A Rapid and Additive-Free Ruthenium-Catalyzed Reductive Amination of Aromatic Aldehydes

Article abstract of DOI:10.1002/ejoc.201600515

The ruthenium complex [(η⁶-cymene)Ru(Cl)(dpmpy)]⁺{dpmpy = 2-[2-(dimethylamino)pyrimidin-4-yl]pyridine} is highly reactive in catalyzing the reductive amination of aromatic aldehydes through in situ generated imines with 2-propanol as the hydrogen source following a transfer-hydrogenation mechanism. This transformation does not require any activating additives and is applicable to a broad variety of aldehydes.

Full text of DOI:10.1002/ejoc.201600515

DOI: 10.1002/ejoc.201600515
Communication
Reductive Amination
A Rapid and Additive-Free Ruthenium-Catalyzed Reductive
Amination of Aromatic Aldehydes
Christian Kerner,[a] Sascha-Dominic Straub,[a] Y. Sun,[a] and Werner R. Thiel*[a]
Abstract: The
ruthenium
complex [(η6-cymene)Ru(Cl)- propanol as the hydrogen source following
a transfer-
(dpmpy)]+ {dpmpy = 2-[2-(dimethylamino)pyrimidin-4-yl]pyr- hydrogenation mechanism. This transformation does not re-
idine} is highly reactive in catalyzing the reductive amination of quire any activating additives and is applicable to a broad vari-
aromatic aldehydes through in situ generated imines with 2- ety of aldehydes.
Introduction
Beller as well as by Vogt and co-workers, who accompanied
their results by mechanistic studies.[17] Starting from alcohols
and amines by using the so-called borrowing hydrogen
method, Esteruelas and co-workers identified an osmium phos-
phine catalyst for reductive amination.[18] Furthermore, the first
examples of gold-catalyzed reductive aminations can be found
in the literature.[19] Aside from phosphine ligands, N-hetero-
cyclic carbenes have also been applied for such transforma-
tions.[20] Common features of many reductive amination reac-
tions include the presence of a strong base and long reaction
times.
From a mechanistic point of view, the transfer hydrogenation
of in situ formed imines (aldehyde and amine in 2-propanol as
the hydrogen source and the solvent) is not trivial at all: given
that aldehydes are expected to react more rapidly with the in-
termediately formed metal hydride species than imines,[1g] the
aldehyde can also undergo transfer hydrogenation. Further-
more, water liberated from the condensation reaction to give
the imine may destroy the catalyst's activity. Finally, given that
the imine or the amine is present in the reaction mixture in
high concentrations, it might act as a ligand and thus influence
the performance of the catalyst.[21]
Whereas the catalytic transfer hydrogenation of ketones and
aldehydes has been developed to broad applications,[1] includ-
ing a wide scope of enantioselective transformations,[2] there is
much less known about the closely related hydrogenation of
imines. The first reports on the N-alkylation of amines with alco-
hols appeared in the early 1980s and postulate preliminary de-
hydrogenation of the alcohol at a ruthenium catalyst to gener-
ate a metal dihydride.[3] Condensation of the resulting carbonyl
derivative with the amine and final hydrogenation of the imine
gives the product. Stimulated by this, the reduction of pre-
formed imines has been gaining increasing interest over the
years, and this has led to a series of new rhodium, iridium,
ruthenium, nickel, iron, and cobalt catalysts.[2a,4–9] However, for
the direct reduction of imines, protecting groups such as sulf-
onyl, phosphinyl, tosylate, and benzyl have to be applied in
most cases. Owing to the poor atom economy of such transfor-
mations, an in situ condensation of the carbonyl derivative and
the amine appears to be the better strategy to follow.[10]
Beller and co-workers published the reductive amination of
benzaldehydes with ammonia by using a rhodium catalyst un-
der typical hydrogenation conditions;[11] recent work also in-
cludes the reductive alkoxylation of phthalimides and succinim-
ides.[12] Kadyrov and co-workers applied a ruthenium–BINAP
catalyst for a Leuckart–Wallach-type reductive amination in the
presence of ammonium formate.[13] Xiao and co-workers de-
scribed a cyclometalated iridium catalyst to be active in the
reductive amination in a water/formate mixture under transfer-
hydrogenation conditions,[14] whereas Zhu recently reported a
protocol based on the Noyori–Ikariya ruthenium catalyst under
similar conditions,[15] related to an early report of Watanabe.[16]
A ruthenium–xanthphos system allowing the direct amination
of primary alcohols with ammonia was recently reported by
Results and Discussion
Recently, we found that the ruthenium complex [(η6-
cymene)Ru(Cl)(dpmpy)]+ {A, dpmpy = 2-[2-(dimethylamino)pyr-
imidin-4-yl]pyridine, Scheme 1} catalyzes the transfer hydrogen-
ation of ketones with good activities even in the absence of a
strong base.[22] By mechanistic studies, C–H activation (rollover
cyclometalation) occurring at the dpmpy ligand turned out to
be the key issue for this activity. Hereby, a carbanion coordi-
nated to ruthenium is generated, which then acts as the base
during the catalysis. This kind of catalyst self-activation, which
is strongly dependent on the steric effects of the amino substit-
uent in the 2-position of the pyrimidine ring, has in the mean-
time been found to be beneficial for other catalytic reactions.[23]
Given that ruthenium catalyst A is completely stable to wa-
ter, which in addition does not even influence the rate of trans-
[a] Fachbereich Chemie, TU Kaiserslautern,
Erwin-Schrödinger-Str. 54, 67663 Kaiserslautern, Germany
E-mail: thiel@chemie.uni-kl.de
https://www.chemie.uni-kl.de/thiel/home/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600515.
