Continuous flow heterogeneous catalytic reductive aminations under aqueous micellar conditions enabled by an oscillatory plug flow reactor

Article abstract of DOI:10.1039/d1gc02039k

Despite the fact that continuous flow processing exhibits well-established technical advances, aqueous micellar chemistry, a field that has proven extremely useful in shifting organic synthesis to sustainable water-based media, has mostly been explored under conventional batch-based conditions. This is particularly because of the fact that the reliable handling of slurries and suspensions in flow has been considered as a significant technical challenge. Herein, we demonstrate that the strategic application of an oscillatory plug flow reactor enables heterogeneous catalytic reductive aminations in aqueous micellar media enhancing mass transport and facilitating process simplicity, stability and scalability. The micellar flow process enabled a broad range of substrates, including amino acid derivatives, to be successfully transformed under reasonably mild conditions utilizing only very low amounts of Pd/C as a readily available heterogeneous catalyst. The preparative capabilities of the process along with the recyclability of the heterogenous catalyst and the aqueous reaction media were also demonstrated. This journal is

Full text of DOI:10.1039/d1gc02039k

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PAPER
Continuous flow heterogeneous catalytic
reductive aminations under aqueous micellar
conditions enabled by an oscillatory plug flow
reactor†
Cite this: Green Chem., 2021, 23,
625
5
a,b
c,d
e
c,d
Michaela Wernik, Gellért Sipos, Balázs Buchholcz, Ferenc Darvas,
f
a,b
a,b
Zoltán Novák,
Sándor B. Ötvös
*
and C. Oliver Kappe
*
Despite the fact that continuous flow processing exhibits well-established technical advances, aqueous
micellar chemistry, a field that has proven extremely useful in shifting organic synthesis to sustainable
water-based media, has mostly been explored under conventional batch-based conditions. This is par-
ticularly because of the fact that the reliable handling of slurries and suspensions in flow has been con-
sidered as a significant technical challenge. Herein, we demonstrate that the strategic application of an
oscillatory plug flow reactor enables heterogeneous catalytic reductive aminations in aqueous micellar
media enhancing mass transport and facilitating process simplicity, stability and scalability. The micellar
flow process enabled a broad range of substrates, including amino acid derivatives, to be successfully
transformed under reasonably mild conditions utilizing only very low amounts of Pd/C as a readily avail-
able heterogeneous catalyst. The preparative capabilities of the process along with the recyclability of the
heterogenous catalyst and the aqueous reaction media were also demonstrated.
Received 8th June 2021,
Accepted 8th July 2021
DOI: 10.1039/d1gc02039k
rsc.li/greenchem
investigated with various surfactants being employed to form
micellar arrays as amphiphile nanoreactors. The lipophilic
Introduction
5
Whilst solvent-free reactions are typically limited to a few part of such micelles functions as the ‘organic solvent’ which
1
special cases, organic solvents constitute the largest part of serves as a non-aqueous environment. In this manner, even
2
6
waste generated in synthetic chemistry. Therefore, the use of water sensitive reactions can be performed in aqueous media.
water as solvent has attracted a great interest towards more It was verified that the particle size and the shape of micelles
3
7
sustainable manufacturing practices. The application of water is crucial in such transformations, therefore novel surfactants
as a naturally abundant reaction medium exhibits obvious have been designed that facilitate fine-tuning of micelle pro-
advantages concerning environmental, safety and economic perties and enabled an array of chemistries, including various
4
aspects in comparison with traditional organic solvents.
cross-couplings, C–H activations, amide bond formations, oxi-
However, water is often overlooked as a solvent due to the inso- dations and reductions, to be realized under aqueous micellar
8
lubility of most organic substrates and the sensitivity of conditions.
numerous reactions towards moisture. To circumvent these
In micellar chemistry, an aggregate of surfactant mole-
limitations, aqueous micellar conditions have extensively been cules forms a colloidal suspension generating a biphasic
mixture where mass transfer of reactants is a limiting phe-
3
a
nomenon. This is especially pronounced in cases where
micellar chemistry is performed in the presence of hetero-
geneous catalysts which must maintain close contact with
the substrates encompassed in the hydrophobic pocket of
a
Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28,
A-8010 Graz, Austria. E-mail: sandor.oetvoes@uni-graz.at, oliver.kappe@uni-graz.at
b
Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, A-8010 Graz, Austria
9
c
the nanomicelles. Aqueous micellar catalysis is typically per-
ThalesNano Inc., Záhony u. 7, 1031 Budapest, Hungary
d
ComInnex Inc., Záhony u. 7, 1031 Budapest, Hungary
formed under conventional batch conditions where mixing
e
5,8
Innostudio Inc., Záhony u. 7, 1031 Budapest, Hungary
and mass transfer is dependent on the batch size.
f
ELTE “Lendület” Catalysis and Organic Synthesis Research Group, Faculty of
Consequently, the scale-up is often challenging due to these
Science, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter stny. 1/a,
10
physical limitations. In contrast, continuous flow reactors
1
117 Budapest, Hungary
offer unique advantages to improve transport phenomena
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1gc02039k
between phases, and due to their extraordinary surface-area-to-
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1
1
volume-ratio, heat transfer is also increased considerably. As
a result, process intensification and simplification become
feasible and scalability is also straightforward, whilst improv-
ing product quality and uniformity by better control over the
reaction parameters. However, the handling of solids, such as
slurries and suspensions, in flow reactors is perceived as one
of the main challenges in continuous processing due to well-
1
2
known clogging and reactor fouling issues. Despite the fact
that numerous reactor concepts have been developed to
1
3
handle solid–liquid biphasic mixtures, there is only one
recent example for performing heterogeneous micellar cataly-
sis under flow conditions, in which Suzuki–Miyaura couplings Fig. 1 Surfactant TPGS-750-M (A), and general scheme of the present
work (B).
