Rhodium-Catalysed Reductive Amination for the Synthesis of Tertiary Amines

Article abstract of DOI:10.1002/adsc.202000746

A procedure for the synthesis of tertiary amines via reductive amination of aldehydes with molecular hydrogen as a reducing agent using homogeneous rhodium catalysis is presented. Using an amine to aldehyde ratio of 4/1 enabled the synthesis of tertiary amines from nine different aldehydes and nine different secondary amines with selectivities up to 99% and turnover frequencies (TOF) up to 7200 h^?1. The reaction showed a high tolerance against alcohol and ester functions allowing the formation of multifunctional molecules. In addition, secondary amines can also be produced by this synthesis. For all compounds, activities were determined by hydrogen gas-uptake. In order to increase the sustainability and efficiency of the procedure, a dosing strategy has been successfully developed. Using the determined reaction indicators enabled the stoichiometric use of aldehydes and amines without significant loss of selectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.202000746

Title: Rhodium-Catalyzed Reductive Amination for the Synthesis of
Tertiary Amines
Authors: Jonas Bianga, Niklas Kopplin, Jonas Hülsmann, Dieter Vogt,
and Thomas Seidensticker
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000746
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10.1002/adsc.202000746
Advanced Synthesis & Catalysis
Very Important Publication
Rhodium-Catalyzed Reductive Amination for the Synthesis of
Tertiary Amines
Jonas Bianga, Niklas Kopplin, Jonas Hülsmann, Dieter Vogt, Thomas Seidensticker*
Laboratory of Industrial Chemistry, Department of Biochemical and Chemical Engineering, TU
Dortmund University, Emil-Figge-Straße 66, 44227 Dortmund, Germany,
* E-mail: thomas.seidensticker@tu-dortmund.de
Abstract
A procedure for the synthesis of tertiary amines via reductive amination of aldehydes with
molecular hydrogen as reducing agent using homogeneous rhodium catalysis is presented.
Using an amine to aldehyde ratio of 4 / 1 enabled the synthesis of tertiary amines from nine
different aldehydes and nine different secondary amines with selectivities up to 99% and
turnover frequencies (TOF) up to 7200 h-1. The reaction showed a high tolerance against
alcohol and ester functions allowing the formation of multifunctional molecules. In addition,
secondary amines can also be produced by this synthesis. For all compounds, acitivities were
determined by hydrogen gas-uptake. In order to increase the sustainability and efficiency of the
procedure, a dosing strategy has been successfully developed. Using the determined reaction
indicators enabled the stoichiometric use of aldehydes and amines without significant loss of
selectivity.
Keywords
Homogeneous Catalysis; Amines; Rhodium; Dosing; Aldehydes
1. Introduction
Tertiary amines are an important class of compounds in the chemical industry, since they are
used in pharmaceuticals, agrochemicals, biological systems or surfactants.[1,2] For their
synthesis, both catalytic and non-catalytic routes exist, however, considering sustainability
aspects, catalytic routes are clearly preferred. Alcohol amination, amination of alkyl halides or
reductive amination of carbonyl compounds are typical representatives.[3] The reductive
amination (RA) with molecular hydrogen (Scheme 1) is a very straightforward synthesis for
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10.1002/adsc.202000746
Advanced Synthesis & Catalysis
tertiary amines since carbonyl compounds are easily available by hydroformylation (aldehydes)
or oxidation (ketones) and only water is formed as co-product.[4]
Scheme 1: Production of tertiary amines via reductive amination (RA) and their potential usage.
