Process intensification for the continuous flow hydrogenation of ethyl nicotinate

Article abstract of DOI:10.1021/op500208j

Here we report a process intensification study for the selective, partial, and full hydrogenation of ethyl nicotinate using a trickle bed reactor for meso-flow transformations (HEL FlowCAT). The process achieved a throughput of 1219 g d^-1 (78 g h^-1 of product per g of active catalyst) for the partial hydrogenation to ethyl 1,4,5,6-tetrahydropyridine-3-carboxylate, whereas the productivity for the full hydrogenation process reached a 1959 g d^-1 of throughput (408 g h^-1 of product per g of active catalyst) on this laboratory-scale flow chemistry platform.

Full text of DOI:10.1021/op500208j

Communication
pubs.acs.org/OPRD
Process Intensification for the Continuous Flow Hydrogenation of
Ethyl Nicotinate
Takashi Ouchi,†,‡ Claudio Battilocchio,† Joel M. Hawkins,§ and Steven V. Ley*,†
†Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, U.K.
‡Takeda Pharmaceutical Company Limited, CMC Center, Chemical Development Laboratories, 17-85 Jusohonmachi 2-chome,
Yodogawaku Osaka 532-8686, Japan
§Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Here we report a process intensification
study for the selective, partial, and full hydrogenation of
ethyl nicotinate using a trickle bed reactor for meso-flow
transformations (HEL FlowCAT). The process achieved a
throughput of 1219 g d−1 (78 g h−1 of product per g of
active catalyst) for the partial hydrogenation to ethyl
1,4,5,6-tetrahydropyridine-3-carboxylate, whereas the pro-
ductivity for the full hydrogenation process reached a 1959
g d−1 of throughput (408 g h−1 of product per g of active
catalyst) on this laboratory-scale flow chemistry platform.
Figure 1. Examples for biologically active molecules containing a
piperidine core.
INTRODUCTION
■
genation6−9 of different pyridine derivatives using for example
In recent years there has been an increasing demand for new
and more efficient chemical processes that cover a wide range
the H-Cube apparatus.10 Although the latter work covered a
of synthetic applications.1 Correspondingly, many enabling
useful range of substrates, the throughput of the particular
system was limited to around 10 g d−1. Subsequent innovation
has led to the development of the H-Cube Midi, which is
designed for scale-up reactions up to 500 g d−1, for larger scale
work.11
We began our investigation with the aim of safely delivering a
throughput in excess of a kilogram per day (kg d−1) in a
research laboratory environment. This, we felt, would need
considerable process intensification with currently available
equipment. We decided to do this by examining the selective
hydrogenation, both partial and full, of ethyl nicotinate (1)
since the products of this process were useful for other
programs.
The selective and efficient partial hydrogenation of pyridine
derivatives is particularly interesting in order to provide a
valuable intermediate for later asymmetric conversion to 3
(Scheme 1).12,13
Our approach was to investigate the suitability of the
commercially available HEL FlowCAT reactor14 (Figure 2) for
the aforementioned processes and to investigate its suitability
for daily production of material using a single charge of catalyst
in the trickle bed reactor system.
technologies have become available to drive this new agenda.2,3
However, a particular challenge that has not been fully met is
how to move rapidly and safely to scale-up reactions in research
laboratories from milligrams to kilograms. It is precisely under
these circumstances where new tools can greatly assist the
process. Indeed, by definition, process intensification is the
“strategy for making dramatic reductions in the size of a
chemical plant so as to reach a given production objective”.4
Accordingly, this approach can involve shrinking the size of
individual pieces of equipment by cutting the number of unit
operations and/or devices involved. Similarly, intensification
can occur through using a relevant apparatus to its limits of
production, e.g., through the use of high pressure, high
temperature, and high substrate concentration. In addition,
interests in greater sustainability through more selective
processes, often under heterogeneous conditions, have become
attractive goals. Nevertheless, working with and scaling up of
hydrogen gas reactions brings with it well-recognized issues
(i.e., safety assessment, mixing, and H2 solubility) despite the
importance of this reductive process in fine chemical
manufacturing. One such process involving precious metal
catalyzed hydrogenation of substituted pyridines is of interest
due to the importance of the functionalized piperidines
products as intermediates in the preparation of many
biologically active molecules (Figure 1).5
The HEL FlowCAT is a compact, benchtop unit which
allows screening, optimization, and scale-up of heterogeneous
Special Issue: Continuous Processes 14
Received: June 26, 2014
Flow chemistry as an enabling technology has proven useful
on a research scale for the continuous catalytic hydro-
© XXXX American Chemical Society
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theless using 5% Pd/C as a catalyst under moderately high
pressure hydrogen (100 psi) gave us 85% conversion for
products 2 and 3 (7:1 average ratio) over 38 h, at room
temperature.
