From Immobilization to Catalyst Use: A Complete Continuous-Flow Approach Towards the Use of Immobilized Organocatalysts

Article abstract of DOI:10.1002/cctc.201901129

The combination of chiral supported-organocatalysts and flow chemistry promotes the sustainable production of enantioenriched compounds providing a very powerful tool for chemical and pharmaceutical industries. However, the rapid deactivation of these cat

Full text of DOI:10.1002/cctc.201901129

Accepted Article
Title: From Immobilization to Catalyst Use: a Complete Continuous-
Flow Approach Towards the Use of Immobilized Organocatalysts
Authors: Fernanda Gadini Finelli, Pedro H. R. de Oliveira, Bruno M.
da S. Santos, Raquel A. C. Leão, Leandro S. M. Miranda,
Rosane A. S. San Gil, and Rodrigo O. M. A. de Souza
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.201901129
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ChemCatChem
10.1002/cctc.201901129
FULL PAPER
From Immobilization to Catalyst Use: a Complete Continuous-
Flow Approach Towards the Use of Immobilized Organocatalysts
[
a]
[a]
[b]
[b]
Pedro H. R. de Oliveira, Bruno M. da S. Santos, Raquel A. C. Leão, Leandro S. M. Miranda,
[
b]
[b]
[a]
Rosane A. S. San Gil, Rodrigo O. M. A. de Souza and Fernanda G. Finelli*
Abstract: The combination of chiral supported-organocatalysts and
merging it with flow chemistry, this area still remains little
explored. In recent years, a small group of homogeneous and
heterogeneous asymmetric reactions were successfully
conducted under continuous-flow conditions, employing certain
flow chemistry promotes the sustainable production of
enantioenriched compounds providing
a very powerful tool for
chemical and pharmaceutical industries. However, the rapid
deactivation of these catalysts in heterogeneous asymmetric
reactions has been limiting the expansion of the area. In this work
we report for the first time the advantages of synthesizing,
immobilizing, and using a silica-supported organocatalyst under a
complete continuous-flow approach, showing the impact of this
method on the morphology, structure and lifetime of the
organocatyst. The first generation MacMillan’s organocatalyst was
prepared from L-phenylalanine and immobilized in silica through a
carbamate linkage under batch and continuous-flow conditions. We
also evaluated the performance of both batch and continuous-flow
organocatalysts in the Diels-Alder reaction for proof of concept.
[
22],[23],[24]
organocatalysts and modes of catalyst activation.
Nevertheless, one of the main limitations of these processes is
the rapid deactivation of organocatalysts, reducing the efficiency
of the transformations and impeding large-scale application.
Undoubtedly, identifying the causes of the organocatalyst
deactivation and solving this problem is an important challenge
[
25-28]
to be overcome for the continued expansion of the area.
Once the method used for organocatalyst immobilization can
impact its performance, herein we report for the first time the
advantages of synthesizing and immobilizing an organocatalyst
under continuous-flow conditions and the impact of this method
on the lifetime of the organocatalysts. For such, we chose the
first generation MacMillan’s organocatalyst and evaluated its
performance in the enantioselective Diels-Alder reaction for
proof of concept.
Introduction
Organocatalysis has emerged as one of the key tools for
asymmetric
synthesis,
promoting
high
yields
and
Results and Discussion
[
1-4]
enantioselectivities for chemical transformations.
Combined
with ease of handling, chiral organocatalysts are also
inexpensive to prepare and versatile, providing different modes
of substrate activation and asymmetric induction, being
We started our investigation preparing the silica-supported
organocatalyst 6a in batch. The modified first generation
MacMillan’s organocatalyst 4 was easily synthesized from L-
phenylalanine (1) after 3 steps and 38% overall yield (Scheme
[
5-8]
employed in various types of reactions.
still some inherent problems with these reactions, such as the
However, there are
1
). Initially, the amino acid 1 was treated with thionyl chloride
[
9]
low turnover and the impossibility of recovering the catalyst. To
overcome these difficulties, some efforts have been made to
support the organocatalysts in a range of solid materials, such
and methanol at room temperature for 24 hours to afford ester 2
in 97% yield, followed by reaction with ethanolamine at room
temperature for 12 hours to formation of the corresponding
amide 3 in 75% yield, introducing the hydroxyl group, essential
for anchoring the organocatalyst on support matrix. Then, 3 was
submitted to a cyclization with acetone in the presence of p-
[
10-16]
as polymers or silica, affording heterogeneous reactions.
This strategy has allowed their usage in continuous-flow
reactors, enabling rapid continuous production of chiral
substances and becoming organocatalysis an even greater tool
a
toluenesulfonic acid in isopropanol and reflux for 12 hours,
[
17-21]
for chemical and pharmaceutical industries.
[29]
providing the 4-imidazolidinone
4
in 53% yield.
The
Despite the exponential growth of the field of asymmetric
organocatalysis in the last decades and the advantages of
immobilization was performed after activation of hydroxyl group
in 4 with 1,1’-carbonyldiimidazole (CDI) in the presence of
triethylamine in dichloromethane at room temperature for 12
hours to furnish the intermediate 5 in 90% yield, followed by
reaction with the commercial 3-aminopropyl-functionalized silica
[a]
Prof. Fernanda G. Finelli, Instituto de Pesquisas de Produtos
Naturais, Universidade Federal do Rio de Janeiro, 21941-902,
Brasil.
-
1
(
particles size 40-63 µm,
1
mmol.g NH
2
loading) and
triethylamine in dichloromethane at room temperature for 72
hours leading to the desired silica-supported organocatalyst 6a
through a carbamate link with 55% of catalyst incorporation,
determined by elemental analysis.
E-mail: finelli@nppn.ufrj.br
[
a]
b]
Pedro H. R. de Oliveira and Bruno M. da S. Santos, Instituto de
Pesquisas de Produtos Naturais, Universidade Federal do Rio de
Janeiro, 21941-902, Brasil.
[
Dr. Raqueal A. C. Leão, Prof. Leandro S. M. Miranda, Prof. Rosane
A. S. San Gil and Prof. Rodrigo O, M. A. de Souza, Instituto de
Química, Universidade Federal do Rio de Janeiro, 21941-902,
Brasil.
Supporting information for this article is given via a link at the end of
the document.
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ChemCatChem
10.1002/cctc.201901129
FULL PAPER
O
O
O
2
H N
O
2
OH
a
b
OH
.9 mol.L-1
1
Ph
OH
Ph
OMe
Ph
N
H
Ph
OH
2
5 µl.min-1
NH2
NH2.HCl
NH2
40 µl.min-1
1
2
3
1
0
NH
3 mL
0 ºC
3 mL
60 ºC
O
5
.94 mol.L-1
N
Ph
OMe
N
NH
90%
.HCl
10 µl.min-1
2
2
OH
O
SO Cl + MeOH
2
O
1.5 mol.L-1
25 µl.min-1
O
O
O
2
N
N
c
Me
Me
d
Me
Me
OH
Bn
Bn
Ph
N
H
N
H
N
H
4
5
NH
90%
3
2
0 µl.min-1
HN
Acetone
+
O
O
p-TSA
20 µl.min-1
O
N
e
Me
Me
Molecular
sieves 4A
catalyst loading
,55 mmol/g
"
Bn
N
H
O
70 ºC
2.4 mL
0
6
a
N
N
N
N
N
a. SOCl , MeOH, 0 ºC - rt, 24 h, 97%; b. Ethanolamine, rt, 12 h, 75%;
0.7 mol.L-1
2
OH
c. Acetone, p-TSA, i-PrOH, reflux, 12 h, 53%; d. CDI, Et N, CH Cl , 0ºC -
N
1 µl.min-1
O
3
2
2
1
O
3 mL
60 ºC
N
rt, 12 h, 90%; e. H2N
, Et N, CH Cl , rt, 72 h, 55%.