were achieved utilizing a series of continuous stirred-tank reac-
tors (CSTRs) in the presence of Fe/Pd nanoparticles as hetero-
1
4
geneous catalyst. Although CSTRs offer a practical solution
1
5
of 1.2 equiv. of Et
Table 1). Although, the direct use of hydrogen gas may have
been more atom economic, we selected Et SiH as reductant
particularly because of safety as well as scalability aspects, and
also due to the fact that the direct involvement of a gaseous
reagent would have made mixing and mass transfer even more
challenging under heterogeneous micellar conditions.
Upon investigating the effects of different amphiphiles, the
corresponding imine intermediate was readily formed in all
reactions, but its subsequent reduction to 1a proved highly
dependent on the surfactant applied (entries 1–5). It was veri-
fied that TPGS-750-M is superior in this transformation com-
pared with other surfactants as well as with the on-water (sur-
factant-free) reaction after 60 min at 50 °C. In fact, SDS, Brij S
3
SiH and various amounts of 5 wt% Pd/C
for handling solids under flow conditions, enlarging the
tank size of each unit may result in inferior mixing behavior.
Therefore, our aim was to take a different approach and to
develop an inherently scalable continuous process for perform-
ing heterogeneous micellar catalysis in water using an oscil-
latory plug flow reactor (OFR). On the basis of our earlier
experiences on continuous flow photocatalytic processes invol-
(
3
16
ving solids in OFRs, we speculated that the intense mixing
by the use of pulsation superimposed to the net flow of the
reaction stream would enhance mass transport, whilst ensur-
ing a stable suspension of the aqueous solid–liquid mixture
alongside the reactor. Additionally, by exclusion of moving
parts from the reaction zone together with the optimization of
the pulsation parameters, we anticipated a robust setup for
handling biphasic micellar media facilitating minimal axial
dispersion and a reasonable residence time distribution.
As a model for our proof of the concept study, we selected
100 and Kolliphore EL did not result any notable micellar
accelerating effect and gave results comparable to the on-water
reaction (90–97% conversion and 17–32% selectivity), which
may be explained by the unfavorable hydrophilic–lipophilic
balance of the surfactants and/or by inadequate size of the
1
7
reductive amination, which is one of the key approaches for
C–N bond construction and thus plays a paramount role in
1
8
pharmaceutical and medicinal chemistry. Despite the fact
that during initial imine formation stoichiometric water is
released and thus reductive aminations performed in water is Table 1 Preliminary batch screening of the most important reaction
1
9
conditions
at first instance not beneficial, Lipshutz and co-workers
recently reported a batch process for reductive aminations
2
0
under aqueous micellar conditions. In this study, Pd/C was
employed as a readily available heterogeneous catalyst and
3
Et SiH as reductant along with the rationally designed surfac-
tant TPGS-750-M, which comprises a lipophilic vitamin E
portion combined with a hydrophilic polyethylene glycol (PEG)
a
b
c
No.
Surfactant
Pd/C [ppm] T [°C] Conv. [%] Select. [%]
2
1
1
2
3
4
5
6
7
8
—
SDS
2000
2000
2000
50
50
50
50
50
50
50
50
50
25
60
96
90
96
97
>99
>99
>99
98
99
>99
>99
27
32
17
19
95
99
99
96
73
25
86
side-chain (Fig. 1A). These literature findings served as start-
ing point for our investigations to develop a novel continuous
flow protocol for heterogeneously catalyzed reductive amin-
ations in water enabled by micellar chemistry (Fig. 1B). Our
results are presented herein.
Brij S 100
Kolliphore EL 2000
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
2000
1500
1000
500
500
500
d
9
1
11
0
e
Results and discussion
500
a
b
1
mL scale, stirring at 500 rpm. Consumption of starting material,
c
Initially, batch screening of the most important reaction con-
ditions was performed utilizing the reductive amination of
benzaldehyde with aniline as a simple model in the presence TPGS-750-M. 30 min reaction time.
based on GC-FID area. Selectivity, determined by GC-FID area. (The
d
corresponding imine was detected as the only side product.) 1 wt%
e
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micelles formed. Gratifyingly, a catalyst loading of 500 ppm is strongly dependent on mixing, which implies an obvious
proved sufficient (entries 5–8), which is a significant decrease limitation of direct scalability under batch conditions. In fact,
compared with earlier metal-catalyzed reductive aminations in typical applications of micellar reaction technology on
and is even lower than the amount reported earlier for reduc- scale, organic co-solvents are employed with the aim to
1
7,20
tive aminations under micellar conditions.
narily low catalyst loading can be explained by the presence of thus to facilitate mass transfer during the process.