Scheme 1. Products obtained from partial (2) and full (3)
reduction of ethyl nicotinate (1)
Then we examined the H-Cube7,8 for comparison and
quickly found we could reproduce the results described
previously by Kappe.10 However, upon extended reaction
time we noticed some variability. Additionally, we were never
able to isolate more than 71% of the partial reduced product,
owing to engineering constraints such as the hydrogen flow
rates and the size of the catalyst cartridges.
In order to deliver material in our target quantities, we
identified the HEL FlowCAT reactor as a potentially suitable
device for scale up and process intensification studies.17 Due to
the capacity of the trickle bed reactor (reactor column 1, RC1,
6 mm i.d., 3 mL internal volume), it was possible to pack the
column with a charge of 2.6 g of catalyst for this particular
column configuration.
One practical aspect of major importance, when dealing with
this kind of process, is the packing of the reactor column.
During our screening we noticed that the performance of the
run was highly dependent on catalyst particle size, as too small
particles were more amenable to frequent blockages whereas
too big particles were associated with channeling and reduced
mixing. In our specific case, the use of particles ranging between
0.1 and 0.8 mm was found to be ideal. Notably, the use of
smaller particle sizes is possible provided that a “filler material”
with bigger particles size is used to “disperse” the smaller
particles and create an efficient bed reactor. To avoid any
inconvenient issue with blockages, we decided to “dilute” the
catalyst particles with inert glass beads with particle sizes
chemistry and is run under fixed-bed, trickle flow conditions.
The system provides a wide range of working pressures and the
processing conditions are controlled via software (Supporting
Information, SI), which accurately controls parameters such as
pressure, temperature, and gas and liquid feed rates (Figure 3).
RESULTS AND DISCUSSION
■
Partial Hydrogenation Process. The first step towards a
full understanding of the advantages of running this trans-
formation in flow was to properly evaluate the constraints of
the batch process. For this we used the Chameleon
technology15 as a single unit stirred autoclave (Scheme 2).
We soon recognized that the chemical transformation was
difficult under the conditions reported previously,16 never-
Figure 2. Picture of the trickle bed reactor (HEL FlowCAT reactor) used for the heterogeneous hydrogenation (left: column reactor; right: whole
system).
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Figure 3. Schematic view of the HEL FlowCAT.
limiting parameter under these conditions and any attempt to
increase the molarity of the solution above 0.05 M failed,
resulting in incomplete consumption of the starting material.
Scheme 2. Hydrogenation of 1 under batch mode conditions
using the Chameleon technology (description within the SI)
We decided therefore to screen different supported forms of
21,22
Pd catalyst and found that Pd/Al2O3
exerted a beneficial
catalytic activity in terms of both productivity and selectivity.23
In this particular case, the catalyst particle size was of extreme
importance, with particles ranging between 0.1 and 0.25 mm
being the most efficient. As shown in Table 2, running the
reaction at 60 °C and a liquid flow rate of 3.0 mL min−1
delivered an improved productivity of over 260 g d−1 (entry 7).
Also of importance was that under those conditions
considerably higher concentrations of the material feedstock
are tolerated (up to 0.4 M).
The robustness of the system was evaluated by conducting an
experiment for 22.5 h, following the conditions reported in
entry 7 (Table 2), without noticing any decrease in either
selectivity or catalytic performance of the system while
producing a throughput of over 240 g of material overall (see
SI).
around 0.2 mm (description of the packing is reported within
the SI).18
For the initial study, we used a Pd/C catalyst (Table 1).19,20
We started to screen our system at room temperature with 10%
Pd/C. Using a H2 feed of 0.2 L min−1 and system pressure of
20 bar, we were able to selectively obtain 78% conversion to 2
(liquid flow rate 2.0 mL min−1) (Table 1, entry 1). Increasing
the temperature to 60 °C and the flow rate to 5.0 mL min−1
(system pressure of 20 bar and gas feed of 0.2 L min−1) gave a
throughput of 54.78 g d−1 with the disadvantage of reducing the
2/3 selectivity (Table 1, entry 5). The best result was achieved
using 5% Pd/C20 (Table 1, entry 6), although this arrangement
gave a lower product output (21.6 g d−1 throughput). We
recognized that the concentration of the starting material was a
Although this productivity was more than 25-fold the
throughput obtained with the H-Cube, we believed further
Table 1. Partial reduction of ethyl nicotinate with Pd/C using HEL FlowCAT reactor RC1
a
ratio (%)
conc. of 1
(M)
flow rate
temp.
