Recyclable silica-supported prolinamide organocatalysts for direct asymmetric Aldol reaction in water

Article abstract of DOI:10.1039/c2gc35227c

Asymmetric organocatalytic materials based on a prolinamide scaffold have been synthesized according to different synthetic routes from a monosilylated precursor: simple or surfactant-assisted co-condensation and grafting on preformed mesostructured silic

Full text of DOI:10.1039/c2gc35227c

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PAPER
Recyclable silica-supported prolinamide organocatalysts for direct
asymmetric Aldol reaction in water†‡
Amàlia Monge-Marcet,a,b Xavier Cattoën,b Diego A. Alonso,c Carmen Nájera,c Michel Wong Chi Manb and
Roser Pleixats*a
Received 15th February 2012, Accepted 15th March 2012
DOI: 10.1039/c2gc35227c
Asymmetric organocatalytic materials based on a prolinamide scaffold have been synthesized according
to different synthetic routes from a monosilylated precursor: simple or surfactant-assisted co-condensation
and grafting on preformed mesostructured silica. The catalytic properties of these materials have been
compared for direct asymmetric aldol reactions. The best catalytic material results from a simple
co-condensation without structure-directing agent. Simple and green conditions are used for the aldol
reaction, the process being performed in water at room temperature, with relatively low amounts of
supported organocatalysts and in the absence of an acid co-catalyst. Good recyclabilities are observed
without the need for catalyst regeneration, with enantioselectivities (ee up to 92%) higher than that of the
parent homogeneous catalysts.
act as effective organocatalysts for enantioselective
Introduction
aldolisations.2–13 Amongst the proline derivatives, substituted
Asymmetric organocatalysis is currently considered a fundamen-
tal and powerful tool for the stereoselective synthesis of
enantiomerically enriched compounds.1 Although the use of
non-metallic catalysts for the acceleration of organic reactions
has been known for more than a century, the recent development
and efficient application of a wide range of small chiral organic
molecules as catalysts to facilitate chemical transformations in a
selective manner, has led to a rediscovery of the concept and to
widespread progress in this field over the last decade.2–11
The aldol reaction is one of the most useful organic transform-
ations leading to the formation of new C–C bonds, with the cre-
ation of one or more stereogenic centers. The asymmetric direct
aldol reaction, involving a ketone in a non-activated form as
nucleophile, is one of the most studied types of synthesis in the
field of asymmetric organocatalysis.12,13 Mimicking the type I
aldolases, which function via an enamine pathway, small
molecules such as the naturally abundant and low cost aminoacid
L-proline or some other proline derivatives have been shown to
prolinamides bearing other stereogenic centers have successfully
been designed as asymmetric organocatalysts for C–C bond
forming processes, showing high activities, diastereo- and
enantioselectivities.14–18 Moreover, they also allow reactions to
be carried out in aqueous conditions, improving the sustainabil-
ity of the process.19
Organocatalysts offer some advantages over transition-metal
based catalysts, such as robustness, ready availability, non-
toxicity, inertness towards moisture and oxygen, simple handling
and storage, in addition to providing easy experimental pro-
cedures under non-inert conditions and precluding any metal
contamination in the final products. This is in accordance with
sustainable and environmentally friendly processes. However,
the preparation of more complex organocatalysts may involve
several steps. Besides, the reactions often require high catalyst
loadings (up to 30 mol%) and tedious purification of the pro-
ducts. Thus, an easy separation, recovery and recycling of the
catalyst remain a scientific challenge of economic and environ-
mental 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.20–25 In this way, proline-
derived organocatalysts have been anchored to different organic
(polystyrene,26–29 polyethyleneglycol,30 cyclodextrines31) or
inorganic supports (zeolites and mesoporous silica), either by
grafting methods24,32,33 or cogelification with tetraethoxysilane
(TEOS).23,34,35
aChemistry Department, Universitat Autònoma de Barcelona, Facultat
de Ciències, 08193 Cerdanyola del Vallès, Barcelona, Spain. E-mail:
roser.pleixats@uab.cat; Fax: (+34) 935812477; Tel: (+34) 935812067
bInstitut Charles Gerhardt Montpellier (UMR 5253, CNRS-UM2-
ENSCM-UM1), 8 rue de l’école normale, 34296 Montpellier, France
cDepartamento de Química Orgánica e Instituto de Síntesis Orgánica
(ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
†Electronic supplementary information (ESI) available: Characterization
of supported organocatalysts M2–M5; preparation of non-silylated orga-
nocatalysts analogues; catalytic tests with homogeneous organocatalysts
6 and 7; spectroscopic data of compounds 4 and 9; NMR and IR spectra
of compounds. See DOI: 10.1039/c2gc35227c
The formation of hybrid silica materials is attractive as a
means to achieve supported organocatalysts. Such materials
combine the advantages of a silica matrix such as high surface
‡This article is dedicated to Prof. Miguel A. Miranda on the occasion of
his 60th birthday.
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area, thermal and mechanical stability and chemical inertness
with the properties of the organic precursor.24,36–38 In addition,
they have been successfully developed using the sol–gel process
to entrap enzymes with enhanced efficiency.39,40 Indeed the
sol–gel hydrolytic condensation of organo-alkoxysilanes41 is a
convenient method for the preparation of organosilica materials
with targeted properties.42,43 Moreover, the surfactant-assisted
sol–gel synthesis or the grafting on a mesostructured silica44,45
are commonly employed routes for the synthesis of mesostruc-
tured organosilicas with a controlled loading of the active frag-
ment on the support, preserving the organic part in the silica
framework due to the strong Si–C covalent bonding. Materials
with high surface areas and large pore sizes, favouring an easy
accessibility of the organic functions in addition to the possible
diffusion of the solvent–soluble reactants within the insoluble
solid, appear attractive for their development and uses, particu-
larly for liquid–solid phase catalytic reactions.
materials derived from a monosilylated precursor, which would
afford a less rigid structure within the silica matrix. Moreover,
the co-gelification of this organosilane with tetraethyl orthosili-
cate (TEOS) would provide porous materials with high surface
area in contrast to the previously described non-porous silses-
quioxane. The surfactant-assisted sol–gel and grafting methods
have also been envisaged. We describe herein the preparation of
the monosilylated precursor, the corresponding hybrid silica
materials derived thereof under different experimental conditions
and the catalytic performance and recyclability in the direct aldol
reaction of these supported organocatalysts.