The catalytic step of the reductive amination is the hydrogenation of either an enamine or an
imine intermediate; in case of tertiary amines it is the hydrogenation of an enamine. In the
literature it is intensively discussed whether the enamine or the iminium ion intermediate is
finally reduced to an amine.[5,6] Since this is a simple hydrogenation of a double bond, mainly
heterogeneous catalysts are applied for this task.[3] However, also a range of homogeneous
hydrogenation catalysts does exist. For instance, it is well-known that homogeneous rhodium
catalysts show high activity in hydrogenation reactions such as Wilkinson´s catalyst
[Rh(PPh3)3Cl].[7]
Surprisingly, only a few examples of RA for the synthesis of tertiary amines using homogeneous
rhodium catalysts are reported despite their high activity in the hydrogenation of C=C double
bonds. More frequently the use of other metals such as ruthenium[8] or manganese[9] are
reported, complemented by homogeneous catalysts for RA via transfer hydrogenation instead of
using molecular hydrogen.[6,10] Markó and Bakos were the first to apply homogeneous rhodium
catalysts in the reductive amination of aldehydes and ketones back in 1974. However, their
focus was more on hydroaminomethylation, which is a tandem reaction consisting of
hydroformylation and reductive amination, and thus RA has been investigated under
carbonylation condiditons.[11] Börner and coworkers investigated the use of Rh(I) catalysts in the
RA of aldehydes and ketones using different amines in the early 2000’s. These investigations
were performed at room temperature in methanol with molecular hydrogen at a pressure of 50
bar within 20 h reaction time and an amine excess of 2 equivalents referred to the aldehyde.
The formation of alcohols from the carbonyl substrates revealed to be a major limitation of this
reaction.[12,13] Recently, Loginov et al. synthesized different rhodium catalysts and proved their
applicability in RA of aldehydes and ketones with different amines in water with carbon
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10.1002/adsc.202000746
Advanced Synthesis & Catalysis
monoxide as reducing agent. A reaction time of 24-48 h and a catalyst loading of 1 mol% were
necessary to reach yields up to 91 %.[14]
Since for aldehydes the aldol condensation is a possible side reaction which significantly
influences the selectivity, the efficient reductive amination of aldehydes seems to be more
challenging than reductive amination of ketones. Our group recently reported on the continuous
RA of undecanal with diethylamine, with a focus on catalyst separation by application of
thermomorphic multiphase systems.[15] A homogeneous rhodium catalyst was used for the
synthesis of primary amines via reductive amination of aromatic aldehydes with ammonia.[16] In
addition, applications for synthesis of asymmetric or chiral amines via RA using homogeneous
rhodium catalysts have been reported.[17]
Moreover, rhodium has frequently been used in different hydroaminomethylation
reactions.[18,19,20]
Our group has a strong interest in the development of sustainable amine syntheses enabled by
homogeneous transition metal catalysts.[1,19,21] However, a general procedure for a selective and
efficient production of tertiary amines via RA of aldehydes using a highly active homogeneous
rhodium catalysts is, to our surprise, not reported so far. In here we report on a procedure for
the synthesis of tertiary amines which enables the application of various aldehydes and amines,
even in the presence of functional groups. Since we used molecular hydrogen in this rhodium
catalysed RA, reaction parameters can be determined by the gas-uptake of the reaction. Finally,
a strategy to avoid the excess use of amines relative to the carbonyl compound and the
associated waste production is presented.
2. Results and discussion
As in all syntheses, for the synthesis of tertiary amines from aldehydes via reductive amination
(RA, Scheme 2) a high selectivity to the product is essential. In principle, the hydrogenation of
the enamine bears no selectivity issues. However, in RA of carbonyl compounds 1x, the
iminium ion 3xy+ respectively the enamine 3xy is the essential intermediate, which is formed in
a condensation of the carbonyl compound 1x and the secondary amine 2y. Selectivity issues
can be caused by this condensation, especially in case for aldehydes as substrates. Ideally, the
enamine 3xy is formed rapidly and subsequently hydrogenated to the tertiary amine 4xy by a
highly active rhodium catalyst. If the condensation does not proceed as fast, the remaining
aldehyde 1x might be hydrogenated to the alcohol 5x. If the hydrogenation of the enamine does
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Advanced Synthesis & Catalysis
not proceed as fast, the simultaneous presence of both, aldehyde 1x and enamine 3x, can lead
to increased formation of aldol condensates 6xx.