3
2
2
O
Me
Me
O
N
Bn
N
Et N +
Me
3
4
H
22 µl.min-1
Bn
N
H
Me 75%
90%
5
Scheme 1. Synthesis and immobilization of organocatalyst 6b in batch.
1
8 µl.min-1
HN
O
During the immobilization reaction we observed that gently and
constant magnetic stirring and long reaction time were essential
With the purpose of evaluating the differences between batch
and continuous-flow conditions, the same organocatalyst was
first synthesized and immobilized in a continuous-flow reactor
O
O
N
Me
Me
NH2
catalyst loading
0.60 mmol/g
Bn
N
H
6b
Et N + imidazole
3
(
Scheme 2).
Under optimized conditions, the esterification of amino acid 1
was carried out at 50 °C in a 3 mL coil (1 hour residence time)
with 90% yield, followed by the formation of ethanolamide 3 at
Scheme 2. Synthesis and immobilization of organocatalyst 6b under
continuous-flow.
6
0 °C, also in a 3 mL coil (1 hour residence time) with same
yield. The 4-imidazolidinone 4 was then obtained in 90% yield by
reacting amide 3 in the presence of acetone and p-TSA through
a 2.4 mL column containing 4 Å molecular sieves at 70 °C with a
residence time of 1 hour. After that, the catalyst 5 was activated
with CDI (3 mL coil) at 60 °C with a residence time of 1.5 hour in
In addition, to differences observed in supported catalyst
production time and the process efficiency in general, we could
also observe that organocatalysts 6a and 6b, respectively
immobilized in batch and under continuous-flow conditions, have
visually different aspects. While 6a is a fine powder, 6b has a
larger particle size.
7
5% yield and anchored in silica by pumping this intermediate
-
1
3
and Et N in acetonitrile in a pumping rate of 18 µL.min through
The morphological analysis of the commercial 3-aminopropyl-
functionalized silica, organocatalyst 6a and organocatalyst 6b
revealed that the immobilization under continuous-flow produces
a material with a similar morphology to the commercial silica,
while the material resulting from the batch process is very
different. The SEM images in Figure 1 show that catalyst 6a
presents a more irregular distribution of particles than catalyst
a
1.2 mL packed-bed reactor containing 3-aminopropyl-
functionalized silica at room temperature with a residence time
of 1.1 hours yielding the silica-supported organocatalyst 6b with
6
0% of catalyst incorporation, determined by elemental analysis.
The synthesis of organocatalyst 5 was accomplished in 60 hours,
steps and 34% overall yield in batch, while under continuous-
4
flow, the same steps have taken 4.5 hours and lead to an overall
yield of 54%. The immobilization process was also affected by
changing from batch to continuous-flow reactors, leading to a
6
b, indicating that silica mechanical degradation occurs in the
batch process due to magnetic stirring, altering the matrix
properties.
4
0% reduction on reaction time (132 hours versus 52.5 hours),
besides an improvement of 1.7 times on overall yield (18% in
batch versus 32% under continuous-flow).
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10.1002/cctc.201901129
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It can be seen that the immobilization occurred, through the
formation of the N-(C=O)-O carbamate linkage, whose was
1
3
confirmed by the presence of the signal at 156.8 ppm in the
C
spectra of batch-prepared 6a (Figure 2, entry B) and continuous-
flow prepared 6b (Figure 2, entry C). Also benzyl
2
imidazolidinone residue (C=O at 175 ppm, benzyl CH at 36.4
ppm and benzyl C and CH at 136 and 128 ppm resp.) could be
clearly seen in both spectra. The whole assignment is listed in
1
3
Table 1. It is worth point out that although in the C CPMAS
spectrum of organocatalyst 6a only one signal could be
observed for the two methyl carbons and amine methylene
carbon (at 24.4 ppm, Figure 2 entry B), in the spectrum of
organocatalyst 6b the signals due to benzyl methylene carbon
and to the methyl groups are clearly resolved (Figure 2, entry C),
confirming that the immobilization under continuous-flow
produced a higher ordered material compared with batch route.
Figure 1. SEM images of commercial silica (left), organocatalyst 6a (middle)
and organocatalyst 6b (right).
The degradation of support material may be responsible for
shortening the lifetime of immobilized organocatalysts. There is
a dichotomy in immobilization of the organocatalyst in batch:
while vigorous stirring provides effective incorporation of the
organocatalyst in matrix at shorter reaction times, degradation of
the solid support is observed under this condition. For this
reason, gently and constant magnetic stirring for 72 hours was
the optimal condition for 55% of catalyst incorporation. In
contrast, immobilization under continuous-flow conditions avoids
degradation and provides silica-supported organocatalysts with
homogeneous particle size at shorter times and 60% of catalyst
incorporation, which seems to be the maximum possible
incorporation in theses systems.
13
Table 1. C NMR data.
N
4
8
18
N
HN
O
19
2
9
2
1
7
O
O
13
13
O
O
1
11
Me
O
1
11
Me
N
N
1
2
12
15, 16
15, 16
Bn
Bn
N
H
10 Me
N
10 Me
5
6a H
type
Solution 13C NMR
(APT)
Solid state
13C CPMAS NMR
carbon
1
3
The organocatalyst 5 was characterized by solution C NMR,
but for immobilized organocatalysts solid state NMR
spectroscopy must be used to this task, and has been used
routinely for the characterization of hybrid silica containing
catalyst 5
catalyst 6a; 6b
1
2
3
4
N-C=O
174.91
148.44
174.5; 175.3
N-(C=O)-O
=C benzyl
N=CH-N
156.8
136.5
-
[
30-32]
13
organocatalysts.
polarization magic angle spinning (CPMAS) spectra of
commercial 3-aminopropyl-functionalized silica and
organocatalysts 6a and 6b.
Figure 2 shows solid state C cross-
1
36.39
130.73
129.58
128.54
128.29
126.94
117.10
76.00
5
,5'
,6'
=C benzyl
=C benzyl
128.3
128.3
6
7
8
9
=C benzyl
C=N
128.3
-
-
C=N
1
0
C(CH3)2
75.9; 76.0
2
9
Si CPMAS solid state NMR spectra of those samples are
shown in Figure 3. In the spectra of commercial silica and
organocatalysts 6a and 6b (Figure 3), signals corresponding to
2
3
2
3
T [C-SiO(OH)
2
], T [C-SiO
2
(OH)], Q [SiO
2
(OH)
2
], Q [SiO
3
(OH)]
4
and Q [SiO
4
] can be clearly seen. Although cross polarization is
not a quantitative pulse sequence, alterations in the Si moieties
2
3
4
2
3
can be followed by measuring the [(Q +Q )/Q ] and T /T ratios
Table 2).
(
1
3
Figure 2. C CPMAS solid state NMR spectra: (A) commercial silica; (B)
silica-supported organocatalyst 6a; (C) silica-supported organocatalyst 6b.
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ChemCatChem
10.1002/cctc.201901129
FULL PAPER
in higher yields, but with
a
significant decrease in
enantioselectivities (Table 3, entry 4).
The organocatalyst 6b was also employed to activate the Diels-
Alder reaction under the same conditions above and after 48
hours afforded a mixture of endo and exo cycloadducts in
slightly higher yields and enantioselectivities than organocatalyst
6
a (Table 3, entry 5). Unexpectedly, the reactions with
organocatalyst 6b lead to lower yields and better
enantioselectivities with longer reaction time and in the first
recycle of organocatalyst (Table 3, entries 6 and 7).
Table 3. Diels-Alder reaction in batch.