Results and discussion
Synthesis and characterization of the supported organocatalysts
M2–M5
We have recently reported the catalytic performance and re-
cycling profiles of a non-porous bridged silsesquioxane prepared
from a bis-silylated prolinamide precursor.46 Its structure was
based on an aminoindane-derived prolinamide previously
described by Nájera’s group14–16 as an efficient promoter of the
direct aldol and Michael reactions. In this case, the prolinamide
moiety was bound to the silica matrix via two different positions
which may restrict the flexibility of the organic fragment
involved in the catalytic reaction. With the aim of finding
efficient and recyclable silica-supported prolinamides with
enhanced selectivities, we undertook the preparation of several
The monosilylated prolinamide precursor 3 and the silica
materials M2–M5 derived thereof were synthesized as
summarized in Scheme 1. Aminoindane-derived prolinamide 1
was obtained from commercial N-benzyloxycarbonyl-4-trans-
hydroxy-L-proline and (R)-2,3-dihydro-1H-inden-1-amine. Sub-
sequent reaction of 1 with (3-isocyanatopropyl)triethoxysilane in
the presence of NEt3 provided the monosilylated protected proli-
namide 2. After the removal of the protecting group by treatment
with cyclohexene and catalytic Pd/C, the organosilane 3 was
obtained with good overall yield. From this precursor, four
different hybrid silica materials were prepared by sol–gel
Scheme 1 Preparation of the supported organocatalysts M2–M5.
1602 | Green Chem., 2012, 14, 1601–1610
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Table 1 Physical and spectroscopic data of M2–M5
29Si SSNMR
N2-sorption measurements
N : Si ratio
Calc.a
Mat.
T3
Q2
Q3
Q4
SBET (m2 g−1
)
Vpore (cm3 g−1
)
Exp.b
Cat. loading (mmol g−1 c
)
M2
M3
M4
M5
−66.9
−67.7
−64.5
−57.7d
−93.0
−92.9
−92.0
−92.7
−102.0
−102.9
−100.9
−101.6
−111.1
−112.2
−107.4
−109.8
<5
450
300
360
—
0.50
0.15
0.13
0.18
0.43
0.19
0.12
0.12
1.19
0.74
0.46
0.50
0.37
0.21
0.83
a Theoretical N : Si ratio according to the stoichiometry of the starting precursors. b Experimental value of N : Si ratio according to the elemental
analyses. c mmol Prolinamide g−1 material calculated from the N elemental analysis. d Value corresponding to a T2 signal.
methodologies and grafting on a SBA-15 type mesostructured
silica M1.47 Organosilicas M2 and M3 were obtained by sol–gel
co-condensation of 3 with different amounts of TEOS (molar
ratios of 1 : 5 and 1 : 19 respectively) under nucleophilic con-
ditions using a fluoride salt (TBAF) as catalyst. Template-
assisted hydrolytic polycondensation of 3 with TEOS under
acidic conditions (1.6 M HCl, P123 as structure directing agent,
EtOH as co-solvent with several drops of DMF) afforded M4
([P123] : [TEOS] : [3] : [H2O] : [HCl] : [EtOH] = 0.37 : 24 : 1.0 :
4390 : 126 : 106). The final suspension was stirred at 40 °C for
24 h and then left at 100 °C for 24 h without stirring. The surfac-
tant was removed from the obtained solid by subsequent Soxhlet
extraction with acidic ethanol and then the resulting material was
treated with a phosphate buffer (pH = 8) to liberate the pyrroli-
dine amino group. Finally, the material M5 was synthesized by
anchoring the precursor 3 to a mesostructured silica M147 under
standard conditions (in refluxing toluene for 24 h).
The materials were characterized by elemental analysis, 29Si
CP MAS solid state NMR, thermogravimetric analysis (TGA),
transmission electron microscopy (TEM), scanning electron
microscopy (SEM) and nitrogen-sorption measurements. The
13C CP MAS solid state NMR (SSNMR) and IR were only
recorded for M2 as in the other materials the high dilution of the
organic moiety in the hybrid silica precludes the observation of
the corresponding signals. Some physical and spectroscopic data
Fig. 1 N2-sorption isotherm and pore size distribution of M1, M3, M4
and M5.
are given in Table 1.
N2-sorption measurements revealed the non-porous nature of
M2, probably due to the low molar ratio TEOS : 3 (5 : 1) used in
the synthesis and to the voluminous organic fragment of the
material.48 A higher amount of TEOS resulted in appreciably
high surface area in the case of M3 and M4, respectively 450
and 300 m2 g−1. Both M3 and M4 present a characteristic type
IV isotherm, showing a hysteresis loop with a relatively sharp
distribution of mesopores (Fig. 1). While M3 was simply pre-
pared by the common sol–gel nucleophilic-catalyzed route as for
M2, M4 was synthesized with a neutral surfactant (P123) as
structuring agent (Scheme 1) and was thus intended to be meso-
structured. However, under the reaction conditions we used, it
was not possible to obtain such a structured porosity as evi-
denced by its N2-sorption isotherm (no H1–type hysteresis
loop),49 most probably due to the bulky organic part of the pre-
cursor 3. This is confirmed by the powder X-ray diffractogram
(Fig. 2), typical for a worm-like mesoporous organization and by
the TEM micrographs.† Indeed it is known that mesostructured
hybrid silica are more easily achievable with low organic-
fragment derived organosilanes.50 Whereas the microporous
Fig. 2 PXRD pattern of M4.
contribution was found negligible for M3, a t-plot micropore
area of 50 m2 g−1 was found for M4 (Fig. 1). Finally the organo-
silica M5 maintained the isotherm profile of the parent
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non-functionalized silica M1 (Fig. 1), suggesting that the orig-
inal mesostructure of M1 had not been affected by the grafting
process, as confirmed by TEM micrographs.† The BET surface
area decreased significantly (from 740 for M1 to 360 m2 g−1 for
M5) clearly indicating that precursor 3 had been successfully
grafted on the surface of M1 and thus somehow filling the pores.
