class have been recently reported as good ligands for different
enantioselective transformations, such as, the Ru (II)-catalyzed asymmetric transfer
hydrogenation of acetophenone,[32-33] or the conjugate addition of dialkylzinc to
chalcones,[34] Zn(II) complexes of related bis(amino amide) ligands 2 (Figure 1) gave
high enantioselectivities in the addition of dialkylzinc reagents to aromatic
aldehydes[35] and their corresponding Cu (I) complexes were effective for the
cypropopanation reaction.[36] Recently, we have shown that Ni (II) complexes of
amino amides are able to efficiently catalyze the addition of dialkylzincs to aldehydes,
achieving an excellent dual stereocontrol just by a proper adjustment of the
stoichiometry of those Ni complexes.[37-39] Taking this into account, we consider the
preparation of the corresponding polymer-supported systems derived from 1, as
heterogeneous catalyst offer many advantages over the homogeneous systems.
Thus, herein we report, in connection with our previous work in this area how a non-
active homogenous system can be transformed, upon immobilization onto a
polystyrene-divinylbenzene polymer, into an active, highly selective and
enantioselective catalytic system. The catalytic behaviour of the corresponding
polymer-supported -amino amides has been investigated for the enantioselective
addition of dialkylzinc compounds to aldehydes.
2. Experimental
2.1. Materials
All reagents were used as received, without any further purification. All samples were
vacuum-dried at 60 ºC for 24 h before 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 conditions: 785 nm laser with a single
monochromator, grating 600 lines·mm-1, slit 0.2 mm, resolution 12.75 cm-1, with a
center wavenumber of 1200 cm-1, 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
1108 apparatus. DSC curves were obtained at 10 K/min under nitrogen atmosphere.
Thermal analyses were carried out using a TG-STDA Mettler Toledo model
TGA/SDTA851e/LF/1600 analyzer under a flow of N2. The temperature range for TGA
was 30-400 ºC at 10 ºC·min-1. TEM and XDS experiments were carried out with a JEOL
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2100 instrument. Access to the above equipment was provided by the SCIC (Servei
Central d’Instrumentació Científica) of the Universidad Jaume I.
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2.2. Catalysts preparation and characterization.
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Synthesis of resins 4a-k. To a suspension of chloromethylated resin 3 (1 mmol) in dry
DMF (10 mL), sodium phthalimide (2.5 mmol in DMF) was slowly added and reaction
mixture was stirred at 50-60 ºC for 18 h. The resulting resin was filtered and washed
with DMF (3×10 mL), methanol, (3×10 mL) water (3×10 mL) and methanol (3×10 mL)
and vacuum dried at 50°C overnight to give polymer 4. The NBP test was applied with
negative results to a sample of the polymer.[40] FT-IR (KBr) νmax 3031, 2921, 1718,
1602, 1492, 1452, 1027, 696 cm-1; FT-Raman νmax 2953, 1770, 1640, 1451, 1170, 1019
cm-1; Elemental analysis (in parentheses theoretical results for a quantitative
transformation) for 4a, 1.20% N (1.22% N); 4b, 1.40% N (1.41% N); 4c, 1.88% N
(1.95% N); 4d, 2.26% N (2.29% N); 4e, 2.58% N (2.74% N); 4f, 2.79% N (2.98% N);
4g, 1.24% N (1.27% N); 4h, 2.08% N (2.15% N); 4i, 2.50% N (2.61% N); 4j, 2.78% N
(2.95% N); 4k, 3.34% N (3.42% N).
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Synthesis of resins 5a-k. To a suspension of resin 4 (1 mmol) in ethanol (10 mL), a
solution of hydrazine (2.5 mmol in ethanol) was added dropwise under an inert
atmosphere and refluxed. The resulting resin was filtered and washed with ethanol
(3×10 mL), diluted KOH solution (3×10 mL), water (3×10 mL) and methanol (3×10
mL) and vacuum dried at 50 °C overnight to give polymer 5. FT-IR (KBr) νmax 3374,
3022, 2921, 1603, 1493, 1452, 1028, 697, 532 cm-1; FT-Raman νmax 2956, 1170, 1636,
1451, 1179, 1014 cm-1; Elemental analysis (in parentheses theoretical results for a
quantitative transformation) for 5a, 1.31% N (1.38% N); 5b, 1.50 % N (1.61% N); 5c,
2.26% N (2.38% N); 5d, 2.79% N (2.90% N); 5e, 3.50% N (3.67% N); 5f, 4.01% N
(4.13% N); 5g, 1.38% N (1.43% N); 5h, 2.55% N (2.69% N); 5i, 3.32% N (3.44% N);
5j, 3.91% N (4.06% N); 5k, 4.89% N (5.02% N).
