Enantioselectivity induced by oxazaborolidine supported on mesoporous silica or by its analog in homogeneous phase

Article abstract of DOI:10.3390/molecules15053643

The impact of immobilization of oxazaborolidines supported on silica via different substituents on the boron and nitrogen atoms is evaluated in the enantioselective reduction of acetophenone. The performances of the homogeneous analog oxazaborolidines and

Full text of DOI:10.3390/molecules15053643

Molecules 2010, 15, 3643-3660; doi:10.3390/molecules15053643
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Enantioselectivity Induced by Oxazaborolidine Supported on
Mesoporous Silica or by Its Analog in Homogeneous Phase
Jeremy H. Yune, Françoise Quignard and Karine Molvinger *
Institut Charles Gerhardt Montpellier, UMR 5253 CNRS/ENSCM/UM2/UM1, Matériaux Avancés
pour la Catalyse et la Santé, « MACS » - 8, rue de l’Ecole Normale, 34296 Montpellier cedex 5,
France
* Author to whom correspondence should be addressed; E-Mail: karine.molvinger@enscm.fr.
Received: 19 April 2010; in revised form: 6 May 2010 / Accepted: 12 May 2010 /
Published: 18 May 2010
Abstract: The impact of immobilization of oxazaborolidines supported on silica via
different substituents on the boron and nitrogen atoms is evaluated in the enantioselective
reduction of acetophenone. The performances of the homogeneous analog
oxazaborolidines and silica-supported ones are compared by varying different parameters.
This article deals with the synthesis, characterization and catalytic evaluation of silica-
supported oxazaborolidines, their recycling capabilities and regeneration limitations.
Keywords: oxazaborolidine; supported catalyst; mesoporous silica; asymmetric reduction
of acetophenone
1. Introduction
Since their discovery by Itsuno et al. in 1981 [1] and their major development by Corey et al., chiral
1,3,2-oxazaborolidines have proven to be highly effective homogeneous catalysts for the
enantioselective reduction of ketones to chiral secondary alcohols by borane. The mechanism has been
elucidated by Corey et al. [2]: in fact the oxazaborolidine (synthesized from an amino alcohol) forms a
complex with the borane and this complex rapidly reduces the ketones with excellent yields and
enantiomeric excesses. Excellent results have been reported by Quallich using (1S,2R)-2-amino-1,2-
diphenylethanol, since one face of the catalyst is shielded due the orthogonal arrangement of the
phenyl substituents [3]. Furthermore, both enantiomers of Quallich’s amino alcohol are available and

Molecules 2010, 15
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not very costly in comparison with Corey’s amino alcohol. Under homogeneous conditions, the
enantioselective properties of oxazaborolidines are structure dependant [2], therefore the nature and the
position of the substituent strongly affect the enantiomeric excess achieved (Figure 1).
Figure 1. Influence of substituent linked to oxazaborolidine boron and nitrogen element on
the enantioselectivity.
Reduction of -tetralone
88% ee
90% ee
94% ee
86% ee
H
O
H
O
H
H
H
O
H
H
H
O
N
B
H
N
B
H
N
B
N
H
B
H
H
CH3
R2
O
R3
B
Reduction of acetophenone
R3
N
97% ee
96% ee
87% ee
R1
R4
O
N
O
N
O
N
B
H
B
H
B
H
Since separation of the alcohol product from the chiral amino alcohol (catalyst precursor) can be
difficult [4], metal [5,6] or polymer [7–14] supported oxazaborolidines have been considered. The
immobilisation was achieved through a covalent bond between the support and one of the substituents
of the oxazaborolidine. Therefore under heterogeneous conditions the substituent chosen to anchor the
enantioselective inductor also influences the enantioselective properties [10–14] (Figure 2).
Figure 2. Supported oxazaborolidines by different substituents on polymer.
R2 : ee up to 98%
R3 X 2 : ee up to 95%
R3 : ee up to 63%
R2
O
R3
B
R3
N
R1
R1 : ee up to 92%
R4
R4 : ee up to 91%
In the case of a polymer supported oxazaborolidine, the ketone must diffuse into the polymer, and
the solvent used has to swell the crosslinked polymer beads in order to increase accessibility to the
catalytic sites. After reduction and hydrolysis, the product removal from the polymeric matrix can be
difficult. In the case of metal-supported oxazaborolidines, these solids have a rather low surface area
and they are not easy to manipulate. In view of these drawbacks, mesoporous silica appears as an
interesting alternative due to its high surface area and mechanical resistance. In this paper, we will
compare the results for the enantioselective reduction of acetophenone for different silica-supported
oxazaborolidines, anchored via substituents of the boron or nitrogen element. The structural
modifications induced by the procedure chosen to graft the oxazaborolidine were simulated under

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homogeneous conditions, and allow a direct evaluation of the homogeneous versus immobilized
oxazaborolidine.
2. Results and Discussion
2.1. Immobilization of oxazaborolidines via boron substituent
Immobilization of oxazaborolidines via the boron substituent is obtained by a multi-step synthesis,
starting with the functionalization of the mesoporous silica by an amino alkoxysilane (aminopropyl- :
S1-1 or aminophenyl- alkoxysilane S1-Ph1) then immobilization of boronic acid and finally synthesis
of the chiral ligand by adding a chiral amino alcohol [(1S,2R)-diphenylaminoethanol, Figure 3). In an
alternative route, the oxazaborolidine has been immobilized by a direct functionalization of silica with
a boronic acid alkoxysilane (Figure 4).
Figure 3. Immobilization of oxazaborolidine via boron function.
Figure 4. Direct immobilization of oxazaborolidine via boron function.

