The use of a continuous flow-reactor employing a mixed hydrogen-liquid flow stream for the efficient reduction of imines to amines

Article abstract of DOI:10.1039/b504854k

Imines have been reduced to amines in high yield, and with excellent chemoselectivity, by catalytic hydrogenation in a continuous flow-reactor, utilising an electrochemically-generated hydrogen source to produce a mixed hydrogen-liquid flow stream. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b504854k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
The use of a continuous flow-reactor employing a mixed hydrogen–
liquid flow stream for the efficient reduction of imines to amines
Steen Saaby,a Kristian Rahbek Knudsen,a Mark Ladlowb and Steven V. Ley*a
Received (in Cambridge, UK) 7th April 2005, Accepted 21st April 2005
First published as an Advance Article on the web 17th May 2005
DOI: 10.1039/b504854k
and over-reduction. In particular, the reduction of aryl imines
often gives rise to secondary amines that are contaminated with
the corresponding primary amine, derived from the desired
product’s over-reduction and debenzylation.
Imines have been reduced to amines in high yield, and with
excellent chemoselectivity, by catalytic hydrogenation in a
continuous flow-reactor, utilising an electrochemically-
generated hydrogen source to produce a mixed hydrogen–
liquid flow stream.
In connection with an ongoing synthesis program, we wished to
establish a procedure for the continuous reduction of imine 1 into
amine 2 that afforded a high purity product suitable for advance-
ment to its next stage in the synthesis process. Initial attempts to
perform this reduction as a flow process, using a reactor cartridge
containing polymer-supported (PS) borohydrides (PS-BH4 and
PS-BH3CN), proved unreliable and typically gave an impure
product contaminated with both inorganic material and by-
products derived from the hydrolysis of 1.
The ever-increasing number of potential therapeutic targets that
are emerging from genomics and proteomics is driving the need to
develop new synthetic technologies able to prepare small molecules
as potential modulators.1 In particular, flow processes, both on
a microfluidic2 and mesofluidic scale,3 are receiving increased
attention and offer a number of potential advantages over existing
batch techniques. For example, reaction conditions (flow rate,
stoichiometry, temperature and pressure) can be independently
varied and precisely controlled. This leads to a high level of
reproducibility, greatly facilitating the reaction optimisation
process, whereby a range of different conditions can be rapidly
investigated. In addition, the incorporation of real time, in-line
monitoring, in combination with intelligent feedback loops, offers
considerable scope for fully automated reaction optimisation. In a
similar way, automated, rapid serial processing may be used to
screen new transformations or generate compound libraries.
The incorporation of in-line modules into flow devices presents
opportunities to effect chromatographic separation, by-product
scavenging, or the isolation of specific products by catch-and-
release protocols. In addition, flow processes are readily scalable—
either by running the flow-reactor for an extended time, or by
employing multi-channel, parallel reactors. However, there is a
considerable need to expand the repertoire of available reactions
and processes available to these techniques, in particular to enable
multi-step, flow-through compound synthesis.
We therefore decided to investigate a continuous, flow-through
hydrogenation using a device that mixes hydrogen gas with a
flowing sample stream in a T-piece mixer. This contained a
titanium frit to ensure efficient gas dispersion (Fig. 1).4 The
hydrogen is generated internally on demand by the electrolysis
of water and the gas–liquid mixture pumped through a suitable
catalyst contained in an interchangeable metal cartridge.5 An
integral Peltier heater enables the cartridge to be heated up to
100 uC, and a responsive back-pressure regulator allows flow
hydrogenation to be performed at pressures up to 100 bar (Fig. 2).6
An important prerequisite in flow chemistry is the choice
of an effective solvent that avoids the precipitation of both
starting materials and products, which may lead to a blockage of
the flow stream. In this case, of the four solvents examined
(DMF, THF, ethyl acetate, toluene), THF was found to be
effective up to 0.5 M and gave the best results under representative
reaction conditions (10% Pd–C, 20 bar, 25 uC, 0.05 M, flow rate
1.0 mL min21), affording 2 in quantitative yield and .95% purity
1
Here we report on the application of a flow-through strategy
to effect the catalytic hydrogenation of imines with high chemo-
selectivity (Scheme 1). Reductive amination is a key transforma-
tion in the synthesis of many drugs; however, problems often arise
due to reversibility, compound/functional group incompatibility
according to H NMR analysis.
Scheme 1 Continuous flow-through reduction of imines into amines.
Fig. 1 H-Cube1 Flow Hydrogenator.
