Hydrogel supported chiral imidazolidinone for organocatalytic enantioselective reduction of olefins in water

Article abstract of DOI:10.1515/chempap-2015-0232

Chiral products play an important role particularly in the field of medicinal chemistry, where it is known that enantiomers often have very different biological properties and effects. One of the most powerful tool to obtain a product as a single enantiomer is asymmetric catalysis. Recently, organocatalysis, i.e. the use of small organic molecules to catalyze enantioselective transformations, has emerged as a prominent field in asymmetric synthesis. In this work, the use of hydrogels as a support for a chiral imidazolidinone organocatalyst (MacMillan catalyst) and its application in the reduction of activated olefins mediated by the Hantzsch ester is reported for the first time. Results showed a good activity of hydrogels in respect to both yield and enantioselection.

Full text of DOI:10.1515/chempap-2015-0232

Chemical Papers
DOI: 10.1515/chempap-2015-0232
ORIGINAL PAPER
Hydrogel supported chiral imidazolidinone for organocatalytic
enantioselective reduction of olefins in water
Alessandro Sacchetti*, Filippo Rossi*, Arianna Rossetti, Roberto Pesa,
Emanuele Mauri
Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano,
via Mancinelli 7, 20131 Milan, Italy
Received 15 July 2015; Revised 15 September 2015; Accepted 22 September 2015
Chiral products play an important role particularly in the field of medicinal chemistry, where it
is known that enantiomers often have very different biological properties and effects. One of the
most powerful tool to obtain a product as a single enantiomer is asymmetric catalysis. Recently,
organocatalysis, i.e. the use of small organic molecules to catalyze enantioselective transformations,
has emerged as a prominent field in asymmetric synthesis. In this work, the use of hydrogels as a
support for a chiral imidazolidinone organocatalyst (MacMillan catalyst) and its application in the
reduction of activated olefins mediated by the Hantzsch ester is reported for the first time. Results
showed a good activity of hydrogels in respect to both yield and enantioselection.
c
ꢀ 2015 Institute of Chemistry, Slovak Academy of Sciences
Keywords: hydrogels, organocatalysis, supported catalysts, MacMillan catalyst
Introduction
organocatalysis the use of transition metal complexes,
which are typically more difficult to prepare and to
handle, is avoided. On the other hand, in comparison
to the organometallic catalysts, organocatalysts suffer
from lower turn over frequency (TOF) and turn over
number (TON) since, in many cases, the catalyst con-
centration of up to 20–30 % mole has to be employed.
This also requires the use of a purification step, in
order to separate and recover the catalysts from the
products. To avoid this problem, many studies on the
use of supported organocatalysts and their application
in the flow chemistry have been reported (Atodiresei
et al., 2015; Itsuno & Hassan, 2014; Munirathinam et
al., 2015). Other key aspects of this process are the re-
quirement for an organic solvent to make the catalysts
soluble and the employment of water organocatalytic
transformation, which is still under-explored (Black-
mond et al., 2007; Davoodnia et al., 2011; Hayashi,
2006). As a consequence of these considerations, we
decided to explore the possibility of using hydrogels
as recoverable supports for organocatalysis in water.
Hydrogels are cross-linked hydrophilic polymeric net-
Organocatalysis has been widely recognized as a
new emerging and promising field in asymmetric or-
ganic synthesis (Dalko & Moisan, 2001, 2004; Don-
doni & Massi, 2008; Seayad & List, 2005). The pro-
cess relies on the use of small chiral organic molecules
able to efficiently catalyze many different asymmet-
ric organic transformations, usually with high yields
and enantiomeric excesses. The mechanisms of action
of these catalysts have been in many cases elucidated
and two main modes of activation have been described
considering the presence of covalent or non-covalent
interactions between the catalyst and the reactant.
Catalysts can be easily produced by conventional or-
ganic synthesis on a multi-gram scale and different
lead molecule derivatives can be prepared allowing
thus efficient tuning of their activity. The possibility
to use organic molecules as catalysts offers a num-
ber of advantages. For instance, such catalysts are
very stable, easy to use and no particular reaction
conditions are required. As the main advantage, in
*Corresponding author, e-mail: alessandro.sacchetti@polimi.it, filippo.rossi@polimi.it
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A. Sacchetti et al./Chemical Papers
works swollen in aqueous media, typically soft and
elastic due to their thermodynamic compatibility with
water (Annabi et al., 2014; Slaughter et al., 2009).
