Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients

Article abstract of DOI:10.1002/ejoc.201601268

The convenient, metal-free reduction of imines that contain an inexpensive and removable chiral auxiliary allowed for the synthesis of the immediate precursors of chiral active pharmaceutical ingredients (APIs). This protocol was carried out under batch and flow conditions to give the correspoding products in high yields with almost complete stereocontrol. In the presence of trichlorosilane, an inexpensive and nontoxic reducing agent, and an achiral Lewis base such as N,N-dimethylformamide, the formal syntheses of Rivastgmine, calcimimetic NPS R-568, and a Rho kinases inhibitor were successfully accomplished. For the first time, both the diastereoselective imine reduction and the auxiliary removal were efficiently performed in a micro- or mesoreactor under continuous-flow conditions, which paved the way towards the development of a practical process for the syntheses of industrially relevant, biologically active, enantiopure N-alkylamines.

Full text of DOI:10.1002/ejoc.201601268

A Journal of
Accepted Article
Title: Stereoselective metal-free reduction of chiral imines in batch and in flow mode.
A convenient strategy for the synthesis of chiral Active Pharmaceutical Ingre-
dients.
Authors: Davide Brenna; Maurizio Benaglia; Riccardo Porta; Silvia Fernandes; An-
thony Burke
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601268
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601268
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601268
Stereoselective metal-free reduction of chiral imines in batch and in flow mode.
A convenient strategy for the synthesis of chiral
Active Pharmaceutical Ingredients.
a
a, b
a
c
c
Davide Brenna, Maurizio Benaglia, * Riccardo Porta, Silvia Fernandes and Anthony J. Burke
a
Dipartimento di Chimica, Universita’ degli Studi di Milano, via Golgi 19, 20133 Milano, Italy;
b
c
Istituto di Scienze e Tecnologie Molecolari ISTM-CNR, Via Golgi, 19 / I-20133 Milano, Italy;
Department of Chemistry and Chemistry Center of Évora, University of Évora, Rua Romão
Ramalho, 59, 7000 Évora, Portugal
Corresponding author: Maurizio Benaglia, tel. +390250314171; fax: +390250314159; e-mail:
maurizio.benaglia@unimi.it; website: http://users2.unimi.it/Benagliagroup.
KEY TOPIC: Flow Chemistry – Chiral APIs
Abstract: A convenient, metal-free reduction of imines, bearing a very cheap and removable
chiral auxiliary, allowed the synthesis of immediate precursors of chiral APIs (Active
Pharmaceutical Ingredients), in batch and in flow mode, in high yields and almost complete
stereocontrol. In the presence of an inexpensive and non toxic reducing agent, like trichlorosilane,
and an achiral Lewis base such as N,N-dimethyl formamide, the formal synthesis of Rivastgmine
and analogous compounds, calcimimetic NPS R-568 and a Rho kinases inhibitor was successfully
accomplished. For the first time, both the diastereoselective imine reduction and the auxiliary
removal were efficiently performed in (micro)-mesoreactors under continuous flow conditions, thus
paving the way towards a development of a practical process in continuo for the synthesis of
industrial relevant, biologically active, enantiopure N-alkyl amines.
Keywords: stereoselective synthesis / mesoreactors / reduction / flow chemistry / active
pharmaceutical ingredients
In the field of pharmaceuticals the industry is gradually progressing towards enantiopure
formulations; currently, most of the newly introduced drugs are chiral and it is expected that nearly
1
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
9
5% of the pharmaceutical drugs would be chiral by 2020.[1] In this context, chiral amines are
unanimously considered a class of paramount importance, due to their widespread diffusion in a
plethora of compounds, not only of pharmaceutical interest, but also in agrochemicals, fragrances,
and fine chemicals.[2] The reduction of C=N is one of the most widely used approach to synthesize
chiral amines and the last ten years have witnessed the development of some successful catalytic
enantioselective methods, either based on metal-promoted[3] or organocatalyzed[4] strategies.
However, when the industrial synthesis of a chiral pharmaceutical product must be planned,
issues like chemical efficiency and robustness of the procedure, general applicability and economic
considerations become crucially important. For these reasons, the application of many of the known
chiral catalytic systems very often is not feasible and the use of inexpensive and readily available
chiral auxiliaries becomes an attractive and economically competitive alternative. This holds true
also for the synthesis of chiral amines,[5] that heavily relies on the diastereoselective reduction of N-
functionalized imines with chiral, removable residues.[6]
We thought to take advantage of this approach to realize an efficient synthesis of both
enantiomers of 1-(m-hydroxyphenyl)-ethylamine, a key intermediate for the preparation of several,
valuable pharmaceutically active compounds (Scheme 1).
