Direct Reductive Amination of Carbonyl Compounds with H2 Using Heterogeneous Catalysts in Continuous Flow as an Alternative to N-Alkylation with Alkyl Halides

Article abstract of DOI:10.1002/adsc.201801457

A general continuous-flow procedure for direct reductive amination of secondary and primary amines with aromatic and aliphatic aldehydes as well as ketones is reported. The use of hydrogen gas and commercially available Pt/C as a heterogeneous catalyst is a key. In addition to exhibiting an excellent functional group tolerance, this method allows the fast formation of C?N bonds without production of any hazardous chemical waste. Applications to the synthesis of key intermediates toward active pharmaceutical ingredients (Donepezil and Arformoterol/Tamsulosin) are also described. (Figure presented.).

Full text of DOI:10.1002/adsc.201801457

Title: Direct Reductive Amination of Carbonyl Compounds with H2
Using Heterogeneous Catalysts in Continuous Flow as an
Alternative to N-Alkylation with Alkyl Halides
Authors: Benjamin Laroche, Haruro Ishitani, and Shu Kobayashi
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801457
Link to VoR: http://dx.doi.org/10.1002/adsc.201801457

10.1002/adsc.201801457
Advanced Synthesis & Catalysis
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DOI: 10.1002/adsc.201801457
Direct Reductive Amination of Carbonyl Compounds with H2
Using Heterogeneous Catalysts in Continuous Flow as an
Alternative to N-Alkylation with Alkyl Halides
Benjamin Laroche,a Haruro Ishitani,b and Shū Kobayashia,b*
a
Dr. B. Laroche, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Dr. H. Ishitani, Prof. Dr. S. Kobayashi
b
Green & Sustainable Chemistry Cooperation Laboratory
Graduate School of Science, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 133-0033 (Japan)
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
other reducible functional groups such as nitro and
cyano groups.[1]
Abstract. A general continuous-flow procedure for direct
reductive amination of secondary and primary amines
with aromatic and aliphatic aldehydes as well as ketones
is reported. The use of hydrogen gas and commercially
available Pt/C as a heterogeneous catalyst is a key. In
addition to exhibiting an excellent functional group
tolerance, this method allows the fast formation of C–N
bonds without production of any hazardous chemical
waste. Applications to the synthesis of key intermediates
toward active pharmaceutical ingredients (Donepezil and
Arformoterol/Tamsulosin) are also described.
R1 R2
X
base
R1 R2
N
N
(1)
(2)
+
+
+
+
HX•base
H
R3
R4
R3 R4
X = Cl, Br, I
R1 R2
N
O
H2
R1 R2
N
H2O
H
R3
R4
R3 R4
Scheme 1. C–N bond formation through substitution (1) and
direct reductive amination of carbonyl compounds
(carbonyl-DRA) (2)
Keywords: flow chemistry; reductive amination;
heterogeneous catalysis; C-N bond formation; flow fine
synthesis
We envisioned that carbonyl-DRA with H2 using
heterogeneous catalysts in flow might address those
issues. Continuous-flow chemistry is now emerging as
a powerful tool in organic synthesis from the
viewpoint of efficiency, scalability, and safety of
chemical transformations.[2] In particular, continuous-
flow methods through heterogeneous catalysis
appeared as an ideal strategy for answering current
manufacturing requirements by replacing typical
tedious and time-consuming batch methods.[3] In the
current transformation, a product and even excess
starting materials and others are released from a
catalyst automatically by flow, assuming that
overreactions and other byproducts formation could be
suppressed and the functional group-compatibility
issue might be solved. In literature, however, examples
of carbonyl-DRA with H2 using heterogeneous
catalysts are very limited; Pd/C,[4] supported FeNi,[5]
and enzyme[6] were used, but substrates are limited and
no general carbonyl-DRA for C–N bond formation
have been reported. Herein, we report a general, fast,
and high-yielding carbonyl-DRA process with H2
C–N bond formation is among the most important
transformations for the synthesis of active
pharmaceutical ingredients (APIs) and other
biologically important compounds. Substitution
reactions with alkyl halides are one of the most popular
approaches (Scheme 1(1)); however, in addition to an
overreaction issue, this reaction is not recommended
from a green organic synthesis point of view towards
sustainable society, because the massive amount of
useless inorganic salts is generated, especially on an
industrial scale. Among other transformations, direct
reductive amination of carbonyl compounds
(carbonyl-DRA) using H2 is promising as an efficient
and greener alternative for C–N bond formation, since
only water is generated as a by-product (Scheme 1(2)).