Molecules 2010, 15
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2.2. Characterization of the materials
Qualitative and quantitative characterizations of the immobilized species for each step of the
materials synthesis are obtained by DRIFT and elemental analysis, respectively. Furthermore, the
textural characterization is realized by nitrogen sorption.
The formation of the grafted species for each step of the synthesis was monitored by DRIFT. All the
spectra are standardised according to Si-O-Si overtone at 1,987 and 1,870 cm-1. Thus, the
functionalization of silica with APTES has been confirmed by both the decrease of the intensity of the
vibration bands of the isolated silanols at 3,747 cm-1 and the apparition of the bands at 3,378, 3,317
and 2,931, 2,867 cm-1 characteristic of ν(NH2) st and ν(Cal-H), respectively, for S1-1. Then, the
presence of ν (BO-H) st (3,300, 3,262 cm-1), the enhancement of ν(Car-H) (3,070, 3,028 cm-1) for S1-
Ph2Br and ν(Cal-H) (2,931, 2,867 cm-1) for S1-2Br concur to confirm the grafting of boronic acids.
Finally, the formation of the oxazaborolidine has been revealed by the presence of ν(B-N) st at 1,452 cm-1
and the (N-H) linked to the bore (1,650 cm-1) and by the increase of the ν(Car-H) st and ν(Cal-H) st
(S1-3Br and S1-Ph3Br).
The composition of each solid is determined by elemental analysis, and as the successive reactions
are not quantitative, the final solid is functionalized by several species. In order to optimize the loading
of the chiral ligand on silica, several parameters have been changed such as reaction time, nature of the
boronic acid, amino alkoxysilane and strategy of immobilization.
Figure 5. Composition of supported oxazaborolidine via boron substituent; blue: amino
species, green: boronic acid species, red: immobilized oxazaborolidine, grey: physisorbed
amino alcohol.
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
HN
HN
O
HN
O
Ph
B
HN
B
O
O
Ph
B
HN
HN
B
B
O
B
O
NH
NH
O
O
O
O
NH
Et
NH
Et
Si
Si
O
O
OSiMe3
OH
Si
O
O
O
Si
O
Si
O
Si
O
O
O
O
O
O
O
* : 5 reaction days
Figure 5 presents the composition of the final materials; blue, green, red and grey plots correspond
respectively to amino, boronic acid, oxazaborolidine grafted and physisorbed amino alcohol.
Increasing reaction time from 24 h to 5 days results in a higher loading of oxazaborolidine supported
on silica, i.e., 0.28 to 0.47 mmol/g. The use of 3-bromomethylphenyl boronic acid allows the

Molecules 2010, 15
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immobilization of the chiral ligand in three instead of four steps with a slight improvement of the
chiral ligand loading, 0.53 mmol/g is obtained via this method. S1-Ph3Br has been synthesized in
order to determine the influence of the grafted species rigidity on enantioselectivity since a phenyl
substituent linked to the surface is known to be less flexible than an alkyl substituent. Finally,
immobilization of the chiral ligand via a direct functionalization of silica with boronic acid
alkoxysilane is the most appropriate method to obtain the highest chiral ligand loading, 0.85 mmol/g,
moreover in fewer steps. Physisorption of the amino alcohol can be avoided by an intermediate
passivation step.
2.3. Immobilization of oxazaborolidines via nitrogen substituent
Immobilization of oxazaborolidines via the nitrogen substituent is achieved by a multi-step
synthesis (Figure 6, pathway A), the first one required the functionalization of the mesoporous silica
by co-condensation of the surface silanols with an alkoxysilane presenting an halogen function.
Several halogens (Cl, Br, I) have been used in order to compare their reactivity in the nucleophilic
substitution reaction. The chiral amino alcohol has been supported thanks to a nucleophilic substitution
between amino and the halogen functions grafted on the mesoporous silica. Finally, the
oxazaborolidine has been synthesized by addition of borane according to classical homogeneous phase
procedures.
Figure 6. Immobilization of oxazaborolidine via nitrogen substituent.
In order to study the influence of residual silanols on conversion of the acetophenone, a passivation
step has been realized (Figure 6, pathway B).