The presence of the organic ligand in the hybrid materials was
ensured by the solid-state NMR spectra (29Si and 13C). The 29Si
CP MAS NMR spectra showed, in all cases, two groups of
chemical shifts: T units from −57 to −68 ppm resulting from the
hydrolysis and condensation of the organosilane 3, and Q units
ranging from −92 to −112 ppm formed from TEOS, as exem-
plified by the 29Si CP MAS NMR spectrum of M2 (Fig. 3b).
Indeed, the presence of T peaks suggested that the integrity of
the Si–C bond was maintained during the formation of the
hybrid material, which was also confirmed in the case of M2 by
the 13C solid state NMR spectrum (Fig. 3a), where a chemical
shift appears at around 10 ppm indicative of the CH2–Si bond.
As shown by 29Si solid state NMR spectra, the condensation is
not complete for these materials and, hence, the experimental
values of elemental analysis are not expected to match the theor-
etical ones.51 For material M3 the experimental N : Si ratio was
slightly higher than the calculated one. Residual DMF remaining
in the materials despite overnight drying under vacuum at 50 °C
may account for the higher nitrogen content than was expected.
A residual signal at 1657 cm−1 in the IR spectra can be attributed
to the CvO vibration of both the prolinamide moiety and DMF.
The catalyst loading was inferred from the nitrogen elemental
analysis (Table 1).
Catalytic activity and recyclability of the supported
organocatalysts M2–M5 in direct aldol reaction
The activity of the new hybrid silica materials was then evalu-
ated via a typically used benchmark for the direct asymmetric
aldolisations, namely the reaction between p-nitrobenzaldehyde
Fig. 3 (a) 13C and (b) 29Si NMR CP MAS spectrum of M2.
Table 2 Catalytic testsa with the supported organocatalysts M2–M5 and some homogeneous analogues
Entry
Catalyst (mol%)
Additiveb (mol%)
t
T (°C)
Conversionc (%)
drd (anti/syn)
eeantie (%)
1
2
3
4
5
6
7
8
M2 (1)
M2 (5)
M2 (10)
M2 (10)
M3 (10)
M3 (10)
M4 (10)
M5 (10)
M5 (10)
5a (20)
5b (20)
5b (20)
6 (10)
—
—
—
—
—
10
—
—
10
20
20
—
—
20
—
6 d
4 d
7 h
6 d
7 h
16 h
24 h
8 h
8 h
3 h
3 h
5.5 h
6 h
rtf
rt
rt
5
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
98
97
86/14
83/17
86/14
84/16
81/19
84/16
82/18
83/17
85/15
77/23
87/13
83/17
72/28
78/22
81/19
88
86
86
86
88
84
88
82
86
72
82
70
62
76
70
>99 (88)
80
>99 (70)
>99g
>99 (97)
>99 (98)
>99
97
95
99
>99
9
10h
11h
12
13
14
15
6 (20)
7 (10)
3 h
5 h
97
>99
a Reaction conditions unless otherwise stated: aldehyde (1 equiv.), cyclohexanone (5 equiv.), water (0.5 mL mmol−1 aldehyde) and the indicated
1
amount of the corresponding catalyst. b p-Nitrobenzoic acid. c Determined by H-NMR spectroscopy. In brackets, isolated yield of the diastereomeric
1
f
mixture after filtration. d Diastereomeric ratio determined by H-NMR spectroscopy. e Enantiomeric excess determined by chiral HPLC. rt Stands for
temperatures between 22 and 25 °C. g 7% of this conversion corresponded to a side product (see text). h Data extracted from ref. 16.
1604 | Green Chem., 2012, 14, 1601–1610
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and cyclohexanone to provide aldol 4 as a diastereomeric
mixture (Table 2). Initial tests were conducted in water using
different temperatures and loading of M2 as catalyst (entries
1–4), complete conversion being achieved after 7 h with 10 mol
% of catalyst at room temperature (entry 3). Lower temperature
(5 °C, entry 4) or lower loading of catalyst (1 and 5 mol%,
entries 1 and 2) resulted in a significant decrease of the reaction
rate but the selectivity was not affected, similar diastereomeric
ratios (dr) and enantiomeric excess (ee) being obtained in all
cases. The catalytic tests with the other materials M3–M5 were
then performed with a 10 mol% catalyst loading at room temp-
erature (entries 5–9). Complete conversions were observed
between 7 and 24 h depending on the catalyst, with higher
dilution of the organics in the silica matrix (M4) resulting in
lower rates. From these results, it seems that the presence of
regular or worm-like mesoporous structures (M4, M5) does not
bring any significant advantage in activity or selectivity with
respect to simple sol–gel co-condensation (M2, M3). Moreover
the effect of p-nitrobenzoic acid as co-catalyst did not signifi-
cantly improve either the activity or the selectivity (compare
entries 5 and 6 for M3 and entries 9 and 10 for M5). Remark-
ably, the crotonization compound52 coming from a dehydration
process was not formed in any case. The only side-product
observed once, in small amount (M3, p-nitrobenzoic acid as
additive, entry 6), was a diastereomeric mixture of the hemiacetal
derived from the final aldol and p-nitrobenzaldehyde.53
For the sake of comparison, we have included in Table 2 the
results reported16 for Najéra’s prolinamides 5a and 5b (Fig. 4)
(entries 10–12) and those we obtained from 6 and 7 (Fig. 4)†
(entries 13–15). Compound 7 bearing a carbamate moiety is a
homogenous analogue of our supported organocatalysts. The
other compounds would allow us to observe the effect of the
presence of a hydroxyl group in the indenyl and pyrrolidine
rings on the selectivity. The substitution of the free hydroxyl of
6 by a carbamate group in 7 displays a positive effect on the
activity, diestereo- and enantioselectivity (compare entries 13
and 15) although the enantiomeric excess was similar or still
lower than those obtained with 5b containing a free hydroxyl in
the indane fragment (compare entry 15 with entries 11 and 12).
It is worth pointing out that the supported organocatalysts M2
and M3 afforded TON (10) and TOF (1.4 h−1) values for this
aldol reaction comparable to those of homogeneous systems
5a–b, 6 and 7 (TON = 4.9, 4.8, 10, 10, respectively) (TOF =
1.6, 1.6, 1.7 and 2.0 h−1, respectively). Moreover, the organosili-
cas M2–M5 prepared from the monosilylated precursor 3 exhibit
higher enantioselectivities for the major diastereoisomer than
these homogeneous prolinamides (compare entries 1–9 and
10–15 in Table 2) and also than the previously described non-
porous bridged silsesquioxane derived from a bis-silylated proli-
namide analogue.46 This last observation seems to support our
hypothesis about the relationship between the degree of flexi-
bility of the immobilized organic moiety and the selectivity. But,
undoubtedly, silica should be far from being a passive support54
and higher activity or selectivity for silica-immobilized catalysts
has been reported in some cases.55,56 This synergetic effect may
be explained in terms of confinement, which can trigger chemi-
cal discrimination and, in some cases, increase the selectivity.
Confinement may also efficiently direct the stereochemical
outcome through space constriction and molecular close
contact.23,57 For the dense material M2, confinement effects may
not be observed and the role of the silica matrix in the selectivity
enhancement remains unclear, although it could be attributed to
some substrate-support interaction.
In the case of the non-porous material M2 the catalytic events
should take place at the external surface of the particles and
therefore the whole process must be fast although only a small
part of the catalyst is accessible by the substrates. On the other
hand, for mesoporous materials M3, M4 and M5, the catalytic
sites located inside the pores should all be accessible at a fast or
low rate. The smallest pore size (30–35 Å) and pore volume
(0.21 cm3 g−1) displayed by M4 might account for the particu-
larly low rate observed for M4 compared to M3 and M5.
Indeed, the pores might be too narrow to allow a good diffusion
of the substrates and the products within the material.
Following these encouraging results of activity and selectivity
we tested the reusability of our supported organocatalysts for the
mentioned direct aldol reaction in water at room temperature
(Tables 3 and 4). Recycling of M2 was performed with two cata-
lyst loadings (5 and 10 mol%, entries 1–5 and 6–10 respectively
Table 3 Recycling experimentsa with M2 in the direct asymmetric
aldol reaction (see reaction in Table 2)
Entry mol% Cycle
t
Yieldb (%) drc (anti/syn) eeantid (%)
1
2
3
4
5
6
7
8
9
10
5
5
5
5
1
2
3
4
5
1
2
3
4
5
4 d
5 d
6 d
7 d
8 d
24 h 88
16 h 95
16 h 88
16 h 97
16 h 95
97e
92
91
95
94
83/17
82/18
81/19
82/18
80/20
86/14
86/14
83/17
85/15
84/16
86
86
76
80
86
86
74
86
86
80
5
10
10
10
10
10
a Reaction conditions: room temperature, aldehyde (1 equiv.),
cyclohexanone (5 equiv.), water (0.5 mL mmol−1 aldehyde) and a
catalytic amount of M2. After the time indicated, the reaction mixture
was filtered and the catalytic material washed several times with AcOEt,
dried under vacuum and directly used in the next cycle. b Unless
otherwise stated: isolated yield of the diastereomeric mixture after
filtration when achieving complete conversion. c Diastereomeric ratio
determined by 1H NMR spectroscopy. d Enantiomeric excess determined
by chiral HPLC. e Conversion determined by 1H NMR spectroscopy.
Fig. 4 Nájera’s prolinamides 5a–b and homogeneous non-silylated
prolinamide analogues 6 and 7.
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Table 4 Recycling experimentsa with M3–M5 in the direct
asymmetric aldol reaction (see reaction in Table 2)
Table 5 Catalytic performancea of M2, M3 and M5 in the
intramolecular asymmetric aldol reaction with triketone 8
Entry Mat. Cycle
t
Yieldb (%) drc [anti/syn] eeantid (%)
1
2
3
4
5
6
7
8
M3
M3
M3
M3
M3
M4
M4
M4
M5
M5
M5
M5
M5
1
2
3
4
5
1
2
3
1
2
3
4
5
7 h
70
81/19
78/22
81/19
77/23
79/21
82/18
82/18
84/16
83/17
82/18
76/24
71/29
68/32
88
92
92
88
86
88
82
86
80
92
88
86
80
16 h 80
16 h 93
24 h 88
30 h 70
1 d
3 d
5 d
8 h
16 h 93
16 h 83
20 h 91
24 h 87
97
98
92
75
Entry
Mat.
Cycle
t (d)
Yieldb (%)
eec (%)
9
1
2
3
4
5
6
7
8
M2
M2
M2
M2
M2
M3
M3
M3
M3
M3
M5
M5
M5
M5
M5
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
2
2
3
5
5
2
2
3
4
5
2
2
3
4
5
61
87
80
90
78
60
59
58
62
72
82
83
78
60
87
44
52
46
46
48
42
42
44
33
40
48
44
44
26
24
10
11
12
13
a Reaction conditions: room temperature, aldehyde (1 equiv.),
cyclohexanone (5 equiv.), water (0.5 mL mmol−1 aldehyde) and
supported organocatalyst (10 mol%). After the time indicated, the
reaction mixture was filtered and the catalytic material washed several
times with AcOEt, dried under vacuum and directly used in the next
cycle. b Isolated yield of the diastereomeric mixture after filtration when
9
10
11
12
13
14
15
1
achieving complete conversion. c Diastereomeric ratio determined by H
NMR spectroscopy. d Enantiomeric excess determined by chiral HPLC.
a Reaction conditions: room temperature, water (0.5 mL mmol−1
substrate), supported organocatalyst (10 mol%), p-nitrobenzoic acid as
co-catalyst (10 mol%). After the time indicated, the reaction mixture was
filtered and the catalytic material washed several times with AcOEt and
MeOH, dried under vacuum and directly used in the next cycle.
b Isolated yield after chromatography on silica gel, the conversion was
complete at the indicated time. c Enantiomeric excess determined by
chiral HPLC.
in Table 3). Selectivity was maintained upon recycling up to 5
runs in both cases. With 5 mol% of M2 the reaction proceeds
slowly and some decrease in the reaction rate was observed in
successive runs whereas with 10 mol%, the reactions ran faster
with the same conversion rate even after 5 runs.