However, this reaction sometimes gives a mixture of
products and low yields, and has a compatibility issue
with compounds containing C–C multiple bonds and
1
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10.1002/adsc.201801457
Advanced Synthesis & Catalysis
using Pt/C under flow conditions, allowing continuous
synthesis of various kinds of amines with a large panel
of substrates. Applications to the continuous synthesis
of key intermediates of APIs (Donepezil and
Arformoterol/Tamsulosin) are also included.[7]
deactivation. Comparing this result with the most
commonly used Pd(OH)2/C catalyst surprisingly
resulted in a lower yield at the initial stage (28% after
3 h) and after 20 h (75%). The same tendency was
observed for the commercial Pd/C catalyst that
afforded 42% yield after 3 h and 97% yield after 19 h,
and similarly to our Pd- DMPSi/SiO2 catalyst with
even lower yields (from 40 to 86%). Changing the
supports to alumina with the Pd-DMPSi/Al2O3 catalyst
was found to be even less efficient (from 16 to 61%
yield). Interestingly, the selectivity between
benzaldehyde 2 reduction and reductive amination
changed over time in favor of the desired reaction with
these Pd catalysts. This catalytic behavior could result
from fast debenzylation of amine 3 into the starting
material 2, highly likely in the presence of Pd catalyst
at this temperature.[11] To continue the catalyst
screening, bone charcoal (BC)-supported Pd-DMPSi
catalyst was also investigated and showed high yield
at the initial stage (95% after 6 h), but gradual
deactivation was observed after 19 h, showing the
crucial role of the support for the outcome of the
reaction. Finally, direct support comparison using
commercial Pt/Al2O3 exhibited very low reactivity
(around 25% yield from 3 to 20 h) underscoring that,
in general, alumina-supported heterogeneous catalysts
were not recommended for this transformation.[12]
Interestingly, Pt/C catalyst was often abandoned in
favor of Pd equivalents in most of the comparable
reports for reactivity and catalyst lifetime reasons.[4a,b]
In addition, Pt-containing catalysts are rarely utilized
in carbonyl-DRA reactions.[13,14] Thereby, impressed
by the supremacy of Pt/C over other candidates, we
thought that exploiting this efficient and selective Pt/C
catalyst could have a major impact on the substrate
scope and functional group tolerance compared with
previous works.
After preliminary investigations in a batch system
(see SI and Table S1), a flow system was designed as
follows. Because of the spontaneous reaction between
secondary amine 1 and benzaldehyde 2 when mixed
together in the same starting material container,
inducing instability, the starting materials were
separated in two different reservoirs at the global
concentration 0.1 M in toluene relative to amine 1.
Subsequently, these starting materials were pumped
using two dual pumps (A and B) at the same flow rate
(0.1 mL/min)[8] and mixed using a Y-shaped mixer
(Figure 1).
O
H2
0.1 mL/min
A
OEt
(15 mL/min)
HN
1
5 °C
O
Cat. (0.05 mmol)
AC (0.4 g)
1 equiv
Et
Y-shape
mixer
O
0.1 M in toluene
O
Ph
N
4.8 x 100 mm SUS
3
0.1 mL/min
B
80 °C
H
2
1.2 equiv
100
90
80
70
60
50
40
30
20
10
Pt/C
Pd(OH)₂/C
Pd/C
Pd-DMPSi/Al₂O₃
Pd-DMPSi/SiO₂
Pd-DMPSi/BC
Pt/Al₂O₃
0
0
Time (h)
5
10
15
20
25
Having the optimized conditions in hand, we
embarked for the substrate scope probe with various
secondary amines (Table 1). As mentioned beforehand,
benzylated amine 3 could be synthesized continuously
in quantitative yield over time, the Pt/C catalyst
expressing a turnover frequency of 24 h–1 and the
system having a very high space-time yield (STY) of
3.9 kg/(L.day).[15] Model substrates such as piperidine
and pyrrolidine also afforded excellent yields
(compounds 4 and 5), even though not quantitative,
certainly because of their intrinsic volatility. Other
Figure 1. Continuous-flow experimental set-up and catalyst
screening
A stream of 15 mL/min of H2 regulated by a mass-
flow controller was connected to the system through a
T-shaped mixer fixed at an inlet of a flow reactor (SUS
column, 4.8  100 mm diameter). The bed reactor was
packed with 0.05 mmol of a catalyst premixed with 0.4
g of activated carbon (AC, neutral) as a diluting agent,
and heated at 80 °C with an aluminum block. So that
the global concentration would not be altered by
evaporation of toluene, the outlet tube was extended to
a 1.4 m loop cooled with an ice bath. The resulting
crude solution was then collected, evaporated, and
analyzed by 1H NMR spectroscopy.