*svl1000@cam.ac.uk
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2909–2911 | 2909

View Article Online
33% conversion to the desired product 2 was obtained. Although
this corresponds to a turnover of 0.16 mmol min21, the mixture of
amine and imine starting material obtained was unsuitable for our
purposes. Having established optimal conditions for the steady
state production of pure 2, we then demonstrated that the flow
process can be readily scaled to provide a preparative quantity of
material (run 12).
A continuous flow hydrogenation was
performed, eluting a 0.05 M THF solution of 1 at 25 uC and
20 bar at a flow rate of 1.0 mL min21 for 70 min. This afforded
1.0 g of 2 in quantitative yield and excellent purity (.95%). Again,
a single 10% Pd–C catalyst cartridge was used throughout.
In order to study the generality of flow-through hydrogenation
for the selective reduction of imines, we prepared a variety of
imines derived from aromatic and aliphatic aldehydes and ketones
(Table 2).7 The imines in entries 1–8 were introduced sequentially
into the H-Cube1 flow-reactor, followed by a short solvent wash
step to purge the catalyst cartridge. The flow conditions employed
were based upon the optimised conditions determined earlier
(i.e. 20 bar, 25 uC, flow rate 1 mL min21). However, a lower
concentration (0.025 M) was used in an attempt to compensate for
the differing reactivities of the imine starting materials, thereby
ensuring maximum conversion in all cases. Under these conditions,
all of the desired amine products were obtained in good to
excellent yields (.80%). Notably, other readily-reducible function-
alities such as pyridines (entry 4) and nitriles (entry 5) were not
affected, nor did the benzylic products of the reaction suffer
further hydrogenolysis to any significant extent.
Fig. 2 H-Cube1 Flow Hydrogenator front panel detail.
The optimisation of flow conditions for the conversion was
systematically investigated by varying concentration, flow rate,
pressure and temperature (Table 1). This process is greatly
facilitated by continuous flow conditions and we were able to
conduct a significant number of runs rapidly, in a sequential
manner and without having to change or renew the catalyst
cartridge (runs 1–11). Specifically, runs 1–4 show a clear correla-
tion between the concentration of the injected sample and the
conversion of 1 into 2.
Increasing the flow rate (runs 5–8) results in a corresponding
decrease in conversion, consistent with a reduction in residence
time in the flow-reactor. Notably, optimal conditions at a flow rate
of 1 mL min21 were obtained with a substrate concentration of
0.05 M, whereas at 2 mL min21, a 0.025 M input afforded
a quantitative conversion to 2. Both of these conditions corres-
pond to quantitative hydrogenation of 1 into 2 at a rate of
0.05 mmol min21, implying that the cartridge has a limiting ability
to process material. This is further illustrated in runs 9–11, where
a more concentrated solution of the imine 1 (0.5 M) was eluted
at 1 mL min21, but at elevated temperature and/or pressure in an
attempt to increase throughput further. In all of these cases, only a
In this work we have described how imines can be selectively
reduced to their corresponding amines in high yield and purity
using in-line hydrogen gas generation as part of a continuous flow
process. The amines obtained were of acceptable purity to advance
to the next stage of a multi-step synthesis program.8 Moreover,
other applications can be envisaged using different gases or
reactive species generated as part of the flow process, potentially in
combination with reaction cartridges containing other catalysts or
immobilised reagents. Efforts to implement multi-step syntheses by
Table 1 Flow hydrogenation optimisation results
Run
Concentration/M
Flow rate/mL min21
Injection volume/mL
Pressure/bar
Temperature/uC
Conversion (%)a
1
2
3
4
5
6
7
8
9
0.5
0.1
0.05
0.025
0.5
1
1
1
1
2
2
2
2
1
1
1
1
5
5
5
5
5
5
5
5
5
20
20
20
20
20
20
20
20
20
40
40
20
25
25
25
25
25
25
25
25
60
25
60
25
17
85
100
100
4
70
85
100
33
0.1
0.05
0.025
0.5
0.5
0.5
10
11
12
a
5
5
70
33
33
95
0.05
Estimated by 1H NMR analysis.
2910 | Chem. Commun., 2005, 2909–2911
This journal is ß The Royal Society of Chemistry 2005

View Article Online
We would also like to acknowledge the Carlsberg Foundation
(to S. S. and K. R. K.) and the Novartis Research Fellowship (to
S. V. L.) for their financial support. We also thank Dr. G. Zinzalla
and L. Milroy for the preparation of imine 8.
Table 2 Study of flow hydrogenation scope
Entry Imine
Yield (%)a Purity (%)
1
quant.