(°C)
pressure
(bar)
H2 flow
throughput of 1
(g min−1
eun
catalyst
(mL min−1
)
(L min−1
)
1
2
3
)
b
b
b
b
b
1
2
3
4
5
6
7
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
0.05
0.05
0.05
0.05
0.05
0.05
0.05
2.0
2.0
2.0
4.0
5.0
2.0
4.0
25
40
25
60
60
40
60
20
20
40
20
20
20
20
0.1
0.1
0.1
0.2
0.2
0.1
0.2
22.0
1.1
78.0
84.2
71.3
78.8
75.1
90.7
78.4
N.D.
14.7
13.5
20.1
20.1
8.3
0.015
0.015
0.015
0.030
0.038 (54.78 g d−1
0.015 (21.60 g d−1
0.030
15.2
1.1
4.8
)
)
c
5% Pd/C
1.0
c
5% Pd/C
1.8
19.8
a
b
c
Ratios are based on crude H NMR data. Particle size 0.40−0.80 mm.19 Particle size 0.30−0.85 mm.20
1
C
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Table 2. Partial reduction of ethyl nicotinate with Pd/Al2O3 using HEL FlowCAT reactor RC1
a
ratio (%)
conc. of 1
(M)
flow rate
temp.
(°C)
pressure
(bar)
H2 flow
throughput of 1
run
catalyst
(mL min−1
)
(L min−1
)
1
2
3
(g min−1
)
b
b
b
c
1
2
3
4
5
6
7
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
0.1
0.2
0.2
0.2
0.2
0.4
2.5
2.5
3.0
4.0
4.0
2.0
40
50
60
50
50
50
60
24
23
24
20
20
20
0.2
0.2
0.2
0.2
0.1
0.2
0.2
ND
88.5
83.3
86.5
83.2
76.7
80.1
84.0
11.5
10.3
11.1
15.0
12.2
16.7
15.1
0.038
0.076
0.091
0.121
0.121
0.121
6.4
2.4
1.8
c
11.0
3.2
c
c
0.4
3.0
20
0.9
0.181 (260.64 g d−1
)
a
b
c
Ratios are based on crude H NMR data. Particle size 0.25−0. 50 mm.21 Particle size 0.10−0.25 mm.22
1
process intensification was possible. For this the reactor column
was increased to 12 mL of internal volume (RC2, Figure 4).
of pyridine to 3 was unsuccessful using the EtOH/Pd/C
conditions” and the transformation was conducted by using Pt/
C and acetic acid (AcOH) as solvent at 100 °C to provide 92%
of the final ethylpiperidine 3-carboxylate (3). However, the use
of Pt/C would be more expensive on scale than a Pd catalyst,
and also AcOH is not a preferred solvent for larger scale
reactions.24
We started screening different solvents in the H-Cube
apparatus using available Pd catalysts (Table 4). Noteworthy
here is that even with 10% Pd/C, which was previously
reported to provide only 50% yield, and by using ethyl acetate
(AcOEt) as solvent, this resulted in a 69.4% yield of material at
100 °C, with a calculated throughput of only just over 5 g d−1.
Interestingly, 10% Pd/Al2O3 gave us almost full conversion to
the desired product 3, with very good selectivity and no by-
product observed (Table 4, entry 7).
Figure 4. Picture of RC1, top, and RC2, bottom.
The new reactor column accommodated a larger quantity of
catalyst (13 g), hence a corresponding increase in productivity
was anticipated.
After screening different parameters (Table 3) using RC2,
the concentration could be increased to 0.8 M and the flow rate
adjusted to 7.0 mL min−1 to obtain a throughput of 1219 g d−1
with complete consumption of the starting material, with
slightly reduced selectivity (Table 3, entry 7).
