Stereoselective Diels-Alder reactions promoted under continuous-flow conditions by silica-supported chiral organocatalysts

Article abstract of DOI:10.1002/ijch.201300106

Silica nanoparticles of different morphological properties were functionalized with enantiomerically pure imidazolidinones, through different immobilization techniques; stainless-steel columns were then loaded with silica bearing chiral organocatalysts to

Full text of DOI:10.1002/ijch.201300106

Full Paper
DOI: 10.1002/ijch.201300106
Stereoselective DielsÀAlder Reactions Promoted under
Continuous-Flow Conditions by Silica-Supported Chiral
Organocatalysts
Riccardo Porta, Maurizio Benaglia,* Valerio Chiroli, Francesca Coccia, and Alessandra Puglisi[a]
Abstract: Silica nanoparticles of different morphological
properties were functionalized with enantiomerically pure
imidazolidinones, through different immobilization tech-
niques; stainless-steel columns were then loaded with silica
bearing chiral organocatalysts to realize chiral “homemade”
reactors. The influence of the material properties and immo-
bilization procedures on the chemical and stereochemical
activities of the chiral HPLC columns was studied by per-
forming organocatalyzed DielsÀAlder reactions between cy-
clopentadiene and a,b-unsaturated aldehydes under contin-
uous-flow conditions. In some cases, excellent enantioselec-
tivities were obtained, thus showing that a catalytic reactor
may work efficiently to continuously produce enantiomeri-
cally enriched cycloadducts for more than 200 h. Regenera-
tion of the organocatalytic column was also partially accom-
plished, although associated with a slightly lower enantiose-
lectivity, thus prolonging the “life” of the reactor to more
than 300 h.
Keywords: Chirality · Cycloaddition · Flow chemistry · Organocatalysis · Supported catalysts
1 Introduction
In the last twenty years, organic synthesis has somehow
been revolutionized by the advent of automation and new
advanced technologies able to facilitate the process of
preparation and isolation of a product.[1] For example,
solid-phase-assisted synthesis,[2] largely employed in the
pharmaceutical and medicinal chemistry, is only one of
the so-called enabling technologies developed with the
aim of speeding up the synthetic transformation and pu-
rification of the final product.[3]
presents several advantages over traditional batch pro-
cess, such as easy product purification procedures, im-
proved catalyst stability, and the possibility of designing
automated processes.[9] Chiral organic catalysts have an
additional positive feature: the metal-free nature of these
compounds avoids, from the outset, the problem of metal
leaching, which often negatively affects and practically
prevents the efficient recycling of a supported organome-
tallic catalyst and may lead to product contamination by
the metal.
However, surprisingly, although in the last decade in-
credibly intense activity focused on the use of different
chiral organometallic catalysts under flow conditions,
only a few examples of chiral organocatalysts were inves-
tigated.[10] After the pioneering work by Lectka et al.
with polystyrene-immobilized cinchona alkaloid deriva-
tives,[11] very recently the groups of Pericꢀs and Massi
have studied the use of polymer-supported proline[12] and
prolinol[13] derivatives in mini flow reactors. Lately, the
groups of Fulop[14] and Wennemers[15] have reported ste-
reoselective Michael additions promoted in continuo by
polymer-supported tripeptides. It should be noted that all
In this context, it must be seen the extraordinary op-
portunity offered by the development and the design of
new reactors, such as continuous-flow and micro reac-
tors.[4] Microreactor technology offers advantages to clas-
sical approaches by allowing miniaturization of structural
features up to the micrometer regime. In recent years,
chemists have recognized this as a very powerful tool and
many reactions have been performed in such devices.
These reactions benefit from the physical properties of
microreactors, such as enhanced mass and heat transfer
due to a very large surface to volume ratio, as well as reg-
ular flow profiles, leading to improved yields with in-
creased selectivities.[5] Also, the recent developments and
excellent results obtained in the synthesis of fine chemi-
cals and complex molecules in flow[6] represent a clear
demonstration of the exciting possibilities given from the
new technological platforms for both homo- and hetero-
geneous transformations.[7]
[a] R. Porta, M. Benaglia, V. Chiroli, F. Coccia, A. Puglisi
Dipartimento di Chimica, Universitꢀ degli Studi di Milano, Via
Golgi 19, 20133, Milan (Italy)
e-mail: maurizio.benaglia@unimi.it
In this regard, the use of immobilized chiral catalysts[8]
under flow conditions is extremely attractive, since it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ijch.201300106.
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of these works were almost exclusively limited to the use
of packed-bed reactors filled with catalyst supported on
inorganic or gel-type organic materials, with substrate ac-
tivation via enamine intermediates.
interesting perspectives and new solutions to these
issues.
Based on our previous experience,[24] and taking the
good preliminary results obtained by using commercial
silica-supported catalysts under continuous-flow condi-
tions into consideration,[16] we decided to further investi-
gate the use of these materials in stereoselective cycload-
ditions performed in flow. Herein, we report the prepara-
tion of silica-supported MacMillan catalysts through dif-
ferent immobilization strategies, the characterization of
the functionalized materials, and the study of their cata-
lytic behavior in a stereoselective DielsÀAlder reaction
under continuous-flow conditions.
