A High Mobility Reactor Unit for R&D Continuous Flow Transfer Hydrogenations

Article abstract of DOI:10.1021/acs.oprd.6b00441

A suitcase sized mobile reactor unit (MRU) weighing in at less than 10 kg was designed for laboratory scale transfer hydrogenations in continuous flow. Simple cyclohexene and a cosolvent in combination with a palladium-on-charcoal packed bed reactor provided a setup with isolation of nearly all products without the need for further purification. Several functional groups including olefins, triple bonds, nitro-groups, carbonyls, and so forth were effectively reduced with retention times as low as 2 min. Additionally, standard protection groups such as Cbz, benzyl, and allyl ether or esters were removed in high yields. To prove the flexibility of the setup an example of the Mizoroki-Heck reaction was also performed on the MRU. Finally, two scale-up transfer hydrogenation experiments were performed affording isolation of the desired target compounds in 0.5 and 0.8 mol scales with less than 4 h of continuous operation on the MRU.

Full text of DOI:10.1021/acs.oprd.6b00441

Subscriber access provided by University of Newcastle, Australia
Full Paper
A High Mobility Reactor Unit for R&D
Continuous Flow Transfer Hydrogenations
Rasmus K Jensen, Nikolaj Thykier, Martin V. Enevoldsen, and Anders T. Lindhardt
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00441 • Publication Date (Web): 08 Feb 2017
Downloaded from http://pubs.acs.org on February 9, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
A High Mobility Reactor Unit for R&D Continuous
Flow Transfer Hydrogenations
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rasmus K. Jensen,‡ Nikolaj Thykier,‡ Martin V. Enevoldsen, Anders T. Lindhardt*
Aarhus University, Department of Engineering, Section of Biological and Chemical Engineering.
Hangøvej 2, 8200 Aarhus C, Denmark.
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 21
1
2
3
4
TOC Graphic
5
6
7
8
Con$nuous
Flow
Hydrogen
Transfer
O
MeO
HO
CH3
NO2
MeO
NH2
HO
Ph
O
O
O
O
9
NHCbz
NH2
Mobile
Reactor
Unit
Ph
OMe
MeO
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
ACS Paragon Plus Environment
2

Page 3 of 21
Organic Process Research & Development
1
2
3
4
5
6
KEYWORDS: Flow Chemistry, Packed Bed Reactor, Palladium Catalysis, Transfer
Hydrogenation, Mobile Reactor Unit.
7
8
9
ABSTRACT: A suitcase sized mobile reactor unit (MRU) weighing in at less than 10 kg was
designed for laboratory scale transfer hydrogenations in continuous flow. Simple cyclohexene
and a co-solvent in combination with a palladium-on-charcoal packed bed reactor provided a
setup with isolation of nearly all products without the need for further purification. Several
functional groups including olefins, triple bonds, nitro-groups, carbonyls, etc. were effectively
reduced with retention times as low as 2 minutes. Additionally, standard protection groups such
as Cbz, benzyl and allyl ether or esters were removed in high yields. To prove the flexibility of
the setup an example of the Mizoroki-Heck reaction was also performed on the MRU. Finally,
two scale-up transfer hydrogenation experiments were performed affording isolation of the
desired target compounds in 0.5 and 0.8 mol scales with less than 4 hours of continuous
operation on the MRU.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
INTRODUCTION
The advantages of applying continuous flow setups in research and development (R&D)
laboratories have become obvious during the last decade.1 The ability to perform chemistry
under conditions that extend beyond the round-bottomed flask combined with precise control of
nearly all reaction parameters has attained significant research interest. Especially, reactions
requiring high-pressure or high temperatures have enjoyed the adaptation to continuous flow
mode, while simultaneously improving the operator safety.2 Even high-energy intermediates can
now be handled safely in telescoped flow reactions, as these reagents are produced and
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 21
1
2
3
4
5
6
7
8
9
transformed continuously with no hold-up or storage.3 Numerous other examples have been
published proving that continuous flow protocols holds the ability to enhance selectivity,
shortened reaction time (ultrafast), enhanced heat and mass transport, etc.4 In addition, once a
reaction has been developed in continuous flow its scale-up to produce large amounts of material
has proven more straightforward.1a,d,2b,5 Despite, all these arguments speaking in favor of the
installation of flow chemistry equipment in any R&D laboratory, there are drawbacks towards
application of these methods, the major one being practicality. Constructing a specific flow-setup
with all needed pumping equipment, mixers, flow-reactors, backpressure regulation and
connecting everything with tubing is inherently time-consuming. So any advantages gained from
continuous flow might be eliminated by time concerns leading to classical round bottom flask
synthesis, especially, if only one or few reactions are to be performed. Alternatively, a given
flow-setup or commercial flow-unit could be permanently installed in a designated fume hood,
however, not all laboratories hold the luxury of being sub-populated given that laboratory space
is costly.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hence, the need to develop complete flow reactor setups that are widely applicable and mobile
would be of great interest. Such mobile systems would allow the R&D chemist to rapidly move
the flow-reactor system into the fume-hood and initiate the desired reaction. Furthermore, if the
flow-setup would cover a series of different reactions types, its applicability would increase
significantly.
In this manuscript, we wish to report on the development of a Mobile Reactor Unit (MRU)
towards transfer hydrogenation in continuous flow. The concept behind the MRU is a robust, yet
simple design based on HPLC parts for all tubing, packed bed reactor and fittings. Standard
ACS Paragon Plus Environment
4