Scheme 2: Reductive amination of carbonyl compounds with secondary amines and side reactions to alcohols and
aldol condensates.
Common homogeneous hydrogenation catalyst such as Wilkinson´s catalyst[7] use monodentate
ligands, since no regioselectivity for the hydrogenation is required. Due to stability issues using
monodentate ligands as triphenylphosphine and related reproducibility challenges in reductive
amination experiments, we decided to use a bidentate ligand for the reductive amination. In
particular, as catalyst system, a combination of Rh(acac)(cod) [acetylacetonato(1,5-
cyclooctadiene)rhodium] as precursor and Xantphos [4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene] as ligand has been chosen, since this system has already been reported to
be active in RA.[22] This and similar catalyst systems with the solvent methanol have frequently
been used in different reductive aminations and are also frequently reported in publications
about hydroaminomethylation (hydroformylation with subsequent reductive amination) allowing
high catalyst activities in these systems.[12,13,19,20,22,23] Moreover Xantphos is a readily available
bidentate ligand and offers the possibility of modification for more special applications such as
catalyst recycling.[23,24] According to a small optimization, we chose methanol as solvent, a
temperature of 100 °C and H2 pressure of 30 bar.
To reach high selectivities, the named side reactions have to be minimized by shifting the
equilibrium of the enamine formation to the product side. Therefore, the most common strategy
described in literature is to apply an excess of the amine.[12,13] Therefore initial experiments on
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10.1002/adsc.202000746
Advanced Synthesis & Catalysis
the reductive amination of undecanal 1a with diethylamine 2a at ratios 2a/1a of 2-4 (Figure 1)
were conducted.
Figure 1: Reductive amination of undecanal 1a with diethylamine 2a at different substrate ratios. Conditions:
mtotal =(m1a + m2a + msolvent) = 100 g, 0.25 mol% Rh(acac)(cod), 1 eq. Xantphos (nRh / nP = 1 / 2), solvent: Methanol,
pH2 = 30 bar, T = 100 °C, Preforming: Without undecanal 1a, t = 60 min, N = 500 rpm. Reaction: Addition of 4 g 1a via
dropping funnel. Yield (Y) and selectivity (Y4aa/X) determined by GC-FID with dibutyl ether as internal standard.
Under these conditions, nearly quantitative conversion and very high yields of the desired
product amine 4aa were already reached for all three amine/aldehyde ratios, the highest yield
and a selectivity of >99% is obtained for an amine/aldehyde ratio of 4/1.
Based on the promising results of the reaction system, a range of substrates will show whether
the system is generally applicable for different aldehydes and amines. For a comparison
between the different substrates two indicators are determined in each case (Figure 6). These
are TOF20 (turnover frequency at X = 20 %) and the time to reach a conversion of X = 90 %.
These values could be determined with reasonable accuracy for all substrate combinations.
Assuming high chemoselectivity, the reaction progress can be monitored by gas consumption.
To this end, the hydrogen pressure drop in the reactor was monitored. At the end of the reaction
conversion and selectivity were determined by GC-FID. The pressure difference was then
normalized with respect to the conversion and plotted versus time. The conversion vs. time plot
of the reaction of undecanal 1a with diethylamine 2a is presented in Figure 2.
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Advanced Synthesis & Catalysis
Figure 2: Progress of conversion (X) over time for the reductive amination of undecanal 1a with diethylamine 2a.
Conditions: mtotal =(m1a + m2a + msolvent) = 100 g, n1x / n2a = 1 / 4, 0.25 mol% Rh(acac)(cod), 1 eq. Xantphos
(nRh / nP = 1 / 2), solvent: Methanol, pH2 = 30 bar, T = 100 °C, Preforming: Without undecanal 1a, t = 60 min,
N = 500 rpm. Reaction: Addition of 4 g 1a via dropping funnel.Yield (Y) and selectivity (Y4aa/X) determined by GC-FID
with dibutyl ether as internal standard.