Scheme 1. Biologically active amines featuring the 1-(m-alcoxyphenyl)-ethylamine moiety.
Rivastgmine finds application in the treatment of mild to moderate dementia in Alzheimer's type
and Parkinson diseases. Miotine, the first synthetic carbamate used clinically, is an
anticholinesterase drug. ROCK inhibitors have proved to be efficacious in animal models of stroke,
2
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
inflammatory diseases, Alzheimer's disease and neuropathic pain, and therefore have potential for
preventing neurodegeneration and stimulating neurodegeneration in various neurological disorders.
(R)-NPS 568 is a calcimimetic compound used in the treatment of hyperparathyroidism, while
Acrylamide (S)-A, a potent and efficacious KCNQ2 opener, is currently under study for the
treatment of neuropathic pain, including diabetic neuropathy. The importance of N-alkyl chiral
amines in medicinal chemistry, that encompasses a large variety of compounds with different
biological activity, has been recently highlighted.[7]
Our aim was not only to develop an efficient, metal-free reduction of imines bearing an
inexpensive and easily removable chiral residue, but also to fulfil the transformation under
continuous flow conditions.[8] Here we report, for the first time, a trichlorosilane mediated C=N
reduction efficiently performed in (micro)-mesoreactors, followed by in flow N-deprotection in
microfluidic device, to afford, virtually pure, both enantiomers of 1-(m-alkoxyaryl)-ethylamine
derivatives, advanced precursors of several valuable APIs.[9]
Our investigation started with the in batch reduction of N-(1-(R)-phenylethyl)-ethan-1-(3-
(
methoxy)phenyl)-1-imine 1,[10] that was successfully accomplished by using 3.5 mol eq. of
trichlorosilane in the presence of 5 mol eq. of DMF, in dry DCM for 18 hours. The corresponding
amine 2, isolated in 95% yield virtually as single isomer,[11] went under Pd/C catalyzed
hydrogenolysis in ethanol, affording in quantitative yield enantiomerically pure (R)-1-(3-
methoxyphenyl)-ethylamine 3, direct precursor of .the calcimimetic (R)-NPS 568 (Scheme 2).
Scheme 2. Synthesis of (R)-1-(3-methoxyphenyl)-ethylamine 3, direct precursor of (R)-NPS 568.
Analogously, the reduction of the 3-benzyloxy protected imine 4 was accomplished in high yield
and complete stereocontrol at -20 °C, in DCM (Scheme 3). It is possible to reduce the reaction time
(6 hour), without appreciable changes in yield and stereoselectivity (Table 1). Additionally, we
performed the transformation in toluene and anisole, considered eco-friendly solvents:[12] good
yields (75%) and very high stereoselectivities (96:4 with anisole) were observed.
3
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
Scheme 3. In batch synthesis of (S)-1-(3-hydroxyphenyl)-ethylamine 6 and of amine 8,
immediate precursors of Rivastgmine and analogous derivatives.
The trichlorosilane-mediated reduction was effective also on the chiral imine 7, featuring the
carbamate group on the aromatic ring, and led to the isolation of N-methyl chiral amine 8 in 81%
[
13]
yield as a single isomer (>98/2 d.r.), immediate precursor to (S)-Rivastgmine. To the best of our
knowledge this is the first example of a stereoselective reduction of that class of imines, achieved in
mild conditions, without observing any degradation of the carbamate moiety.
Table 1. In batch reduction of O-Bn protected chiral imine 4.
a
b
Entry T (°C) DMF (eq) Solvent Yield (%)
d.r.
1
2
3
4
5
6
7
0
-20
0
-20
-20
-20
-20
10
10
5
5
5
DCM
DCM
DCM
DCM
DCM
85
81
91
90
83
67
77
92:8
>98:2
92:8
97:3
97:3
92:8
96:4
c
5
5
Toluene
Anisole
a
b
1
c
Isolated yield; reaction time: 18h; Determined by H-NMR spectroscopy; Reaction time: 6 h.