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2.4. Characterization of the materials
Regarding the synthesis for S2-2X and S2-2pX, the functionalization of the silica by the
halogenopropyltriethoxysilane has been confirmed by the decrease of the intensity of the vibration
bands of the isolated silanols at 3,747 cm-1 and the apparition of the bands at 2,931 and 2,867 cm-1
characteristic of as(Cal-H) and s(Cal-H), respectively. Then, immobilization of the chiral amino
alcohol converts a secondary into primary amino alcohol; this procedure is evidenced by the presence
of the bands at 3,070, 3,028 cm-1 and 3,340 cm-1 characteristic of (Car-H) and N-H) st, respectively
and the increase of (Cal-H). Although DRIFT is not quantitative, we can observe that in the case of
the Cl grafted on silica, less amino alcohol reacts due to the less nucleophile character of the Cl
compared to Br and I. The passivation step is confirmed by the decrease of the vibration bands of the
isolated silanols at 3,747 cm-1. A lower amount of amino alcohol grafted on S2-2pI compared to S2-2I
is expected since the vibration bands intensity of (Car-H) and N-H st are lower.
Figure 7 describes the composition of the final material with oxazaborolidine supported via the
nitrogen substituent. The blue plots represent the loading of efficiently grafted halogeno fragment, the
red and grey plots correspond to grafted and physisorbed amino alcohol, respectively. To reach high
loadings of immobilized amino alcohol, it is preferable to use iodo- and bromo- rather than chloro-
alkoxysilane. Passivation of residual silanols prevents the physisorption of the amino alcohol.
Nevertheless, the reactivity seems to be altered since the loading of grafted amino alcohol is lower
with each alkoxysilane due to the hydrophobisation of the surface. Effectively, as observed in DRIFT,
no amino alcohol is grafted in the case of the chloro propyl functionalization, it is just physisorbed.
Figure 7. Composition of supported oxazaborolidine through nitrogen substituent; blue:
halogeno species, red: chemisorbed amino alcohol, grey: physisorbed amino alcohol.
2.5. Textural properties of the materials
The textural properties of the materials have been obtained by nitrogen sorption experiments and all
the isotherms have been standardised according to the inorganic part. For both pathway, pores volume
and diameter decrease after each step as the size of the organic species grafted on the silica increases,
which prove immobilization of species inside the pore. C parameter attests the surface polarity and
diminishes according to the augmentation of organic species. As expected, this parameter is lower for
the material S2-1pI, where a passivation step has been realized. Furthermore, the nature of the halogen

Molecules 2010, 15
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does not affect the texture of the materials. In Table 1, the textural properties of the supported
oxazaborolidines which are used in catalysis are reported.
Table 1. Textural properties of supported oxazaborolidines.
Surface area
(m2.g-1)
523
Vpores
(cm3.g-1)
1.93
Pore diameter
Samples
C
(Ǻ)
160
98
SG
S2-3Br
S2-3pBr
S2-3dI
S1-3Br
S1-Ph3Br
S3-2
105
40
29
43
43
47
55
27
457
1.56
390
1.40
98
423
1.47
100
93
382
1.27
455
1.50
92
346
1.11
93
S3-2p
333
1.17
96
2.6. Catalytic results
The final solid is functionalized by several species, and in order to check the influence of these
residual species on the silica, the reduction of acetophenone by BH3 has been realized in the presence
of various samples presenting a precise surface environment (Table 2). The reaction involves
0.7 equivalents of borane in THF with acetophenone to achieve a complete conversion since the
borane provides two hydrides and thus can reduce two equivalents of ketone [15,16] (entry 1). Borane
(BH3 Lewis acid) can coordinate to an OH function (Lewis base), resulting in its loss of activity, as
previously observed by Asefa et al.[17]. The comparison of entries 2 and 3 proves without ambiguity
the negative influence of the silanol on conversion. Since the passivation of all the silanols cannot be
completed, some residual silanols are still available, leading to an incomplete conversion. Through
coordination between amino, halogen and borane, formation of halogenoborane species can occur [18].
As a consequence, conversion is not complete in the presence of S2-1I and S1-1 (entries 4 and 6).
According to entry 5, a lower conversion compared to entry 2 is obtained, which can be the result of
the potential coordination of the borane on both residual silanol and physisorbed amino alcohol. Since
this physisorbed species can form a chiral ligand by the addition of borane during the catalytic
reaction, two reduction cycles have been realized in order to evaluate its influence on enantiomeric
excess. No chiral induction has been observed during the reduction of acetophenone for both cycles,
evidencing the fact than the potential oxazaborolidine physisorbed cannot induce chirality in this
precise environmental configuration. Indeed, silanol could interact with the endocyclic boron of the
ligand leading to the impediment of the required complexation of the ketone. Boronic acid species also
damage the conversion due to the complexation of borane on OH groups of the boronic acid mentioned
by Caze et al. and Martens et al.[19,20] and confirmed by the comparison between entries 6 and 7.
As a consequence, activities of the supported oxazaborolidine are expected to be lower than the
homogeneous analog but none of the residual fragments will act as a chiral inductor. Thus the
enantioselectivity will be directly coupled with the presence of immobilized oxazaborolidine.