From Figure 2, tX=90% was determined at 6.5 min. A TOF20 of 7200 h-1 was obtained. Figure 3
shows the results of the RA with diethylamine of a range of aldehydes. For each reaction,
conversion, yield, tx=90% and TOF20 are presented.
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Advanced Synthesis & Catalysis
Figure 3: RA of different aldehydes with diethylamine. Conditions: mtotal =(m1x + m2a + msolvent) = 100 g,
n1x / n2a = 1 / 4, 0.25 mol% Rh(acac)(cod), 1 eq. Xantphos (nRh / nP = 1 / 2), solvent: Methanol, pH2 = 30 bar,
T = 100 °C, Preforming: Without carbonyl compound 1x, t = 60 min, N = 500 rpm. Reaction: Addition of 4 g 1x via
dropping funnel. Yield (YGC) was determined by GC-FID. Isolation of individual components (Yisol) via vacumm
distillation. For not determined yields, n.d. is indicated.
The TOF20 was reached 7200 h-1 for 1a and 1b while the time to the reach 90% conversion
(X = 90 %) differs by 2.5 min. C5-aldehydes such as pentanal, 2-methyl butyl aldehyde and 3-
methyl butyl aldehyde (1b-1d) were investigated and TOFs between 4800 h-1 and 7200 h-1 were
obtained and the reactions needed 8-9 min to reach a conversion of 90%. The overall activity
seems to depend on the branching of the molecule but the differences are relatively minor. The
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10.1002/adsc.202000746
Advanced Synthesis & Catalysis
difference in TOF20 between 4ba (7200 h-1) and 4ca (4800 h-1) emerged due to a time difference
of 10 s in which both reactions attained a value of X = 20 %. Ketones seem not to be applicable
under the chosen conditions because amine 4ea was not obtained from ketone 1e. Within 18 h
of reaction time, a conversion of 30 % was reached and a range of by-products were formed,
which were not identified in the progress of this work. Furthermore, different cyclic and aromatic
molecules were investigated (1f-1i). The progress of the reductive amination of cyclic aliphatic
aldehydes is similar to that of aliphatic aldehydes. 90% of cyclohexane carboxaldehyde 1f were
converted within 6 min. and a TOF20 of 4800 h-1 was reached. Using cyclohexene
carboxaldehyde 1g revealed that there is no chemoseletivity for the hydrogenation of double
bonds. Due to the hydrogenation of enamine and the additional double bond, this reaction
reached a TOF20 of 4400 h-1 and the time to reach a conversion of 90 % was determined at a
time of 13 minutes. For benzaldehyde 1h, the reaction time increased significantly to 35 min for
X = 90% and led to a TOF20 = 3000 h-1. Due to the proximity to the phenyl group and the
associated increased electron density, the electrophilicity of the carbonyl carbon is reduced.
This impedes the nucleophilic attack of the secondary amine, causes a slower RA and enables
the hydrogenation to benzyl alcohol. Since a small part of benzaldehyde is hydrogenated to the
alcohol, the selectivity to the product only reaches 92%. Using 3-phenyl propionaldehyde 1i with
a larger distance between the carbonyl group and the aromatic ring, a higher TOF20 of 5200 h-1
was obtained. 90 % conversion was reached after 5 min.
12-oxo-1-methyl dodecanoate 1j is a bifunctional aldehyde ester and can be converted into
long-chain amine ester using this method. In comparison to undecanal, the ester function
decreases the reaction time to reach 90% conversion from 9 min to 18 min. The TOF20 thus
decreased from 7200 h-1 to 2200 h-1. 1j is synthesized by hydroformylation of methyl
10-undecenoate, which is made from castor oil.[24,25] This is a promising result for the conversion
of other bifunctional aldehydes.