Organosilicas M3–M5 also proved to be reusable in the same
aldol reaction using a 10 mol% catalyst loading, up to three or
five runs being carried out for each material batch (Table 4). An
increase of the reaction times required for complete conversion
was observed upon recycling but, interestingly, high selectivities
were retained. We should emphasize that the developed pro-
cedure is very simple and environmentally friendly (aqueous
media, room temperature, no acid co-catalyst, relatively low
loadings of supported catalyst compared with the corresponding
homogeneous catalysts and which can be recovered easily by
simple filtration, avoiding chromatography separation from the
diastereomeric aldol mixture, reuse of the catalyst).
Finally, the catalytic performance and recyclability of hybrid
silica materials M2, M3 and M5 were also assayed for the
intramolecular aldol reaction with triketone 8 in water at room
temperature (Table 5). In this particular reaction, the use of
p-nitrobenzoic acid as additive (10 mol%) and column chromato-
graphy of the reaction crude mixture were required to achieve
Wieland-Miescher ketone 9 in good isolated yields. Although
moderate asymmetric induction was obtained (ee up to 52%), all
three materials could be reused for 5 consecutive cycles, without
a significant decrease in enantioselectivity for M2 and M3 upon
recycling. To the best of our knowledge, there are few recent
reports for the catalyst recycling in this Robinson
annulation.46,58
common nucleophilic-catalyzed sol–gel hydrolysis-condensation
with two different molar ratios of TEOS:3 (5 and 19) affording a
non-porous M2 and a mesoporous M3 hybrid materials respect-
ively; (ii) with a neutral surfactant as structure-directing agent
affording a worm-like mesoporous material M4 and (iii) grafting
of 3 on a SBA-15 silica, M1, yielding preserved mesostructured
M5. The evaluation tests of these catalysts together with related
homogeneous catalysts (5a, 5b, 6 and 7) in the direct intermole-
cular aldol reaction show that the immobilized catalysts, though
less reactive, allow reproducibly a better selectivity than the
homogeneous ones. Interestingly, increasing the porosity does
not affect neither the yield nor the selectivity although the reac-
tion rate was slower for the non-porous catalyst M2. Moreover,
the presence of additives which was beneficial in the case of the
homogeneous catalysts did not improve the selectivity at all.
These immobilized catalysts are furthermore easily recovered by
simple filtering and could be re-used up to five times with
similar performance as for the first runs. Finally the intramolecu-
lar asymmetric aldol reaction with triketone 8 was successfully
realized and although the selectivity was moderate in this case,
these catalysts could also be recycled at least three times. Inter-
estingly, these results demonstrate that a sol–gel material
obtained by simple co-condensation of an organosilane and a
silica source without using any structure-directing agent can be
as efficient as the related mesostructured materials M4 and M5,
which are both obtained using an important amount of
Conclusions
In summary, the immobilisation of a monosilylated prolinamide
derivative 3 has been achieved according to three routes: (i)
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surfactant. Efficient catalysts can thus be obtained without the
use of any template, which require tedious extraction processes
or calcination for their elimination. It is also worth mentioning
that these reactions were performed exclusively in water as
solvent without a co-catalyst and result in easier isolation of the
product and good recycling of the catalyst. Greener materials
and synthetic procedures will result from the development of
such approaches.
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 prior to use. Dry
solvents and reagents were obtained following standard pro-
cedures: 1,2-dichloroethane, pentane, triethylamine were distilled
over CaH2; THF and Et2O over Na/benzophenone and ethanol
was distilled from Mg/I2. Distilled and deionized water (MilliQ)
was used for the sol–gel process. Triketone 858,59 and meso-
structured non-functionalized silica M147 were prepared accord-
ing to a previously described procedure. Compounds 4 and 9
were previously described and their spectral and analytical data
were consistent with literature values.14
Experimental
General
The 1H and 13C NMR spectra in solution were recorded on
Bruker DRX-250 MHz, DPX-360 MHz or AVANCE-III
400 MHz and are referenced to solvent signals (CDCl3: δ =
7.26 ppm; DMSO-d6: δ = 2.50 ppm). The 29Si and 13C CP
MAS solid state NMR spectra were obtained from a Bruker
AV400WB; the repetition time was 5 s with contact times
of 5 ms. These NMR instruments belong to the Servei de
Ressonància Magnètica Nuclear of the Universitat Autònoma de
Barcelona or to the University of Montpellier II. From the Servei
d’Anàlisi Química of the Universitat Autònoma de Barcelona the
following experimental data were acquired: infrared spectra (IR),
specific rotation ([α]D) and high-resolution mass-spectrometry
(HRMS). IR was recorded with a Bruker Tensor27 with an ATR
Golden Gate. Specific rotation values were obtained at 22 °C in
