Expanding the Toolbox of Heterogeneous Asymmetric Organocatalysts: Bifunctional Cyclopropenimine Superbases for Enantioselective Catalysis in Batch and Continuous Flow

Article abstract of DOI:10.1002/adsc.202100757

A strategy for the immobilization of chiral 2,3-bisaminocyclopropenium salt (pre-catalyst) onto polystyrene and silica supports is presented together with a suitable procedure for the conversion into the corresponding cyclopropenimine superbase catalysts.

Full text of DOI:10.1002/adsc.202100757

Title: Expanding the Toolbox of Heterogeneous Asymmetric
Organocatalysts: Bifunctional Cyclopropenimine Superbases for
Enantioselective Catalysis in Batch and Continuous-Flow
Authors: Costanza Leonardi, Arianna Brandolese, Lorenzo Preti, Olga
Bortolini, Eleonora Polo, Paolo Dambruoso, Daniele Ragno,
Graziano Di Carmine, and Alessandro Massi
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202100757
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10.1002/adsc.202100757
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Expanding the Toolbox of Heterogeneous Asymmetric
Organocatalysts: Bifunctional Cyclopropenimine Superbases
for Enantioselective Catalysis in Batch and Continuous Flow
Costanza Leonardi,a Arianna Brandolese,a Lorenzo Preti,a Olga Bortolini,a Eleonora
Polo,b Paolo Dambruoso,b Daniele Ragno,a Graziano Di Carmine,a,* and Alessandro
Massia,*
In memory of Professor Giancarlo Fantin
a
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via L. Borsari, 46, 44121
Ferrara (Italy); graziano.dicarmine@unife.it; alessandro.massi@unife.it.
Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via P. Gobetti, 101, 40129
b
Bologna, Italy.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A strategy for the immobilization of chiral 2,3- The preferred silica-supported cyclopropenimine behaved
bisaminocyclopropenium salt (pre-catalyst) onto polystyrene very similarly to the soluble counterpart in the reaction of
and silica supports is presented together with a suitable glycine imine with different Michael acceptors (48-92%
procedure for the conversion into the corresponding yield; 60-98% ee) and it could be utilized as packing
cyclopropenimine superbase catalysts. The activity and material for the fabrication of fixed-bed mesoreactors
recyclability of polystyrene- and silica-supported (pressure-resistant stainless-steel columns). Continuous-
cyclopropenimines were initially tested under batch flow experiments were performed with satisfactory long-
conditions in a model Michael addition detecting comparable term stability (24 h on stream) with unaltered conversion
efficiencies but
a
superior stability of the latter efficiency and enantioselectivity.
heterogeneous catalyst (5 cycles, accumulated TON of 27.1).
Keywords: asymmetric catalysis; Brønsted base; c-c
coupling; flow chemistry; heterogeneous catalysis;
immobilization; Michael addition; organocatalysis; packed-
bed reactor.
bases with advantageous properties such as better
solubility in organic media, good moisture resistance,
decreased nucleophilicity, countercation coordination
ability by the protonated conjugated acid and,
importantly, the possibility to induce stereoselectivity.
In recent years, chiral versions of organic superbases
have been emerging as effective Brønsted base
Introduction
According to Caubère definition,[1] organic
superbases are neutral compounds with basicity
greater than Proton-sponge® (pKBH+ 18.8 in MeCN),
which are characterized by the structural combination
of two different types of basic functionalities. To date, catalysts in enantioselective reactions by HOMO
the list of compounds belonging to this class of
Brønsted bases is quite narrow and it mainly includes,
in order of increasing basicity, amidines, guanidines,
activation of pronucleophiles with high pKa values,
which are generally unreactive towards Brønsted
bases employed so far.[4] Excellent results in terms of
stereoselectivity have been obtained by exploiting
synergistic mechanisms by installing H-bonding
donor groups on the catalyst structure.[5] Indeed,
bifunctional superbase organocatalysts have been
successfully engaged in a number of asymmetric
cyclopropenimines,
iminophosphoranes-
phosphazenes, and azaphosphatranes (Figure 1).[2] In
particular, the strong basicity of cyclopropenimines
(pKBH+ ~26 in MeCN) is attributable to the presence
of the latent, aromatic 2-electron cyclopropenium
ion, which is generated by protonation of the head
imino nitrogen and further stabilized by
delocalization of the three nitrogen lone pairs.[3]
Organic superbases are complementary to inorganic
processes,
including
Michael,[6]
Mannich,[7]
oxyamination,[8] and cycloaddition[9] reactions.
Nevertheless, the field of asymmetric catalysis
mediated by organic superbases is still in its infancy
1
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10.1002/adsc.202100757
Advanced Synthesis & Catalysis
compared to other organocatalytic activation modes
such as Lewis base, Brønsted acid, and counterion
catalysis;[10] thus, further improvements are needed
especially regarding the ease of access to superbases,
whose preparation and purification are sometimes
complicated by their inherent strong reactivity.
Organocatalyst heterogenization may offer unique
opportunities in this direction by facilitating the
catalyst handling and recycling, with the advantage of
the simple product/catalyst separation and the
possible adaptability to flow chemistry.[11] To the best
of our knowledge, the immobilization of bifunctional
chiral superbases have been achieved for guanidine-
and iminophosphorane-derived organocatalysts[12]
recording, however, high levels of stereoselectivity
only with the second type of supported catalysts
(Figure 1).[12c]
comparable, high efficiency of both polystyrene- and
silica-supported cyclopropenimines in model Michael
additions (yield > 90%; ee up to 98%), the greater
stability (recyclability) of the silica-based catalyst
was exploited to demonstrate for the first time the
compatibility of asymmetric organo-superbase
catalysis with a continuous-flow setup through the
fabrication and long-term operation of the
corresponding packed-bed mesoreactor.
OH
OH
N
N
Cy2N
NCy2
Cy2N
NCy2
batch
flow
supported
Lambert
catalyst
Lambert
catalyst
polystyrene
silica
this work
Figure 2. Lambert catalyst and heterogeneous versions
thereof.
Results and Discussion
Our study commenced with the synthesis of the
polystyrene-supported version of the Lambert catalyst,
that was initially approached adopting the same
strategy developed for the preparation of the
homogeneous counterpart (Schemes 1 and 2).[6e]
Accordingly, 4-bromo-D-phenylalaninol
1
was
readily obtained by reduction of the corresponding
commercially available amino acid;[19] then, the
Suzuki-Miyaura cross-coupling of
1
with 4-
vinylphenylboronic acid 2 was deeply investigated
under different conditions with PdCl2(PPh3)2 catalyst
to introduce the styryl functionality, which was
necessary for the copolymerization of the expected
adduct 3 with styrene (STY) and divinylbenzene
(DVB)
leading
to
the
polymer-supported
phenylalaninol PS-7 (Scheme 1). Unfortunately, any
attempt to obtain the styryl derivative 3 failed
because of the formation of a gummy, unmanageable
reaction mixture, which was likely due to
uncontrolled Pd-catalyzed homopolymerization of 3.
Hence, we reasoned that protection of the amino
alcohol functionality of 1 could suppress Pd
complexation, which was assumed to be responsible
for the in situ formation of Pd species capable to
promote the self-oligomerization of 3.[20] Indeed, the
N-Boc oxazolidine-protected derivative 4, which was
easily obtained from 1 by standard chemistry,
underwent Suzuki-Miyaura coupling with 2 under
PdCl2(PPh3)2 catalysis affording the styryl adduct 5 in
satisfactory 80% isolated yield. After a brief
polymerization study, macroporous PS-6 was then
prepared with a satisfactory loading of oxazolidine
units (f: 0.68 mmol g-1) using the optimal reaction
mixture, which was composed of STY (19.5 % w/w),
DVB (7% w/w), the co-monomer 5 (13% w/w), 1-
dodecanol (50% w/w) and toluene (10% w/w) as the
porogens, and AIBN (0.1% w/w) as the radical
initiator. Deprotection of triturated PS-6 was finally
Figure 1. Structures and pKBH+ values (MeCN) of organic
superbases and known bifunctional heterogeneous
superbase organocatalysts for asymmetric catalysis.
Actually, preserving in heterogeneous phase the
reactivity and stereoinduction ability of chiral
organocatalysts is a challenging goal at the forefront
of catalysis, which mainly depends on the linker
nature,[13] the solvent effect[14] and, ultimately, on the
choice of the solid matrix.[15] In continuation of our
research on asymmetric organocatalysis in
heterogeneous conditions,[16] we herein report on the
immobilization onto polystyrene and silica gel of
chiral
2,3-bisaminocyclopropenimine
(Lambert
catalyst),[17] which is a privileged bifunctional
organocatalyst
for
highly
enantioselective
Michael,[6e,18] Mannich,[7c] and [3+2] cycloaddition
reactions (Figure 2).[9c] Once we established the
2
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10.1002/adsc.202100757
Advanced Synthesis & Catalysis
carried out with TFA/chloroform followed by
treatment with Et3N/THF to give the target polymer-
supported phenylalaninol PS-7 (Scheme 1).
with STY and DVB (Scheme 3). Actually, this
approach proved to be practicable since the
cyclopropenium salt 11 could be obtained in high
yield (85% over two steps) and used as crude material
in the polymerization to PS-9 (80 °C, 24 h).
