A general and environmentally benign catalytic reduction of nitriles to primary amines

Article abstract of DOI:10.1002/chem.200801600

An easily accessible in situ catalyst composed of [Ru(cod)methylallyl ₂] and DPPF was developed for the environmentally benign hydrogenation of various nitriles to give primary amines. A solution of benzonitrile in toluene was transferred by syringe into an autoclave that contained argon and KOtBu. The catalyst was generated in situ by stirring [Ru(cod)methylallyl₂] and DPPF in toluene for 10 min and transferring the solution by syringe into the autoclave. the reaction mixture was filtered through a short plug of silica gel and the yield was measured by GC. A superior catalyst activity with a TOF of up to 5783 h^-1 is achieved in the model reaction under optimized conditions. The results also show that [Ru(cod)methylallyl₂]/DPPF catalyst system exhibit a broad functional group tolerance.

Full text of DOI:10.1002/chem.200801600

COMMUNICATION
DOI: 10.1002/chem.200801600
A General and Environmentally Benign Catalytic Reduction of
Nitriles to Primary Amines
[
b]
[a]
[a]
[a]
Stephan Enthaler, Daniele Addis, Kathrin Junge, Giulia Erre, and
[
a]
Matthias Beller*
Dedicated to Professor Günther Oehme on the occasion of his 70th birthday
A vast number of amines are produced by both the bulk
and fine chemical industries, and a plethora of naturally oc-
curring nitrogen compounds, such as alkaloids, amino acids,
nously catalyzed hydrogenation of nitriles has been scarcely
investigated, in comparison with C=CÀN, C=N, and NO re-
2
[6]
ductions. More specifically, homogeneous reductions in the
[1]
[7]
[8]
[9]
and nucleotides, play a pivotal role in biological processes.
presence of few ruthenium, rhodium, and iridium com-
plexes are known. Notably, all these catalysts reveal the for-
mation of significant amounts of side products, such as sec-
ondary amines and imines, which lower the selectivity and
the overall yield of the desired primary amines. This is also
a typical problem associated with heterogeneous catalysts.
Interestingly, an improvement in primary amine selectivity
was reported by Hidai and co-workers when the hydrogena-
tion was carried out with ruthenium complexes tailored with
bis(diarylamido)thioether ligands in the presence of catalytic
During recent decades, several novel catalytic methods
have been established for the synthesis of amines, such as
[2]
palladium-catalyzed amination of aryl halides, hydroami-
[
3]
nations
and hydroaminomethylation of olefins or al-
[
4]
[5]
kynes, and homogeneous reductive aminations. Never-
theless, the development of new and improved methods for
the efficient and selective production of amines continues to
be a challenging goal. Among the different known methods
used, reductions are probably the most important due to the
availability of starting materials (aldehydes, ketones,
amides), price (hydrogen), and high atom efficiency. In this
respect, the catalytic hydrogenation of nitriles also offers an
interesting means of access to amines, which is used in in-
dustry for several products. In organic synthesis, nitriles are
commonly reduced with stoichiometric amounts of metal hy-
drides, or in the presence of heterogeneous catalysts based
on Pd, Ni, Co, etc. The former approach is expensive and
not environmentally benign (over-stoichiometric amounts of
waste), whereas the latter has limitations with respect to
functional group tolerance and the excess of ammonia
needed for high chemoselectivity. Surprisingly, the homoge-
[10]
amounts of base.
As shown in Scheme 1, the chemoselectivity of the overall
hydrogenation should be improved by using catalysts with
activity towards imine 2 and/or by addition of ammonia,
[11]
which shifts the equilibrium between 2 and 4 towards 2.
Scheme 1. Selectivity in the catalytic reduction of nitriles.
[
a] D. Addis, Dr. K. Junge, Dr. G. Erre, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Straße 29a
Herein, we describe for the first time the successful appli-
cation of an easy-to-adopt catalytic system formed from
1
8059 Rostock (Germany)
Fax : (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
commercially available [Ru(cod)methylallyl ] (cod=1,5-cy-
A
H
R
U
G
2
clooctadiene) and DPPF (1,1ꢀ-bis(diphenylphosphino)ferro-
cene) for the homogeneous hydrogenation of a variety of ar-
omatic and aliphatic nitriles, with excellent catalyst activity
and high chemoselectivity.
[
b] Dr. S. Enthaler
Massachusetts Institute of Technology, Department of Chemistry
7
0
7 Massachusetts Ave
2139 Cambridge, MA (USA)
Chem. Eur. J. 2008, 14, 9491 – 9494
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9491