In the attempt to realize the one-step double deprotection of amine 5, the hydrogenolysis was
performed under the same, previously reported conditions: (S)-1-(3-hydroxyphenyl)-ethylamine 6
was isolated in 83% yield, after chromatographic purification, as pure enantiomer. The chiral amine
represents a key intermediate for the synthesis of Rivastgmine, Miotine and KCNQ2 opener
Acrylamide (S)-A, while its enantiomer is the immediate precursor of a very promising class of
Rho-kinases inhibitors (Scheme 1).
4
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
Once the chemistry in batch has been successfully developed, we turned our attention to set up
a continuous flow process.[14] The safe manufacturing of organic (chiral) intermediates under
continuous flow conditions and, more in general, all the advantages that continuous processing may
offer, are emerging topics, that can significantly impact the synthesis of APIs.[15] Therefore, the
development of a continuous flow process for the preparation of both enantiomers of 1-(m-
alkoxyphenyl)-ethylamine derivatives is an attractive option. As far as we know, there are no
reports of continuous flow processes for the synthesis of those valuable intermediates and no
examples of “in flow” stereoselective imines reductions using HSiCl as reducing agent.
3
A coil-reactor, realized by using PTFE tubing (1.58 mm outer diameter, 0.58 mm inner
diameter, 1.89 m length, 500 μL effective volume) coiled in a bundle and immersed in a bath
cooled to the desired temperature, was employed for first preliminary studies (Scheme 4, see
supporting information for pictures and further experimental details).
Scheme 4. Continuous flow reduction of chiral imines and removal of the chiral auxiliary by
continuous flow hydrogenation to afford pure primary amines.
In the reduction of OBn protected imine 4, operating with short residence time (5 minutes) at
1
5 °C in DCM, 70% yield was obtained, but a low diasteroisomeric ratio (90:10) was observed. As
expected, at 0° C, with a residence time of 10 minutes, better results were achieved: 80% of yield
and 93:7 dr were reached (Table 2). At -20 °C the continuous flow reduction afforded amine 5 in
7
5% yield and an almost complete stereoselection. Increasing the reaction concentration from 0.1 M
to 0.5 M the reduction proceeds with comparable yields and stereoselectivity, thus demonstrating
the possibility to further reduce the solvent volumes and realize a more sustainable process.
With the best conditions in our hands, the reduction of OMe functionalized ketoimine 1 and
chiral imine 7, direct precursor of the Rivastigmine was also investigated. Excellent results for
chemical yield as for stereoselectivity were obtained in both cases (entries 6 and 7, Table 2).
5
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
Table 2. Reduction of chiral imines 1, 4 and 7 under continuous flow conditions.
Imine
Residence
Time
Flow rate
a
b
Entry
R
T (°C)
Yield (%)
d.r.
(
l/min)
(
min)
5
1
2
Bn
Bn
4
4
4
4
4
1
7
15
0
0
-20
0
-20
-20
50
50
25
25
25
25
25
70
57
83
81
75
82
80
90:10
96:4
93:7
98:2
96:4
95:5
98:2
5
3
Bn
10
10
10
10
10
4c
5
Bn
Bn
6
Me
7
CONMeEt
a
Yields given as average of five different samples collected at different times; reaction
b
1
c
concentration: 0.1M; Determined by H-NMR spectroscopy; Reaction concentration: 0.5M.
The continuous hydrogenolysis[16] of chiral amines was performed with a ThalesNano H-Cube
Mini™, equipped with a 10% Pd/C cartridge and it was preliminarily studied on chiral amine 2 (eq.
a, Scheme 5). At 50 °C and 50 bar no conversion was observed and the starting material was
recovered unreacted; by rising the temperature to 80 °C and the pressure to 80 bar, chiral amine 3
was isolated in 70% yield. A further increase in temperature and pressure had no appreciable
effects, while for longer reaction times 80% of conversion was obtained. In order to avoid too harsh
conditions and to increase the yield, we decided to perform the reaction for longer times, using a
closed loop system. In 2 hours the reaction gave a 95% of isolated yield at 80 bar and 90 °C, while
at 70 °C, 6 hours were necessary to achieve 93% of yield, without any appreciable epimerization at
the benzylic stereocenter (Table 3).
Scheme 5. Continuous flow deprotection of amines 2 and 5 to afford chiral primary amines.