Cross-links and interconnections that bring polymer
chains together can be formed by physical entangle-
ments leading to physical hydrogels or by covalent
bonds leading to chemical hydrogels.
Because of the low operating values of temperature
and pressure, the polymer chains were expected to re-
tain the same conformation they had in wet conditions
(Rossi et al., 2012). A comparative evaluation of the
superficial and internal morphology of the investigated
samples was carried out.
In this work, preliminary investigations on the use
of organic hydrogels as a support for an imidazolidi-
none MacMillan catalyst (Lelais & MacMillan, 2006;
MacMillan, 2008) to be employed in the reduction of
olefins (Ouellet et al., 2005, 2007) in water are pre-
sented. The biocatalyzed version of this reaction has
been already thoroughly investigated by our research
group (Brenna, et al., 2012a, 2012b, 2012c, 2013a,
2013b, 2015). Here, the possibility of using a hydrogel
previously described by our group (Sacchetti et al.,
2014; Santoro et al., 2011) and obtained by means
of a synthesis from statistical block polycondensa-
tion between agarose, poly(acrylic acid) (PAA), and
polyethylene glycol (PEG) was explored. Among the
PEG-supported versions of both organic and metal-
based catalysts (Danelli et al., 2003; Puglisi et al.,
2004), our catalyst was first linked with PEG 2000 via
a click azide-alkyne reaction and the obtained prod-
uct was used to prepare the gel. As an alternative,
an MeOPEG 5000-supported catalyst was prepared in
the same manner and then incorporated in the poly-
meric network during its synthesis.
Synthesis of (5S)-3-butyl-5-[(4-hydroxyphenyl)
methyl]-2,2-dimethylimidazolidin-4-one (I)
Thionyl chloride (10 mL, 139 mmol) was added
drop-wise to a stirred solution of L-tyrosine (10.0 g,
55.25 mmol) in dry MeOH (100 mL) at 0◦C and
the reaction mixture was stirred at ambient temper-
ature for 24 h. Volatiles were removed under dimin-
ished pressure to afford L-tyrosine methyl ester hy-
drochloride (IUPAC name: methyl (2S)-2-amino-3-(4-
hydroxyphenyl)propanoate hydrochloride) as a white
solid (11.73 g, 91.6 % yield). 1H NMR (400 MHz,
DMSO-d6) δ: 9.49 (brs, 1H), 8.66 (brs, 3H), 7.0 (d,
J = 8.4 Hz, 2H), 6.76–6.68 (m, 2H), 4.19–4.06 (m, 1H),
3.65 (s, 3H), 3.11 (dd, J = 14.1 Hz, J = 5.7 Hz, 1H),
3.02–2.95 (dd, J = 14.1 Hz, J = 7.1, 1H). 13C NMR
(100 MHz, DMSO-d6) δ: 35.08, 52.51, 53.47, 115.43,
124.34, 130.36, 156.70, 169.44.
L-Tyrosine methyl ester hydrochloride (11.73 g,
50.6 mmol) (see above) was added to 1-butylamine
(35 mL, 354.5 mmol) and the resulting mixture was
stirred at ambient temperature for 48 h. The excess of
1-butylamine was removed under diminished pressure
to afford the corresponding N-butyltyrosyl amide (IU-
PAC name: (2S)-2-amino-N-butyl-3-(4-hydroxyphe-
nyl)propanamide) as a white solid (10 g, 85 % yield).
1H NMR (400 MHz, CDCl3) δ: 6.93 (t, J = 5.8 Hz,
1H), 6.26 (d, J = 8.3 Hz, 2H), 5.99 (d, J = 8.3 Hz,
2H), 2.70 (dd, J = 8.3 Hz, J = 4.8 Hz, 1H), 2.40 (q,
J = 6.7 Hz, 2H), 2.20 (dd, J = 13.6 Hz, J = 4.8 Hz,
1H), 2.00 (t, J = 7.4 Hz, 2H), 1.85 (dd, J = 13.6 Hz,
J = 8.3 Hz, 1H), 0.81 (quint, J = 7.4 Hz, 2H), 0.17 (t,
J = 7.2 Hz, 3H).