We recently reported on the preparation of a “home-
made” silica-based HPLC column,[16] functionalized with
a supported enantiomerically pure organic catalyst, that
promoted stereoselective reactions via an iminium inter-
mediate. The silica-supported MacMillan catalyst was em-
ployed for the first time to perform stereoselective cyclo-
addition under continuous-flow conditions, in high yields
and enantioselectivities. The so-called MacMillan cata-
lysts are chiral imidazolidinones, which are one of the
most popular and versatile classes of chiral metal-free
catalysts.[17] These compounds have been covalently im-
mobilized both on soluble[18] and insoluble supports.[19]
Lately, properly modified enantiopure imidazolidinones
were anchored to novel siliceous mesocellular foams,[20]
and to silica gel with the aid of an ionic liquid,[21] while in
another work hollow periodic mesoporous organosilica
spheres were exploited.[22] Recently, Pericꢀs and co-work-
ers reported the anchoring of first-generation MacMillan
imidazolidinone onto polystyrene resins and magnetic
nanoparticles[23a] and our group also reported the use of
magnetic nanoparticles conjugated to chiral imidazolidi-
none as a recoverable catalyst.[23b] Despite this variety of
proposed solutions, however, the development of an
easily available, inexpensive, truly efficient, recoverable
MacMillan catalyst has still to be realized. Lower enan-
tioselectivities with respect to those of the nonsupported
system and recyclability are issues that are still waiting
for a satisfying solution: the use of MacMillan catalysts in
reactors under continuous-flow conditions might open up
2 Results and Discussion
2.1 Synthesis of Silica-Supported Catalysts
The use of (S)-tyrosine instead of (S)-phenylalanine to
generate an imidazolidinone offers the possibility to syn-
thesize the desired chiral catalyst, which is already
equipped with a properly located and chemically suitable
handle for the heterogenization process (Figure 1).[18]
Thus, starting from (S)-tyrosine methyl ester hydrochlo-
ride, imidazolidinone 1 was easily obtained in 77% yield
by N-butyl amide formation and treatment with acetone
(Scheme 1). Reaction with allyl bromide in acetonitrile in
the presence of Cs2CO3 allowed the introduction of the
carbonÀcarbon double bond, which was further function-
alized by platinum-catalyzed hydrosilylation, leading to
compound 2, featuring the key structural element to real-
ize catalyst immobilization. Grafting of functionalized
Figure 1. MacMillan catalyst and silica-supported imidazolidinones.
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Scheme 1. Synthesis of supported imidazolidinone type A. PTSA=p-toluenesulfonic acid.
imidazolidinone 2 onto silica nanoparticles in toluene at
608C for 24 h afforded supported catalyst type A.
ticles to afford silica-supported azide 5, which was sub-
jected to copper-catalyzed cycloaddition with derivative 3
to give catalyst B1. The same intermediate 4 was also em-
ployed to prepare a mesoporous azide-functionalized
silica (5-MSN) through a co-condensation method. Start-
ing from the modified MacMillan catalyst 3, a click
chemistry strategy allowed the preparation of a chiral or-
ganocatalyst anchored to a mesoporous silica material,
B2. After the copper(I)-catalyzed click reaction, the ma-
terials were washed with ammonia solution and analyzed
by energy-dispersive X-ray spectroscopy (EDX), which
showed no traces of residual copper.[25]
With regard to catalyst type A, three types of commer-
cially available silica were used as supports (particle sizes
of 8, 10, and 25 mm) to study the influence of the morpho-
logical properties on the catalytic behavior. However,
preliminary studies convinced us to focus our attention
on the first two silica types only (particle size of 8 and
10 mm). Materials of different morphological properties
were purchased from different companies: catalyst A8-
1 was prepared by grafting imidazolidinone 2 onto Apex
Prepsil Silica Media 8 mm (Grace Davison – Discovery
Sciences, asymmetry 0.9, pore diameter 120 ꢁ, mean par-
ticle size 8.4 mm, and surface area 162 m2/g), obtaining
a loading of 0.39 mmol/g (determined by weight differ-
ence of the materials before and after grafting; see below
for further characterization details). To study the influ-
ence of the catalyst loading on the catalyst performances,
two other functionalized materials were prepared using
8 mm silica, namely, material A8-2 (loading of 0.33 mmol/
g) and catalyst A8-3 (loading of 0.1 mmol/g). Catalyst
A10-1 was prepared by grafting imidazolidinone 2 onto
Luna Silica 10 mm (pore diameter 101 ꢁ, mean particle
size 8.57 mm, and surface area 380 m2/g); the loading was
found to be 0.53 mmol/g (see below for further details).
Following the same strategy, catalyst type B was also
easily prepared by reacting the same intermediate 1 with
propargyl bromide and imidazolidinone 3, bearing
a carbonÀcarbon triple bond, was obtained after a single
chromatographic purification step (Scheme 2).
2.2 Characterization of Supported Catalysts
The supported catalysts were characterized by performing
cross-polarization (CP) and direct-polarization (DP)
magic-angle spinning (MAS) 13C and 29Si NMR spectros-
copy experiments to obtain evidence for the presence of
the organic moieties in the siliceous materials and con-
firm their chemical structure.
2.2.1 13C CPMAS NMR Spectroscopy
The 13C spectra of the prepared catalysts demonstrated
that the materials were indeed functionalized as expected
and the organic residues were stably bound to the inor-
ganic material (see the chemical shifts of carbon atoms C-
1 and C-3). For comparison, we report the 13C resonances
of catalyst A10-1, in which the imidazolidinone moiety is
directly linked to the silica surface, and catalyst B2, bear-
ing a triazole spacer between the imidazolidinone and the
silica surface. The 13C resonances reported in Table 1 are
assigned based on the chemical shifts found in the solu-
tion spectra of organic precursors (see the Experimental
Section and the Supporting Information).
The modified MacMillan catalyst was then reacted with
the properly derivatized siliceous material; siloxane 4 was
readily prepared from commercially available 3-chloro-
propyl triethoxysilane and sodium azide in CH3CN, and
grafted to the commercially available 8 mm silica nanopar-
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Scheme 2. Synthesis of supported azide 5 and supported catalyst type B. TBAB=tetra-n-butylammonium bromide, TEOS=tetraethoxysi-
lane, CTAB=cetyltrimethylammonium bromide, DIPEA=N,N-diisopropylethylamine.
Table 1. 13C NMR resonances [ppm] in the solid-state spectra of catalysts A10-1 and B2.
C1
C2
C3
C4
C5
C5’
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
A10-1 7.60 22.1 68.8 175.2 58.5 39.3 76.2 50.7 31.4 19.7 11.5 130.2 130.2 114.7 158.4
B2
9.0
23.0 51.8 174.0 58.0 40.0 76.0 50.0 28.0 19.7 13.0 129.0 129.0 114.0 157.4 62.0 143.3
2.2.2 29Si DP and CPMAS NMR Spectroscopy
As expected, based on previous experiments, the 13C
spectrum of catalyst B2, synthesized by cycloaddition of
imidazolidinone 3 with the supported azide 5-MSN, re-
vealed about 25% of unreacted azide starting material.