6
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
With the reaction conditions in our hands we explored the removal of the auxiliary in amine 5.
In this case the deprotection at 90 °C after 2 hours gave the O-debenzylated product 9 in 90% yield.
After 4 hours of reaction at 80 °C, the desired chiral amine 6 was isolated in 70% yield, that was
further increased up to 85% running the hydrogenolysis in continuo for 6 hours.
Table 3. Continuous flow hydrogenolysis of chiral amines 2 and 5.
Entry Amine
Flow rate Pressure
Reaction
Time (min)
a
T (°C)
Yield (%)
(
ml/min)
(bar)
50
80
1
2
2
2
2
2
2
5
5
5
50
80
95
95
80
70
90
80
80
1
1
10
10
20
n.r.
70
70
80
95
93
2
3
0.5
0.3
1
95
95
80
4b
23
5
120
360
120
240
360
b
b
b
b
6
7
8
9
1
70
c
1
80
90
1
80
70
85
1
80
a
b
c
Isolated yield, reaction concentration: 0.1M; Reaction run using a closed loop system; Product
was obtained as major product in 90% yield.
9
In conclusion, we have developed an efficient protocol for the synthesis of both enantiomers of
1
-(m-hydroxyphenyl)-ethylamine, a key intermediate for the preparation of several, valuable
pharmaceutically active compounds. For the first time, a stereoselective trichlorosilane-mediated
reduction was successfully performed in mesoreactors and, followed by a continuous flow
hydrogenolysis, afforded enantiomerically pure 1-(3-alkoxyphenyl)-ethylamines in good yields,
short reaction times and reduced solvent volumes. The development of a highly efficient “all in
flow” multistep, sequential procedure, starting from the ketone, including reductive amination and
deprotection, to afford enantiomerically pure pharmaceutically relevant amines is currently under
investigation.
Experimental Section
General procedures for batch imines reduction with HSiCl : dry DMF (5 eq.) and a 0.9 M solution
3
of the imine in dry solvent were introduced in a 10 mL round bottomed flask under N atmosphere
2
and further diluted in 2 mL of dry solvent. The mixture was cooled to the desired reaction
temperature. A 1.6 M solution of HSiCl (0.7 mmol, 3.5 eq.) in the selected solvent was added to
3
the reaction mixture. After the desired time, the reaction was quenched with a of a 0.1 M solution of
7
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
NaOH until the basic pH was reached. The resulting slurry was stirred at room temperature for 10
minutes, then Na SO was added as drying agent. The mixture was filtered over a celite pad and
2
4
washed with CH Cl (10 mL) and ethyl acetate (10 mL). The solvent was removed under reduced
2
2
pressure and the diasteroisomeric ratio was evaluated on the crude mixture. The amines were
purified by flash chromatography on silica gel or by crystallization.
General procedures for continuous flow imines reduction with HSiCl : The 500 μL coil-reactor at
3
the desired temperature was fed with two 2.5 ml Hamilton gastight syringes, at the desired flow
rate. Syringe A was filled with a solution of imine (1 mol eq.) and dry DMF (5 mol eq.) in dry
DCM. Syringe B: was filled with a solution of HSiCl in DCM. The concentration of the reagents in
3
the syringes was fixed according to the desired concentration in the reactor.
The reaction mixture was collected into a one round bottomed flask, filled with a 0.1 M solution of
NaOH at the same reaction temperature.
After the first volume was discharged, the steady-state conditions were reached; the reported yield
values are given as average of five different samples collected at different times.
General procedure for batch amine deprotection:
To a 0.5 M solution of the amine in ethanol charged into a vial for high pressure hydrogenation
(PARR instrument), 10% of Pd/C was added to the solution and the hydrogenation was carried out
at 10 bar for 48 hours.
Compound 3: The ethanol suspension was filtered through a celite pad and washed with 50 mL of
MeOH, the solution was then treated with 1 equivalent of a 2M solution of HCl in Et O. The
2
solvents were removed under pressure. The residue was dissolved in DCM and treated with
Amberlyst IRA-400 (OH-) resin in order to isolate the amine as neutral compound.
Compound 6: The ethanol suspension was filtered through a celite pad and washed with 50 mL of
MeOH, the solvents were removed under pressure and the compound was obtained as neutral
amine.