Page 5 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
palladium on charcoal (Pd/C) in combination with cyclohexene served as the hydrogen source
allowing reaction work-up to be fast and simple. The fully constructed MRU was fitted inside an
alumina suitcase (dimensions 46 cm x 33 cm x 15 cm) and weighed in below 10 kilograms!
Several common functional groups underwent successful hydrogen transfer reduction with flow
reactor residence times between 2.5 minutes and 40 minutes. Other transformations based on the
inherent reactivity of the palladium catalyst were investigated including Tjusi Trost type
deprotection of allylic ethers or esters and Mizoroki-Heck reactions. Finally, fume hood scale-up
hydrogen transfer reduction on the MRU was performed affording 137.7 g and 82.6 g isolation
of reduced eugenol and ethyl 4-nitrobenzoate, respectively. The latter of these scale-up studies
was also applied to gain insight to potential catalyst leaching and/or deactivation of the packed
bed reactor.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and Discussion
During the construction of the Mobile Reactor Unit for transfer hydrogenation the following
considerations were taken into account. Although, hydrogen gas is the most atom- and cost
efficient reagent used in reductions, the handling of this gaseous molecule has some
drawbacks.6,7 Hydrogen is typically stored and transported in pressurized cylinders
compromising the desired simplicity of the MRU. Online production of hydrogen could also be
facilitated by smart systems such as the H-cube.6a,8
Figure 1. Schematic Representation and Suitcase Installed Transfer Hydrogenation MRU.
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 21
1
2
3
4
5
6
7
8
9
Sample Loop
MeO
HO
1
Packed Bed
Reactor
Hydrogen
Donor
Solvent
MeO
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeOH or
EtOAc
Palladium on
Charcoal
H
H
2
BPR
HPLC Pump
However, the use of hydrogen will always result in two-phase systems due to the low solubility
of this gaseous reagent in common laboratory solvents.9 We therefore decided to apply a transfer
hydrogenation approach, as this would allow the hydrogen source, typically salts or liquids, to be
part of the reaction mixture.10 Palladium on charcoal (Pd/C) was chosen as the catalyst as this
material often already is present in chemical laboratories or readily available through several
chemical vendors.6,9,10c,11 The Pd/C catalyst was loaded into an empty HPLC column, as a packed
bed reactor, thereby allowing the reaction mixture to pass the catalyst without the need for
subsequent removal by filtration.12 An additional advantage to the application of the packed bed
reactor approach is the presence of super-stoichiometric amounts of catalyst, resulting in a
significant reduction in the required residence time. Despite this super stoichiometric amount of
Pd/C experienced by the limiting substrate, at any given time, in the reactor the overall flow-
ACS Paragon Plus Environment
6