Elemental analysis of this resin confirmed a
satisfactory loading of cyclopropenium units (f: 0.45
mmol g-1), while a control experiment with an
authentic sample of 10 (toluene, 80 °C, 24 h)
confirmed the maintenance of the structural integrity
of the chiral amino alcohol functionality under the
quite harsh conditions of the cross-coupling and
polymerization steps (1H NMR analysis; see the
Experimental Section for details).
B(OH)2
2
OH
PdCl2(PPh3)2
NH2
X
OH
THF-H2O, 60 °C
NH2
Br
1
3
1. Boc2O, Et3N
2. 2-MP, CSA
67%
2, PdCl2(PPh3)2
O
BocN
O
THF-H2O, 60 °C
BocN
Br
80%
4
5
Cl
-
Cl
AIBN
STY (19.5% w/w)
70 °C, 24 h DVB (7% w/w)
OH
Cy2N
NCy2
8
HN
1. TFA
Et3N
Br
1
-
CHCl3, 50 °C
OH
O
Cl
DCM
95%
BocN
2, PdCl2(PPh3)2
THF-H2O, 60 °C
2. Et3N-THF
NH2
PS
90%
Cy2N
NCy2
PS
10
PS-7
(f: 0.65 mmol g-1
PS-6
(f: 0.68 mmol g-1
)
)
OH
Scheme 1. Synthesis of polystyrene-supported D-
phenylalaninol PS-7.
OH
STY (19.5% w/w)
DVB (7% w/w)
HN
HN
PS
-
-
80 °C, 24 h
Cl
Cl
Cy2N
NCy2
Cy2N
NCy2
In agreement with the Lambert protocol,[6e] the
heterogeneous chiral amino alcohol PS-7 was
coupled with bis(dicyclohexylamino)cyclopropenium
chloride 8[17b] exploring different reaction conditions
(variation of base, solvents, temperature, and excess
8; Scheme 2).[21] Disappointingly, the lower reactivity
of PS-7 compared to homogeneous phenylalaninol
could not be compensated by the increase of
temperature (60 °C vs. RT), the larger amount of 8
(up to 5 equiv.), and the use of a good swelling
solvent (CHCl3), which provided the target
cyclopropenium salt pre-catalyst PS-9 in only 17%
PS-9
11
(f: 0.45 mmol g-1
)
Scheme 3. Effective approach to the synthesis of
polystyrene-supported cyclopropenium salt pre-catalyst
PS-9.
Next, formation of the cyclopropenimine superbase
catalyst PS-12 was considered by testing different
activation conditions and using the Michael reaction
of glycine imine 13 with methyl acrylate 14a as the
benchmark (Table 1). Hence, by mimicking in the
heterogeneous phase the activation protocol
optimized for the homogenous Lambert catalyst,[6e]
PS-9 was initially suspended in a 0.5M aqueous
NaOH-THF (1:1) mixture and subsequently washed
with several portions of THF and EtOAc to remove
any trace of hydroxyl anion, which could be
eventually responsible for a racemic background
reaction. Unfortunately, application of the supposed
PS-12 (25 mol%) generated under the above
conditions to the model 13/14a coupling resulted in
no formation of the expected Michael adduct 15a
(entry 1). Reasonably, excess water of the activation
procedure consumed the in situ generated superbase
PS-12 producing the unactive cyclopropenium
hydroxide PS-16; as a matter of fact, this side-
reaction can be avoided in the homogeneous phase
because deprotonation of the soluble cyclopropenium
pre-catalyst occurs at the organic solvent/water
interface in a separation funnel.[6e] Promisingly,
utilization of anhydrous conditions (DCM, RT, 1 h)
in combination with DBU (3 equiv.) as organic base
furnished at least a portion of active PS-12 since
formation of the target product 15a could be achieved
1
conversion, as determined by quantitative H NMR
analysis (internal standard) of the supernatant
solution.
Cl
-
Cl
Cy2N
NCy2
OH
8
OH
Et3N
HN
PS
-
NH2
CHCl3, 60 °C
Cl
PS
17%
Cy2N
NCy2
PS-7
(f: 0.65 mmol g-1
)
PS-9
Scheme 2. Ineffective approach to the synthesis of
polystyrene-supported cyclopropenium salt pre-catalyst
PS-9.
A more effective route to PS-7 was investigated by
considering the homogeneous coupling of 8 with 4-
bromo-phenylalaninol 1 to give the cyclopropenium
salt 10, followed by Suzuki-Miyaura cross-coupling
with boronic acid
2
and subsequent co-
polymerization of the resulting styryl derivative 11
3
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10.1002/adsc.202100757
Advanced Synthesis & Catalysis
in very poor yield (6%) but with good enantiomeric
excess (92% ee; entry 2). Increasing the excess of
DBU to 20 equivalents (entry 3) and the use of the
stronger TBD base in DCM or THF slightly
improved the outcome of the model reaction (entries
4 and 5), thus suggesting still a partial activation of
PS-7. The rise in temperature (50 °C, TBD, THF)
determined a marked decrease of conversion
efficiency of the so-generated PS-12 (entry 6); in
agreement with Lambert’s proposal,[6e] this result was
explained by preferential formation of undesired
oxazolidine PS-17 via internal deprotonation of the
pendant hydroxyl group and subsequent cyclization
triggered by the temperature increase. Similar
unsatisfactory outcomes were also detected with n-
BuLi or NaHMDS (3 equiv.) as the bases (entries 7-
8). Optimal conditions for PS-12 generation were
finally achieved with complete reproducibility by
treating PS-7 with 0.05M LiOH in anhydrous MeOH
(RT, 1 h); gratifyingly, by this activation procedure,
PS-12 (25 mol%) promoted the formation of adduct
15a in almost quantitative yield and 98% ee (EtOAc,
RT, 16 h; entry 9).
At the beginning of this study we were aware of the
strict structural requirements to guarantee activity,
stability, and enantioinduction ability of the
homogeneous Lambert catalyst, including the key
intramolecular CH...O interaction between the
dicyclohexylamino and hydroxyl groups in the
ground state of the catalyst.[17b] On the other hand, it
is well known that the nature of support may deeply
affect the activity and selectivity of heterogeneous
(organo)catalysts because of unfavorable interactions
between the catalytic active sites and the solid
surface.[15] Hence, the matrix effect was also explored
by considering the immobilization of Lambert
cyclopropenimine onto silica gel through thiol-ene
coupling (TEC)[22] of the styryl cyclopropenium salt
11 with the suitably prepared mercaptopropyl silica
gel Si-SH[16b] (Scheme 4). By this strategy,
heterogeneous pre-catalyst Si-9 was readily obtained
(AIBN, 90 °C, 16 h) with a satisfactory level of
functionalization (f: 0.47 mmol g-1) and subsequently
converted into the corresponding cyclopropenimine
free base Si-12 by application of the same protocol
optimized for the polystyrene-supported analogue
PS-9 (0.05M LiOH in anhydrous MeOH, RT, 1 h).
Table 1. Optimization of catalyst PS-12 formation and its
activity in the model Michael reaction.[a]
OH
SH
HN
activation
AIBN
Si
+
2
-
Toluene, 90 °C
Cl
Si-SH
(f: 1.11 mmol g-1
OH
)
OH
Cy2N
NCy2
HN
base
N
11
PS
PS
-
solvent, RT
Cl
Cy2N
NCy2
OH
Cy2N
NCy2
OH
PS-12
PS-9
(f: 0.45 mmol g-1
N
0.05M LiOH
HN
Si
Si
)
-
MeOH-THF
Cl
benchmark
Cy2N
NCy2
Cy2N
NCy2
PS-12
(25 mol%)
Ph
N
CO2tBu
Si-12
Si-9
(f: 0.47 mmol g-1
Ph
N
CO2tBu
CO2Me
+
)
EtOAc, RT, 16 h
Ph
Ph
13
14a
CO2Me
Scheme 4. Synthesis of silica-supported cyclopropenium
15a
salt pre-catalyst Si-9 and cyclopropenimine superbase Si-
12.
Entry Base
Solvent
ee
(%)[b] (%)[c]
15a
1
0.5M NaOH
DBU
DBU
TBD
TBD
TBD
n-BuLi
NaHMDS
0.05M LiOH
H2O-THF
DCM
DCM
DCM
THF
THF
THF
THF
MeOH
-
6
18
30
28
5
7
9
>95
-
2[d]
3[e]
4[e]
5[e]
6[e,f]
7[d]
8[d]
9
92
93
96
95
84
88
84
98
The catalytic activity and recyclability of the newly
prepared heterogeneous cyclopropenimine superbases
PS-12 and Si-12 were duly investigated (Table 2). As
previously mentioned, PS-12 (25 mol%) afforded the
Michael adduct 15a in quantitative yield and 98% ee
in 16 h using EtOAc as the solvent (entry 1). With the
aim to improve the conversion efficiency of PS-12,
the solvent effect was also examined (entries 2-5).
The diffusion and adsorption of reactive species over
the matrix surface is, in fact, strictly dependent on the
reaction medium, affecting the catalytic performance
OH
O
N
HN
PS
PS
-
OH
Cy2N
NCy2
Cy2N
NCy2
of immobilized (organo)catalysts significantly.[14]
A
PS-16
PS-17
[a]Activation: PS-9 (100 mg, 0.045 mmol); benchmark: 13
(0.07 mmol), 14a (0.21 mmol), PS-12 (0.017 mmol based
on PS-9 loading), EtOAc (1.5 mL).
