New Mesoporous silica-supported organocatalysts based on (2S)-(1,2,4-Triazol-3-yl)-Proline: Efficient, reusable, and heterogeneous catalysts for the asymmetric aldol reaction

Article abstract of DOI:10.3390/molecules25194532

Novel organocatalytic systems based on the recently developed (S)-proline derivative (2S)-[5-(benzylthio)-4-phenyl-(1,2,4-triazol)-3-yl]-pyrrolidine supported on mesoporous silica were prepared and their efficiency was assessed in the asymmetric aldol rea

Full text of DOI:10.3390/molecules25194532

molecules
Article
New Mesoporous Silica-Supported Organocatalysts
Based on (2S)-(1,2,4-Triazol-3-yl)-Proline: Efficient,
Reusable, and Heterogeneous Catalysts for the
Asymmetric Aldol Reaction
Omar Sánchez-Antonio 1 , Kevin A. Romero-Sedglach 1 , Erika C. Vázquez-Orta 1 and
Eusebio Juaristi 1,2,
*
1
Departamento de Química, Centro de Investigación y de Estudios Avanzados, Avenida IPN # 2508,
07360 Ciudad de México, Mexico; sancheza@cinvestav.mx (O.S.-A.); sedglach13@gmail.com (K.A.R.-S.);
caritovazquez23@gmail.com (E.C.V.-O.)
El Colegio Nacional, Luis González Obregón # 23, Centro Histórico, 06020 Ciudad de México, Mexico
Correspondence: juaristi@relaq.mx or ejuarist@cinvestav.mx
2
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editor: Derek J. McPhee
Received: 16 September 2020; Accepted: 1 October 2020; Published: 3 October 2020
Abstract: Novel organocatalytic systems based on the recently developed (S)-proline derivative
(2S)-[5-(benzylthio)-4-phenyl-(1,2,4-triazol)-3-yl]-pyrrolidine supported on mesoporous silica were
prepared and their efficiency was assessed in the asymmetric aldol reaction. These materials were fully
characterized by FT-IR, MS, XRD, and SEM microscopy, gathering relevant information regarding
composition, morphology, and organocatalyst distribution in the doped silica. Careful optimization
of the reaction conditions required for their application as catalysts in asymmetric aldol reactions
between ketones and aldehydes afforded the anticipated aldol products with excellent yields and
moderate diastereo- and enantioselectivities. The recommended experimental protocol is simple,
fast, and efficient providing the enantioenriched aldol product, usually without the need of a special
work-up or purification protocol. This approach constitutes a remarkable improvement in the field
of heterogeneous (S)-proline-based organocatalysis; in particular, the solid-phase silica-bonded
catalytic systems described herein allow for a substantial reduction in solvent usage. Furthermore,
the supported system described here can be recovered, reactivated, and reused several times with
limited loss in catalytic efficiency relative to freshly synthesized organocatalysts.
Keywords: (S)-proline; supported organocatalysts; asymmetric aldol reaction; reusable organocatalysts
1. Introduction
In the last two decades organocatalysis has developed into an important strategy in asymmetric
organic synthesis because of its enormous potential in the efficient preparation of chiral molecules [
In this regard, immobilization and recycling of asymmetric organic catalysts is of significant current
interest [ ]. Of particular relevance is research involving immobilization and recycling of organic
catalysts such as proline and proline derivatives [ ]. In order to provide useful catalytic materials to
1–5].
6
7,8
be applied in stereoselective transformations, one important challenge with catalyst immobilization is
to retain the activity and stereoselectivity of the immobilized catalysts. Furthermore, the separation
and recovery of the immobilized catalysts should be readily achieved by a simple operation such
as filtration.
In this context, polymeric materials are widely used as useful supports in heterogeneous organic
synthesis and catalysis [
9]. For example, several small peptides have been immobilized on insoluble
supports such as silica in order to get easily recyclable catalytic materials [10]. Thus, immobilization
Molecules 2020, 25, 4532; doi:10.3390/molecules25194532
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Molecules 2020, 25, 4532
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of organocatalysts on insoluble supports allows recovery and recycling of organic catalysts, thus
providing more sustainable synthetic protocols [11].
In this context, several representative organocatalysts present two or more functional groups
that act in cooperative or bifunctional strategies [12
–
18]. Several research groups have used natural
40], and chiral
and unnatural amino acids and peptides [19 31], chiral ureas and thioureas [32
–
–
amides [41–45] as building blocks or templates in organocatalyst design. In this context, a significant
number of (S)-proline derivatives have been developed while searching for an improvement in the
catalytic efficiency and stereoselectivity [46–53].
The present work was inspired by recent studies describing novel mesoporous and nanoporous
materials based on modified silicas, PEG-resins, zeolites, and MOFs that function as solid supports
for the corresponding organocatalytic modules and are capable to catalyze organic reactions such as
the Henry reaction, Negishi coupling, and the aldol reaction [54
–68]. Remarkably, mesoporous and
nanoporous silicas [58 62 67 69 71] have been widely used as hosts for organocatalytic acids or bases,
,
,
,
–
which by comparison with other solid supported-materials are more affordable, versatile and more
resilient in a variety of synthetic organic transformations [72,73].
On the other hand, our research group recently reported the preparation of three novel and efficient
(S)-proline-derived organocatalysts containing a 1,2,4-triazolyl-5-thione moiety, that proved highly
efficient in asymmetric aldol reactions [74]. Relevantly, this organocatalytic system does not require of
the presence of any additive to accomplish the desired transformation affording an eco-friendly protocol
that avoids extra purification procedures to obtain the corresponding aldol products. Furthermore,
one can take advantage of the 1,2,4-triazole moiety as a hydrogen bridge inducer to potentially anchor
electrophilic aldehydes used in the aldol reaction (see ref. [74] for more details about the reaction’s
mechanism and the synthesis of the catalyst).
Herein we report the development of four novel supported catalysts that incorporate such
(S)-proline-based organocatalysts on mesoporous commercial silica. Significantly, the resulting
heterogeneous organocatalysts proved highly efficient providing the desired aldol products without
the need of laborious purification procedures. Furthermore, the silica-supported organocatalysts can
be conveniently recycled and reused in a green aldol reaction protocol.
2. Results and Discussion
Nowadays the chemical literature describes two main methodologies employed to covalently bind
organic catalysts to silica. The first one is called “co-condensation method” [75–77], which consists of
the initial synthesis of the required precursors, is followed by a second step involving the coupling or
incorporation on the solid support. The second methodology is denominated “post-synthetic grafting”,
which focuses on the step-by-step construction of the catalyst on the silica surface [78–81]. As it turned
out, the present development required a hybrid synthetic approach starting from commercial silica
and involving both co-condensation and post-synthetic grafting starting from commercial silica, as
illustrated in the preparation of compound (S)-5 (Scheme 1).
Thus, seeking to increase the reactivity of the halide as leaving group for SN2 reactions,
a Finkelstein-type reaction was carried out on (3-chloropropyl)triethoxysilane
corresponding iodide derivative in quantitative yield [82]. Siloxyiodide was subjected to an SN2
substitution reaction with thiol (S)- (synthetized according to the previously described procedure [74])
under basic conditions to obtain thioether (S)- in 72% yield. Subsequently 1.0 mmol of thioether
(S)- was exposed to 2.64 g of commercial silica and heated to reflux for 24 h. The silica-supported
derivative (S)- was filtered and treated with five drops of conc. HCl to remove the N-tert-butoxy
1 to obtain the
2
2
3
4
4
5
carbonyl (N-Boc) protecting group. Lastly, the resulting suspension of the silica-supported catalyst
was filtered, and impurities were removed under Soxhlet extraction (see general procedure 7). Finally,
the solid product (S)-
mmol, 44.22 mg) of (S)-
organocatalyst on the support.
5
was filtered, dried, and isolated. According to gravimetric analysis, 18% (0.18
4
was incorporated to 2.64 g of silica; this amount represents 1.67% w/w of the