Initial studies on the influence of reaction conditions were
carried out with benzonitrile 6 as the model substrate by
using 0.5 mol% ruthenium catalyst and 10 mol% base (po-
tassium tert-butoxide) in toluene with an initial hydrogen
pressure of 50 bar at 808C. All hydrogenation reactions
were performed in an 8-fold parallel reactor array with a re-
ligand (Table 1, entry 6). A DPPPe-based system also gave a
high yield (86%) of benzylamine within 1 hour (Table 1,
entry 4). The catalyst performance dropped with decreasing
carbon chain length in the chelating ligands in the following
order: DPPPe>DPPB>DPPP>DPPE (Table 1, entries 1–
4). Phosphorus ligands with a rigid or sterically demanding
backbone (Table 1, entries 7 and 8) gave complete reduction
of benzonitrile at longer reaction times (24 h). Next, the cat-
[12,13]
actor volume of 3.0 mL.
Because the influence of li-
gands on homogeneous catalysis is crucial, we first examined
the effect of several bidentate phosphorus-containing li-
gands (shown in Table 1; ligand abbreviations used herein:
alyst performance of the [Ru
A
H
R
U
G
studied in more detail. Decreasing the reaction time to
1
0 min still led to a 93% yield of benzylamine, which corre-
À1
sponds to a catalyst TOF of 1116 h (Table 2, entry 2).
Table 1. Influence of the ligand structure in the ruthenium-catalyzed re-
[
a]
duction of benzonitrile.
Table 2. Reduction of benzonitrile by using an in situ ruthenium/DPPF
[
a]
catalyst.
[
b]
[c]
[d]
À1
Entry
1
Ligand
Time [h] Yield [%] TOF [h ]
24
6
34
3
3
51(2
42
[
b]
[c]
Entry Catalyst
mol%]
Base
[mol%]
T
t
Yield
TOF
8
9
À1
[
[8C] [min] [%]
[h
]
2
3
4
5
>99)
1
2
3
4
5
6
7
8
9
1
0.25
0.50
20
20
40
80
10
80
80
80
100
120
140
140
1440
10
88
–
[
d]
931116
120
79
66
10
1
21
0.50
–
80
10
1
0
1
0.25
0.25
10
20
20
20
20
20
20
140
10
10
10
10
10
1896
1590
495
1012
4752
4800
5783
1 (24)
86 (99)
938
172
0.125
0.125
0.125
0.125
0.06
1
1
21
99
24
1
2
10 >99
10 60
0
6
7
>99
>200
11
0.0320
10
5783
[
1
a] Reactions were carried out for the given time at temperatures of 40–
408C in toluene (2.0 mL) under hydrogen (50 bar). [b] The yield was de-
1
1
3
termined by GC (30 m HP Agilent Technologies column, 50–3008C; ben-
zonitrile: 7.08 min, benzylamine: 7.60 min) with nitrobenzene as the in-
ternal standard. [c] TOFs based on stated reaction time. [d] [Ru-
6 (24)
62 (>99)
21
A
H
R
U
G
2
]
(0.0019 mmol), ligand (0.0019 mmol), KOtBu
(
0.076 mmol), and benzonitrile (0.38 mmol).
4
5
8
24
91
9
It is worth noting that at lower catalyst loading
(
0.125 mol%), full conversion and excellent yield (>99%)
are obtained within 10 min, albeit at higher temperatures
1
(
(
120–1408C; Table 2, entries 8, 9). The highest TOF
5783h ) observed for this reaction to date was obtained at
[
a] L=ligand. Reactions were carried out at 808C for 24 h with [Ru-
(cod)methylallyl (0.0019 mmol), ligand (0.0019 mmol), KOtBu
0.038 mmol), and benzonitrile (0.38 mmol) in toluene (2.0 mL) under
À1
A
C
H
T
R
E
U
N
G
2
]
(
1408C with 0.06 mol% catalyst loading (Table 2, entry 10).
hydrogen (50 bar). [b] The yield after 24 h is given in parentheses. [c] The
yield was determined by GC (30 m HP Agilent Technologies column, 50–
3
as the internal standard. [d] Turnover frequencies (TOFs) based on
stated reaction time.
It is important to note that even at low temperature
(
(
408C) the catalyst showed good activity and selectivity
Table 2, entry 1). In contrast with most heterogeneously
008C; benzonitrile: 7.08 min, benzylamine: 7.60 min) with nitrobenzene
[14]
catalyzed reductions of nitriles, there is no need to add am-
monia to this system.
After demonstrating the advantages of the Ru/DPPF
system for the hydrogenation of benzonitrile, we examined
a number of substrates under optimized reaction conditions
(808C, 1 h, 50 bar).
DPPPe=1,5-bis(diphenylphosphino)pentane, DPPB=1,4-
bis(diphenylphosphino)butane,
DPPP=1,3-bis(diphenyl-
phosphino)propane, DPPE=1,2-bis(diphenylphosphino)-
ethane). To our delight, in most cases excellent chemoselec-
tivity (>99%) was attained. The best catalyst activity
As shown in Table 3, eighteen different nitriles were suc-
cessfully hydrogenated with excellent chemoselectivity to
give the corresponding primary amines within 1 to 2 h.
(
>99% yield within 1 h) was observed with DPPF as the
9492
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Chem. Eur. J. 2008, 14, 9491 – 9494

