Ruthenium-catalyzed reductive amination without an external hydrogen source

Article abstract of DOI:10.1021/ol503595m

A ruthenium-catalyzed reductive amination without an external hydrogen source has been developed using carbon monoxide as the reductant and ruthenium(III) chloride (0.008-2 mol %) as the catalyst. The method was applied to the synthesis of antianxiety agent ladasten.

Full text of DOI:10.1021/ol503595m

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Reductive Amination without an External
Hydrogen Source
Pavel N. Kolesnikov, Niyaz Z. Yagafarov, Dmitry L. Usanov,† Victor I. Maleev, and Denis Chusov*
A. N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, 119991, Vavilova St. 28, Moscow,
Russian Federation
S
* Supporting Information
ABSTRACT: A ruthenium-catalyzed reductive amination without an
external hydrogen source has been developed using carbon monoxide as
the reductant and ruthenium(III) chloride (0.008−2 mol %) as the
catalyst. The method was applied to the synthesis of antianxiety agent
ladasten.
n 1991, Trost introduced the concept of atom economy,1
While we developed a highly efficient methodology of Rh-
Iwhich emphasized the importance of maximizing incorpo- catalyzed reductive amination of carbonyl compounds using
carbon monoxide as a deoxygenative agent,8 the high cost of
ration of all the atoms of the starting materials into the product
rhodium represents an important problem for the application of
the protocol on preparative scale. We therefore considered
development of an alternative catalytic system for this
transformation which would possibly employ a less expensive
metal component than a rhodium species. Ruthenium was a
particularly interesting candidate being the cheapest metal of
the platinum group.13
We started our studies using ruthenium trichloride in the
presence of 10% of triphenylphosphine which was supposed to
stabilize the catalytic species (Table 1, entry 1). The use of
bidentate ligands led to inferior outcomes (entries 2−3);
of a given reaction thereby minimizing the amounts of chemical
waste. Subsequently, valuable concepts of step and redox
economies were proposed by Wender and Baran, respec-
tively.2,3 It is clear that, in the context of growing concerns
associated with depletion of natural resources and pollution of
the environment, atom-economical processes will receive
increasing attention in both the industrial and academic
world. While a substantial number of atom-economical
chemical methods have been developed,3,4 atom-economical
redox processes remain understudied.5
Reductive amination represents one of the most convenient
and versatile methods of amine synthesis.6 Besides an amine
and a carbonyl compound, this transformation naturally
requires a source of hydrogen, usually hydrogen gas itself.
Most hydrogen is industrially produced from methane via a
sequence of three high-temperature catalytic processes
(conducted at 190−800 °C) followed by separation of the
resulting gaseous side products (mainly carbon dioxide).7 Thus,
even though hydrogen gas represents an accessible and
inexpensive reducing agent, it is important to keep in mind
that the use of H2 is not as perfectly atom-economical as it
might seem if one considers the entire production scheme
starting from the natural sources. We have recently reported a
novel atom-economical methodology for Rh-mediated reduc-
tive amination8 and reductive alkylation9 of carbonyl
compounds, which does not require an external hydrogen
source but rather takes advantage of the deoxygenative
potential of carbon monoxide. The use of CO instead of
hydrogen gas or hydride agents is particularly interesting in
light of the fact that carbon monoxide is produced in multiton
quantities as a byproduct of the steel industry10 and thus
represents an abundant source for chemical synthesis. In fact,
most of the worldwide production of acetic acid involves
reaction of purified CO with methanol;11 also, recent reports
demonstrate growing interest of the academic community in
the use of CO in novel synthetic methodologies.12
Table 1. Investigation of the Effects of Additives and Carbon
Monoxide Pressure on Ru-Catalyzed Reductive Amination
a
entry
pressure, bar
additive
yield, %
1
2
90
90
90
90
90
90
90
50
20
10
10
PPh3 (10 mol %)
Dppe (10 mol %)
Dppp (10 mol %)
PPh3 (20 mol %)
PPh3 (15 mol %)
PPh3 (5 mol %)
none
22
8
3
6
4
1
5
2
6
60
81
81
72
56
89
7
8
none
9
none
10
none
b
11
none
a
0.2 mmol scale. Yields were determined by NMR with internal
b
standard. The reaction time was increased to 24 h; the catalyst
loading was decreased to 1 mol % in MeCN. PMP = p-methoxyphenyl.
Received: October 17, 2014
Published: December 31, 2014
© 2014 American Chemical Society
173
DOI: 10.1021/ol503595m
Org. Lett. 2015, 17, 173−175