the PEG-containing nanomicelles formed by TPGS-750-M, With sufficient data on the batch reaction in our hands, we
which have a tendency to aggregate around palladium nano- next turned our attention to continuous flow method develop-
particles thus facilitating close contact between the catalyst and ment. For this purpose, commercially available OFR
The extraordi- improve physical properties of the bulk reaction medium and
1
0,22
a
9
the reaction partners housed within the micelles. The reaction (HANU™ HX 15 Flow Reactor, Creaflow) was chosen which
worked the best with 2 wt% of TPGS-750-M (entry 8); the use of comprises a linear plate-like process channel equipped with a
only 1 wt% surfactant resulted in a significant decrease in amine series of cubic static mixing elements. Besides a metering
formation (entry 9). Successful reduction of the imine intermedi- pump delivering the net flow of the reaction components, the
ate required gentle heating, 50 °C or 60 °C was therefore con- system contained an oscillatory diaphragm pump providing a
sidered as an optimum value (entries 8, 10 and 11). Besides acti- tunable symmetrical pulse. In cooperation with the well-
vated charcoal, various further catalyst supports were tested defined static mixing elements, this ensured split and recom-
under batch conditions. SiO , BaCO and Al O provided compar- bine mixing of the process stream. Additionally, strategically
2
3
2 3
able results to activated charcoal, whereas BaSO
plete imine reduction (Table S1†).
4
resulted incom- placed vibrator motors facilitated suspension of particles in
the peripheral tubings of the system, whilst the narrow reac-
Having acquired a clear picture on the effects of the reac- tion channels increased pulsation velocity thereby mitigating
tion conditions of the reductive amination between benz- the risk of settling even at low flow rates. In a typical experi-
aldehyde and aniline under aqueous micellar conditions in ment, the slurry of the starting materials was continuously
batch, the reaction was next repeated on different scales streamed through the reactor using a peristaltic pump. The
ranging from 1 mL to 100 mL, with the aim to investigate system also comprised a 3-bar backpressure regulator (BPR) to
mixing effects and also to explore possible limitations in scal- prevent cavitation or suction of air from the reactor outlet
ability. As shown in Fig. 2, the yield drastically decreased with during backward pulsation. The HANU reactor was originally
1
6,23
the batch size despite adjustment of the stirring rate upon designed for multiphasic flow photochemistry.
However,
scale-up. For example, at 800 rpm stirring rate, the reaction we anticipated that because of the beneficial combination of
furnished 92% 1a formation on 1 mL scale; however, yield active and passive mixing, it would enable a significantly
decreased steeply to 62%, 18% and 14% upon increasing the improved mass transfer compared with batch processes and
batch size to 10 mL, 50 mL and 100 mL, respectively. It was CSTRs, and would ensure a stable suspension of the biphasic
also observed that in case of reactions performed on the same medium alongside the reactor, thereby furnishing a robust
scale, the yield was clearly increasing with the stirring speed. and scalable platform for performing aqueous micellar reac-
These findings demonstrate that the biphasic micellar reaction tions under continuous flow conditions. The schematic repre-
sentation of the flow setup is depicted in Fig. 3.
After setting up the OFR, a flow optimization study was per-
formed, which initially focused on pulsation amplitude (mL
displaced per pump stroke) and frequency (number of strokes
per second, Hz), the novel process parameters in this reactor
setup. Fine-tuning of these parameters allowed us to establish
a stable suspension of the biphasic reaction mixture, whilst
minimizing axial dispersion in the reaction zone. As far as resi-
dence time distribution in the OFR is concerned, our control
Fig. 2 Investigation of the reductive amination of benzaldehyde with
aniline under aqueous micellar conditions at different batch scales (yield
Fig. 3 Schematic representation of the continuous flow setup used for
was determined by GC-FID area%).
reductive aminations under aqueous micellar conditions.
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experiments in accordance with literature findings suggested (density of activated charcoal: 2.01 g mL− ), stable and clog-
that lower amplitudes typically imply narrow distribution ging-free operation was achieved along with quantitative and
curves, while the applied pulsation frequencies exert a similar selective formation of 1a (entry 7). Upon comparing 1 wt% and
1
1
6b,23a
trend but to a lower extent (Fig. S3†).
Upon investigating 5 wt% Pd/C (500 ppm Pd in both cases), no difference in stabi-
the effects of the pulsation parameters on the Et SiH- lity of the suspension was found, further experiments were
3
mediated, Pd/C-catalyzed reductive amination of benzaldehyde therefore carried out with 5 wt% Pd/C (entry 8). In further
with aniline in the presence of TPGS-750-M as surfactant, attempts to optimize the reaction conditions, the application
inconsistent conversions and an intense foam formation was of 250 ppm 5 wt% Pd/C and the decrease of residence time to
found at lower amplitudes (Table 2, entries 1 and 2). 20 min resulted in somewhat reduced yields (entries 9 and 10),
Gratifyingly, by increasing the amplitude to 0.24 mL (approx. therefore 500 ppm catalyst loading and 30 min residence time
0% of displaced volume), quantitative and selective reaction (corresponding to 500 µL min− flow rate) were selected as
1
5
was achieved, whilst maintaining a stable suspension of the optimum values. Regarding the effects of other surfactants
reaction mixture (entry 3). To further decrease the potential of than TPGS-750-M in flow mode, a similar negative trend could
foam formation, the frequency was reduced to 0.6 Hz (entry 4). be observed than in batch together with occasional clogging
One of the main challenges of continuous flow process (Table S2†).
development under heterogeneous catalytic micellar con-
In order to demonstrate the applicability of the process, a
ditions was occasional settling and deposition of particles range of aldehydes and amines were next submitted to reduc-
2
4
along the reactor. We anticipated that in addition to fine- tive amination under optimized micellar flow conditions.