Molecules 2020, 25, 4532
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Scheme 1. Synthetic route for the preparation of supported organocatalyst (S)-5.
On the other hand, an alternative, step-by-step strategy for the incorporation of the organocatalyst
to the silica s surface was explored. Scheme 2 shows the corresponding procedure: triethoxide silane
was reacted with silica, under microwave activation (MW) for 1.5 h in the presence of 0.1 equiv.
of pyridine and toluene as solvent [79]. The crude product was filtered and washed with hexane,
EtOAc, acetone, water and MeOH before it was dried under vacuum to afford pure silica-supported
chloride in quantitative yield. Siloxy-chloride was subjected to a Finkelstein reaction to exchange
chloride for iodide to afford derivative in quantitative yield. Subsequently, siloxy-iodide was
´
1
6
6
6
7
7
suspended in acetonitrile and treated with thiol (S)-3 in the presence of base and under MW irradiation
to afford silica-supported, N-Boc-protected organocatalyst (S)-8. Finally, removal of the N-Boc group
was achieved with conc. HCl to give (S)-5 in 96% yield.
Scheme 2. Optimized synthetic route for the preparation of silica-supported organocatalyst (S)-5.
Once the supported organocatalyst (S)-5 was available in sufficient quantity, its load on the silica
support was determined by TGA and gravimetric analysis (see Supplementary Materials), finding
that heterocycle (S)-3 had been incorporated in a ratio of 114.6 mg (0.4641 mmol) per gram of silica,
which represents a 4.34% w/w ratio. This load is significantly higher than the one observed according
to the synthetic route described in Scheme 1. For this reason, the approach described in Scheme 2 was
employed in the preparation of additional silica-supported organocatalysts. In terms of composition,
morphology, and organocatalyst’s distribution in different batches of material, the reproducibility of
the synthetic protocol was rather good, as evidenced by the appearance of representative micrographs.

Molecules 2020, 25, 4532
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In the case of particle size, conventional heating results in reduced fragmentation of the samples,
relative to preparation under microwave heating; nevertheless, the difference is not significant.
Scheme 3 depicts the synthetic route followed to incorporate a 1,2,3-triazole group as a connecting
block within the organocatalytic system. According to previous reports, the triazole segment could act
as a good hydrogen bond acceptor at the transition state of the aldol reaction increasing the rigidity of
such transition state and in this way possibly increasing the stereoselectivity of the organocatalytic
system [83]. In the present system, the triazole fragment was used as spacer and connector between the
silica support and the prolinol group that is involved in enamine formation, since it was anticipated
that this would enable hydrogen bond interactions to anchor electrophilic substrates during the aldol
reaction [83–87].
O
O
i)
O
Si
N3
O
Si
Cl
O
Si O
O
O
O
N
9
6
O
N
(S)
N
iii)
N
+
Boc
(S)-11
OH
(S)
O
(S)
ii)
N
N
Boc
Boc
iv)
(S
)-N
-Bo
c-pr
olin
ol
(S)-10
O
O
Si
N
O
O
N
(S)
N
NH
(S)-12
Conditions:
i) 1.5 equiv. NaN3, 0.8 equiv. TBAI, MeCN, MW, 1h. quantitative yield.
ii) NaH, 1.1 equiv. propargyl bromide, dry CH2Cl2, 0°C, 24h. 88% yield of (S)-10.
iii) DMSO:H2O (4:1) , 10 mol% NaOH, 10 mol% ascorbic acid, 1 mol% CuSO4.5H2O, 18h, rt. 87% yield of (S)-11
iv) conc. HCl, MeOH, 4h, rt, then saturated aqueous NaHCO3. quantitative yield of (S)-12.
Scheme 3. Convergent synthetic route followed for the preparation of (S)-12 using the “in situ
generation” approach.
Firstly, chloride
6 was subjected to an SN2 reaction to introduce an azide group in derivative
9
. This substitution reaction proceeded in quantitative yield. On the other hand, N-Boc-(S)-prolinol,
which was prepared according to previous literature reports [88], was used as starting material to
generate, by means of NaH treatment followed by propargyl bromide addition, the corresponding
propargyl ether derivative (S)-10 in 88% yield [89
,
90]. Subsequently, compounds
9 and (S)-10 reacted
under the conditions of a Huisgen type-reaction [79
,
84,91], followed by a deprotection process in acidic
media. Following neutralization with NaHCO3, a silica-anchored organocatalyst (S)-12 was obtained
in 87% yield (Scheme 3).
Organocatalysts (2S,4R,10S)-18 and (2S,4R,10R)-18 incorporate an amide functional group in the
(S)-proline-framework. This structural feature has proved rather successful in other organocatalysts
derived from (S)-proline [42–44]. Furthermore, the fragment of (R)- or (S)-phenylethylamine was
introduced to examine the potential effect of an additional center of chirality in the organocatalytic
system. The synthetic route is outlined in Scheme 4. Firstly, trans-(2S,4R)-hydroxyproline was
N-protected with benzyl chloroformate to provide the substrate (2S,4R)-13, which was activated with
ethyl chloroformate before treatment with (R)- or (S)-phenylethylamine [(R)-14 or (S)-14]. Then the