medicinally
privileged
substrates
like
N-
ethylpiperazine and morpholine could also be
benzylated in almost perfect yields (6, 7). In addition,
the carbamate moiety survived entirely throughout the
process (compound 8). The more sterically hindered
N-methylcyclohexylamine,
2-methyl-
and
2-
ethylpiperidine as well as diethylamine required
100 °C to achieve flawless outcomes (9–12).
Gratifyingly, all the examples afforded excellent
yields between 93% and 100%, a TOF of
approximately 24 h–1 for this period, and a STY in the
range 2.45–4.4 kg/(L.day).
The screening of different commercially available Pd
and Pt heterogeneous catalysts was undertaken under
these conditions for a period of about 20 h, along with
our
previously
reported
Pd-DMPSi/support
catalysts.[3a,b,9] A quantitative yield of the desired
tertiary amine 3 was obtained continuously with Pt/C
catalyst[10] from 3 to 21 h without any sign of catalyst
This reaction also showcased a broad scope with
respect to the functional group tolerance. By varying
2
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10.1002/adsc.201801457
Advanced Synthesis & Catalysis
Table 1. Reductive amination substrate scope under continuous-flow conditions
[a] Reaction performed at 100 °C; [b] Reaction performed at 40 °C; [c] Reaction performed at 60 °C; [d] Reaction performed
at 140 °C; [e] 0.2 g of activated carbon was used
the aromatic aldehyde substituents, ether, phenol, and simple optimization clearly highlights the advantage of
acetal were tolerated (compounds 13–15). Interestingly, flow versus standard batch method for tuning the
halogens remained intact (compounds 16, 17) during selectivity, especially with highly reactive substrates.
the process, as well as a nitrile moiety even though the Then, aliphatic aldehydes such as butyraldehyde and 3-
yield was lower (compound 18). For this specific cyclohexen-1-carboxaldehyde were also successful,
substrate, the lower yield came from the relative providing the corresponding tertiary amines 32 and 33
stability of the hemiaminal intermediate.[16] in quantitative yields at 60 °C. It is noteworthy that the
Gratifyingly, heteroaromatics such as pyridine, furyl, double bond remained untouched for the latter substrate
and thiophene (compounds 19–21) could also be used 33. Finally, relatively harsher conditions were required
with excellent yields at 100 °C. The furfural and for acetophenone, achieving an acceptable 87% yield of
thiophene cases are particularly remarkable because 34 at 140 °C.
furfural is usually reduced under mild conditions with
The application of flow systems toward biologically
Pt catalysts,[17] and sulfur-containing compounds are
relevant target synthesis constitutes a major advantage
often known for permanent poisoning of transition-
for the time-record access of natural products and
metal catalysts.[18] The substrate scope was further
APIs,[19] and is also a tremendous inspirational source
extended to anilines, affording almost perfect yields at
for designing efficient synthetic plans, ideally without
only 40 °C regardless of electronic substituents
extra chemical waste.[3] Donepezil (35) is a current
(compounds 22-24). To achieve the same result,
medicine used in the palliative treatment of Alzheimer’s
sterically hindered compound 25 required 60 °C.
