Prolinamide bridged silsesquioxane as an efficient, eco-compatible and recyclable chiral organocatalyst

Article abstract of DOI:10.1039/c1nj20516a

A new organic-inorganic hybrid silica material derived from a bis-silylated prolinamide by sol-gel methodology has been successfully applied as a supported organocatalyst in asymmetric aldol and Michael reactions. Our immobilized system presents similar performances to homogeneous prolinamides and added advantages of easy recovery and good recyclability. It fits green chemistry requirements as the reactions are performed in water, at room temperature, with low catalyst loadings (2-16 mol%).

Full text of DOI:10.1039/c1nj20516a

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PAPER
Prolinamide bridged silsesquioxane as an efficient, eco-compatible and
recyclable chiral organocatalystwz
a
b
Amalia Monge-Marcet,ab Roser Pleixats,* Xavier Cattoen,
¨
Michel Wong Chi Man, Diego A. Alonso and Carmen Najera
b
c
c
´
Received (in Montpellier, France) 13th June 2011, Accepted 1st September 2011
DOI: 10.1039/c1nj20516a
A new organic–inorganic hybrid silica material derived from a bis-silylated prolinamide by sol–gel
methodology has been successfully applied as a supported organocatalyst in asymmetric aldol and
Michael reactions. Our immobilized system presents similar performances to homogeneous
prolinamides and added advantages of easy recovery and good recyclability. It fits green
chemistry requirements as the reactions are performed in water, at room temperature, with low
catalyst loadings (2–16 mol%).
require high catalyst loadings (up to 30 mol%) and tedious
Introduction
purification of the products. Thus the recycling of the catalyst
remains a scientific challenge of economic and environmental
relevance. One of the most widely used strategies for this
purpose consists in immobilising the homogeneous catalyst
on an insoluble support, with the advantages of easy handling,
clean separation of the products and the catalyst by filtration and
facile recovery and reuse of the latter.6 In this way, proline
derived organocatalysts have been anchored to organic polymers
(polystyrene, polyethyleneglycol) and to cyclodextrins.7
Zeolites and mesoporous silica have also been reported as
inorganic supports using grafting methods6b,8 or cogelification
with tetraethoxysilane (TEOS).6a,9
Asymmetric molecular catalysis is a powerful tool for the
stereoselective synthesis of highly valuable chiral building
blocks.1 This field has experienced exponential progress in the
recent years due to the efficient development and application of
organic molecules as catalysts in a wide range of transformations
where new carbon–carbon bonds are formed without any
metallic species.2
Mimicking the very efficient biocatalysts, small molecules
such as simple, naturally abundant, and low cost amino-acids
have been shown to be able to induce chirality for a broader
range of reactions and substrates. Among them L-proline has
traditionally been the most frequently used organocatalyst in
enantioselective reactions such as aldolisations, Michael additions,
Robinson annulations or Mannich reactions.3 In addition to
L-proline, substituted prolinamides have successfully been designed
as asymmetric organocatalysts.4 Moreover, many of these
derivatives show not only higher reactivity, diastereo- and
enantioselectivities, but they also allow performing reactions
under aqueous or solvent-free conditions, improving the
greenness of the process.5
Hybrid silica materials are attractive supports for organo-
catalysts as they have been successfully used to entrap enzymes
with enhanced efficiency.10 Indeed, they combine the advantages
of a silica matrix such as high surface area, thermal and
mechanical stability and chemical inertness with the properties
of the organic precursor.6b,11 The most commonly used routes
to immobilize homogeneous catalysts as silica materials are
the surfactant-assisted sol–gel synthesis, or the grafting on a
mesostructured silica,12 which allow a high and controlled
loading of the active fragment on the support, preserving the
organic part in the silica framework due to the strong Si–C
covalent bonding. However, the use of large amounts of template
molecules and the energy needed for their removal are limiting
factors for their use as supports in the context of sustainable
chemistry.13 Bridged silsesquioxanes14 represent an interesting
class of organosilicas, obtained by the sol–gel process from
bridged organosilanes, where the inorganic network is directly
built around the organic fragments. These materials feature an
inherently high homogeneity and the best possible loading of
organic groups, but most often they suffer from a low porosity.
However, recent examples have evidenced excellent catalytic
properties in several reactions, despite their low surface areas.6b,15
However, the preparation of more complex organocatalysts
usually involves several steps. Besides, the reactions often
a
`
Chemistry Department, Universitat Autonoma de Barcelona,
08193-Cerdanyola del Valles, Barcelona, Spain.
