Stereoselective reduction of imines with trichlorosilane using solid-supported chiral picolinamides

Article abstract of DOI:10.3390/molecules21091182

The stereoselective reduction of imines with trichlorosilane catalyzed by chiral Lewis bases is a well-established procedure for the synthesis of enantio-enriched amines. Five supported cinchona-based picolinamides have been prepared and their activity te

Full text of DOI:10.3390/molecules21091182

molecules
Article
Stereoselective Reduction of Imines with
Trichlorosilane Using Solid-Supported
Chiral Picolinamides
Sílvia D. Fernandes 1, Riccardo Porta 2,*, Pedro C. Barrulas 1, Alessandra Puglisi 2,
Anthony J. Burke 1,* and Maurizio Benaglia 2,
*
1
Department of Chemistry and Chemistry Center of Évora, School of Science and Technology and Institute
for Research and Advanced Studies, University of Évora, Rua Romão Ramalho 59, Évora 7000, Portugal;
silvia.fernandes@gmail.com (S.D.F.); pedro.barrulas@gmail.com (P.C.B.)
Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, Milano 20133, Italy;
alessandra.puglisi@unimi.it
2
*
Correspondence: riccardo.porta@unimi.it (R.P.); ajb@uevora.pt (A.J.B.); maurizio.benaglia@unimi.it (M.B.);
Tel.: +39-0250-314-178 (R.P.); +351-266-745-310 (A.J.B.); Tel./Fax: +39-0250-314-171 (M.B.);
Fax: +351-266-745-394 (A.J.B.)
Academic Editor: Derek J. McPhee
Received: 28 July 2016; Accepted: 1 September 2016; Published: 6 September 2016
Abstract: The stereoselective reduction of imines with trichlorosilane catalyzed by chiral Lewis
bases is a well-established procedure for the synthesis of enantio-enriched amines. Five supported
cinchona-based picolinamides have been prepared and their activity tested in a model reaction.
The comparison of different supporting materials revealed that polystyrene gave better results than
silica in terms of stereoselectivity. The applicability of the solid-supported catalyst of choice to the
reduction of different imines was also demonstrated. Additionally, for the first time, a catalytic reactor
containing a polymer-immobilized chiral picolinamide has been employed for the stereoselective
reduction of imines with trichlorosilane under continuous flow conditions.
Keywords: supported catalysis; catalytic reactors; trichlorosilane; chiral picolinamides; organocatalysis
;
flow chemistry
1. Introduction
Nowadays, chiral organocatalysts can be successfully employed as alternative catalytic species to
enzymes or chiral organometallic complexes to perform stereoselective transformations [1]. However,
the main issue associated with the use of organic molecules as catalysts is the need of high loadings
(typically 1–10 mol %) when compared to other systems. The immobilization of the catalysts onto a
solid support can overcome this drawback favoring an easy recovery and recycling of the catalytic
species [
2
–4]. More recently, the combination of supported catalysts with continuous flow processes
resulted in the development of catalytic reactors: [5,6] in these systems, the insoluble catalyst is confined
to the reactors and purification steps necessary to isolate the product are significantly reduced [7]. Due to
the absence of coordinated metal species, solid supported organocatalysts are particularly suitable to
the application in catalytic reactors, since the risk of metal leaching is intrinsically avoided [8,9].
Among the metal-free methodologies available for the enantioselective reduction of imines [10,11],
the use of trichlorosilane represents one of the most successful ways. The low cost of the reducing
agent made the reduction method very attractive and pushed numerous groups to develop several
different classes of chiral Lewis bases able to guarantee excellent levels of enantioselectivity in the
reduction of differently functionalized ketoimines [12–16].
Molecules 2016, 21, 1182; doi:10.3390/molecules21091182
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In the literature, only a few reports on the stereoselective reduction of imines with trichlorosilane
promoted by solid supported chiral organocatalysts have appeared. Kocovsky’s research group
reported the use of supported chiral formamides derived from N-methyl valine for the reduction of
ketoimines with HSiCl3. These catalysts were supported onto insoluble [17] and soluble polymers [18
]
as well as onto soluble dendrons [19]. These systems showed good reactivity, enantioselectivities up to
91%, and could be easily recycled. However, the application of supported chiral organocatalysts in a
catalytic reactor for the reduction of imines with HSiCl3 is still unknown. Here we wish to report the
first example of a continuous flow process for the stereoselective synthesis of chiral amines mediated
by trichlorosilane using solid supported picolinamides.