The GC yields and isolated yields differ significantly in most cases. All products were via
vacuum distillation in order to transfer the general applicability of the reaction system also to the
isolation of the respective component. For the model reaction of undecanal 1a with diethylamine
2a, the calibration of substrates, product 4aa and possible byproducts such as the alcohol 5a
and the aldol condensate 6aa were calibrated in the experimental matrix. Using this calibration,
a yield of 99% of 4a and no other byproducts were observerd in the reaction mixture after
reaction. However, only 68% of 4a were isolated. One reason for this is that a very low
substrate loading was used. Since the product has a higher boiling point, the solvent methanol
and diethylamine 2a had to be removed initially by vacuum and thus carried out some small
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10.1002/adsc.202000746
Advanced Synthesis & Catalysis
parts of the product. After this, the remaining mixture consisting of the product 4a and the
catalyst were separated by vacuum distillation. The catalyst was not stable under these
conditions and thus caused that parts of the product remained in the mixture. These problems
have occurred similarly for almost all formed products and thus similar isolated yields were
obtained in most cases.
Due to the high boiling compared to the other products point of 4ja the distillation turned out to
be very challenging and only 43% of the product could be isolated.
The developed method for synthesis of tertiary amines is generally applicable to various amines
and therefore, a range of amines is applied in the reductive amination with undecanal 1a (Figure
4).
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10.1002/adsc.202000746
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Figure 4: Different amines in reductive amination with undecanal. Conditions: mtotal = (m1a + m2y + msolvent) = 100 g,
n1a / n2y = 1 / 4, 0.25 mol% Rh(acac)(cod), 1 eq. Xantphos (nRh / nP = 1 / 2), solvent: Methanol, pH2 = 30 bar,
T = 100 °C, Preforming: Without carbonyl compound 1x, t = 60 min, N = 500 rpm. Reaction: Addition of 4 g 1a via
dropping funnel. Yield (YGC) was determined by GC-FID. Isolation of individual components (Yisol) via vacumm
distillation. For not determined yields, n.d. is indicated.
To our delight, conversion of undecanal was quantitative in all cases. First, differently
substituted amines and the influence of branching on the reaction rate (2a-2e) were
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Advanced Synthesis & Catalysis
investigated. For dipropylamine 2b and dibutylamine 3b very similar reaction parameters were
obtained. Time to reach 90% (tX = 90 %) conversion has been determined after 11 min and 13 min,
respectively. The TOF20 shows a contrary trend (3300 h-1 to 3900 h-1). However, the difference
of 600 h-1 is related to a time difference of 17 seconds only and thus does not prove a significant
difference. Selectivity is slightly decreasing with increasing size of the amine, and more
byproducts like aldol condensates and undecanol are formed in the presence of dipropyl- and
dibutylamine, respectively. In addition, the branched amine diisopropylamine 2d was
significantly slower converted (tX = 90 % = 130 min) and also showed lower selectivity (80%) than
the linear dipropylamine. If a sterically demanding amine such as dicyclohexylamine 2e is used,
the reaction time to reach 90% conversion is 110 min and TOF20 decreases to 300 h-1. It seems
that a longer hydrocarbon chain leads to a lower reaction rate and thus to lower selectivity of the
reaction. This is consistent with the assumptions made for the conditions of the initial
experiments (Figure 1).
By application of cyclic amines pyrrolidine 2f and piperidine 2g, 90% conversion is achieved
after approx. 9 min and 6 min which is comparable to the reaction with diethylamine (10 min).
High TOF20 of 4600 h-1 (2f) and 5100 h-1 (2g) are obtained. For morpholine 2h, the tX = 90 %
increases again to 17 min and thereby TOF20 decreases to 3200 h-1. In principle, oxygen-
containing functional groups appear to have a negative effect on the reaction rate, since they
cause a lower nucleophilicity of the amine.