[b]Detected by 1H NMR analysis of reaction mixture.
[c]Determined by chiral HPLC.
brief screening of aprotic solvents with different
polarity confirmed EtOAc as the best performing
medium. Additionally, the increase of temperature to
45 °C left the reaction conversion almost unchanged
but determined a rather lower enantioselectivity (95%
ee, entry 6).
[d]Base (0.14 mmol).
[e]Base (9.00 mmol).
[f]Activation of PS-9 at 50 °C.
4
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10.1002/adsc.202100757
Advanced Synthesis & Catalysis
Table 2. Activity and recyclability test with PS-12 and Si-
12.[a]
mol%) behaved quite similarly to PS-12, as the
adduct 15a was formed in quantitative yield and 98%
ee using EtOAc as the preferred solvent (entry 7).
Gratifyingly, this result validated our catalyst design
criteria based on utilization of a quite flexible spacer
to maintain the local molecular structure of the chiral
cyclopropenimine moiety and avoid disruption of the
transition state organization by H-bonding with the
free hydroxyl groups of the silica support. Notably, a
significant difference in reusability was observed for
PS-12 and Si-12. Recycling tests were performed by
treating the recovered catalyst with 0.05 M LiOH
(MeOH) to completely restore the active
cyclopropenimine free base after each run (poorer
results were detected with the simply washed and
filtered catalyst). Indeed, while the enantioinduction
ability of both PS-12 and Si-12 was kept almost
unaltered after five runs, the conversion efficiency of
PS-12 markedly decreased after the first recycle
(68%, entry 10); by contrast, Si-12 could be reused
five times without considerable deactivation (entry
13).[23] In addition, the extension of the reaction time
to 24 h allowed the reduction of Si-12 loading to 15
mol% with little variation of reaction yield (entry 14)
and maintenance of recycling performance (entries 15
and 16). Overall, these results indicated Si-12 as the
more effective heterogeneous bifunctional superbase
organocatalyst with an accumulated turnover number
(TON) of 27.1 (Figure 3). Remarkably, the catalytic
activity of Si-12 remained unchanged over several
days when kept at 0 °C, as confirmed by a control
reaction promoted by a sample of Si-12 stored in the
fridge for one week (entry 17). Finally, the successful
gram-scale experiment of entry 18 indicated the
potential of Si-12 for practical applications.
OH
N
Ph
N
CO2tBu
Cy2N
NCy2
Ph
Ph
N
CO2tBu
13
PS-12 or Si-12
(mol%)
Ph
+
Solvent, 25 °C
CO2Me
CO2Me
14a
polystyrene
silica
15a
Entry Catalyst
(mol%)
Solvent
EtOAc
THF
Time
(h)
16
ee
15a
(%)[b] (%)[c]
>95
98
98
52
68
98
95
98
74
97
98
95
98
98
98
98
98
98
98
PS-12
(25)
1
16
51
PS-12
(25)
2
Toluene 16
70
PS-12
(25)
3
DCM
Et2O
16
16
16
16
10
PS-12
(25)
4
27
PS-12
(25)
5
EtOAc
EtOAc
>95
>95
43
PS-12
(25)
6[d]
Si-12
(25)
7
Toluene 16
Si-12
(25)
8
Et2O
16
16
16
16
16
24
24
24
24
24
>95
68
Si-12
(25)
9
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
PS-12
(25)
10[e]
17
PS-12
(25)
11[f]
92
Si-12
(25)
12[e]
83
Si-12
(25)
13[f]
92
Si-12
(15)
14
90
Si-12
(15)
15[e]
77
Si-12
(15)
16[f]
91
Si-12
(15)
17[g]
93
Si-12
(15)
18[h]
[a]Reaction conditions: 13a (0.07 mmol), 14a (0.21 mmol),
Figure 3. Recycling experiments (13/14a coupling with 15
mol% of Si-12 ).
solvent (0.5-1.5 mL).
1
[b]Detected by H NMR analysis of the crude reaction
mixture.
[c]Determined by chiral HPLC.
[d]Reaction performed at 45 °C
[e]First recycle.
The structural analysis of the stable silica-supported
pre-catalyst Si-9 was performed by FTIR
spectroscopy (Supporting Information) and by a
preliminary high-resolution magic angle spinning
(HR-MAS) NMR study based on the direct
comparison with a homogeneous precursor. Figure 4a
[f]Forth recycle.
[g]Reaction run with catalyst stored at 0 °C for one week.
[h]Gram-scale experiment: 13a (3.39 mmol).
1
illustrates the H NMR spectrum of the soluble
cyclopropenium salt 10 and the assignment of the
diagnostic signals associated to the protons of the
In parallel experiments (entries 7-9), we found that
the silica-supported cyclopropenimine Si-12 (25
5
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10.1002/adsc.202100757
Advanced Synthesis & Catalysis
alaninol and cyclohexyl units ( = 4.0-2.5 ppm). The
chalcone resulted a suitable substrate as well yielding
15i as a sole diastereoisomer (d.r. > 19:1) with high
enantioselectivity (96% ee).
Asymmetric catalysis promoted by heterogeneous
organo-superbases in continuous-flow (CF) regime is
a completely unexplored area of research, which may
offer new opportunities for the efficient production of
high added-value chiral molecules such as
enantioenriched synthons and active pharmaceutical
ingredients (APIs).[11]
1
CPMG filtered H HR-MAS-NMR spectrum of Si-9
(Figure 4b) displays a high degree of homology with
that of 10, thus allowing to confirm the covalent
immobilization of the cyclopropenium moiety on
support through the thioether linkage. The complete
activation of Si-9 by the optimized basic procedure
1
was confirmed by H HR-MAS-NMR analysis of Si-
12, detecting the expected upfield shift of the alaninol
diagnostic
peaks
(Supporting
Information).
Formation of the cyclopropenimine unit on support
was further demonstrated by argentometric
titration,[24] which did not reveal any significant
amount of chloride anion left in Si-12 (Experimental
Section).
Table 3. Scope of the Michael addition of glycine imine 13
with different acceptors 14 catalyzed by Si-12 under batch
conditions.[a]
OH
N
Si
Ph
N
CO2tBu
Cy2N
NCy2
Ph
N
CO2tBu
Ph
Si-12
(15 mol%)
EtOAc, RT, 24 h
13
Ph
+
EWG
EWG
15
14
Ph
N
CO2tBu
Ph
N
CO2tBu
Ph
N
CO2tBu
Ph
Ph
Ph
CO2Me
15a
(92%; 98% ee)[b]
CO2Et
15b
(91%; 97% ee)[b]
CO2nBu
15c
(90%; 70% ee)[b]
Ph
N
CO2tBu
Ph
N
CO2tBu
Ph
N
CO2tBu
Ph
Ph
Ph
CO2tBu
CO2Bn
O
Me
15d
(78%; 96% ee)[b,c]
15e
(70%; 96% ee)[b]
15f
(90%; 96% ee)[b]
Ph
N
CO2tBu
Ph
N
CO2tBu
Ph
N
CO2tBu
Ph
Ph
Ph
Ph
SO2Ph
CN
O
Ph
15g
(48%; 66% ee)[b,c,d]
15h
(61%; 60% ee)[b,c,d]
15i
(70%; 96% ee)[b]
1
Figure 4. H NMR spectrum (CDCl3) of 10 (a); CPMG
[a]Reaction conditions: 13 (0.10 mmol), 14 (0.30 mmol),
EtOAc (0.5 mL).
filtered 1H HR-MAS-NMR spectrum (CDCl3) of Si-9 (b).
[b]In bracket: isolated yield and enantiomeric excess as
determined by chiral HPLC.
In analogy with the homogeneous study, the catalytic
performance of Si-12 was tested in the reaction of
glycine imine 13 with different Michael acceptors
14a-i (Table 3). Satisfyingly, heterogeneous Si-12
behaved very similarly to the soluble Lambert
catalyst in all the substrate combinations investigated
(comparable results in terms of yield and
enantioselectivity were also detected for PS-12).
Indeed, ethyl, n-butyl, t-butyl, and benzyl acrylates
effectively participated in the conjugate addition
furnishing the products 15b-e in good to high yields
and with excellent enantioselectivities apart from 15c
(70% ee). Methyl vinyl ketone, acrylonitrile, and
phenyl vinyl sulfone afforded the corresponding
adducts 15f, 15g and 15h in lower yields but still
satisfactory enantioselectivities (60-96% ee). Finally,
[c]Reaction time: 48 h.
[d]Si-12: 25 mol%.
Therefore, driven by our experience in process
intensification by fabrication of organocatalytic
fixed-bed mesoreactors,[16] we next investigated the
transition of the model Michael addition from batch
to continuous-flow conditions. Accordingly, the
silica-supported cyclopropenimine Si-12 (loading
0.47 mmol g-1) was selected as the packing material
(pore size 60 Å, particle size ~ 50 mm, superficial
area 500 m2 g-1) in virtue of its superior stability
compared to the polystyrene analogue. Then, the
mesoreactor R was fabricated by slurry packing Si-12
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100757
Advanced Synthesis & Catalysis
Table 5. Continuous-flow production of Michael addition
products 15.[a]
(EtOAc as solvent) into a pressure-resistant stainless-
steel column (length 10 cm, 0.46 cm internal
diameter); the hold-up (dead) volume (V0) and the
total porosity (εtot) of reactor R were determined by
pycnometry measurements, thus permitting the
calculation of the residence time at different flow
rates (Table 4).