Molecules 2020, 25, 4532
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coupling products were treated with propargyl bromide to afford the propargylic ethers (2S,4R,10S)-16
and (2S,4R,10R)-16 in 67% overall yield. These terminal alkynes were subjected to a Huisgen-type
protocol [79,84,91] with azide 9
and deprotected under basic conditions to afford (2S,4R,10R)-18 or
(2S,4R,10S)-18 in 77% of yield in both cases.
O
Ph
*
N
OH
O
O
(S)
(R)
O
N
(R)
NH2
HO
H
(S)
O
(R)
(S)
N
N
Si
N
O
*
i), ii)
N
iii)
Cbz
+
O
N
OH
O
N
*
H
Cbz
Cbz
OH
(S)-14 or (R)-14
(2S,4R)-13
(2S,4R,1'S)-17 or (2S,4R,1'R)-17
(2S,4R,1'S)-16 or (2S,4R,1'R)-16
Conditions
iv)
i) (S)-14 or (R)-14, ClCOOEt, N-MM, THF/EtOH, 0°C to rt, 18h, (2S,4R,1'S)-15 or (2S,4R,1'R)-15.
Yield: 85% and 88%, respectively.
ii) (2S,4R,1'S)-15 or (2S,4R,1'R)-15, NaH, 1.1 equiv. propargyl bromide, CH2Cl2, 0°C, 72h.
(2S,4R,1'S)-16 or (2S,4R,1'R)-16. Yield: 70% and 76%, respectively.
iii) 9, DMSO:H2O (4:1) , 1 mol% CuSO4*5H2O, 10 mol% NaOH, 18h, rt.
(2S,4R,1'S)-17 or (2S,4R,1'R)-17; yield: 74% and 77%, respectively.
iv) 1 M NaOH 1M, 6h, 60°C, quantitative yield.
Ph
O
*
N
OH
(S)
H
O
(R)
N
N
Si
NH
O
O
O
N
OH
(2S,4R,1'S-18 or (2S,4R,1'R)-18
Scheme 4. Synthetic route followed to generate (2S,4R,10S)-18 and (2S,4R,10R)-18.
Figure 1 presents the four silica-supported organocatalysts developed in this work to carry out
asymmetric aldol-type reactions.
O
Ph
(S)
N
O
O
Si
S
N
H
(S)-12
(S)
(A)
O
O
N
H
N
N
N
O
N
Si
(B)
N
(A)
(B)
O
(S)-5
OH
O
OH
O
O
N
Si
N
Si
O
O
N
O
O
N
N
O
(R)
N
(R)
(C)
OH
(C)
OH
(S)
(S)
O
O
N
N
(A)
H
(A)
H
(R)
N
(S)
N
H
H
(2S,4R,1'R)-18
(2S,4R,1'S)-18
(D)
Ph
(D)
Ph
(A) Enamine formation.
(B) Hydrogen bond acceptor.
(C) Spacer between the organocatalyst and the silica.
(D) Effect of additional chiral centrer.
Figure 1. Novel silica-supported organocatalysts synthesized in this work.

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Evaluation of Organocatalysts (S)-5, (S)-12, (2S,4R,10S)-18 and (2S,4R,10R)-18
With the four novel silica-supported organocatalysts at hand, their catalytic efficiency in the
enantioselective aldol reaction between cyclohexanone and 4-nitrobenzaldehyde was assessed. Table 1
summarizes the outcome of the reactions that were carried out initially. First, and according to previous
work [74] it was assumed that best results would be observed under neat conditions or in the presence
of water. However, as it can be appreciated in entries 1 and 2, although reaction yields were quite high,
the observed stereoselectivities turned out to be low. Therefore, the potential beneficial effect of various
additives that are commonly used as adjuvant to increase the strength of non-covalent interactions in
the transition state of the catalytic cycle [92–95] was examined (entries 3–6 in Table 1).
Table 1. Asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde in the presence
of organocatalysts (S)-5, (S)-12, (2S,4R,10S)-18 and (2S,4R,10R)-18.
dr[c]
(anti/syn)
er[d]
(anti/syn)
Yield % [e]
Entry
Catalyst
Additive
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
[a]
Commercial silica
(S)-5 [a]
None
None
H2O
96
20
24
24
24
36
36
36
36
36
22
24
[b]
-
-
-
78:21
74:25
70:30
70:30
76:24
75:25
75:25
80:20
70:30
70:30
70:30
65:35/60:40
70:30/65:35
85:15/60:40
65:35/60:40
96:4/70:30
95:5/60:40
90:10/80:20
90:10/80:20
90:10/60:40
65:35/65:30
60:40/60:40
[c]
98
99
99
99
99
98
99
96
96
96
97
(S)-5 [a]
(S)-5 [a]
p-nitro benzoic acid
salicylic acid
p-nitro-benzoic acid
salicylic acid
None
(S)-5 [a]
(S)-5 [a,f]
(S)-5 [a,f]
(S)-12 [b]
(S)-12 [b]
H2O
(S)-12 [b,f]
(2S,4R,10S)-18 [a,f]
(2S,4R,10R)-18 [a,f]
p-nitro- benzoic acid
None
None
An amount of 10 mol% of catalyst was employed;
5 mol% of catalyst was employed.
4.90, dd, J = 8.4 Hz. syn: 5.47 ppm.
The relative
configuration was determined by 1H-NMR spectroscopy, anti:
δ
δ
Absolute
[d]
[e]
configuration was determined by HPLC analysis with an AD-H chiral column.
Following filtration. Extracted
with 5 mL of EtOAc and purified in a small silica column after concentration. At 1 ◦C. The aldehyde substrate is
[f]
[g]
the limiting reagent, 37 mg (1.0 equiv.) of p-nitrobenzaldehyde.
Entry 1 is the control reaction; commercial silica
was employed; the aldol reaction does not proceed in the absence of organocatalyst.
Best results, in terms of yield (99%) and enantioselectivity (92% ee) were recorded with
silica-supported organocatalyst (S)-5, employing an amount of silica equivalent to 10 mol% of
catalyst and 10 mol% of p-nitrobenzoic acid as additive, under solvent-free conditions (Table 1, entry
6). Nevertheless, the diastereoselectivity was only moderate.
In the case of organocatalyst (S)-12, although the reaction yield is comparable to those observed
with (S)-5, the catalyst has the capacity to give moderate-to-high diastereoselectivity in the presence of
water as additive (see entry 10 in Table 1). Similar stereoselectivity was observed with diastereomeric
organocatalysts (2S,4R,10S)-18 and (2S,4R,10R)-18. This observation suggests that the
α-phenylethyl
group is not sufficiently close to the reacting site to provoke noticeable stereoinduction.
Once the best reaction conditions had been established (Table 1, entry 6), substrate screening was
performed in aldol-type reactions. Several aromatic aldehydes were tested as electrophiles obtaining
excellent yields in all cases and moderate diastereo- and enantio-selectivities (Table 2).
As seen in Table 2, rather high yields are recorded in all cases, although the observed diastereomeric
and enantiomeric values are moderate. With these results on hand it was decided to extend the