The influence of other functional groups such as an alcohol group on the reaction has been
investigated (1i-1j). With diethanolamine 2i, approx. 80 min are needed for 90% conversion and
a TOF20 of 1800 h-1 has been determined. In this case a lower nucleophilicity of the amine is
combined with a higher steric demand compared to other amines such as diethylamine (2a)
which decreases the reaction rate significantly.
For 3-(N-methylamino)propionitrile 2j, not only the resulting enamine but also the nitrile group is
hydrogenated. In addition, a large number of different byproducts are produced by different side
reactions such as the nitrile hydrogenation. The end of the reaction by applying pressure uptake
is therefore not valid in terms of conversion and the isolation of the product was also not
possible. Interestingly, secondary amines can also be produced selectively using the developed
method. Finally, the primary amine n-butylamine 2k was applied instead of a secondary amine
to check if tertiary amines with two undecyl rests can be selectively produced by this method as
well. Surprisingly, the secondary amine is formed instead with an excellent selectivity of 99%. In
Comparison to di-n-butylamine 2c (TOF20 = 3900 h-1), n-butylamine (TOF20 = 400 h-1) is less
active in the reductive amination, which could be caused by a higher nucleophilicity of
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Advanced Synthesis & Catalysis
secondary amines compared to primary amines. Another reason could be that the intermediate
product is an imine instead of an enamine/iminium ion in case of using primary amines as
starting materials. Nevertheless, the resulting secondary amine 2ak does not react, which may
be caused by the low aldehyde loading in the reaction.
In case of the investigation of different amines, the GC yields and the isolated yields also differ
due to the low used substrate loading. In case of product 4ae the product decomposed partially
within the distillation and only an isolated yield of 28% was reached. For product 4ad the
isolation via distillation was not possible. For future investigations other isolation methods
should be considered.
Overall, the concept presented is applicable to a wide variety of aldehydes and amines. The
biggest limitations of the method are the high catalyst amount and the low loading of the
aldehyde.
Dosing strategy
As it has been shown before, a highly active and highly selective RA is possible using a
homogeneous rhodium catalyst. However, a high amine/aldehyde ratio of 4/1 is necessary to
supress the byproduct formation. A higher aldehyde concentration would lead to the formation
of alcohol 5a or aldol condensate 6a. An Experiment for the model reaction of undecanal 1a and
diethylamine 2a was done, to prove this assumption and set a benchmark for further
improvements. In this experiment, the initial undecanal (1a) loading (4 w%, 23 mmol) has been
increased by a factor of five (20 w%, 117 mmol) and a stoichiometric amount of diethylamine 2a
(117 mmol) has been used. The complete amount of undecanal 1a has been added in one step
via dropping funnel to the reaction mixture containing amine, methanol, catalyst and ligand. In
this experiment, a selectivity of only 12 % to the amine 4aa was reached at a conversion of
77 % after a reaction time of 1h. Mainly aldol condensate 6aa is formed (Y6aa = 48%). The use
of an excess amount of amine compared to the aldehyde seems unavoidable.
Obviously, the use of excess amine would result in a large amount of amine remaining at the
end of the reaction. Occasionally, the dosing of the aldehyde has been reported to keep the
aldehyde concentration low within the reaction.[26] To our knowledge, a proof of this concept is
not reported and a generally applicable instruction for the dosing has to be developed. For this
the reaction indicators obtained from the pressure uptake of the reaction were used. The aim
was to adjust the dosing in such a way, that a higher amount of product could be produced with
the same amount of catalyst. Moreover, only stoichiometric amount of diethylamine 2a is to be
used without compromising selectivity. As it has been shown in Figure 2, the reaction needed
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6.5 min to reach a conversion of 90 %. To achieve high selectivities for higher undecanal 1a
loadings, this time value has been translated into a pump rate which means that over a time of
6.5 minutes, the same amount of undecanal 1a (4 w%, 23.4 mmol) has been pumped into the
reactor. This corresponds to a flow of 0.63 g/min which has been kept constant for 32.5 min.