General procedure for H-Cube Mini deprotection:
For the synthesis of amine 6: a 0.1M solution of the amine (1.51 mmol, 0.5 g) in ethanol (15 mL)
was charged into a vial connected with the pump of the H CUBE Mini, equipped with a 30 mm
cartridge of 10% Pd/C. The instrument was previously stabilized at the desired temperature and
pressure and at 1 mL/min as flow rate. The reaction was run in a close loop for the desired time.
8
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European Journal of Organic Chemistry
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1
-S-(3-hydroxy)-phenylethanamine
1
H NMR (300 MHz, MeOD) δ 7.19 (t, J = 8.1 Hz, 1H), 6.91–6.81 (m, 2H), 6.82–6.72 (m, 1H),
4
.27–4.13 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H).
[
α]D: (c. 1 in methanol) = -22.1°
[
17]
The spectroscopic data and the [α] were in agreement with the literature.
D:
GC method: injector 200 °C; flow 2mL/min; temperature program 100 °C/hold 2 min.; 130 °C/rate
°C per min./hold 5 min; 170 °C/rate 2 °C per min/hold 5 min.: t : 58.219 min.
1
ret
Supporting Information. Synthesis of starting materials (ketones and ketoimines), synthesis of
chiral amines 2, 3, 5, 6 and 8, detailed experimental procedures for reduction and hydrogenolysis
procedures, characterization of compounds.
Acknowledgements. R.P. and D.B. acknowledge UNIMI for PhD fellowships. M.B. 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”.
A.J.B. thanks bilateral project FCT/CNR 2015-2016 (Ref. 441.00).
References and Notes
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[
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2
007, 40, 1237-1419.
[
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
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8] Recent reviews: a) I. Atodiresei, C. Vila, M. Rueping, ACS Catal. 2015, 5, 1972-1985; b) A.
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9] For examples of diastereoselective reductions aimed to the synthesis of Rivastigmine, see: a)
ref. 6b; b) V. R. Arava, L. Gorentla, P. K. Dubey, Der Pharma Chemica 2011, 3, 426-433;
c) see also ref. 13.
1
0
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
[
[
[
10] For experimental details of the synthesis of ketones and chiral ketoimines, please see the
Supporting Information.
11] Different experimental conditions were studied; for example, the reduction at 0 °C afforded
the product 2 in quantitative yield and 93/7 r.d.
12] R. K. Henderson, C. Jemenez-Gonzalez, D. C. Constable, S. R. Alston, G. G. A. Inglis, G.
Fisher, J. Sherwood, S. P. Binks, A. D. Curzons, Green Chem. 2011, 13, 854-862.
13] H., Meng, Z. Fu-Li, X. Mei-Hua Synth. Commun. 2009, 39, 1527-1533.
14] For the application of flow chemistry for multistep organic synthesis see: a) S. Newton, C. F.
Carter, C. M. Pearson, L. C. Alves, H. Lange, P. Thansandote, S. V. Ley, Angew. Chem. Int.
Ed. 2014, 53, 4915-4919; b) J. Wegner, S. Ceylan, A. Kirschning, Adv. Synth. Catal. 2012,
[
[
3
54, 17-57; c) M. Baumann, I. R. Baxendale, S. V. Ley, Mol. Divers. 2011, 3, 613-630. For
some other recent, representative contributions see also: d) M. Chen, S. Buchwald, Angew.
Chem. Int. Ed. 2013, 52, 4247-4250 and e) I. R. Baxendale, S. V. Ley, A. C. Mansfield, C. D.
Smith, Angew. Chem. Int. Ed. 2009, 48, 4017-4021.
[
15] Reviews on the synthesis of APIs under continuous flow conditions: a) B. Gutmann, D.
Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54, 6688-6728; b) R. Porta, M. Benaglia,
A. Puglisi, Org. Process Res. Dev. 2016, 20, 2-25.
[
[
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European Journal of Organic Chemistry
10.1002/ejoc.201601268
Graphical Abstract
A metal-free diastereoselective reduction of chiral imines and chiral auxiliary removal were
efficiently performed in mesoreactors. Continuous flow trichlorosilane-promoted C=N reduction in
a coil reactor, followed by in flow N-deprotection in microfluidic device, afforded
stereoisomerically pure both enantiomers of 1-(3-alkoxyphenyl)-ethylamine derivatives, advanced
precursors of several valuable APIs.
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This article is protected by copyright. All rights reserved