2. Results and Discussion
2.1. Catalyst Synthesis
In this work, we prepared five solid supported chiral picolinamides derived from cinchona
alkaloid primary amines using silica and polystyrene as supporting material. The general strategy
to prepare silica supported catalysts involved the functionalization of the double bond of the
quinuclidine ring with a trimethoxysilyl derivative, necessary to graft onto commercially available silica
nanoparticles. The synthesis of catalysts
A and B is illustrated in Figure 1. The primary amine derived
from cinchona alkaloids (1a or 1b) was converted into the corresponding picolinamide by reaction with
picolinic acid and isobutyl chloroformate in the presence of triethylamine (TEA) in THF. The double
bonds of compounds 2a and 2b were then quantitatively converted into trimethoxysilyl derivatives
3
by reaction with trimethoxysilane HSi(OMe3) using dcpPtCl2 as a catalyst for the hydrosilylation
reaction. Final grafting was performed in the presence of commercially available SiO2 nanoparticles
(Apex Prepsil Silica Media 8
weight difference.
µ
m) in toluene at 80 ◦C for 24 h. Catalyst loadings were determined by
Figure 1. Synthesis of silica-supported catalysts A and B.
As illustrated in Figure 2, polystyrene supported catalyst
, a supported organocatalyst available in our laboratories [20]. 4
C
was prepared starting from compound
was reacted with picolinic acid and
4
thionyl chloride in the presence of triethylamine in DMF for 18 h at room temperature. The loading of
C (0.4 mmol/g) was determined from the loading of the starting material 3 [21].

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Figure 2. Synthesis of polystyrene-supported catalyst C.
For the preparation of polystyrene supported catalyst
(Figure 3): chiral picolinamide 2c derived from 9-amino-epi-cinchonine was subjected to radical
initiated thiol-ene coupling (initiated by AIBN) with solid , a polystyrene bearing a thiol
functionality [22]. The loading of D (0.3 mmol/g) was determined by weight difference.
D an alternative strategy was employed
5
Figure 3. Synthesis of polystyrene-supported catalyst D.
Catalyst
E (loading = 0.2 mmol/g) was prepared starting from picolinamide 2b following the
same strategy used for the preparation of D (Figure 4).
Figure 4. Synthesis of polystyrene-supported catalyst E.
2.2. Stereoselective Reduction of Imines with HSiCl3 in Batch
The solid-supported catalysts were tested in the reduction of imine 6a with HSiCl3 in CH2Cl2
at room temperature for 18 h. Silica supported catalyst gave the corresponding amine 7a in moderate
yield and low ee (Table 1, entry 1). The use of catalyst resulted in a complete conversion of the starting
material and the enantioselectivity improved up to 62% (entry 2). The use of polystyrene-supported
catalyst afforded chiral amine 7a in 95% yield but very low ee of 23% (entry 3); this was probably
due to an incomplete conversion of primary amine into 23]. Gratifyingly, upon using polystyrene
supported catalyst , the reaction proceeded in quantitative yield and 90% ee (entry 4), a result
comparable to the one obtained with the homogeneous catalyst [24]. Lowering the catalyst loading to
10 mol % did not alter the reaction outcome (entry 5), while using 5 mol % of resulted in slightly
amine 7a obtained a 98% yield and a lower
A–E
A
B
C
4
C [
D
D
lower ee (entry 6). Using the pseudo enantiomer catalyst
ee of 63% (entry 7).
E

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Table 1. Screening of supported catalysts in the reduction of imine 6a with HSiCl3.
Entry 1
Catalyst
Yield (%) 2
ee (%) 3
1
2
3
A
B
64
95
95
98
95
95
95
30 (S)
62 (S)
23 (S)
90 (R)
91 (R)
79 (R)
63 (S)
C
D
D
D
E
4
5 4
6 5
7
1
Reaction conditions: 0.1 mmol 6a, 0.02 mmol supported catalyst, 0.5 mmol HSiCl3 in CH2Cl2 (1 mL); 2 isolated
yield; 3 determined by HPLC on chiral stationary phase; 4 10 mol % of D was used; 5 5 mol % of D was used.
Having established the best reaction conditions, we tested catalyst of choice
D in the reduction
of different substituted imines with HSiCl3 (Table 2). Electron poor imine 6b was converted into the
corresponding chiral amine 7b with 93% yield and 85% ee (entry1). 4-Fluoro-substituted imine 6c and
4-trifluoromethyl-substituted imine 6d afforded the corresponding products 7c and 7d in quantitative
yield and 87% and 84% ee, respectively (entries 2 and 3). The reaction with electron rich imine 6e
afforded amine 7e in 96% ee and 85% ee (entry 4).