The ratio between the two organic moieties (the azide
and the imidazolidinone) can be calculated by integrating
the signal of carbon atoms C-1 (9.0 ppm) and C-10
(13.0 ppm). (The data should be considered within the
limit of the analytical technique.)
The 29Si NMR spectra of siliceous materials are extensive-
ly used to determine the degree of functionalization of
the materials, as well as to give insights into the substitu-
tion of the surface silicon atoms. It is well recognized that
a given surface silicon atom bearing a functional group
can have a variable number, n, of Si-O-Si bonds, leading
to so-called T1, T2, and T3 substructures. The bonding
schemes for these hybrid materials containing organic
functionalities lead to very different geometries on the
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Figure 2. Possible Si substitution on the silica surface.
surface, as illustrated in Figure 2. The 29Si spectra also
gives information about the bulk surface species Q4
((SiO)4 Si) and proton-rich Qn sites: Q3 ((SiO)3 SiOH),
Q2 ((SiO)2 Si(OH)2), and Q1 ((SiO) Si(OH)3; Figure 2).
Knowledge of the surface incorporation patterns and the
conformations of functional groups for such materials is
an essential step toward developing efficient functional
substrates.
structure of the siliceous material, in which the organic
moiety can cover the interior wall of the mesopores. Cat-
alyst A10-1, derived from grafting of a trialkoxysilane to
a commercially available silica, presents smaller T2 and T3
values, leading to a smaller SC. In the case of A10-1, the
calculated loading (MC) is in good agreement with that
obtained by weight difference of a silica sample before
and after functionalization (0.67 vs. 0.53 mmol/g); the MC
of B2, on the other hand, is overestimated (0.95 vs.
0.40 mmol/g). Even if in the quantification of organic resi-
dues on silica matrix some discrepancies among different
analytical techniques arise, MAS-NMR spectroscopy re-
mains a powerful method for the characterization of func-
tionalized siliceous materials, since it can be used not
only to study different surface incorporation patterns, but
also to determine the ratio between two different organic
residues.
29Si DP/MAS experiments, carried out according to
previously described methods,[26] were performed in this
study for the prepared catalysts. As expected, the 29Si
solid-state spectra are dominated by resonance lines at
À113, À103 and À96 ppm, representing silicon sites Q4,
Q3, and Q2 , respectively. On the other hand, different
patterns were found in the spectra of the catalysts with
regard to the functionalized Tn species, in which the sili-
con atoms were directly bound to at least one organic
moiety.
The presence of signals assigned to T3, T2, and T1 con-
firmed that the organic groups were indeed covalently
bound to the surface. Quantitative measurements of Tn
and Qn silicon groups could be properly achieved by 29Si
DP/MAS experiments, as reported previously,[24,26] to de-
termine the relative concentrations of Tn and Qn, surface
coverage, and molar concentrations of the organic moiet-
ies. For comparison, in Table 2 we report the data of cata-
lyst A10-1, in which the imidazolidinone moiety is direct-
ly linked to the silica surface, and catalyst B2, bearing
a triazole spacer between the imidazolidinone and the
silica surface.
2.2.3 Morphological Properties
The morphological examination of the sample particles
was performed by collecting images of the surfaces by
SEM analysis. The images of the surfaces of all of the in-
organicÀorganic hybrid materials compared with those of
bare silica showed a variety of particle shapes and sizes
densely agglomerated.
Figure 3 presents the SEM image of catalyst B1: the
micrograph clearly shows some aggregation of the materi-
al; this particle aggregation can explain the experimental
observation that, after prolonged fluxing of the column
(six volumes of column), no reagents or products, pre-
Notably, catalyst B2 has a larger surface coverage, esti-
mated as SC=(T1+T2+T3)/(Q2+Q3+T1+T2 +T3), due the
Table 2. 29Si DP/MAS NMR chemical shifts, relative concentrations of Tn and Qn silicon groups (in %), surface coverage (SC, in %), and
molar concentrations of organic moieties (MC, in mmol/g) of catalysts A10-1 and B2.
Catalyst
T1 %
T2 %
T3 %
Q2 %
Q3 %
Q4 %
SC [%]
MC [mmol/g]
À54 ppm
À60 ppm
À68 ppm
À96 ppm
À103 ppm
À113 ppm
A10-1
B2
–
–
2.5
4.1
2.8
13.0
0
4.4
22.5
30.5
72.2
48.0
19.1
33.0
0.67
1.43[a]
[a] Overall (catalyst+azide).
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Figure 3. SEM image of a sample of catalyst B1.
Figure 5. SEM image of a sample of catalyst A8-1.
sumably retained inside the reactor, were detected at the
exit (see below for catalytic experiments).
presence of different acid additives. A few selected results
are summarized in Table 3.
Figure 4 shows the micrographs of catalyst B2 at two
different magnifications: as expected,[24] rod-shaped parti-
cles of different lengths and diameters (ca. 0.4 mm in
length and 500 nm in diameter), with a curved hexagonal-
shaped tubular morphology, completely cover irregular
polyhedral-shaped grains associated with the silica mor-
phology.
Since MacMillan catalyst requires an acidic additive,
among different possibilities, we focused on the use of
tetrafluoroboric (HBF4) and trifluoroacetic acid (TFA).
In explorative studies it was noted that pre-forming the
catalyst led to a marked decrease of both yield and ster-
eoselection; therefore, in situ addition of the acid to the
reaction mixture was preferred.
A SEM image of catalyst A8-1 (Figure 5) shows a regu-
lar distribution of particle sizes and confirms that no me-
chanical degradation occurs after functionalization of the
siliceous material.