tuning of the pulsation parameters, the stability of the reaction Besides benzaldehyde, its 4-fluoro- as well as 4-methoxy-substi-
suspension can also be facilitated by varying the nature of tuted derivative were quantitatively and selectively reacted in
solids involved in the reaction. Therefore, the effects of catalyst reductive amination with aniline furnishing the corresponding
supports which provided good results in batch were re-evalu- secondary amines (1b and 1c) in high yields (84% and 81%,
ated under continuous flow conditions. Although with 5 wt% respectively; Fig. 4A). 1-Naphtaldehyde exhibited somewhat
2 3 3
Pd/Al O and 5 wt% Pd/BaCO (500 ppm both) amine 1a was lower reactivity in reaction with aniline; however, upon increas-
furnished with quantitative conversion and with reasonable ing the catalyst loading to 1000 ppm, amine 1d could success-
selectivities (62% and 95%, respectively) under flow conditions fully be isolated in 58% yield. Furfural and 2-phenylpropanal
too (entries 5 and 6), due to the high density of these support showed high conversions and good selectivities, and resulted
−
1
−1
2 3 3
materials (Al O : 4.00 g mL ; BaCO : 4.49 g mL ), settling of in amines 1e and 1f in 73% and 61% yield, respectively.
particles and clogging occurred in both cases preventing any Reductive amination of various aliphatic aldehydes with
practical applications (Fig. S4†). In contrast, with 5 wt% Pd/C aniline also furnished good results. 2-Ethylhexanal reacted
smoothly to give amine 1g in 75% yield. In reactions of cyclo-
pentane- and cyclopropanecarbaldehyde, the corresponding
amines (1h and 1i) were isolated in yields >70%; however, in
these cases the catalyst loading was increased to 2000 ppm.
The scope of amines was investigated using benzaldehyde
as reaction partner (Fig. 4B). Various substituted aniline
derivatives as well as benzylamine and phenylethylamine gave
excellent conversions and high selectivities and resulted in the
appropriate amines (2a–d) in 70–89% yields. Reductive amin-
ation of a diverse set of aliphatic amines, including open
chain, α- and β-branched as well as alicyclic primary amines
went smoothly under flow conditions. In these reactions, selec-
tivities were ≥90% and the corresponding secondary amine
products (2e–h) were isolated in yields up to 85%.
Additionally, the secondary amine pyrrolidine was quantitat-
ively and selectively converted to tertiary amine 2i and furn-
ished 79% yield. Notably, for most of the amine substrates
investigated, the catalyst loading was increased to 1000 or
2000 ppm.
Table 2 Optimization of the continuous flow reaction conditions
b
c
d
e
A
ν
t
res
Conv.
[%]
Select.
[%]
a
No.
Catalyst
[mL]
[Hz]
[min]
h
1
2
3
4
5
6
5 wt% Pd/C
5 wt% Pd/C
5 wt% Pd/C
5 wt% Pd/C
5 wt% Pd/Al
5 wt% Pd/BaCO
5 wt% Pd/C
1 wt% Pd/C
5 wt% Pd/C
5 wt% Pd/C
0.12
0.20
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
1.5
1.5
1.5
0.6
0.6
0.6
0.6
0.6
0.6
0.6
30
30
30
30
30
30
30
>99
>99
>99
>99
>99
>99
>99
>99
99
57–99
90–99
>99
>99
62
h
h
h
h
2
O
3
h
3
95
g
h
7
8
>99
>99
90
h
30i
9
20
30
f
h
10
99
72
Natural amino acids are frequently employed as chiral
building blocks in the synthesis of various biologically active
a
c
b
2
5 mL scale. Pulsation amplitude (mL displaced per pump stroke).
25
d
compounds and active pharmaceutical ingredients. To verify
Frequency (number of strokes per second). Consumption of starting
e
material, based on GC-FID area%. Selectivity, determined by GC-FID the scope and applicability further, a small library of
area% (the corresponding imine was detected as the only side
N-benzylated amino acid derivatives was prepared by reductive
amination of benzaldehyde with L-phenylalanine, L-leucine,
L-proline and L-methionine methyl esters under micellar flow
f
g
product).
250 ppm catalyst.
Stability test, 60 mL scale.
h
−1
i
Corresponding to 500 µL min flow rate. Corresponding to 750 µL
min flow rate.
−
1
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cated by the appearance of benzyl alcohol as a side product
arising from competing aldehyde reduction. In these reactions,
catalyst loading was typically set to 2000 ppm, and in some
instances, temperature was increased to 65 °C.
To verify the stability and preparative capabilities of the
developed flow process, the reductive amination of 4-fluoro-
benzaldehyde with aniline was performed as a long-run.