Experimental
Materials and methods
All chemicals were purchased from Sigma–Aldrich
(Deisenhofen, Germany) and they were used as re-
ceived. Solvents (methanol (MeOH), ethyl acetate
(EtOAc), acetonitrile (ACN), dimethylformamide
(DMF), diethyl ether (Et2O), tetrahydrofuran (THF),
dichloromethane (DCM), chloroform, acetone) were of
laboratory grade. Synthesized compounds were char-
N-Butyltyrosyl amide (10 g, 36.7 mmol) (see
above) dissolved in a mixture of dry MeOH (80 mL)
and dry acetone (15 mL), was stirred at 90◦C for 24 h,
cooled to ambient temperature and then concentrated
under diminished pressure to afford crude product I.
This was purified on a column of silica gel using hex-
ane/EtOAc (ϕr = 3 : 7) as the eluent to isolate I as
1
acterized by H and 13C NMR spectra recorded on a
Bruker AC (400 MHz) spectrometer using deuterated
chloroform (CDCl3) or dimethyl sulfoxide (DMSO-d6)
as solvents and chemical shifts were reported as δ with
respect to TMS as the internal standard. FTIR spec-
tra of the hydrogel samples, after being dipped in ex-
cess of solvent for 24 h, freeze-dried and laminated
with KBr, were recorded on a Thermo Nexus 6700
spectrometer coupled to a Thermo Nicolet Contin-
uum microscope equipped with a 15× Reflachromat
Cassegrain objective at the resolution of 4 cm−1. En-
vironmental scanning electron microscopy (E/SEM)
analysis was performed on gold sputtered samples at
10 kV with Evo 50 EP Instrumentation (Zeiss, Jena,
Germany). To preserve the actual morphology of the
hydrogel under complete swelling, freeze-drying was
applied to remove all the liquid phase by sublimation.
1
a white solid (7.3 g, 72 % yield). H NMR (400 MHz,
CDCl3) δ: 7.09–7.01 (m 2H), 6.79–6.69 (m, 2H), 3.74
(t, J = 5.2 Hz, 1H), 3.31 (ddd, J = 13.9 Hz, J =
9.5 Hz, J = 6.1 Hz, 1H), 3.10–2.96 (m, 2H), 1.34–
1.22 (m, 2H), 1.28 (s, 3H), 1.18 (s, 3H), 0.91 (t, J =
7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 13.96,
20.56, 26.52, 28.11, 31.58, 35.88, 40.63, 59.14, 76.55,
115.87, 127.81, 130.95, 155.63, 174.32. These data are
in accordance with those already published (Shi et al.,
2011).
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iii
Synthesis of (5S)-5-{[(4-(2-azidoethoxy)
phenyl]methyl}-3-butyl-2,2-dimethylimid-
azolidin-4-one (II)
2H), 3.72 (t, J = 5.3 Hz, 1H), 3.30 (ddd, J = 13.8 Hz,
9.4 Hz, 6.1 Hz, 1H), 3.04 (dd, J = 5.3 Hz, 2.3 Hz, 2H),
2.90 (ddd, J = 13.8 Hz, 9.4 Hz, 5.8 Hz, 1H), 2.50 (t,
J = 2.4 Hz, 1H), 1.58–1.37 (m, 2H), 1.34–1.22 (m, 2H),
1.26 (s, 3H), 1.16 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ: 14.03, 20.61, 26.76, 28.33,
31.68, 36.22, 40.54, 56.11, 59.11, 75.66, 76.30, 78.81,
115.24, 130.13, 130.95, 156.75, 174.08. These data are
in accordance with those already published (Shi et al.,
2011).
A mixture of I (1 g, 3.6 mmol), 1,3-dibromopro-
pane (732 mg, 3.6 mmol), NaH (173 mg, 7.2 mmol),
and tetrabutylammonium bromide (0.1 g) in ACN (40
mL) was vigorously stirred under reflux for 10 h. Af-
ter cooling and solvent evaporation, the resulting foam
was dissolved in chloroform (50 mL) and washed with
water (3 × 200 mL). The organic layer was dried
with anhydrous sodium sulfate and concentrated un-
der diminished pressure. The crude product was pu-
rified by silica gel column chromatography using hex-
ane/EtOAc (ϕr = 6 : 4) as the eluent affording the de-
sired 3-bromopropyl derivative (820 mg, 57 % yield).