Table 2. Reduction of various imines with HSiCl3 using polystyrene supported catalyst D.
Entry 1
R
PG
Yield (%) 2
ee (%) 3
1
2
3
4
6b: 4-NO2-C6H4-
6c: 4-F-C6H4-
6d: 4-CF3-C6H4-
6e: Naphtyl
PMP
PMP
PMP
Ph
93
98
97
96
85
87
84
85
1 Reaction conditions: 0.1 mmol , 0.5 mmol HSiCl3 in CH2Cl2 (1 mL); 2 isolated yield; 3 determined
6, 0.01 mmol D
by HPLC on chiral stationary phase.
2.3. Continuous Flow Reaction
We next decided to focus our attention on the preparation of catalytic reactors in order to
perform the stereoselective reduction of imines with trichlorosilane under continuous flow conditions.
Preliminary studies showed that recovery and recycling of the immobilized catalyst were feasible: in
the same conditions of Table 1, entry 4, polystyrene-supported picolinamide
D was recycled three
times. However, while after the first recycle (second run) the reaction promoted a 90% yield and 88%
ee, already after the second recycle a clear decrease in enantioselectivity was observed (80% yield,
67% ee), that further dropped in the fourth run (77% yield, 37% ee). However, the behavior of the
supported catalyst under continuous flow conditions was investigated.
A Omnifit glass column (i.d. = 1 cm, l = 10 cm) was filled with catalyst
D (170 mg, 0.05 mmol)
and was equipped with one fixed-length endpiece and one adjustable-length endpiece (bed length
= 1 cm, internal volume = 0.78 mL): See Supplementary Materials. A 0.05 M solution of imine 6b
and trichlorosilane (5 equiv.) in dry dichloromethane was injected to the reactor through a syringe
pump with a flow rate of 0.02 mL/min (residence time 25 min, determined experimentally) at room

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temperature. The outcome of the reactor was collected into a flask containing NaOH 10% solution. After
phase separation and concentration, the product was isolated with no need for further purifications.
Every 25 min, the product was collected and analyzed in order to determine the conversion and the ee.
Results of the continuous flow experiments are reported in Table 3.
Table 3. Continuous flow stereoselective reduction of imine 6b with HSiCl3.
Entry
Running Time (min)
Yield (%) 1
ee (%) 2
1
3
4
5
6
7
1
0–50
50–75
75–100
100–125
125–150
150–175
98
98
93
93
87
86
47
44
30
25
22
20
Determined by 1H-NMR; 2 determined by HPLC on chiral stationary phase.
As reported in Table 3, the continuous flow process was run for 3 h and chiral amine 7b was
continuously obtained in very high yield. Unfortunately, the enantioselectivity of the process was
quite low and it dropped to 47% ee (Table 3, entry 1) and to 20% after 150 h of operation (entry 7).
Some organic residues coming from the catalyst degradation have been detected in the crude reaction
mixture and that may account for the low enantioselectivity observed.
Overall, these results demonstrate how the use of a catalytic reactor can be advantageous in
terms of product isolation and unit operations, however the system requires further studies in order to
increase the stereoselectivity of the process.
3. Materials and Methods
3.1. General Information
Dry solvents were purchased and stored under nitrogen over molecular sieves (bottles with crown
caps). Reactions were monitored by analytical thin-layer chromatography (TLC) using silica gel 60 F
254 pre-coated glass plates (0.25 mm thickness) and visualized using UV light. Flash chromatography
was carried out on silica gel (230–400 mesh). Proton NMR spectra were recorded on spectrometers
operating at 300 MHz (Bruker Fourier 300 or AMX 300, Milano, Italy). Proton chemical shifts are
reported in ppm (
internal standard (CDCl3
δ
) with the solvent reference relative to tetramethylsilane (TMS) employed as the
= 7.26 ppm). Commercial grade reagents and solvents were used without
δ
further purifications. Commercially available HSiCl3was freshly distilled under nitrogen atmosphere
before use. Reagents mixtures were fed to continuous flow reactors using Syringe Pump Chemix Fusion
100. Continuous flow catalytic reactors were prepared using Glass Omnifit columns (Sigma-Aldrich,
Milano, Italy) equipped with one adjustable-length end piece.