Page 7 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
system will become catalytic upon prolonged operation. As all reactants are mixed prior to
entering the packed bed reactor a one-pump setup could be designed, and the reaction mixture
would either be pumped continuously by feeding on a stock reservoir (for large-scale
applications) or loaded by injection into a loop (10 mL) positioned between the pump and
packed bed reactor (See figure 1). As the heating source, a heating mantle, connected to a PID
temperature controller, was placed around the packed bed reactor. The mantle was heated using
cartridge heaters and isolated with vermiculite for safety reasons and to minimize heat exchange
with the surroundings. The heating mantle allows the packed bed reactor to reach the desired
reaction temperature in few minutes. Finally, the flow-setup was fitted with a backpressure
regulator set to 1000 psi, permitting reaction temperature settings above solvent boiling points.
During this study two different packed bed reactor designs were tested, differing in the method
of packaging and the amount of Pd/C catalyst loaded. Pd/C was mixed with silica in order to
reduce the pressure drop over the packed bed reactor. Finally, both ends of the HPLC column
were sealed with additional silica and cotton plugs to prevent small particles of Pd/C from
exiting the reactor.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. MRU Transfer Hydrogenation of Eugenol.
Sample Loop
MeO
HO
γ-Terpinene
3.0 M
1 - 0.5 M
MeO
Palladium on
EtOAc
Charcoal
2
HO
140 °C
HPLC Pump
Entry
Flowrate
Residence
Yielda
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 21
1
2
3
4
5
6
[ml/min]
time
[min]
[%]
7
8
9
1
1
15 min
90 sec
(100)b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
10
8
91
3c
113 sec
86.3 (137.7 grams)
a Isolated yield. Conversion based on H-NMR analysis of crude reaction mixture. Large
scale experiment – See supporting information for reaction setup.
b
1
c
The void volume of the packed bed reactor was determined by the weight difference of the dry
and ethyl acetate loaded column at room temperature correlated to the density of the liquid.
Besides the heating mantle, all parts for the MRU design was constructed from commercially
available HPLC parts (See the Supporting Information for a full description of the MRU setup).
The reduction of eugenol was used as test system applying γ-terpinene as the hydrogen donor
(See Scheme 1). Eugenol (1) (0.5 M) and γ-terpinene (3.0 M) dissolved in ethyl acetate was
loaded onto the sample loop (10 mL – 5 mmol reaction scale) and then pumped through the
packed bed reactor set at 140 °C. Operating the system at a flow rate of 1 mL/min, corresponding
to a residence time of 15 minutes, resulted in full conversion of eugenol to 2-methoxy-4-
1
propylphenol (2) as determined by H-NMR analysis. Interestingly, increasing the flowrate in a
stepwise manner all the way to the maximum HPLC pump-capacity of 10 mL/min (residence
time = 1.5 min) still afforded the fully reduced compound (2) in an isolated yield of 91%. Next, a
large-scale reduction of eugenol was initiated. An ethyl acetate stock solution of 1 mol of
eugenol and γ-terpinene, in the same ratios as above, was pumped through the packed bed
reactor at 8 mL/min (residence time = 1 min 53 sec). Collection of material was initiated after
clearing two reactor volumes assuming that flow reactor operation had reached steady state.
ACS Paragon Plus Environment
8