O
CH CN, rt
3
Ph
CHO
Ph
+
Ph
H
+
CHO
HCl (20 mol%)
7
8
endo-9a
exo-9b
2
9
time yield endo:exo ee (endo, exo)b
Pc
Figure 3. Si CPMAS solid state NMR spectra: (A) commercial silica; (B)
organocatalyst 6a; (C) organocatalyst 6b.
entry
catalyst
loading
1
2
3
4
5
6
6a
6a
6a
20 mol% 24 h 15%
20 mol% 48 h 52%
20 mol% 72 h 65%
54:46
54:46
54:46
52:48
53:47
54:46
53:47
80%, 86%
75%, 78%
78%, 82%
64%, 78%
78%, 80%
83%, 81%
82%, 83%
0.31
0.54
0.45
0.79
0.58
0.30
0.27
2
9
Table 2. Si CPMAS NMR data.
6a-recyclea 20 mol% 48 h 76%
Q2
Q3
Q4
T
2
3
entrya
[(Q +Q )
/
T2/T3
6b
6b
20 mol% 48 h 56%
20 mol% 72 h 43%
(C-Si)
[Si(OSi) (OH) ] [Si(OSi) (OH)] [Si(OSi)4]
2
2
3
4
Q ]
ppm
-58.3;-67.6 26.9 -94.7 4.6
58.5;-67.8 22.6 -92.5 2.4
-56.7;-66.4 20.4 -92.1 3.6
%
ppm
%
ppm
-102.1 29.2 -110.9 39.2 0.86
-100.6 34.8 0.92
-100.9 33.8 -109.8 42.1 0.89
%
ppm
%
1
2
3
0.34
0.25
0.49
7
6b-recyclea 20 mol% 48 h 26%
-
-110.5 40.2
aFirst reuse after 72 h. bDetermined by GC analysis using a chiral β-Dex 325 column
30 mm x 0.25 µm ID). cProductivity: mmol(product).h-1.mmol-1(catalyst).
(
Considering the best results in which the products 9a and 9b
were obtained in both good yields and enantioselectivities, the
productivities of organocatalysts 6a and 6b in batch were
a. (1) commercial silica, (2) organocatalyst 6a, (3) organocatalyst 6b.
2
3
4
As can be observed in Table 2 and Figure 3, while [(Q +Q )/Q ]
-
1
-1
similar: 0.45 and 0.58 mmol(product).h .mmol (catalyst),
respectively (Table 3, entries and 5). The process of
ratios are similar for commercial silica and organocatalysts 6a
2
3
3
and 6b, T /T ratios are quite different. Apparently, the
organocatalyst immobilization did not have a significant impact
in these Diels-Alder reactions.
functionalized surface of the silica has structural differences
between 6a and 6b, where C-SiO(OH)
2
is more present than C-
The responses of organocatalysts 6a and 6b in the activation of
Diels-Alder in batch were just a little different. Organocatalyst 6a
showed an improvement in its efficiency with increasing time,
while 6b decreased it. Although the organocatalyst 6a led to the
products 9a and 9b with higher yields, the organocatalyst 6b
presented better enantioselectivities.
SiO (OH) in organocatalysts immobilized under continuous-flow
2
conditions. These evidences suggest that the type of
immobilization in silica causes not only morphological but also
structural differences in organocatalysts.
Subsequently, the performances of organocatalysts 6a and 6b
were evaluated by running the enantioselective Diels-Alder
reactions between cyclopentadiene (7) and E-cinnamaldehyde
Following, the performances of organocatalysts 6a and 6b were
evaluated by running the enantioselective Diels-Alder reactions
between cyclopentadiene (7) and E-cinnamaldehyde (8) under
continuous-flow conditions.
(
8) both in batch and continuous-flow. Selected results for the
batch experiments are summarized in Table 3.
The first reaction was carried out in acetonitrile employing
We started the investigation of these flow reactions using a
looping system. In this process, the reaction was conducted in a
continuous-flow reactor using a 0.7 mL packed-bed containing
the silica-supported organocatalyst 6a, under a flow rate of 3.8
2
0 mol% of silica-supported organocatalyst 6a in the presence
of hydrochloric acid at room temperature and after 24 hours
afforded a mixture of endo and exo cycloadducts 9a and 9b in
high enantioselectivities but only 15% yield (Table 3, entry 1).
The increase in reaction time to 48 and 72 hours provided better
yields but slightly lower enantioselectivities (Table 3, entries 2
and 3). Afterwards, the catalyst 6a used in the reaction by 72
hours was recycled and the products were surprisingly obtained
-1
µL.min and residence time of 3 hours.
Before the solutions of the reagents were pumped, the silica-
supported organocatalyst was treated with 0.4 M HCl solution in
acetonitrile at room temperature for activation of the
organocatalyst. Then cyclopentadiene (7) and aldehyde 8 in
acetonitrile were pumped through the packed-bed reactor
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ChemCatChem
10.1002/cctc.201901129
FULL PAPER
containing the supported organocatalyst 6a and the collected
possibly influenced by chemical degradation of the support
material.
reaction mixture was recirculated through the loop system. After
4
8 hours, the cycloadducts 9a and 9b were obtained in 50%
In contrast, under the same conditions, the reaction employing
organocatalyst 6b was able to produce 9a and 9b in yields from
73% to 97% for 72 hours with enantioselectivities ranging from
80% to 90% for 26 hours and 48% to 80% for further 45 hours
(Table 4, entries 6 to 12).
yield and 77% ee and 78% ee, with productivity of 0.50
-
1
-1
mmol(product).h .mmol (catalyst). This result was very similar
to the results found in batch (Table 3, entries 2 and 5).
Faced to that, the reactions were conducted in a continuous-flow
reactor using a 1.2 mL packed-bed containing the silica-
The productivities of organocatalysts 6a and 6b were very
similar during the reactions under continuous-flow and the total
-
1
supported organocatalysts 6a and 6b, flow rate of 2.5 µL.min
and residence time of 8 hours, without recirculation of the
productivity
of
both
catalysts
was
1.01
-
1
-1
reaction mixture. Since the immobilized organocatalysts 6a and
mmol(product).h .mmol (catalyst).
6
b have different particle sizes, the 1.2 mL packed-bed reactor
Although 6a and 6b have similar productivities, the
organocatalyst 6b, immobilized under continuous-flow conditions,
has a lifetime 7 times greater than the organocatalyst 6a,
immobilized in batch. Analysing the results of table 2, it is clear
that the conditions of immobilization process have a large
influence in the time of deactivation of supported organocatalyst,
showing that immobilization under continuous-flow conditions is
the best choice for these silica-supported organocatalysts.
Besides, when we compare the results of enantioselective Diels-
Alder reactions carried out under continuous-flow and batch, we
observe higher enantioselectivities and productivities using the
flow process. The productivities of flow experiments were 2
times higher then the ones of the batch experiments. We also
observed that the flow reaction conditions leaded to simpler
reaction mixtures, containing essentially the products and the
starting materials, simplifying the purification steps.
was totally filled with 0.25 mmol of 6a (450 mg) and 0.35 mmol
of 6b (580 mg). The selected results are summarized in Table 4.
The silica-supported organocatalyst was also treated with 0.4 M
HCl solution in acetonitrile for activation of the organocatalyst
before the solutions of the reagents were pumped. After
optimizations, it was observed the necessity for a conditioning
time of 10 and 9 hours to achieve a steady-time regime of
chemical and enantioselective activities of both organocatalysts
6
a and 6b, respectively. The same was observed in batch
conditions, since the reaction had very low yield in 24 hours,
being necessary longer times to reach more efficiency.
Table 4. Diels-Alder reaction under continuous-flow.
O
catalyst 6
+
Ph
CHO
Ph
13
+
Ph
H
Figure 4 shows solid state C CPMAS spectra of recycled
CHO
CH3CN, rt, 2.5 µL.min-1
residence time = 8 h
7
8
endo-9a
exo-9b
catalyst 6a from the Diels-Alder batch reaction, recycled catalyst
6
a from the Diels-Alder continuous-flow reaction, recycled
entry
catalyst
t (h)
yield (%)
dr endo:exo
ee endo:exoa
Pb
catalyst 6b from the Diels-Alder batch reaction and recycled
catalyst 6b from the Diels-Alder continuous-flow reaction.