3.2. Catalysts Synthesis
Compound 2a: Picolinic acid (1.5 mmol) was placed into a two necked flask and dissolved in dry
THF (12 mL) under nitrogen atmosphere. Triethylamine (2.2 mmol) was added and the mixture was
cooled to 0 ◦C. Ethyl chloroformate (1.5 mmol) was added dropwise and the mixture was stirred for

Molecules 2016, 21, 1182
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15 min at the same temperature, then 2 h at room temperature. After reaction time, a solution of
1a 25] (1.5 mmol) in dry THF (8 mL), was added slowly. The reaction was stirred at room temperature
[
for 3 h. After reaction time, H2O (3 mL) was added and the crude was concentrated in vacuum,
diluted with AcOEt and then washed with H2O. Collected organic phases were dried with Na2SO4,
concentrated in a vacuum, and the residue was purified by column chromatography on silica gel
eluting with CH2Cl2:MeOH 95:5. Compound 2a was obtained as brownish oil (1.04 mmol, 77% yield).
1
All analytical data are in agreement with literature [24]. H-NMR (300 MHz, CDCl3) δH 8.88 (br s, 1H),
8.70 (d, J = 4 Hz, 1H), 8.46 (d, J = 4 Hz, 1H), 8.03–7.96 (m, 2H), 7.75 (d, J = 3 Hz, 1H), 7.71–7.66 (m, 1H),
7.42 (d, J = 4 Hz, 1H), 7.34–7.26 (m, 2H), 5.80–5.69 (m, 1H), 5.62 (br s, 1H), 5.01–4.91 (m, 2H), 3.94 (s,
3H), 3.44–3.36 (m, 1H), 3.33–3.23 (m, 2H), 2.81–2.68 (m, 2H), 2.27 (br, 1H), 1.66–1.48 (m, 4H), 0.96–0.88
(m, 1H).
Compound 2b: prepared starting from 1b
[
25] according to the procedure described for 2a (1.25 mmol,
1
75% yield). H-NMR (300 MHz, CDCl3) δH 8.98 (br s, 1H), 8.89 (d, J = 4 Hz, 1H), 8.48–8.43 (m, 2H),
8.13 (d, J = 7 Hz, 1H), 8.03 (d, J = 2 Hz, 1H), 7.75–7.69 (m, 1H), 7.65–7.60 (m, 1H), 7.50–7.49 (d, J = 4 Hz,
1H), 7.37 (dd, J = 2 Hz, 5 Hz, 1H), 5.80–5.69 (m, 1H), 5.64 (br s, 1H), 5.03–4.94 (m, 2H), 3.42–3.18 (m,
3H), 2.88–2.73 (m, 2H), 2.31 (br s, 1H), 1.71–1.53 (m, 3H), 1.50–1.42 (m, 1H), 0.99–0.92 (m, 2H).
Compound 2c: prepared starting from 1c
[
25] according to the procedure described for 2a (1.17 mmol,
1
78% yield). H-NMR (300 MHz, CDCl3) δH 9.04–8.93 (m, 1H), 8.85 (d, J = 4 Hz, 1H), 8.56 (d, J = 5 Hz,
1H), 8.46–8.40 (m, 1H), 8.11 (d, J = 8 Hz, 1H), 8.02–7.99 (m, 1H), 7.76–7.68 (m, 2H), 7.62–7.57 (m, 1H),
7.50–7.46 (m, 1H), 7.37–7.33 (m, 1H), 5.95–5.84 (m, 1H), 5.60 (br s, 1H), 5.15–5.07 (m, 2H), 3.28–3.19
(m, 1H), 3.11–2.91 (m, 4H), 2.33–2.22 (m, 1H), 1.67–1.61 (m, 1H), 1.57–1.45 (m, 2H), 1.35–1.24 (m, 1H),
1.04–0.93 (m, 1H).
Compound 3a: 2a (0.5 mmol) and (dcp)PtCl2 (0.025 mmol) were dissolved in dry THF (8 mL) under
nitrogen atmosphere and trimethoxysilane HSi(OMe)3 (1.5 mmol) was slowly added. The mixture
was stirred at 60 ◦C for 24 h. After reaction time, the solvent was evaporated under vacuum and 3a
was obtained as brownish oil (0.5 mmol, 99% yield). It was used in the following step without any
1
further purification (the product easily degrades during column chromatography). H-NMR (300 MHz,
CDCl3) δH 8.94 (bs, 1H), 8.71 (d, 1H), 8.52 (bs, 1H), 7.97–8.05 (m, 2H), 7.74 (bs, 2H), 7.43 (s, 1H), 7.33 (d,
2H), 6.61 (bs, 1H), 3.96 (s, 3H), 3.59 (s, 9H), 3.26–3.34 (m, 2H), 3.06 (bs, 1H), 2.80 (bs, 1H), 2.48 (bs, 1H),
1.86 (m, 2H), 1.59–1.72 (m, 3H), 1.35 (m, 2H), 0.98 (bs, 1H), 0.52 (m, 2H) ppm.