Page 9 of 21
Organic Process Research & Development
1
2
3
4
Collection was continued for 4 hours, corresponding to processing 0.96 mol of eugenol. The
5
6
1
reaction progress was followed by H NMR and showed full consumption of 1 throughout the
7
8
9
entire process. 2 was isolated by basic washing of the crude reaction mixture followed by
acidification and extraction of the aqueous phase. This resulted in the isolation of 2 in 86.3 %
(137.7 grams) corresponding to a catalytic palladium loading of 0.054 mol % (TON = 1851).
We then turned our attention to other hydrogen transfer reagents to substitute the γ-terpinene.
Although, γ-terpinene worked well in the reduction of eugenol, its removal from the crude
reaction mixture is complicated by high boiling points of this compound and its fully oxidized
counterpart (182 °C and 177 °C, respectively). A brief look in the literature provides numerous
alternatives including, formic acid,14 ammonium formate,15 1,3- or 1,4-cyclohexadienes,16 silane
derivatives,11a, 17 cyclohexene,10, 18 etc.10,19 After testing several combinations, the most reliable
system for the reduction was found to be: eugenol (0.1 M) dissolved in a 1:1 solvent:cyclohexene
mixture passed through the packed bed reactor set at 120 °C with a residence time of 10 minutes
(Tabel 1 – entry 1). Cyclohexene (bp = 83 °C) proved highly useful as this hydrogen donor and
its oxidation products 1,3-cyclohexadiene, 1,4-cyclohexadiene or benzene (bp = 80 °C, 88 °C
and 80 °C, respectively) all could be removed by simple rotary evaporation, hence eliminating
the need to perform workup on the crude reaction mixture.18a Benzene, which is most likely
formed during transfer hydrogenation, is a toxic substance and a known carcinogenic. If benzene
is to be completely avoided in the obtained products, 1-, or 4-methylcyclohexene could possibly
be used to substitute cyclohexene, leading to the formation of more benign toluene instead.20
With this setup in hand, we set out to test the utility of the transfer hydrogenation MRU, the
results of which are shown in Table 1. All entries are batch-flow experiments and were
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 21
1
2
3
4
5
6
optimized for individual required residence times tested at 0-10 min, 20, 30 or 40 minutes (See
Supporting Information).
7
8
9
The reactor output was collected for 2.5 x residence times followed by removal of all volatiles
under reduced pressure, and apart from a few examples, no further product purification was
required. Simple reduction of eugenol (1) afforded 2 in a similar 93% isolated yield (entry 1).
Subjection of the alkyne derivative (3) to the conditions afforded the fully reduced methyl 3-
phenylpropanoate (4) in a good 94% isolated yield (entry 2). Next, two nitro-functionalized
analogues (5 and 7) and one 4-azido substituted acetophenone (9) were tested all affording the
target anilines in yields ranging from 87-99% with residence times as low as 2 minutes (entries
3-5). Reduction of ketones and aldehydes also proved possible applying trifluoroacetic acid as a
reaction additive affording 11 and 15 in 95% and 88% isolated yields (entries 6 and 8).21
Interestingly, benzonitrile (12) did not undergo reduction using the current setup (entry 7).
Attention was then turned towards application of the flow setup as a tool for the removal of
classical oxygen and nitrogen protection groups. Cbz-protected 4-methoxyaniline (16) and 2-
phenylethanamine (18) both afforded their corresponding free amines in 99% and 85% isolated
yield with a retention time of 20 minutes (Entries 9 and 10).16 Hydrogenolysis of benzylethers
(20 and 21) and benzyl ester (23) was accomplished in near quantitative isolated yields applying
retention times of 20-40 minutes (entries 11, 12 and 13).16 Successful dechlorination of 25
required the addition of triethylamine, to remove the in situ formed HCl, and an isolated yield of
95% with a retention time of 20 minutes was obtained.22 Reductive cleavage of the azo-
derivative 27 afforded 4-methoxyaniline (17) and 4-aminophenol (28) in a combined yield of
95% for the two compounds.23
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
10

Page 11 of 21
Organic Process Research & Development
1
2
3
4
Table 1. Transfer Hydrogenation Reaction Scopea
5
6
7
8
Reactant (0.05-0.5 M)
cyclohexene:solvent (1:1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Palladium on
Charcoal
EtOAc
Product
120 °C
Time
Yieldb
[%]
Concentration [M] /
Solvent / additive
Entry
1
Substrate
Product
[Min]
MeO
HO
MeO
[0.1] / MeOH
10
20
93
94
2
1
HO
O
O
4
2
3
[0.1] / EtOAc
[0.1] / EtOAc
OMe
Ph
OMe
NH2
6
3
Ph
NO2
4
93
99
87
5
O
O
NO2
NH2
EtO
EtO
4
5
[0.5] / EtOAc
[0.1] / EtOAc
2
7
8
O
O
N3
NH2
2.5
6
9
O
O
O
[0.05] / MeOH
TFA (2 equiv)
6
7
8
95
11
Ph
10
Ph
CN
NH2
[0.05] / MeOH
20
40
ND
88
12
13
O
MeO
HO
[0.05] / MeOH
TFA [0.1]
MeO
HO
H
15
14
NHCbz
NH2
9
[0.05] / MeOH
20
20
30
40
99
95
99
96
17
16
MeO
MeO
[0.05] / MeOH
TFA [0.1]
NH2
NHCbz
18
Ph
Ph
10
11
12
19
OMe
OH
OMe
OBn
[0.05] / MeOH
TFA [0.1]
2
20
[0.05] / MeOH
TFA [0.1]
OBn
OH
22
Ph
Ph
21
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 21
1
2
3
4
5
6
7
8
9
OMe O
OMe O
[0.05] / MeOH
MeO
MeO
OBn
13
14
15
20
99
93
95c
OH
23
24
Cl
[0.05] / MeOH
20
26
25
TsO
TEA [0.06]
TsO
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH2
OH
N
[0.05] /MeOH
20
N
MeO
H2N
17
28
27
MeO
OMe
O
OMe
OH
0.05 / MeOH
NO Cyclehexene
0.05 / MeOH
16
17
30
20
99
95
2
29
O
O
30
31
Ph
OH
Ph
O
NO Cyclehexene
a See general methods for reaction conditions. All reactions performed on reactor design 2 and
solvents were chosen to ensure a homogeneous reaction mixture. Isolated yields. Combined
yield of 17 and 28.
b
c
Deallylation of compounds 29 and 30 proved possible with retention times of 30 and 20 minutes,
respectively. Importantly, applying methanol as the solvent and transfer allylation acceptor,
deallylation was performed in the absence of the hydrogen donor and 2 and 31 were obtained in
95% and 92% isolated yields (entries 16 and 17).24 Importantly, due to the absence of a hydrogen
donor, deprotection of 30 was possible without concurrent reduction of the α,β-unsaturation in
the formed cinnamic acid.
Adaptation of the Pd/C packed bed reactor to other reaction types would extend the
applicability of the MRU flow setup considerably and an example of the Mizoroki-Heck reaction
was attempted (Scheme 2).25 After some experimentation it was found that passing a mixture of
4-iodobenzonitrile (0.33 M), butyl acrylate (1.3 M) and triethyl amine (0.49M) dissolved in
MeCN through the MRU flow-reactor set at 150 °C with a retention time of only 10 minutes
afforded the desired cinnamic acid derivative 32 in an good 80% isolated yield after column
chromatography. Compound 32 was then passed through the packed bed reactor again, but this
time subjected to the transfer hydrogenation conditions developed above, affording the reduced
ACS Paragon Plus Environment
12