1H NMR (400 MHz, CDCl3) δ: 7.36 (dd, J = 8.5 Hz,
4.0 Hz, 2H), 6.87 (dd, J = 8.5 Hz, 4.6 Hz, 2H), 4.31
(s, 1H), 4.05 (t, J = 5.8 Hz, 1H), 3.43 (d, J = 15.3 Hz,
1H), 3.10–2.93 (m, 1H), 2.34–2.18 (m, 1H), 2.16 (d,
J = 0.5 Hz, 1H), 1.68 (s, 3H), 1.50 (s, 8H), 0.97–0.84
(m, 3H).
Sodium azide (270 mg, 4.1 mmol) was added to
a solution of a 3-bromopropyl derivative (800 mg,
2.02 mmol) (see above) in DMF (15 mL) and the mix-
ture was stirred and heated at 100◦C for 10 h. After
cooling, water (20 mL) and Et2O (20 mL) were added
and the organic phase was separated, washed with
brine solution (3 × 20 mL), dried with sodium sulfate
and concentrated under diminished pressure to obtain
pure II (550 mg, 76 % yield). 1H NMR (400 MHz,
CDCl3) δ: 7.36 (dd, J = 8.5 Hz, 4.0 Hz, 2H), 6.87 (dd,
J = 8.5 Hz, 4.6 Hz, 2H), 4.31 (s, 1H), 4.05 (t, J =
5.8 Hz, 1H), 3.12 (d, J = 15.3 Hz, 1H), 3.10–2.93 (m,
1H), 2.34–2.18 (m, 1H), 2.16 (d, J = 0.5 Hz, 1H), 1.68
(s, 3H), 1.50 (s, 8H), 0.97–0.84 (m, 3H).
Synthesis of functionalized PEG 2000 (IV)
A mixture of PEG 2000 (5 g, 2.5 mmol) dissolved
in anhydrous DCM (35 mL) and triethylamine (1.01 g,
10 mmol) was added to a solution of methanesulfonyl
chloride (1 g, 8.75 mmol) in THF (50 mL) and the
solution was stirred at 25◦C for 48 h under anhydrous
conditions. DCM and THF were subsequently evapo-
rated under diminished pressure; the residue was re-
dissolved in water (100 mL) and extracted with DCM
(5 × 200 mL). The combined organic phase was dried
with sodium sulfate and the solvent was removed un-
der diminished pressure. The polymer was recovered
by precipitation from Et2O, collected and dried un-
der diminished pressure, yielding a white solid. A part
of this product (1.25 g, 0.23 mmol) was dissolved in
DMF (20 mL), then sodium azide (521 mg, 8.01 mmol)
was added and the mixture was stirred at ambient
temperature for two days followed by an addition of
DCM (200 mL) and washing a mixture with brine
(2 × 200 mL) and water (2 × 200 mL). The organic
phase was dried with sodium sulfate, concentrated un-
der diminished pressure followed by an addition of
Et2O to precipitate IV, which was collected by suc-
tion filtration and dried under diminished pressure
1
(1 g, 71 % yield) (Hiki & Kataoka, 2007). H NMR
Synthesis of (5S)-3-butyl-2,2-dimethyl-5-{[(4-
(prop-2-yn-1-yloxy)phenyl]methyl)imidazoli-
din-4-one (III)
(400 MHz, CDCl3) δ: 3.46 (t, 2H), 3.63 (s, 180H).
Synthesis of functionalized monomethoxy-
PEG 5000 (V)
A mixture of potassium carbonate (1.5 g, 10.8
mmol), propargyl bromide (80 % solution in toluene,
0.52 g, 4.34 mmol) and I (1 g, 3.62 mmol) in DMF
(20 mL) was stirred at ambient temperature for 48 h.
Subsequently, saturated ammonium chloride solution
(30 mL) was added and the reaction mixture was
stirred for 2 h. EtOAc (30 mL) was then added and the
stirring continued for 30 min. The organic phase was
separated and the aqueous phase was extracted with
EtOAc (2 × 20 mL). The combined organic layers were
stirred with a brine solution for 1 h, separated and
dried with anhydrous sodium sulfate. The crude prod-
uct was purified by silica gel column chromatography
using hexane/EtOAc (ϕr = 3 : 7) to afford III (2.5 g,
Sodium hydride (48 mg, 2 mmol) was added to
MeOPEG 5000 (5 g, 1 mmol) dissolved in anhydrous
THF (35 mL) followed by the drop-wise addition of
propargyl bromide (80 % solution in toluene, 0.48 g,
4 mmol) under stirring for 24 h. THF was then evap-
orated under diminished pressure, the residue was re-
dissolved in water (100 mL) and extracted with DCM
(5 × 200 mL). The combined organic phase was dried
with sodium sulfate, filtered and the solvent was re-
moved under diminished pressure. The polymer was
recovered by precipitation from Et2O, collected and
dried under diminished pressure to yield V as a white
solid (4.97 g, 96 % yield). 1H NMR (400 MHz, CDCl3)
δ: 4.20 (d, J = 2.4 Hz, 2H), 3.64 (s, 450 H), 3.37 (s,
3H), 2.42 (t, J = 2.4 Hz, 1H).