Compound 3b: prepared starting from 2b according to the procedure described for 3a (0.5 mmol, 99%
yield). It was used in the following step without any further purification (the product easily degrades
1
during column chromatography). H-NMR (300 MHz, CDCl3) δH 9.28 (m, 1H), 8.91 (d, 1H), 8.49–8.54
(m, 2H), 8.13 (d, 1H), 8.06 (d, 1H), 7.63–7.76 (m, 4H), 7.36 (m, 1H), 5.97 (bs, 1H), 3.55 (s, 9H), 3.26–3.31
(m, 2H), 3.08 (bs, 1H), 2.80 (bs, 1H), 2.45 (bs, 1H), 1.88 (m, 2H), 1.54–1.72 (m, 3H), 1.33 (m, 2H), 1.09 (bs,
1H), 0.85 (m, 2H) ppm.
Catalyst
A: Compound 3a (0.5 mmol) was dissolved in dry toluene (10 mL) under a nitrogen
atmosphere and then Apex Prepsil Silica Media 8
µ
m (0.5 g) was added. The mixture was stirred at
80 ◦C for 48 h after which it was then filtered. The solid was washed with dichloromethane (10 mL)
and methanol (10 mL), and it was recovered and dried under high vacuum for 3 h. The organic layer
was concentrated under a vacuum and unreacted compound 3a was recovered.
yellowish solid; the loading was determined by weight difference (0.52 g, 0.5 mmol/g).
A
was obtained as a
(0.52 g,
4 [20] (0.25 g, 0.1 mmol) and triethylamine (0.5 mmol) in dry THF (6 mL)
Catalyst
0.4 mmol/g).
Catalyst
B
: prepared starting from 3b according to the procedure described for
A
C
: a mixture of
was cooled to 0 ◦C. Then a solution of picolynoil chloride (0.3 mmol) in dry THF (3 mL)◦was slowly
added under nitrogen atmosphere. The mixture warmed to rt and then stirred at 60 C for 24 h.
After reaction time the solid was filtered, washed with dichloromethane (10 mL) and methanol (10 mL),

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and it was recovered and dried under a high vacuum for 3 h. The loading of C was determined from
the loading of the starting material (0.26 g, 0.4 mmol/g).
Catalyst
D: 5 [22] (0.63 g, 1.0 mmol/g) was suspended in dry toluene (10 mL) under nitrogen
atmosphere and then a solution of 2c (1.0 mmol, g) and AIBN (1.0 mmol) in dry chloroform (3 mL) was
◦
slowly added. The mixture was stirred at 80 C for 24 h under nitrogen atmosphere. After this reaction
time, the solid was filtered and washed with CH2Cl2 (10 mL) and methanol (10 mL) and then dried
under high vacuum for 3 h. The organic layer was concentrated in vacuum and unreacted compound 2c
was recovered and purified by column chromatography. The loading of
D was determined by weight
difference (0.65 g, 0.3 mmol/g). So far, solid state NMR spectroscopy did not give well defined spectra:
further studies are underway to characterize the immobilized catalysts, also through solid-state IR
spectroscopy and electron microscopy (SEM, TEM).
Catalyst E: prepared starting from 2b and 5 according to the procedure described for D (0.65 g,
0.2 mmol/g).
3.3. Stereoselective Reduction of Imines
General procedure for batch reaction: supported catalyst (0.02 mmol) and imine (0.1 mmol) were
introduced into a vial and dissolved in dry CH2Cl2 (1 mL) under inert atmosphere. HSiCl3 (1 M
◦
solution in CH2Cl2, 5 equiv.) was added at 0 C and then the reaction was stirred at room temperature
for 18 h. After this reaction time, the supported catalyst was removed by filtration and washed with
dichloromethane. The organic layer was treated with NaOH 10% aq. until basic pH = 9. The organic
layer was collected, dried with Na2SO4, and concentrated under a vacuum. The residue was purified
by column chromatography on silica gel. The enantiomeric excess was determined by HPLC on chiral
stationary phase.