Compound 2 could be isolated in 73% yield (purity >99%)
just via concentration under vacuo, followed by dissolution of
the material collected in CH2Cl2 and then washing away the
byproduct 3 with citric acid 10% solution.10 The reaction was
run for 10 h under the optimized conditions, processing 507 g
of starting material (entry 7). Additionally, negligible leaching
of Pd catalyst (below 9.5 ppb) was detected by inductively
coupled plasma-mass spectrometry (ICP-MS) analyses.
Full Hydrogenation Process. To achieve the full hydro-
genation of 1 to 3, we followed a similar optimization approach.
Kappe and co-workers10 had reported that “full hydrogenation
The hydrogenation process was then transferred to the HEL
platform using the RC1 trickle bed reactor. Given the results
22
obtained with Pd/Al2O3 as catalyst, we decided to use this
material to perform the full hydrogenation. After very few
experiments, it was easily found that by running the reaction at
100 bar hydrogen, 160 °C, and 3 mL min−1, with a hydrogen
feed equating to 0.2 L min−1 and a 0.8 M solution of 1, we
could obtain pure product 3 free from partially hydrogenated
by-product (2). This system successfully delivered a throughput
of 522 g d−1 of compound (3) (Scheme 3).
During further process intensification studies, it was
anticipated that the use of the larger reactor RC2 should be
able to increase the throughput to >1000 g d−1. Accordingly,
with the 12 mL reactor (RC2), we were pleased to generate the
equivalent of 1524 g d−1, using a 1.0 M solution of the starting
material. In one long run experiment a quantity of 242 g
(isolated yield 99%, purity >99%) of material was collected over
just 3 h and 45 min simply via removal of AcOEt by
Table 3. Partial reduction of ethyl nicotinate using HEL FlowCAT reactor RC2
a
ratio (%)
c
conc. of 1
(M)
flow rate
temp.
pressure
(bar)
H2 flow
throughput of 1
(g min−1
b
run
catalyst
(mL min−1
)
(°C)
(L min−1
)
1
2
3
)
1
2
3
4
5
6
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
0.5
0.8
0.8
0.8
0.8
0.8
0.8
10.0
6.0
6.0
6.0
8.0
8.0
7.0
65
45
65
65
65
55
55
20
20
12
20
20
20
20
0.6
0.6
0.6
0.6
0.6
0.4
0.6
0.6
74.4
78.7
62.9
61.3
69.9
67.5
75.8
25.0
20.1
37.1
38.7
30.1
13.3
24.2
0.756 (1088.35 g d−1
0.726 (1044.82 g d−1
0.726
)
)
1.2
ND
ND
ND
19.2
trace
0.726
0.967 (1393.09 g d−1
0.967 (1393.09 g d−1
0.846 (1218.95 g d−1
)
)
)
d
7
a
b
c
d
Ratios are based on crude H NMR data. Particle size 0.10−0.25 mm.22 Temperature of the external heating jacket. 10 h run.
1
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Table 4. Solvent and catalyst optimization study for the full hydrogenation of ethyl nicotinate 1 with different Pd catalysts, using
the H-Cube apparatus
c
ratio (%)
ab
,
entry
catalyst
solvent
1
2
3
throughput of 3 (g min−1
)
1
2
3
4
5
6
7
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
5% Pd/C
EtOH
THF
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
39.4
32.4
41.7
30.6
73.0
50.5
9.3
60.4
67.6
58.3
69.4
27.0
49.5
90.7
0.00375
0.00375
0.00375
0.00375
0.00375
0.00375
toluene
AcOEt
AcOEt
EtOH
AcOEt
10% Pd/Al2O3
10% Pd/Al2O3
0.00375
a
b
c
The data reported are only related to representative examples. Conditions: full hydrogen mode, 100 °C, 0.5 mL min−1. Ratios are based on crude
1H NMR.
Scheme 3. Full reduction of ethyl nicotinate with Pd/Al2O3
using HEL FlowCAT reactor (RC1)
Scheme 5. (a and b) Full reduction of ethyl nicotinate with
Rh/Al2O3 using HEL FlowCAT reactor RC1
concentration (Scheme 4). As in many other fixed bed reactor
processes, here the use of continuous flow represents a huge
Scheme 4. Full reduction of ethyl nicotinate with Pd/Al2O3
using HEL FlowCAT reactor (RC2)
−1
[(0.6 L min−1)/22.4 L mol−1)]/[(3.0 mol L )
(0.003 L min−1)]
= 2.98 mol H2/mol ethyl nicotinate
This calculation suggests we are working at the current limit of
the gas feed to the RC1.26
advantage as it enables the removal of troublesome operations
(i.e., filtration of catalyst, washing procedure).