Molecules 2020, 25, 4532
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reaction scope using acetone as enamine precursor. It is well known that it is difficult to control the
selectivity of enantioselective aldol reaction employing acetone [96 101] owing to its high symmetry.
Initially, an optimization of the reaction conditions to obtain (R)-27 was carried out finding that best
–
results are obtained under solvent-free reaction conditions, employing (S)-5 as organocatalyst and at a
temperature of 1 ◦C (Table 3).
Table 2. Scope of the asymmetric aldol reaction between cyclohexanone and aromatic aldehydes
catalyzed by (S)-5.
dr[a]
(anti/syn)
er[b]
Yield % [c]
Entry
Product
R
Time (h)
(for anti isomer)
1
2
3
4
5
6
7
20
21
22
23
24
25
26
2-NO2
3-NO2
2-CF3
4-Cl
4-CF3
4-Br
36
36
72
48
36
36
48
70:30
75:25
85:15
70:30
75:25
80:20
70:30
70:30
70:30
60:40
70:30
65:35
80:20
60:40
95
95
95
94
96
99
94
-H
[a] The relative configuration was assigned by analysis of 1H-NMR coupling constants. [b] The absolute configuration
[c]
was determined by HPLC analysis with chiral columns (by comparison with literature data). Determined after
filtration, extraction with 5 mL of EtOAc, evaporation and purification through a small silica column. The aldehyde
substrate is the limiting reagent: 37 mg (1.0 equiv.) of p-nitrobenzaldehyde.
Table 3. Asymmetric aldol reaction between acetone and aromatic aldehydes employing (S)-5 as catalyst.
er[a]
Yield % [b]
Entry
Product
R
Time (h)
1
2
3
4
5
6
7
8
9
27
28
4-NO2
2-NO2
2-Cl
4-CF3
4-Br
4-Cl
4-F
-H
4-CH3
3-Br
48
48
48
36
36
72
48
96
96
48
70:30
65:35
65:35
60:40
65:35
70:30
65:35
60:40
60:40
60:40
98
98
98
98
97
97
99
98
98
99
29
30c
31
32c
33
34
35c
36c
10
[a]
[b]
Determined by HPLC analysis with chiral columns, by comparison with retention times reported in the literature.
Determined after filtration. Extracted with 5 mL of EtOAc and dried. Determined after filtration. Extraction
[c]
with 5 mL of EtOAc and purification by silica column chromatography.
Table 3 shows the results achieved in the asymmetric aldol reaction employing acetone as enamine
precursor and several aromatic aldehydes as electrophiles. In a control experiment, the reaction does
not proceed in the absence of organocatalyst. By contrast, excellent reaction yields were recorded when
catalyzed by (S)-5, although the enantioselectivity changed from low to moderate. In entries 4, 6, 9 and
10, a purification process was necessary to isolate the pure aldol products because of minor impurities;
nevertheless, in the rest of the cases, no purification was necessary. The product was simply filtered
and dried, which represents a great advantage in terms of sustainability of the process, because of the
minimal amount of solvent required to purify the products [102–105].

Molecules 2020, 25, 4532
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A silica-supported organocatalyst (S)-
5
was also evaluated in the aldol reaction between the
enamine derived from cyclohexanone and relevant isatins. Table 4 summarizes the results that exhibit
excellent yields and moderate diastereo- and enantio-selectivities. It is worthy of mention that recovery
of the catalyst required a reactivation process (see Material and Methods section).
Table 4. Asymmetric aldol reaction between isatin derivatives and aromatic aldehydes catalyzed by (S)-5
.
O
O
O
HO
20 mol %(S)-5
O
(S)
(R)
+
Neat
Benzoic acid
1°C
NH
O
R
N
R
H
1 equiv.
2.5 equiv.
(R,S)−
dr (anti) [a]
er (anti) [b]
Yield % [c]
Product
-R
Time (h)
38
39
40
-H
5-NO2
7-Cl
10
9
12
70:30
75:25
80:20
70:30
60:40
60:40
88
85
90
[a]
[b]
[c]
Determined by 1H-NMR spectroscopy.
Determined by HPLC analysis with chiral columns. Determined
after extraction with 5 mL of EtOAc, concentration and purification through a small silica column.
One important advantage when using immobilized catalysts and supported organocatalytic systems
is that the catalyst can be recovered and reused. The reuse of organocatalyst (S)-5, which is covalently
bonded to the supporting material-silica in the present study, is no exception. Indeed, recovery and reuse of
the organocatalyst was feasible up to 15 catalytic cycles in the aldol reaction between the enamine derived
from acetone and 4-nitrobenzaldehyde, as can be appreciated in Table 5. Although the stereoselectivity
was slightly diminished with each cycle, the high reaction yield was maintained.
The decrease in catalytic efficiency suggests that the silica support possibly suffers a contamination
provoked by an impurity that could be generated during each reaction process. Indeed, comparison of
XRD and SEM images of fresh and reused catalyst (S)-5, shows that both materials present an irregular
shape with a smooth surface characteristic of mesoporous amorphous solids (see Figure 2, A1 to C2).
Although the particle size corresponds to a mesoporous solid, the micrographic analysis exhibits
significant fragmentation of the material apparently provoked by microwave irradiation. Furthermore,
comparison of recovered catalyst with commercial silica shows that the former material does not
present the characteristic roughness exhibited in commercial silica. In Figure 2, C2 shows the formation
of some clusters that can be formed by the accumulation of additive used in each reaction. It is also
worthwhile to point out that TGA analysis of a reused catalyst showed that rather than decreasing, the
amount of organic material increased (see Supplementary Materials).