`
E-mail: roser.pleixats@uab.cat; Fax: +34 93 581 1265;
Tel: +34 93 581 2067
b Institut Charles Gerhardt Montpellier (UMR 5253 CNRS-UM2-
ENSCM-UM1), 8 rue de l’e´cole normale, 34296-Montpellier, France
c
´
Departamento de Quımica Organica and Instituto de Sıntesis
Organica (ISO), Universidad de Alicante, Apdo. 99, 03080-Alicante,
´
´
´
Spain
w Dedicated to the memory of Professor Rafael Suau.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c1nj20516a
c
2766 New J. Chem., 2011, 35, 2766–2772
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The recent advent of asymmetric organocatalysis2 prompted
us to investigate a bridged silsesquioxane obtained from a new
bis-silylated prolinamide precursor. Its structure is based on
an aminoindane-derived prolinamide, previously described
by Najera’s group4a,b as an efficient promoter of the direct
aldol and Michael reactions. We report here its synthesis, its
catalytic performances as well as its recyclability.
Results and discussion
Preparation of the bridged silsesquioxane M1
The synthesis of M1 is summarized in Scheme 1. Prolinamide
1 was obtained from commercial N-benzyloxycarbonyl-4-
trans-hydroxy-L-proline and (1S, 2R)-cis-1-amino-2-indanol.
Subsequent treatment with 3-(isocyanatopropyl)triethoxysilane
in the presence of NEt3 provided the bis-silylated protected
prolinamide 2. After the removal of the protecting group by
catalytic hydride transfer, precursor 3 was obtained with good
overall yield. The supported organocatalyst M1 was prepared
by hydrolytic polycondensation of monomer 3 with a fluoride
salt (TBAF) as catalyst.
Fig. 1 29Si solid state NMR of M1.
Material M1 was fully characterized by elemental analyses,
CP-MAS 13C and 29Si solid state NMR (Fig. 1 and 2), IR, TGA,
TEM and SEM microscopies and N2-sorption measurements,
which revealed its non-porous nature (no adsorption of N2 was
detected; see ESIz). The hybrid material M1 was found to
contain 1.82 mmol of organocatalyst/g, according to nitrogen
elemental analysis (see the experimental section). The solid state
29Si NMR spectrum (Fig. 1) shows chemical shifts corresponding
to T2 and T3 units at around ꢀ58 and ꢀ68 ppm resulting from
the hydrolysis–condensation of the corresponding monomer 3.
This fact proved that no Si–C bond cleavage occurred during the
Fig. 2 13C solid state NMR of M1.
hydrolysis process and was confirmed by the corresponding
chemical shifts of the organic fragments in the 13C solid
state NMR (Fig. 2) with a typical peak at around 14 ppm
characteristic of the C–Si bond.
Scheme 1 Synthesis of bis-silylated monomer 3 and hybrid material M1.
c
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Catalytic activity and recyclability of the hybrid material M1 in
the aldol reaction
but lower than those obtained with 5b. The comparison of
ee achieved with M1 and 6 did not reveal significant differences;
therefore the immobilization of the catalyst did not imply any
drawback in terms of selectivity. Furthermore, the addition of
p-nitrobenzoic acid as a cocatalyst did not seem to have a positive
effect on the selectivity for the supported catalyst M1, whereas in
the case of Najera’s prolinamide this additive is necessary to
increase both the reaction rate and selectivity in those reactions
involving an enamine pathway (entries 7–9, Table 1).4a,b
With these considerations in mind we set the optimal
conditions and carried out recycling experiments (Table 2).
Supported catalyst M1 proved to be reusable for 5 runs with
excellent yields and good dr and ee, using a very simple
experimental procedure. The reaction was performed in water
at room temperature without additives and 16 mol% of M1
(this loading seems to provide the best balance between
performance and the amount of the catalyst used).
The activity of this new hybrid material was then evaluated in the
direct asymmetric aldol reaction between p-nitrobenzaldehyde
and cyclohexanone, which is typically used as a benchmark for
these reactions.
Initial catalytic tests were performed in water using different
catalyst loadings and reaction temperatures, and the presence
of p-nitrobenzoic acid as an additive was also evaluated
(Table 1). Good diastereo- and enantioselectivities were
achieved (dr 4/1, ee up to 76%). Furthermore, complete
conversion was obtained within 24 h in all cases, except when
using 2 mol% of M1 (Table 1, entry 1), although selectivity was
not affected. After filtration and evaporation of volatiles,
compound 4 was isolated in excellent yields as a diastereomeric
mixture. Interestingly, with lower loading of our hybrid catalyst
M1, we obtained quite similar results to those reported with the
homogeneous prolinamide4a (Table 1, entry 7).