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Table 2. Influence of residual species on conversion.
Entry
Sample
Conversion (%)*
100
ee (%)
1
1
BH3
0
OH
OH
2
3
67
0
0
SiMe3
O
89
OH
Grace Davison silica end-
capped
O
O Si
I
4
5
70
0
O
S2-1I
O
H
H2N
Ph
Ph
OH
O
40
0
0
H
61 2
H
H
O
O Si
NH2
6
7
77
52
0
0
O
S1-1
O
O Si
N
H
O
OH
B
OH
S1-2Br
* Selectivity of 100%; reaction time: 2 h; 1 Ratio surface species/BH3/ketone: 0/0.7/1; 2 2nd cycle.
As previously mentioned, under homogeneous conditions, the enantioselective properties of
oxazaborolidines are structure dependant [2] and the nature and the position of the substituent strongly
affect the enantiomeric excess achieved. Grafting the oxazaborolidine leads de facto to the
modification of the boron or nitrogen atom substituents. Thus, the enantiomeric excess differences
observed can be induced by the immobilization, rather by these substituent modifications. In order to
discriminate between these two hypotheses, the same structural modifications have been introduced on
soluble oxazaborolidines. Comparing the results in Table 3 from entries 1 to 4, as expected, the bulkier
the substituent is, the lower the ee are, from H linked to the boron (93% ee) to
triethoxy(phenylethyl)silane (80%). The oxazaborolidine (entry 4) can be considered as the
homogeneous analog of the heteregeneous catalyst; in this case, the ee is only moderate.

Molecules 2010, 15
Table 3. Influence of the substituent linked to the boron on the ee.
3651
Entry
Catalyst
ee (%)
H
N
Ph
Ph
H
B
O
1
93
H
N
Ph
2
3
4
B
76
80
80
O
Ph
H
N
Ph
Ph
B
O
Et
Et
O
O
O
H
N
Ph
Si
B
O
Et
Ph
Ratio oxazaborolidine/BH3/acetophenone = 0.1/0.7/1; Reaction time: 1 h; Conversion: 100%.
When oxazaborolidine is immobilized on silica via the nitrogen atom, the decrease of the reactivity
of complex ligand.borane toward borane can affect its enantioselectivity. The influence of a propyl
group has been evaluated in homogenous phase. The enantioselectivity decreases dramatically when
the hydrogen is replaced by a propyl function (Table 4). In this latter case, the steric hindrance of the
propyl group blocks the complexation of borane on the nitrogen atom, the reduction by the borane
alone is favored, and the enantiomeric excess (ee) diminishes. Moderate ee can be achieved by
increasing the amount of oxazaborolidine used. These observations are in agreement with those
reported by Quallich in the case of the reduction of tetralone [3]. He reported that the substitution of a
hydrogen atom by a methyl group on nitrogen leads to a dramatic drop of the ee (94% to 0%). By
using a stoechiometric ratio, 30% of ee is reached. In our case, increasing the ratio until one equivalent
leads to an improvement of the ee, but is still low (45%).
Table 4. Influence of the nitrogen substituent of the oxazaborolidine on the enantioselectivity.
Ratio
Time
conversion
(%)*
ee
(%)
Entry
Oxazaborolidine
Oxazaborolidine/BH3/ketone (hours)
H
Ph
H
Ph
1
0.1/0.7/1
0.1/0.7/1
1
100
93
N
O
H
HB
1
2
86
100
10
10
H
Ph
Ph
1
2
71
100
45
45
2
0,3/0.7/1
1/0.7/1
N
O
H
HB
1
2
47
100
45
45

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Whatever the strategy used, the enantiomeric excesses obtained with supported oxazaborolidine are
higher than those obtained in homogenous phase (Table 5, entries 1 and 2, Table 5, entries 3 and 4).
Total conversion cannot be reached because of the presence of residual species on the silica, but the
enantioselectivity is improved.
Table 5. Enantioselectivity comparison between homogeneous and supported oxazaborolidine.
Ratio
conversion
(%)
ee
(%)
Entry
Oxazaborolidine
Oxazaborolidine/BH3/cétone
Et
O
Et
O
O
0.1/0.7/1
1/0.7/1
100
100
80
84
H
N
Ph
Ph
Si
1
B
O
Et
O
O Si
N
H
0.1/0.7/1
57
50
80
81
O
H
N
B
O
Ph
2
0.16/0.7/1
Ph
0.3/0.7/1
0.1/0.7/1
40
94
10
S1-3Br
100
H
Ph
Ph
3
4
0.3/0.7/1
1/0.7/1
100
100
84
45
45
35
72
N
O
H
HB
H
Ph
O
Ph
0.1/0.7/1
0.3/0.7/1
O Si
N
O
O
H
HB
OH
72
S2-3Br*
Selectivity: 100%.
In homogeneous phase, the optimal temperature to obtain the highest enantioselectivity depends on
the solvent, reductant and oxazaborolidine used [21,22]. Moreover, this defined temperature is not
necessary equivalent when the chiral ligand is immobilized on polymers due to their swelling. The
influence of this parameter has been realized with the silica-immobilized oxazaborolidine. In both
homogeneous and heterogeneous phase, the influence of the temperature on enantioselectivity is
similar and the best enantioselectivity is obtained at 28 ºC (Table 6).
Table 6. Influence of the temperature on the enantioselectivity.
Temperature of
reaction (ºC)
conversion
(%)
Oxazaborolidine
time (h)
ee (%)
H
N
Ph
B
0
28
60
1
1
1
100
100
100
60
80
56
O
Ph
(4S,5R)-2,4,5-triphenyl-1,3,2-
oxazaborolidine
O
O
Si
N
H
O
H
0
28
60
2
2
2
53 (56)
40 (42)
54 (54)
75
94
72
N
B
O
Ph
Ph
S1-3Br
() results after 24 h; Selectivity: 100%; oxazaborolidine/BH3/ketone ratio: 0.3/0.7/1.

