Solid Supported Chiral N-Picolylimidazolidinones: Recyclable Catalysts for the Enantioselective, Metal- and Hydrogen-Free Reduction of Imines in Batch and in Flow Mode

Article abstract of DOI:10.1002/adsc.201700376

A new class of solid supported chiral imidazolidinone organocatalysts for the catalytic reduction of imines with trichlorosilane has been developed. Polystyrene proved to be a more effective support than silica in terms of both chemical and stereochemical

Full text of DOI:10.1002/adsc.201700376

Title: Solid supported chiral N-picolylimidazolidinones: recyclable
catalysts for the enantioselective, metal- and H2-free reduction of
imines in batch and in flow mode
Authors: Riccardo Porta, Maurizio Benaglia, Rita Annunziata,
Alessandra Puglisi, and Giuseppe Celentano
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700376
Link to VoR: http://dx.doi.org/10.1002/adsc.201700376

10.1002/adsc.201700376
Advanced Synthesis & Catalysis
Solid supported chiral N-picolylimidazolidinones: recyclable catalysts for the
enantioselective, metal- and H2-free reduction of imines
in batch and in flow mode. #
Riccardo Porta,a Maurizio Benaglia,a* Rita Annunziata,a Alessandra Puglisia* and Giuseppe
Celentanob
aDipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy;
bDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli, 25,
Milano, Italy
Corresponding author: Maurizio Benaglia, tel. +390250314171; fax: +390250314159; e-mail:
maurizio.benaglia@unimi.it; Alessandra Puglisi, e mail: alessandra.puglisi@unimi.it
# Dedicated to Prof. Cesare Gennari on the Occasion of his 65th Birthday
Abstract: A new class of solid supported chiral imidazolidinones organocatalysts for the catalytic
reduction of imines with trichlorosilane was developed. Polystyrene proved to be a more effective
support than silica in terms of both chemical and stereochemical efficiency. Even with a loading as
low as 1 mol % the best performing supported catalyst showed a remarkable activity and
stereocontrol ability, promoting the reduction with stereoselectivities reaching 98% e.e. and in most
cases ranging between 90-95% e.e. The general scope of the methodology and the good recyclability
of the immobilized catalyst were demonstrated. The polystyrene-anchored chiral catalyst was also
used to prepare packed bed reactors for the continuous flow synthesis of chiral amines, that were
obtained in excellent yields and enantioselectivities. By exploiting the chiral organocatalytic reactor,
the in-flow stereoselective synthesis of a common, immediate precursor of rivastigmine, of the
calciomimetic (R)-NPS 568 and of Acrylamide (S)-A, currently under study for the treatment of
neuropathic pain, was successfully accomplished.
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Advanced Synthesis & Catalysis
Keywords: Supported catalysts, chiral amines, catalytic reactors, imine reduction, asymmetric
catalysis.
Chiral amines are very important pharmacophore that can be found in several biologically active
molecules and agrochemical compounds. The reduction of ketomines either by metal-catalyzed
hydrogenation[1] or by organocatalytic methodologies[2] is a very convenient strategy to access to this
class of molecules. Among the available catalytic methods, the stereoselective reduction of imines
with trichlorosilane (HSiCl3) promoted by chiral Lewis bases has been investigated by several
research groups and has proved to be very efficient.[3] The possibility to use in a catalytic continuous
flow process a very cheap, readily available and atoxic reagent like HSiCl3 is extremely attractive, in
view of a large scale preparation of enantiopure amines of industrial interest.[4] The immobilization
of the chiral catalyst would allow not only to recycle the heterogenized chiral catalytic species in the
in-batch reaction,[5] but also to assembly a catalytic reactor to be employed in the enantioselective
reduction under continuous flow conditions [6] with the catalyst permanently residing in the reactor.
We have recently reported a new class of highly active chiral Lewis bases, able to promote the
reduction of a wide variety of imines with low catalyst loading (down to 0.1% mol), occurring in
quantitative yields and enantioselectivities usually higher than 90% (Figure 1, catalyst type I).[7]
Here we report the immobilization of this new class of imidazolidinone-based picolinamides and
their use in the enantioselective C=N bonds reduction; despite it was often observed that the
heterogenization of chiral catalysts led to a decreased catalytic efficiency, in the present study the
polymer-support Lewis base of choice showed a remarkable behavior, even at 1 mol % loading,
promoting the reaction in high yields and stereoselectivities up to 98 % e.e.. Not only the
recyclability was demonstrated under batch conditions, but, for the first time, a chiral organocatalytic
reactor for the enantioselective, trichlorosilane-mediated imine reduction under continuous flow
conditions was successfully prepared and employed for the in-flow synthesis of chiral amines,
including advanced intermediates of pharmaceutically relevant compounds.[8]
For the preparation of the supported picolinamide, we started from (L)-Tyrosine to build up the
chiral scaffold and exploited the phenolic residue as site to anchor the catalyst onto a solid support
(Figure 1, catalyst type II).