General procedure for continuous flow reaction: a 0.05 M mixture of imine 6b and HSiCl3 (5 equiv.) in
dry CH2Cl2 was charged into a 2.5 mL SGE gas tight syringe and fixed on a syringe pump. The syringe
was connected to the packed bed reactor and flushed at 0.02 mL/min. The reactor was then washed
with pure CH2Cl2 at the same flow rate. Reactor outcome was collected into a flask containing CH2Cl2
and NaOH 10%. The outcome of the reactor was collected into a flask containing NaOH 10% solution.
After phase separation and concentration, the product was isolated. Each 25 min the product was
collected and analyzed. The yield was determined by NMR and the ee was determined on HPLC on
chiral stationary phase.
3.4. Product Characterization
(R)-4-Methoxy-N-(1-phenylethyl)aniline 7a: prepared according to the general procedure. The crude
mixture was purified by column chromatography on silica gel eluting with hexane/ethyl acetate 95:5.
1
7a was obtained as a yellowish solid. All analytical data are in agreement with literature. H-NMR
(300 MHz, CDCl3) δH 7.43–7.26 (m, 5H), 6.73 (d, 2H), 6.58 (d, 2H), 4.46 (q, 1H), 3.74 (s, 3H), 1.58
(d, 3H) ppm. The enantiomeric excess was determined by HPLC on chiral stationary phase with
Daicel Chiralcel OD-H column: eluent Hexane/iPrOH = 99/1, flow rate 0.8 mL/min,
λ = 254 nm,
τmajor = 22.3 min, τminor = 25.1 min.
(R)-4-Methoxy-N-(1-(4-nitrophenyl)ethyl)aniline 7b: prepared according to the general procedure.
The crude mixture was purified by column chromatography on silica gel eluting with hexane/ethyl
acetate 95:5. 7b was obtained as a yellowish solid. All analytical data are in agreement with the
literature. 1H-NMR (300 MHz, CDCl3) δH 8.16–8.19 (m, 2H), 7.53–7.56 (d, 2H), 6.68–6.71 (m, 2H),
6.39–6.42 (m, 2H), 4.47–4.52 (q, 1H), 3.86 (bs, 1H), 3.69 (s, 3H), 1.52–1.53 (d, 3H) ppm. The enantiomeric
excess was determined by HPLC on a chiral stationary phase with Daicel Chiralcel OD-H column:
eluent Hexane/iPrOH = 8/2, flow rate 0.8 mL/min, λ = 254 nm, τmajor = 31.6 min, τminor = 37.7 min.
(R)-N-(1-(4-Fluorophenyl)ethyl)-4-methoxyaniline 7c: prepared according to the general procedure.
The crude mixture was purified by column chromatography on silica gel eluting with hexane/ethyl
acetate 95:5. 7c was obtained as a yellowish solid. All analytical data are in agreement with the

Molecules 2016, 21, 1182
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literature. 1H-NMR (300 MHz, CDCl3) δH 7.28–7.33 (m, 2H), 6.95–7.00 (m, 2H), 6.68 (d, 2H), 6.43
(d, 2H), 4.37 (q, 1H), 3.68 (s, 4H), 1.45 (d, 3H) ppm. The enantiomeric excess was determined by HPLC
on chiral stationary phase with Daicel Chiralcel OD-H column: eluent Hexane/iPrOH = 97/3, flow
rate 1.0 mL/min, λ = 254 nm, τmajor = 14.2 min, τminor = 16.5 min.
(R)-4-Methoxy-N-(1-(4-(trifluoromethyl)phenyl)ethyl)aniline 7d: prepared according to the general
procedure. The crude mixture was purified by column chromatography on silica gel eluting with
hexane/ethyl acetate 95:5. 7d was obtained as a yellowish solid. All analytical data are in agreement
1
with literature. H-NMR (300 MHz, CDCl3) δH 7.56 (d, 2H), 7.47 (d, 2H), 6.69 (d, 2H), 6.42 (d, 2H), 4.44
(q, 1H), 3.81 (bs, 1H), 3.68 (s, 3H), 1.48 (d, 3H) ppm. The enantiomeric excess was determined by HPLC
on chiral stationary phase with Daicel Chiralcel OD-H column: eluent Hexane/iPrOH = 98/2, flow
rate 0.8 mL/min, λ = 254 nm, τmajor = 17.7 min, τminor = 21.9 min.