1
73 % yield). H NMR (400 MHz, CDCl3) δ: 7.19–7.14
(m 2H), 6.91 (d, J = 8.6 Hz, 2H), 4.66 (d, J = 2.4 Hz,
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A. Sacchetti et al./Chemical Papers
Synthesis of PEG 2000-catalyst polymer (VI)
Table 1. Hydrogel composition
Hydrogel components
VIII
IX
Copper iodide (3 mg, 0.0158 mmol) and sodium
ascorbate (3 mg, 0.0152 mmol) were added to a mix-
ture of IV (2.7 g, 1.35 mmol) dissolved in water
(20 mL) and III (424 mg, 1.35 mmol) dissolved in ace-
tone (20 mL). Tetramethylethylenediamine (5 drops)
was then added and the mixture was stirred at 50◦C
for 36 h, cooled to 25◦C and extracted with DCM
(3 × 20 mL). The combined organic phase was dried
with anhydrous sodium sulfate and the solvent was
evaporated under reduced pressure to afford solid VI
PBS/mL
9
50
580
100
0
9
50
580
0
100
50
Carbomer 974P/mg
PEG 2000/mg
VI/mg
VII/mg
Agarose/mg
50
1
(2.5 g, 81.5 % yield). H NMR (400 MHz, DMSO-d6)
was microwave-irradiated (500 W irradiated power for
20 s) and heated up to 70–80◦C to induce condensation
reactions through interconnections of hydroxyl groups
(reactions between carbonyl groups of Carbomer 974P
and OH terminals of agarose and used PEG resulted
in ester bonds formation and, consequently, in the
three-dimensional matrix of the hydrogel). After elec-
tromagnetic stimulation, the solution was cooled to
55◦C, diluted with distilled water (ϕr = 1 : 1), placed
in steel cylinders (150 L each, with the cylinder diam-
eter of 0.2 cm) and left at ambient temperature until
reaching complete gelation and thermal equilibrium.
Composition of the hydrogels is reported in Table 1.
δ: 7.80 (s, 1H), 7.13 (d, J = 8.1 Hz, 2H), 6.90 (d, J =
8.1 Hz, 2H), 4.52 (t, J = 5.1 Hz, 2H), 3.86 (t, J =
5.1 Hz, 2H), 3.62 (s, 183H), 3.44 (dd, J = 5.9 Hz, J =
4.0 Hz, 1H), 3.36 (t, J = 5.1 Hz, 1H), 3.00 (d, J =
5.1 Hz, 2H), 2.93 (s, 4H), 2.86 (s, 4H), 1.32–1.22 (m,
9H), 0.90 (t, J = 7.4 Hz, 3H).
Synthesis of MeOPEG 5000-catalyst polymer
(VII)
Copper iodide (5 mg, 0.0263 mmol), sodium ascor-
bate (5 mg, 0.0253 mmol) and tetramethylethylenedi-
amine (5 drops) were added to a mixture of V (2.1 g,
0.42 mmol) dissolved in water (15 mL) and II (350 mg,
1 mmol) dissolved in THF (15 mL) and the mixture
was stirred at 50◦C for 36 h, cooled to 25◦C and ex-
tracted with DCM (3 × 15 mL). The combined or-
ganic phase was dried with anhydrous sodium sulfate,
filtered and concentrated under reduced pressure fol-
lowed by an addition of Et2O to precipitate VII, which
was collected by suction filtration and dried (brown
solid) under diminished pressure (2.5 g, 82.5 % yield).