Catalyst A8-1 afforded the cycloadducts in 75% yield
with 75% ee for the endo isomer and 76% ee for the exo
isomer, in the presence of tetrafluoroboric acid as an ad-
ditive; comparable yields and slightly better enantioselec-
tivities were observed with trifluoroacetic acid.[27] It
should be mentioned that the endo/exo ratio remained
almost unvaried in all catalytic reactions and was compa-
rable to the ratio obtained by the original MacMillan imi-
dazolidinone.[28] Very similar results were obtained with
the catalyst anchored to 10 mm silica nanoparticles, A10-
1 (Table 3, entries 3 and 4 versus entries 1 and 2). When
recycling of the supported imidazolidinones was studied,
2.3 Catalytic Behavior of the Immobilized Catalysts
The behavior of silica-anchored imidazolidinones type A
and B was first investigated by running a model reaction
in batch; DielsÀAlder cycloaddition between cinnamic al-
dehyde (1 equiv) and cyclopentadiene (5 equiv) in
CH3CN/H2O as a solvent system using 30 mol% of the
supported catalyst was performed for 40 h at 258C in the
Figure 4. SEM images of a sample of catalyst B2 magnified at 2000ꢀ (left) and 50000ꢀ (right).
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Table 3. DielsÀAlder reactions promoted by catalysts type A and B in batch.
Entry
Catalyst
HX
Yield [%][a]
endo/exo[b]
ee [%] (endo,exo)[c]
1
2
3
4
A8-1
A8-1
A10-1
A10-1
A10-1
A10-1
B2
HBF4
TFA
HBF4
TFA
HBF4
TFA
HBF4
TFA
75
69
78
66
15
12
75
52
91
53 :47
51:49
52 :48
53 :47
55 :45
56 :44
54 :46
55 :45
55 :45
75, 76
80, 82
78, 77
83, 86
n.d.
5[d]
6[d]
7
n.d.
91, 89
87, 97
93, 91
8
B2
B2
9[e]
HBF4
1
[a] Reaction conditions: 48 h, 258C, isolated yield after chromatographic purification. [b] Evaluated by H NMR spectroscopy on the crude re-
action mixture. [c] Evaluated by HPLC on a chiral stationary phase after reduction to the corresponding alcohol. [d] Recovered supported cat-
alyst was employed. [e] A second portion of cyclopentadiene was added after the first 24 h.
disappointingly an evident decrease in the chemical yield
was detected, which was a clear indication of rapid cata-
lyst deactivation after only 48 h.
MacMillan catalyst immobilized through click chemis-
try on silica showed similar chemical activity, but promot-
ed the cycloaddition with higher enantioselectivities, com-
parable to those obtained with the non-supported organo-
catalysts.[28]
Then the same materials were employed to promote
stereoselective DielsÀAlder under continuous-flow condi-
tions. A standard HPLC column (0.4 cm i.d.ꢂ12.5 cm,
1.6 mL total volume) was filled with functionalized silica
nanoparticles. Tetrafluoroborate salt of catalyst A8-1 was
first studied (Table 4).
A conditioning time was necessary to reach a steady-
state regime of high chemical and stereochemical activi-
ties; probably an effective exchange between the solid-
supported catalyst and the liquid phase containing the re-
actants must be realized before the column may work ef-
ficiently. As also demonstrated by the reaction under
batch conditions, after 24 h only 50% yield was observed,
and longer reaction times were necessary to reach higher
yields. However, after the first 22 h, the column produced
for the next 8 h the product with constant yield, although
with low enantioselectivity; lowering the flow rate al-
lowed the stereoselectivity of the process to be improved,
without loss in chemical yield. Indeed, after the first 30 h,
the reactor produced the cycloadducts with yields con-
stantly higher than 91% and enantioselectivities typically
Table 4. DielsÀAlder reaction promoted by catalyst type A8-1 under continuous-flow conditions.
Entry
t [h]
Flow rate [mL/min]
Residence time [h]
HX
Yield [%][a]
endo/exo[b]
ee [%] (endo,exo)[c]
1
2
3
4
5
6
10–22
22–26
26–30
30–50
50–96
96–150
2.5
2.5
2.5
1.5
1.5
1
10
10
10
16.5
16.5
25
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
45
86
88
91
92
95
46:54
47:53
47:53
47:53
42:58
44:56
38, 58
47, 60
49, 63
71, 73
85, 81
83, 80
7
8
9
10
11
10–20
20–96
96–120
120–150
150–170
2.5
2.5
2.5
2.5
2.5
10
10
10
10
10
TFA
TFA
TFA
TFA
TFA
94
84
78
77
60
48:52
47:53
48:52
49:51
49:51
85, 85
85, 83
73, 71
77, 73
75, 74
1
[a] Isolated yield after chromatographic purification. [b] Evaluated by H NMR spectroscopy on the crude reaction mixture. [c] Evaluated by
HPLC on a chiral stationary phase after reduction to the corresponding alcohol (see the Supporting Information).
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Table 5. DielsÀAlder reaction promoted by catalyst type A10-1 under continuous-flow conditions.
Entry
t [h]
Flow rate [mL/min]
Residence time [h]
HX
Yield [%][a]
endo/exo[b]
ee [%] (endo,exo)[c]
1
2
3
4
10–24
24–48
48–72
72–96
2.5
2.5
2.5
2.5
10
10
10
10
HBF4
HBF4
HBF4
HBF4
54
76
76
60
n.d
n. d.
52 :48
51:49
51:49
71, 68
69, 66
68, 58
5
6
7
8
10–24
24–48
48–72
72–96
2.5
2.5
2.5
2.5
10
10
10
10
TFA
TFA
TFA
TFA
60
50
32
25
62 :37
53 :47
52 :48
53 :47
60, 80
67, 70
68, 70
63, 63
1
[a] Isolated yield after chromatographic purification. [b] Evaluated by H NMR spectroscopy on the crude reaction mixture. [c] Evaluated by
HPLC on a chiral stationary phase after reduction to the corresponding alcohol (see the Supporting Information).
higher than 80%, working for more than 150 h with high
stereochemical efficiency; it must be said that, after 96 h,
to maintain the production over a threshold of 90% yield
it was necessary to further slow down the flow rate; thus
increasing the retention time (Table 4, entry 6).