disease and is one of the top 200 most important
Aliphatic primary amines were also very reactive, all
pharmaceutical products by prescription in 2016.[20,21]
working at 40 °C (compounds 26-31), while sometimes
The actual manufacturing processes of Donepezil
giving some double benzylation products. This by-
include the formation of benzylamine 3 through
product formation could be drastically lowered by
nucleophilic substitution of benzyl chloride or bromide
adjusting the retention time, for example by decreasing
with amine 1 under a stoichiometric amount of a base
the amount of AC diluent (compounds 28-31). This
3
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10.1002/adsc.201801457
Advanced Synthesis & Catalysis
forming a stoichiometric amount of inorganic salts as
In summary, we have developed a straightforward
waste.[22] We thought that our reductive amination and efficient carbonyl-DRA method combining H2 and
procedure developed herein could replace the previous Pt/C catalyst in a completely safe manner, allowing the
one while achieving better efficiency and sustainability. continuous formation of C–N bonds without production
For instance, the lab-scale continuous-flow method of any hazardous chemical waste. This procedure was
allowed the formation of 7.2 g per day of the key applied to 33 different substrates, including
intermediate 3 without any deactivation for at least 7 primary/secondary amines and aromatic/aliphatic
days or chemical waste after evaporation of the solvent aldehydes as well as ketones, highlighting a very good
and volatile benzaldehyde residues (Scheme 2).
functional group tolerance. Moreover, this work also
highlights the tremendous role of Pt/C, an accessible,
robust, but too rarely used catalyst for such a
fundamental transformation. Finally, we have
successfully demonstrated the continuous-flow
synthesis of two API intermediates toward Donepezil
and Arformoterol/Tamsulosin drugs, along with a
promising diastereomeric control. Further investigation
to combine this method with other atom-efficient
transformations through sequential flow processes is
ongoing in our laboratory.
Experimental Section
Typical procedure for reductive amination under
continuous-flow conditions
A 100 x 4.8 mm diameter SUS column was packed with a
previously prepared mixture of Pt/C (5%, 195.1 mg, 0.05
mmol) and activated carbon AC (neutral, 0.4 or 0.2 g). Dry
THF was flowed at 0.2 mL/min at 25 °C for 1h into the
column for the removal of water contained into the catalyst,
then replaced by toluene for 15 min before heating up to the
reaction temperature. A H2 stream (15 mL/min) was
connected through a T-shape mixer, and the resulting set-up
was run for 1h before starting the pumping of starting
materials. So that the global concentration would not be
altered by evaporation of toluene, the outlet tube was
extended to a 1.4 m loop cooled with an ice bath.The yields
Scheme 2. Continuous synthesis of key intermediates toward
Donepezil, Arformoterol and Tamsulosin drugs
It is also significant to point out that no Pt leaching was
observed during the process, and no Pt residue was
found within the crude product solution (under
detection limit, <0.14%).[23] Scale-up of the process is
currently ongoing in our laboratory. In addition,
catalytic stereoselective reactions are a major concern
in organic synthesis, especially when carried out under
heterogeneous and continuous-flow systems.[24]
Whereas hydrogen gas stereoselective DRA of carbonyl
compounds have already been studied,[25] no report
mentioned its application to flow chemistry.
Delightfully, flowing the chiral amine 37 with ketone
36 at 60 °C promoted a quantitative yield of the
corresponding chiral amine 38 with a good 85%
diastereomeric ratio in favor of the anti-conformation.
Telescoping this transformation with a stereoretentive
chiral auxiliary removal catalyzed by Pd/C in the same
column reactor afforded chiral amine 39 with 70%
enantiomeric excess.[26] In addition to being the first
catalytic diastereoselective DRA in flow mode, chiral
amine 39 is the direct precursor of two commercialized
drugs: Arformoterol 40, a long-acting β2-agonist
(LABA) used for asthma and chronic obstructive
pulmonary disease (COPD) and Tamsulosin 41, an
alpha-adrenergic blocking agent used to treat
symptomatic benign hyperplasia.[27]
1
were measured by H NMR spectroscopy using 1,2,4,5-
tetramethylbenzene as internal standard, relying on three
measurements between 3 and 24h to provide accurate yields
ranges during this period.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS), Global COE Program, The University of Tokyo, MEXT,
Japan, the Japan Science and Technology Agency (JST), and Japan
Agency for Medical Research and Development (AMED).
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This article is protected by copyright. All rights reserved.
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Advanced Synthesis & Catalysis
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6

10.1002/adsc.201801457
Advanced Synthesis & Catalysis
COMMUNICATION
Reductive amination with heterogeneous catalysts
in continuous-flow as an alternative to N-alkylation
with alkyl halides
Adv. Synth. Catal. Year, Volume, Page – Page
Benjamin Laroche, Haruro Ishitani, Shū
Kobayashi*
7
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