1H NMR (400 MHz, CDCl3) δ: 7.57 (s, 1H), 7.13 (s,
4H), 6.86–6.81 (m, 4H), 4.55 (t, J = 6.9 Hz, 2H), 3.99
(dt, J = 24.1 Hz, J = 5.9 Hz, 4H), 3.81 (t, J = 5.1 Hz,
3H), 3.64 (s, 429H), 3.37 (s, 3H), 2.94–2.83 (m, 1H),
2.37 (d, J = 6.4 Hz, 1H), 2.02 (d, J = 6.4 Hz, 1H),
1.15 (d, J = 5.8 Hz, 6H).
General procedure for catalytic reaction
Obtained hydrogels VIII and IX were tested in
catalytic reduction of aldehydes as follows: Hantzsch
ester (65 mg, 0.25 mmol) was added to cinnamalde-
hyde (13 mg, 0.1 mmol) or β-methyl cinnamaldehyde
(15 mg, 0.1 mmol) suspended in distilled water (2 mL)
in a polypropylene syringe (size 10 mL) equipped with
a porous polypropylene disc at the bottom (porosity
70 m). Subsequently, the desired number of hydrogel
VIII or IX tablets was added (Table 2) and the result-
ing suspension was shaken at ambient temperature for
the indicated time (Table 2). Finally, the used tablets
of gel were recovered by suction filtration of the reac-
tion mixture through the bottom of the syringe and
washed with distilled water.
Synthesis of hydrogels VIII and IX
Results and discussion
PEG, both functionalized and pure, was added to
Carbomer 974P dissolved in a PBS-based solution and
the mixture was stirred at ambient temperature for
45 min and left to settle for 30 min. (Note: The use
of two PEG types was justified by the need of a poly-
mer acting as the organocatalyst in the reaction mix-
ture, the role of PEG functionalized with catalyst, and
a polymer able to react chemically in hydrogel scaf-
fold formation via cross-linking with other chains to
achieve adequate hydrophilicity and permeability, the
role of pure PEG). A 1 M NaOH solution was then
added to adjust pH to 7 and subsequently, agarose
powder (1 mass %) was added. Due to its insolu-
bility at ambient temperature, the reaction mixture
Starting from L-tyrosine, catalyst I was easily
obtained by a three-step procedure (via the corre-
sponding L-tyrosine methyl ester in the first step and
N-butyltyrosyl amide in the second step) in a 61 %
overall yield (after purification) by a procedure simi-
lar to that already published (Shi et al., 2011). Prod-
uct III was then obtained from a reaction of I with
propargyl bromide (an analogy with Shi et al., 2011),
whereas azide II was prepared by a reaction of I with
1,3-dibromopropane followed by a treatment with
sodium azide in DMF as shown in Fig. 1.
Mono azido-PEG 2000 derivative (IV ) was synthe-
sized via the activation of the hydroxyl group with
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v
Table 2. Results of catalyzed reduction reactionsa
Aldehyde
Hydrogel
Catalyst loadingb/%
Time/h
Yieldc/%
eed/%
VIII
0.1
0.3
0.3
1
24
24
96
24
6
19
21
49
–
–
–
–
IX
0.1
0.3
0.3
1
24
24
96
24
8
24
41
61
–
–
–
–
VIII
IX
0.1
1
24
24
6
51
83
79
0.1
1
24
24
7
64
83
81
a) Reactions were carried out in water with 0.1 mol of the substrate and 0.25 mol of the Hantzsch ester; b) mole % with respect to
substrate; c) percentage of enantiomeric excess calculated from the GC/MS analysis of the crude product; d) percentage determined
by chiral GC analysis.
Fig. 1. Synthesis of the azido (II) and propargyl (III) catalysts. Reaction conditions: i) thionyl chloride, MeOH; ii) 1-butylamine;
iii) MeOH, acetone, 61 % overall yield; iv) NaH, 1,3-dibromopropane; v) NaN3, DMF, 43 % overall yield; vi) propargyl
bromide, K2CO3, DMF, 73 % overall yield; Bu = 1-butyl.
Fig. 2. Synthesis of functionalized PEG polymers IV and V. Reaction conditions: i) methanesulfonyl chloride, THF, triethylamine,
DCM; ii) NaN3, DMF; iii) NaH, THF, toluene.
methanesulfonyl chloride (MsCl) and a subsequent
substitution reaction with sodium azide, whereas the
reaction of propargyl bromide with MeOPEG 5000 di-
rectly afforded polymer V, as illustrated in Fig. 2.