Page 13 of 21
Organic Process Research & Development
1
2
3
4
butyl 3-(4-cyanophenyl)propanoate (33) in an excellent 93% isolated yield, again with no sign of
5
6
concurrent cyano-group reduction (Scheme 2).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Mizoroki-Heck coupling followed by transfer hydrogenation.
I
O
NC
TEA (0.49 M)
(0.33 M)
MRU
O-nBu
Pd/C
Dissolved in
MeCN
80% - 32
O
NC
150 °C
O-nBu
(1.3 M)
: EtOAc
O
:
1
1
MRU
Pd/C
O-nBu
NC
93% - 33
120 °C
Rt = 30 min
As the final part of this study, it was decided to address the question regarding lifetime of the
packed reactor bed. Besides catalyst deactivation, palladium leaching was considered to be most
significant problem effectively leading to required reactor reloading. However, from the initial
large scale study seen in Scheme 1 a high turnover number of 1851 was observed without reactor
failure indicating good reactor stability. It was then speculated that the reduction of eugenol
probably did not serve as the correct experiment to test the reactor bed stability, as its reduced
counterpart (2) does not contain functionalities that would coordinate Pd(0) strongly. Instead, the
experiment on the reduction of 4-ethyl nitrobenzoate (7 – Table 1 entry 4) was revisited,
expecting that the formed aniline would perform better as a ligand to palladium potentially
causing a higher degree of catalyst leaching. Hence, 7 (195,17 g, 1 mol, 0.5 M) dissolved in
cyclohexene: EtOAc 1:1 was pumped directly onto a freshly packed bed reactor (reactor design
2) set at standard operating temperature of 120 °C. The reduction was performed with a retention
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 21
1
2
3
4
5
6
7
8
9
time of 2 minutes corresponding to 3.5 mmol/min conversion of 7. Collection of the reduced
aniline (8) was initiated after clearing two reactor volumes thereby ensuring the reactor was
operating at steady state. A batch was collected every 30 minutes and analyzed for conversion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
determined by H NMR analysis of the crude reaction mixture. The results of this study are
shown in scheme 3.
Scheme 3. Scale-out experiment to test reactor stability.
NO2
EtO
NH2
Palladium on
Charcoal
7
O
EtO
8
O
: EtOAc
120 °C
Residence =me = 2 min
82,6 grams (0.5 mol)
1 : 1
Conversion / %
Entry Time (minutes)
Conversion
100
1
2
3
4
5
6
7
30
60
100
100
100
98
80
60
90
Conversion of 7 over ,me
120
150
180
210
40
20
0
93
69
Time/Min
45
0
30
60
90
120
150
180
210
240
From the data seen in scheme 3, full conversion was retained for the first 90 minutes of
operation. Batch 4 begins to show traces of unconverted starting material and in batch number 5
the average conversion had dropped 93%. After this point (batches 6 and 7) catalyst activity
drops dramatically and the experiment was stopped.26 Batches 4 and 5 were recrystallized and
combined with batches 1-3 to afford a combined yield of 82.6 grams (0.5 mol) of analytically
pure 8. 1.5 grams of Pd/C (10% w/w) was loaded into the packed bed reactor correlating to a
ACS Paragon Plus Environment
14