Thus, five times as much undecanal 1a (20 w%, 117 mmol) as in the experiments before was
fed into the reactor. diethylamine 2a in a 1/1 ratio (117 mmol) has been added in the reaction
mixture before starting the dosing. Figure 5 shows the results of this experiment and the results
of the benchmark reaction without using the dosing strategy.
Figure 5: Reductive amination of undecanal 1a with diethylamine 2a with dosing of the aldehyde using a pump to
achieve stoichiometric substrate ratio. Conditions: mtotal = (m1a + m2a + msolvent) = 100 g, n1a / n2a = 1 / 1,
0.25 mol% Rh(acac)(cod), 1 eq. Xantphos (nRh / nP = 1 / 2), solvent: Methanol, pH2 = 30 bar, T = 100 °C, Preforming:
Without undecanal 1a, t = 60 min, N = 500 rpm. Reaction: Addition of 20 g 1a via HPLC-pump (ṁ1a = 0,63 g / min).
Yield (Y) and selectivity (Y4aa/X) determined by GC-FID. The bar “without dosing” shows the experiment without the
dosing strategy. Here the total amount of undecanal 1a has been added in one step into the reaction mixture. The
reaction time was 60 minutes. The other reaction conditions were the same.
The dosing strategy allows the production of almost 5 times as much amine 4aa with the same
amount of catalyst, corresponding to an improvement of the turnover number (TON) from 400 to
1860. A selectivity of 93 % has been reached using a stochiometric amount of diethylamine 2a.
Up to a dosing of about 40 mmol undecanal 1a very high selectivities are reached. Subsequent,
both alcohol 5aa and aldol condensate 6aa are formed in small amounts. The formation of by-
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products was detected after 30 minutes and is related to a previous accumulation of undecanal
2a due to a lower reaction rate of the RA. This decreasing reaction rate might be caused by the
change in the amine/aldehyde ratio within the reaction progress. However, the pump ratio
seems to be too fast to reach the selectivities shown before.
The application of dosing leads to a dramatically higher selectivity of 93 % compared to 11 %
(without dosing) in case of stoichiometric substrate ratio, which proves the functionality of a
dosing strategy for rhodium catalysed RA. To further improve the selectivity using a
stoichiometric aldehyde/amine ratio, the aldehyde pump rate should be directly controlled by the
hydrogen consumption. This could allow an almost complete conversion to the desired tertiary
amine 4aa using the shown method.
3. Conclusions
The development of a generally applicable procedure for the synthesis of tertiary amines via
rhodium-catalysed reductive amination of aldehydes is presented. An amine/aldehyde ratio of
4/1 enabled the conversion of nine different aldehydes and nine secondary amines to the
corresponding tertiary amines with excellent yields and selectivities of up to 99 % and TOF20 of
up to 7200 h-1. Limitations were only found for the use of the ketone butanone 1e and
bifunctional amino nitriles 2j, which were not selectively convertible to the desired product.
However, the reaction proved to be tolerant towards different functional groups such as
alcohols, esters and aromatics. Surprisingly, the synthesis of secondary amines was possible as
well using di-n-butylamine 2k as amine compound. Currently, this reaction is under investigation
in order to be utilized for the potential sequential synthesis of differently substituted amines.
These good results are maintained because the amine was used in excess amounts to the
aldehyde. However, considering all collected knowledge about the control of selectivity, the
excess amine can be avoided and with a specific dosing of the aldehyde at the previously
determined reaction rate, similarly good selectivities but much higher productivities can be
obtained with a stoichiometric amine/aldehyde ratio. The TON for the model reaction of
undecanal 1a with diethylamine 2a was thus increased from 400 to 1860 with very good
selectivities of up to 93 %. This also facilitates an easier purification step after reaction. In
further research, the direct coupling of hydrogen gas consumption and feed-pump rate to
increase the selectivity and its general applicability on other substrates will be investigated.