When the trifluoroacetate salt of supported imidazoli-
dinone A8-1 was employed, it was observed that the
column reached a high efficiency in a shorter time than
the tetrafluoroborate salt. After 10 h only, the products
were obtained in 94% yield and 85% ee (Table 4,
entry 5); however, it was also observed that the catalytic
efficiency started to decrease after 96 h only (Table 4,
entry 7).
The influence of the morphological characteristics of
the material on the catalytic activity was then studied.
Therefore, silica nanoparticles of different sizes were em-
ployed; in Table 5 selected results of the cycloaddition
performed in flow in a catalytic reactor filled with func-
tionalized 10 mm silica nanoparticles are reported (cata-
lyst A10-1). By comparing the activities of the trifluoroa-
cetate and the tetrafluoroborate salts, the same behavior
as the previous columns with 8 mm particles was ob-
served: longer times were required by the HBF4 salt to
reach a constant level of catalytic efficiency; with TFA-
treated supported imidazolidinones higher ee were pro-
duced (Table 5, entries 5–8 versus entries 1–4). However,
the catalytic columns filled with catalyst A8-1 performed
generally better than those loaded with A10-1-type silica-
supported catalysts, both in terms of chemical and stereo-
chemical efficiency.
flow conditions were evaluated, and compared to the
data obtained with the reactor containing catalyst A8-1.
A few selected results are briefly summarized in
Table 6. It is clear that lower loadings dramatically re-
duced the activity of the catalytic columns. The A8-2-sup-
ported catalyst (loading 0.3 mmol/g vs. loading of
0.4 mmol/g of catalyst A8-1) employed in flow promoted
the DielsÀAlder reaction in lower yields and enantiose-
lectivities than A8-1. Silica-supported catalysts A8-3
showed almost no appreciable catalytic activity (Table 6,
entries 4–6 and entries 7–9).
Finally, the nature of the material and the immobiliza-
tion strategies were also taken in consideration. Type B
catalysts were prepared by exploiting the click chemistry
approach; in the case of material B1 commercially avail-
able silica nanoparticles were employed, whereas for cat-
alysts B2 ad hoc synthesized mesoporous silica nanoparti-
cles were used (Scheme 3).
Surprisingly, when the cycloaddition reaction was per-
formed in continuo by pumping the reagents in a column
loaded with material B1, neither unreacted starting mate-
rials nor products were observed, even after prolonged
fluxing of the reactor (six volumes of column were flush-
ed into the column, see the comments of the SEM
images). However, when the column was discharged and
the recovered silica was suspended in CH2Cl2 and stirred
for 1 h, evaporation of the filtered organic phase afforded
the expected cycloadducts in 95% yield and 90% ee for
both isomers. Extensive particle aggregation evidenced
by SEM images may partially account for the unusual be-
havior of the column that seemed to entrap the organic
molecules.
Based on these data, two other types of silica-support-
ed catalysts were prepared by using 8 mm silica particles,
but with lower chiral catalyst loadings than A8-1. The
performances of the two new HPLC columns (filled with
materials A8-2 and A8-3) in the model cycloaddition of
cinnamic aldehyde to cyclopentadiene under continuous-
On the other hand, it was possible to perform organo-
catalyzed reactions under continuous-flow conditions with
catalyst type B2. The results are reported in Table 7.
The catalytic column loaded with mesoporous function-
alized silica B2 was able to continuously produce the cy-
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Table 6. Comparison of the catalytic behavior of materials A8-1, A8-2, and A8-3 in DielsÀAlder reactions under continuous-flow conditions.
Entry
t [h]
Flow rate [mL/min]
Residence time [h]
Catalyst
Yield [%][a]
endo/exo[b]
ee [%] (endo,exo)[c]
1
2
3
10–30
30–50
50–96
2.5
1.5
1.5
10
16.5
16.5
A8-1
A8-1
A8-1
55
91
92
46 :54
47:53
42 :58
40, 60
71, 73
85, 81
4
5
6
10–30
30–50
50–72
2.5
1.5
1.5
10
16.5
16.5
A8-2
A8-2
A8-2
31
41
21
49 :51
48 :52
51:49
n.d.
46, 56
45, 55
7
8
9
10–30
30–50
50–96
2.5
1.5
1.5
10
16.5
16.5
A8-3
A8-3
A8-3
11
15
12
50 :50
53 :47
51:49
n.d.
43, 47
n.d.
1
[a] Isolated yield after chromatographic purification. [b] Evaluated by H NMR spectroscopy on the crude reaction mixture. [c] Evaluated by
HPLC on a chiral stationary phase after reduction to the corresponding alcohol (see the Supporting Information).
Scheme 3. Use of supported catalysts B under continuous-flow conditions.
Table 7. DielsÀAlder reaction promoted by catalyst B2 under continuous-flow conditions.
Entry
t [h]
Flow rate [mL/min]
Residence time [h]
HX
Yield [%][a]
endo/exo[b]
ee [%] (endo,exo)[c]
1
2
3
10–30
30–50
50–72
2.5
2.5
2.5
10
10
10
HBF4
HBF4
HBF4
60
50
35
50 :50
47:53
49 :51
74, 91
80, 94
82, 97
1
[a] Isolated yield after chromatographic purification. [b] Evaluated by H NMR spectroscopy on the crude reaction mixture. [c] Evaluated by
HPLC on a chiral stationary phase after reduction to the corresponding alcohol (see the Supporting Information).
cloadducts with high enantioselectivities (up to 97%), but
in lower yield than catalyst A8-1. Also, it is worth men-
tioning that material B2 seems to rapidly lose catalytic ac-
tivity; after 50 h, although the level of enantioselection
remains very high, the chemical yield shows a clear de-
crease (Table 7, entries 2 and 3).
All data for the catalytic behavior of the different col-
umns are summarized in Figure 6. The curves are intend-
ed to fit the data reported in Tables 4–7 and to show the
trends of conversions and enantioselectivities during the
reactions performed under continuous-flow conditions.
Figure 6a reports the conversions at different reaction
times: it is clearly evidenced how catalyst A8-1 main-
tained a higher chemical efficiency than the other materi-
als for longer operation times. Figure 6b illustrates the
enantioselectivities guaranteed by the different supported
catalysts, highlighting the excellent performances of mate-
rials A8-1 and B2, but with the second one penalized by
a quick chemical deactivation (see Figure 6a).
Finally, it is worth mentioning that the regeneration of
the catalytic column is possible. A used HPLC column
filled with tetrafluoroborate salt (after 180 working
hours) was first washed with aqueous acetonitrile, and
then fluxed with 0.33 mL of an aqueous solution of HBF4
in acetonitrile. The regenerated catalytic column was em-
ployed again in the cycloaddition of cyclopentadiene with
cinnamic aldehyde (Table 8). Longer times were necessa-
ry to reach satisfactory conditions at steady-state regime
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Figure 6. Comparison of yields and ee obtained with different catalytic columns. Steady flow rates (2.5 mL/min) and residence times (10 h)
were used for all reported catalysts.
(Table 8, entries 1 and 2). However, after 30 h the prod-
ucts were collected in yields comparable to those ob-
tained with a freshly prepared reactor.[29] Notably, if one
considers the performance of the catalytic column before
and after regeneration, the simple homemade catalytic re-
actor was demonstrated to work for more than 300 h
under continuous-flow conditions.
Figure 7 shows how, after the regeneration procedure,
the chemical activity of the column may be restored, al-
though it must be said that it was necessary to set up
a longer residence time for the regenerated column to
guarantee yields of >85%.
Finally, it is interesting to compare some results ob-
tained in the organocatalyzed cycloaddition performed
with supported catalysts in batch or under continuous-
flow conditions; the data are collected in Table 9, in
which TON and productivity of the different materials
are reported.
Considering the results obtained with the TFA salt of
A8-1 in batch after 48 h, the TON (calculated as mmol of
product per mmol of catalyst) is 2.3, while in flow almost
a threefold increase was obtained. For longer times, the
process in flow offers even better performances; a clear
advantage over the batch process, reaching a TON of 24.4
after 170 h. Outstandingly, for the trifluoroacetate salt of
supported imidazolidinone A8-1 a remarkable value of
productivity, 143, was calculated (as mmol of product
per mmol of catalyst per hour).
Further studies are underway to investigate the origin
of catalyst deactivation to optimize flow reaction condi-
tions and to improve the applicability of the chiral col-
umns.
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Table 8. Catalytic behavior of a regenerated chiral reactor under continuous-flow conditions.
Entry
t [h]
Flow rate [mL/min]
Residence time [h]
HX
Yield [%][a]
endo/exo[b]
ee [%] (endo,exo)[c]
1
2
3
4
5
0–20
1.5
1.5
1.5
1.5
2.5
16.5
16.5
16.5
16.5
10
HBF4
HBF4
HBF4
HBF4
TFA
40
55
87
85
78
48 :52
49 :51
48 :52
47:53
48 :52
60, 57
71, 75
80, 73
75, 71
70, 66
20–30
30–50
50–168
168–192
1
[a] Isolated yield after chromatographic purification. [b] Evaluated by H NMR spectroscopy on the crude reaction mixture. [c] Evaluated by
HPLC on chiral stationary phase after reduction to the corresponding alcohol (see the Supporting Information).
Figure 7. Representation of conversion versus time of a catalytic reactor before and after regeneration.
Table 9. A comparison of batch and continuous-flow conditions.
Entry
Catalyst
t [h]
Productivity[a]
TON[b]
TON[b]
TON[b]
Batch 48 h
Flow 48 h
Flow total
1
2
A8-1 (TFA)
A8-1 (HBF4)
170
150
143
44
2.3
2.5
6.3
2.1
24.4 (170 h)
6.5 (150 h)
12.3 (342 h)
3.2 (120 h)
5.4 (96 h)
3
4
5
A10-1 (TFA)
A10-1 (HBF4)
B2 (HBF4)
120
96
72
33
57
41
2.2
2.6
2.5
1.9
2.4
1.1
2.9 (72 h)
[a] Productivity is measured in mmol(product) hÀ1 mmol(catalyst)À1 ꢂ103. [b] Turnover number (TON) is measured in mmol(product) mmol-
(catalyst)À1
.
With the tetrafluoroborate salt, which behaved better
in batch, for long operation times, the flow process favor-
ably compares with the reaction performed in a flask; re-
generation of the column allowed the TON to be further
increased up to 12.3.
3 Conclusion
Silica nanoparticles of different morphological properties
were functionalized with enantiomerically pure imidazoli-
dinones, through different immobilization techniques, in-
cluding grafting and click cycloaddition-based strategies.
Stainless-steel columns were then loaded with silica bear-
ing the chiral organocatalysts to realize chiral “home-
made” reactors and their catalytic behavior was studied
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by performing a model DielsÀAlder reaction between cy-
clopentadiene and cinnamic aldehyde. By operating
under the best experimental conditions, it was demon-
strated that a simple HPLC column, filled with commer-
cially available silica-supported MacMillan catalyst, may
work as a catalytic reactor for 150 h, affording the prod-
uct in high yields and enantioselectivities. A regeneration
procedure may restore the catalytic efficiency of the
column, allowing the activity of the reactor to be further
extended to more than 300 operating hours. The flow pro-
cess performed clearly better than the batch process, and
reached a TON of 24 (against 2.3 for the batch) and 143
of productivity. Additionally, it should be considered that
the continuous-flow methodology does not require any
workup, separation, and recovery operations; this allows
for the easy isolation of the reaction products in a time-
saving procedure.
(50 ml sample volume) spinning at 13 kHz and at a tem-
perature of 300 K. DP and variable-amplitude CP meth-
ods (contact time, tc, 1 ms) were used for recording the
29Si spectra with 400 scans and a delay of 300.0 s and
20000 scans and a delay of 3.0 s, respectively. The 13C ex-
periments were performed with the CP method using
a contact time, tc, of 1.5 ms, 70000 scans, and 3.0 s of
delay. All chemical shifts were externally referenced to
TMS.
The 29Si resonances were assigned following previous
reports in the literature,[26] while those of 13C were re-
ferred to the chemical shifts found in the solution spectra
of the corresponding unbound compounds.
Scanning Electron Microscopy
SEM micrographs were obtained by using a Zeiss
SIGMA FE-SEM instrument operating at 0.2–30 kV. The
powder samples were coated with gold before analysis.
Although TON and reaction rates need to be im-
proved, it was already demonstrated that the process in
continuo may positively compete with the reaction in
batch, affording, in the same time, larger amounts of
product, in a user-friendly experimental procedure, which
leads to cleaner crude reaction mixtures.
Synthesis of 5-MSN
A solution of CTAB (365 mg, 1 mmol) in water (88 mL)
and 2m NaOH (1.3 mL) was mechanically stirred at
550 rpm at 808C for 30 min. The stirring speed was de-
creased to 200 rpm and TEOS (1.82 mL, 8.16 mmol) and
siloxane 4 (0.26 g, 1.05 mmol) were rapidly added. After
2 min stirring at 200 rpm a precipitate was formed. Stir-
ring at 500–600 rpm was continued for 2.0 h at 808C and
the mixture was filtered while still hot. The solid was
washed with water (150 mL) and MeOH (150 mL), and
dried under high vacuum for 3 h to afford a white materi-
al (794 mg). This was then treated with a solution of con-
centrated HCl (0.6 mL) in MeOH (80 mL) under me-
chanical stirring for 2.5 h at 608C to remove the surfac-
tant. The cooled mixture was filtered and the solid was
washed again with water and MeOH (100 mL each). The
white solid was dried under high vacuum for 3 h at 908C
and subjected to alkaline wash with saturated a solution
of Na2CO3 in methanol (100 mL/g). After 3 h of stirring
at 550 rpm at room temperature, the mixture was filtered
and the solid was washed with water and methanol and
dried under high vacuum at 808C for 3 h. The material
was finally suspended in distilled water (100 mL/g) and
mechanically stirred at 550 rpm at room temperature for
2 h, filtered on a porous septum, washed with methanol,
and dried under high vacuum at 608C to give a constant
weight.
Experimental Section
Materials
Trimethoxysilane (Aldrich reagent grade 99%), TEOS
(Aldrich reagent grade 98%), CTAB (Sigma reagent
grade 98%) and chloroplatinic acid (H2PtCl6 ·6H2O; Al-
drich ACS reagent) were purchased from Sigma-Aldrich
and used without further purification.
All reactions were carried out in oven-dried glassware
with magnetic stirring under a nitrogen atmosphere,
unless otherwise stated. Dry solvents were purchased and
stored under nitrogen over molecular sieves (bottles with
crown caps). Reactions were monitored by analytical
TLC using silica gel 60 F254 pre-coated glass plates
(0.25 mm thickness) and visualized using UV light or
phosphomolybdic acid.
NMR Spectroscopy
1
The H and 13C NMR spectra were recorded on a Bruker
Avance 500 spectrometer operating at 500.0 and
125.62 MHz, respectively. The spectra are performed in
CDCl3 and the chemical shifts externally referenced to
tetramethylsilane (TMS).
Synthesis of 2
Imidazolidinone 2 was prepared according to a published
Solid-State NMR Spectroscopy
procedure.[16]
The 13C and 29Si solid-state NMR spectra were recorded
at 125.62 and 99.36 MHz, respectively, on a Bruker
Avance 500 spectrometer, equipped with a 4 mm MAS
broad-band probe (spinning rate, nR, up to 13 kHz). The
MAS spectra were performed on solid samples (typically
0.12 g); each sample was packed into a 4 mm MAS rotor
Preparation of Imidazolidinone 3
To a stirred portion of butylamine (10 mL, 101.2 mmol)
kept under nitrogen, (S)-tyrosine methyl ester (6 g,
30.8 mmol) was added and the mixture was stirred for
24 h at room temperature. After addition of CH2Cl2, the
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reaction was evaporated under vacuum to give a pale
yellow solid (7.2 g) that was used for the next reaction
without any further purification step. The compound was
dissolved in CH3OH (60 mL) and acetone (60 mL), and
PTSA (60 mg) was added. The mixture was heated at
reflux for 24 h and concentrated under vacuum to afford
the crude imidazolidinone (8.4 g), which was used for the
next reaction without any further purification step. M.p.
phere at reflux for 48 h. The supported catalyst was iso-
lated by centrifugation, washed with CH2Cl2 (2ꢂ10 mL),
and dried under vacuum.
General Procedure for the Click Reaction (Catalysts B1 and B2)
The azide-derived siliceous material (1 g) and imidazolidi-
none derivative 3 (1.56 mmol) were suspended in tetrahy-
drofuran (10 mL) and allowed to stir in the presence of
DIPEA (15 mmol) and copper(I) iodide (0.01 mmol) at
358C for 40 h. The supported catalyst was isolated by cen-
trifugation, washed with CH2Cl2 (2ꢂ10 mL), with ammo-
nia solution (15 mL), and dried under high vacuum.
1
99–1018C; [a]D23 =À78.2 (c=0.72 in CH2Cl2); H NMR
3
(CDCl3/D2O): d=7.04 (B part of AB system, J (H,H)=
8.5 Hz, 2H; aromatic protons), 6.74 (A part of AB
3
system, J (H,H)=8.5 Hz, 2H; aromatic protons), 3.73 (t,
3J (H,H)=5.8 Hz, 1H; CHN), 3.29 (ddd, 2J (H,H)=
3
Catalysis: General Procedure
12.0 Hz, J (H,H)=6.7 and 3.2 Hz, 1H; one H of NCH2),
2
3
3.04 (ddd, J (H,H)=12.0 Hz, J (H,H)=5.8 and 5.4 Hz,
The continuous-flow packed-bed reactor was prepared
filling a stainless-steel HPLC column (length 12.5 cm, i.d.