The PEG polymers were coupled with the respec-
tive catalyst by a Cu(I) catalyzed azide–alkyne Huis-
gen reaction (“click” reaction) (Kolb et al., 2001;
Moses & Moorhouse, 2007) as shown in Fig. 3. Each
reaction proceeded smoothly in a water/acetone mix-
ture and afforded the desired product in an almost
quantitative yield. The structure of polymers was con-
firmed by H NMR data.
Once the PEG-supported catalysts were obtained,
hydrogels VIII and IX were prepared by microwave
irradiation of a PBS solution of Carbomer 974P, PEG
2000, agarose and a PEG-supported catalyst. The hy-
1
drogels were obtained in form of cylinders (150
L
each, with the cylinder diameter of 0.2 cm) and were
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vi
A. Sacchetti et al./Chemical Papers
Fig. 3. Synthesis of the polymer supported catalysts. Reaction conditions: i) CuI, acetone/water, 50◦C.
Fig. 4. SEM analysis of hydrogel VIII. Magnification: 95× (A); 150× (B); 500× (C); 750× (D); scale bars: 100 m (A and B);
20 m (C); 30 m (D). Analogous images were observed by SEM analysis of a sample of hydrogel IX.
characterized by SEM (Fig. 4) and FTIR (Fig. 5). The
samples were prepared by a freeze-drying method, fol-
lowed by coating with a thin layer of gold prior to
SEM imaging. Some previously published works on
SEM morphology of dried PEG-based hydrogels can
be found; however, much care must be taken when
preparing dried samples for SEM analysis since the
removal of water entrapped within the porous hydro-
gel scaffolds may disrupt the structural stability and
result in collapse of the structure or the formation of
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A. Sacchetti et al./Chemical Papers
vii
Fig. 5. FTIR spectrum of hydrogel VIII showing two distinct peaks of amide I and II bands at 1670 cm−1 and 1560 cm−1
,
respectively, indicating the presence of catalysts within the hydrogel polymeric network.
artifacts upon drying (Ford et al., 2006; Zhu et al.,
2009). Our results revealed that dried hydrogels pos-
sess a highly entangled structure. More details were
observed from the SEM image with higher amplifica-
tion (Fig. 4d); there are some bigger pores containing
small holes and some fibrillar networks on the pore
walls.
In addition, most of the pores are interconnected,
which demonstrates that hydrogels present a micro-
scopic porous structure with a complex 3D construc-
tion in the dried state and, compared with previous
studies (Sacchetti et al., 2014), the presence of a cat-
alyst does not affect the polymer network.
FTIR spectrum of hydrogel VIII (Fig. 5) showed a
broad peak at ∼ 3450 cm−1 due to the stretching vi-
bration of O—H bonds, whereas peaks at ∼ 2940 cm−1
are due to the C—H stretch. According to our previous
studies, the formation of ester bonds is demonstrated
by symmetric (∼ 1600 cm−1) and asymmetric (∼ 1400
cm−1) COO stretches.
groups (Zhu et al., 2009). The same considerations can
be also referred to the FTIR spectrum of hydrogel IX.
Referring to the hydrogel formulations it can be
estimated that each tablet of hydrogel VIII contained
0.6 mg of catalyst VI, whereas 1.1 mg of catalyst VII
were enclosed in the polymeric matrix of IX. Next,
hydrogel-supported catalysts were tested in the re-
duction of cinnamaldehyde and β-methyl cinnamalde-
hyde, respectively, using the Hantzsch ester. In order
to increase the catalyst loading, an increasing num-
ber of tablets was used in different experiments. The
reactions were performed in water at ambient temper-
ature under gentle mechanical shaking to preserve the
integrity of the tablets. Obtained results are reported
in Table 2.
All hydrogel tablets were able to convert the olefin
to the respective saturated aldehyde. As expected,
the higher the catalyst loading was (i.e., adding more
tablets to the reaction mixture), the higher the yields
were (up to 64 %). Catalyst in hydrogel IX proved
to be slightly more efficient regarding the conversion,
although in the β-methyl cinnamaldehyde reduction,
both catalysts showed similar enantiomeric excess (ee)
of the final product (up to 83 %). At the end of each
reduction cycle, used catalysts were easily recovered
by filtration of the mixture. However, the reuse of
the hydrogel tablets afforded very low yields due to
extensive degradation of the polymeric network. For
comparison purposes, the reduction of β-methyl cin-
namaldehyde with the Hantzsch ester and free catalyst
I (20 mole %) was performed. It was observed that due
to the limited solubility of both the catalyst and the
substrate, a THF/water (ϕr = 1 : 4) mixture had to
be used as a solvent to provide the desired product.