Synthesis of resins 6a-k. To a suspension of resin 5a (1 mmol) in dry THF (5 mL), a
solution of Cbz-(S)-2-amino-N-benzyl-3-phenylpropanamide (2.3 mmol in THF) was
added dropwise under an inert atmosphere. The reaction mixture was stirred at 50-60 ºC
for 12 h. The resulting resin was filtered and washed with THF (3×10 mL), methanol
(3×10 mL), water (3×10 mL) and methanol (3×10 mL) and vacuum dried at 50°C
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overnight to give polymer 6a. 13C RMN (75 MHZ, gel phase, CDCl3) : 42.6, 50.3,
61.2, 68.8 ppm; FT-IR (KBr) νmax 3412, 3032, 2925, 1716, 1671, 1605, 1493, 1452,
1027, 697 cm-1; FT-Raman νmax 2954, 1770, 1639, 1451, 1172, 1033 cm-1; Elemental
analysis (in parentheses theoretical results for a quantitative transformation) for 6a,
2.11% N (2.16% N); 6b, 2.31% N; (2.44% N) 6c, 3.12% N (3.22% N); 6d, 3.44% N
(3.67% N); 6e, 4.11% N (4.22% N); 6f, 4.40% N (4.51% N); 6g, 2.11% N (2.23% N);
6h, 3.32% N (3.50% N); 6i, 3.98% N (4.07% N); 6j, 4.31% N (4.47% N); 6k, 4.93% N
(5.00% N).
Synthesis of resins 7a-k. To a suspension of resin 6a (1 mmol) in CH2Cl2 (10 mL), a
solution of HBr/AcOH (33%) was slowly added and the mixture was stirred at rt during
18 h. The resulting resin was filtered and washed with diethylether (3×10 mL),
methanol (3×10 mL), water (3×10 mL), diluted KOH solution (3×10 mL), methanol
(3×10 mL) and CH2Cl2 (3×10 mL) and vacuum dried at 50 °C overnight to give
polymer 7a. 13C RMN (75 MHz, gel phase, CDCl3) : 42.1, 51.3, 61.6 ppm; FT-IR
(KBr) νmax 34180, 3020, 2923, 1674, 1602, 1492, 1455, 1274, 696 cm-1; FT-Raman νmax
2952, 1639, 1454, 1174, 1029 cm-1; Elemental analysis (in parentheses theoretical
results for a quantitative transformation) for 7a, 2.23% N (2.41% N); 7b, 2.64% N
(2.76% N); 7c, 3.59% N (3.80% N); 7d, 4.38% N (4.45% N); 7e, 5.14% N (5.30% N);
13f, 5.58% N (5.76% N); 7g, 2.38% N (2.49% N); 7h, 4.05% N (4.20% N); 7i, 4.88% N
(5.06% N); 7j, 5.48% N (5.69% N); 7k, 6.36% N (6.57% N).
Synthesis of the Zn complex derived from 7a.
To a toluene suspension of resin 7a 2.2 equivalents of Et2Zn (1.1 M in toluene) were
slowly added under inert atmosphere at 0 ºC during 30 minutes. After washing with dry
toluene and drying with a stream of N2, the resulting zinc complex was isolated and
kept under inert atmosphere. FT-IR νmax: 3023, 2923, 1662, 1594, 1488, 1446, 1025,
751, 696 cm-1.