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Table 5.
Asymmetric aldol reaction between acetone and aromatic aldehydes employing
silica-supported (S)-5 as organocatalyst.
O
O
OH
O
5 mol % (S)-5
H
+
Neat, 48 h, 1°C
NO2
NO2
2.5 equiv.
1 equiv.
(R)-27
Er [a]
Yield % [b]
Cycle
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
70:30
65:35
65:35
65:35
66:34
65:35
65:35
65:35
60:40
60:40
60:40
60:40
60:40
60:40
60:40
[b]
98
98
99
98
98
97
97
99
98
98
98
99
96
97
96
[a]
Determined by HPLC analysis with AS-H chiral columns.
EtOAc and dried.
Determined after filtration. Extracted with 5 mL of
Figure 2. Cont.

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Figure 2. SEM and XRD imaging: A1–A3 commercial silica. B1–B3 Silica-supported organocatalyst
(S)-5. C1–C3 Silica-supported organocatalyst (S)-5 after 10 catalytic cycles.
As for an XRD analysis, commercial silica Figure 2(A3) exhibits the anticipated diffractogram
characteristic of mesoporous material; that is, no peaks are visible. By contrast, in the case of (S)-5
Figure 2(B3) a broad signal at ca. 22.2◦ is recorded, with absence of other peaks confirming that our
material conserves its mesoporous structure and suggest that our organocatalyst is well-distributed.
Finally, for the recycled (S)-5 material Figure 2(C3), one encounters an intense diffraction pattern that
apparently is caused by the presence of additive (p-nitrobenzoic acid), arising from condensation with
active Si-OH groups. Additionally, in order to expand the study of the composition and distribution of
the organocatalyst on silica, an FT-IR analysis exhibited some characteristics bands (3500, broad signal
from 3300 to 3000 cm−1 and 2200 to 1900 cm−1). These signals appear to confirm the presence of the
organocatalyst in the material (S)-5 (see Supplementary Materials, page S72). Indeed, TGA analysis
shows that the amount of organic material present on the silica-supported catalyst (Figure 2(C3)) is
greater than that found in freshly prepared (S)-5 (Figure 2(B3)). Furthermore, substantial weight loss
takes place in the temperature range between 200 and 450 ◦C, which is in line with leaking of organic
material, suggesting that the additive (p-nitrobenzoic acid) had incorporated to the silica surface.
Indeed, the amount of organic material on the silica-supported material (Figure 2(C3)) is greater than
that found in freshly prepared (S)-5 (Figure 2(B3)). Therefore, the weight loss that takes place in the
temperature range between 200 and 450 ◦C is in line with the leaking of organic compounds [106
,107].
3. Materials and Methods
3.1. Starting Materials and Their Analysis
Unless otherwise indicated, all reagents were purchased from Sigma-Aldrich and used without
further purification. The progress of reactions was routinely monitored by TLC on silica gel 60

Molecules 2020, 25, 4532
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(precoated F254 Merck plates) under UV lamp (254 nm) irradiation to visualize starting materials and
products. Flash chromatography was performed using silica gel (230−400 mesh).
NMR spectra were acquired on JEOL ECA 500 and Bruker 400 Avance III HD spectrometers. For
the acquisition of 1H NMR and 13C NMR spectra, CDCl3 (7.26 and 77.0 ppm, respectively) or DMSO-d6
(2.50 and 39.5 ppm, respectively) were used as internal references. Chemical shifts (δ) are reported in
parts per million (ppm). Multiplicity was abbreviated as follows: s = singlet, bs = broad singlet, d =
doublet, dd = doublet of doublets, t = triplet, q = quartet, quint = quintet, sext = sextet, hept = heptet,
m = multiplet. High resolution mass spectra were recorded on an HPLC 1100 coupled to MSD-TOF
Agilent series HR-MSTOF mass spectrometer model 1969 A.
The HPLC analysis was performed in a Dionex HPLC Ultimate 3000 with a UV/Visible detector,
and with diode array, at 210 and 254 nm, chiral columns such as AD-H for compounds (R,S)-38,
(R,S)-39, (R,S)-40, AS-H for compounds (R)-27-37 and OD-H for (R,S)-26 compound, were employed.
IR spectra were acquired on an ATR-IR Varian-640 and are expressed in wave number (cm−1). Optical
rotations were measured on an Anton Paar MCP-100 Polarimeter with reagent grade solvents. Melting
points were taken on a Büchi B-540 apparatus and are uncorrected. Microwave-assisted procedures
were performed on the Biotage-Initiator microwave system. The micrographic images were taken in a
JEOL SEM 5600LV apparatus with an acceleration voltage of 20 kV.
XRD analyses were carried out in a Bruker Advance eco. Goniometer: 280 mm. Axis movement:
theta/theta. Detector: one-dimensional “lynx eye”. Generator: 1 kW, Samples are measured with: 25
mA, 30 KV. Radiation: Cu (Kalpha1 + Kalpha2) (1.5416 A). Sample rotation speed: 20 r.p.m. Counting
time: 5 s. Step size: 0.02. Degree2-theta measurement interval: 5–55 degrees, and 5–70 degrees.
Measurement software: DIFFRAC.MESUREMENT. Analysis Software: DIFFRAC.EVA.
3.2. Procedures and General Methods
3.2.1. General Procedure 1: Finkelstein Reaction
In a 50-mL round bottom flask provided with a magnetic bar, the corresponding halide derivative
(0.264 g, 1 equiv.), NaI (0.300 g, 2 equiv.) and 10 mL of MeCN or acetone were added. The resulting
mixture was stirred for 24 h at room temperature, the solvent was evaporated, and the residue washed
with diethyl ether (3 × 10 mL) to give the corresponding iodide product.
3.2.2. General Procedure 2: Propargylation Reaction, in the Synthesis of (S)-10, (2S,4R,10-S)-16 and
(2S,4R,10-R)-16
In a 50-mL round bottom flask provided with a magnetic bar, the corresponding alcohol (1 mmol,
1 equiv.), propargyl bromide (1.1 mmol, 1.1 equiv.), NaH (2 mmol, 2 equiv.) and 5 mL of dry CH2Cl2
were added. The resulting suspension was stirred for 72 h at ambient temperature, the solvent was
removed at reduced pressure and the solid residue was washed with diethyl ether (3
purification of the organic phase was achieved on a chromatographic column using hexane-EtOAc
eluent [89,90].
×
10 mL). Final
3.2.3. General Procedure 3: Huisgen 1,3-dipolar Cycloaddition-Type Reaction (12h), in the Synthesis of
(S)-11, (2S,4R,10-S)-17 and (2S,4R,10-R)-17
In the following order, in a 25-mL round bottom flask provided with a magnetic bar, 0.1 equiv. of
NaOH, 0.1 equiv. of ascorbic acid and 5 mL of DMSO:H2O (4:1) were added. The resulting mixture
was stirred for two minutes before the addition of the corresponding azide derivative (1 equiv.) and
CuSO4 5 H2O (0.1 mol). The reaction mixture was stirred for two minutes and then the propargyl ether
·
derivative was added. The resulting mixture was stirred for 18 h at ambient temperature. The solid
that was obtained was filtered and washed with small portions of water, methanol, ethyl acetate, and
hexanes. Finally, the residue was dried in a muffle for 24 h at 65 ◦C [89–91].