Molecules 2010, 15
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According to the nature of the solvent used [23,24], oxazaborolidines can exist in homogeneous
phase as dimers. As a matter of fact, B-N interaction between two ligands inhibits its complexation
with the ketone leading to a loss of activity and consequently of ee. With the heterogeneous form, the
dilution of the active site can be reached by anchoring iodopropyltrimethoxysilane and
propyltrimethoxysilane (1:2 ratio) on the surface. The enantioselectivity remains the same (Table 7,
entry 3), but a longer reaction time is necessary to reach high conversion. An improvement of the
conversion is achieved by the attenuation of residual silanol after a passivation step from 72% to 82%
(Table 7, entry 2). A better isolation of the active sites accomplished by its dilution does not improve
the enantioselectivity of the final supported chiral ligand (Table 7, entry 3). It appears that
immobilization is sufficient to avoid the dimerization form of oxazaborolidine.
Table 7. Quantification of surface species and catalytic results for the supported
oxazaborolidine at 28 ºC.
Quantity
of ligand
(mmol/g)
conversion
(%)*
ee
(%)
Entry
Oxazaborolidine supported
H
Ph
O
O Si
O
Ph
N
1
0.61
0.58
72
82
72
72
O
H
HB
OH
S2-3Br
H
Ph
O
O Si
O
Ph
N
O
H
2
3
OH
HB
O
SiMe3
S2-3pBr
H
Ph
O
O Si
O
Ph
N
O
H
HB
OH
0.36
33
72
O
O Si
O
S2-3dI
Oxazaborolidine/BH3/ketone ratio = 0.3/0.7/1; Reaction time: 2 h.
With immobilized oxazaborolidine, diffusion limitations can affect the catalytic behaviour.
Diffusion limitation can result from some intrinsic textural properties of the support, like pore size, or
from the textural modifications induced by the surface functionalisation. Thus, two different kinds of
experiments have been realized. In the first case, oxazaborolidine supported on silica with pore
diameter at least two-fold smaller leads to a decrease of the enantioselectivity, 80% vs. 65% (Table 8).
In the second case S1-Ph3Br presents a bulkier substituent than S1-3Br (structure in Figure 5) which
may limit the accessibility to the pore. As a result, minor enantiomeric excess is obtained with
S1-Ph3Br, 68% vs. 94% (Table 9, entries 1,2). As a consequence, an increased amount of the chiral
inductor ratio (to 0.3/0.7/1) is necessary to compensate for the diffusion limitations.

Molecules 2010, 15
Table 8. Influence of the silica’s structural properties on enantioselectivity.
3654
Entry Oxazaborolidine supported Surface area (m2/g) Pore volume (cm3/g) Pore diameter (nm) ee (%)
O
O
Si
N
H
O
H
N
B
O
Ph
1
2
284
382
0.41
1.27
4.4
9.3
65
80
Ph
S1-4
O
O
Si
N
H
O
H
N
B
Ph
O
Ph
S1-3Br
Oxazaborolidine/BH3/ketone ratio: 0.1/0.7/1.
The recycling of the solids was studied (Table 9). Six runs were conducted with the catalyst
reactivated under vacuum before re-use. The results are really convincing: the enantiomeric excess are
maintained for the six runs, whatever the solid used. Moreover, conversion increases after each cycle
due to the passivation of the residual surface species by the borane (BH3) which can potentially be
coordinated to these functions. In addition, leaching of the chiral ligand has been evaluated by GC/MS,
and the presence of oxazaborolidine in solution was never detected.
Table 9. Recycling of supported oxazaborolidine, ratio: 0.3/0.7/1(time: 2 h).
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Supported
oxazaborolidine
Entry
ee Conv ee Conv ee Conv ee Conv ee Conv ee Conv
(%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
O
O
Si
N
H
O
H
N
B
O
Ph
1
2
3
94
68
90
40
50
46
91
68
90
58
57
50
90
68
90
64
64
57
90
68
90
71
67
67
90
68
90
75
72
73
90
68
90
79
75
81
Ph
S1-3Br
H
Ph
Ph
N
B
O
O Si
O
NH
O
S1-Ph3Br
Et
Si
O
O
O
H
N
Ph
B
O
Ph
OH
S3-2
Et
O
Si
O
O
H
Ph
Ph
N
B
O
4
5
90
72
60
72
90
72
74
75
90
72
85
80
90
72
88
80
90
72
90
80
90
72
90
80
O
SiMe3
S3-2p
H
Ph
O
Ph
O Si
N
O
O
H
H
HB
OH
S2-3Br
H
Ph
O
O Si
O
Ph
N
O
OH
HB
6
7
72
72
82
33
72
72
92
40
72
72
92
49
72
72
92
58
72
72
92
64
72
72
92
64
O
SiMe3
S2-3pBr
H
Ph
O
Ph
O Si
N
O
O
H
HB
OH
O
O Si
O
S2-3dI

