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.

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Figure 1. Examples for biologically active molecules containing a
piperidine core.
INTRODUCTION
In recent years there has been an increasing demand for new genation6−9 of different pyridine derivatives using for example
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
technologies have become available to drive this new agenda.2,3 system was limited to around 10 g d−1. Subsequent innovation
However, a particular challenge that has not been fully met is has led to the development of the H-Cube Midi, which is
how to move rapidly and safely to scale-up reactions in research designed for scale-up reactions up to 500 g d−1, for larger scale
laboratories from milligrams to kilograms. It is precisely under work.11
these circumstances where new tools can greatly assist the We began our investigation with the aim of safely delivering a
process. Indeed, by definition, process intensification is the throughput in excess of a kilogram per day (kg d−1) in a
“strategy for making dramatic reductions in the size of a research laboratory environment. This, we felt, would need
chemical plant so as to reach a given production objective”.4 considerable process intensification with currently available
Accordingly, this approach can involve shrinking the size of equipment. We decided to do this by examining the selective
hydrogenation, both partial and full, of ethyl nicotinate (1)
individual pieces of equipment by cutting the number of unit
since the products of this process were useful for other
operations and/or devices involved. Similarly, intensification
programs.
can occur through using a relevant apparatus to its limits of
The selective and efficient partial hydrogenation of pyridine
production, e.g., through the use of high pressure, high
derivatives is particularly interesting in order to provide a
temperature, and high substrate concentration. In addition, valuable intermediate for later asymmetric conversion to 3
interests in greater sustainability through more selective (Scheme 1).12,13
processes, often under heterogeneous conditions, have become Our approach was to investigate the suitability of the
attractive goals. Nevertheless, working with and scaling up of commercially available HEL FlowCAT reactor14 (Figure 2) for
hydrogen gas reactions brings with it well-recognized issues the aforementioned processes and to investigate its suitability
(i.e., safety assessment, mixing, and H2 solubility) despite the for daily production of material using a single charge of catalyst
importance of this reductive process in fine chemical in the trickle bed reactor system.
manufacturing. One such process involving precious metal The HEL FlowCAT is a compact, benchtop unit which
catalyzed hydrogenation of substituted pyridines is of interest allows screening, optimization, and scale-up of heterogeneous
due to the importance of the functionalized piperidines
products as intermediates in the preparation of many
Special Issue: Continuous Processes 14
biologically active molecules (Figure 1).5
Flow chemistry as an enabling technology has proven useful Received: June 26, 2014
on a research scale for the continuous catalytic hydro-

© XXXX American Chemical Society A dx.doi.org/10.1021/op500208j | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development Communication

Scheme 1. Products obtained from partial (2) and full (3) theless using 5% Pd/C as a catalyst under moderately high
reduction of ethyl nicotinate (1) pressure hydrogen (100 psi) gave us 85% conversion for
products 2 and 3 (7:1 average ratio) over 38 h, at room
temperature.
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.
chemistry and is run under fixed-bed, trickle flow conditions. One practical aspect of major importance, when dealing with
The system provides a wide range of working pressures and the this kind of process, is the packing of the reactor column.
processing conditions are controlled via software (Supporting
During our screening we noticed that the performance of the
Information, SI), which accurately controls parameters such as
pressure, temperature, and gas and liquid feed rates (Figure 3). run was highly dependent on catalyst particle size, as too small

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particles were more amenable to frequent blockages whereas
RESULTS AND DISCUSSION too big particles were associated with channeling and reduced
Partial Hydrogenation Process. The first step towards a mixing. In our specific case, the use of particles ranging between
full understanding of the advantages of running this trans- 0.1 and 0.8 mm was found to be ideal. Notably, the use of
formation in flow was to properly evaluate the constraints of smaller particle sizes is possible provided that a “filler material”
the batch process. For this we used the Chameleon with bigger particles size is used to “disperse” the smaller
technology15 as a single unit stirred autoclave (Scheme 2). particles and create an efficient bed reactor. To avoid any
We soon recognized that the chemical transformation was inconvenient issue with blockages, we decided to “dilute” the
difficult under the conditions reported previously,16 never- catalyst particles with inert glass beads with particle sizes

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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Organic Process Research & Development Communication

Figure 3. Schematic view of the HEL FlowCAT.