The newly developed experimental protocol was then
applied to other aromatic aldehydes as acceptors, and also an
intramolecular reaction was tested with triketone 9 (Table 3). In
all cases the reaction afforded the desired aldol product in good
yields and M1 could be recycled. Clear asymmetric induction was
observed with acceptors such as benzaldehyde and 2-chloro-
benzaldehyde, even though it implied an increase in the reaction
times and a drop in both dr and ee, 3/1 (anti/syn) and 51–57%
respectively (Table 3, entries 1–4).
It is noteworthy that although M1 displays non-detectable
porosity, similar TON and TOF are achieved compared with
the homogeneous systems. We believe that the catalytic events
take place at the external surface of the particles and that most
of the prolinamide entities remain non-accessible inside the
bulk material. Furthermore, unlike homogeneous systems, M1
proceeds without the use of any acid cocatalyst. Indeed, in our
hands, the use of p-nitrobenzoic acid did not improve the
selectivity results (Table 1, compare entries 2 and 3). Lower
temperature did not affect the selectivity either (Table 1, entry 5),
whereas the use of water was critical, and under solvent-free
conditions the reaction did not proceed.
Material M1 bears a carbamate moiety in the indenyl ring,
instead of the hydroxyl of Najera’s prolinamide 5b. The latter
functional group has a significant effect on selectivity, since
both ee and dr are lower for Najera’s prolinamide 5a (Table 1,
entry 7) than for 5b (Table 1, entry 8). Nevertheless the
carbamate moiety did not display the same positive effect regarding
the performance of a homogeneous non-silylated bis-carbamate
prolinamide analogue 6 (Fig. 3, Table 1, entry 10)z which
showed comparable activity and selectivity with respect to 5a,
Fig. 3 Najera’s prolinamides and
a homogeneous non-silylated
bis-carbamate prolinamide analogue.
Table 1 Direct aldol reaction of cyclohexanone with p-nitrobenzaldehyde catalyzed by M1: optimisation of the reaction conditionsa
Yieldb (%)
anti/sync
d
eeant i (%)
Entry
Catalyst (mol%)
Additive (p-NO2C6H4COOH, mol%)
Time/h
T/1C
1
2
3
4
5
6
7
8
9
10
M1 (2)
M1 (8)
M1 (8)
M1 (16)
M1 (16)
—
—
5
—
—
—
20
20
—
—
144
16
8
6
24
6
3
3
5.5
5
22
22
22
22
5
22
22
22
22
22
97
78/22
86/14
84/16
82/18
80/20
72/28
77/23
87/13
83/17
82/18
70
70
64
74
66
76
71
81
70
73
90
99e
97
89
92
M1 (24)
Najera’s prolinamide 5af (20)
Najera’s prolinamide 5bf (20)
Najera’s prolinamide 5b (20)
6 (10)
97e
95e
99e
100e
a
b
Reaction conditions: aldehyde (1 equiv.), cyclohexanone (5 equiv.), water (0.5 mL mmolꢀ1 aldehyde) and a catalytic amount of M1. Isolated
yield of a diastereomeric mixture after filtration when achieving complete conversion. Determined by 1H NMR spectroscopy. Determined by
e
chiral-phase HPLC. Conversion. Data extracted from ref. 4a.
c
d
f
c
2768 New J. Chem., 2011, 35, 2766–2772
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Table 2 Recycling experiments using M1 (16 mol%) in water at 22 1C
Table 4 Catalytic performance of M1 in Michael additiona
Yielda (%)
anti/synb
c
eeanti (%)
Cycle
Time/h
1
2
3
4
5
6
16
24
24
24
97
94
91
97
96
82/18
82/18
83/17
79/21
85/15
74
73
70
68
69
Time (days) Conv.b (%) anti/synb eesyn (%)
c
Entry Cycle
R
1
2
3
4
1
2
1
2
Et
Et
Me
Me
5
7
7
7
11 (97)
11 (60)
12 (99d)
12 (40e)
21/79
24/76
20/80
24/76
66
60
66
70
a
b
diastereomeric mixture. Determined by
Isolated yield of
a
1H NMR spectroscopy. Determined by chiral-phase HPLC.
c
a
Reaction conditions: trans-b-nitrostyrene (0.21 mmol), ketone
In the intramolecular reaction of 9 to obtain the Wieland–
Miescher ketone, 10, the use of p-nitrobenzoic acid as an additive
was necessary to achieve good conversions in reasonable times,
and moderate enantioselectivity (43% ee) was observed. In this
particular case, the purification of the final compound required
column chromatography, and remarkably, M1 could be reused
for 5 consecutive cycles (Table 3, entries 5–9). To the best of our
knowledge, this is the first example of catalyst recycling in this
Robinson annulation.