0.4 cm) with 1 g of silica-supported imidazolidinone cata-
lyst (A or B). It was flow-treated with TFA solution (0.2m
in 10 mL of a 95/5 CH3CN/H2O mixture) or with a 48%
solution in water of HBF4 (0.2m, in 10 mL of a 95/5
CH3CN/H2O mixture). The DielsÀAlder cycloaddition re-
action was then carried out at 258C by pumping a solution
of the reagents (trans-cinnamaldehyde (2.5 mmol) and cy-
clopentadiene (17 mmol) in a 95/5 CH3CN/H2O mixture
(10 mL)) through the reactor by a syringe pump. After
48 h of operation the flow was stopped, the syringe was
recharged with freshly distilled cyclopentadiene and cin-
namic aldehyde (to limit reagents degradation), and the
flow was started again.
The endo/exo ratio was established on the crude prod-
uct by using the CHO signals at d=9.60 (endo) and 9.93
(exo) ppm. This product is known[16] and was purified by
flash column chromatography on silica gel with 8:2
hexane/ethyl acetate as the eluant, affording a mixture of
endo and exo DielsÀAlder adducts. For ee determination,
the aldehyde was converted into the corresponding alco-
hol by reduction with an excess of NaBH4 in CH3OH, at
248C, for 1 h.
2
3
2H; ArCH2), 2.89 (ddd, J (H,H)=12.0 Hz, J (H,H)=6.2
and 3.1 Hz, 1H; one H of NCH2), 1.43–1.49 (m, 2H;
NCH2CH2), 1.21–1.31 (m, 2H; CH3CH2), 1.27 (s, 3H;
3
CMe), 1.17 (s, 3H; CMe), 0.90 ppm (t, J (H,H)=7.3 Hz,
3H; CH2CH3); 13C NMR: d=174.2, 155.8, 130.7, 127.2,
115.7, 76.4, 58.9, 40.4, 35.5, 31.3, 27.8, 26.3, 20.3,
13.7 ppm; IR: 3270, 1675, 1620 cmÀ1; elemental analysis
calcd (%) for C16H24N2O2 (276.4): C 69.53, H 8.75, N
10.14; found: C 69.71, H 8.64, N 10.23.
To a solution of the crude imidazolidinone (5 g, 18 mmol)
in dry acetonitrile (40 mL), potassium carbonate (20 g,
145 mmol) was added and the mixture was cooled to 08C
with an external ice water bath; propargyl bromide solution
(80 wt% in toluene, 8 mL, 72 mmol) was added dropwise
over 15 min and the resulting mixture was allowed to warm
to room temperature and stirred under an inert atmosphere
for 24 h. The reaction mixture was then filtered through
a Celite plug and the solvent was removed under vacuum;
the crude product was purified by flash column chromatog-
raphy (eluent: CH2Cl2/MeOH=98/2) to afford compound 3
as a brownish oil (15.9 mmol, 88%). Rf =0.47 (CH2Cl2/
1
MeOH=98/2); H NMR (300 MHz, CDCl3): d=7.12 (d,
2H; Ar-H), 6.85 (d, 2H; ArÀH), 4.59 (d, 2H; ÀOÀCH2),
3.65 (t, 1H; ÀNHÀCHÀ), 3.23–3.20 (m, 1H; ÀNÀCH2À),
2.97 (dd, 2H; ArÀCH2À), 2.96–2.84 (m, 1H; ÀNÀCH2À),
2.46 (t, 1H; ÀCꢀCH), 1.41 (m, 2H; ÀNÀCH2ÀCH2À), 1.29–
1.24 (m, 2H; CH2ÀCH3), 1.20 (s, 3H; ÀCÀCH3), 1.09 (s, 3H;
ÀCÀCH3), 0.86 ppm (t, 3H; ÀCH2ÀCH3); 13C NMR
(75 MHz, CDCl3): d=174.1 (1C, ÀC=O), 156.8 (1C, ArÀCÀ
OÀ), 131.0 (2C, ArÀCH), 130.1 (1C, ArÀCÀ), 115.2 (2C,
ArÀCH), 78.8 (1C, ÀCꢀCH), 76.3 (1C, ÀNÀCÀNH-), 75.7
(1C, ÀCꢀCH), 59.1 (1C, ÀNHÀCHÀC=O), 56.1 (1C, ÀOÀ
CH2À), 40.5 (1C, ÀNÀCH2À), 36.2 (1C, ArÀCH2À), 31.7 (1C,
ÀNÀCH2ÀCH2À), 28.3 (1C, ÀCÀCH3), 26.8 (1C, ÀCÀCH3),
20.6 (1C, ÀCH2ÀCH3), 14.0 ppm (1C, ÀCH2ÀCH3).
Supporting Information Available. The contents of Sup-
porting Information include the following: synthetic de-
tails for the preparation of functionalized materials, NMR
spectra of functionalized silica particles, analytical data of
the non-supported catalysts, NMR and HPLC spectra of
the cycloadducts.
Acknowledgments
This work was supported by MIUR-PRIN (Nuovi metodi
catalitici stereoselettivi e sintesi stereoselettiva di molec-
ole funzionali), the Cariplo Foundation (Milano) within
the project 2011-0293 “Novel chiral recyclable catalysts
for one-pot, multi-step synthesis of structurally complex
molecules”, and FIRB project RBFR10BF5V “Multifunc-
tional hybrid materials for the development of sustainable
catalytic processes”. M. B. thanks COST action CM9505
General Procedure for the Grafting Reaction (Catalysts A8-1,
A8-2, A8-3, and A10)
Commercial silica particles (1 g) and the properly modi-
fied organotrimethoxysilane (2 mmol) were suspended in
toluene (10 mL) and allowed to stir under an inert atmos-
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Fan, S. Sayalero, M. Pericꢀs, Adv. Synth. Catal. 2012, 354,
2971–2976; c) O. Bortolini, L. Caciolli, A. Cavazzini, V.
Costa, R. Greco, A. Massi, L. Pasti, Green Chem. 2012, 14,
992–1000; d) O. Bortolini, A. Cavazzini, P. Giovannini, R.
Greco, N. Marchetti, A. Massi, L. Pasti, Chem. Eur. J. 2013,
19, 7802–7808, and references cited.
“ORCA” Organocatalysis. We thank Angelo Magri
(T. F. B.) for technical support.
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Received: September 12, 2013
Accepted: January 13, 2014
Published online: March 20, 2014
Isr. J. Chem. 2014, 54, 381 – 394
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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