1
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
11
13
14
18
20
10
15
36
42
57
64
81
60
64
67
70
70
73
89
97
92
95
89
97
54:46
54:46
54:46
54:46
54:46
54:46
54:46
54:46
53:47
53:47
53:47
52:48
86%, 89%
85%, 89%
87%, 89%
86%, 89%
84%, 87%
90%, 87%
89%, 91%
86%, 79%
80%, 70%
78%, 69%
71%, 59%
62%, 48%
0.90
0.96
1.01
1.05
1.05
0.78
0.95
1.04
0.99
1.02
0.95
1.04
1
0
11
1
2
aDetermined by GC analysis using a chiral β-Dex 325 column (30 mm x 0.25 µm ID).
bProductivity: mmol(product).h-1.mmol-1(catalyst).
After this conditioning time, the reaction using organocatalyst 6a
was able to produce the products 9a and 9b in yields from 60%
to 70% with enantioselectivities from 84% to 89% for around 10
hours (Table 4, entries 1 to 5). However, after this time, a drastic
drop in yields and enantioselectivities was observed. Then the
column was treated again with 0.4 M HCl solution in acetonitrile,
but low yields and enantioselectivities continued to be observed,
indicating that there was an irreversible loss of catalyst activity,
1
3
Figure 4. C CPMAS solid state NMR spectra: (A) recycled 6a from the batch
reaction; (B) recycled 6a from the continuous-flow reaction; (C) recycled 6b
from the continuous-flow reaction; (D) recycled catalyst 6b from the batch
reaction.
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ChemCatChem
10.1002/cctc.201901129
FULL PAPER
These spectra are comparable worse resolved than the spectra Conclusions
shown in Figure 3, with the signals broadened. Although the
carbamate linkage can be clearly seen, the signal corresponding
to the carbonyl group of imidazolidinone portion (around 175
ppm) has disappeared, evidencing some sort of organocatalyst
degradation.
In conclusion, we observed improvements in overall yields and a
large decrease in time during the synthesis and immobilization
of organocatalyst under continuous-flow conditions when
compared to the batch process. It has also leaded to a longer
lifetime silica-supported organocatalyst, with morphological and
structural differences. Finally, the Diels-Alder reactions
conducted in continuous-flow reactors using the silica-supported
organocatalyst showed higher yields, higher enantioselectivities
and a simpler reaction mixture when compared to the batch
process.
2
9
The recycled organocatalysts were also analyzed by
Si
CPMAS solid state NMR (Figure 5). All recycled catalysts
spectra showed an increase of the signals corresponding to Si-
2
OH (-102 ppm) and Si(OH) (-92 ppm), when compared with
catalysts 6a and 6b spectra.
In the last decade, 4-imidazolidinones have been widely used in
enantioselective reactions activated by enamine or iminium
intermediates to promote various types of reactions such as
conjugate Friedel-Crafts, aldehyde and ketone Diels-Alder,
Mukaiyama-Michael reaction, conjugate hydride reduction,
[
33]
amination, oxygenation, sulphenylation, etc..
However, these
applications have not yet been explored in flow chemistry and
the expansion of this scope must be one of the challenges in this
field.
Considering these aspects, the application of continuous-flow in
processes of synthesis, immobilization and use of
organocatalysts overcome the reported limitations and has a
huge potential to increase exploration in this area.
Experimental Section
2
9
General Methods
Figure 5. Si CPMAS solid state NMR spectra: (A) recycled 6a from the batch
reaction; (B) recycled 6a from the continuous-flow reaction; (C) recycled 6b
from the continuous-flow reaction; (D) recycled catalyst 6b from the batch
reaction.
Dry solvents were purchased and stored properly. All reactions were
monitored by thin layer chromatography (TLC) using silica gel F254 pre-
coated aluminium backed plates (250 µm thickness) and visualized using
UV light or phosphomolibdic acid. Purifications were done by flash
1
13
chromatography with silica gel (230-400 mesh). H and C NMR data
were recorded at 25 ºC using Varian 400 MHz and 500 MHz
spectrometer. Chemical shifts values (δ) are reported in part per million
The areas of these peaks were measured and [(Q
2
+Q
] ratio showed
to increase from 0.89-0.92 (immobilized organocatalysts) to
.34-1.87 (recycled organocatalysts), thus evidencing that part
3 4
)/Q ] and
2
3
2 3 4
T /T ratios were calculated (Table 5). [(Q +Q )/Q
(
ppm). Peak multiplicity is summarized as br (broad), s (singlet), d
1
(doublet), t (triplet), m (multiplet). The endo/exo ratios was established on
the purified product using the CHO signals at 9.59 ppm (endo) (9a) and
of ordered Si-O structure was lost. Besides, a larger increase
from 0.49 (Table 2, entry 3 and Figure 3, entry C) to 1.15 (Table
1
3
29
9.91 ppm (exo) (9b). C and Si solid state NMR data were obtained
2
3
using a Bruker Avance III400 WB (9.4T) and a Bruker DRX300 NB
5
, entry 3 and Figure 5, entry C) in T /T ratio of the recycled
(
7.05T) superconducting magnets, operating at Larmor frequencies of
organocatalyst 6b after 80 hours of use in Diels-Alder reaction
under continuous-flow was observed. This means that after a
long period of exposure to Diels-Alder reaction, in addition to the
1
3
29
1
00.5 MHz (for C) and 59.3 MHz (for Si), using a Bruker CPMAS
rotors with Kel-F stoppers. Samples were
probeheads and 4mm ZrO
2
powered on a mortar and packed into a rotors and spinning at 10 KHz
1
3
degradation of the catalyst structure observed in C CPMAS,
13
and 5 KHz resp. C spectra were acquired using cross polarization with
1
there is also an increase of C-SiO(OH)
SiO
organocatalysts.
2
and a decrease of C-
H amplitude 50-100 ramped, a contact pulse of 2.5 ms duration and
2
9
2
(OH) contributing to deactivation of immobilized
recycle time of 3 s, whereas for Si spectra the contact time was 4 ms
1
and recycle time of 4 s. TPPM-15 H decoupling was employed for both
1
3
29
C and Si spectra. The spectra were referenced externally by using
3
13
2
9
adamantane (CH at 38.6 ppm) and caulinite (Q at -91.5 ppm) for
C
Table 5. Si CPMAS NMR data.
2
2
9
and Si chemical shifts. Enatiomeric excess determinations for 9a and
9b were performerd by Chiral GC analysis on a Shimadzu GC-2010
chromatograph equipped with a FID, an AOC-20i auto sampler and a
chiral β-Dex 325 (30 mm × 0.25 µm ID) column using hydrogen as carrier
gas in 46 mL/min. Injector temperature was set at 200 ºC and detector
temperature was set at 220 ºC. GC-FID temperature program: after 1 min
Q2
Q3
Q4
T
2
3
entrya
[(Q +Q )
/
T2/T3
(C-Si)
2 2 3
[Si(OSi) (OH) ] [Si(OSi) (OH)] [Si(OSi)4]
ppm
4
Q ]
ppm
%
%
ppm
%
ppm
%
1
2
3
4
-57.8;-67.0 14.7 -92.1 4.3
-58.1;-67.3 16.2 -91.2 3.3
-58.4;-67.1 15,7 -92.4 4.1
-58.4;-66.7 16.6 -92.3 5.8
-102.2 48.6 -110.9 31.9 1.65
-101.9 47.6 -110.9 31.8 1.34
-102.1 50.0 -110.9 29.4 1.83
-101.9 48.5 -111.6 28.9 1.87
0.40
0.36
1.15
0.34
-
1
at 115 ºC the temperature was increased in 15 ºC.min to 140 ºC, then
-
1
after 1 more min increased in 5 ºC.min to 150 ºC and kept for 1 min until
a. (1) recycled 6a from the batch reaction; (2) recycled 6a from the continuous-flow reaction; (3)
recycled 6b from the continuous-flow reaction; (4) recycled catalyst 6b from the batch reaction.
This article is protected by copyright. All rights reserved.

ChemCatChem
10.1002/cctc.201901129
FULL PAPER
-
1
increase again at 1 ºC.min to 160 ºC to be kept at that temperature for 5
min. All reactions under continuous flow were performed using an Asia
system, which consists of a syringe pump, liquid phase PTFE coil, a solid
phase glass column reactor (Omnifit column; 900 PSI) and a heater. All
equipment was purchased from Syrris. Scanning electron microscopy
136.73, 129.46, 128.58, 126.90, 76.58, 61.25, 58.78, 43.49, 36.98, 27.70,
-
1
!"
26.36. IR = 2852, 2283, 1670 cm . [ꢀ]
!
= -76.6º (c = 1.0, MeOH).
Preparation of (S)-2-(4-benzyl-2,2-dimethyl-5-oxoimidazolidin-1-
yl)ethyl 1H-imidazole-1-carboxylate (5):
(
SEM) was obtained by a Phenom Prox Desktop operating at 10 kV.
Fourier-transform infrared spectroscopy (FTIR) analysis were acquired
on a Shimadzu FTIR Spectrometer (IRPrestigie-21).
2 2
A stirred portion of imidazolidinone 4 (0.43 g, 1.5 mmol) in CH Cl (3 mL)
was dissolved after dropwise addition of triethylamine (0.21 mL, 1.5
mmol). The resulting mixture was then slowly added to a 25 mL round
bottomed flask containing a solution of 1,1’-carbonyldiimidazole (0.40 mg
Synthesis and immobilization of organocatalyst in batch
2
.46 mmol) in CH
reaction was stirred for 24 h at room temperature and then concentrated
in vacuum. Saturated NaHCO was added to the crude mixture and
extracted with AcOEt (3x 20 mL). The combined organic phase was dried
over anhydrous MgSO , filtered and evaporated in vacuum giving a light
brown oil (0.46 g, 90%). HRMS-ESI (m/z): found for C18
2 2
Cl (3 mL) and triethylamine (0.21 mL, 1.5 mmol). The
Preparation
of
(S)-methyl
2-amino-3-phenylpropanoate
hydrochloride (2):
3
A suspension of L-Phenylalanine (1) (10 g, 61 mmol) in methanol (70
mL) was cooled in an ice/water bath. Thionyl chloride (5.30 mL, 73 mmol)
was added dropwise creating a clear solution that was kept stirring at
room temperature for 24 h. Volatiles were removed in vacuo giving our L-
4
+
H
22
N
4
O
3
[M+H]
) δ = 8.07 (s,
H, Ar-H), 7.38 (t, J = 1.4 Hz, 1H, Ar-H), 7.15 – 7.25 (m, 5H, Ar-H), 7.07
CH ), 3.78 – 3.83 (m,
H, CH), 3.71 (dt, J = 14.6, 5.5 Hz, 1H, HCH), 3.30 (ddd, J = 14.6, 7.0,
.5 Hz, 1H, HCH), 3.08 (qd, J = 14.2, 5.4 Hz, 2H, NCH CH ), 1.28 (s, 3H,
) δ = 174.91, 148.44,
:
+
1
3
1
43.1765 , [M+Na] : 365.1584. H NMR (500 MHz, CDCl
3
phenylalanine methyl ester hydrochloride (2) as a white solid. (12.8 g,
(
dd, J = 1.6, 0.8 Hz, 1H), 4.43 – 4.55 (m, 2H, NCH
2
2
1
9
6
8%). H NMR (400 MHz, CD
3
OD): δ = 7.23 – 7.39 (m, 1H), 4.32 (t, J =
), 3.76 (s, 3H, OCH ), 3.24 (d, J = 6.7 Hz, 2H PhCH ).
C NMR (100 MHz, CDCl ) δ = 168.97, 133.98, 129.13, 128.73, 127.50,
3.88, 52.28, 35.91. IR = 2852, 2615, 1707 cm . [ꢀ]
1
5
.5 Hz, 1H, CHNH
3
3
2
1
3
2
2
3
13
3 3 3
CH ), 1.14 (s, 3H, CH ). C NMR (101 MHz, CDCl
-
1
!"
5
!
= +36.4º (c = 2.0,
1
5
3
36.39, 130.73, 129.58, 128.54, 128.29, 126.91, 117.10, 76.00, 65.24,
EtOH).
-1
!"
8.64, 38.96, 36.68, 27.90, 26.41. IR = 2974, 1759, 1693 cm . [ꢀ]
!
= -
4.6º (c = 1.0, MeOH).
Preparation of (S)-2-amino-N-(2-hydroxyethyl)-3-phenylpropanamide
(
3):
Preparation of silica-supported organocatalyst 6a:
(
S)-methyl 2-amino-3-phenylpropanoate hydrochloride (2) (10 g, 0,056
The aminopropyl functionalized silica (1.12 g 1.12 mmol) was added to a
mmol) was dissolved in ethanolamine (23 mL, 371 mmol) with vigorous
magnetic stirring, forming a deep yellow solution that was stirred at room
temperature overnight. The reaction was then diluted in 100 mL of
solution of (S)-2-(4-benzyl-2,2-dimethyl-5-oxoimidazolidin-1-yl)ethyl-1H-
2 2
imidazole-1-carboxylate (5) (460 mg 1.35 mmol) in CH Cl . Thereafter
triethylamine (0.21 ml 1.5 mmol) was added and the reaction mixture
kept stirring at 150 rpm for 72 h at room temperature to furnish the
catalyst 6a as a white solid. The product is obtained by filtration of the
CH
2
Cl
2
and washed with a 20% solution of K
2 3
CO . The aqueous phase
was extracted three times with CH
2
2
Cl and the combined organic layers
were dried over MgSO4, and evaporated under vacuum, affording the
crude mixture, washed with CH
vacuum. (Catalyst loading 0.564 mmol/g, by CHN analysis) C NMR
101 MHz) δ = 174.5, 156.8, 136.5, 128.3, 128.3, 128.3, 75.9, 58.9, 58.9,
2 2
Cl (2x 10 mL) and dried under high
pure amide 4 as a pale yellow solid (10.2 g, 85%). HRMS-ESI (m/z):
1
3
+
+
1
found for C11
H
16
N
2
O
2
[M+H] : 209.1284 , [M+Na] : 231.1103. H NMR
) δ = 7.62 (s, 1H), 7.18 – 7.34 (m, -, Ar-H), 3.67 (t, J =
OH), 3.61 (dd, J = 9.1, 4.3 Hz, 1H, CHNH ), 3.40 (dd, J =
0.5, 5.5 Hz, 2H, NHCH ), 3.23 (dd, J = 13.7, 4.2 Hz, 1H, PhCH ), 2.73
) δ = 175.42,
37.71, 129.27, 128.69, 126.85, 77.35, 77.09, 76.84, 61.75, 56.52, 42.11,
(
(
500 MHz, CDCl
3
4
1
2.2, 42.2, 42.2, 24.4, 24.4, 24.4, 9.1. CHN analysis: C: 10.37%, H:
5
1
.0 Hz, 2H, CH
2
2
.52%, N: 2.37%.
2
2
1
3
(
2 3
dd, J = 13.7, 9.1 Hz, 1H, PhCH ). C NMR (125 MHz, CDCl
Synthesis and immobilization of organocatalyst under continuous-
flow
1
4
-
1
!"
1.13. IR = 3352, 2939, 1640 cm . [ꢀ]
!
= +15.4º (c = 1.0, MeOH).