(1.07 mmol), water (106 mL), p-NO2C6H4COOH (0.02 mol) and M1
b
c
(0.035 mmol). Determined by 1H NMR spectroscopy. Determined
d
e
by chiral-phase HPLC. 16% of the regioisomer observed. 14% of
the regioisomer observed.
Conclusions
In summary, we have presented the first hybrid silica material
derived from a bis-silylated prolinamide by sol–gel methodology,
without TEOS addition, which has been applied as a supported
recyclable asymmetric organocatalyst in aldol and Michael
reactions. Using relatively low catalyst loading for a supported
organocatalyst, a simple, efficient and environmentally friendly
procedure has been developed in aqueous media, no acid
additives being required in some cases. Despite its very low
porosity, this material exhibits performances similar to those
found for homogeneous organocatalysts. Further studies are
currently in progress to find hybrid silica materials with improved
catalytic activities and selectivities, as well as to broaden their
applications in other asymmetric transformations.
Catalytic activity and recyclability of the hybrid material M1 in
the Michael reaction
Finally, the versatility of the catalytic system was evaluated by
the Michael addition of 3-pentanone and butanone to trans-
b-nitrostyrene (Table 4). In these reactions, addition of the
co-catalyst was necessary for good conversions, which required
longer reaction times. In agreement with previous results
reported in the literature,4b the syn diastereomer was the major
product obtained.
Similar enantioselectivity but lower diastereoselectivity was
observed for the reaction with 3-pentanone to give 11 (up to
66% eesyn, anti/syn 21/79, Table 4, entry 1) when compared
with Najera’s prolinamide4b (95% conversion in 3 days, anti/syn 7/
93, 64% eesyn, MeOH as solvent and 20 mol% of the catalyst).
More interesting is the use of butanone, which may give rise to
regioisomers. The target compound 12 was obtained in a 1/4 anti/
syn ratio and 66% ee for the syn isomer. In addition, the formation
of the regioisomeric product was reduced to only 16% instead of
the 40% described for the homogeneous prolinamide.4b Material
M1 could be recycled in both cases.
Experimental
General
The 1H, 13C NMR spectra in solution were recorded on Bruker
DXP-250 MHz, DXP-360 MHz, AVANCE-II 400 MHz or
AVANCE 600 MHz. The CP-MAS 29Si and 13C solid state
NMR spectra were obtained from a Bruker AV400WB; the
repetition time was 5 s with contact times of 5 ms. All NMR
Table 3 Aldol reaction with other substrates catalysed by hybrid silica material M1a
Entry Cycle Time (days) Product (yieldb, %) anti/sync eed (%) Acceptor
Donor
Product
1
1
7
7 (96)
63/37
50
2
3
4
1
2
3
3
5
7
8 (499)e
8 (99)e
72/28
68/32
69/31
52
51
57
8 (499)e
5f
6f
7f
8f
9f
1
2
3
4
5
1
3
3
3
4
10 (74)
10 (68)
10 (71)
10 (81)
10 (79)
—
—
—
—
—
43
34
33
27
27
a
Reaction conditions: aldehyde (1 equiv.), ketone (5 equiv.), water (0.5 mL mmolꢀ1 aldehyde), p-NO2C6H4COOH (10 mol%) and M1 (16 mol%).
b
c
d
e
Isolated yield. Determined by 1H NMR. Enantiomeric excess of the anti-diastereomer determined by chiral-phase HPLC. Conversion
determined by 1H NMR. Triketone, water (0.5 mL mmolꢀ1), M1 (16 mol%) and p-NO2C6H4COOH (10 mol%), purification by flash
chromatography.
f
c
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` `
instruments belong to the ‘‘Servei de Ressonancia Magnetica
Nuclear’’ of the Universitat Autonoma de Barcelona. From
in THF (60 mL) and the solution was cooled to 0 1C with an ice
bath. At this temperature ethyl chloroformate (0.770 mL,
1.319 g cmꢀ3, 9.17 mmol) was added dropwise and the resulting
mixture was stirred at 0 1C for 30 min. Then (1S, 2R)-(ꢀ)-cis-
1-amino-2-indanol (1.20 g, 7.98 mmol) was added slowly at 0 1C.