2.3. Catalytic tests
General Procedure for the Asymmetric Addition of Diethylzinc to Aldehydes
Catalyzed by PS Catalysts. To a stirred suspension of the polymer-supported catalyst
(10 mol %) in toluene (1 mL) was added a solution of aldehyde in hexanes under argon,
and the stirring was continued at r.t. for 30 min. After the addition of diethylzinc (1.1 M
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in toluene) at 0°C, the reaction mixture was stirred at r.t. for a further 36 h, and was then
quenched with 1 M HCl (4 mL). The resulting mixture was filtered and the filtrate was
extracted with CH2Cl2 (310 mL). The combined organic layers were dried with
anhydrous MgSO4 and concentrated under reduced pressure. Purification of the residue
by flash chromatography (PE/AcOEt 15:1) afforded the desired alcohol. The
enantiomeric excess and the absolute configuration of the resulting alcohols were
determined by HPLC and optical rotation. The catalyst was collected by filtration,
washed with dry CH2Cl2, vacuum dried and used for a new run. For regeneration, the
polymer was stirred with 1 M HCl-THF (1:2 mL) for 1 h, and then washed successively
with CH2Cl2 (315 mL), THF (215 mL) and MeOH (215 mL). After vacuum dried at
50 °C for 5 h, the resin could be reused in the successive catalytic reactions. A typical
analysis of the reaction products separated reveals (R)- and (S)-1-phenyl-1-propanol
(12), and a small amount of benzyl alcohol (13), as the side-product. The selectivity was
calculated by the following equation based on the 1H NMR peak areas:
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Conditions for the Analysis of Chiral Secondary Alcohols. Chiral Capillary GC
column VF-5 ms; 30 m  0.25 mm, 0.25 m. Carrier Gas: H2 (5 mL·min-1). Inyector
230 ºC, Detector (FID) 300 ºC, oven 60-130 ºC, 10 ºC min-1. Chiral HPLC: Chiralcel
OD columm; 254 nm UV detector. The racemic alcohols products were obtained by
addition of Et2Zn and Me2Zn to aldehydes. The conditions of analysis and retention
times of the R and S isomers have been reported elsewhere.[42-43]
3. Results and discussion
3.1. Synthesis of polymer-supported chiral -amino amides
Considering the advantages of immobilized catalysts in asymmetric synthetic reactions,
we considered to anchor -amino amide ligands onto a polystyrene-divinylbenzene
resin. Initial attempts of synthesizing polymer-supported chiral -amino amides were
carried out by direct reaction of ligand 1 with commercial Merrifield resins with a low
level of crosslinking (gel-type chloromethylated PS-DVB, 1% DVB), but the analysis of
the resulting functionalized polymers suggested that polyalkylation of the amine groups
was taking place, as inferred from elemental analysis data. In order to avoid this
problem, an alternative grafting methodology was designed (Figure 1). For this strategy,
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both, gel-type commercially available Merrifield resins and monolithic macroporous
chloromethylated resins were used as the starting polymers 3. In the case of
macroporous polymers, monolithic resins were prepared by polymerization of a mixture
of styrene (8), divinylbenzene (9) and chloromethylstyrene (10) under radical conditions
(Supplementary Material), using AIBN as the initiator and toluene/dodecanol as the
porogenic mixture, following previously described procedures.[44-45] Under the
studied conditions , polymerizations proceed in general in quantitative yields obtaining
polymers with crosslinking degrees of 1 and 2% for gel-type resins (see Table 1) and 20
% for the monoliths.
FIGURE 1
As shown in Figure 1, treatment of polymers 3 with potassium phtalimide in DMF at 50
ºC gave resins 4 with quantitative yields.[46-47] The reaction was easily monitored
using FT-IR and FT-Raman spectroscopy.[48] Thus, FT-IR spectra showed the
appearance of new bands at 1717 cm-1, for the phthalimide moiety, as well as the
complete disappearance of the C-Cl band at 1265 cm-1, which was even clearer in the
FT-Raman spectra. Complete substitution of the chloride was also confirmed by
elemental analysis and by the NBP test, which showed negative results.[40] The NBP
test is able to easily determine the presence of reactive chloride groups and was found to
be very important to characterize this step. After, phtalimide treatment, reaction of
resins 4 with hydrazine hydrate in refluxing ethanol overnight provided the
transformation of phthalimide groups into amine groups, affording resins 5, whose IR
spectra showed the absence of bands at 1717 cm-1. The conversion of the aminomethyl
resins 5 into functionalized polymers 6 was carried out by reaction with N-Cbz-L-
phenylalanine in THF. The resulting resins 6 displayed IR bands at 1671 and 1716 cm-1,
corresponding to the Cbz-N-protected amino amide moiety, showing the effective
immobilization of the ligand onto the polymeric support. Final deprotection of the
amine groups was obtained by overnight treatment with 33% HBr/HOAc in CH2Cl2 to
afford the desired amino amide polymers 7, following a similar protocol to that used for
the preparation of related compounds in solution.[49-53] These functionalized resins
showed the complete absence of the Cbz band at 1716 cm-1 in their IR spectra. By using
this methodology, functionalized resins with final loadings ranging from 0.80 to 2.27
mmol/g, according to the elemental analyses, were obtained. (Table 1) These values are
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in good agreement, within the experimental error, with the values expected for a
quantitative transformation from 3.