Nonetheless, we wanted to check the suitability of the system
for higher productivity. After a more careful screening of
different catalysts, we realized that the use of a 0.05 M solution
of 1 in AcOEt could be fully hydrogenated with Rh/Al2O3
catalyst, using the H-Cube platform. However, the daily
throughput could not be increased under these conditions on
this equipment.
Pleasingly, ICP-MS analyses showed that leaching of Rh
catalysts is very low with all values detected below 10 ppb.
CONCLUSIONS
■
In conclusion, we reported a study for a specific process
intensification program for hydrogenation reactions that can be
carried out in a research laboratory environment. The use of
flow technologies allowed operating at high pressure and
temperature which enabled the use of high substrate
concentrations and high flow rates. Under the agreements of
departmental safety protocols (University of Cambridge) with
appropriate excess hydrogen venting (operating under
parameters within the safety criteria of the equipment), this
provided very high throughput from a benchtop reactor, with
potential throughput to multikilogram scale through extended
run times. Studies on catalyst degradation are ongoing and our
future plans involve the engineering improvements of the flow
machinery in order to increase the throughput of material using
even larger column reactors.
25
The use of the FlowCAT system with RC1 and Rh/Al2O3
catalyst gave an outstanding 1741 g d−1 throughput which was
seen as genuine improvement over previously reported
procedures (Scheme 5a). We also were very pleased to find
out that the system could tolerate even higher concentrations of
starting material as we could process a 3 M solution of ethyl
nicotinate successfully (Scheme 5b).
Under the optimized conditions, we were able to
continuously produce 81.6 g of material in just 1 h (99%
purity), and the total amount of material processed over five
different experiments was 530 g using the same catalyst bed
(overall 6.5 h), which equates to 1959 g d−1 throughput of
material. An examination to the gas stoichiometry for b
(Scheme 5) shows that the ratio of hydrogen to substrate is
represented as follows:
E
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Organic Process Research & Development
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Perni, R. B.; Berry, M.; Rutter, A.; Watson, S. A. Org. Process Res. Dev.
2014, DOI: 10.1021/op400090a. (p) Hessel1, V.; Kralisch, D.;
ASSOCIATED CONTENT
* Supporting Information
Characterization of compounds, analytical data, and technical
information on the catalysts used. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
Kockmann, N.; Noel1, T.; Wang, Q. ChemSusChem 2013, 746−789.
̈
(q) Johnson, M. D.; May, S. A.; Calvin, J. R.; Remacle, J.; Stout, J. R.;
Diseroad, W. D.; Zaborenko, N.; Haeberle, B. D.; Sun, W.-M.; Miller,
M. T.; Brennan, J. Org. Process Res. Dev. 2012, 16, 1017−1038.
(4) Stankiewicz, A.; Moulijn, J. A. Ind. Eng. Chem. Res. 2002, 41,
1920−1924.
AUTHOR INFORMATION
Corresponding Author
*E-mail address: svl1000@cam.ac.uk, Tel.: +44 (0)1223
336398, Fax: +44 (0)1223 336442; webpage: http://www.
leygroup.ch.cam.ac.uk/.
■
(5) (a) Cossy, J. Chem. Rec. 2005, 5, 70−80. (b) Degenhardt, C. R.;
Eickhoff, D. J. World Patent WO0232869 (A2), 2002. (c) Baldwin, J.
J.; Claremon, D. A.; Tice, C. M.; Cacatian, S.; Dillard, L. W.;
Ishchenko, A. V.; Yuan, J.; Xu, Z.; Mcgeehan, G.; Zhao, W.; Simpson,
R. D.; Singh, S. B.; Jia, L.; Flaherty, P. T. European Patent EP2074108
(A1), 2009.
Notes
The authors declare no competing financial interest.
(6) Battilocchio, C.; Baumann, M.; Baxendale, I. R.; Biava, M.;
Kitching, M. O.; Ley, S. V.; Martin, R. E.; Ohnmacht, S. A.; Tappin, N.
D. C. Synthesis 2012, 635−647.
ACKNOWLEDGMENTS
■
(7) Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem. Commun.
2005, 2909−2911.
We are grateful to Takeda Pharmaceutical Company Limited
(T.O.), Pfizer Worldwide Research and Development (C.B.
and J.M.H.), and the EPSRC (S.V.L.) for financial support. We
are also grateful to Dr. David Cork (Takeda Pharmaceutical
Company Limited) for helpful discussion; Jasbir Singh, Andrew
Coleman, Roderick Mcintosh, Mark Appleton (H.E.L. Group),
Bashir Harji (Cambridge Reactor Design, CRD), and Steve
Hawker (Johnson & Matthey) for their technical support.
(8) Knudsen, K. R.; Holden, J.; Ley, S. V.; Ladlow, M. Adv. Synth.
Catal. 2007, 349, 535−538.
(9) Ingham, R. J.; Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Beilstein
J. Org. Chem. 2014, 10, 641−652.
(10) Irfan, M.; Petricci, E.; Glasnov, T. N.; Taddei, M.; Kappe, C. O.
Eur. J. Org. Chem. 2009, 1327−1334.
(11) ThalesNano. H-Cube Midi description. http://thalesnano.com/
h-cube-midi (accessed June 15, 2014). For examples of reductions
using the H-Cube Midi, see: (a) Cooper, C. G. F.; Lee, E. R.; Silva, R.
A.; Bourque, A. J.; Clark, S.; Katti, S.; Nivorozhkin, V. Org. Process Res.
Dev. 2012, 16, 1090−1097. (b) Carter, C. F.; Baxendale, I. R.; Pavey, J.
B. J.; Ley, S. V. Org. Biomol. Chem. 2010, 8, 1588−1595.
(12) Blaser, H.-U.; Honig, H.; Studer, M.; Wedemeyer-Exl, C. J. Mol.
Catal. A: Chem. 1999, 139, 253−257.
ABBREVIATIONS
RC1, reactor column 1; RC2, reactor column 2
■
REFERENCES
■
(1) (a) Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res.
Dev. 2005, 9, 253−258. (b) Jimen
́
ez-Gonzal
́
ez, C.; Poechlauer, P.;
(13) Newton, S.; Ley, S. V.; Arce,
Catal. 2012, 354, 1805−1812.
(14) HEL Group. FlowCAT overview. http://www.helgroup.com/
reactor-systems/hydrogenation-catalysis/flowcat/ (accessed June 15,
2014).
́
E. C.; Grainger, D. M. Adv. Synth.
Broxterman, Q. B.; Yang, B. S.; Ende, D.; Baird, J.; Bertsch, C.;
Hannah, R. E.; Dell’Orco, P.; Noorman, H.; Yee, S.; Reintjens, R.;
Wells, A.; Massonneau, V.; Manley, J. Org. Process Res. Dev. 2011, 15,
900−911.
(2) For recent reviews, see: (a) Hartman, R. L.; McMullen, J. P.;
Jensen, K. F. Angew. Chem., Int. Ed. 2011, 50, 7502−7519. (b) Wegner,
J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17−57.
(c) Wiles, C.; Watts, P. Green Chem. 2012, 14, 38−54. (d) Malet-Sanz,
L.; Susanne, F. J. Med. Chem. 2012, 55, 4062−4098. (e) Baxendale, I.
R. J. Chem. Technol. Biotechnol. 2013, 88, 519−552. (f) Pastre, J. C.;
Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849−8869.
(3) For selected examples, see: (a) Kim, H.; Nagaki, A.; Yoshida, J.-i.
Nat. Commun. 2011, 2, 264. (b) Alvarez, A. J.; Myerson, A. S. Cryst.
Growth Des. 2010, 10, 2219−2228. (c) Levesque, F.; Seeberger, P. H.
Angew. Chem., Int. Ed. 2012, 51, 1706−1709. (d) Viviano, M.; Glasnov,
T. N.; Reichart, B.; Tekautz, G.; Kappe, C. O. Org. Process Res. Dev.
2011, 15, 858−870. (e) Deadman, B. J.; Battilocchio, C.; Sliwinski, E.;
Ley, S. V. Green Chem. 2013, 15, 2050−2055. (f) He, Z.; Jamison, T.
(15) Cambridge Reactor Design. Chameleon Adaptable Reactor
Technology. http://www.cambridgereactordesign.com/reactor-
technology.html (accessed June 15, 2014).
(16) Lei, A.; Chen, M.; He, M.; Zhang, X. Eur. J. Org. Chem. 2006,
4343−4347.
(17) Hawkins, J. M. Trickle bed flow hydrogenation using shallow
beds of fine catalyst particles: Enhanced diastereoselectivity, purity
control, and catalyst activity relative to batch hydrogenations. From
Abstracts of Papers, 242nd ACS National Meeting & Exposition;
Denver, CO, United States, August 28−Sept1, 2011.
(18) Glass beads acid-washed 0.212−0.300 mm available from
Sigma−Aldrich (cod. G1277).
(19) The catalyst was kindly provided by Johnson & Matthey
(particle size 0.40−0.80 mm, product code 110002CPR10-20/lot.
M13225), website: http://www.matthey.com/ (accessed June 15,
2014).
(20) The catalyst was kindly provided by Johnson & Matthey
(particle size 0.30−0.85 mm, product code 110002CPS10-20/lot.
M14058), website: http://www.matthey.com/ (accessed June 15,
2014).
(21) The catalyst was kindly provided by Johnson & Matthey
(particle size 0.25−0.50 mm, product code 110002APR5-10/lot.
M14040), website: http://www.matthey.com/ (accessed June 15,
2014).
(22) The catalyst was kindly provided by Johnson & Matthey
(particle size 0.10−0.25 mm, product code 110002APR10-20/lot.
M14017), website: http://www.matthey.com/ (accessed June 15,
2014).
́
F. Angew. Chem., Int. Ed. 2014, 53, 3353−3357. (g) Rincon, J. A.;
Barberis, M.; Gonzales-Esguevillas, M.; Johnson, M. D.; Niemeier, J.
K.; Sun, W.-M. Org. Process Res. Dev. 2011, 15, 1428−1432.
(h) Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9,
1613−1619. (i) Newton, S.; Carter, C. F.; Pearson, C. M.; de C. Alves,
L.; Lange, H.; Thansandote, P.; Ley, S. V. Angew. Chem., Int. Ed. 2014,
53, 4915−4920. (j) Hartwig, J.; Ceylan, S.; Kupracz, L.; Coutable, L.;
Kirschning, A. Angew. Chem., Int. Ed. 2013, 52, 9813−9817.
(k) Newman, S. G.; Gu, L.; Lesniak, C.; Victor, G.; Meschke, F.;
Abahmaneb, L.; Jensen, K. F. Green Chem. 2014, 16, 176−180.
(l) Nightingale, A. M.; Phillips, T. W.; Bannock, J. H.; de Mello, J. C.
Nat. Commun. 2014, 5, 3777. (m) Sedelmeier, J.; Lima, F.; Litzler, A.;
Martin, B.; Venturoni, F. Org. Lett. 2013, 15, 5546−5549. (n) Fan, X.;
Sans, V.; Yaseneva, P.; Plaza, D. D.; Williams, J.; Lapkin, A. Org. Process
Res. Dev. 2012, 16, 1039−1042. (o) Broom, T.; Hughes, M.;
Szczepankiewicz, B. G.; Ace, K.; Hagger, B.; Lacking, G.; Chima, R.;
Marchbank, G.; Alford, G.; Evans, P.; Cunningham, C.; Roberts, J. C.;
(23) We speculate that the specific properties of Al2O3 support are
responsible for the increased activity over carbon support.
F
dx.doi.org/10.1021/op500208j | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Communication
(24) (a) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.;
Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.;
Stefaniak, M. Green Chem. 2008, 10, 31−36. (b) Prat, D.; Pardigon,
O.; Flemming, H.-W.; Letestu, S.; Ducandas, V.; Isnard, P.; Guntrum,
E.; Senac, T.; Ruisseau, S.; Cruciani, P.; Hosek, P. Org. Process Res. Dev.
2013, 17, 1517−1525.
(25) The catalyst used in the trickle bed reactor was a mixture (RhA
and RhB, 1:1, w/w) of two different sizes of Rh/Al2O3 materials kindly
provided by Johnson & Matthey (RhA particle size 0.02−0.10 mm,
product code 110002 CPR 10−20/lot. DJZ0052 and RhB particle size
0.30−0.80 mm, 110003APO5-10/lot. M14102), website: http://www.
matthey.com/.
(26) A gas feed set at 0.6 L min−1 produced a gas flow which
oscillated in the range 0.675−0.599 L min−1.
G
dx.doi.org/10.1021/op500208j | Org. Process Res. Dev. XXXX, XXX, XXX−XXX