The mixture was stirred for 1 h at 0 1C overnight at room
temperature and 3 h under reflux. After this, the mixture was
cooled to room temperature and diluted with AcOEt (20 mL).
The precipitated ammonium salt was filtered. Filtrates were
concentrated under reduced pressure and the residue recrystallized
in AcOEt/MeOH, thus obtaining the pure product 1 as a white
solid (2.53 g, 80%). Mp 175–176 1C; [a]D: ꢀ16.5 (c. 0.06 in
MeOH). IR nmax (ATR)/cmꢀ1 3429 (OH), 3293 (NH), 3072 and
3025 (QCH), 2938 (CH), 1682 and 1654 (CO), 1557 (ar C–C),
1466, 1428, 1359, 1180, 1132, 1083, 1052, 978, 732; dH
(600 MHz, DMSO-d6, rotamers mixture) 2.06–2.00 (1H, m,
OCCHCH2), 2.14–2.10 (0.5H, m, OCCHCH2), 2.21–2.17
(0.5H, m, OCCHCH2), 2.80 (0.5H, d, J 7.2 Hz, CCH2CHOH),
2.83 (0.5H, d, J 7.2, CCH2CHOH), 3.08–3.01 (1H, m,
CCH2CHOH), 3.44–3.39 (1H, m, NCH2), 3.52 (0.5H, dd,
J 11.1, J 4.8, NCH2), 3.55 (0.5H, dd, J 11.1, J 4.2, NCH2),
4.34–4.29 (1H, m, NCH2CHOH), 4.43–4.37 (1H, m,
NHCHCHOH), 4.52 (0.5H, t, J 12.0, NCHCO), 4.57 (0.5H,
t, J 7.8, NCHCO), 4.95 (0.5H, d, J 7.8, OH), 5.02 (0.5H, d, J 4.2,
OH), 5.16–5.05 (3H, m, PhCH2, OH), 5.17 (0.5H, dd, J 9.0,
J 5.4, OCNHCH), 5.21 (0.5H, dd, J 8.4, J 4.8, OCNHCH), 6.91
(0.5H, d, J 7.2, HAr), 7.00 (0.5H, t, J 7.8, HAr), 7.56–7.14 (8H, m,
`
´
the ‘‘Servei d’Analisi Quımica’’ of Universitat Autonoma de
Barcelona the following experimental data were acquired:
infrared spectra (IR), specific rotation (ORD) and high-
resolution mass-spectrometry (HR-MS). IR was recorded with
a Bruker Tensor27 with an ATR Golden. Specific rotation
values [a]D were obtained in a JASCO J-175 polarimeter at
589.6 nm and they are given in 10ꢀ1 deg cm2 ꢀ1. HR-MS
g
were determined using a microTOF-Q instrument with direct
injection of the sample. Elemental analyses were done by the
´
`
Serveis Cientıfico-Tecnics of the Universitat de Barcelona.
Elemental analyses of C, N and H were performed using an
elemental analyser EA-1108 CE Instrument of Thermo Fisher
Scientific with BBOT as an internal standard. The content of
Si was determined by ICP in a Perkin-Elmer Optima 3200RL
instrument. Melting points were determined using a Koffler-
Reichert apparatus and were not corrected. The enantiomeric
excess (ee) of the products was determined by chiral stationary
phase HPLC (chiral columns Daicel Chiralpak AD-H, Daicel
Chiralpak IC, Daicel Chiralcel OD) with a Waters 2960
instrument using a UV photodiode array detector. At the
Institut Charles Gerhardt of Montpellier, surface areas were
determined by the Brunauer–Emmet–Teller (BET) method
from N2 adsorption–desorption isotherms obtained with a
Micromeritics ASAP2020 analyzer after degassing samples
for 30 h at 55 1C under vacuum. The average pore diameter
was calculated by the BJH method. Thermogravimetric
HAr), 8.01–7.99 (1H, two d, J 8.4, J 9.0, OCNH); dC (62.5 MHz,
`
analysis of hybrid materials was done at ‘‘Institut de Ciencia
DMSO-d6, rotamers mixture) 26.5, 39.8, 40.6, 40.7, 41.0, 56.2,
56.6, 58.6, 58.8, 60.2, 60.8, 68.3, 68.8, 70.1, 70.8, 73.7, 74.0,
125.4, 125.7, 126.0, 127.7, 127.8, 128.7, 128.9, 129.0, 129.1,
129.5, 137.9, 138.0, 141.6, 141.9, 142.1, 156.7, 157.0, 175.1,
175.4; ESI-MS: calc. for C22H24N2O5Na: 419.1577, found:
419.1580.
dels Materials de Barcelona (ICMAB)’’ using a STA 449 F1
Netzsch instrument under atmospheric conditions. When
required, experiments were carried out with standard high
vacuum and Schlenk techniques. Chromatographic purifications
were performed under N2 pressure using 230–400 mesh silica gel
(flash chromatography).