Considering that the viscosity and density of the starting
material solution may change over time due to background
imine formation, a modified three-feed system was used to
separately introduce a suspension containing the aqueous sur-
factant solution and the Pd/C catalyst as feed 1, a neat mixture
of the aldehyde and the reductant as feed 2 and neat aniline
as feed 3 (Fig. 5A). All other reaction conditions were set to the
previously optimized values. A 7 h reaction window was moni-
tored under steady state conditions with conversion and
2
6
selectivity being checked in every hour. To our delight, the
system proved very robust during the experiment, no clogging
or other issues occurred. Since quantitative conversion and a
selectivity of ≥98% were achieved in all fractions, after extrac-
tive work-up, a simple silica filtration was sufficient to remove
any excess components and to achieve analytically pure
product. The isolated yield was thus readily determined in all
Fig. 4 Substrate scope of the continuous flow Pd/C-catalyzed reduc-
tive amination under aqueous micellar conditions (conversion and
selectivity were determined by GC-FID area%; yields shown are isolated
a
b
c
yields). 1000 ppm 5 wt% Pd/C. 2000 ppm 5 wt% Pd/C. At 65 °C.
conditions (Fig. 4C). To our delight, the desired adducts (3a–d)
could successfully be prepared in yields up to 75%; however,
in these cases, imine formation was more difficult than in
Fig. 5 Long run experiment under optimized flow conditions (A), and
recycling of the catalyst as well as the surfactant solution in the same
reaction (B). Conversion and selectivity were determined by GC-FID
reactions of simpler model substrates (Fig. 4A and B), as indi- area%.
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portions collected providing in total 15.0 g of amine 1b (85%
To the best of our knowledge, this is the first demonstration
overall yield). This correlates to a space–time–yield (STY) of of aqueous micellar catalysis in an OFR system. Notably, the
43 g L−
1
h
−1
and a productivity of 2.14 g h . Practically no process developed herein offers a straightforward scaling-up
−1
1
leaching occurred during the experiment as verified by a palla- strategy by using a commercially available pilot-scale reactor,
dium content of 1.4 ppm measured in the crude product, which maintains all the major process characteristics, includ-
which could readily be decreased to <0.05 ppm by simple silica ing channel dimensions, residence time distribution and heat-
2
3a,29
gel filtration. These amounts meet the current FDA guidelines and mass transfer.
on maximum acceptable limits of residual palladium in drug scale-up possibilities.
We are currently investigating these
2
7
substances and excipients. Importantly, the process gener-
ated a low amount of waste as indicated by an E-factor of 1.2,
which is significantly lower than typically found in pharma- Experimental section
2
8
ceutical manufacturing.
General information on the flow setup
With the aim to further enhance the sustainable aspects of
the current process, the recycling of the heterogeneous catalyst
as well as of the surfactant solution was attempted utilizing
the same reaction and the same conditions than in the long-
run. Between each cycle, the amine product was removed from
the reaction mixture by extraction with EtOAc; the catalyst was
filtered off and washed with minimal amounts of EtOAc and
water, dried at room temperature and used again in the next
run. The residual organic solvent was removed from the surfac-
tant solution under reduced pressure before reusing. In this
manner, 91–95% of Pd/C along with >99% of the surfactant
solution could be recovered in each run (see Table S3†).
Gratifyingly, no loss of the initially quantitative conversion
occurred during five consecutive runs, and selectivity
remained steady at >98% (Fig. 5B).
Flow experiments were carried out in a commercially available
OFR, consisting of a HANU HX 15 Flow Reactor (Hastelloy,
15 mL internal volume) containing 2 × 2 × 2 mm cubic static
mixers and a pulsator (customized ProMinent Beta/4 pump,
PTFE/carbon pump head) from Creaflow. The feed mixtures
were introduced using a Vapourtec SF-10 peristaltic pump and
a Syrris Asia syringe pump module. Pressure was applied by an
adjustable Zaiput BPR. Thermal regulation was managed by
using a Huber CC304 thermostat. Parts of the setup were con-
nected using 1/8″ OD (1.6 mm ID) or 1/16″ OD (0.8 mm ID)
PTFE or PFA tubes along with PEEK or stainless steel fittings.
Representative procedure for the batch experiments
A vial containing 500 ppm 5 wt% Pd/C (0.05 mol% Pd) was
charged with 0.5 mmol of benzaldehyde (1 equiv.), 0.75 mmol of
aniline (1.5 equiv.) and 1 mL of a 2 wt% TPGS-750-M solution in
H O. After the addition of 0.6 mmol Et SiH (1.2 equiv.) the vial
2
3
Conclusions
was sealed and the mixture was heated in an aluminum block at
A continuous flow process has been demonstrated for reduc- 60 °C for 30 min. The reaction mixture was next extracted with
tive aminations under heterogeneous catalytic micellar con- 1.5 mL EtOAc and the organic phase was filtered using a syringe
ditions in water using an OFR. The process relied on Et
3
SiH as filter (0.45 µm), dried over Na SO , diluted with acetonitrile
2 4
reducing agent along with ppm amounts of Pd/C as hetero- (10 µL in 1 mL), and submitted to GC-FID analysis.