Molecules 2010, 15
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Oxazaborolidines are known to be air moisture sensitive in homogeneous phase and this is also the
case for the supported materials. Indeed, when the supported material is deliberately removed from an
inert atmosphere, a complete loss of enantiomeric excess is observed (Table 10, cycle 7). Nevertheless,
its enantioselectivity can be partially recovered when the residual physisorbed water is eliminated by
azeotropic distillation with toluene via a Dean Stark apparatus (Table 10, cycle 8).
Table 10. Regeneration of the supported oxazaborolidine.
Cycle 1
Cycle 6
Cycle 7a
Cycle 8b
Supported oxazaborolidine
ee Conv ee Conv ee Conv ee Conv
(%) (%) (%) (%) (%) (%) (%) (%)
O
O Si
O
N
H
H
N
B
O
94
40
90
90
0
46
63
40
Ph
Ph
S1-3Br
a) in the presence of air; b) regeneration via a Dean Stark apparatus with anhydrous toluene for 24 h.
3. Experimental
3.1. General
All the substrates were purchased from Aldrich and used as received. THF was distilled under argon
on sodium/benzophenone. Toluene was distilled under argon on sodium. All the experiments were
carried under argon atmospheres with Schlenk techniques. The GC column is a Restek Rt-DEXsm
chiral column, length 30 m, diameter 0.25 mm.
3.2. Preparation of the homogeneous catalysts
(4S,5R)-4,5-Diphenyl-1,3,2-oxazaborolidine (Table 3, entry 1). (1S,2R)-()-2-Amino-1,2-diphenyl-
ethanol (1 g, 4.69 mmol) is dissolved in anhydrous THF (10 mL), then a solution of borane in THF
(9.38 mL, 1 M, 9.38 mmol) is added at -78 ºC for 30 min. The resulting solution is gradually warmed
to 30 ºC and stirred at 30 ºC during 10 h. The excess of borane is eliminated under vacuum. IR (KBr),
1
3,070, 3,028, 2,931, 2,867, 1,599, 1,452 cm-1, H-NMR (250 MHz, CDCl3)  ppm, 7.40–7.29 (m,
10 H, Ar-H), 5.13–5.11 (d, 1 H, C-H), 4.39–4.37 (d, 1H, C-H), 2.18–2.12 (s, 1 H, N-H), yield 100%.
See procedure described by Itsuno et al. [1,8].
(4S,5R)-2,4,5-Triphenyl-1,3,2-oxazaborolidine (Table 3, entry 2). (1S,2R)-()-2-Amino-1,2-diphenyl-
ethanol (1 g, 4.69 mmol) and phenylboronic acid (4.69 mmol) are combined with anhydrous toluene
(40 mL) and water is removed using a Dean-Stark apparatus for 24 h. The solvent is removed under
vacuum to provide the oxazaborolidine as a colorless oil. IR (KBr), 3,070, 3,028, 2,931, 2,867, 1,599,
1
1,452 cm-1, H-NMR (250 MHz, CDCl3)  ppm, 7.99–7.96 (d, 1 H, Ar-H), 7.40–7.30 (m, 3 H, Ar-H),
7.20–7.10 (m, 9 H, Ar-H), 4.79–4.76 (d, 7Hz, 1 H, C-H), 4.12–4.10 (d, 7Hz, 1 H, C-H), 2.18–2.12 (s,
1 H, N-H), yield 100%. See procedure described by Quallich et al. [3].