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10.1002/adsc.201700376
Advanced Synthesis & Catalysis
Figure 1. General synthetic strategy for the preparation of solid supported picolinamides.
The synthesis of silica supported picolinamide involved the preparation of O-allyl protected
picolinamide 2 starting from the known intermediate 1 (Scheme 1).[9] Compound 2 was then
converted into the corresponding trimethoxysilyl derivative 3, that was grafted onto commercially
available SiO2 (Apex Prepsil Silica Media 8 µm) to afford the silica-supported catalyst S1 (loading:
0.25 mmol/g, as determined by weight difference).
Scheme 1. Synthesis of silica supported catalyst S1.
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10.1002/adsc.201700376
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Another silica supported picolinamide, featuring a longer linker between the catalyst's active site
and the solid support, was also synthesized (Scheme 2). Starting from imidazolidinone 4,[10] a click
reaction with 1-(allyloxy)-4-(azidomethyl)benzene gave compound 5 that was then converted into
the corresponding picolinamide 6. Platinum catalyzed hydrosilylation with HSi(OMe)3 followed by
grafting onto commercially available SiO2(Apex Prepsil Silica Media 8 µm) afforded the
immobilized catalyst S2 (load = 0.3 mmol/g).
Scheme 2. Synthesis of silica supported catalyst S2.
The synthetic strategy for the preparation of the polymer supported catalyst takes advantage of the
known imidazolidinone 8[10] featuring a styrene moiety to be employed in the polymerization step of
the synthesis. Intermediate 8 was converted into the corresponding picolinamide 9 by reaction with
picolinic acid and ethylchloroformate in the presence of N-methyl morpholine as a base. Monomer 9
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10.1002/adsc.201700376
Advanced Synthesis & Catalysis
was then polymerized by AIBN-promoted radical copolymerization with divinylbenzene as co-
monomer, in the presence of toluene and 1-dodecanol as porogens (Scheme 3). The loading of P1
was evaluated to be 0.57 mmol/g, based on the stoichiometry of polymerization reaction.
Scheme 3. Synthesis of polymer supported catalyst P1.
The trichlorosilane-mediated reduction of imines N-phenyl 10a and N-PMP (p-methoxyphenyl)
protected 10b derived from acetophenone was chosen as model reaction to test the solid supported
catalysts (Table 1).
Catalyst S1 promoted the reduction of both substrates in excellent yields and very good
enantioselectivities (entries 1 and 2). The presence of a longer linker as in catalyst S2 did not
improve the chemical efficiency, but had a detrimental effect on the stereoselectivity, that was
markedly reduced (entries 3 and 4). Polystyrene supported picolinamide P1 proved to be the best
catalytic system, affording the desired products (11a and 11b) in very good yields and excellent
stereoselectivities (97% e.e., entries 5 and 6).
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Table 1. Catalyst screening.
Entrya Catalyst PG Yield (%)b ee (%)c
1
2
3
4
5
6
Ph
PMP
Ph
PMP
Ph
97
98
70
95
92
94
82
86
21
75
97
97
S1
S1
S2
S2
P1
P1
PMP
a) Reaction conditions: imine (0.1 mmol), HSiCl3 (0.5 mmol), DCM(1 mL). b) Isolated yield after
chromatography. c) Enantiomeric excess was determined by HPLC on chiral stationary phase; the absolute
configuration was confirmed by comparison with literature data, see ref. 7.
On the basis of these preliminary investigations, P1 was selected for further studies (Table 2).
Table 2. Screening of catalyst loading.
Yield (%)b ee (%)c
Entrya P1 (mol%)
1
2
3
4
5
6
20
10
5
94
94
92
82
96
46
97
96
95
94
95
93
5d
1
1d
a) Reaction conditions: imine (0.1 mmol), HSiCl3 (0.5 mmol), DCM(1 mL). b) Isolated yield after
chromatography. c) Enantiomeric excess was determined by HPLC on chiral stationary phase. d) Reaction
time: 4h.