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3.2.4. General Procedure 4: Coupling Reaction, in the Synthesis of (2S,4R,10S)-15 or (2S,4R,10R)-15
In a 100-mL round bottom flask, previously purged with argon and provided with a magnetic
stirring bar, trans-4-hydroxy-L-N-Cbz-proline (1 equiv. 1.0 g, 3.77 mmol) and triethylamine (1.05 equiv.,
0.55 mL, 3.96 mmol) were added. Then, 16 mL of dry THF was added and the reaction flask was
submerged in an ice bath before the dropwise addition of ethyl chloroformate (1.05 equiv. 0.37 mL,
3.96 mmol). Subsequently, the reaction mixture was allowed to react under vigorous stirring for 15
min at 0 ◦C. The insoluble Et3N
·
HCl salt that precipitated was filtered off and washed with THF (2
×
6
mL) and the combined filtrate was slowly added to a solution of (R)-14 or (S)-14 (1.05 equiv. 0.50 mL,
3.96 mmol) in 14 mL of EtOH at 0 ◦C. The reaction mixture was stirred for 30 min at 0 ◦C and then at
room temperature for 12 additional hours. The solvents were removed under reduced pressure and
the resulting colorless oil was dissolved in 30 mL of EtOAc and washed as follows: 5 mL of 1 M HCl, 5
mL of saturated aqueous solution of NaHCO3, and brine (2
anhydrous Na2SO4, concentrated, and purified by flash column chromatography with EtOAc-hexanes
(1:1) as eluent to afford pure (2S,4R,10S)-15 or (2S,4R,10R)-15.
×
5 mL). The crude product was dried over
3.2.5. General Procedure 5: N-Boc Catalyst Deprotection Under Acidic Conditions
In a round flask provided with a magnetic stirring bar◦and MeOH (3 mL), (S)-
4 or (S)-11 was
suspended and the resulting suspension was cooled to 0 C before the addition of six drops of
concentrated HCl (approx. 0.6 mL). The reaction mixture was left standing at room temperature for 4
h, and the product was filtered under vacuum and washed with water. Finally, general procedure 7
was followed until a constant weight of the product was achieved.
3.2.6. General Procedure 6: N-Cbz Catalyst Deprotection Under Basic Conditions
An amount of 1 M NaOH (3 mL) and (2S,4R,10S)-17 or (2S,4R,10R)-17 was added to a round flask
provided with a magnetic stirring bar and the resulting mixture was heated to 60 ◦C for 4 h. The crude
product was filtered under vacuum and washed with 1 M HCl and water and finally general procedure
7 was followed.
3.2.7. General Procedure 7: Activation of Catalysts (S)-5, (S)-12, (2S,4R,10S)-18 and (2S,4R,10R)-18.
Previous to the first use of the corresponding catalyst, it was treated as follows: each
silica-supported organocatalyst was placed in a Soxhlet distillation apparatus and washed under
continuous refluxing mode with a mixture MeOH:H2O:EtOAc (2:1:1) for 14 h. The recovered material
was placed on a heating plate for 18 h at 115 ◦C and finally filtered.
General Procedure 7a: Reactivation of Used Silica-Supported Organocatalysts
The recovered silica-supported organocatalyst was washed with methanol and dried in a muffle
at 85 ◦C for 24 h. Once this operation was finished, the catalyst was then ready to be reused.
3.2.8. General Procedure 8: Aldol Reaction
In a round bottom flask provided with a magnetic stirrer, 2.5 equiv. (0.612 mmol) of the
corresponding ketone, the corresponding amount of silica-supported organocatalyst (equivalent to 5
or 10 mol%) and the corresponding aldehyde (0.24 mmol, 37 mg, 1 equiv.) were deposited. In case of
the use of additive, this was added in the same proportion as the catalyst. The resulting mixture was
stirred at the indicated temperature (see Tables 1–4) until complete reaction. The solid catalyst was
recovered by filtration and the filtrate was evaporated at reduced pressure. The purity of samples was
evaluated using TLC, and the assessment of the aldol product was established by chromatography.