a JASCO J-175 polarimeter at 589.6 nm and they are given in
10−1 ° cm2 g−1. HRMS were determined using a microTOF-Q
instrument with direct injection of the sample. Elemental ana-
lyses were done by Serveis Científico-Tècnics of the Universitat
de Barcelona. Elemental analyses of C, N and H were performed
using an elemental analyser EA-1180 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 and Daicel
Chiralpak IC) with a Waters 2960 instrument using a UV photo-
diode array detector. At the Institut Charles Gerhardt Montpel-
lier, surface areas were determined by the Brunauer–Emmet–
Teller (BET) method from N2 adsorption–desorption isotherms
obtained with a Micromeritics ASAP2020 analyzer after degas-
sing samples for 30 h at 55 °C under vacuum. The pore diameter
distribution was calculated by the BJH method. Thermogravi-
metric analysis of hybrid materials was done at Institut de
Ciència 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%, (R)-(−)-1-aminoindane 97%, ethyl
chloroformate 98%, (3-isocyanatopropyl)triethoxysilane 95%,
n-butylisocyanate 98%, tetrabutylammonium fluoride (TBAF,
1 M solution in anhydrous THF), p-nitrobenzaldehyde 98%,
p-nitrobenzoic acid 99%, Pd/C 10 wt%, tetraethyl orthosilicate
98%, Pluronic P123 and dry DMF were purchased from
(2S,4R)-Benzyl-2-[(R)-2,3-dihydro-1H-inden-1-ylcarbamoyl]-4-
hydroxypyrrolidine-1-carboxylate, 1
Commercial
N-Cbz-4-trans-hydroxy-L-proline
(2.17
g,
,
8.00 mmol) and NEt3 99.5% (1.12 mL, 0.726 g cm−3
8.00 mmol) were dissolved in THF (30 mL) and the solution
cooled to 0 °C with an ice bath. At this temperature ethyl chloro-
formate 98% (0.765 mL, 1.14 g cm−3, 8.00 mmol) was added
dropwise and the resulting mixture was stirred at 0 °C for
30 min. Then the (R)-(−)-1-aminoindane (1.10 g, 8.00 mmol)
was added slowly at 0 °C. The mixture was stirred for 1 h at
0 °C, overnight at room temperature and 3 h at reflux. After this
time, the mixture was cooled to room temperature and diluted
with AcOEt (20 mL). The precipitated ammonium salt was
filtered. The filtrates were concentrated under reduced pressure
and the residue was recrystallized from AcOEt–methanol to
furnish 1 as a white solid (2.59 g, 85%). Mp 178–179 °C; [α]D
+84.1° (c. 0.56 in EtOH); IR νmax (ATR)/cm−1 3459 and 3285
(OH and NH), 3024 (Csp2-H), 2974, 2939 and 2883 (Csp3-H),
1688 and 1651 (CvO) cm−1; δH (400 MHz, DMSO-d6,
rotamers mixture, aprox. 60/40) 8.38 (1H, m, CONH), 7.39–6.91
(9H, m, 9H, HAr), 5.41 (0.4H, t, J 7.2, CONHCH), 5.30 (0.6H, t,
J 8.0, CONHCH), 5.12 (2H, m, PhCH2O), 4.43 (2H, m, CHOH
and NCHCO), 3.66 (1H, m, Cbz-NCHH), 3.61–3.55 (1H, m,
Cbz-NCHH), 3.00–2.93 (1H, m, NHCHCH2CHH), 2.89–2.78
(1H, m, NHCHCH2CHH), 2.51–2.36 (1H, m, NHCHCHHCH2),
2.26–2.10 (1H, m, HOCHCHHCH), 2.09–2.03 (1H, m,
HOCHCHHCH), 1.90–1.71 (1H, m, NHCHCHHCH2), the
signal of the OH was not observed due to exchanges with water
of the deuterated solvent; δC (100 MHz, DMSO-d6, rotamers
mixture, aprox. 60/40) 173.5, 173.3, 155.5, 155.4, 143.0, 142.9,
142.8, 142.7, 136.7, 128.1, 127.7, 127.5, 127.4, 127.3, 126.2,
126.0, 124.1, 124.0, 123.8, 69.4, 68.7, 66.9, 66.8, 59.4, 58.9,
55.3, 54.8, 54.4, 47.6, 39.6, 38.5, 32.8, 32.7, 29.6; ESI-HRMS:
calcd for C22H24N2O4 + Na+: 403.1628; found: 403.1630.
(2S,4R)-Benzyl-2-[(R)-2,3-dihydro-1H-inden-1-ylcarbamoyl]-4-
[3-(triethoxysilyl)propylcarbamoyloxy]pyrrolidine-1-
carboxylate, 2
A few drops of dry DMF were added to a stirred suspension of
1 (1.18 g, 3.09 mmol) in dry ClCH2CH2Cl (15 mL) at 70 °C
under an inert atmosphere, until a homogeneous solution
was obtained. Then freshly distilled (3-isocyanatopropyl)-
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triethoxysilane (1.30 mL, 0.999 g cm−3, 5.21 mmol) and dry
NEt3 (0.45 mL. 0.726 g cm−3, 3.22 mmol) were added and the
mixture was stirred at 80 °C under inert atmosphere of Ar for
48 h. After this time, the volatiles were removed under vacuum
and the excess of isocyanate was distilled off. The residue was
dissolved in the minimum amount of dry THF. The product pre-
cipitated upon addition of dry Et2O. The solid was filtered off
and purified by flash chromatography (silica gel, hexane–AcOEt
1 : 2) to afford 2 as a white solid (1.50 g, 75%). Mp
107–109 °C; Rf 0.11 (hexane–AcOEt 1 : 2); [α]D = +0.2° (c. 1.0
in EtOH); IR νmax (ATR)/cm−1 3290 (NH), 3066 (NH), 2973
and 2883 (Csp3-H), 1688 (CvO), 1651 (CvO); δH (360 MHz,
DMSO-d6, rotamers mixture, aprox. 50/50) 8.42 (0.5H, d, J 8.2,
CONH), 8.40 (0.5H, d, J 8.0, CONH’), 7.39–6.90 (10H, m, HAr
and OCONH), 5.24 (1H, m, NHCH), 5.10 (3H, m, PhCH2 and
CHOH), 4.31 (1H, m, NCHCO), 3.73 (6H, q, J 6.8, OCH2CH3),
3.64 (1H, dd, J 12.2 J 4.5, Cbz-NCHH), 3.55 (1H, m, Cbz-
NCHH), 2.93 (3H, m, OCONHCH2 and NHCHCHH), 2.79 (1H,
m, NHCHCHH), 2.36–2.29 (2H, m, OCHCHHCHCO and
NHCHCH2CHH), 2.10 (1H, m, NCHCHH), 1.75 (1H, m,
HNCHCH2CHH), 1.44 (2H, m, NHCH2CH2), 1.14 (9H, t, J 6.8,
OCH2CH3), 0.52 (2H, m, CH2Si); δC (100 MHz, DMSO-d6,
rotamers mixture, aprox. 50/50) 171.3, 171.0, 155.5, 153.9,
153.8, 144.0, 142.9, 142.7, 136.9, 136.8, 128.4, 128.3, 127.8,
127.7, 127.5, 127.3, 127.2, 126.3, 126.2, 124.4, 124.3, 124.2,
123.9, 72.4, 71.6, 66.1, 58.7, 58.1, 57.7, 53.7, 53.1, 43.0, 37.3,
36.0, 32.8, 29.7, 7.2. ESI-HRMS: calcd for C32H45 N3O8Si +
Na+: 650.2868; found: 650.2860.