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Communication
solvent (Table 1, entries 12–15). The optimal catalyst loading
turned out to be 1.5 mol-%, but the productivity was still high
at catalyst loadings of 1.0 and even 0.5 mol-% (Table 1, en-
tries 16 and 17).
Table 1. Screening of the reductive amination of benzaldehyde with aniline
and 2-propanol catalyzed by A.[a]
Entry
1
2
A
iPrOH
[mL]
Yield of 5
[%] (time [h])
Scheme 1. Ruthenium(II) catalyst A.
[mmol] [mmol]/[equiv.] [mol-%]
1[b]
2
2
2.0/1
1.0
1.0
1.5
2.0
1.5
1.5
1.5
6.0
6.0
6.0
6.0
6.0
6.0
6.0
58 (24)
86 (48)
16 (24)
16 (48)
19 (24)
21 (48)
15 (24)
20 (48)
29 (24)
36 (48)
70 (24)
87 (48)
64 (2)
fer hydrogenation, investigations on the reductive amination of
aldehydes appeared promising. To overcome the instability of
certain imines and to keep the whole process as simple as pos-
sible, the imine should be formed in equilibrium in situ by con-
densation of an aromatic aldehyde and an appropriate aromatic
amine according to Scheme 2.
2
2.4/1.2
2.4/1.2
2.4/1.2
1.8/1.2
1.2/1.2
0.6/1.2
3
2
4
2
5
1.5
1
6
7
0.5
85 (3)
100 (4)
79 (2)
100 (3)
86 (2)
100 (3)
90 (2)
100 (3)
77 (2)
100 (3)
68 (2)
89 (3)
86 (2)
93 (3)
74 (2)
95 (3)
77 (2)
96 (3)
57 (2)
85 (3)
63 (2)
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.6/1.2
0.6/1.2
0.6/1.2
0.6/1.2
0.5/1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1.0
7.0
8.0
9.0
10.0
9.0
9.0
9.0
9.0
9.0
9.0
9
10
11
12
13
14
15
16
17
0.55/1.1
0.65/1.3
0.95/1.9
0.6/1.2
0.6/1.2
Scheme 2. In situ imine formation and catalytic reduction.
Screening of the reductive amination with benzaldehyde (1)
and aniline (2; R, R′ = H) as the substrates is summarized in
Table 1 (for characterization of the products see the Supporting
Information). In entry 1, commercially available N-benzylidene-
aniline (4) was applied as the starting material to prove the
general concept. Moderate yields of N-benzylaniline (5) after
24 h and a high yield after 48 h were obtained with a catalyst
loading of just 1.0 mol-%. Turning to a mixture of 1 and 2,
which generates N-benzylideneaniline (4) in equilibrium, made
the conversion drop dramatically (yield of 5: 16 %; Table 1, en-
try 2). Increasing the catalyst loading to 1.5 and 2.0 mol-% did
not increase the yield significantly (Table 1, entries 3 and 4). In
contrast, reducing the amount of starting materials to 1.5 mmol
and 1.0 mmol, which is equivalent to a decrease in the sub-
strate/solvent ratio, gave considerably higher yields (Table 1,
entries 5 and 6). A dramatically higher conversion of 85 % after
only 3 h (100 % after 4 h) was obtained by using 0.5 mmol of
84 (3)
[a] T = 82 °C; amounts of catalyst A, benzaldehyde (1), aniline (2), and iPrOH
as given in the table; the yields were monitored by GC. [b] N-Benzylidene-
aniline (4) was used instead of a mixture of benzaldehyde (1) and aniline (2).
Under the conditions of entry 10 (Table 1), ruthenium(II) cat-
alyst A does not act as a condensation catalyst. Within the first
hour of the reaction, around 80 % of imine 4 is formed in the
presence and absence of A. At this point it can be concluded
that an applicable protocol for rapid transformation of benz-
aldehyde (1) and aniline (2) into N-benzylaniline (5) could be
set up.
According to Scheme 2, some side products might appear.