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3.2.9. Procedure for Functionalization of Siloxy-OH Groups on Silica; Obtention of 6
In a 20-mL Biotage+ initiator microwave system vial, provided with a magnetic stirrer, 2.64 g
of commercial silica (previously activated to 250 ◦C) was placed before the addition of 0.1 equiv. of
pyridine, 1.2 mmol (1.0 equiv.) of 3-chloro-triethoxide silane and 10 mL of toluene. The reactor vial
was closed and placed in the microwave oven at 150 ◦C, 150 Watts for 1.5 h, with the cooler mode
activated. The resulting white suspension was filtered and washed with EtOAc (3
the excess of 3-chloro-triethoxide silane, and finally dried. Yield: quantitative. With this procedure it
was possible to functionalize 2.64 g of silica with 1.15 mmol of 3-chloro-triethoxide silane.
×
25 mL) to remove
3.3. Procedure for SN2 Type Reaction. Preparation of (S)-8
In a 20-mL Biotage+ initiator microwave vial, provided with a magnetic stirrer, 2.70 g of
placed, before the addition of 1.1 mmol (0.381 g, 1.0 equiv.) of (S)- , 2.4 mmol (0.212 g, 2 equiv.) of
7 was
3
NaCO3 and 10 mL of MeCN. The resulting suspension was stirred for 10 min, the vial was then closed
and placed in the microwave oven at 150 ◦C, 180 Watts for 2.0 h, with the cooler mode activated. The
resulting lightly yellow suspension was filtered and washed with EtOAc (3
×
25 mL) and methanol
(3 25 mL) to remove the excess of . Yield: 96% of the dried product. With this procedure it was
×
7
possible to functionalize 2.64 g of silica with 1.12 mmol of 7.
H and 13C NMR Spectra, Mass Spectra and Physical Properties
(S)-tert-Butyl-2-(4-phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate, (S)-3, was
synthetized according to the procedure described in reference 11 starting from (S)-proline. White solid,
25
1
mp 210–212 ◦C. Yield: 1.21 g (78%) for 3 steps. [
MHz, DMSO-d6, 120 ◦C)
13.33 (s, 1H, NH), 7.62–7.26 (m, 5Har), 4.45 (d, 1H, J = 4 Hz, CH), 3.25 (s, 1H,
CHH), 3.15 (s, 1H, CHH), 2.07–1.70 (m, 4H, 2 CH2, 1.32 (s, 9H, 3
CH3) ppm. 13C NMR (125.76
MHz, DMSO-d6, 120 ◦C)
169.3, 154.0, 134.4, 129.9, 128.9, 128.7, 79.7, 53.5, 46.8, 31.8, 28.9, 23.3 ppm. IR
(neat)
3212, 2969, 2972, 2879, 1769, 1707, 1658, 1521, 1408, 1401, 1272, 1198, 1127, 774 cm−1. HRMS
α
]
= +13.5◦, c = 0.33, CHCl3. H NMR (500.16
D
δ
×
×
δ
ν
max
(MS-TOF) calcd. for C17H23N4O2S (M)+ 347.1536, found 347.1533.
Triethoxy(3-iodopropyl)silane,
yield. Yellow oil. H NMR (500 MHz, CDCl3)
CH2), 3.19 (t, J = 7.1 Hz, 2H, CH2), 1.19 (t, J = 7.0 Hz, 9H, 3
(125 MHz, CDCl3) δ 58.3, 27.5, 18.2, 12.2, 10.5 ppm.
2
. General procedure 1 was followed to obtain silane
3.79 (q, J = 7.0 Hz, 6 H, 3 CH2), 1.75–2.00 (m, 2H,
CH3), 0.63–0.77 (m, 2H, CH2). 13C NMR
2 in quantitative
1
δ
×
×
(S)-tert-Butyl-2-((prop-2-yn-1-yloxy)methyl)pyrrolidine-1-carboxylate, (2S,4R)-10. General procedure 2 was
25
1
followed to obtain (2S,4R)-10 as a white wax, 1.28 g (88% yield). [
NMR (400.0 MHz, CDCl3)
4.16 (s, 2H, CH2), 3.94 (s, CH), 3.67(dd, 1H, J1 = 3.45 Hz, J2 = 9.04 CH),
3.55–3.24 (m, 3H), 2.03–1.61 (m, 5H), 1.48 (s, 9H, 3 154.6,
CH3) ppm; 13C NMR (125.76 MHz, CDCl3)
α
]
= +25.9◦, c = 0.33, CHCl3. H
D
δ
×
δ
79.9, 79.3, 74.3, 70.6, 58.4, 56.3, 46.7, 28.5, 23.8, 22.9 ppm. HRMS (MS-TOF) calcd. for C13H22NO3 (M)+
240.1594, found 240.1598.
(2S,4R,1’S)-Benzyl-4-hydroxy-2-(((S)-1-phenylethyl)carbamoyl)pyrrolidine-1-carboxylate, (2S,4R,10S)-15
.
General procedure 4 was followed to obtain (2S,4R,10S)-15 as a white foam. Yield: 1.18 g (85%).
1
[
α
]
D
25 = +7.2, c = 0.33, CHCl3. H NMR (500.0 MHz, CDCl3)
δ
7.48–7.01 (m, 10H, CHar), 6.74 (d, 1H,
NH), 5.21–5.03 (m, 1H, CH), 5.03–4.86 (dd, 2H, J1 = J2 = 4.98, CH2), 4.49–4.33 (m, 1H, CH), 4.26 (m, 1H,
OH), 4.19–3.94 (m, 1H, CH), 3.68–3.35 (m, 2H, CH2), 2.26–1.82 (m, 2H, CH2), 1.52–1.20 (m, 3H, CH3)
ppm. 13C NMR (125.76 MHz, CDCl3)
δ 171.2, 156.0, 143.3, 136.7, 128.7, 128.2, 127.9, 127.2, 126.08, (d)
68.4, (d) 67.5, (d) 59.5, (d) 55.2, 39.7, 38.5, 22.0. HRMS (MS-TOF): calcd. for C21H25N2O4 (M)+ 369.1736,
found: 369.182041.
(2S,4R,1’R)-Benzyl-4-hydroxy-2-(((R)-1-phenylethyl)carbamoyl)pyrrolidine-1-carboxylate, (2S,4R,10R)-15
.
General procedure 4 was followed to obtain (2S,4R, 10R)-15 as a white foam, 1.22 g, yield: 88%.
1
[α]D25 = −2.5, c = 0.33, CHCl3. H NMR (500.0 MHz, CDCl3) δ 7.39–7.07 (m, 10H, CHar), 6.27–6.10 (s,