Preparation of hybrid material M2
To a stirred solution of 3 (0.324 g, 0.661 mmol) and TEOS
(0.750 mL, 0.940 g cm−3, 3.31 mmol) in anhydrous DMF
(4 mL) at 40 °C, MilliQ water (273 μL, 15.2 mmol, H2O/EtO =
1) and a commercial solution of 1 M TBAF in anhydrous THF
(40.0 μL, 0.040 mmol, 1 mol% F with respect to Si) were added.
The resulting solution was stirred for 10 min at 40 °C, then the
stirring was stopped and the mixture was cooled to room temp-
erature. After 1 h a gel was formed which was left to age at
room temperature for 5 days. At that time, the gel was crushed,
filtered off and washed with water (2 × 7 mL), EtOH (2 × 7 mL)
and acetone (2 × 7 mL). The solid was dried overnight at 50 °C
under vacuum (0.7 mbar) affording M2 (0.483 g) as a pale
yellow solid. SBET < 5 m2 g−1 (non-porous material); TGA (air,
20 to 700 °C) residual mass 56.86%; IR νmax (ATR)/cm−1 3292
(NH), 1655 (CvO), 1521, 1246, 953, 765; 13C CP MAS NMR
(100.6 MHz) δ 175.1, 143.6, 126.6, 76.8, 60.4, 54.5, 43.7, 34.4,
30.6, 23.9, 18.1, 14.3, 9.8; 29Si CP MAS NMR (79.5 MHz) δ
−66.9 (T3), −93.0 (Q2), −102.9 (Q3), −111.0 (Q4); elemental
anal. found: N 4.99, C 28.03, H 3.54, Si 22.8 (1.19 mmol proli-
namide g−1 material); calcd for C18H24N3O3SiO1.5·5SiO2
6.15, C 31.66, H 3.54, Si 24.68 assuming total condensation.
The hydrolysis and condensation is never complete in these
hybrid materials.
N
Preparation of hybrid material M3
To a stirred solution of 3 (0.499 g, 1.01 mmol) and TEOS
(4.40 mL, 0.940 g cm−3, 19.5 mmol) in anhydrous DMF
(10 mL) at room temperature was added a solution of MilliQ
water (1.50 mL, 83.3 mmol, H2O/EtO = 1) and TBAF (1 M in
anhydrous THF, 0.220 mL, 0.220 mmol, 1 mol% F with respect
to Si) in anhydrous DMF (10 mL). The resulting solution was
stirred for 10 min at room temperature then the stirring was
stopped; after 10 min a gel was formed, which was left to age at
room temperature for 6 days. At that time, the gel was crushed,
filtered off and washed with water (2 × 10 mL), ethanol (2 ×
10 mL) and acetone (2 × 10 mL). The final solid was dried over-
night at 50 °C under vacuum (0.7 mbar) affording M3 (1.73 g)
as a white solid. SBET 455 m2 g−1; pore diameter distribution
centered around 30–40 Å, average pore diameter (4V/A, BET):
32 Å, pore volume: 0.37 cm3 g−1; TGA (air, 20 to 700 °C)
residual mass 72.5%; 29Si CP MAS NMR (79.5 MHz) δ −58.7
(T2), −67.7 (T3), −92.9 (Q2), −102.9 (Q3), −112.2 (Q4);
elemental anal. found: N 3.09, C 14.07, H 2.05, Si 32.2
(0.74 mmol prolinamide g−1 material); calcd for C18H24N3O3-
SiO1.5·19SiO2 N 2.77, C 14.26, H 1.60, Si 37.05 considering
complete condensation.
(3R,5S)-5-[((R)-2,3-Dihydro-1H-inden-1-yl)carbamoyl]
pyrrolidin-3-yl (3-(triethoxysilyl)propyl)carbamate, 3
Compound 2 (2.45 g, 3.90 mmol) and cyclohexene (2.00 mL,
0.814 g cm−3, 19.6 mmol) were dissolved in dry EtOH (35 mL).
Then Pd/C 10% (0.51 g, 0.48 mmol) was added and the mixture
stirred at reflux under an inert atmosphere. When TLC showed
that all starting material was consumed (about 1 h), the reaction
was cooled to room temperature and filtered through Celite®.