geneous catalyst and TPGS-750-M as a commercially available
surfactant. Due to the beneficial combination of an oscillatory
Representative procedures for the flow experiments
flow regime and multiple static mixing elements, the flow For investigating the substrate scope under flow conditions, a
system proved as a robust and scalable platform for perform- single-feed setup was used as shown in Fig. 4 and also in
ing reactions under aqueous micellar conditions, whilst ensur- Fig. S1.† A Duran bottle was charged with 31.5 mg 5 wt% Pd/C
ing enhanced mixing and mass transfer between the reacting (500 ppm or 0.05 mol% Pd), 30 mmol of the corresponding
phases. Following thorough optimization of the most impor- aldehyde (1 equiv.), 36 mmol of the corresponding amine (1.2
tant reaction conditions, such as pulsation parameters, temp- equiv.), 60 mL 2 wt% aqueous TPGS-750-M solution and
erature, residence time and catalyst carrier, high yielding 15 mmol Et SiH (1.2 equiv.). While being stirred using a mag-
3
reductive aminations were achieved applying comparatively netic stirrer, the mixture was continuously pumped through
mild conditions, whilst maintaining a stable suspension of the the OFR at 500 µL min− flow rate, while maintaining 3 bar
biphasic micellar media alongside the reactor. Reductive pressure and 60 °C temperature. During the reaction, the pul-
aminations of a diverse set of aldehydes with various amines sator was set to 0.24 mL (approx. 50%) pulsation amplitude
were achieved, including a number of amino acid derivatives and 0.6 Hz (20%) pulsation frequency. The product mixture
as pharmaceutically relevant building blocks. The preparative was collected for 20 min under steady state conditions and
utility of the flow process was verified by a 7 h long-run fur- was next extracted with a minimal amount of EtOAc (2 ×
nishing straightforward multigram-scale production with low 5 mL). The organic layers were combined and the solvent was
waste formation. The sustainable nature of the process was removed under reduced pressure. The obtained material was
further elaborated by successfully recycling the heterogenous purified by flash chromatography on silica gel using mixtures
catalyst as well as the aqueous surfactant solution over 5 con- of cyclohexane and EtOAc as eluent to afford the corres-
1
secutive runs.
ponding analytically pure product.
5630 | Green Chem., 2021, 23, 5625–5632
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Paper
For the long-run experiment, a modified three-feed system
was used as shown in Fig. 5 and also in Fig. S5.† Feed 1 con-
sisted of the aqueous surfactant solution (2 wt% TPGS-750-M;
P. S. Branco and R. S. Varma, ChemSusChem, 2014, 7, 24–
44.
2 (a) H. C. Erythropel, J. B. Zimmerman, T. M. de Winter,
L. Petitjean, F. Melnikov, C. H. Lam, A. W. Lounsbury,
K. E. Mellor, N. Z. Janković, Q. Tu, L. N. Pincus,
M. M. Falinski, W. Shi, P. Coish, D. L. Plata and
P. T. Anastas, Green Chem., 2018, 20, 1929–1961;
(b) M. C. Bryan, P. J. Dunn, D. Entwistle, F. Gallou,
S. G. Koenig, J. D. Hayler, M. R. Hickey, S. Hughes,
M. E. Kopach, G. Moine, P. Richardson, F. Roschangar,
A. Steven and F. J. Weiberth, Green Chem., 2018, 20, 5082–
5103; (c) D. Prat, A. Wells, J. Hayler, H. Sneddon,
C. R. McElroy, S. Abou-Shehada and P. J. Dunn, Green
Chem., 2016, 18, 288–296; (d) R. K. Henderson, C. Jiménez-
González, D. J. C. Constable, S. R. Alston, G. G. A. Inglis,
G. Fisher, J. Sherwood, S. P. Binks and A. D. Curzons, Green
Chem., 2011, 13, 854–862.
2
0
40 mL) and Pd/C (126 mg 5 wt% Pd/C – 500 ppm or
.05 mol% Pd). Feed 2 contained a neat mixture of 4-fluoro-
benzaldehyde and 1.2 equiv. of Et
3
SiH, while feed 3 comprised
neat aniline. Feed 1 was pumped at a flow rate of 415 µL
−
1
−1
−1
min , feed 2 at 62 µL min and feed 3 at 22 µL min
.
Similarly as in the single feed experiments, the flow reactor
was pressurized at 3 bar and heated at 60 °C, while the pulsa-
tor was set to 0.24 mL (approx. 50%) pulsation amplitude and
0
.6 Hz (20%) pulsation frequency. The product mixture was
collected for 7 h under steady state conditions into separate
fractions in every hour. Each fraction was extracted with a
minimal amount of EtOAc (2 × 10 mL). The organic layers were
combined and the solvent was removed under reduced
pressure. The obtained material was purified by filtration
through a silica plug in order to afford the corresponding ana-
lytically pure product (15.0 g, 85% yield over 7 h collection
time).
3 (a) M. Cortes-Clerget, J. Yu, J. R. A. Kincaid, P. Walde,
F. Gallou and B. H. Lipshutz, Chem. Sci., 2021, 12, 4237–
4266; (b) T. Kitanosono, K. Masuda, P. Xu and
S. Kobayashi, Chem. Rev., 2018, 118, 679–746;
(
c) B. H. Lipshutz and S. Ghorai, Green Chem., 2014, 16,
Conflicts of interest
3660–3679; (d) M. B. Gawande, V. D. B. Bonifácio,
R. Luque, P. S. Branco and R. S. Varma, Chem. Soc. Rev.,
There are no conflicts to declare.
2013, 42, 5522–5551; (e) A. Chanda and V. V. Fokin, Chem.
Rev., 2009, 109, 725–748; (f) D. Dallinger and C. O. Kappe,
Chem. Rev., 2007, 107, 2563–2591.
R. Breslow, in Handbook of Green Chemistry, ed.
P. T. Anastas, Wiley–VCH, 2010, pp. 1–29.
Acknowledgements
4
5
The CCFLOW Project (Austrian Research Promotion Agency
FFG no. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Climate
Protection, Environment, Energy, Mobility, Innovation and
Technology (BMK), the Austrian Federal Ministry for Digital
and Economic Affairs (BMDW), and by the State of Styria
(a) B. H. Lipshutz, J. Org. Chem., 2017, 82, 2806–2816;
(
b) B. H. Lipshutz, F. Gallou and S. Handa, ACS Sustainable
Chem. Eng., 2016, 4, 5838–5849; (c) G. La Sorella, G. Strukul
and A. Scarso, Green Chem., 2015, 17, 644–683.