Preparation
of
(S)-methyl
2-amino-3-phenylpropanoate
(
S)-5-benzyl-3-(2-hydroxyethyl)-2,2-dimethylimidazolidin-4-one
hydrochloride (2):
hydrochloride (4):
-
1
In different tubes, a solution of L-phenylalanine (1) (0.94 mol.L ) and
(
S)-2-amino-N-(2-hydroxyethyl)-3-phenylpropanamide (3) (3.4 g, 16.4
mmol) was dissolved under magnetic stirring in a mixture of propanone
16 mL, 215 mmol) and isopropanol (22 mL) containing p-TSA (0.085 g,
.49 mmol). The reaction was refluxed overnight under argon
-
1
thionyl chloride (1.5 mol.L ) were prepared in methanol. Both solutions
were pumped employing a Syrris Asia system at 25 µL/min, mixed by a T
mixer and reacted into PTFE reactor coil (3 mL) heated around 50 ºC
(
0
during 1 h. The solution obtained was concentrated in vacuo giving our
atmosphere with a Dean-Stark trap, and then evaporated in vacuo to
form a deep yellow oil. This oil was dissolved in MeOH (10 mL) and the
mixture was cooled in an ice-bath for the dropwise addition of acetyl
chloride (3 mL, 42 mmol). Under vigorous stirring, cold ethyl ether was
added until turbidity of reaction media. The stirring was continued for 1 h
at room temperature and the product 4 obtained as a white solid after
1
product 2 as a white solid. (0.24 g, 80%). H NMR (400 MHz, CD
3
OD) δ =
), 3.76 (s, 3H, OCH ),
). C NMR (100 MHz, CDCl ) δ = 168.97,
33.98, 129.13, 128.73, 127.50, 53.88, 52.28, 35.91. IR = 2852, 2615,
7
3
1
1
.23 – 7.39 (m, 1H), 4.32 (t, J = 6.5 Hz, 1H, CHNH
3
3
1
3
.24 (d, J = 6.7 Hz, 2H PhCH
2
3
-
1
!"
707 cm . [ꢀ]
!
= +36.4º (c = 2.0, EtOH)
2
vacuum filtered and washed with Et O. (2.8 g, 85%). HRMS-ESI (m/z):
+
+
1
found for C14
500 MHz, CD
Hz, 1H, CH), 3.74 (m, 2H, NCH
H
20
N
2
O
2
[M+H] : 249.1597 , [M+Na] : 271.1416. H NMR
OD) δ = 7.29 – 7.47 (m, 5H, Ar-H), 4.66 (dd, J = 10.5, 2.7
CH ), 3.48 – 3.59 (m, 2H, NCH CH ),
.43 (dd, J = 13.2, 7.0 Hz, 1H, HCH), 3.02 – 3.14 (m, 1H, HCH), 1.78 (s,
Preparation of (S)-2-amino-N-(2-hydroxyethyl)-3-phenylpropanamide
(
3
(3):
2
2
2
2
3
3
In different tubes, a solution of (S)-methyl 2-amino-3-phenylpropanoate
1
3
-
1
3 3 3 3
H, CH ), 1.63 (s, 3H, CH ). C NMR (101 MHz, CD Cl ) δ = 175.46,
(
2) (0.33 mol.L ) in isopropyl alcohol and a solution of ethanolamine (1.9
-
1
mol.L ) was prepared in the same solvent. Both solution were pumped at
This article is protected by copyright. All rights reserved.

ChemCatChem
10.1002/cctc.201901129
FULL PAPER
1
0 µl/min and 40 µl/min, respectively, mixed in a T-mixer and reacted
Preparation of silica-supported organocatalyst 6b:
into a 3 mL PTFE reactor coil heated around 60 ºC during 1 h. The
solution obtained was concentrated in vacuo, followed by dilution with 20
A
1.2 mL stainless steel column was filled with 590 mg of the
mL of CH
phase was extracted three times with CH
layers were dried over MgSO and evaporated under vacuum, affording
the pure amide 3 as a pale yellow solid (0.12 g, 92%). HRMS-ESI (m/z):
2
Cl
2
and extraction with a 20% solution of K
2 3
CO .The aqueous
commercially available 3-aminopropyl-functionalized silica gel particles
2
Cl and the combined organic
-1
2
(
loading 1mmol/g NH
2 3
), and packed with CH CN for 30 min (200 µl.min ).
4
Thereafter, a 3.8 mL solution of (S)-5-benzyl-3-(2-hydroxyethyl)-2,2-
-
1
-1
dimethylimidazolidin-4-one hydrochloride
5
(2.27x10 mol.L ) with
CN was pumped through the reactor at
8 µl.min . The reaction was performed in a looping fashion during 48 h
at room temperature. At the end of the process, the column was washed
with CH CN for more 30 min and then opened to yield the supported
organocatalyst 6b as a white solid. The organocatalyst was filtered,
washed with CH Cl (2x10 mL) and dried under high vacuum. (Catalyst
loading 0.597 mmol/g, by CHN analysis) C NMR (101 MHz) δ = 175.3,
56.8, 136.5, 128.3, 128.3, 128.3, 76.0, 58.3, 58.3, 42.1, 42.1, 36.4, 25.5,
+
+
1
found for C11
H
16
N
2
O
2
[M+H] : 209.1284 , [M+Na] : 231.1103. H NMR
-1
triethylamine (0.24 mol.L ) in CH
3
-
1
(
500 MHz, CDCl ) δ = 7.62 (s, 1H), 7.18 – 7.34 (m, 5H, Ar-H), 3,67 (t, J =
3
1
5
1
.0 Hz, 2H, CH
2
OH), 3.61 (dd, J = 9.1, 4.3 Hz, 1H, CHNH
2
), 3.40 (dd, J =
), 2.73
) δ = 175.42,
0.5, 5.5 Hz, 2H, NHCH
2
), 3.23 (dd, J = 13.7, 4.2 Hz, 1H, PhCH
2
3
1
3
(
dd, J = 13.7, 9.1 Hz, 1H, PhCH
2
)
C NMR (125 MHz, CDCl
3
1
4
37.71, 129.27, 128.69, 126.85, 77.35, 77.09, 76.84, 61.75, 56.52, 42.11,
2
2
-
1
!"
1.13. = 3352, 2939, 1640 cm [ꢀ]
!
= +15.4º (c = 1.0, MeOH).
13
1
(
S)-5-benzyl-3-(2-hydroxyethyl)-2,2
dimethylimidazolidin-4-one
23.1, 20.7, 9.1. CHN analysis: C: 11.05%, H: 1.62%, N: 2.51%.
hydrochloride (4):
Enantioselective Diels-Alder reactions in batch
A solution of (S)-2-amino-N-(2-hydroxyethyl)-3-phenylpropanamide (3) in
-
1
isopropranol (0.5 mol.L ) and in a different tube, a solution of p-TSA
(
(
1S,2S,3S,4R)-3-Phenylbicyclo
[2.2.1]hex-5-ene-2-carboxaldehyde
-
3
-1
were prepared in acetone (1.9x10 mol.L ). Both solutions were pumped
9a) and (1R,2S,3S,4S)-3-Phenylbicyclo[2.2.1]hex-5-ene-2-
-
1
at 20 µl.min , mixed in a T-mixed and reacted into an Omnifit glass
column (2,4 mL) filled with dry molecular sieves at 80 ºC during 1h. The
system is also adapted with a backpressure device on its end. The
mixture obtained was concentrated under vacuum to give a light brown
oil. The oil was diluted with MeOH (1.5 mL) and kept at 0 ºC for the
addition of acetyl chloride (0.28 mL). The warm solution was diluted with
carboxaldehyde (9b).
The supported catalyst 6a (330 mg, loading 0.564 mmol/g) or 6b (330 mg,
loading 0.597 mmol/g) hydrochloric acid (0,4
cinnamaldehyde (8) (110 ml 0.9 mmol) in 3 mL of CH
and stirred for 5 min before the addition of cyclopentadiene (7) (740 ml
.8 mmol). After stirring the reaction at room temperature for 48 h or 72 h,
M
0.4 mL) and (E)-
3
CN were mixed
Et
crystals. After being stirred for 1h, the suspension was filtered by vacuum,
washed with Et O and dried at room temperature to give 4 as a white
powder (0.33 g, 77 %). HRMS-ESI (m/z): found for C14
2
O (15 mL) slowly under vigorous stirring, to give a suspension of white
8
the supported catalyst was isolated by filtration. The filtrate is evaporated
under high vacuum followed by purification through flash chromatography
2
+
H
20
N
2
O
2
[M+H]
OD) δ = 7.29 –
.47 (m, 5H, Ar-H), 4.66 (dd, J = 10.5, 2.7 Hz, 1H, CH), 3.74 (m, 2H,
CH ), 3.48 – 3.59 (m, 2H, NCH CH ), 3.43 (dd, J = 13.2, 7.0 Hz, 1H,
HCH), 3.02 – 3.14 (m, 1H, HCH), 1.78 (s, 3H, CH ), 1.63 (s, 3H, CH ).
) δ = 175.46, 136.73, 129.46, 128.58, 126.90,
6.58, 61.25, 58.78, 43.49, 36.98, 27.70, 26.36. IR = 2852, 2283, 1670
:
(
10 % AcOEt/Hexane) to afford the title compound as a light yellow oil.
+
1
2
7
49.1597 , [M+Na] : 271.1416. H NMR (500 MHz, CD
3
Retention time: t
endo-minor) = 16.5 min, t
NMR (400 MHz, CDCl
H, Ar-H), 6.41 (dd, J = 5.4, 3.3 Hz, 1H, HC=CH), 6.17 (dd, J = 5.6, 2.7
R
(exo-minor) = 15.8 min, t
R
(exo-major) = 16.1 min, t
R
1
(
R
(endo-major) = 16.9 min. Data for endo:
H
NCH
2
2
2
2
3
) δ 9.59 (d, J = 2.1 Hz, 1H, CHO), 7.33 – 7.12 (m,
3
3
5
1
3
3 3
C NMR (101 MHz, CD Cl
Hz, 1H, HC=CH), 3.32 (brs, 1H, CHCH=CHCH), 3.12 (brs, 1H,
7
CHCH=CHCH), 3.08 (d, J = 4.7 Hz, 1H, CHPh), 2.98 (dd, J = 4.4, 2.6 Hz,
-
1
!"
cm [ꢀ]
!
= -76.6º (c = 1.0, MeOH).
1
1
1
H, CHCHO), 1.80 (d, J = 8.7 Hz, 1H, CHH), 1.55 (dd, J = 8.8, 1.5 Hz,
1
H, CHH). Data for exo: H NMR (400 MHz, CDCl
3
) δ 9.91 (d, J = 2.1 Hz,
Preparation of (S)-2-(4-benzyl-2,2-dimethyl-5-oxoimidazolidin-1-
H, CHO), 7.33 – 7.12 (m, 5H, Ar-H), 6.33 (dd, J = 5.2, 3.3 Hz, 1H,
yl)ethyl 1H-imidazole-1 carboxylate (5)
HC=CH), 6.07(dd, J = 5.2, 2.6 Hz, 1H, HC=CH), 3.72 (t, J = 3.9 Hz 1H,
CHCH=CHCH), 3.22 (m, 2H, CHCH=CHCH, CHPh), 2,59 (dd, J = 3.5,
1.8 Hz, 1H, CHCHO), 1.63 – 1.60 (dd, 2H, J = 7.0, 5.4 Hz, 1H, CHH).
A solution of (S)-5-benzyl-3-(2-hydroxyethyl)-2,2-dimethylimidazolidin-4-
-
1
-1
one hydrochloride (4) (0.25 mol.L ) with thiethylamine (0.25 mol.L )
were dissolved in CH Cl and another solution of 1,1’-carbonyldiimidazole
0.70 mol.L ) were prepared in the same solvent. Each solution were
3
Enantioselective Diels-Alder reactions under continuous-flow
-
1
(
-
1
-1
pumped at 11 µl.min and 22 µl.min , respectively, into a PTFE coil (3
Looping Reaction for (1S,2S,3S,4R)-3-Phenylbicyclo [2.2.1]hex-5-
mL) adapted with a backpressure device and heated around 60 °C during
ene-2-carboxaldehyde
(9a)
and
(1R,2S,3S,4S)-3-
1
.5 h. The mixture obtained was concentrated in vacuum, diluted with
NaHCO and extracted with AcOEt (3x20 mL). The combined organic
phase was dried over anhydrous MgSO , filtered and evaporated in
vacuum to yield the pure product 5 as a light brown oil. (0.96 g, 75%).
Phenylbicyclo[2.2.1]hex-5-ene-2-carboxaldehyde (9b).
3
4
A 0,7 mL stainless steel column was filled with 200 mg of the supported
+
+
catalyst 6a (loading 0.564 mmol/g) packed with CH
treated with HCl (0,4 M in 5 mL of CH CN). The Diels-Alder reaction was
then carried out at room temperature for 48 h by pumping a CH CN
solution of (E)-Cinnamaldehyde (8) (0.24 mol.L ) and Cyclopentadiene
3
CN and then flow
HRMS-ESI (m/z): found for C18
H
22
N
4
O
3
[M+H] : 343.1765 , [M+Na]
) δ = 8.07 (s, 1H, Ar-H), 7.38 (t, J =
.4 Hz, 1H, Ar-H), 7.15 – 7.25 (m, 5H, Ar-H), 7.07 (dd, J = 1.6, 0.8 Hz,
H), 4.43 – 4.55 (m, 2H, NCH CH ), 3.78 – 3.83 (m, 1H, CH), 3.71 (dt, J
14.6, 5.5 Hz, 1H, HCH), 3.30 (ddd, J = 14.6, 7.0, 5.5 Hz, 1H, HCH),
.08 (qd, J = 14.2, 5.4 Hz, 2H, NCH CH ), 1.28 (s, 3H, CH ), 1.14 (s, 3H,
) δ = 174.91, 148.44, 136.39, 130.73,
:
1
3
3
65.1584. H NMR (500 MHz, CDCl
3
3
1
-
1
1
2
2
-
1
-1
(
7) (3.52 mol.L ) at 3.8 µl.min directly to the vial containing the starting
=
materials
.
3
2
2
3
1
3
CH
3
)
C NMR (101 MHz, CDCl
3
1
3
29.58, 128.54, 128.29, 126.91, 117.10, 76.00, 65.24, 58.64, 38.96,
-
1
1
!"
6.68, 27.90, 26.41. IR = 2974, 1759, 1693 cm . [ꢀ]
!
= -34.6º (c = 1.0,
MeOH).
This article is protected by copyright. All rights reserved.

ChemCatChem
10.1002/cctc.201901129
FULL PAPER
(
(
1S,2S,3S,4R)-3-Phenylbicyclo
[2.2.1]hex-5-ene-2-carboxaldehyde
[10] E. Alza, S. Sayalero, P. Kasaplar, D. Almaşi, M. A. Pericàs, Chem. -
Eur. J. 2011, 17, 11585-11595.
9a) and (1R,2S,3S,4S)-3-Phenylbicyclo[2.2.1]hex-5-ene-2-
carboxaldehyde (9b).
[11] S. Guizzetti, M. Benaglia, J. S. Siegel, Chem. Commun. (Cambridge, U.
K.) 2012, 48, 3188-3190.
[
12] L. Osorio-Planes, C. Rodriguez-Escrich, M. A. Pericas, Org. Lett. 2012,
4, 1816-1819.