The filtrates were concentrated under vacuum to afford 3 as a
solid (1.72 g, 90%). Mp 150–152 °C; [α]D: +40.3° (c. 1.29 in
EtOH); IR νmax (ATR)/cm−1 3297 (NH), 2972, 2926, 2881
(Csp3-H), 1698 (CvO), 1658 (CvO); δH (360 MHz, DMSO-
d6) 8.16 (1H, d, J 8.7, CONH), 7.24–7.09 (5H, m, HAr and
OCONH), 5.26 (1H, m, CONHCH), 4.99 (1H, br,NHCH2CHO),
3.73 (7H, m, OCH2CH3 and NHCHCONH), 3.04 (1H, dd, J
12.0 J 4.8, NHCHH), 2.95 (3H, m, NHCH and OCONHCH2),
2.84–2.74 (2H, m, NHCHCH2CH2), 2.38 (1H, m,
NHCHCH2CHH), 2.06 (1H, m, NHCH(CO)CHH), 1.94 (1H, m,
NHCH(CO)CHH), 1.82 (1H, m, NHCHCH2CHH), 1.44 (2H, m,
OCONHCH2CH2), 1.14 (9H, t, J 6.8 Hz, OCH2CH3), 0.51 (2H,
m, SiCH2). the signal of the NH of the pyrrolidine ring was not
observed, probably due to exchanges with water present in the
deuterated solvent; δC (100 MHz, DMSO-d6) 173.0, 155.9,
144.0, 142.9, 127.4, 126.4, 124.5, 123.6, 75.4, 59.5, 57.8, 53.3,
52.7, 42.9, 37.4, 32.9, 29.7, 23.0, 18.2, 7.2; ESI-MS m/z (%)
Preparation of hybrid material M4
In a 250 mL round bottom flask equipped with magnetic stirrer,
P-123 (1.76 g, 0.30 mmol) was dissolved in aqueous HCl
(1.6 M, 64.0 mL, 102 mmol) at 40 °C. When the solution was
homogeneous, TEOS (3.50 mL, 0.940 g cm−3, 19.6 mmol) was
added and the resulting suspension was stirred for 20 min at
40 °C. At that time, a solution of 3 (0.400 g, 0.81 mmol) in a
minimum amount of EtOH (ca. 5 mL, some drops of DMF were
494.2 (100) [M
+
H+], 316.2 (8.7) [M-CH2Si(OEt)3]+;
ESI-HRMS calcd for C24H39N3O6Si + Na+: 516.2500; found:
516.2499.
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necessary to completely dissolve 3) was added and the final sus-
pension stirred at 40 °C for 24 h. Then a reflux condenser was
coupled to the flask, the stirring was stopped and the mixture
was heated at 100 °C for 24 h. The mixture was cooled down to
room temperature, then filtered and the solid was washed with
water (3 × 30 mL), EtOH (3 × 30 mL) and acetone (3 × 30 mL).
It was continuously extracted with acidic EtOH (10 v/v% conc.
HCl–EtOH) for 4 days using a Soxhlet apparatus. After this
time, the solid was treated with a phosphate buffer (pH = 8)
until the filtrates reached pH 8. The final solid was dried over-
night at 50 °C under vacuum (1.0 mbar) and finally M4
(0.955 g) was obtained as a white solid. SBET 300 m2 g−1; pore
diameter distribution centred around 30–35 Å, average pore
diameter (4V/A, BET): 28 Å, pore volume: 0.21 cm3 g−1; TGA
(air, 20 to 700 °C) residual mass 75.4%; 29Si CP-MAS NMR
(79.5 MHz) δ −57.1 (T2), −64.5 (T3), −92.0 (Q2), −100.9 (Q3),
−107.4 (Q4); PXRD max at 0.781 nm−1, repeating distance 2π/
qmax = 8.05 nm (worm-like); elemental anal. found: N 1.93, C
9.56, H 1.92, Si 33.0 (0.46 mmol prolinamide g−1 material);
calcd for C18H24N3O3SiO1.5·24SiO2 N 2.31, C 11.90, H 1.33, Si
38.65 considering complete condensation.
catalytic material was dried under vacuum and directly used in
the next cycle.
Typical procedure for catalytic test in intramolecular aldol
reaction with supported organocatalyst
A mixture of triketone 8 (0.042 g, 0.215 mmol, 1 equiv.), milliQ
water (0.5 mL mmol−1 ketone), p-nitrobenzoic acid (0.10 equiv)
and the catalytic amount of the supported organocatalyst was
stirred in a vial at room temperature until 1H NMR showed com-
plete 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 com-
bined filtrates were concentrated under vacuum. Purification by
flash chromatography afforded compound 9 as an oil (hexane–
AcOEt, from 9 : 1 to 7 : 3). The catalytic material was dried
under vacuum and directly used in the next cycle.
Acknowledgements
We acknowledge financial support from Ministerio de Ciencia e
Innovación (MICINN) and Ministerio de Educación (MEC)
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 National de la
Recherche (CP2D-MESORCAT), Generalitat Valenciana (Pro-
jects GV/2007/142 and PROMETEO/2009/039) and the Univer-
sity of Alicante.
Preparation of hybrid material M5
In a 100 mL round bottom flask equipped with a Dean-Stark
apparatus, compound 3 (0.262 g, 0.536 mmol) and non-functio-
nalized mesostructured silica M147 0.529 g, 8.81 mmol) were
refluxed in dry toluene (50 mL) for 24 h. After this time the sus-
pension was filtered. The solid was washed with EtOH (3 ×
20 mL), acetone (3 × 20 mL) and CH2Cl2 (3 × 20 mL), then
dried overnight at 50 °C under vacuum (1.0 mbar) affording M5
as a white solid (0.603 g). SBET 360 m2 g−1; pore diameter distri-
bution centred around 50–100 Å, average pore diameter (4V/A,
BET): 92 Å, pore volume: 0.83 cm3 g−1; TGA (air, 20 to
700 °C) residual mass 77.98%; 29Si CP MAS NMR (79.5 MHz)
δ −52.9 (T1), −57.7 (T2), −92.7 (Q2), −101.6 (Q3), −109.8
(Q4); elemental anal. found: N 2.12, C 12.90, H 1.59H, Si 34.1
(0.70 mmol prolinamide g−1 material); calcd considering com-
plete grafting N 2.95, C 16.86, H 2.05, Si 35.48.
Notes and references
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Typical procedure for catalytic test in intermolecular aldol
reaction with supported organocatalyst
In a vial, cyclohexanone (110 μL, 0.947 g cm−3, 1.07 mmol, 5
equiv.), milliQ water (106 μL, 0.5 mL mmol−1 aldehyde) and the
catalytic amount of the supported catalyst were stirred together
for 20 min at the temperature indicated in the tables. After this
time, the p-nitrobenzaldehyde (0.033 g, 0.214 mmol, 1 equiv.)
was added and the mixture was stirred for the time and tempera-
ture 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 cyclohexa-
none remained, the residue was washed with pentane and filtered
off to afford a white solid. From this solid, diastereomeric anti:
syn ratio, isolated yield of the mixture and enantiomeric excess
for the major anti diastereomer (eeanti) were determined. The
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