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10.1002/adsc.201700376
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Remarkably, the amount of the supported catalyst could be reduced to just 1 mol%, without an
appreciable loss of the chemical or stereochemical activity (Table 2, entry 1 vs entry 5). When
reaction time was reduced to 4 hours, a loading of 5 mol% of P1 was sufficient to afford chiral amine
11b in 82% yield and 94% e.e., thus confirming the excellent chemical behavior of the heterogenized
chiral Lewis base.
The general scope of the reaction was then studied. Different C-aryl substituted imines were
reacted with HSiCl3 in the presence of polymer-supported catalyst P1 (Scheme 4).
Scheme 4. Reaction scope.
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10.1002/adsc.201700376
Advanced Synthesis & Catalysis
Substrates bearing both electron withdrawing (11e-11i) and electron donating groups (11c, 11d, and
11j) were reduced in very good yields and excellent e.e., up to 97%. Notably, amine 11k, a direct
precursor of rivastigmine (see below, Figure 2), was obtained in 80% yield and 95% e.e.. In all cases,
the supported catalyst showed to behave like the non-immobilized catalyst under homogeneous
conditions, and afforded the products with the (R) absolute configuration, thus suggesting that
polymer-supported P1 promotes the reduction according to the same mechanism proposed for the
homogeneous catalyst. [7]
The -amino ester 11m was obtained in 96% yield and only 65% e.e., amino esters 11n, 11o and
11p, precursors of chiral lactams, were isolated in quantitative yields and good e.e., up to 84%.
In order to demonstrate the practical applicability of the heterogeneous catalyst P1, both its
recovery and recycle were studied in the reduction of imine 10k, a key common intermediate for the
preparation of several, pharmaceutically relevant molecules (Figure 2).
Figure 2. Some biologically active chiral amines featuring 3-alcoxyaryl residue.
With a two hours reaction time for each cycle, the same immobilized catalyst could be used for
seven reaction cycles, affording a constant yield, typically ranging between 80 and 85%, and a
reproducible, high level of enantioselectivity, of about 94% e.e. (Table 3).[11]
Table 3. Recycling experiments.
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10.1002/adsc.201700376
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Cyclea Yield (%)b ee (%)c
1st
2nd
3rd
4th
5th
6th
7th
80
81
80
79
87
84
76
94
94
94
93
93
90
87
a) Reaction time of each cycle: 2 hours. b) Isolated yield. c) E.e. was determined by HPLC on chiral stationary phase
Polystyrene supported catalyst P1 was then employed for the fabrication of packed bed reactors,
required for developing an efficient and convenient continuous flow reduction of imines with HSiCl3.
P1 (0.3 g) was packed into a stainless-steel HPLC column (l: 6 cm, id: 0.4 cm, V: 0.75 mL). A 0.05
M solution of 10b and HSiCl3 in CH2Cl2 was pumped into the reactor through a syringe pump at 0.4
mL/h (res time: 30 min) at room temperature. The outcome of the reactor was collected into a flask
containing NaOH 10% solution and the product isolated by extraction and solvent evaporation. After
the first two operating hours, the product was collected at 1 h intervals and analyzed in order to
determine the conversion and the ee. Results of the continuous flow experiments are reported in
Table 4.
Table 4. Continuous flow synthesis of amine 11b.
Running
time (min)
Yield (%)a ee (%)b
Entry
1
2
3
4
5
6
0-120
92
94
93
94
94
94
85
83
81
80
75
73
120-180
180-240
240-300
300-360
360-420
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10.1002/adsc.201700376
Advanced Synthesis & Catalysis
a) Isolated yield after chromatography. b) Enantiomeric excess was determined by HPLC on chiral stationary phase
As reported in Table the flow system was stable for seven hours, producing chiral amine 11b in
excellent yield (always higher than 90%) and good e.e.. The stereoselectivity of the process slightly
decreased with time, probably because of a very slow, but constant, partial degradation of the
imidazolidinone ring of the catalyst.[12]
Then, we decided to study the in-flow synthesis of a valuable compound such as 1-(m-
benzyloxyphenyl)-ethylamine 11k, precursors, among others, of rivastigmine, of the calciomimetic
(R)-NPS 568 and of Acrylamide (S)-A, currently under study for the treatment of neuropathic pain
(Figure 2).[13]
By employing the packed-bed reactor P1 the continuous flow process afforded chiral amine
11k in 82% yield and 83% e.e. for the first three operation hours (Scheme 5). The chiral amine was
continuously produced for other 2 hours with similar yield and enantioselectivity, while, in the
course of the sixth hour, a process of comparable yield and a minimally decreased selectivity was
observed (79% yield and 77% e.e).[14]
Scheme 5. Continuous flow synthesis of amine 11k.