A 1,2 mL stainless steel column was filled with 450 mg of organocatalyst
1
6
a (loading 0.564 mmol/g) or 580 mg of organocatalyst 6b (loading 0.597
mmol/g), packed with CH CN and then flow treated with HCl (0,4 M in 5
mL of CH CN). The Diels-Alder reaction was carried out at room
temperature by pumping a CH CN solution of (E)-cinnamaldehyde (8)
[
[
13] A. M. Goldys, M. G. Núñez, D. J. Dixon, Org. Lett. 2014, 16, 6294-6297.
14] A. M. P. Salvo, F. Giacalone, R. Noto, M. Gruttadauria,
ChemPlusChem 2014, 79, 857-862.
3
3
3
-
1
-1
-1
[
[
[
[
15] J. Xu, J. Pang, D. Feng, X. Ma, Mol. Cat. 2017, 443, 139-147.
16] G. Szőllősi, V. Kozma, ChemCatChem 2018, 10, 4362-4368.
17] L. Malet-Sanz, F. Susanne, J. Med. Chem. 2012, 55, 4062-4098.
18] R. Porta, F. Coccia, R. Annunziata, A. Puglisi, ChemCatChem 2015, 7,
1490-1499.
(
0.24 mol.L ) and cyclopentadiene (7) (3.52 mol.L ) at 2.5 µl.min . After
4h of operation, the flow was stopped, and our vial recharged with
freshly distilled cyclopentadiene (7) and cinnamaldehyde (8). Retention
2
time: t
minor) = 16.5 min, t
400 MHz, CDCl
Ar-H), 6.41 (dd, J = 5.4, 3.3 Hz, 1H, HC=CH), 6.17 (dd, J = 5.6, 2.7 Hz,
H, HC=CH), 3.32 (brs, 1H, CHCH=CHCH), 3.12 (brs, 1H,
CHCH=CHCH), 3.08 (d, J = 4.7 Hz, 1H, CHPh), 2.98 (dd, J = 4.4, 2.6 Hz,
R
(exo-minor) = 15.8 min, t
R
(exo-major) = 16.1 min, t
R
1
(endo-
R
(endo-major) = 16.9 min. Data for endo: H NMR
[
[
[
19] R. Porta, M. Benaglia, A. Puglisi, Org. Process Res. Dev. 2016, 20, 2-
(
3
) δ = 9.59 (d, J = 2.1 Hz, 1H, CHO), 7.33 – 7.12 (m, 5H,
2
5.
20] D. Ragno, G. Di Carmine, A. Brandolese, O. Bortolini, P. P. Giovannini,
A. Massi, ACS Catalysis 2017, 7, 6365-6375.
1
21] J. Lai, S. Sayalero, A. Ferrali, L. Osorio-Planes, F. Bravo, C.
Rodriguez-Escrich, M. A. Pericas, Adv. Synth. Catal. 2018, 360, 2914-
1
1
H, CHCHO), 1.80 (d, J = 8.7 Hz, 1H, CHH), 1.55 (dd, J = 8.8, 1.5 Hz,
1
3
H, CHH). Data for exo: H NMR (400 MHz, CDCl ) δ = 9.91 (d, J = 2.1
2
924.
Hz, 1H, CHO), 7.33 – 7.12 (m, 5H, Ar-H), 6.33 (dd, J = 5.2, 3.3 Hz, 1H,
HC=CH), 6.07(dd, J = 5.2, 2.6 Hz, 1H, HC=CH), 3.72 (t, J = 3.9 Hz 1H,
CHCH=CHCH), 3.22 (m, 2H, CHCH=CHCH, CHPh), 2.59 (dd, J = 3.5,
[
[
22] I. Atodiresei, C. Vila, M. Rueping, ACS Catalysis 2015, 5, 1972-1985.
23] F. G. Finelli, L. S. M. Miranda, R. O. M. A. de Souza, Chem. Commun.
(
Cambridge, U. K.) 2015, 51, 3708-3722.
24] C. Rodríguez-Escrich, M. A. Pericàs, Eur. J. Org. Chem. 2015, 2015,
173-1188.
1
.8 Hz, 1H, CHCHO), 1.63 – 1.60 (dd, 2H, J = 7.0, 5.4 Hz, 1H, CHH).
[
1
[
[
25] E. Alza, M. A. Pericàs, Adv. Synth. Catal. 2009, 351, 3051-3056.
26] V. Chiroli, M. Benaglia, F. Cozzi, A. Puglisi, R. Annunziata, G.
Celentano, Org. Lett. 2013, 15, 3590-3593.
Acknowledgements
The authors thank CAPES and CNPq for financial support.
[27] A. Puglisi, M. Benaglia, R. Annunziata, V. Chiroli, R. Porta, A. Gervasini,
J. Org. Chem. 2013, 78, 11326-11334.
[
[
[
28] R. Porta, M. Benaglia, V. Chiroli, F. Coccia, A. Puglisi, Isr. J. Chem.
014, 54, 381-394.
Keywords: heterogeneous catalysis • enantioselective
organocatalysis • continuous-flow • supported organocatalyst •
MacMillan’s organocatalysts
2
29] T. E. Kristensen, K. Vestli, M. G. Jakobsen, F. K. Hansen, T. Hansen, J.
Org. Chem. 2010, 75, 1620-1629.
30] S. D. T. Barros, A. V. Coelho, E. R. Lachter, R. A. S. San Gil, K.
Dahmouche, M. I. P. Silva, A. L. F. Souza, Renewable Energy 2013, 50,
[
[
[
1]
2]
3]
P. I. Dalko, L. Moisan, Angew. Chem., Int. Ed. 2004, 43, 5138-5175.
J. Alemán, S. Cabrera, Chem. Soc. Rev. 2013, 42, 774-793.
B. S. Donslund, T. K. Johansen, P. H. Poulsen, K. S. Halskov, K. A.
Jorgensen, Angew. Chem., Int. Ed. 2015, 54, 13860-13874.
Y. Qin, L. Zhu, S. Luo, Chemical Reviews 2017, 117, 9433-9520.
D. W. C. MacMillan, Nature 2008, 455, 304-308.
5
85-589.
[
31] E. C. C. Gomes, A. F. de Sousa, P. H. M. Vasconcelos, D. Q. Melo, I. C.
N. Diógenes, E. H. S. de Sousa, R. F. do Nascimento, R. A. S. San Gil,
E. Longhinotti, Chem. Eng. J. 2013, 214, 27-33.
[
[
[
[
[
[
4]
5]
6]
7]
8]
9]
[
[
32] A. L. De Lima, A. Mbengue, R. A. S. San Gil, C. M. Ronconi, C. J. A.
Mota, Catal. Today 2014, 226, 210-226.
C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167-178.
V. Marcos, J. Aleman, Chem. Soc. Rev. 2016, 45, 6812-6832.
M. Silvi, P. Melchiorre, Nature 2018, 554, 41-49.
33] Y. Qin, L. Zhu, S. Luo, Chem. Rev. 2017, 117, 9433-9520.
S. Y. Park, J.-W. Lee, C. E. Song, Nat. Comm. 2015, 6, 7512-7512.
This article is protected by copyright. All rights reserved.

ChemCatChem
10.1002/cctc.201901129
FULL PAPER
FULL PAPER
Pedro H. R. de Oliveira, Bruno M. da S.
Santos, Raquel A. C. Leão, Leandro S.
M. Miranda, Rosane A. S. San Gil,
Rodrigo O. M. A. de Souza, Fernanda
G. Finelli*
continuous-flow
HN
O
O
O
N
Me
Me
batch
Bn
N
H
Page No. – Page No.
A major issue of silica-supported organocatalysts is the degradation of the solid
material and the erosion of the matrix properties during its immobilization and
usage in batch. In this work, we report for the first time, the advantages of a
complete continuous-flow approach towards the synthesis, immobilization and use
of MacMillan’s silica-supported organocatalyst.
From Immobilization to Catalyst Use:
a Complete Continuous-Flow
Approach Towards the Use of
Immobilized Organocatalysts
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