Page 15 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
TON of 355 of 7 to 8. Still, the presented design allows for the conversion of >0.5 mol of
material before repacking of the reactor bed would be required.27 This in turn corresponds to
running hundreds of 1-2 mmol scale transfer hydrogenations on the MRU before maintenance
would be needed thereby emphasizing the high durability and usability of this flow setup for
laboratory scale synthesis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, a mobile reactor unit (MRU) was designed for laboratory scale transfer
hydrogenations. The entire flow setup was fitted inside a 46 cm x 33 cm x 15 cm alumina
suitcase weighing in at less than 10 kilograms. General catalytic conditions were developed
using a 1:1 mixture of cyclohexene with a co-solvent, typically methanol or ethyl acetate, as the
hydrogen donor. These conditions were chosen in order to minimize workup as all regents and
products thereof are removable by simple evaporation. Reductions of standard functional groups,
including double bonds, triple bonds, nitro group, ketones and aldehydes was carried out on the
MRU applying retention times between 2-40 minutes operating the Pd/C packed bed reactor at
120 °C. Furthermore, Cbz and benzyl ether protection groups were effectively removed in high
yields. Examples of allyl-ether and allyl esters protection groups were effectively removed on the
same catalyst bed, in the absence of hydrogen donor, by the use of methanol as solvent.
Performing a Mizoroki-Heck coupling proved additional flexibility of the MRU, affording a
cinnamic ester derivative, which was subsequently reduced under the developed transfer
hydrogenation conditions. Finally, two different scale-up experiments were performed, providing
the desired target compounds in >0.5 mol scale. The latter experiment was conducted in order to
study potential catalyst leaching or deactivation of the reactor bed, indicating that hundreds of 1-
2 mmol scale reactions can be performed on the MRU before maintenance would be required.
ACS Paragon Plus Environment
15

Organic Process Research & Development
Page 16 of 21
1
2
3
4
5
6
ASSOCIATED CONTENT
7
8
9
Supporting Information. A detailed description of the mobile reactor unit, general procedure,
experimental details including 1H NMR, 13C NMR spectra for all reported compounds.
The following file are available free of charge.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information (PDF)
AUTHOR INFORMATION
Corresponding Author
Tel.: (+45 23823086). E-mail: Lindhardt@eng.au.dk
ORCID ID:
Anders T Lindhardt:0000-0001-8941-4899
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript. ‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors are deeply appreciative of generous financial support of the Carlsberg Foundation,
Danish Counsel of Independent Research – Technology and Production (Grant number 4148-
00031) and Aarhus University.
ACS Paragon Plus Environment
16