13C gel-phase NMR spectroscopy could also be applied to monitor those synthetic
transformations and to characterize the final polymers in the case of low crosslinked (1-
2%) gel-type resins.[54-55] The 13C gel-phase NMR spectrum reveals several broad and
intense peaks around 40 and 130 ppm corresponding to the C atoms of the PS-DVB
resin. The appearance new peaks of aliphatic carbons at 42.1, 51.3 and 61.6 ppm
indicates the successful anchoring of the -amino amide on the polymeric matrix (see
Supplementary material). Likewise, these polymers were characterized by DSC and
TGA, showing thermal stabilities over 210 ºC (see Supplementary Material). Similar
behavior was observed for the catalytic complex.
TABLE 1
In general, for the synthesis of the different polymer-supported chiral -amino amides,
very good yields could be achieved for all the considered transformations. This is
clearly illustrated by the data shown in Table 1, which shows the values obtained for
conversion and loading for the final polymer-supported ligands from the corresponding
elemental analysis data.
3.2. Catalytic activity in the asymmetric addition of diethylzinc to aldehydes
The catalytic efficiency of the functionalized polymers 7 was tested for the addition of
Et2Zn to benzaldehyde leading to the formation of 1-phenyl-propanol. This benchmark
reaction is a commonly used method for synthesizing chiral secondary alcohols, which
are useful intermediates for the preparation of biologically active compounds and are
often components of natural products. Although previous studies in solution with ligand
1 and related compounds had shown that an efficient enantioselective catalysis of the
addition of Et2Zn to benzaldehyde required the previous formation of their Ni (II)
complexes,[37] preliminary experiments were carried out with resin 7a (10 % molar),
1.0 equivalent of benzaldehyde (1.1 M in toluene) and 2.2 equivalents of Et2Zn (1.1 M
in toluene) at 0 ºC. Rather surprisingly, (see Table 2, entry 1) after 18 h, (S)-1-
phenylpropanol was obtained in 87% yield, with 91% ee. After 36 h, the yield was
raised to 94% and the enantioselectivity slightly increased up to 92%. When compared
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to the results for the homogeneous system (see entry 12, Table 3), this represents one of
the more dramatic positive effects of the polymeric backbone up to now reported for
polymer-supported reagents or catalysts.
FIGURE 2
The “in situ” formation of the catalyst during the addition reaction was supported by
experimental ATR-FTIR studies in inert atmosphere. Thus, the zinc complex was
prepared by treatment of the resin 7a with 2.2 equivalents of Et2Zn (1.1 M in toluene) at
0 ºC during 30 minutes under inert atmosphere, subsequent washing with dry toluene
and drying by a stream of N2. As shown in Figure 2, the vibrational band observed for
7a at 1672 cm-1, assigned to the C=O stretching, is shifted to lower wavenumbers (1594
cm-1) indicating the participation of the deprotonated amide group in the coordination to
the zinc atom, as observed in related systems.[56-59] Additionally, transmission
electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDS) were used
to characterize the catalytic zinc complex and results confirmed the presence of this
metal in the polymeric matrix (see Supplementary Material). As illustrated by the inlet
in Figure 2, TEM images and EDX (Supplementary Material) also confirm the presence
of zinc in the polymeric matrix. No changes occur after the reaction if the sample is
handled with care, under an inert atmosphere. In the presence of humidity, the catalytic
complex is destroyed as revealed by the appearance of the C=O band at 1674 cm-1 (see
Supplementary Material). Under those circumstances, zinc oxide seems to be formed.