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(4S,5R)-2-(4-Butylphenyl)-4,5-diphenyl-1,3,2-oxazaborolidine (Table 3, entry 3). See procedure
described for (4S,5R)-2,4,5-triphenyl-1,3,2-oxazaborolidine. IR (KBr), 3,070, 3,028, 2,931, 2,867,
1
1,599, 1,452 cm-1, H-NMR (250 MHz, CDCl3)  ppm, 7.96–7.95 (d, 1 H, Ar-H), 7.60–7.50 (d, 1 H,
Ar-H), 7.30–7.10 (m, 11 H, Ar-H), 7.10–6.90 (d, 1 H, Ar-H), 4.77–4.74 (d, 7Hz, 1 H, C-H), 4.13–4.11
(d, 7Hz, 1 H, C-H), 2.61–2.55 (t, 7Hz, 2 H, C-H), 2.10–2.08 (s, 1 H, N-H), 1.60–1.50 (m, 7Hz, 2 H,
C-H), 1.35–1.25 (m, 7.5 Hz, 2 H, C-H), 0.89–0.84 (t, 8Hz, 3 H, C-H), 2.18–2.12 (s, 1 H, N-H).
(4S,5R)-4,5-Diphenyl-2-(4-(2-(triethoxysilyl)ethyl)phenyl)-1,3,2-oxazaborolidine (Table 3, entry 4).
4-vinylphenylboronic acid (1 g, 6.75 mmol) is dissolved in anhydrous ethanol (20 mL) then
triethoxysilane (1.66 g, 10.1 mmol) and Karsted’s catalyst (0.1 equiv. with respect to the complex) is
added. The solution color changed to yellow and it was heated at 50 ºC for 12 h, at which point the
solution becomes brown. The oxazaborolidine were prepared using the same procedure as described
for (4S,5R)-2,4,5-triphenyl-1,3,2-oxazaborolidine. IR (KBr), 3,070, 3,028, 2,931, 2,867, 1,599,
1
1,452 cm-1, H-NMR (250 MHz, CDCl3)  ppm, 7.99–7.96 (d, 2 H, Ar-H), 7.74-7.55 (m, 3 H, Ar-H),
7.20–7.10 (m, 9 H, Ar-H), 5.23–5.20 (d, 7 Hz, 1H, C-H), 4.79–4.70 (d, 7 Hz, 1 H, C-H), 3.85–3.70 (q,
8 Hz, 6 H, C-H), 2.63–2.57 (t, 7 Hz, 2 H, C-H), 1.99–1.98 (s, 1 H, N-H), 1.20–1.15 (t, 8 Hz, 9 H, C-H),
0.92–0.88 (t, 7 Hz, 2H, C-H).
(4S,5R)-4,5-Diphenyl-3-propyl-1,3,2-oxazaborolidine (Table 4, entry 2). 1-bromopropane (0.123 mL,
1.35 mmol), (1R,2S)-2-amino-1,2-diphenylethanol (0.29 g, 1.35 mmol) and triethylamine (0.63 mL,
4.5 mmol) are mixed and heated at reflux during for 18 h. After cooling at 28 ºC, distilled water is
added until neutral pH, then the organic phase is recovered with ethyl acetate without further
purification. The product is then analyzed by GC/MS. 1H-NMR (250 MHz, CDCl3)  ppm, 7.40–7.29
(m, 10 H), 5.12 (d, 8 Hz, 1 H), 4.37 (d, 8 Hz, 1 H), 3.6 (s, 1 H), 2.55 (t, 7 Hz, 2 H), 1.45 (q, 7 Hz, 2 H),
0.9 (t, 7 Hz, 3 H).
3.3. Preparation of the heterogeneous catalyst
3.3.1. Functionalization of the Grace silica (S1-1)
Grace Davison silica (1 g) was activated at 150 ºC under vacuum for 3 h. After cooling the silica
under argon, anhydrous toluene (40 mL) and 3-aminopropyltriethoxysilane (0.89 g, 4 mmol) is added
and the mixture heated at 130 ºC for 12 h; the ethanol formed during the reaction is removed by the
Dean-Stark method. The solid is filtered with toluene (3 × 20 mL), methanol (3 × 20 mL),
dichloromethane (3 × 20 mL), diethyl ether (3 × 20 mL), then washed in a Soxhlet apparatus for 24 h
(dichloromethane/diethylether = 1/1). Finally the solid is dried at 70 ºC for 3 h.
3.3.2. Immobilization of the boronic acid (S1-2Br)
S1-1 (1 g) was activated at 100 ºC under vacuum for 3 h. After cooling the silica under argon,
boronic acid (3 mmol) dissolved in anhydrous toluene (40 mL) and triethylamine (1.01 g, 10 mmol)
are added and the mixture then heated at 120 ºC for 36 h. The solid is filtered with toluene