(R)-4-Methoxy-N-(1-(naphthalen-2-yl)ethyl)aniline 7e: Prepared according to the general procedure.
The crude mixture was purified by column chromatography on silica gel eluting with hexane/ethyl
acetate 95:5. 7e was obtained as a yellowish solid. All analytical data are in agreement with literature.
1H-NMR (300 MHz, CDCl3) δH 7.78–7.82 (m, 4H), 7.41–7.51 (m, 3H), 6.65–6.69 (m, 2H), 6.48–6.52
(m, 2H), 4.53–4.58 (q, 1H), 3.88 (br, 1H), 3.66 (s, 3H), 1.55–1.57 (d, J = 6.8 Hz, 3H) ppm. The enantiomeric
excess was determined by HPLC on chiral stationary phase with Daicel Chiralcel OD-H column: eluent
Hexane/iPrOH = 98/2, flow rate 1.0 mL/min, λ = 254 nm, τmajor = 41.7 min, τminor = 52.7 min.
4. Conclusions
In conclusion, the immobilization of chiral Cinchona alkaloid-derived catalysts for the
enantioselective, trichlorosilane-mediated reduction of ketoimines was investigated. A polystyrene-
supported picolinamide was identified as a successful heterogeneous organocatalyst able to promote
the C=N reduction of imines in high enantioselectivities, typically higher than 85% ee and up to 91%
ee. Additionally, for the first time, a polymer-supported chiral organocatalyst was used in a catalytic
reactor to perform the enantioselective reduction of imines in a continuous flow process. The flow
systems showed promising results in terms of chemical activity, but lower enantioselectivities than
those obtained in batch. Further studies aimed to improve the stereoselectivity of the process and the
stability of the supported chiral catalyst are currently underway in our laboratories.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
9/1182/s1.
Acknowledgments: RP thanks UNIMI for a doctoral fellowship. MB thanks CNR for the bilateral project
FCT/CNR 2015-2016 (Ref. 441.00) “Exploring novel organocatalytic enantioselective reductions for accessing key
drugs for Neurodegenerative disease treatment”. AJB thanks bilateral project FCT/CNR 2015-2016 (Ref. 441.00).
Author Contributions: P.C.B., A.J.B. and M.B. conceived and designed the experiments; S.D.F. and R.P. performed
the experiments; R.P., M.B. and A.J.B. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
References and Notes
1.
Okhuma, T.; Noyori, R. Comprehensive Asymmetric Catalysis; Jacobsen, E.N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, NY, USA, 2004.
2.
3.
Benaglia, M. Recoverable and Recyclable Catalysts; Wiley-VCH: Weinheim, Germany, 2009.
Trindade, A.F.; Gois, P.M.P.; Afonso, C.A.M. Recyclable Stereoselective Catalysts. Chem. Rev. 2009, 109, 418.
[CrossRef] [PubMed]
4.
5.
6.
Haraguchi, N; Itsuno, S. Polymeric Chiral Catalyst Design and Chiral Polymer Synthesis; John Wiley & Sons:
Hoboken, NJ, USA, 2011.
Puglisi, A.; Benaglia, M.; Chiroli, V. Stereoselective organic reactions promoted by immobilized chiral
catalysts in continuous flow systems. Green Chem. 2013, 15, 1790–1813. [CrossRef]
Tsubogo, T.; Ishiwata, T.; Kobayashi, S. Asymmetric Carbon-Carbon Bond Formation under Continuous-Flow
Conditions with Chiral Heterogeneous Catalysts. Angew. Chem. Int. Ed. 2013, 52, 6590. [CrossRef] [PubMed]

Molecules 2016, 21, 1182
9 of 9
7.
8.
Porta, R.; Benaglia, M.; Puglisi, A. Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical
Products. Org. Proc. Res. Dev. 2016, 20, 2–25. [CrossRef]
Cantillo, D.; Kappe, C.O. Immobilized Transition Metals as Catalysts for Cross-Couplings in Continuous
Flow—A Critical Assessment of the Reaction Mechanism and Metal Leaching. ChemCatChem 2014, 6, 3286.
[CrossRef]
9.
Gursel, I.V.; Noel, T.; Wang, Q.; Hessel, V. Separation/recycling methods for homogeneous transition metal
catalysts in continuous flow. Green Chem. 2015, 17, 2012. [CrossRef]
10. Benaglia, M.; Genoni, A.; Bonsignore, M. Enantioselective organocatalytic reductions. In Stereoselective
Organocatalysis: From C-C to C-Heteroatom Bond Formation; Torres, R.R., Ed.; Wiley: Hoboken, NJ, USA, 2012.