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4. Experimental Section
Reactor and equipment
A 300 mL pressure autoclave was used for the experiments. To provide a continuous hydrogen
pressure of 30 bar in the reactor a pressure reactor (V = 1 L) was used. In order to reduce the
pressure in the reaction a pressure controller was used. For dosing of the aldehyde two different
options were available, a dropping funnel with pressure equilibration and an HPLC-pump.
dropping
funnel
HPLC-
pump
pressure reactor
H2
aldehyde
aldehyde
PI
70 bar
30 bar
reactor
Figure 6: Reactor and equipment for reductive amination in a basic scheme.
General procedure of reductive amination using dropping funnel
To carry out the reaction, the catalyst (0.25 mol%) and ligand (0.50 mol%), the solvent and the
used amine (4 eq.) were filled in the reactor. The autoclave was then closed and rinsed with
argon. Afterwards it was supplied with 5 bar hydrogen. After the reaction temperature of 100 °C
had been reached, the hydrogen pressure was increased to 30 bar. After saturation of methanol
with hydrogen and catalyst preforming of 1 h the aldehyde (4 g) was then fed into the reactor via
valve using the dropping funnel. The total mass used for all experiments was 100 g. The
pressure time curves were recorded with the pressure sensor from BD SENSORS, which was
attached to the pressure reactor. After reaction, the reactor has been cooled with an ice bath
and carefully depressurized. A sample has been taken from the reaction mixture for GC-FID
analysis.
Procedure of product purification
For purification the resulting product solution containing the catalyst, methanol the substrate
amine and product amine has been distilled under vacuum.
15
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10.1002/adsc.202000746
Advanced Synthesis & Catalysis
Procedure for reductive amination with aldehyde dosing
For the experiments with aldehyde addition an HPLC pump was used. The pump is connected
to the pressure autoclave via valve. The autoclave was then closed and rinsed with argon.
Afterwards it was supplied with 5 bar hydrogen. Before reaction the pump tube was filled with
the aldehyde. After the reaction temperature of 100 °C had been reached, the hydrogen
pressure was increased to 30 bar. After saturation of methanol with hydrogen and catalyst
preforming of 1 h the aldehyde had been pumped into reactor in different pump rates [ml/min].
Every ten minutes a sample for the gas chromatography has been taken manually.
Snythesis of 12-oxo-1-methyl dodecanoate
For the synthesis, a hydroformylation methyl 10-undecenoate has been done. 80 g cyclohexane
were filled into the reactor with Rh(acac)(CO)2 (0.05 mol%) and the ligand Biphephos
(nRh / nL = 1/5). After heating (T = 90 °C) and pressurizing (p
CO/H = 20 bar, CO/H2 = 1) the
2
30 g of methyl 10-undecenoate were filled into the reactor via dropping funnel. After
reactor,
reaction the product mixture was distilled and 12-oxo-1-methyl dodecanoate has been obtained
in a purity of about 95 %.
Analytical Data
The analytical data is provided in SI.
5. Acknowledgements
Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - TRR 63 "Integrierte chemische
Prozesse in flüssigen Mehrphasensystemen" (Teilprojekt A11, D3) – 56091768 – Funded by the
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - TRR 63 "Integrated
Chemical Processes in Liquid Multiphase Systems” (subprojects A11, D3) - 56091768. We
thankfully acknowledge UMICORE for donation of the rhodium precursors.
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Table of contents
The Synthesis of tertiary amines via rhodium catalyzed reductive amination is presented. In
order reach a high selectivity the concentration of used substrates had to be conscientiously
chosen. For a higher productivity, substrate a dosing strategy hat to be developed.
19
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