TABLE 2
Initially, a screening of solvents was carried out under identical conditions to study the
solvent effect. Positive results were also obtained using other solvents such as THF,
CH2Cl2 or hexane, although the enantioselectivities obtained were significantly lower
(see Table 2). Lowering the reaction temperature for the addition to -20 ºC, resulted in a
slight increase of enantioselectivity (93% ee) but at the expenses of an important
decrease in the reaction rate. Next, in order to determine the optimal amount of the
ligand needed for the addition of diethylzinc to benzaldehyde, several experiments using
variable quantities of functionalized resin 7a were carried out. In these studies, the
concentrations of benzaldehyde and diethylzinc were kept constant at 0.5 and 1.1 mM,
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respectively, and the reaction was conducted at 0 ºC in toluene. Decreasing the catalyst
loading to 5% reduced slightly the enantioselectivity to 90% ee, maintaining the
conversion. Most likely, this indicates that for this catalyst loading the uncatalyzed
reaction starts to provide a significant contribution to the process. This is confirmed
when a further decrease in catalyst loading (3 and 1%) is studied (see Supplementary
Material), as, in this case, also the conversion is reduced for the same reaction time. The
selectivity also decreases, as reducing the rate of the process increases the relative
importance of the alternative reaction of aldehyde reduction. Thus, optimal conditions
seems to correspond to the use of 5 molar % of functionalized resin in toluene at 0 ºC
for 36 h.
TABLE 3
The different resins 7, containing variable levels of cross-linking and ligand
functionalization, were then assayed for this benchmark reaction. The results are
summarized in Table 3. The reaction was studied at 0 ºC in toluene, using a 5% molar
amount of the supported catalyst for 36 hours. All of them promoted the
enantioselective addition of diethylzinc to benzaldehyde, with enantioselectivities from
moderate to high and in good yields. The predominant enantiomer of 1-phenyl-1-
propanol formed in the reactions possessed the S configuration, which suggest the
prevalence of the mechanistic model established by Noyori and coworkers for the amino
alcohol mediated reaction.[60-61]
FIGURE 3
A similar mechanism can be proposed for the polymer-supported -amino amides, as
shown in Figure 3. After elimination of an ethane molecule from diethylzinc, the zinc
atom can be coordinated by the amide and amine sites to form a five-membered
intermediate, involving deprotonation of amide, as inferred from IR spectra. This zinc
complex coordinates to benzaldehyde through the zinc atom activating the carbonyl
group. Interaction with a second diethylzinc molecule, provides the product forming
complex, facilitating the ethyl migration to benzaldehyde via a tricyclic transition state.
Based on this model, the product forming complex is regenerated upon reaction with
diethylzinc and benzaldehyde, after elimination of a stable dialkylzinc alkoxyde and
10
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completing the catalytic cycle. The stereochemistry of the alkoxyde product is
kinetically determined by the relative energy of the two most stable diastereomeric
transition states, namely anti-trans and anti-cis, which favour the formation of the (S)-
and (R)-product, respectively. In this case, an energy difference of 2.8 kcal/mol is
calculated between the two transition states (Supplementary Material) using DFT
calculations with the Spartan 10 software package.[62] Thus, calculations predict a high
enantioselectivity with the S stereoisomer being the main product, which is consistent
with the experimental results.