Running
time (min)
Yield (%)a ee (%)b
Entry
1
2
3
0-180
180-300
300-360
82
80
79
83
81
77
a) Isolated yield after chromatography. b) Enantiomeric excess was determined by HPLC on chiral stationary phase
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10.1002/adsc.201700376
Advanced Synthesis & Catalysis
In conclusion, a new class of solid supported chiral Lewis bases for the catalytic reduction of
imines with trichlorosilane was studied. Polystyrene-immobilized catalysts promoted the reaction in
very high enantioselectivites for a wide variety of substrates, up to 97% e.e. The possibility to
decrease the catalyst's loading down to 1 mol % and to recycle the catalyst six times was
demonstrated. The polymer-supported catalyst of choice was used to prepare packed bed reactors for
the synthesis of chiral amines under continuous flow conditions and applied to the preparation of an
advanced precursor of important pharmaceutically active compounds. The combination of catalytic
reactors with recently developed synthetic and analytical devices for the in-flow processes, will offer
new unforeseen and readily exploitable opportunities for the automated synthesis of complex
molecules.[15]
Experimental Section
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 hours. 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 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 (0.1 mmol) and HSiCl3 (5 equiv.) in dry CH2Cl2 (2 mL) 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 the indicated flow rate. The reactor was then washed with pure
CH2Cl2 at the same flow rate. The outcome of the reactor was collected into a flask containing NaOH
10% solution. After phase separation and concentration the product was isolated. At predetermined
intervals of time the product was collected and analyzed. The yield was determined by
chromatography and the ee was determined on HPLC on chiral stationary phase.
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10.1002/adsc.201700376
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Supporting Information. Synthesis of catalysts, substrates, general procedures for batch and flow
synthesis, products characterization, NMR spectra and HPLC traces.
Acknowledgements. M.B. thanks University of Milano for the Transition Grant 2015-17-Horizon
2020. R.P. thanks University of Milano for a PhD fellowship.
References and Notes
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[8] Recently we reported the use of solid supported Cinchona alkaloid-based Lewis bases as catalysts
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Advanced Synthesis & Catalysis
preliminary study, a packed bed reactor employed in a continuous flow reaction suffered from poor
enantioselectivity and very low stability: a) S. D. Fernandes, R. Porta, P. C. Barrulas, A. Puglisi, A.
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[11] The supported catalyst showed to be highly efficient for a limited operating time; when
recycling experiments were conducted for 20 hours for each cycle, amine 11k was obtained as
racemic mixture already at the 2nd run (40 hours of activity, overall).
[12] For previous studies on the immobilization of chiral imidazolidinones and their recyclability
see: a) M. Benaglia, G. Celentano, M. Cinquini, A. Puglisi, F. Cozzi, Adv. Synth. Catal. 2002, 344,
149; b) S. A. Selkälä, J. Tois, P. M. Pihko, A. M. P. Koskinen, Adv. Synth. Catal. 2002, 344, 941; c)
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synthesis exploiting mesoreactor technology of important chiral pharmaceutical amine derivatives,
see: c) D. Brenna, M. Benaglia, R. Porta, S. D. Fernandes, A. J. Burke, Eur. J. Org. Chem, 2016,
doi:10.1002/ejoc.201601268; d) D. Brenna, M. Pirola, L. Raimondi, A. J. Burke, M. Benaglia,
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[14] For experimental details of the in-batch and in-flow synthesis of the chiral amines and their
characterization, please see the Supporting Information.
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[15] Review: S. V. Ley, D. E. Fitzpatrick, R. J. Ingham, R. M. Myers, Angew. Chem. Int. Ed. 2015,
54, 3449. For a few, representative, recent examples of continuous flow synthetic applications for
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17; c) M. Chen, S. Buchwald, Angew. Chem. Int. Ed. 2013, 52, 4247; d) S. Newton, C. F. Carter, C.
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Graphical Abstract
A new recyclable, polystyrene supported catalyst of wide general applicability, promoted the
trichlorosilane-mediated imine reduction with a remarkable activity, even with a loading as low as 1
mol %; excellent stereocontrol ability, up to 98% e.e. was observed, in most cases ranging between
90-95% e.e. By exploiting packed bed chiral organocatalytic reactors, the in-flow stereoselective
synthesis of chiral amines, precursors of valuable APIs, was accomplished in satisfactory yields and
enantioselectivities.
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