OH
NCy2
Ph
N
Ph
N
CO2tBu
NCy2
Ph
pump
13
N
CO2tBu
R
+
Ph
Rate (5 mL min-1
)
Table 4. Main features of packed-bed mesoreactor R.
EWG
14
EtOAc, RT
EWG
15
OH
N
Si
Entry
ee
TOF[d]
13
14
15
(c [M]) (c [M]) (conv.[%])[b] (%)[c]
Cy2N
NCy2
Si-12
0.04
0.04
0.04
0.04
0.03
0.03
98
98
97
70
96
96
0.43
0.41
0.41
0.4
14a
(1.20)
14a
(1.20)
14b
(1.20)
14c
(1.20)
14d
(1.20)
15a
(>95)
15a
(95)
15b
(95)
15c
(92)
15d
(90)
15e
(f: 0.47 mmol g-1
)
1
2e
3
4
5
6
VG
Vo
Total
Time
p
Si-12
[g][a] [mL][b] [mL][c] Porosity[d]
[min][e] [bar][f]
1.50
1.66
1.16
0.70
116
5
[a]Loaded catalyst: calculated by difference with catalyst
amount in the residual slurry solution.
[b]Geometric volume (VG) of the stainless-steel column.
[c]Void volume (V0) determined by pycnometry.
[d]Total porosity εtot= V0/VG.
0.29
0.29
14e
(1.20)
[e]Residence time (t0) calculated at 10 μLmin-1.
[f]Backpressure measured at 50 μLmin-1 (RT, EtOAc).
(91)
[a]See the Experimental section for a description of the flow
apparatus.
[b]Instant conversion in the steady-state regime as
determined by 1H NMR analysis.
Flow experiments were aimed at reaching complete
conversion of glycine imine 13 in single pass-flow
mode to facilitate the purification of the adduct 15a
by simple evaporation of the solvent and excess
acrylate 14a (Table 5). After some experimentation,
the optimal turnover frequency (TOF) was achieved
by pumping a solution in EtOAc of 13 (0.04 M) and
14a (0.12 M) with a flow rate of 5 L min-1 (15a:
0.43 mmolprod d-1 mmolcat-1; entry 1). While a quite
long residence time (t0 = 232 min) was required to get
full consumption of imine 13 (steady-state regime in
 5 h), the mesoreactor R could be operated for
additional 24 h with unaltered values of conversion
efficiency (>95%) and enantioselectivity (98% ee;
Figure 5-blue line). After that time, however, a
progressive loss of productivity was observed (~50%
conversion at 48 h). Importantly, the catalytic activity
of the packing material Si-12 could be completely
restored by feeding R with a 0.05M solution of LiOH
in anhydrous methanol, as confirmed by the
subsequent 13/14a coupling performed with the
regenerated reactor (entry 2; Figure 5-red line).
Satisfyingly, the selected acceptors 14b-e also reacted
with glycine imine 13 with high instant conversions
(>90%) by suitably adjusting the initial reagent
concentrations (flow rate: 5 L min-1; entries 3-6).
[c]Determined by chiral HPLC.
[d]Turnover frequency (TOF) is measured in mmolprod d-1
-1
mmolcat
.
[e]Experiment run with regenerated
Experimental Section for details).
R
(see the
Figure 5. Long-term stability experiment (13/14a
coupling). Conversion [%], dotted line; ee [%], dashed line.
In blue color: experiment run with fresh packing material
Si-12. In red color: experiment run with regenerated
packing material Si-12.
Conclusion
In summary, we have presented polystyrene- and
silica-supported
versions
of
the
valuable
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100757
Advanced Synthesis & Catalysis
cyclopropenimine Lambert catalyst, which have been
demonstrated to be active in Michael additions with
levels of enantioselectivity comparable to those
achieved with the homogeneous counterpart. Crucial
for the success of our research has been the
identification of suitable conditions for the
conversion of the cyclopropenium salt pre-catalyst
into the active cyclopropenimine promoter in the
heterogeneous phase. A good recyclability of the
silica-based catalyst was detected in batch
experiments, thus paving the way for its utilization as
packing material of fixed-bed mesoreactors for the
continuous-flow production of Michael adducts with
high enantiomeric purity. To the best of our
knowledge, the application of heterogeneous
superbase organocatalysts in stereoselective flow
processes is unprecedented in the literature; therefore,
we believe that the herein disclosed silica-supported
Lambert catalyst might represent a new opportunity
for further progress in the field of asymmetric
Brønsted base catalysis.
temperature and drying gas were kept at 350 °C and 5
L min−1, respectively. The MS analyzer was
externally calibrated with ESI-L low concentration
tuning mix from m/z 118 to 2700 to yield accuracy
below 5 ppm. Accurate mass data were collected by
directly infusing samples in 40/60 H2O/ACN 0.1%
TFA into the system at a flow rate of 0.4 μL min−1.
All commercially available compounds were used as
received. Amino alcohol 1 was synthetized following
a
literature
procedure.[19]
Chloro[bis(dicyclohexylamino)]cyclopropenium
chloride 8 was synthetized following a literature
procedure.[17b] Mercaptopropyl silica gel was prepared
according to a literature procedure.[16b]
tert-Butyl
(R)-4-(4-bromobenzyl)-2,2-
dimethyloxazolidine-3-carboxylate (4). Amino
alcohol 1 (1.35 g, 5.87 mmol) was dissolved in
anhydrous THF (15.0 mL, 0.40 M) in an oven dried
round bottom flask and the solution was degassed
under vacuum and saturated with argon (by an Ar-
filled balloon) three times. Triethylamine (0.80 mL,
8.87 mmol) was added, and the reaction was cooled
to 0 °C. Later, an anhydrous solution of di(tert)-butyl
dicarbonate in THF (3 mL, 1.75 M, 5.87 mmol) was
added and the reaction was allowed to reach room
temperature. The formation of the product was
Experimental Section
General Information. All moisture-sensitive
reactions were performed under an argon atmosphere
using oven-dried glassware. Solvents were dried over
a standard drying agent and freshly distilled prior to
use. Reactions were monitored by TLC on silica gel
60 F254 with detection by charring with potassium
permanganate or phosphomolybdic acid. Flash
column chromatography was performed on silica gel
60 (230-400 mesh). Optical rotations were measured
at 25 ± 2 °C in the stated solvent; [α]D values are
given in 10−1 deg cm2 g−1 (concentration c given as
1
monitored through H NMR and after 3 h the solvent
was removed under vacuum. The residue was taken
up with dichloromethane (10 mL), washed with
NaHCO3 saturated solution (3 × 20 mL) and dried.
After the solution was filtered, removal of the solvent
afforded the Boc-protected amino alcohol tert-butyl
(R)-(1-(4-bromophenyl)-3-hydroxypropan-2-
yl)carbamate (1.72 g, 88%) as an amorphous white
solid with spectroscopic data in accordance with the
literature.[4]
1
1
13
g/100 mL). H (300 MHz), H (400 MHz), C (101
MHz) and 13C (75 MHz) NMR spectra were recorded
in CDCl3 solution at room temperature. The chemical
The protected amino alcohol (952 mg, 2,88 mmol)
was then dissolved in anhydrous dichloromethane (20
mL) under inert atmosphere and the solution was
cooled to 0 °C. Later, 2-methoxypropene (0.69 mL,
7.21 mmol) and camphorsulfonic acid (67 mg, 0.29
mmol) were added and the reaction was allowed to
stir at 0 °C for almost 2 h until complete by NMR
analysis. The mixture was sequentially washed with
NaHCO3 saturated solution (15 mL) and water (15
mL). The organic layer was dried (Na2SO4), filtered
and concentrated under reduced pressure to give
compound 4 (853 mg, 80%) as a yellowish oil. [α]D
= 35.3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.42 (m, 2H, ArH), 7.09 (m, 2H, ArH), 4.12 – 3.87
(m, 1H, NCHBnCH2O), 3.79 (dd, J = 9.2, 5.5 Hz, 1H,
1
13
shifts in H and C NMR spectra were referenced to
trimethylsilane (TMS). Peak assignments were aided
by H−1H COSY and gradient HMQC experiments.
1
Enantiomeric excess (ee %) was evaluated by HPLC
using Lux amylose 2 column. CPMG filtered 1H HR-
MAS NMR experiments were registered in CDCl3 at
499.84 MHz Larmor frequency and 2 KHz
spinning frequency with Agilent DD2 NMR System,
PremiumCompact superconducting magnet 11.7
Tesla (54-mm bore, 500 MHz 1H) equipped with an
Agilent Nanoprobe. FT-IR analyses were performed
using the Bruker Instrument Vertex 70. Elemental
analyses were performed using a FLASH 2000 series
CHNS/O analyzer (ThermoFisher Scientific). ESI-
MS routine analyses were performed in positive ion
mode with samples dissolved in 10 mM solution of
ammonium formate in 1:1 MeCN/H2O. For high
resolution mass spectrometry (HRMS), the
compounds were analyzed in positive ion mode using
an Agilent 6520 HPLC-Chip Q/ TOF-MS
(nanospray) with a quadrupole, a hexapole, and a
time-of-flight unit to produce the spectra. The
capillary source voltage was set at 1700 V; the gas
NCHBnCH2O), 3.71 (d,
J
=
9.2 Hz, 1H,
NCHBnCH2O), 3.19 (s, 1H, CH2Ph ), 3.16 – 2.98 (m,
1H, CH2Ph), 2.63 (dd, J = 12.9, 10.3 Hz, 1H), 1.59 –
1.44 (m, 15H, C(CH3)3 , NC(CH3)2O); 13C NMR (101
MHz, CDCl3) δ 152.1*, 137.4, 131.7* (2C), 131.0 *
(2C), 120.4*, 94.1*, 80.2*, 65.7*, 58.9, 39.0 *, 28.4*
(3C), 26.9*, 24.5* (* signals appear as doublet due to
the presence of conformers). HRMS (ESI): m/z [M +
H]+ calcd for C12H16BrNO 269.0415; found:
269.0456.