Molecules 2020, 25, 4532
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1H, NH), 5.23–5.03 (m, 2H, CH2), 5.03–4.92 (p, 1H, J = 10 Hz, CH), 4.55–4.45 (bs, 1H, OH), 3.81–3.45 (m,
2H, 2 CH), 2.67–1.64 (m, 4H, 2
CH2), 1.52–1.17 (m, 3H, CH3) ppm. 13C NMR (125.76 MHz, CDCl3)
170.3, 155.7, 143.4, 136.2, 128.8, 128.3, 128.0, 127.2, 126.0, (d) 68.3, (d) 60.5, (d) 54.5, (d) 49.2, 38.7, 38.5,
×
×
δ
22.1. HRMS (MS-TOF): calcd. for C21H25N2O4 (M)+ 369.1736, found: 369.183627.
(2S,4R)-2-Benzyl-(((S)-1-phenylethyl)carbamoyl)-4-(prop-2-yn-1-yloxy)pyrrolidine-1-carboxylate,
(2S,4R,10S)-16
foam, 0.425 g, yield: 70%. [
.
General procedure 2 was followed to obtain (2S,4R,10S)-16 as a pale-yellow
1
α
]
25 = +11.7, c = 0.33, CHCl3. H NMR (500.0 MHz, CDCl3)
δ
7.49–7.05
D
(m, 10H, CHar), 6.51 (s, 1H, NH), 5.17 (d, 1H, J = 13 Hz, CHH), 5.08 (d, 1H, J = 12.6 Hz, CHH), 5.01 (p,
1H, J = 6.72 Hz, CH), 4.49–4.32 (m, 1H, CH), 4.32–4.17 (m, 1H, CH), 4.16–3.97 (m, 2H, CH2), 3.82–3.56
(m, 1H, CH), 3.48 (dd, 1H, J1 = 12.6, J2 = 5.36 Hz, CH), 2.55–2.25 (m, 2H, CH2), 2.19–2.01 (bs, 1H,
CH), 1.80–1.67 (m, 3H, CH3) ppm. 13C NMR (125.76 MHz, CDCl3).
δ 170.2, 156.3, 143.5, 136.4, 128.6,
128.2, 128.0, 127.1, 126.0, 79.5, 75.1, 67.5, 59.2, 56.6, 51.6, 49.1, 33.8, 22.5. HRMS (MS-TOF) calcd. for
C24H27N2O4 (M)+ 407.1892, found: 407.205297
(2S,4R)-2-Benzyl-(((R)-1-phenylethyl)carbamoyl)-4-(prop-2-yn-1-yloxy)pyrrolidine-1-carboxylate
(2S,4R,1’R)-16
foam. 0.450 g, yield: 76%. [
10H, CHar), 6.75 (s, 1H, NH), 5.1 (bs, 1H, CH), 5.06–4.91 (m, 2H, CH2), 4.44–4.31 (m, 1H, CH), 4.31–4.18
(m, 1H, CH), 4.11–3.96 (m, 2H, CH2), 3.85–3.61 (m, 1H, CH), 3.61–3.50 (m, 1H, CH), 2.53–2.38 (m, 1H,
CH), 2.35–2.20 (m, 1H, CHH) 2.17–2.00 (m, 1H, CHH), 1.50–1.13 (m, 3H, CH3) ppm. 13C NMR (125.76
.
General procedure 2 was followed to obtain (2S,4R,1’R)-16 as a pale-yellow
25
1
α
]
D
= −6.8, c = 0.33, CHCl3. H NMR (500.0 MHz, CDCl3) δ 7.50–7.05 (m,
MHz, CDCl3) δ 170.6, 155.8, 143.3, 136.4, 128.7, 128.6, 128.2, 127.9, 127.2, 126.1, 79.6, 75.3, 67.4, 59.4, 56.5,
52.1, 48.9, 34.3, 22.1 ppm. HRMS (MS-TOF) calcd. for C24H27N2O4 (M)+ 407.1892, found: 407.196976.
4. Conclusions
In this work, four novel silica-supported organocatalysts were synthesized and characterized:
(S)-5
, (S)-12, (2S,4R,10S)-18 and (2S,4R,10R)-18. These catalytic systems turned out to be efficient and
versatile organocatalysts for the asymmetric aldol reaction, affording the desired aldol products in
excellent yields and moderate enantio- and diastereo-selectivities usually without the need of an acidic
or basic additive. In addition, these mesoporous materials could be reused and recycled with only a
minor loss in their catalytic activity even after 15 or more cycles. The novel organocatalysts provide a
significant advantage over other homogeneous and heterogeneous organocatalysts because they make
viable sustainable aldol condensations with a drastic reduction of solvent usage.
Supplementary Materials: The following are available online. HPLC Analytical Data for aldol products, NMR
Spectra for new and previous characterized compounds and aldol products, Gravimetric, TGA and DSG Analysis
Data, and FR-IR.
Author Contributions: Conceptualization, E.J. and O.S.-A.; methodology, O.S.-A.; investigation, E.J. and O.S.-A.
K.A.R.-S., E.C.V.-O.; resources, E.J.; writing—original draft preparation, E.J. and O.S.-A.; writing—review and
editing, E.J. and O.S.-A.; project administration, E.J.; funding acquisition, E.J. All authors have read and agreed to
the published version of the manuscript.
Funding: This research was funded by CONACYT and Fund SEP-CINVESTAV via grants 220945 and 126,
respectively. O. S
by MDPI.
ánchez-Antonio thanks CONACYT for scholarship number 397321. The APC was funded
Acknowledgments: We are grateful to T. Cortez-Picasso and V. M. González-Díaz for their assistance in the
acquisition of NMR spectra. We thank M. A. Leyva-Ramírez for his support in the acquisition and processing of
XRD data, to Geiser Cuellar for his assistance in the acquisition of MS-TOF spectra. In addition, we are grateful to
Instituto de Física, UNAM, Laboratorio Central de Microscopía, J. G. Morales Morales and M. Aguilar Franco, for
the images of SEM and TEM microscopy. We are also grateful to A. Obreg
ón-Zuñiga, UANL, for his support in
the acquisition and processing of TGA and DSC data.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.

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