The dramatic effect on activity observed upon immobilization could be related with the
formation of inactive aggregated species for the homogeneous system.[63-64] As a
matter of fact, formation of some colloidal particles is observed after some time,
although complete precipitation does not take place. To get further information in this
regard, several solvents where tested using 1 as ligand. Again, no activity was observed
in hexane, THF and CH3CN. Previous formation of the Zn complex by treatment by
Zn(OAc)2 provided some activity but without any enantioselectivity. Although the
reaction rate and enantioselectivity of immobilized catalysts are sometimes lower than
those of the homogeneous system,[29] mainly because the chiral selective sites may be
more hindered when anchored onto the solid supports, this steric hindrance, associated
with the rigidity of the polymeric matrix, can also avoid the formation of such
aggregated systems (Supplementary Material). This is confirmed by the results shown
in Table 3 that show how the enantioselectivity decreases when the functionalization
degrees are increased. Rather interestingly, monolithic resins always give place to
significantly lower enantioselectivities (see entries 7-11). This suggests that the
polymerization of the monomeric mixture, under the conditions used, does not provide a
uniform distribution of the chloromethyl functional groups through the polymer, and
accordingly of the catalytic sites, probably concentrated on the accessible surfaces. This
decreases the efficiency of the pseudodilution effect required to achieve a higher
enantioselectivity.[65]
A kinetic study was performed under the optimized conditions (catalyst 7b, toluene, 0
ºC) and Figure 4 displays the conversion of benzaldehyde and product yields as a
function of the reaction time. The graph also includes the variation of selectivity and
enantioselectivity during the reaction period considered. The concentration of
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397
benzaldehyde decreases with time while that of the main product (1-phenyl-1-propanol)
increases almost linearly during the first reaction period of ca. 10 h. Then, the
conversion slows down and the product yield approaches a plateau after a period of ca.
20 h. In comparison, the yield of the minor 1-phenyl-1-methanol by-product increases
during the initial reaction period but slows down after 10 h. The addition was essentially
complete after 30 h. In this way, the selectivity slightly increases with time, while the
enantioselectivity remains essentially constant.
FIGURE 4
The general applicability of resin 7b was tested on a variety of aldehydes, including
aromatic and aliphatic aldehydes, under the optimized reaction conditions (catalyst 7b
(10% mol) in toluene at 0 ºC, 36 h.). The desired sec-alcohols were obtained in high
conversions and some results are gathered in Table 4. For the aromatic aldehydes
studied, the products were isolated in excellent yields (83-90%) and enantioselectivities
(86-95%). In all cases, the (S)-enantiomer of the addition product was obtained as the
major isomer. The substitution on the aromatic ring in aromatic aldehydes has an
appreciable effect on the enantioselectivity. Thus, the presence of a strong electron-
releasing group (methoxy) in para gives place to the higher yields and
enantioselectivities (see entry 2 in Table 4), whiles the presence of an electron-
withdrawing group, such as chlorine, reduces both yield and enantioselectivity (entry 4,
Table 4). The aliphatic aldehydes tested were also ethylated with a high degree of
enantioselectivity (73 and 80%, entries 7 and 8). This is noteworthy, as this process is,
in general, less efficient with most of the homogeneous and heterogeneous systems
studied.[66-68] When the enantioselective addition of dimethylzinc to aldehydes was
investigated (entries 9-11), good to excellent enantioselectivities could be achieved for
various aromatic aldehydes. It was also found that this catalyst was efficient for the
addition of dimethylzinc to aliphatic aldehydes (entry 11), although with lower
conversions and enantioselectivity.
TABLE 4
Finally, the potential reuse of the resin 7b, using a 5 % catalyst loading, was examined
for the enantioselective addition of Et2Zn to benzaldehyde. After 36 h of reaction, the
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426
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431
resin was filtered, washed with CH2Cl2 and vacuum dried. The resulting resin was
directly used for a new catalytic cycle at 0 ºC. The results in Figure 5 show that the
resin could be used for five consecutive runs to afford (S)-1-phenyl-1-propanol in
excellent yields (87-90%) with only a minor drop in enantioselectivity (from 91 to
87%). Both yield and enantioselectivity dropped significantly (to 70 and 62
respectively) for the sixth run, most likely for a non-appropriate washing. Nevertheless,
a thorough washing protocol including the use of 1 M HCl, allowed to regenerate the
resin that could be used for a 7th cycle with similar results to those obtained in the
initial series of experiments. These results indicate that the polymer-supported -amino
amides are stable during the reaction and can be easily regenerated and reused after
filtration and washing with acid. It is important to note that although TON values for
each batch reaction using catalysts like 7b are clearly lower than those using the
corresponding Ni complexes, the easy reuse of this supported system clearly
compensates for this and the TON values attained after 5 reuses (TON ~ 100) are fully
comparable with those reported for the Ni complexes.[38]
FIGURE 5
4. Conclusions
In summary, the results here presented clearly demonstrate the immobilization of a
catalytic system onto a polymeric matrix can be accompanied by a dramatic increase in
the observed enantioselectivity. Most likely this can be associated with the reduced
formation of aggregates taking place in the supported system due to the pseudodilution
effect. The resulting polymer-supported -amino amide is highly effective for the
catalysis of the addition of dialkylzinc reagents to a variety of aldehydes, including
some aliphatic aldehydes. The polymer supported system can be used for at least 5
cycles without an appreciable loss of its efficiency, and, more importantly, can be easily
regenerated to achieve essentially, the same results than the original system.