Organic Letters
Letter
likewise, increasing the amount of triphenylphosphine was
deleterious to the product yield (entries 4−5). In fact,
decreasing the content of the additive improved the perform-
ance, and the maximum yield in the series (81%) was observed
when the process was conducted ligand-free (entries 6 and 7).
We then investigated the effect of the carbon monoxide
pressure on the reaction outcome (Table 1, entries 7−11). The
reaction was found to proceed equally well when the pressure
was decreased from 90 to 50 bar (entry 8). However, when the
process was conducted under 20 and 10 bar of CO, the product
yield dropped to 72% and 56% respectively (entries 9 and 10).
Fortunately, increasing the reaction time to 24 h compensated
for the loss of activity at 10 bar of CO, furnishing the product in
89% yield (entry 11). Ruthenium-mediated reductive amination
could therefore be conducted at substantially lesser pressure
than the one previously employed under rhodium catalysis.8
As the next step, we investigated the influence of the solvent
on the efficiency of reductive amination (Table 2); the amount
Scheme 1. Studies on the Substrate Scope of Ruthenium-
Catalyzed Reductive Amination
a
Table 2. Screening of Solvents, Temperature, and Catalyst
Loadings
a
entry
solvent
THF
catalyst, mol %
yield, %
1
2
58
13
26
20
61
13
15
20
21
11
25
96
96
95
87
67
63
94
2
dioxane
2
3
MeOH
2
4
EtOH
2
5
i-PrOH
2
6
water
2
7
EtOAc
2
8
toluene
2
9
benzene
2
10
11
12
13
14
15
16
17
18
hexane
2
solvent-free
MeCN
2
a
2
Yields were determined by NMR with internal standard. Isolated
b
c
MeCN
1
yields are shown in parentheses. 1 mol % of RuCl3 was employed.
The product was isolated as a trifluoroacetamide derivative.
MeCN
0.5
0.5
0.5
0.5
1
MeCN, 135 °C
MeCN, 130 °C
MeCN, 125 °C
MeCN, 125 °C
The methodology was also perfectly applicable to ketones (1n,
1t, 1u, 1v).
a
0.2 mmol scale. Yields were determined by NMR with internal
The scalability and preparative utility of the developed
methodology was exemplified on the synthesis of antianxiety
agent ladasten. Despite the lower intrinsic reactivity of 2-
adamantanone with respect to less sterically challenged
substrates, the gram-scale reaction with bromoaniline pro-
ceeded well and furnished product 1v in 90% yield (Scheme 2).
Importantly, as low as 0.008 mol % of the catalyst could be
used; the model product between p-anisaldehyde and p-
anisidine demonstrated a turnover number up to 2465 (Scheme
3).
standard.
of the catalyst was decreased to 2 mol %. Acetonitrile appeared
to be an exceptionally well suited solvent for the reaction,
furnishing the product in 96% yield (entry 12). Subsequent
studies showed that whereas the catalyst loading could be
further decreased to as low as 0.5 mol % without any loss of
efficiency of the process conducted at 140 °C, lowering the
temperature resulted in inferior yields (entries 15−17). Yet, the
product could be synthesized in 94% yield when the reaction
was conducted at 125 °C and the catalyst loading was increased
to 1 mol % (entry 18).
Scheme 2. Synthesis of Ladasten on a Preparative Scale
With these results in hand, we proceeded to investigate the
substrate scope of the developed methodology under the
optimized reaction conditions (Scheme 1). A wide range of
aldehydes could be successfully employed, including variously
substituted aromatic, heteroaromatic, and aliphatic substrates.
174
DOI: 10.1021/ol503595m
Org. Lett. 2015, 17, 173−175

Organic Letters
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Scheme 3. Performance of the Developed Catalytic System
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In conclusion, we have reported an atom-economical
reductive amination process catalyzed by ruthenium trichloride,
which takes advantage of the unique deoxygenative potential of
carbon monooxide and does not require an external hydrogen
source. The synthetic value of the developed methodology was
demonstrated by efficient preparation of a representative range
of amines including gram-scale synthesis of antianxiety agent
ladasten.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and full spectroscopic data
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chusov@ineos.ac.ru; denis.chusov@gmail.com.
Present Address
†Harvard University, Department of Chemistry and Chemical
Biology, 12 Oxford Street, Cambridge, MA 02138.
Notes
The authors declare no competing financial interest.
(13) Rhodium(II) acetate dimer and ruthenium(III) trichloride
hydrate (2g, 99.99% metal basis) can be purchased from AlfaAesar for
$1040 and $131 respectively.
ACKNOWLEDGMENTS
■
Dedicated to Professor Henri B. Kagan (University of Paris-
Sud) on the occasion of his 84th birthday. We thank the
Russian Academy of Sciences, Russian Foundation for Basic
Research for a P-8 grant (Grant No. 15-03-02548 A) and the
Council of the President of the Russian Federation (grant for
young scientist No. MK-6137.2015.3) for the financial support.
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