Page 17 of 21
Organic Process Research & Development
1
2
3
4
REFERENCES
5
6
7
8
9
1
For reviews on chemistry in continuous flow, see: (a) McQuade, D. T:; Seeberger, P. H. J.
Org. Chem. 2013, 78, 6384. (b) Malet-Sanz, L.; Susanne, F. J. Med. Chem. 2012, 55, 4062. (c)
Hartman, R. L.; McMullen, J. P.; Jensen, K. V. Angew. Chem. Int. Ed. 2011, 50, 7502. (d)
Calabrese, G. S.; Pissavini, S. AIChE J. 2011, 57, 828. (e) Wegner, J.; Ceylan, S.; Kirschning, A.
Chem. Commun. 2011, 47, 4583. (f) Yoshida, J-I.; Kim, H.; Nagaki, A. ChemSusChem. 2011, 4,
331. (g) Jas, G.; Kirschning, A. Chem. Eur. J. 2003, 9, 5708. (h) Baxendale, I. R. J. Chem.
Technol. Biotechnol. 2013, 88, 519. (i) Baxendale, I. R.; Brocken, L.; Mallia, C. J. Green
Process Synth. 2013, 2, 211.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
(a) Razzaq, T.; Kappe, C. O. Chem. Asian. J. 2010, 5, 1274. (b) Gutmann, B.; Cantillo, D.;
Kappe, C. O. Angew. Chem. Int. Ed. 2015, 54, 6688. (c) Hartwig, J.; Ceylan, S.; Kupracz, L.;
Coutable, L.; Kirschning, A. Angew. Chem. Int. Ed. 2013, 52, 9813. (d) Bogdan, A. R.;
Charaschanya, M.; Dombrowski, A. W.; Wang, Y.; Djuric, S. W. Org. Lett. 2016, 18, 1732.
3
(a) Broek, S. A. M. W.; Leliveld, J. R.; Becker, R.; Delville, M. M. E.; Nieuwland, P. J.;
Koch, K.; Rutjes, F. P. J. T. Org. Process. Res. Dev. 2012, 16, 934. (b) Chernyak, N.; Buchwald,
S. L. J. Org. Chem. 2012, 134, 12466. (c) Mastronardi, F.; Gutmann, B.; Kappe, C. O. Org. Lett.
2013, 15, 5590. (d) Hutchings, M.; With, T. J. Flow Chem. 2016, 6, 202.(e) Yu, Z.; Tong, G.;
Xie, X.; Zhou, P.; Lv. Y.; Su, W. Org. Process. Res. Dev. 2015, 19, 892. (f) Teci, M.; Tilley, M.;
McGuire, M. A.; Organ, M. G. Org. Precess. Res. Dev. 2016, 20, 1967.
4 For selected examples, see: (a) Webb, D.; Jamison, T. F. Org. Lett. 2012, 14, 568. (b) Snead,
D. R.; Jaminson, T. F. Angew. Chem. Int. Ed. 2015, 54, 983. (c) Noël, T.; Maimone, T. J.;
ACS Paragon Plus Environment
17

Organic Process Research & Development
Page 18 of 21
1
2
3
4
5
6
7
8
Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 8900. (d) Yoshida, J-I.; Takahashi, Y.; Nagaki,
A. Chem. Commun. 2013, 49, 9896. (e) Hafner, A.; Meisenbach, M.; Sedelmeier, J. Org. Lett.
2016, 18, 3630. (f) Wirth, T. Angew. Chem. Int. Ed. 2016 ASAP.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
(a) Sedelmeier, J.; Lima, F.; Litzler, A.; Martin, B.; Venturoni, F. Org. Lett. 2013, 15, 5546.
(b) Baxendale, I. Chem. Eng. Technol. 2015, 38, 1713. (c) Müller, S. T. R.; Murat, A.; Wirth, T.
Org. Process. Res. Dev. 2016, 20, 495. (d) Hartman, R. L.; McMullen, J. P.; Jensen. K. F.
Angew. Chem. Int. Ed. 2011, 50, 7502.
6 (a) Irfan, M.; Glasnov, T. N.; Kappa, C. O. ChemSusChem. 2011, 4, 300. (b) Roberge, D. M.;
Noti, C.; Irle, E.; Eyholzer, M.; Rittiner, B.; Penn, G.; Sedelmeier, G.; Schenkel, B. J. Flow.
Chem. 2014, 4, 26.
7
For a examples on hydrogenation using a tube-in-tube system, see: (a) Mercadante, M. A.;
Kelly, C. B.; Lee, C.; Leadbeater, N. E. Org. Process. Res. Dev. 2012, 16, 1064. (b) O´Brien, M.;
Taylor, N:, Polyzos, A.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 1250. (c) Mallia, C. J.;
Baxendale, I. R. Org. Process. Res. Dev. 2016, 20, 327.
8
(a) Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem. Commun. 2005, 2909. (b)
Winterbottom, J. M.; Khan, Z.; Boyes, A. P.; Raymahasay, S. Catal. Today 1999, 48, 221. (c)
Knudsen, K. R.; Holden, J.; Ley, S. V.; Ladlow, M. Adv. Synth. Catal. 2007, 349, 535.
9 (a) Elamin, B.; Park, J.-W.; Means, G. E. Tetrahedron Lett. 1988, 29, 5599. (b) Haywood, T.;
Miller, P. W. ChemCatChem 2014, 6, 1199.
ACS Paragon Plus Environment
18