Acknowledgements
Financial support from Ministerio de Ciencia e Innovación (CTQ2011-28903-C02-01),
and Generalitat Valenciana PROMETEO 2012/020 is gratefully acknowledged.
References
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17
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563
564
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566
567
LIST OF FIGURE AND TABLE CAPTIONS
Figure 1. Structures of -amino amide 1 and bis(amino amide) 2 ligands and synthesis
of PS-amino amides.
Figure 2. Partial ATR-FTIR spectra for 7b (blue), Zn complex for 7b (blue) and TEM
images of the zinc-supported catalyst (inlet).
Figure 3. Possible mechanism for the enantioselective addition of diethylzinc to
benzaldehyde catalyzed by polymer-supported -amino amides.
Figure 4. Diethylzinc addition to benzaldehyde. Conversion of benzaldehyde (11), 1-
phenyl-1-propanol (12) and benzyl alcohol (13) as a function of reaction period
obtained by using the catalyst 7b at 0ºC in toluene. Evolution of selectivity and
enantioselectivity with time.
Figure 5. Reuse of the polymer supported catalyst 7b. Reaction conditions: toluene,
0ºC, 36 h, 5 % catalyst loading.
Table 1. Loadings for the different polymers 7.
Table 2. Enantioselective addition of Et2Zn to benzaldehyde catalyzed by resins 7a in
different solvents.
Table 3. Enantioselective addition of Et2Zn to benzaldehyde catalyzed by resins 7a-k.
Table 4. Enantioselective addition of R2Zn to aldehydes catalyzed by resin 7b.
18
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567
568
569
Figure 1. Structures of -amino amide 1 and bis(amino amide) 2 ligands and synthesis
of PS-amino amides
570
571
572
573
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Page 19 of 29

573
574
575
Figure 2. Partial ATR-FTIR spectra for 7b (green), Zn complex for 7b (blue) and TEM
images of the zinc-supported catalyst (inlet).
1674 cm-1
1594 cm-1
576
577
578
20
Page 20 of 29

578
579
Figure 3. Possible mechanism of enantioselective addition of diethylzinc to
benzaldehyde catalyzed by polymer-supported -amino amides.
580
581
582
583
584
21
Page 21 of 29

584
585
586
587
588
589
Figure 4. Conversion of benzaldehyde (11) and relative yields for 1-phenyl-1-propanol
(12) and benzyl alcohol (13) as a function of time, using the catalyst 7b at 0ºC in
toluene. Evolution of selectivity (red line) and enantioselectivity (blue dotted line) is
also given.
590
591
592
22
Page 22 of 29

592
593
594
Figure 5. Reuse of the polymer supported catalyst 7b. Reaction conditions: toluene,
0ºC, 36 h, 5 % catalyst loading.
595
596
597
23
Page 23 of 29

597
598
599
Table 1. Loadings for the different polymers 7.
Crosslinking Loading
Entry Resin
Loading
Yield (%) [c]
degree (%) Found [a] Calculated [b]
7a[d]
7b[d]
7c[d]
7d[d]
7e[d]
7f[d]
7g[e]
7h[e]
7i[e]
1
2
1
1
0.80
0.94
1.28
1.56
1.84
1.99
0.85
1.45
1.74
1.96
2.27
0.86
0.99
1.36
1.59
1.89
2.06
0.89
1.50
1.81
2.03
2.35
93
95
94
98
97
97
96
97
96
97
97
3
2
4
1
5
2
6
1
7
20
20
20
20
20
8
9
7j[e]
7k[e]
10
11
600
601
602
603
[a] Calculated by N elemental analysis (mmol functional group/g resin). [b] Based on a quantitative
conversion for all the steps in Scheme 1 (mmol functional group/g resin). [c] Calculated as
(loadingfound/loadingcalculated) × 100. [d] Gel type [e] Monolith.
604
605
24
Page 24 of 29

605
606
Table 2. Enantioselective Addition of Et2Zn to Benzaldehyde Catalyzed by resins 7a in
607
608
different solvents.[a]
Entry Solvent T (ºC) Time Conversion (%)[b] Selectivity (%)[b] ee (%)[c]
1
2
3
4
5
6
7
8
Toluene
Toluene
Hexane
CH3CN
CH2Cl2
THF
0
0
18
36
36
36
36
36
36
36
91
99
95
96
90
92
97
58
99
99
92
89
91
85
86
99
91 (S)
92 (S)
51 (S)
55 (S)
61 (S)
32 (S)
71 (S)
93 (S)
0
0
0
0
Toluene
Toluene
25
-20
609
610
611
612
[a] Reaction conditions: Benzaldehyde (1 equiv), Et2Zn (2.2 equiv), and catalyst 7a (10% mol), 36 h. [b]
Determined by 1H NMR. [c] Determined by chiral HPLC (Chiralcel OD) or GC; the major enantiomer is
indicated in parenthesis.
613
614
25
Page 25 of 29

614
615
616
617
Table 3. Enantioselective Addition of Et2Zn to Benzaldehyde Catalyzed by resins 7a-f
[a]
.
Entry Catalyst Conversion (%)[b] Selectivity (%)[b] ee (%)[c]
7a[d]
7b[d]
7c[d]
7d[d]
7e[d]
7f[d]
7g[e]
7h[e]
7i[e]
7j[e]
7k[e]
1
1
2
88
92
95
99
99
99
99
99
98
99
99
---
98
99
97
95
96
96
91
92
89
91
89
---
92 (S)
92 (S)
87 (S)
87 (S)
84 (S)
82 (S)
62 (S)
62 (S)
55 (S)
52 (S)
48 (S)
---
3
4
5
6
7
8
9
10
11
12
618
619
620
621
622
[a] Reaction conditions: Benzaldehyde (1 equiv), Et2Zn (2.2 equiv), and catalyst (10% mol) in toluene at
1
0 ºC, 36 h. [b] Determined by H NMR. [c] Determined by chiral HPLC (Chiralcel OD); the major
enantiomer is indicated in parenthesis. [d] Gel type [e] Monolith.
26
Page 26 of 29

622
623
Table 4. Enantioselective Addition of R2Zn to Aldehydes Catalyzed by resin 7b.[a]
624
Entry
Aldehyde
R
Conversion (%)[b] Selectivity (%)[b] ee (%)[c]
1
2
Benzaldehyde
Et
91
97
89
88
87
88
85
65
87
86
69
99
98
99
98
99
99
97
95
98
97
94
92 (S)
95 (S)
89 (S)
86 (S)
88 (S)
90 (S)
73 (S)
80 (S)
75 (S)
77 (S)
67 (S)
4-Methoxybenzaldehyde Et
3
4-Methylybenzaldehyde
4-Chlorobenzaldehyde
1-Naphtaldehyde
Et
Et
Et
Et
4
5
6
2-Naphtaldehyde
7
3-Phenylpropionaldehyde Et
8
Hexanal
Et
9
Benzaldehyde
Me
10
11
4-Methoxybenzaldehyde Me
Hexanal Me
625
626
627
628
629
[a] Reaction conditions: Aldehyde (1 equiv), Et2Zn (2.2 equiv), and catalyst 7b (10% mol) in toluene at 0
ºC, 36 h. [b] Determined by 1H NMR. [c] Determined by chiral HPLC (Chiralcel OD) or GC; the major
enantiomer is indicated in parenthesis.
27
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629
630
631
632
633
634
Highlights
Immobilization of catalytic -amino amide system onto a polymeric matrix
Increase in the enantioselectivity due to the pseudodilution effect.
Supported catalyst are effective for the addition of dialkylzinc reagents to aldehydes
The supported system can be used for 5 cycles without lost of its efficiency
28
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