11. Rossi, S.; Benaglia, M.; Massolo, E.; Raimondi, L. Organocatalytic strategies for enantioselective metal-free
reductions. Catal. Sci. Technol. 2014, 9, 2708. [CrossRef]
12. Guizzetti, S.; Benaglia, M. Trichlorosilane-Mediated Stereoselective Reduction of C=N Bonds. Eur. J.
Org. Chem. 2010, 5529. [CrossRef]
13. Jones, S.; Warner, C.J.A. Trichlorosilane mediated asymmetric reductions of the C=N double bon.
Org. Biomol. Chem. 2012, 10, 2189. [CrossRef] [PubMed]
14. For a seminal work in this field see: Malkov, A.V.; Mariani, A.; MacDougall, K.N.; Kocovsy, P. Role of
Noncovalent Interactions in the Enantioselective Reduction of Aromatic Ketimines with Trichlorosilane.
Org. Lett. 2004, 6, 2253. [CrossRef] [PubMed]
15. For recent works in the field see the following: Ye, J.; Wang, C.; Chen, L.; Wu, X.; Zhou, L.; Sun, J. Chiral
Lewis Base-Catalyzed, Enantioselective Reduction of Unprotected β-Enamino Esters with Trichlorosilane.
Adv. Synth. Catal. 2016. [CrossRef]
16. Wang, T.; Di, X.; Wang, C.; Li, Z.; Sun, J. Reductive Hydrazination with Trichlorosilane: A Method for the
Preparation of 1,1-Disubstituted Hydrazines. Org. Lett. 2016. [CrossRef] [PubMed]
17. Malkov, A.V.; Figlus, M.; Kocovsy, P. Polymer-Supported Organocatalysts: Asymmetric Reduction of Imines
with Trichlorosilane Catalyzed by an Amino Acid-Derived Formamide anchored to a Polymer. J. Org. Chem.
2008, 73, 3985. [CrossRef] [PubMed]
18. Malkov, A.; Figlus, M.; Prestly, M.R.; Rabani, G.; Cooke, G.; Kocovsky, P. Soluble Polymer-Supported
Organocatalysts: Asymmetric Reduction of Imines with Trichlorosilane Catalyzed by an Amino Acid
Derived Formamide Anchored to a Soluble Polymer. Chem. Eur. J. 2009, 15, 9651–9654. [CrossRef] [PubMed]
19. Figlus, M.; Caldwell, S.T.; Walas, D.; Yesilba, G.; Cooke, G.; Kocovsy, P.; Malkov, A.V.; Sanyal, A.
Dendron-anchored organocatalysts: The asymmetric reduction of imines with trichlorosilane, catalysed by
an amino acid-derived formamide appended to a Dendron. Org. Biomol. Chem. 2010, 8, 137–141. [CrossRef]
[PubMed]
20. Porta, R.; Benaglia, M.; Coccia, F.; Cozzi, F.; Puglisi, A. Solid Supported 9-Amino-9-deoxy-epi-quinine as
Efficient Organocatalyst for Stereoselective Reactions in Batch and Under Continuous Flow Conditions.
Adv. Synth. Catal. 2015, 357, 377. [CrossRef]
21. Attempts to monitor the reaction from
3 to C via solid state NMR were unsuccessful; a complete conversion
of the primary amine into the corresponding picolinamide could not be confirmed.
22. Braslau, R.; Rivera, F.; Tansakul, C. Reversible crosslinking of polymers bearing pendant or terminal thiol
groups prepared by nitroxide-mediated radical polymerization. React. Funct. Polym. 2013, 73, 624. [CrossRef]
23. The reaction in the presence of polystyrene supported primary amine
yield as a racemic mixture.
4 as catalyst gave amine 7a in 45%
24. Barrulas, P.C.; Genoni, A.; Benaglia, M.; Burke, A.J. Cinchona-Derived Picolinamides: Effective
Organocatalysts for Stereoselective Imine Hydrosilylation. Eur. J. Org. Chem. 2014, 7339. [CrossRef]
25. Brunner, H.; Bugler, J.; Nuber, B. Preparation of 9-amino-(9-deoxy) cinchona alkaloids. Tetrahedron Asymmetry
1995, 6, 1699. [CrossRef]
Sample Availability: Samples of the compounds 7a–e are available from the authors.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
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(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).