Molecules 2010, 15
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(3 × 20 mL), dichloromethane (3 × 20 mL), diethyl ether (3 × 20 mL), then washed with a Soxhlet
apparatus for 24 h (dichloromethane/diethyl ether = 1/1). Finally the solid is dried at 70 ºC for 3 h (S1-
2Cl or S1-2Br).
3.3.3. Formation of the oxazaborolidine (S1-3Br)
S1-2Br (1 g) was activated at 100 ºC under vacuum for 3 h. After cooling the silica under argon,
anhydrous toluene (20 mL) is added. (1S,2R)-()-2-Amino-1,2-diphenylethanol (0.288 g, 1.35 mmol)
was suspended in anhydrous toluene (40 mL) and heated to 80 ºC to afford a colourless solution. The
solution is added to the silica solution then heated at 130 ºC for 5 days, with the water formed being
removed by the Dean-Stark method. The solid is then filtered under argon with anhydrous toluene at
80 ºC (3 × 20 mL) and anhydrous THF (3 × 20 mL) (S1-3Br).
3.3.4. Functionalization of the Grace silica (S2-1X)
Grace silica (1 g) was activated at 150 ºC under vacuum for 3 h. After cooling the silica under
argon, anhydrous toluene (40 mL) and 3-halogenopropyltriethoxysilane (0.89 g, 4 mmol) are added
and the mixture heated at 130 ºC for 12 h, with the ethanol formed during the reaction being removed
with a Dean-Stark apparatus. The solid is filtered with toluene (3 × 20 mL), methanol (3 × 20 mL),
dichloromethane (3 × 20 mL), diethyl ether (3 × 20 mL), then washed with a Soxhlet apparatus for
24 h (dichloromethane/diethyl ether = 1/1). Finally the solid is dried at 70 ºC for 3 h (S2-1X).
3.3.5. Passivation step of residual silanols
S2-1X (1 g) was activated at 100 ºC under vacuum for 3 h. After cooling the silica under argon,
anhydrous toluene (40 mL) and N,O-bis(trimethylsilyl)trifluoroacetamide (0.57 mL, 3 mmol) are
added and the mixture heated at 80 ºC for 3 h. Then the solid is filtered with toluene (3 × 20 mL),
methanol (3 × 20 mL), dichloromethane (3 × 20 mL), diethyl ether (3 × 20 mL), and washed with a
Soxhlet apparatus for 24 h (dichloromethane/diethyl ether = 1/1). Finally the solid is dried at 70 ºC for
3 h (S2-1pX).
3.3.6. Immobilization of chiral amino alcohol
S2-1Br (1 g, 0.92 mmol) was activated at 100 ºC under vacuum for 3 h. After cooling the silica
under argon, anhydrous toluene (30 mL), (1R,2S)-2-amino-1,2-diphenylethanol (0.29 g, 1.38 mmol)
and triethylamine (0.64 mL, 4.6 mmol) are added and the mixture heated at reflux during 72 h. The
solid is filtered with toluene (3 × 20 mL), methanol (3 × 20 mL), dichloromethane (3 × 20 mL), diethyl
ether (3 × 20 mL), then washed with a Soxhlet apparatus for 24 h (dichloromethane/diethyl ether = 1/1).
Finally the solid is dried at 70 ºC for 3 h (S2-1pX).

Molecules 2010, 15
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3.3.7. Oxazaborolidine formation
S2-2Br (1g, 0.72 mmol) was activated at 100 ºC under vacuum for 3 h. After cooling the silica
under argon, anhydrous THF (15 mL) and 1M BH3·THF solution (1.44 mL, 1.44 mmol) is added to the
solid and allowed to react at -78 ºC for 30 min then heated to 28 ºC for 12 h. Then the excess of borane
and the solvent are eliminated under vacuum at 85 ºC for 1 h.
3.4. Catalysis tests
S2-3I (0.5 g, 0.65 mmol/g, 0.325 mmol) is activated during 3 h at 100 ºC under vacuum, then put
under argon. 1M BH3·THF solution (0.65 mL, 0.65 mmol) is added to the solid and allowed to react at
40 ºC for 20 min then cooled to 28 ºC. 0.1 mL of acetophenone (3.25 mmol) diluted in THF (3 mL) is
added dropwise during 30 minutes. Catalytic solution is sampled prior to analysis. Hydrolysis is
performed by addition of HCl (2M) to the analytical sample (0.5 mL). The organic phase is extracted
with ethyl acetate, washed with a NaOH solution, dried on MgSO4 and filtered. The sample is analysed
by GC with dodecane as standard (Restek Rt-DEXsm chiral column, length 30 m, diameter
0.25 mm). The solid catalyst is washed three times with anhydrous THF in order to recover
physisorbed product. This way the material is reactivated for the next catalytic cycle.
4. Conclusions
Immobilization of oxazaborolidines on mesoporous silica via their boron and nitrogen substituents
has been successfully achieved. In order to obtain a high density of active sites, several parameters
have been studied: reaction time, nature of the boronic acid, nature of the alkoxysilane and synthesis
strategies. Thus, for chiral ligand linked via a boron substituent, the best strategy to reach high density
is obtained via the direct functionalization of silica with a boronic acid alkoxysilane (0.85 mmol/g).
Regarding immobilization via the nitrogen substituent, the use of a bromo- or iodoalkoxysilane is more
suitable (up to 0.72 mmol/g). The silanol passivation step is beneficial for the restriction of
physisorbed amino alcohol and consequently, the conversion for the reduction of acetophenone is
improved. Moderate to high ee (up to 95%) are obtained with supported oxazaborolidines. Although
the presence of a substituent linked to nitrogen or boron element of the chiral ligand leads to a decrease
of ee, a higher ee than its equivalent in homogeneous phase is obtained as the result of a better
isolation of the active site induced by its immobilization. Finally, no loss of the ee has been observed
with any of the supported oxazaborolidines after five reuses.
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Sample Availability: Samples of the compounds are available from the authors.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an Open Access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).