Scheme 2. Hydrogenation of 1 under batch mode conditions limiting parameter under these conditions and any attempt to
using the Chameleon technology (description within the SI) increase the molarity of the solution above 0.05 M failed,
resulting in incomplete consumption of the starting material.
We decided therefore to screen different supported forms of
Pd catalyst and found that Pd/Al2O321,22 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
around 0.2 mm (description of the packing is reported within reaction at 60 °C and a liquid flow rate of 3.0 mL min−1
the SI).18 delivered an improved productivity of over 260 g d−1 (entry 7).
For the initial study, we used a Pd/C catalyst (Table 1).19,20 Also of importance was that under those conditions
We started to screen our system at room temperature with 10% considerably higher concentrations of the material feedstock
Pd/C. Using a H2 feed of 0.2 L min−1 and system pressure of are tolerated (up to 0.4 M).
20 bar, we were able to selectively obtain 78% conversion to 2 The robustness of the system was evaluated by conducting an
(liquid flow rate 2.0 mL min−1) (Table 1, entry 1). Increasing
experiment for 22.5 h, following the conditions reported in
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 entry 7 (Table 2), without noticing any decrease in either
throughput of 54.78 g d−1 with the disadvantage of reducing the selectivity or catalytic performance of the system while
2/3 selectivity (Table 1, entry 5). The best result was achieved producing a throughput of over 240 g of material overall (see
using 5% Pd/C20 (Table 1, entry 6), although this arrangement SI).
gave a lower product output (21.6 g d−1 throughput). We Although this productivity was more than 25-fold the
recognized that the concentration of the starting material was a throughput obtained with the H-Cube, we believed further

Table 1. Partial reduction of ethyl nicotinate with Pd/C using HEL FlowCAT reactor RC1
ratio (%)a
conc. of 1 flow rate temp. pressure H2 flow throughput of 1
eun catalyst (M) (mL min−1) (°C) (bar) (L min−1) 1 2 3 (g min−1)
1 10% Pd/Cb 0.05 2.0 25 20 0.1 22.0 78.0 N.D. 0.015
2 10% Pd/Cb 0.05 2.0 40 20 0.1 1.1 84.2 14.7 0.015
3 10% Pd/Cb 0.05 2.0 25 40 0.1 15.2 71.3 13.5 0.015
4 10% Pd/Cb 0.05 4.0 60 20 0.2 1.1 78.8 20.1 0.030
5 10% Pd/Cb 0.05 5.0 60 20 0.2 4.8 75.1 20.1 0.038 (54.78 g d−1)
6 5% Pd/Cc 0.05 2.0 40 20 0.1 1.0 90.7 8.3 0.015 (21.60 g d−1)
7 5% Pd/Cc 0.05 4.0 60 20 0.2 1.8 78.4 19.8 0.030

a
Ratios are based on crude 1H NMR data. bParticle size 0.40−0.80 mm.19 cParticle size 0.30−0.85 mm.20

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Table 2. Partial reduction of ethyl nicotinate with Pd/Al2O3 using HEL FlowCAT reactor RC1
ratio (%)a
conc. of 1 flow rate temp. pressure H2 flow throughput of 1
run catalyst (M) (mL min−1) (°C) (bar) (L min−1) 1 2 3 (g min−1)
1 5% Pd/Al2O3b 0.1 2.5 40 24 0.2 ND 88.5 11.5 0.038
2 5% Pd/Al2O3b 0.2 2.5 50 23 0.2 6.4 83.3 10.3 0.076
3 5% Pd/Al2O3b 0.2 3.0 60 24 0.2 2.4 86.5 11.1 0.091
4 5% Pd/Al2O3c 0.2 4.0 50 20 0.2 1.8 83.2 15.0 0.121
5 5% Pd/Al2O3c 0.2 4.0 50 20 0.1 11.0 76.7 12.2 0.121
6 5% Pd/Al2O3c 0.4 2.0 50 20 0.2 3.2 80.1 16.7 0.121
7 5% Pd/Al2O3c 0.4 3.0 60 20 0.2 0.9 84.0 15.1 0.181 (260.64 g d−1)
a
Ratios are based on crude 1H NMR data. bParticle size 0.25−0. 50 mm.21 cParticle size 0.10−0.25 mm.22

process intensification was possible. For this the reactor column of pyridine to 3 was unsuccessful using the EtOH/Pd/C
was increased to 12 mL of internal volume (RC2, Figure 4). 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.
Figure 4. Picture of RC1, top, and RC2, bottom. Interestingly, 10% Pd/Al2O3 gave us almost full conversion to
the desired product 3, with very good selectivity and no by-
The new reactor column accommodated a larger quantity of product observed (Table 4, entry 7).
catalyst (13 g), hence a corresponding increase in productivity The hydrogenation process was then transferred to the HEL
was anticipated. platform using the RC1 trickle bed reactor. Given the results
After screening different parameters (Table 3) using RC2, obtained with Pd/Al2O322 as catalyst, we decided to use this
the concentration could be increased to 0.8 M and the flow rate material to perform the full hydrogenation. After very few
adjusted to 7.0 mL min−1 to obtain a throughput of 1219 g d−1 experiments, it was easily found that by running the reaction at
with complete consumption of the starting material, with 100 bar hydrogen, 160 °C, and 3 mL min−1, with a hydrogen
slightly reduced selectivity (Table 3, entry 7). feed equating to 0.2 L min−1 and a 0.8 M solution of 1, we
Compound 2 could be isolated in 73% yield (purity >99%) could obtain pure product 3 free from partially hydrogenated
just via concentration under vacuo, followed by dissolution of by-product (2). This system successfully delivered a throughput
the material collected in CH2Cl2 and then washing away the of 522 g d−1 of compound (3) (Scheme 3).
byproduct 3 with citric acid 10% solution.10 The reaction was During further process intensification studies, it was
run for 10 h under the optimized conditions, processing 507 g anticipated that the use of the larger reactor RC2 should be
of starting material (entry 7). Additionally, negligible leaching able to increase the throughput to >1000 g d−1. Accordingly,
of Pd catalyst (below 9.5 ppb) was detected by inductively with the 12 mL reactor (RC2), we were pleased to generate the
coupled plasma-mass spectrometry (ICP-MS) analyses. equivalent of 1524 g d−1, using a 1.0 M solution of the starting
Full Hydrogenation Process. To achieve the full hydro- material. In one long run experiment a quantity of 242 g
genation of 1 to 3, we followed a similar optimization approach. (isolated yield 99%, purity >99%) of material was collected over
Kappe and co-workers10 had reported that “full hydrogenation just 3 h and 45 min simply via removal of AcOEt by

Table 3. Partial reduction of ethyl nicotinate using HEL FlowCAT reactor RC2
ratio (%)a
conc. of 1 flow rate temp.c pressure H2 flow throughput of 1
run catalystb (M) (mL min−1) (°C) (bar) (L min−1) 1 2 3 (g min−1)
1 5% Pd/Al2O3 0.5 10.0 65 20 0.6 0.6 74.4 25.0 0.756 (1088.35 g d−1)
2 5% Pd/Al2O3 0.8 6.0 45 20 0.6 1.2 78.7 20.1 0.726 (1044.82 g d−1)
3 5% Pd/Al2O3 0.8 6.0 65 12 0.6 ND 62.9 37.1 0.726
4 5% Pd/Al2O3 0.8 6.0 65 20 0.6 ND 61.3 38.7 0.726
5 5% Pd/Al2O3 0.8 8.0 65 20 0.6 ND 69.9 30.1 0.967 (1393.09 g d−1)
6 5% Pd/Al2O3 0.8 8.0 55 20 0.4 19.2 67.5 13.3 0.967 (1393.09 g d−1)
7d 5% Pd/Al2O3 0.8 7.0 55 20 0.6 trace 75.8 24.2 0.846 (1218.95 g d−1)

a
Ratios are based on crude 1H NMR data. bParticle size 0.10−0.25 mm.22 cTemperature of the external heating jacket. d10 h run.

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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
ratio (%)c
entrya,b catalyst solvent 1 2 3 throughput of 3 (g min−1)
1 10% Pd/C EtOH N.D. 39.4 60.4 0.00375
2 10% Pd/C THF N.D. 32.4 67.6 0.00375
3 10% Pd/C toluene N.D. 41.7 58.3 0.00375
4 10% Pd/C AcOEt N.D. 30.6 69.4 0.00375
5 5% Pd/C AcOEt N.D. 73.0 27.0 0.00375
6 10% Pd/Al2O3 EtOH N.D. 50.5 49.5 0.00375
7 10% Pd/Al2O3 AcOEt N.D. 9.3 90.7 0.00375
a
The data reported are only related to representative examples. bConditions: full hydrogen mode, 100 °C, 0.5 mL min−1. cRatios are based on crude
1
H NMR.

Scheme 3. Full reduction of ethyl nicotinate with Pd/Al2O3 Scheme 5. (a and b) Full reduction of ethyl nicotinate with
using HEL FlowCAT reactor (RC1) 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)

[(0.6 L min−1)/22.4 L mol−1)]/[(3.0 mol L−1)

(0.003 L min−1)]
= 2.98 mol H 2 /mol ethyl nicotinate

advantage as it enables the removal of troublesome operations This calculation suggests we are working at the current limit of
(i.e., filtration of catalyst, washing procedure). the gas feed to the RC1.26
Nonetheless, we wanted to check the suitability of the system Pleasingly, ICP-MS analyses showed that leaching of Rh
for higher productivity. After a more careful screening of catalysts is very low with all values detected below 10 ppb.

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different catalysts, we realized that the use of a 0.05 M solution
of 1 in AcOEt could be fully hydrogenated with Rh/Al2O3 CONCLUSIONS
catalyst, using the H-Cube platform. However, the daily
throughput could not be increased under these conditions on In conclusion, we reported a study for a specific process
this equipment. intensification program for hydrogenation reactions that can be
The use of the FlowCAT system with RC1 and Rh/Al2O325 carried out in a research laboratory environment. The use of
catalyst gave an outstanding 1741 g d−1 throughput which was flow technologies allowed operating at high pressure and
seen as genuine improvement over previously reported
temperature which enabled the use of high substrate
procedures (Scheme 5a). We also were very pleased to find
out that the system could tolerate even higher concentrations of concentrations and high flow rates. Under the agreements of
starting material as we could process a 3 M solution of ethyl departmental safety protocols (University of Cambridge) with
nicotinate successfully (Scheme 5b). appropriate excess hydrogen venting (operating under
Under the optimized conditions, we were able to parameters within the safety criteria of the equipment), this
continuously produce 81.6 g of material in just 1 h (99% provided very high throughput from a benchtop reactor, with
purity), and the total amount of material processed over five potential throughput to multikilogram scale through extended
different experiments was 530 g using the same catalyst bed
(overall 6.5 h), which equates to 1959 g d−1 throughput of run times. Studies on catalyst degradation are ongoing and our
material. An examination to the gas stoichiometry for b future plans involve the engineering improvements of the flow
(Scheme 5) shows that the ratio of hydrogen to substrate is machinery in order to increase the throughput of material using
represented as follows: even larger column reactors.
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Organic Process Research & Development

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Communication

ASSOCIATED CONTENT Perni, R. B.; Berry, M.; Rutter, A.; Watson, S. A. Org. Process Res. Dev.
*
S Supporting Information
2014, DOI: 10.1021/op400090a. (p) Hessel1, V.; Kralisch, D.;
Kockmann, N.; Noël1, T.; Wang, Q. ChemSusChem 2013, 746−789.
Characterization of compounds, analytical data, and technical (q) Johnson, M. D.; May, S. A.; Calvin, J. R.; Remacle, J.; Stout, J. R.;
information on the catalysts used. This material is available free Diseroad, W. D.; Zaborenko, N.; Haeberle, B. D.; Sun, W.-M.; Miller,
of charge via the Internet at http://pubs.acs.org.

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M. T.; Brennan, J. Org. Process Res. Dev. 2012, 16, 1017−1038.
(4) Stankiewicz, A.; Moulijn, J. A. Ind. Eng. Chem. Res. 2002, 41,
AUTHOR INFORMATION 1920−1924.
Corresponding Author (5) (a) Cossy, J. Chem. Rec. 2005, 5, 70−80. (b) Degenhardt, C. R.;
*E-mail address: svl1000@cam.ac.uk, Tel.: +44 (0)1223 Eickhoff, D. J. World Patent WO0232869 (A2), 2002. (c) Baldwin, J.
336398, Fax: +44 (0)1223 336442; webpage: http://www. J.; Claremon, D. A.; Tice, C. M.; Cacatian, S.; Dillard, L. W.;
leygroup.ch.cam.ac.uk/. 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
Notes (A1), 2009.
The authors declare no competing financial interest.

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(6) Battilocchio, C.; Baumann, M.; Baxendale, I. R.; Biava, M.;
Kitching, M. O.; Ley, S. V.; Martin, R. E.; Ohnmacht, S. A.; Tappin, N.
ACKNOWLEDGMENTS D. C. Synthesis 2012, 635−647.
We are grateful to Takeda Pharmaceutical Company Limited (7) Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem. Commun.
2005, 2909−2911.
(T.O.), Pfizer Worldwide Research and Development (C.B.
(8) Knudsen, K. R.; Holden, J.; Ley, S. V.; Ladlow, M. Adv. Synth.
and J.M.H.), and the EPSRC (S.V.L.) for financial support. We Catal. 2007, 349, 535−538.
are also grateful to Dr. David Cork (Takeda Pharmaceutical (9) Ingham, R. J.; Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Beilstein
Company Limited) for helpful discussion; Jasbir Singh, Andrew J. Org. Chem. 2014, 10, 641−652.
Coleman, Roderick Mcintosh, Mark Appleton (H.E.L. Group), (10) Irfan, M.; Petricci, E.; Glasnov, T. N.; Taddei, M.; Kappe, C. O.
Bashir Harji (Cambridge Reactor Design, CRD), and Steve Eur. J. Org. Chem. 2009, 1327−1334.
Hawker (Johnson & Matthey) for their technical support. (11) ThalesNano. H-Cube Midi description. http://thalesnano.com/

■ ABBREVIATIONS
RC1, reactor column 1; RC2, reactor column 2
h-cube-midi (accessed June 15, 2014). For examples of reductions
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A.; Bourque, A. J.; Clark, S.; Katti, S.; Nivorozhkin, V. Org. Process Res.

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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.
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(l) Nightingale, A. M.; Phillips, T. W.; Bannock, J. H.; de Mello, J. C. 2014).
Nat. Commun. 2014, 5, 3777. (m) Sedelmeier, J.; Lima, F.; Litzler, A.; (22) The catalyst was kindly provided by Johnson & Matthey
Martin, B.; Venturoni, F. Org. Lett. 2013, 15, 5546−5549. (n) Fan, X.; (particle size 0.10−0.25 mm, product code 110002APR10-20/lot.
Sans, V.; Yaseneva, P.; Plaza, D. D.; Williams, J.; Lapkin, A. Org. Process M14017), website: http://www.matthey.com/ (accessed June 15,
Res. Dev. 2012, 16, 1039−1042. (o) Broom, T.; Hughes, M.; 2014).
Szczepankiewicz, B. G.; Ace, K.; Hagger, B.; Lacking, G.; Chima, R.; (23) We speculate that the specific properties of Al2O3 support are
Marchbank, G.; Alford, G.; Evans, P.; Cunningham, C.; Roberts, J. C.; responsible for the increased activity over carbon support.

F dx.doi.org/10.1021/op500208j | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development 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