Page 19 of 21
Organic Process Research & Development
1
2
3
4
5
6
10
(a) Johnstone, R. A. W.; Wilby, A. H. Chem. Rev. 1985, 85, 129. (b) Brieger, G.; Nestrick,
7
8
T. J. Chem. Rev. 1974, 74, 567. (c) Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11
For examples on hydrogen transfer protocols in continuous flow, see: (a) Hutchings, M.;
Wirth, T. Synlett 2016, 27, 1832. (b) Neumann, K.; Klimczyk, S.; Burhardt, M. N.; Bang-
Andersen, B.; Skrydstrup, T.; Lindhardt, A. T. ACS Catal. 2016, 6, 4710. (c) Rojo, M .V.;
Guetzoyan, L.; Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 1768. (d) Battilocchio, C.;
Hawkins, J. M.; Ley, S. V. Org. Lett. 2013, 15, 2278.
12
For an excellent review on solid supported reagents, see: Ley, S. V.; Baxendale, I. R. Nat.
Rev. Drug Discovery 2002, 1, 573.
14 Selected examples: (a) Boudjouk, P.; Han, B.-H. J. Catal. 1983, 79, 489. (b) Gowda, D. C.;
Gowda, S. Indian J. Chem. B 2000, 39, 709. (c) Prasad, K.; Jiang, X.; Slade, J. S.; Clemens, J.;
Repic, O.; Blacklock, T. J. Adv. Synth. Catal. 2005, 347, 1769. (d) Weir, J. D.; Patel, B. A.;
Heck, R. F. J. Org. Chem. 1980, 45, 4926.
15
Selected examples: (a) Bieg, T.; Szeja, W. Synthesis 1985, 76. (b) Jnaneshwara, G. K.;
Sudalai, A.; Deshpande, V. H. J. Chem. Res. (S) 1998, 160. (c) Anwer, M. K.; Spatola, A. F.
Tetrahedron Lett. 1985, 26, 1381.
16
Selected examples: (a) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;
Meienhofer, J. J. Org. Chem. 1978, 43, 4194. (b) Quinn, J. F.; Razzano, D. A.; Golden, K. C.;
Gregg, B. T. Tetrahedron Lett. 2008, 49, 6137.
ACS Paragon Plus Environment
19

Organic Process Research & Development
Page 20 of 21
1
2
3
4
5
6
7
8
17
329.
18
Selected example: Maddani, M. R.; Moorthy, S. K.; Prabhu, K. R. Tetrahedron, 2010, 66,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Selected examples: (a) Carrá, S.; Beltrame, P.; Ragaini, V. J. Catal. 1964, 3, 353. (b)
Nishiguchi, T.; Imai, H.; Hirose, Y.; Fukuzumi, K. J. Catal. 1976, 41, 249. (c) Anantharamaiah,
G. M.; Sivanandaiah, K .M. J. Chem. Soc., Perkin Trans. 1 1977, 490. (d) Rampulla, R. A.;
Russel, R. K. Synthetic Commun. 1896, 16, 1229.
19 For examples on diimide as the hydrogen donor in flow see: (a) Pieber, B.; Martinez, S. T.;
Cantillo, D.; Kappe, C. O. Angew. Chem. Int. Ed. 2013, 52, 10241. (b) Kleinke, A. S.; Jamison,
T. F. Org. Lett. 2013, 15, 710.
20 For an example og the use of methylcyclohexenes in transfer hydrogenations, see:
Chapman, N.; Conway, B.; O´Grady, F.; Wall, M. D. Synlett, 2006, 7, 1043.
21 (a) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1988, 29, 3741. (b) Brieger, G.; Nestrick, T. J.; Fu,
T-H. J. Org. Chem. 1979, 44, 1876.
22 Imai, H.; Nishiguchi, T.; Tanaka, M.; Fukuzumi, K. J. Org. Chem. 1977, 42, 2309.
23
Compounds 17 and 28 were separated by column chromatography to ensure their correct
identification. See supporting information.
24
Deallylation of compounds 29 and 30 is believed to occur through a Tsuji Trost type
mechanism. See reference 22.
25 Carxola, C.; Billamboz, M.; Bricout, H.; Monflier, E.; Len, C. Eur. J. Chem. 2016, ASAP.
ACS Paragon Plus Environment
20

Page 21 of 21
Organic Process Research & Development
1
2
3
4
5
6
26 The mode of catalyst deactivation, i.e. leaching or poisoning, was not determined.
7
8
9
27 Additionally, almost 1 mol of eugenol was reduced under similar conditions without signs of
catalyst deactivation. See Scheme 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
21