1 and 1.2 equiv. of 2 (Table 1, entry 7). By continuously increas- They were not observed. From this result a series of conclusions
ing the solvent/substrate ratio, the yield of 5 was increased to can be drawn: The transfer hydrogenation of 1 to give the
90 % after 2 h and 100 % after 3 h (Table 1, entries 8–10). The benzylic alcohol 6 has to be noticeably slower than the conver-
optimum conditions were found to be those given in entry 10. sion of 1 into 5, and the production of intermediate imine 4
A further increase in the solvent volume to 10 mL resulted in a proceeding via aminal 3 has to be faster than the reduction of 4
slightly lower yield (Table 1, entry 11). Variation of the benzal- to 5. Given that electron-rich imines react faster than electron-
dehyde/aniline ratio led to only small changes in the yield but deficient ones, hydride transfer should not be the rate-deter-
did not affect the catalysis as dramatically as the amount of mining step. The positive effect of dilution may be explained
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Communication
by inhibition of the catalyst's activity by either the product or
one of the intermediates. Benzanilide, another possible side
product (not shown in Scheme 2) derived from the dehydro-
genation of 3,[24] was also not observed.
Table 3. Aniline scope of the reductive amination of benzaldehyde (1) cata-
lyzed by A.[a]
To determine the scope of this reaction, different substrates
were converted under the optimized conditions. Results accord-
ing to variations of the aldehyde are summarized in Table 2;
Table 3 shows variations of the aniline. Generally, high yields
were obtained. However, there is a clear trend in activity related
to the electronic and steric effects of the substrates (Table 2):
the more electron rich and the less sterically hindered the alde-
hyde, the higher the reaction rate. As already found for the
model system [benzaldehyde (1) and aniline (2)], the formation
of the imine is rapid. Electron-withdrawing groups at the alde-
hyde should accelerate this reaction.
Table 2. Aldehyde scope of the reductive aminations with aniline (2) catalyzed
by A.[a]
[a] Reaction conditions: 82 °C, A (1.5 mol-%), benzaldehyde (1, 0.5 mmol),
aniline (0.6 mmol), iPrOH (9 mL); yields were monitored by GC; all compounds
were characterized by HRMS.
However, the reduction of the imine is faster as long as the
aldehyde site is functionalized by an electron-donating group.
Therefore, the substrates investigated in entries 4–7 of Table 2
gave residual amounts of the imine and/or the corresponding
benzylic alcohol. As depicted in Scheme 2, the aldehyde may
also undergo transfer hydrogenation. Steric effects are clearly
depicted by the differences between the ortho- and para-func-
tionalized substrates and by the behavior of the two naphthyl-
aldehydes (Table 2, entries 10 and 11). Investigations concern-
ing limitations at the aniline site were focused on the steric and
electronic limits of the reaction.
For anilines equipped with sterically demanding groups in
the ortho position (Table 3, entry 1), as well as for substrates
bearing a strongly electron-withdrawing group (Table 3, en-
try 2), there was no reductive amination at all, as probably the
formation of the corresponding aminals is too slow. Therefore,
the only product was benzylic alcohol. In contrast to the situa-
tion with unfunctionalized aniline, a small amount of benzylic
alcohol accompanied by some imine was detected for 4-
methoxyaniline, whereas the main product was the desired
amine (Table 3, entry 3). The formation of the imine is expected
to proceed rapidly for electron-rich anilines,[25] which is con-
firmed by the almost quantitative conversion of 4-methoxyani-
line. Under the given reaction conditions, we were not able to
convert aliphatic aldehydes and amines other than anilines.
Conclusions
We herein described a well-applicable protocol for the catalytic
reductive amination of aromatic aldehydes without additives
required to activate the catalyst. The reaction operates under
transfer hydrogenation conditions in iPrOH. Catalyst A is a mois-
ture- and air-stable catalyst and is accessible in yields up to
95 % in a few steps. According to mechanistic studies per-
formed with a focus on the transfer hydrogenation activity of
this catalyst, its activation takes place in situ by rollover cyclo-
metalation; this generates a carbanion coordinated to ruth-
[a] Reaction conditions: 82 °C, A (1.5 mol-%), aldehyde (0.5 mmol), aniline (2,
0.6 mmol), iPrOH (9 mL); yields were monitored by GC; all compounds were
characterized by HRMS.
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Communication
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Experimental Section
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The authors gratefully acknowledge the University of Kaisers-
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Keywords: Homogeneous catalysis · Ruthenium ·
Hydrogenation · Reduction · Amination · Aldehydes
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Received: April 26, 2016
Published Online: ■
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Reductive Amination
C. Kerner, S.-D. Straub, Y. Sun,
W. R. Thiel* ........................................... 1–6
A Rapid and Additive-Free Ruth-
enium-Catalyzed Reductive Amin-
ation of Aromatic Aldehydes
A
2-[2-(dimethylamino)pyrimidin-4- absence of any activating additives
yl]pyridine-coordinated
ruthenium with high reaction rates, allowing the
complex catalyzes the reductive ami- conversion of a broad scope of sub-
nation of aromatic aldehydes in the strates.
DOI: 10.1002/ejoc.201600515
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim