Angewandte
Chemie
DOI: 10.1002/anie.201201360
Reductive Amination
Knçlkerꢀs Iron Complex: An Efficient In Situ Generated Catalyst for
Reductive Amination of Alkyl Aldehydes and Amines**
Anastassiya Pagnoux-Ozherelyeva, Nicolas Pannetier, Mbaye Diagne Mbaye, Sylvain Gaillard,
and Jean-Luc Renaud*
During the past two decades, procedures for the highly
selective catalytic reduction of imines have been developed,
but unfortunately in these procedures the imines, which have
limited stability, have to be synthesized and isolated in an
additional step. Thus, the reductive amination of aldehydes
and ketones constitutes a more efficient and direct route for
their syntheses.[1] Such advantage allows its application into
pharmaceutical and agrochemical processes, as well as
materials science.[2]
environmentally friendly metal derivatives. Iron-catalyzed
reduction is a recent intensive research area.[13] Although
impressive progress has been made in iron-catalyzed transfer
hydrogenation[14] and hydrosilylation,[15] still little is known
about hydrogenation of alkenes, alkynes,[16] and C X
=
bonds.[17] Iron has consequently been scarcely investigated
in reductive amination.[18] Enthaler demonstrated that iron
chloride catalyzed reductive amination through Lewis acid
activation in the presence of silyl hydride derivatives.[19]
Finally, Beller and co-workers recently showed that iron–
carbonyl complexes are active in the reductive amination of
carbonyl compounds with aromatic amines.[20]
To the best of our knowledge, there are no reports on iron-
catalyzed challenging reductive amination of aliphatic amines
and aliphatic aldehydes under smooth reaction conditions
with a well-defined catalyst and using molecular hydrogen as
reducing agent. As a result, we report our work on reductive
amination catalyzed by iron complexes under low hydrogen
pressure and mild reaction conditions. To define the best
reaction conditions, the reductive amination at 858C under
5 bar of hydrogen in ethanol between citronellal and piper-
idine was used as a model reaction (see Table in the
Supporting Information).
The two commonly protocols for reductive amination are
based on either the use of a stoichiometric amount of
borohydrides reagents[3] or heterogeneous hydrogenation.[4]
The former method suffers from severe drawbacks such as
high toxicity and wastes generation. Taking into account the
ecological point of view, the latter is more promising, as the
reducing agent is molecular hydrogen and has found several
applications in industry. However, heterogeneous hydroge-
nation is poorly chemoselective, and the reaction conditions
are not compatible with some other unsaturated functional
groups (namely, reduction of alkenes, alkynes, and nitro
functions can occur with the same catalyst). Homogeneous
reductive amination in the presence of a catalyst and
a reducing agent was also developed. Various reducing
agents[5–8] were previously employed. However, again, the
most appealing reducing agent is molecular hydrogen.[1] In
such reaction conditions, water is the only side-product in the
overall transformation. In homogeneous catalysis, many
catalysts rely on precious metals.[9–12] However, the limited
availability, toxicity, and high price diminish their attractive-
ness. Thus, their replacement by more easily available metals
is of great interest. Iron salts are usually nontoxic and very
abundant, and accordingly among the most inexpensive and
Iron(II) and FeCl3 salts did not provide any alkylated
amine. With these salts, only the corresponding enamine was
detected by 1H NMR spectroscopic analysis. As shown in
Figure 1, some iron complexes were also evaluated. As
observed previously by Beller and co-workers, iron dodeca-
carbonyl did not give any amino derivative.[20] Iron(II)
complexes 1[16a–c] and 2[15c] were inactive as well. We turned
then our attention to Morris iron complexes (3a, 3d)[14b–e,17b]
or related complexes (3b, 3c). Whereas 3a and 3d were
known to be active either in hydrogenation or hydride
transfer reduction of acetophenone,[14c] they proved to be
poorly active or inactive in the reductive amination. Complex
3a led to a 68:32 ratio of alcohol/amine, and 3d provides
a mixture of aldehyde and enamine. Related complexes 3b
and 3c did not give any improvement, and only aldehyde and
[*] A. Pagnoux-Ozherelyeva, Dr. N. Pannetier, Dr. M. D. Mbaye,
Dr. S. Gaillard, Prof. J.-L. Renaud
Laboratoire de Chimie Molꢀculaire et Thioorganique
UMR 6507, INC3M, FR 3038, ENSICAEN-University of Caen
14050 Caen (France)
1
E-mail: jean-luc.renaud@ensicaen.fr
enamine were observed by H NMR spectroscopic analysis.
Dr. M. D. Mbaye
University of Ziguinchor, BP 523 Ziguinchor (Senegal)
However, to our delight, the Knçlkerꢀs complex 4a led to the
alkylated amine with a total conversion.[21] While complex 4a
is an active catalyst, it is air-sensitive and decomposes quickly
after exposure to air.[22] By contrast, compound 4b is air- and
moisture-stable, but is not active in this reaction. However,
treatment of the tricarbonyl precursor 4b with trimethyl-
amine N-oxide oxidatively removed a CO ligand and
generated the 16-electron species.[23] The latter can react
with hydrogen and then generate 4a in situ. Application of
this in situ generated complex 4a in the reductive amination
[**] The “Ministꢁre de la Recherche et des Nouvelles Technologies” is
gratefully acknowledged for a PhD grant (A.P.-O.). The CNRS
(Centre National de la Recherche Scientifique) and “Rꢀgion Basse-
Normandie” are acknowledged for financial support. We thank Oril
Industries for a Post-Doc. fellowship (N.P.) and the University of
Ziguinchor for a fellowship to M.D.M. Rhodia is acknowledged for
the generous gift of bistriflimide.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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