Angewandte
Chemie
DOI: 10.1002/anie.201400059
Atom Economy
Reductive Amination without an External Hydrogen Source**
Denis Chusov* and Benjamin List*
Abstract: A method of reductive amination without an
external hydrogen source is reported. Carbon monoxide is
used as the reductant. The reaction proceeds efficiently for
a variety of carbonyl compounds and amines at low catalyst
loadings and is mechanistically interesting as it does not seem
to involve molecular hydrogen.
a single step, using only one catalyst. Indeed, in addition to
being a very useful C1 building block,[4–9] CO is also known to
act as a reductant.[10] However, most of such reductions
proceed by the water–gas shift reaction and therefore utilize
hydrogen as the terminal reductant.[11,12] We now describe
how carbon monoxide can also act as a reductant in catalytic
reductive aminations without any external hydrogen source.
To the best of our knowledge, this process is unprecedented.
Amines are a very useful and irreplaceable class of
compounds that are industrially produced, for example, as
pharmaceuticals and dyes, and for gas treatment, but also as
reagents and catalysts.[13] One of the most important methods
to synthesize amines is the reduction of imines. As a more
direct and economical approach, the reductive amination of
carbonyl compounds with amines avoids the separate step of
imine formation. This method is more atom economical
therefore requires fewer purification steps and generates less
solvent waste. Alternatively, aminations of alcohols instead of
carbonyl compounds, proceeding through an internal redox
process have recently been developed.[14–17]
T
he reductive amination of carbonyl compounds is key for
the production of amines and requires a source of hydrogen,
commonly hydrogen gas (H2) itself. However, while hydrogen
is inexpensive and used on an industrial scale, mixtures with
air are explosive over a wide concentration range. Other
hydrogen sources may be less atom economical,[1] unstable to
moisture and air, and expensive. We now report an efficient,
robust, and general catalytic reductive amination that does
not require an external hydrogen source but rather utilizes the
existing hydrogen atoms of the amine substrate, and carbon
monoxide (CO) as the reductant. This novel process poten-
tially has economic and safety advantages.
According to the U.S. Department of Energy, most
hydrogen today is produced from fossil materials, such as
natural gas. The main process to accomplish this is steam
methane reforming (SMR),[2] which consists of two steps. The
first involves reacting methane (CH4) with steam at 750–
8008C to produce H2 and CO. The CO byproduct is then
channeled into the second step, known as the water–gas shift
(WGS) reaction, in which it reacts with more steam in the
presence of a catalyst to form additional H2 and carbon
dioxide (CO2). This process itself occurs in two stages: a high-
temperature shift at 3508C and a low-temperature shift at
190–2108C. In the final step, hydrogen gas has to be separated
from carbon dioxide, unreacted methane, and carbon mon-
oxide, and water.[3] Once purified, the resulting supply of
hydrogen is utilized in a myriad of applications including
reductive aminations.
We have studied several potential catalysts for the
reductive amination of benzaldehyde (1) with p-anisidine
(2) in the presence of carbon monoxide (Table 1). We
Table 1: Catalyst screening.
Entry
Cat.
Products [% yield]
1
3
4
1
2
3
4
5
6
RuCl2(PPh3)3
Ru3(CO)12
Pd(OAc)2
PdCl2
Pd/C
Pt/C
<1
<1
1
21
trace
2
98
97
99
79
>99
98
1
2
0
0
0
0
50
76
Using CO directly as a reductant offers distinct advan-
tages as three steps (with heating up to 3508C and three
different catalysts) would potentially be converted into
7[a]
8
Rh/C
Rh2(OAc)4
1
0
49
24
[*] Dr. D. Chusov
[a] Catalyst loading: 5 mol% of rhodium; aniline was used instead of p-
anisidine; 100 bar CO, 1408C, 42 h.
A. N. Nesmeyanov Institute of Organoelement Compounds
of the Russian Academy of Sciences
Vavilova St. 28, Moscow (Russia)
E-mail: Denis.chusov@gmail.com
identified the rhodium acetate dimer as an efficient catalyst
for this process, furnishing N-benzyl-4-methoxyaniline (4) in
good yield (Table 1, entry 8). Catalysts based on ruthenium
gave only traces of the product (Table 1, entries 1 and 2).
Palladium- and platinum-based catalysts also did not lead to
the reductive amination product under the reaction condi-
tions (Table 1, entries 3–6). Upon solvent screening it was
found that the reaction catalyzed by rhodium acetate
proceeded efficiently in a variety of solvents, with the highest
Prof. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mꢀlheim an der Ruhr (Germany)
E-mail: List@mpi-muelheim.mpg.de
[**] We thank Dr. Christophe Farꢁs and Markus Leutzsch for their
support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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