(a) S. R. K. Minkler, N. A. Isley, D. J. Lippincott, N. Krause
and B. H. Lipshutz, Org. Lett., 2014, 16, 724–726;
6
(
Styrian Funding Agency SFG). Z.N. acknowledges the support
of National Research, Development and Innovation Office
NKFIH, K132077) and the ELTE Thematic Excellence
(
b) A. Krasovskiy, C. Duplais and B. H. Lipshutz, Org. Lett.,
010, 12, 4742–4744; (c) A. Krasovskiy, C. Duplais and
B. H. Lipshutz, J. Am. Chem. Soc., 2009, 131, 15592–15593;
d) S. Shirakawa and S. Kobayashi, Org. Lett., 2007, 9, 311–
14.
2
(
Programme 2020 Supported by NKFIH - TKP2020-IKA-05. This
research was partially financed by the Ministry of Innovation
and Technology of Hungary from the National Research,
Development and Innovation Fund (2019-1.1.1-PIACI-KFI-2019-
(
3
7
8
(a) B. H. Lipshutz, N. A. Isley, J. C. Fennewald and
E. D. Slack, Angew. Chem., Int. Ed., 2013, 52, 10952–10958;
0
0070). The authors would like to thank Creaflow for the gen-
(
b) B. H. Lipshutz, S. Ghorai, W. W. Y. Leong, B. R. Taft and
erous loan of the HANU Reactor used in this study. The assist-
ance of Dr. Alejandro Mata-Gomez in the preliminary batch
experiments is gratefully acknowledged. The authors also
thank Prof. Walter Goessler for ICP-MS analysis.
D. V. Krogstad, J. Org. Chem., 2011, 76, 5061–5073.
(a) T. Lorenzetto, G. Berton, F. Fabris and A. Scarso, Catal.
Sci. Technol., 2020, 10, 4492–4502; (b) A. Steven, Synthesis,
2
019, 2632–2647; (c) B. H. Lipshutz, S. Ghorai and
M. Cortes-Clerget, Chem. – Eur. J., 2018, 24, 6672–6695;
d) D. Paprocki, A. Madej, D. Koszelewski, A. Brodzka and
R. Ostaszewski, Front. Chem., 2018, 6, 502.
(
References
1
(a) P. Cintas, S. Tabasso, V. V. Veselov and G. Cravotto,
Curr. Opin. Green Sustainable Chem., 2020, 21, 44–49;
9 B. H. Lipshutz, Johnson Matthey Technol. Rev., 2017, 61,
196–202.
(
b) M. Tavakolian, S. Vahdati-Khajeh and S. Asgari, 10 (a) M. Parmentier, M. Wagner, R. Wickendick,
ChemCatChem, 2019, 11, 2943–2977; (c) Z. Sainath and
P. Pravinkumar, Curr. Org. Chem., 2019, 23, 2295–2318;
M. Baenziger, A. Langlois and F. Gallou, Org. Process Res.
Dev., 2020, 24, 1536–1542; (b) D. J. Lippincott,
E. Landstrom, M. Cortes-Clerget, B. H. Lipshutz,
(
d) M. B. Gawande, V. D. B. Bonifácio, R. Luque,
This journal is © The Royal Society of Chemistry 2021
Green Chem., 2021, 23, 5625–5632 | 5631

View Article Online
Paper
K. Buescher, R. Schreiber, C. Durano, M. Parmentier, N. Ye,
Green Chemistry
(c) M. R. Chapman, M. H. T. Kwan, G. King, K. E. Jolley,
M. Hussain, S. Hussain, I. E. Salama, C. González Niño,
L. A. Thompson, M. E. Bayana, A. D. Clayton, B. N. Nguyen,
N. J. Turner, N. Kapur and A. J. Blacker, Org. Process Res.
Dev., 2017, 21, 1294–1301; (d) Y. Mo and K. F. Jensen, React.
Chem. Eng., 2016, 1, 501–507.
B. Wu, M. Shi, H. Yang, M. Andersson and F. Gallou, Org.
Process Res. Dev., 2020, 24, 841–849.
1
1 (a) M. Guidi, P. H. Seeberger and K. Gilmore, Chem. Soc.
Rev., 2020, 49, 8910–8932; (b) L. Rogers and K. F. Jensen,
Green Chem., 2019, 21, 3481–3498; (c) M. B. Plutschack,
B. Pieber, K. Gilmore and P. H. Seeberger, Chem. Rev., 16 (a) P. Bianchi, J. D. Williams and C. O. Kappe, Green Chem.,
2
017, 117, 11796–11893; (d) B. Gutmann, D. Cantillo and
C. O. Kappe, Angew. Chem., Int. Ed., 2015, 54, 6688–6728;
e) V. Hessel, D. Kralisch, N. Kockmann, T. Noël and
2021, 23, 2685–2693; (b) C. Rosso, S. Gisbertz,
J. D. Williams, H. P. L. Gemoets, W. Debrouwer, B. Pieber
and C. O. Kappe, React. Chem. Eng., 2020, 5, 597–604.