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100757
Advanced Synthesis & Catalysis
(loading = 0.68 mmol g−1); FT-IR (KBr) ν 1699
tert-Butyl
(R)-2,2-dimethyl-4-((4'-vinyl-[1,1'-
(C=O), 1602 (C=C) cm−1.
biphenyl]-4-yl)methyl)oxazolidine-3-carboxylate
(5). Protected amino alcohol 4 (0.60 g, 1.62 mmol),
PdCl2(PPh3)2 (57 mg, 0.08 mmol, 5 mol %), 4-vinyl
phenylboronic acid 2 (0.36 g, 2.43 mmol), and
potassium phosphate (0.69 g, 3.24 mmol) were
loaded into a glass vial. Subsequently, freshly
distilled THF (10 mL) was added, followed by
degassed water (3.4 mL). The mixture was degassed
under vacuum and saturated with argon (by an Ar-
filled balloon) three times. Later, the vial was sealed,
and the reaction mixture was stirred at 60 °C. After 6
h, an additional amount of 4-vinyl phenylboronic acid
(0.20 g, 1.35 mmol) and PdCl2(PPh3)2 (28 mg, 0.04
mmol) was added. The mixture was degassed under
vacuum and saturated with argon (by an Ar-filled
balloon) three times and let stirring at 60 °C for 16 h.
The reaction was then cooled to room temperature,
quenched with water (7.0 mL), and extracted with
EtOAc (2 × 7.0 mL). The combined organic phases
were dried over Na2SO4, concentrated, and purified
by flash silica column chromatography (9:1
cyclohexane: EtOAc) to give 5 (570 mg, 80%) as a
pale yellow amorphous solid. [α]D = 31.2 (c 1.0,
(PS-7). PS-6 (0.30 g, loading = 0.68 mmol g−1) was
suspended in a 1:1 CHCl3: TFA mixture (10 mL) and
stirred at 50 °C for 4 days. After cooling, the solvent
was removed under vacuum. The resin was
suspended in THF (5.0 mL) and sequentially
centrifuged with portions of THF (3 × 7.0 mL), 1:1
THF : Et3N (3 × 7.0 mL), 1:1 THF : EtOH (3 × 7.0
mL), THF (1 × 7.0 mL) and n-hexane (1 × 7.0 mL).
After vacuum drying (0.1 mbar, 40 °C, 6 h), PS-7
resin was further submitted to elemental and FT-IR
analyses. Elemental analysis (%) found: N 0.92
(loading = 0.65 mmol g−1); FT-IR (KBr): ν 3580 (N-
H), 3424 (O-H) cm−1. Furthermore, complete
deprotection has been corroborated by mean Kaiser
test on the resin. Accordingly, PS-7 (2 mg) was
suspended in 1 mL of deionized water followed by 1
mL of acetate buffer (pH = 5.5). The resulting
suspension was sonicated for 15 minutes; Then, 1 mL
of a solution of KCN in pyridine (0.03 M) and 1 mL
of a solution of phenol (0.04 M) was added and the
suspension was heated at 120 °C for 10 minutes.
After that, 1 mL of ninhydrin solution (5% in EtOH)
was added and heated for additional 10 minutes. The
suspension was allowed to cool and 5 mL of the
EtOH/water solution (3:2 v/v) was added. The solid
was separated by centrifugation and the resulting
supernatant was analyzed by UV-vis spectrometer.
The primary amine loading was obtained by matching
the Abs of genuine sample with the calibration curve
(benzylamine as standard) following the protocol
reported by Krueger.[21] Kaiser test (loading = 0.62
mmol g−1).
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.55 (d, J =
8.0 Hz, 4H, ArH), 7.48 (d, J = 8.0 Hz, 2H, ArH), 7.37
– 7.26 (m, 2H, ArH), 6.75 (dd, J = 17.5, 11.0 Hz, 1H,
ArCHCH2), 5.79 (d, J = 17.5 Hz, 1H, PhCHCH2),
5.27 (d, J = 11.0 Hz, 1H, ArCHCH2), 4.25 – 3.94 (m,
1H, NCHBnCH2O), 3.81 (d, J = 3.1 Hz, 2H,
NCHBnCH2O), 3.36 – 3.04 (m, 1H, CH2Ph), 2.82 –
2.61 (m, 1H, CH2Ph), 1.62 – 1.44 (m, 15H, C(CH3)3 ,
NC(CH3)2O); 13C NMR (101 MHz, CDCl3) δ 151.8*,
140.2, 139.0, 138.9, 137.8, 136.5, 129.8* (2 C), 127.2
(2 C), 127.1 (2 C), 126.7 (2 C), 114.0, 94.2*, 79.8*,
66.2*, 59.3, 39.4*, 28.7* (3 C), 27.0*, 23.4 (* signals
appear as doublet due to the presence of conformers).
HRMS (ESI): m/z [M + H]+ calcd for C20H23NO
293.1780; found: 293.1731.
(PS-9). Route A (Scheme 2). PS-7 (80 mg, loading =
0,65 mmol g−1) was suspended in anhydrous CHCl3
followed by the addition of cyclopropenium salt 8 (39
mg, 0,10 mmol) and stirred at 60 °C. After 16 h
triethylamine (17 µL, 0.12 mol) was added and
stirred at 60 °C for three days. After cooling, the
resulting PS-9 was centrifugate and washed with
THF (3 × 9.0 mL) and n-hexane (1 × 9.0 mL). The
composition of the collected supernatants was
(PS-6). A homogeneous mixture of styryl derivative
5 (0.30 mg, 0.76 mmol), styrene (0.61 mL, 5.30
mmol), divinylbenzene (0.21 μL, 1.51 mmol), toluene
(0.30 mL, 2.83 mmol), 1-dodecanol (1.57 mL, 7.06
mmol), and AIBN (10 mg, 0.06 mmol) was degassed
under vacuum and saturated with argon (by an Ar-
filled balloon) three times. The mixture was then
poured into a glass column sealed at both ends
(placed in vertical position) and heated at 60 °C in a
standard oven for 16 h. After cooling of the reaction
column, the glass was broken, and the resulting
monolith PS-6 was triturated to obtain a yellow
powder. This powder was suspended in THF (5.0
mL) and centrifuged with portions of THF (4 × 5.0
mL). The composition of the collected supernatants
1
analyzed by H NMR. After vacuum drying (0.1
mbar, 40 °C, 6 h), PS-7 resin was further submitted
to elemental and FT-IR analyses. Elemental analysis
(%) found: N 1.10 (loading = 0.13 mmol g−1); FT-IR
(KBr): ν 3582 (N-H), 3424 (O-H) cm−1.
Route B (Scheme 3). A homogeneous mixture of
styryl derivative 11 (533 mg, 0.76 mmol), styrene
(0.35 mL, 3.05 mmol), divinylbenzene (0.12 mL,
0.87 mmol), toluene (0.21 mL, 2.64 mmol), 1-
dodecanol (1.09 mL, 7.03 mmol), and AIBN (7.0 mg,
0.04 mmol) was degassed under vacuum and
saturated with argon (by an Ar-filled balloon) three
times. The mixture was then poured into a glass
column sealed at both ends (placed in vertical
position) and heated at 80 °C in a standard oven for
24 h. After cooling of the reaction column, the glass
was broken, and the resulting monolith PS-9 was
1
was analyzed by H NMR to confirm the full
incorporation of the monomer 5 into the polymer.
After vacuum drying (0.1 mbar, 40 °C, 6 h), PS-6
resin was further submitted to elemental and FT-IR
analyses. Elemental analysis (%) found: N 0.95
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100757
Advanced Synthesis & Catalysis
triturated to obtain a yellow powder. This powder
was suspended in THF (5.0 mL) and centrifuged with
portions of THF (4 × 5.0 mL). The composition of
Et2O (2 × 3mL) to give 11 (554 mg, 90%) at least
90% pure (1H NMR analysis) as a dark yellow
amorphous solid. 1H NMR (300 MHz, CDCl3) δ 7.66-
7.40 (m, 6H, ArH), 7.29 (d, J=8.2 Hz, 2H, ArH), 6.74
(dd, J = 17.6, 10.8 Hz, 1H, ArCHCH2), 5.78 (d, J =
17.6 Hz, 1H, ArCHCH2), 5.27 (d, J = 10.8 Hz, 1H,
ArCHCH2), 4.07 (m, 1H, NCHBnCH2OH), 3.90 (m,
2H, NCHBnCH2OH, NCHBnCH2OH), 3.26 (dd,
J=16.1, 7.8 Hz, 4H, NCyH), 3.19-2.97 (m, 2H,
1
the collected supernatants was analyzed by H NMR
to confirm the full incorporation of the monomer 11
into the polymer PS-9. After vacuum drying (0.1
mbar, 40 °C, 6 h), PS-9 resin was further submitted
to elemental and FT-IR analyses. Elemental analysis
(%) found: N 1.95 (loading = 0.45 mmol g−1); FT-IR
(KBr): ν 3585 (N-H), 3421 (O-H) cm−1.
13
CH2Ph), 1.98-1.13 (m, 40H, NCyH); C NMR (101
MHz, CDCl3) δ 140.0, 138.8, 137.4, 136.5, 132.0* (2
C), 129.9* (2 C), 128.6* (2 C), 126.7* (2 C), 117.1,
115.7, 114.9, 114.0, 63.9, 61.8, 59.4(4 C), 58.3,38.3,
33.0 (4C), 32.3* (4C), 26.6 (4C), 25.6* (4C), 24.7
(4C) (*signals appear as doublet due to the presence
of conformers). ESI MS (666.5): 664.2 (M - Cl).
(R)-2-((2,3-Bis(dicyclohexylamino)cycloprop-2-en-
1-ylidene)amino)-3-(4-bromophenyl)propan-1-ol
hydrochloride salt (10). The amino alcohol 1 (300
mg, 1.30 mmol) was dissolved in anhydrous
dichloromethane (13.0 mL) followed by the addition
of
chloro[bis(dicyclohexylamino)]cyclopropenium
chloride 8 (0.51 g, 1.18 mmol) and the solution was
stirred at room temperature for 16 h. Then, the crude
reaction mixture was washed with 1.0 M HCl (3 × 15
mL), dried with anhydrous sodium sulfate and
concentrated in vacuo to yield cyclopropenimine
hydrochloride salt 10 at least 90% pure (1H NMR
analysis) as a white amorphous solid (0.81 g, 95%
yield). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.8
Hz, 1H, NH), 7.33 (d, J = 8.2 Hz, 2H, ArH), 7.12 (d,
J = 8.2 Hz, 2H, ArH), 3.92 (m, 2H, NCHBnCH2OH),
3.78 (bs, 1H, NCHBnCH2OH), 3.24 (m, 4H, NCyH),
3.14 (dd, J = 13.8, 9.4 Hz, 1H, CH2Ph), 2.96 (dd, J =
13.8, 5.0 Hz, 1H, CH2Ph), 1.94 – 1.19 (m, 40H,
(PS-12). Cyclopropenimine supported-catalyst PS-12
was obtained by suspending the corresponding
hydrochloride salt PS-9 (80 mg, loading = 0.45 mmol
g−1) in 0.05 M LiOH solution in MeOH (2.0 mL).
The mixture was stirred at room temperature for 30
minutes. Then the solution was centrifugated and the
catalyst was suspended in a fresh portion of 0.05 M
LiOH solution in MeOH (2.0 mL). The mixture was
stirred at room temperature for other 30 minutes.
After centrifugation and removal of the basic solution,
the resin was sequentially washed with MeOH (2 ×
9.0 mL), THF (3 × 9.0 mL) and EtOAc (1 × 9.0 mL).
Later, after drying, activated polystyrene supported
cyclopropenimine superbase PS-12 was directly used
13
NCyH); C NMR (101 MHz, CDCl3) δ 137.6, 131.4
(2C), 131.3 (2C), 120.2, 117.1, 114.8 (2C), 64.1, 61.7, as catalyst. Elemental analysis (%) found: N 1.94
59.5 (4C), 37.7, 32.4 (4C), 32.2 (4C), 25.7 (4C), 25.7
(4C), 24.6 (4C). ESI MS (642.4): 642.2 (M - Cl).
Thermal stability of 10. Adduct 10 (20 mg, 0.03
mmol) was loaded into a glass vial. Subsequently,
anhydrous THF (2.0 mL) was added. The mixture
was degassed under vacuum and saturated with argon
(by an Ar-filled balloon) three times. Later, the vial
was sealed, and the reaction mixture was stirred at
80 °C for 20 h. Then, the crude reaction mixture was
concentrated in vacuo to yield cyclopropenimine
hydrochloride salt 10 whose 1H NMR was identical
to that of the authentic sample before thermal
treatment.
(loading = 0.45 mmol g−1); FT-IR (KBr) ν 3306 (O-
H), 2924 (C-H) cm−1.
(Si-9). A stirred solution of 11 (240 mg, 0.35 mmol),
3-mercaptopropyl silica gel (266 mg, 0.24 mmol,
loading = 1.11 mmol g−1), AIBN (39 mg, 0.24 mmol),
and anhydrous toluene (2.0 mL) was degassed under
vacuum and saturated with argon (by an Ar-filled
balloon) three times. The mixture was stirred and
heated to 90 °C overnight. After cooling to room
temperature, the mixture was centrifuged with fresh
portions of THF (4 × 5 mL) and Et2O (2 × 5 mL).
The resulting silica-supported pre-catalyst Si-9 was
finally dried (0.1 mbar, 40 °C, 6 h) and submitted to
elemental and FT-IR analyses FT-IR (KBr): ν = 3440
(N-H), 2997 (C-H) cm−1. Elemental analysis (%)
found N 1.98 (loading = 0.47 mmol g−1). Similar
loading was obtained by argentometric titration; 0.2 g
of Si-9 was suspended in 1 mL of water. Then, 0.2 g
of NaNO3 was added and the suspension was kept
stirring for 5 hours. Then, the mixture was titrated by
0.005 M of AgNO3 solution with potassium chromate
as indicator (loading = 0.45 mmol g−1).
(R)-2-((2,3-Bis(dicyclohexylamino)cycloprop-2-en-
1-ylidene)amino)-3-(4'-vinyl-[1,1'-biphenyl]-4-
yl)propan-1-ol hydrochloride salt (11). Adduct 10
(600 mg, 0.90 mmol), PdCl2(PPh3)2 (30 mg, 0.04
mmol, 5 mol %), 4-vinyl phenylboronic acid 2 (268
mg, 1.8 mmol), and potassium phosphate (384 mg,
1.81 mmol) were loaded into a glass vial.
Subsequently, freshly distilled THF (6.5 mL) was
added, followed by degassed water (2.1 mL). The
mixture was degassed under vacuum and saturated
with argon (by an Ar-filled balloon) three times.
Later, the vial was sealed, and the reaction mixture
was stirred at 80 °C for 16 h. The reaction was then
cooled to room temperature and the layers separated.
The combined organic phases were dried over
Na2SO4, concentrated, and purified by washing with
(Si-12). Cyclopropenimine supported-catalyst Si-12
was obtained by suspending the corresponding
hydrochloride salt Si-9 (80 mg, loading = 0.47 mmol
g−1) in 0.05 M LiOH solution in MeOH (2.0 mL).
The mixture was stirred at room temperature for 30
minutes. Then the solution was centrifugated and the
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100757
Advanced Synthesis & Catalysis
catalyst was suspended in a fresh portion of 0.05 M
LiOH solution in MeOH (2.0 mL). The mixture was
stirred at room temperature for other 30 minutes.
mmol), Si-12 (1.08 g, loading = 0.47 mmol g−1, 15
mol%), EtOAc (15 mL): 15a (1.20 g, 93%; 98% ee).
After centrifugation and removal of the basic solution, (R)-1-tert-Butyl-5-ethyl
2-
(15b).
the resin was sequentially washed with MeOH (2 ×
9.0 mL), THF (3 × 9.0 mL) and EtOAc (1 × 9.0 mL).
Later, after drying, activated silica supported
cyclopropenimine superbase Si-12 was directly used
as catalyst. Elemental analysis (%) found N 1.96 C
27.38 H 3.43 S 2.56 (loading = 0.47 mmol g−1). FT-
IR (KBr) ν 2937 (C-H), 2856 (C-H) cm−1.
Argentometric titration was performed on Si-12 as
described for Si-9 observing no chloride anion left
after basic treatment.
(diphenylmethyleneamino)pentanedioate
Column chromatography on silica gel (9:1
cyclohexane : EtOAc) afforded 15b (36 mg, 91%) as
a colorless oil with spectroscopic data in accordance
with the literature.[6e] [α]D = 74.9 (c 1.2 CHCl3);
Chiral HPLC analysis Lux-Amylose-2 (92:8 hexane :
IPA, flow rate 1 mLmin−1, 270 nm, 20 °C) tR (R): 8.7
1
min, tR (S): 10.3 min, 98.32:1.68 er; H NMR (400
MHz, CDCl3) δ 7.71 – 7.62 (m, 2H, ArH), 7.49 –
7.42 (m, 3H, ArH), 7.42 – 7.37 (m, 1H, ArH), 7.37 –
7.30 (m, 2H, ArH), 7.23 – 7.14 (m, 2H, ArH), 4.06 (q,
J = 7.1 Hz, 2H, CO2CH2CH3), 3.98 (dd, J = 6.9, 5.7
Hz, 1H, HCCO2tBu), 2.42 – 2.31 (m, 2H, -CH2-),
2.30 – 2.15 (m, 2H, -CH2-), 1.46 (s, 9H, C(CH3)3),
1.21 (t, J = 7.1 Hz, 3H, CO2CH2CH3); 13C NMR (101
MHz, CDCl3) δ 170.2 (2C), 170.0, 135.9 (2C), 129.7,
128.2 (2C), 128.0, 127.8 (2C), 127.4 (2C), 127.2 (2C),
80.6, 64.3, 59.7, 30.2, 28.1, 27.5 (3C), 13.6; HRMS
(ESI): m/z [M + H]+ calcd for C24H29NO4 396.2175;
found: 396.2147.
General procedure for the synthesis of racemic 15.
Derivative 13 (40 mg, 0.14 mmol) and CsOH (20 mg,
0.14 mmol) were dissolved in anhydrous toluene (1.0
mL). Michael acceptor (0.20 mmol, 1.5 equiv.) 14
was then added to the vial and the reaction solution
was stirred at room temperature. Upon complete
consumption of starting material (1H NMR analysis),
the reaction solution was concentrated, and the crude
material was purified by flash silica column
chromatography.
(R)-1-tert-Butyl-5-
butyl
2-
(15c).
General procedure for the synthesis of 15 under
batch conditions. Si-12 (32 mg, loading = 0.47
mmol g-1, 15 mol%) or PS-12 (55 mg, loading = 0.45
mmol g−1, 25 mol%) were suspended in anhydrous
EtOAc (0.5 mL for Si-12; 1.5 mL for PS-12). Then,
13 (20 mg, 0.10 mmol) and the Michael acceptor 14
(0.30 mmol) were added to the vial and the reaction
was degassed under vacuum and saturated with argon
(by an Ar-filled balloon) three times. The mixture
was stirred at room temperature for 24 h. Then, the
mixture was centrifuged with fresh portions of THF
(4 × 7.0 mL) and Et2O (2 × 7.0 mL). The collected
supernatants were concentrated under vacuum and
elution of the resulting residue from a column of
silica with the suitable elution system afforded 15.
(diphenylmethyleneamino)pentanedioate
Column chromatography on silica gel (9:1
cyclohexane: EtOAc) afforded 15c (38 mg, 90%
yield) as a colorless oil with spectroscopic data in
accordance with the literature.[6e] [α]D = 78.2 (c 1.4
CHCl3); Chiral HPLC analysis Lux-Amylose-2 (92:8
hexane : IPA, flow rate 1 mL min−1, 254 nm, 20 °C)
1
tR (R): 8.3 min, tR (S): 9.8 min, 84.72:15.28 er; H
NMR (300 MHz, CDCl3) δ 7.64 (dd, J = 8.2, 1.4 Hz,
2H, ArH), 7.50 – 7.28 (m, 6H, ArH), 7.17 (dd, J = 6.7,
t
2.9 Hz, 2H, ArH), 4.09 – 3.87 (m, 3H, HCCO2 Bu,
CO2CH2 ), 2.42 – 2.27 (m, 2H, -CH2-), 2.27 – 2.15
(m, 2H, -CH2-), 1.61 – 1.48 (m, 2H, -CH2-), 1.44 (s,
9H, C(CH3)3), 1.39 – 1.20 (m, 2H, -CH2-), 0.90 (t, J =
7.3 Hz, 3H, -CH3); 13C NMR (101 MHz, CDCl3) δ
173.2, 170.8, 170.6, 139.4, 136.5, 130.3, 128.8 (2C),
128.5, 128.4 (2C), 128.0 (2C), 127.8 (2C), 81.1, 64.9,
64.2, 30.8, 30.6, 28.7, 28.0 (3C), 19.1, 13.7; HRMS
(ESI): m/z [M + H]+ calcd for C26H34NO4 424.2488;
found: 424.2450.
(R)-1-tert-Butyl-5-methyl
(diphenylmethyleneamino)pentanedioate
2-
(15a).
Column chromatography on silica gel (9:1
cyclohexane : EtOAc) afforded 15a (35 mg, 92%) as
a colorless oil with spectroscopic data in accordance
with the literature.[6e] [α]D = 73.2 (c 0.8 CHCl3); CSP
HPLC analysis Lux-Amylose-2 (92:8 hexane : IPA,
flow rate 1 mL min−1, 254 nm, 20 °C) tR (R): 9.1 min,
(R)-di-tert-Butyl
(diphenylmethyleneamino)pentanedioate
2-
(15d).
Reaction time: 48 h. Column chromatography on
silica gel (9:1 cyclohexane : EtOAc) afforded 15d (33
mg, 78%) as a colorless oil with spectroscopic data in
accordance with the literature.[6e] [α]D = 79.3 (c 0.9
1
tR (S): 10.5 min, 98.75:1.25 er; H NMR (400 MHz,
CDCl3) δ 7.67 – 7.59 (m, 2H, ArH), 7.48 – 7.37 (m,
3H, ArH), 7.42 – 7.30 (m, 1H, ArH), 7.35 – 7.25 (m,
2H, ArH), 7.21 – 7.10 (m, 2H, ArH), 3.96 (dd, J = 6.8, CHCl3); Chiral HPLC analysis Lux-Amylose-2 (92:8
5.7 Hz, 1H, HCCO2tBu), 3.59 (s, 3H,
-
hexane : IPA, flow rate 1 mL min−1, 254 nm, 20 °C)
1
CH2CH2CO2CH3) 2.42 – 2.32 (m, 2H, -CH2-), 2.27 –
2.15 (m, 2H, -CH2-), 1.44 (s, 9H, C(CH3)3). 13C NMR
(100 MHz, CDCl3) δ 173.7, 170.9, 170.8, 139.6,
136.6, 130.4, 128.9, 128.7, 128.6, 128.1, 127.9, 81.3,
64.9, 51.6, 30.6, 28.8, 28.2 (3C); HRMS (ESI): m/z
[M + H]+ calcd for C23H28NO4 382.4800; found:
382.4821. Gram-scale experiment: 13a (1.00 g, 3.39
tR (R): 7.2 min, tR (S): 8.6 min, 99.16:1.84 er; H
NMR (400 MHz, CDCl3) δ δ 7.70 – 7.59 (m, 2H,
ArH), 7.45 – 7.28 (m, 6H, ArH), 7.22 – 7.09 (m, 2H,
t
ArH), 3.93 (dd, J = 14.0, 8.2 Hz, 1H, HCCO2 Bu),
2.34 – 2.22 (m, 2H, -CH2-), 2.21 – 2.12 (m, 2H, -
CH2-), 1.43 (s, 9H, C(CH3)3), 1.38 (s, 9H, C(CH3)3);
13C NMR (101 MHz, CDCl3) δ 172.4, 170.9, 170.5,
11
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100757
Advanced Synthesis & Catalysis
139.5, 136.5, 130.2, 128.8 (2C), 128.5, 128.4 (2C),
128.0 (2C), 127.8 (2C), 81.0, 80.1, 65.0, 32.0, 28.9,
28.0 (6C); HRMS (ESI): m/z [M + H]+ calcd for
C29H32NO4 458.2331; found: 458.2322.
(3C), 14.1; HRMS (ESI): m/z [M + H]+ calcd for
+
C22H25N2O2 349.1916; found: 349.1929.
(R)-tert-Butyl
2-(diphenylmethyleneamino)-4-
(phenylsulfonyl)butanoate (15h). Reaction time: 48
h. Si-12: 53 mg (25 mol%). Column chromatography
on silica gel (45:55 cyclohexane : EtOAc) afforded
15h (28 mg, 61%) as a colorless oil with
spectroscopic data in accordance with the
literature.[6e] Chiral HPLC analysis Lux-Amylose-2
(85:15 hexane : IPA, flow rate 1 mL min−1, 240 nm,
20 °C) tR (R): 9.6 min, tR (S): 18.5 min, 80.02:19.98
er; 1H NMR (400 MHz, CDCl3) δ 7.96 – 7.83 (m, 2H,
ArH), 7.70 – 7.61 (m, 1H, ArH), 7.61 – 7.49 (m, 4H,
ArH), 7.49 – 7.35 (m, 4H, ArH), 7.36 – 7.27 (m, 2H,
ArH), 7.18 – 7.05 (m, 2H, ArH), 4.00 (dd, J = 6.6, 5.0
(R)-5-Benzyl-1-tert-butyl
(diphenylmethyleneamino)pentanedioate
2-
(15e).
Column chromatography on silica gel (92:8
cyclohexane : EtOAc) afforded 15e (32 mg, 70%) as
a colorless oil with spectroscopic data in accordance
with the literature.[6e] [α]D = 57.3 (c 1.1 CHCl3);
Chiral HPLC analysis Lux-Amylose-2 (92:8 hexane :
IPA, flow rate 1 mL min−1, 254 nm, 20 °C) tR (R):
1
10.6 min, tR (S): 13.5 min, 98.13:1.87 er; H NMR
(300 MHz, CDCl3) δ 7.71 – 7.56 (m, 2H, ArH), 7.46
– 7.27 (m, 10H, ArH), 7.20 – 7.07 (m, 2H, ArH), 5.03
(s, 2H, CO2CH2Ph ), 3.97 (dd, J = 7.0, 5.5 Hz, 1H,
t
Hz, 1H, HCCO2 Bu), 3.38 – 3.12 (m, 2H, CH2SO2Ph),
2.31 – 2.04 (m, 2H, CH2CH2SO2Ph), 1.39 – 1.36 (m,
t
13
HCCO2 Bu), 2.47 – 2.36 (m, 2H, -CH2-), 2.30 – 2.18
9H, C(CH3)3); C NMR (101 MHz, CDCl3) δ 171.5,
(m, 2H, -CH2-), 1.43 (s, 9H, C(CH3)3); 13C NMR (101
MHz, CDCl3) δ 172.9, 170.7 (2C), 139.4, 136.4,
135.9, 130.3, 128.8 (2C), 128.5 (2C), 128.5 (2C),
128.4 (2C), 128.1 (2C), 128.0 (2C), 127.7 (2C), 81.2,
66.2, 64.8, 30.7, 28.6, 28.0 (3C); HRMS(ESI+): m/z
[M + H]+ calcd for C26H34NO4 424.2488; found:
424.2449.
170.0, 139.1, 139.0, 136.2, 133.7, 130.7 (2C), 129.4
(2C), 128.9 (2C), 128.7 (2C), 128.2 (2C), 128.1 (2C),
127.7 (2C), 81.80, 63.6, 52.9, 28.0 (3C), 27.1; HRMS
(ESI): m/z [M + H]+ calcd for C27H30NO4S 464.1896;
found: 464.1867.
tert-Butyl-2-(diphenylmethyleneamino)-5-oxo-3,5-
diphenylpentanoate (15i). Column chromatography
on silica gel (45:55 cyclohexane : EtOAc) afforded
15i (35 mg, 70%) as a colorless oil with
spectroscopic data in accordance with the
literature.[6e] [α]D = 57.8 (c 0.8 CHCl3); Chiral HPLC
analysis Lux-Amylose-2 (85:15 Hexane:IPA, flow
rate 1 mL min−1, 240 nm, 20 °C) tR major: 9.6 min, tR
(R)-tert-Butyl
2-(diphenylmethyleneamino)-5-
oxohexanoate (15f). Column chromatography on
silica gel (9:1 cyclohexane : EtOAc) afforded 15f (33
mg, 90%) as a colorless oil with spectroscopic data in
accordance with the literature.[6e] [α]D = 64.3 (c 1.3
CHCl3); Chiral HPLC analysis Lux-Amylose-2 (92:8
hexane : IPA, flow rate 1 mL min−1, 270 nm, 20 °C)
1
minor: 18.5 min, 98.75:1.25 er; H NMR (400 MHz,
1
tR (R): 10.6 min, tR (S): 12.5 min, 97.80:2.20 er; H
CDCl3) δ 8.02 – 7.89 (m, 2H, ArH), 7.74 – 7.61 (m,
2H, ArH), 7.57 – 7.49 (m, 1H, ArH), 7.49 – 7.27 (m,
8H, ArH), 7.21 – 7.05 (m, 5H, ArH), 6.77 – 6.61 (m,
NMR (400 MHz, CDCl3) δ 7.68 – 7.58 (m, 2H, ArH),
7.50 – 7.27 (m, 6H, ArH), 7.20 – 7.12 (m, 2H, ArH),
t
t
3.95 (t, J = 6.1 Hz, 1H, HCCO2 Bu), 2.61 – 2.41 (m,
2H, ArH), 4.26 – 4.10 (m, 2H, NCHCO2 Bu, CHPh),
2H, -CH2-), 2.21 – 2.13 (m, 2H, -CH2-), 2.12 (s, 3H, -
COCH3), 1.43 (s, 9H, C(CH3)3); 13C NMR (101 MHz,
CDCl3) δ 208.3, 171.0, 170.5, 139.5, 136.5, 130.4,
3.74 (dd, J = 16.9, 9.5 Hz, 1H, CH2COPh), 3.60 (dd,
J = 16.9, 3.6 Hz, 1H, CH2COPh), 1.31 (s, 9H,
C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 198.7,
128.8 (2C), 128.7, 128.5 (2C), 128.1 (2C), 127.8 (2C), 171.2, 170.1, 141.4, 139.4, 137.3, 136.4, 132.9 (2C),
81.2, 64.8, 39.9, 30.0, 28.1 (3C), 27.8; HRMS (ESI):
m/z [M + H]+ calcd for C23H28NO3 366.2069; found:
366.20780.
130.4, 128.9 (2C), 128.6 (2C), 128.5 (2C), 128.4,
128.3 (2C), 128.2 (2C), 128.1 (2C), 127.6 (2C), 126.6,
81.4, 71.0, 44.8, 40.1, 27.9 (3C); HRMS (ESI): m/z
[M + H]+ calcd for C34H34NO3 504.2539; found:
504.2510.
(R)-tert-Butyl
4-cyano-2-
(15g).
(diphenylmethyleneamino)butanoate
Reaction time: 48 h. Si-12: 53 mg (25 mol%).
Column chromatography on silica gel (9:1
cyclohexane : EtOAc) afforded 15g (17 mg, 48%) as
a colorless oil with spectroscopic data in accordance
with the literature.[6e] [α]D = 29.1 (c 1.2 CHCl3);
Chiral HPLC analysis Lux-Amylose-2 (92:8 hexane :
IPA, flow rate 1 mL min−1, 254 nm, 20 °C) tR (R): 9.8
Recycle of Si-12. The solid supported catalyst of
Table 2 entries 12 and 13 (32 mg) was collected via
centrifugation from the reaction mixture after each
run, washed with EtOAc (3 × 9.0 mL), dried, and
suspended in 0.05 M LiOH solution in MeOH (2.0
mL). The mixture was stirred at room temperature for
30 minutes. Then the mixture was centrifugated and
the reactivation protocol was repeated. After
centrifugation and removal of the basic solution, the
silica was sequentially washed with MeOH (2 × 9.0
mL), THF (3 × 9.0 mL) and EtOAc (1 × 9.0 mL).
Later, before being used in the next cycle, the
restored solid supported cyclopropenimine superbase
was weighed to exclude any loss of mass and the
integrity of organic moiety was confirmed by
1
min, tR (S): 11.1 min, 82.82:17.18 er; H NMR (300
MHz, CDCl3) δ 7.71 – 7.59 (m, 2H, ArH), 7.53 –
7.29 (m, 6H, ArH), 7.24 – 7.13 (m, 2H, ArH), 4.05
t
(dd, J = 7.7, 4.6 Hz, 1H, HCCO2 Bu), 2.62 – 2.38 (m,
2H, -CH2-), 2.38 – 2.10 (m, 2H, -CH2-), 1.43 (s, 9H,
C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 172.4, 170.2,
139.5, 136.4, 131.0 (2C), 129.2 (2C), 129.0 (2C),
128.4 (2C), 128.0 (2C), 119.8, 82.1, 64.1, 29.8, 28.3
12
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100757
Advanced Synthesis & Catalysis
elemental analysis (Elemental analysis (%) found N
1.91 C 25.83 H 3.29 S 2.62).
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Fabrication of mesoreactor R. A slurry solution
was prepared suspending an excess of catalyst Si-12
in anhydrous EtOAc. A stainless-steel column (10 ×
0.46 cm) was filled with the slurry solution under
constant pressure (300 bars, 30 min, EtOAc as
solvent) by using an air driven liquid pump.
Microreactor void volume (V0) was determined by
pycnometry, filling and weighting accurately the
mesoreactor with two different solvents (solvent 1:
chloroform; solvent 2: n-hexane). V0 was calculated
according to the following formula where w1 and w2
are the weights of the microreactor filled respectively
with solvents 1 and 2 and δ1 and δ2 are the solvent
densities: V0 = (w1- w2)/( δ1- δ2)
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Experimental set-up for flow experiments. The
system used for the flow reaction was made of one
pump (Agilent 1100 micro series) connected to the
reactor by a feeding channel. The channel was used
to deliver a continuously degassed solution of 13
(0.04 M) and 14a (0.12 M) in anhydrous EtOAc . The
feed solution was pumped with a flow rate of 5 L
min-1 into R for 24 h. The collected solution was
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1
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Long-term stability experiment. The long-term
stability investigation was performed restoring the
catalytic activity of the packing material Si-12 after
24 h of usage. Mesoreactor R packed with Si-12 was
washed with EtOAc for 1 h with a flow rate of 10 L
min-1. Then a 0.05 M solution of LiOH in anhydrous
MeOH was fluxed inside R for 2 h (10 L min-1 flow
rate), which was subsequently washed with
anhydrous MeOH (1 h, 10 L min-1 flow rate) and
anhydrous EtOAc (1 h; 10 L min-1 flow rate). The
restored activity of the catalyst Si-12 was determined
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Acknowledgements
We gratefully acknowledge the University of Ferrara (fondi FAR)
for financial support. Thanks are also given to Paolo Formaglio
for NMR experiments, to Tatiana Bernardi for HRMS analyses,
and to Ercolina Bianchini for elemental analyses.
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14
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Advanced Synthesis & Catalysis
FULL PAPER
Expanding the Toolbox of Heterogeneous
Asymmetric Organocatalysts: Bifunctional
Cyclopropenimine Superbases for Enantioselective
Catalysis in Batch and Continuous Flow
Adv. Synth. Catal. Year, Volume, Page – Page
organic superbase
OH
N
Si
TOC Graphic
Ph
N
CO2tBu
Cy2N
recyclable
NCy2
Ph
N
CO2tBu
Ph
+
Ph
- batch process
- flow process
EWG
EWG
up to 92% yield
up to 98% ee
Costanza Leonardi,a Arianna Brandolese,a Lorenzo
Preti,a Olga Bortolini,a Eleonora Polo,b Paolo
Dambruoso,b Daniele Ragno,a Graziano Di
Carmine,a,* and Alessandro Massia,*
15
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