.95
Steen Saaby,a Kristian Rahbek Knudsen,a Mark Ladlowb and
Steven V. Ley*a
aDepartment of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: svl1000@cam.ac.uk;
Fax: 44 (0) 1223 336442; Tel: 44 (0) 1223 336398
bGlaxoSmithKline Cambridge Technology Centre, University of
Cambridge, Cambridge, UK CB2 1EW
2
3
4
93
.95
Notes and references
1 S. V. Ley and I. R. Baxendale, Nat. Rev. Drug Discovery, 2002, 1,
573.
quant.
quant.
95
2 (a) W. Ehrfeld, V. Hessel and H. Lo¨we, Microreactors: New Technology
for Modern Chemistry, Wiley-VCH, Weinheim, 2000; (b) A. M. Hafez,
A. E. Taggi, H. Wack, W. J. Drury, III and T. Lectka, Org. Lett., 2000,
2, 3963; (c) A. M. Hafez, A. E. Taggi, T. Dudding and T. Lectka, J. Am.
Chem. Soc., 2001, 123, 10853; (d) N. G. Anderson, Org. Process Res.
Dev., 2001, 5, 613; (e) M. Sands, S. J. Haswell, S. M. Kelly, V. Skelton,
D. O. Morgan, P. Styring and B. Warrington, Lab Chip, 2001, 1, 64; (f)
S. J. Haswell, R. J. Middleton, B. O’Sullivan, V. Skelton, P. Watts and
P. Styring, Chem. Commun., 2001, 5, 391; (g) P. D. I. Fletcher,
S. J. Haswell, E. Pombo-Villar, B. H. Warrington, P. Watts, S. Y. F. Wong
and X. Zhang, Tetrahedron, 2002, 58, 4735; (h) A. M. Hafez, A. E. Taggi
and T. Lectka, Chem.–Eur. J., 2002, 8, 4115; (i) G. Jas and A. Kirschning,
Chem.–Eur. J., 2003, 9, 5708; (j) P. Watts and S. J. Haswell, Curr. Opin.
Chem. Biol., 2003, 7, 380; (k) P. Watts and S. J. Haswell, Drug Discovery
Today, 2003, 8, 586; (l) A. Kirschning and G. Jas, Top. Curr. Chem.,
2004, 209; (m) D. Jo¨nsson, B. H. Warrington and M. Ladlow, J. Comb.
Chem., 2004, 6, 584; (n) H. R. Luckarift, L. J. Nadeau and J. C. Spain,
Chem. Commun., 2005, 383; (o) G. N. Doku, W. Verboom,
D. N. Reinhoudt and A. van den Berg, Tetrahedron, 2005, 61, 2733
and all the references cited therein (a)–(o).
84
5
96
85
3 (a) R. A. Kautz, W. K. Goetzinger and B. L. Karger, J. Comb. Chem.,
2005, 7, 14; (b) D. M. Ratner, E. R. Murphy, M. Jhunjhunwala,
D. A. Snyder, K. F. Jensen and P. H. Seeberger, Chem. Commun., 2005,
5, 578.
6
7
8
92
.95
90
4 The Thales Nanotechnology H-Cube1 flow hydrogenator is currently a
prototype that is due to become available in the coming months.
For further details, please refer to the product details on the company
website: http://www.thalesnano.com. Address: Thales Nanotechnology,
H-1031 Budapest, Za´hony utca 7 (Graphisoft Park), Hungary.
Fax: +36 16666 190. Tel: +36 1 6666 100.
quant.
quant.
5 Pre-packed cartridges (CatCart1) containing catalyst are available from
Thales Nanotechnology. In this study 30 6 4 mm cartridges
(CatCart130) were used throughout.
90
6 For other applications of flow hydrogenation see: (a) A. J. Sandee,
D. G. I. Petra, J. N. H. Reek, P. C. J. Kamer and P. W. N. M. van
Leeuwen, Chem.–Eur. J., 2001, 7, 1202; (b) N. Ku¨nzle, T. Mallat and
A. Baiker, Appl. Catal., 2003, 238, 251; (c) J. Kobayashi, Y. Mori,
K. Okamoto, R. Akiyama, M. Ueno, T. Kitamori and S. Kobayashi,
Science, 2004, 304, 1305; (d) N. Yoswathananont, K. Nitta, Y. Nishiuchi
and M. Sato, Chem. Commun., 2005, 1, 40.
7 All the imines used in this study were prepared by standard methods
involving reaction of the appropriate carbonyl compound with amines in
the presence of 3 s molecular sieves.
a
quant. 5 quantitative.
linking flow reactors that perform specific synthetic transforma-
tions are currently under way in our laboratory.
8 S. V. Ley, M. H. Bolli, B. Hinzen, A.-G. Gervois and B. J. Hall, J. Chem.
Soc., Perkin Trans. 1, 1998, 353.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2909–2911 | 2911