Also, in accordance with literature, the addition of
trifluoroacetic acid (TFA) to the solution in equimo-
lar ratio with respect to the catalyst was necessary.
Under such conditions, the product was obtained in
a 94 % yield and 84 % ee after 18 h. Lowering the
catalyst loading to 5 mole % led to similar results
The spectrum also shows peaks related to the
C—O—C stretching vibration in the range of 900–
1000 cm−1 that represent the glycosidic bond between
the monosaccharide units (typical of the agarose struc-
ture) and ester groups. In general, building blocks or
subunits of macromolecules form a stable structure
made up mostly of C—C bonds, usually referred to
as the “carbon skeleton”. C—C and C—H bonds are
nonpolar and thus tend to be less reactive and some-
times result in an inert under the applied degradation
conditions. Building blocks of macromolecules act as
discrete subunits because their internal structure con-
sists of C—C bonds. Furthermore, C—O bonds link
the subunits representing degradable bonds consti-
tuted by oxygen or nitrogen atoms. Here, the obtained
FTIR results allow stating that the most important
groups in the studied gels are: OH, CH, COO (car-
boxylates), vinyl groups and C—O—C. The presence
of the catalyst is evident from peaks corresponding to
amine I (*, 1670 cm−1) and amine II (**, 1560 cm−1
)
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viii
A. Sacchetti et al./Chemical Papers
after 72 h. The most relevant observation was that
when using our hydrogel-supported catalysts, no TFA
addition was required. This is most probably due to
the presence of free carboxylic groups from PAA in
the hydrogel, which are able to provide the required
acidic environment. It was also observed that satis-
factory yields were achieved when using 1 mole % of
the loaded catalyst. This remarkable result is in agree-
ment with recent reports on low loading organocatal-
ysis even with water as the solvent (Park et al., 2015;
Giacalone et al., 2012).
multienzymatic cascade reduction of α,β-unsaturated alde-
hydes. The Journal of Organic Chemistry, 78, 4811–4822.
DOI: 10.1021/jo4003097.
Brenna, E., Gatti, F. G., Monti, D., Parmeggiani, F., Sacchetti,
A., & Valoti, J. (2015). Substrate-engineering approach to
the stereoselective chemo-multienzymatic cascade synthesis
of Nicotiana tabacum lactone. Journal of Molecular Cataly-
sis B: Enzymatic, 114, 77–85. DOI: 10.1016/j.molcatb.2014.
12.011.
Dalko, P. I., & Moisan, L. (2001). Enantioselective organocatal-
ysis. Angewandte Chemie International Edition, 40, 3726–
3748. DOI: 10.1002/1521-3773(20011015)40:20<3726::aid-
anie3726>3.0.co;2-d.
Dalko, P. I., & Moisan, L. (2004). In the golden age of
organocatalysis. Angewandte Chemie International Edition,
43, 5138–5175. DOI: 10.1002/anie.200400650.
Conclusions
Danelli, T., Annunziata, R., Benaglia, M., Cinquini, M., Cozzi,
F., & Tocco, G. (2003). Immobilization of catalysts derived
from Cinchona alkaloids on modified poly(ethylene glycol).
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4166(02)00830-3.
Davoodnia, A., Allameh, S., Fazli, S., & Tavakoli-Hoseini, N.
(2011). One-pot synthesis of 2-amino-3-cyano-4-arylsubstitu-
ted tetrahydrobenzo[b]pyrans catalysed by silica gel-suppor-
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reusable catalyst. Chemical Papers, 65, 714–720. DOI:
10.2478/s11696-011-0064-8.
In this work, the first application of a hydrogel as
the support for a chiral imidazolidinone based cata-
lyst for the reduction of activated olefins is described.
Results are promising for further applications of this
strategy; however, some improvement in the loading
of the catalyst and in the hydrogel mechanical stabil-
ity is still necessary. These issues are currently under
investigation in our laboratory.
Dondoni, A., & Massi, A. (2008). Asymmetric organocatalysis:
From infancy to adolescence. Angewandte Chemie Interna-
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(2006). A macroporous hydrogel for the coculture of neural
progenitor and endothelial cells to form functional vascular
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Hayashi, Y. (2006). In water or in the presence of water? Ange-
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