The Catalytic Reduction of Nitriles to Amines
Table 3. Scope and limitations of the ruthenium catalyst.
COMMUNICATION
[
a]
Thereby, the [Ru(cod)methylallyl ]/DPPF catalyst system
A
H
R
U
G
2
exhibited a broad functional group tolerance. For example,
amino-, ester-, and bromo-substituted benzonitriles gave the
corresponding benzylamines in yields of 69–98% (Table 3,
entries 4, 6, and 7). When aromatic nitriles with electron-
withdrawing or electron-donating substituents were used, no
general trend on the reactivity was found. Both electron-de-
ficient (Table 3, entries 2 and 6) and electron-rich com-
pounds (Table 3, entry 3) showed high reactivity and selec-
tivity. If the results for the ortho- and para-substituted
[
b]
Entry
1
Substrate
T [8C]
t [h]
Yield [%]
80
1
99
80
1
1
85
92
2
3
4
5
6
7
8
9
140
A
H
R
U
G
A
T
E
N
pared, it can be seen that the sterically hindered substrate
needed a higher temperature for a similar hydrogenation
result. The potential of the catalyst is demonstrated by ap-
plying more challenging heterocyclic and alkyl nitriles. Al-
though in some cases (Table 3, entries 12–14) a higher reac-
tion temperature was required, to the best of our knowledge
these are the first examples in which heterocyclic nitriles
were successfully hydrogenated in high yields within 1–2 h.
8
40
0
1
1
86
87
1
140
80
1
1
1
1
69
86
98
Finally, the catalytic system [Ru
was also adapted for the reduction of aliphatic nitriles
Table 3, entries 17 and 18). Here, the addition of 10 mol%
A
H
R
U
G
80
(
[c]
80
78
of NH Cl proved to be necessary for the hydrogenation pro-
4
cess to occur. For example, 2-phenethylamine is produced
from readily available benzyl cyanide in 91% yield.
In summary, an easily accessible in situ catalyst composed
80
2
2
46
95
140
of [Ru(cod)methylallyl ] and DPPF has been developed for
A
H
R
U
G
2
80
1
1
93
86
the environmentally benign hydrogenation of various nitriles
to give primary amines. Under optimized conditions, a supe-
À1
rior catalyst activity with a TOF of up to 5783h has been
1
0
140
achieved in the model reaction. The general applicability
and functional group tolerance of the presented system is
shown in the reduction of 18 different aromatic and aliphat-
ic nitriles.
1
1
2
80
2
2
92
84
1
140
Experimental Section
1
3
140
2
99
General procedure: A solution of benzonitrile (0.38 mmol) in toluene
(
1.0 mL) was transferred by syringe into an autoclave that contained
KOtBu (0.038 mmol) and argon. The catalyst was generated in situ by
stirring [Ru(cod)methylallyl ] (0.0019 mmol) and DPPF (0.0019 mmol) in
1
1
4
5
140
80
1
1
79
63
A
H
R
U
G
2
toluene (1.0 mL) for 10 min and afterwards transferring the solution by
syringe into the autoclave. Then hydrogen (50 bar) was added to the au-
toclave and the mixture was stirred for 1 h at 808C. After the predeter-
mined time, the hydrogen was released and nitrobenzene or diglyme
were added as internal standards. After stirring for 10 min, the reaction
mixture was filtered through a short plug of silica gel. The yield was mea-
sured by GC (30 m HP Agilent Technologies column, 50–3008C, benzoni-
trile: 7.08 min, benzylamine: 7.60 min).
80
2
2
60
98
16
17
18
140
140
140
[
[
d]
d]
2
2
91
87
[
a] Reactions were carried out at 80 or 1408C for either 1 h with [Ru-
(cod)methylallyl (0.0019 mmol), ligand (0019 mmol), KOtBu
0.038 mmol), nitrile (0.38 mmol), and toluene (2.0 mL) in an 8-fold par-
allel autoclave or 2 h with [Ru(cod)methylallyl ] (0.019 mmol), ligand
A
C
H
T
R
E
U
N
G
2
]
Acknowledgements
(
A
T
E
N
2
The authors thank Dr. C. Fischer, S. Buchholz, and B. Wendt (all at the
Leibniz-Institut für Katalyse e.V.) for analytical and technical support. R.
Kadyrov (Evonik-Degussa AG) is acknowledged for the donation of
ligand 15.
(0.019 mmol), KOtBu (0.38 mmol), nitrile (3.8 mmol), and toluene
(20 mL) in a 50 mL Parr autoclave. [b] The yield was determined by GC
(30 m HP Agilent Technologies column, 50–3008C) with diglyme as the
4
internal standard. [c] Isolated yield. [d] 10 mol% NH Cl was added.
Chem. Eur. J. 2008, 14, 9491 – 9494
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9493

M. Beller et al.
Keywords: homogeneous catalysis
nitriles · P ligands · primary amines · ruthenium
·
hydrogenation
·
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H
R
U
G
2 2
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2
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Received: August 4, 2008
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Published online: September 24, 2008
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Chem. Eur. J. 2008, 14, 9491 – 9494