17 K. Murugesan, T. Senthamarai, V. G. Chandrashekhar,
K. Natte, P. C. J. Kamer, M. Beller and R. V. Jagadeesh,
Chem. Soc. Rev., 2020, 49, 6273–6328.
(
Q. Wang, ChemSusChem, 2013, 6, 746–789.
2 (a) Y. Chen, J. C. Sabio and R. L. Hartman, J. Flow Chem.,
1
1
2
2
2
015, 5, 166–171; (b) K. J. Wu and S. Kuhn, Chim. Oggi,
014, 32, 62–66; (c) R. L. Hartman, Org. Process Res. Dev., 18 O. I. Afanasyev, E. Kuchuk, D. L. Usanov and D. Chusov,
012, 16, 870–887. Chem. Rev., 2019, 119, 11857–11911.
3 (a) P. Bianchi, J. D. Williams and C. O. Kappe, J. Flow 19 (a) S. Sato, T. Sakamoto, E. Miyazawa and Y. Kikugawa,
Chem., 2020, 10, 475–490; (b) M. Jiang and X.-W. Ni, Org.
Process Res. Dev., 2019, 23, 882–890; (c) P. Filipponi,
A. Gioiello and I. R. Baxendale, Org. Process Res. Dev., 2016,
Tetrahedron, 2004, 60, 7899–7906; (b) K. Manabe, S. Iimura,
X.-M. Sun and S. Kobayashi, J. Am. Chem. Soc., 2002, 124,
11971–11978.
2
0, 371–375; (d) S. Falß, G. Tomaiuolo, A. Perazzo, 20 R. R. Thakore, B. S. Takale, G. Casotti, E. S. Gao, H. S. Jin
P. Hodgson, P. Yaseneva, J. Zakrzewski, S. Guido,
and B. H. Lipshutz, Org. Lett., 2020, 22, 6324–6329.
A. Lapkin, R. Woodward and R. E. Meadows, Org. Process 21 B. H. Lipshutz, S. Ghorai, A. R. Abela, R. Moser,
Res. Dev., 2016, 20, 558–567; (e) A.-K. Liedtke, F. Bornette,
R. Philippe and C. de Bellefon, Chem. Eng. J., 2016, 287,
T. Nishikata, C. Duplais, A. Krasovskiy, R. D. Gaston and
R. C. Gadwood, J. Org. Chem., 2011, 76, 4379–4391.
9
2–102; (f) T. McGlone, N. E. B. Briggs, C. A. Clark, 22 C. M. Gabriel, N. R. Lee, F. Bigorne, P. Klumphu,
C. J. Brown, J. Sefcik and A. J. Florence, Org. Process Res.
Dev., 2015, 19, 1186–1202; (g) S. Mascia, P. L. Heider,
M. Parmentier, F. Gallou and B. H. Lipshutz, Org. Lett.,
2017, 19, 194–197.
H. Zhang, R. Lakerveld, B. Benyahia, P. I. Barton, 23 (a) W. Debrouwer, W. Kimpe, R. Dangreau, K. Huvaere,
R. D. Braatz, C. L. Cooney, J. M. B. Evans, T. F. Jamison,
K. F. Jensen, A. S. Myerson and B. L. Trout, Angew. Chem.,
Int. Ed., 2013, 52, 12359–12363; (h) D. L. Browne,
B. J. Deadman, R. Ashe, I. R. Baxendale and S. V. Ley, Org.
Process Res. Dev., 2011, 15, 693–697; (i) S. Kuhn, T. Noël,
H. P. L. Gemoets, M. Mottaghi, S. Kuhn and K. Van Aken,
Org. Process Res. Dev., 2020, 24, 2319–2325; (b) Z. Wen,
A. Maheshwari, C. Sambiagio, Y. Deng, G. Laudadio, K. Van
Aken, Y. Sun, H. P. L. Gemoets and T. Noël, Org. Process
Res. Dev., 2020, 24, 2356–2361.
L. Gu, P. L. Heider and K. F. Jensen, Lab Chip, 2011, 11, 24 In contrast to the optimization experiments, the amine
2
488–2492; ( j) L. Liguori and H.-R. Bjørsvik, Org. Process
excess was reduced to 1.2 equiv.
Res. Dev., 2011, 15, 997–1009.
4 A. B. Wood, K. Y. Nandiwale, Y. Mo, B. Jin, A. Pomberger,
25 R. Vardanyan and V. Hruby, Synthesis of Best-Seller Drugs,
Academic Press, London, 2016.
1
V. L. Schultz, F. Gallou, K. F. Jensen and B. H. Lipshutz, 26 The system reached steady state in 90 min.
Green Chem., 2020, 22, 3441–3444.
5 (a) A. Pomberger, Y. Mo, K. Y. Nandiwale, V. L. Schultz,
27 For more information, see the corresponding FDA gui-
dance: https://www.fda.gov/media/135956/download.
1
R. Duvadie, R. I. Robinson, E. I. Altinoglu and K. F. Jensen, 28 R. A. Sheldon, Green Chem., 2017, 19, 18–43.
Org. Process Res. Dev., 2019, 23, 2699–2706; (b) Y. Mo, 29 For further details see: https://www.creaflow.be/hanutm-hx-
H. Lin and K. F. Jensen, Chem. Eng. J., 2018, 335, 936–944;
150-flow-reactors.
5632 | Green Chem., 2021, 23, 5625–5632
This journal is © The Royal Society of Chemistry 2021