N-Benzyloxycarbonyl-4-trans-hydroxy-L-proline 98%, (1S, 2R)-
(ꢀ)-cis-1-amino-2-indanol 99%, ethyl chloroformate 98%,
3-(isocyanatopropyl)triethoxysilane 95%, n-butylisocyanate
98%, tetrabutylammonium fluoride (TBAF, 1 M solution in
anhydrous THF), p-nitrobenzaldehyde 98%, 3-pentanone
98%, trans-b-nitrostyrene 98%, p-nitrobenzoic acid 99%,
Pd/C 10% wt and dry DMF were purchased from Sigma-
Aldrich. Cyclohexene 99% and cyclohexanone 99% were
obtained from Merck. All reagents and analytical grade solvents
were used as received except the 3-(isocyanatopropyl)triethoxy-
silane 95%, which was distilled under vacuum just before use.
Dry solvents and reagents were obtained following standard
procedures: 1,2-dichloroethane, pentane and triethylamine were
distilled over CaH2, THF and Et2O over Na/benzophenone,
and ethanol was distilled over Mg/I2. Distilled and deionized
water (MilliQ) was used for the sol–gel process. Triketone 9 was
prepared according to a previously described procedure.16
(2S, 4R)-Benzyl 4-(3-(triethoxysilyl)propylcarbamoyloxy)-2-
{(1S, 2R)-2-[3-(triethoxysilyl)propylcarbamoyloxy]-2,3-dihydro-
1H-inden-1-ylcarbamoyl}pyrrolidine-1-carboxylate, 2. Some
drops of dry DMF were added to a stirred suspension of 1
(1.50 g, 3.77 mmol) in dry ClCH2CH2Cl (5 mL) at 70 1C under
inert atmosphere, until a homogeneous solution was obtained.
Then, freshly distilled 3-(isocyanatopropyl)triethoxysilane
(3.80 mL, 0.990 g cmꢀ3, 15.2 mmol) and dry NEt3 (1.20 mL,
0.726 g cmꢀ3, 8.60 mmol) were added and the mixture was
stirred at 80 1C under an inert atmosphere of Ar for 48 h. Then
volatiles were removed under vacuum and the excess of
isocyanate was distilled off (0.03 mbar, 65 1C). The residue
was dissolved in a minimum amount of dry THF and the
product precipitated upon addition of dry diethyl ether. The
solid was filtered under a nitrogen atmosphere and washed
with dry pentane to give 2 as a pale brown powder (2.56 g,
76%). Mp 208–210 1C; [a]D +55.2 (c. 0.58 in EtOH); IR nmax
(ATR)/cmꢀ1 3319 and 3290 (NH), 2973, 2927 and 2884 (CH),
1687 and 1656 (CO), 1534, 1279, 1258, 1232, 1074 (SiO), 954,
767 and 734 (SiC); dH (400 MHz, DMSO-d6, rotamers
mixture) 0.51 (4H, pseudo t, J 8.4 Hz, CH2Si), 1.14 (18H, t,
J 7.0, OCH2CH3), 1.44 (4H, m, CH2CH2Si), 2.40–2.11 (2H, m,
OOCNCHCH2), 2.93 (5H, m, OCONHCH2, NHCHCHCH2),
3.17 (1H, m, NHCHCHOHCH2), 3.53 (2H, m, NCH2),
Syntheses
(2S, 4R)-Benzyl 4-hydroxy-2-((1S, 2R)-2-hydroxy-2,3-dihydro-
1H-inden-1-ylcarbamoyl)pyrrolidine-1-carboxylate, 1. N-Benzyl-
oxycarbonyl-4-trans-hydroxy-L-proline (2.12 g, 7.98 mmol) and
NEt3 99.5% (1.20 mL, 0.726 g cmꢀ3, 8.56 mmol) were dissolved
c
2770 New J. Chem., 2011, 35, 2766–2772
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3.57 (12H, q, J 7.0, OCH2CH3), 4.50 (1H, m, OCCHN), 5.09
(3H, m, PhCH2, NHCHCHOCH2), 5.32 (1H, m, NCH2CHO),
5.40 (1H, m, NHCH), 6.83–6.73 (1H, m, HAr), 7.08–7.04
(0.5H, m, HAr), 7.26–7.18 (4H, m, HAr, OCONH), 7.37–7.30
(4.5H, m, HAr), 8.13 (1H, m, OCNH); dC (100 MHz, DMSO-
d6, rotamers mixture) 7.6, 8.9, 18.6, 19.0, 23.4, 25.6, 36.0, 36.2,
43.5, 45.8, 53.2, 53.6, 55.8, 56.5, 58.1, 66.6, 67.4, 72.2, 72.9,
75.1, 75.4, 79.7, 124.3, 124.6, 125.1, 127.0, 127.1, 127.7, 127.9,
128.2, 128.3, 128.8, 128.9, 137.2, 137.3, 140.5, 141.2, 141.7,
154.4, 156.0, 156.1, 162.8, 171.8, 172.1; ESI-MS: calc. for
C42H66N4O13Si2Na: 913.4057, found: 913.4059.
N/Si: found 1.97; calc. 2.00. The hydrolysis and condensation
are never complete in these hybrid materials.
Catalytic testing
Typical procedure for catalytic test in intermolecular aldol
reaction with heterogeneous organocatalyst, M1. In a vial,
cyclohexanone (5 equiv.), MilliQ water (0.5 mL mmolꢀ1 aldehyde)
and a catalytic amount of material M1 (1.82 mmol gꢀ1, the
number of equivalents indicated in the tables) were stirred
together for 20 min at the temperature indicated in the tables.
After this, the aldehyde (1 equiv.) was added and the mixture
was stirred for the time and temperature indicated in the
tables. Then the crude mixture was diluted with AcOEt and
filtered. The insoluble catalytic material was washed several
times with AcOEt and the combined filtrates were concentrated
under vacuum. If some residual cyclohexanone remained, the
residue was washed with pentane and filtered to afford a white
solid. From this solid, anti: syn ratio, isolated yield of the
mixture and ee were determined. The catalytic material was
dried under vacuum and directly used in the next cycle.
Compounds 4, 7 and 8 have been previously described and
their spectral and analytical data were consistent with literature
values.4az
(2S, 4R)-Benzyl 4-[3-(triethoxysilyl)propylcarbamoyloxy]-2-
{(1S, 2R)-2-[3-(triethoxysilyl)propylcarbamoyloxy]-2,3-dihydro-
1H-inden-1-ylcarbamoyl}pyrrolidine-1-carboxylate, 3. Compound
2 (0.048 g, 0.054 mmol) and cyclohexene (0.030 mL, 0.811 g
cmꢀ3, 0.29 mmol) were dissolved in dry EtOH (4 mL). Then
Pd/C 10% (0.016 g, 0.015 mmol Pd) was added and the
mixture stirred at reflux under an inert atmosphere. After
1 h (TLC monitoring) all starting material was consumed, the
reaction mixture was cooled to room temperature and filtered
under nitrogen. Filtrates were concentrated under vacuum to
give product 3 as a sticky white solid (0.041 g, 99%). [a]D
ꢀ10.7 (c. 0.59 in EtOH); IR nmax (ATR)/cmꢀ1 3308br, 2972,
2928 and 2882 (CH), 1687 and 1651 (CO), 1534, 1256, 1165, 1074
(SiO), 953, 775 (SiC); dH (250 MHz, DMSO-d6) 0.52 (4H, m,
CH2Si), 1.15 (18H, t, J 7.0 Hz, OCH2CH3), 1.44 (4H, m,
CH2CH2Si), 2.05 (1H, m, NHCH2CHCH2), 2.16 (1H, t, J 7.2,
NHCH2CHCH2), 2.93 (6H, m, OCONHCH2, NHCHCHCH2),
3.19 (1H, d, J 4.4, NHCHCHCH2), 3.3 (1H, under H2O peak,
NHCH2), 3.74 (12H, q, J 7.0, OCH2CH3), 3.88 (1H, t, J 7.9,
NHCHCO), 5.03 (1H, m, NHCH2CH), 5.36 (1H, m,
OCNHCH), 5.46 (1H, m, NHCHCH), 7.37–7.09 (6H, m,
OCONH, HAr), 8.19 (1H, d, J 8.8 Hz, OCNH); dC (62.5 MHz,
DMSO-d6) 7.6, 18.6, 23.3, 23.4, 37.4, 37.8, 43.4, 53.0, 55.2, 58.1,
59.8, 75.6, 75.9, 79.7, 123.7, 125.3, 127.2, 128.2, 140.4, 141.9,
156.0, 156.2, 173.7; ESI-MS calc. for C34H60N4O11Si2Na:
779.3689; found: 779.3685.
Typical procedure for catalytic test in intramolecular aldol
reaction with heterogeneous organocatalyst, M1. A mixture
of triketone 8 (1 equiv.), water (0.5 mL mmolꢀ1 ketone), p-
nitrobenzoic acid (0.10 equiv.) and material M1 (1.82 mmol gꢀ1
,
0.16 equiv.) was stirred in a vial at room temperature until
1H-NMR showed complete conversion of triketone. Then the
crude mixture was diluted with AcOEt and filtered. The
insoluble catalytic material was washed several times with AcOEt
and MeOH and the combined filtrates were concentrated under
vacuum. After column chromatography of the residue on silica
gel using hexane/AcOEt (solvent gradient, from 9/1 to 7/3),
pure compound 10 was obtained as oil. The catalytic material
was dried under vacuum and directly used in the next cycle.
Compound 10 has been previously described and their spectral
and analytical data were consistent with literature values.4az
Preparation of material M1. To a solution of 3 (1.48 g,
1.95 mmol) in anhydrous DMF (6 mL) at 40 1C was added
under stirring MilliQ water (206 mL, 11.4 mmol, H2O/EtO = 1)
and a commercial solution of 1 M TBAF in anhydrous THF
(40 mL, 0.04 mmol, 1 mol% Fꢀ with respect to Si). The resulting
solution was stirred for 10 min at 40 1C, then the stirring was
stopped and the mixture cooled to room temperature. After 2 h
a gel was formed which was aged at room temperature for
5 days. After that, the gel was crushed, filtered and washed with
water (2 ꢁ 5 mL), ethanol (3 ꢁ 5 mL) and acetone (2 ꢁ 5 mL).
The final solid was dried overnight under vacuum (0.7 mbar) at
50 1C and finally M1 (1.02 g) was obtained as a pale yellow
solid. SBET: o5 m2 gꢀ1 (non-porous material); IR nmax (ATR)/
cmꢀ1 3309br (NH), 2934br (CH), 1694br and 1657br (CO),
1512br, 1247br, 1100br, 1035br, 645br; 29Si CP-MAS NMR
(79.5 MHz) d ꢀ58.3 (T2), ꢀ68.4 (T3); 13C CP-MAS NMR
(100.6 MHz) d 174.4, 163.1, 156.7, 140.6, 127.0, 76.3, 60.6, 55.2,
43.6, 37.5, 31.3, 24.2, 10.9; elemental anal. Found: N 10.21, C
45.15, H 6.01, Si 10.40%. Calc. for C22H30N4O8Si2: N 10.49, C
49.44, H 5.62, Si 10.49% assuming total condensation.
Typical procedure for catalytic test in the Michael reaction
with heterogeneous organocatalyst, M1. In a vial, ketone
(5 equiv.), MilliQ water (0.5 mL mmolꢀ1 trans-b-nitrostyrene),
material M1 (1.82 mmol gꢀ1, 0.16 equiv.) and p-nitrobenzoic
acid (0.10 equiv.) were stirred together for 20 min. After this,
trans-b-nitrostyrene (1 equiv.) was added and the mixture was
stirred at room temperature for the time indicated in Table 4.
Then the mixture was diluted with AcOEt and filtered. The
insoluble catalytic material was washed several times with
AcOEt and MeOH and the combined filtrates were concentrated
under vacuum. From the resulting solid, conversion, anti :syn
ratio and ee were determined. The catalytic material was dried
under vacuum and directly used in the next cycle. Compounds
11 and 12 have been previously described and their spectral and
analytical data were consistent with literature values.4b,17
z
Acknowledgements
We acknowledge financial support from Ministerio de Ciencia
´ ´
e Innovacion (MICINN) and Ministerio de Educacion (MEC)
c
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New J. Chem., 2011, 35, 2766–2772 2771

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of Spain (Projects CTQ2010-20387, CTQ2009-07881/BQU,
CTQ2007-62771/BQU and a grant to A. M-M.), Consolider
Ingenio 2010 (Project CSD2007-00006), FEDER, Generalitat
de Catalunya (Project SGR2009-01441), the Agence Nationale
de la Recherche (CP2D-MESORCAT), Generalitat Valenciana
(Projects GV/2007/142 and PROMETEO/2009/039) and the
University of Alicante.
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c
2772 New J. Chem., 2011, 35, 2766–2772
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011