Selective catalytic transfer hydrogenation of nitriles to primary amines using Pd/C

Article abstract of DOI:10.1039/c3cy00854a

The catalytic transfer hydrogenation of (hetero)aryl nitriles using ammonium formate has been investigated in detail. In the presence of commercially available Pd/C, a straightforward and selective reduction is achieved without any additives under mild conditions.

Full text of DOI:10.1039/c3cy00854a

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Selective catalytic transfer hydrogenation
of nitriles to primary amines using Pd/C
Cite this: DOI: 10.1039/c3cy00854a
Marcelo Vilches-Herrera, Svenja Werkmeister, Kathrin Junge, Armin Börner
Received 29th October 2013,
Accepted 17th December 2013
*
and Matthias Beller
DOI: 10.1039/c3cy00854a
www.rsc.org/catalysis
The catalytic transfer hydrogenation of (hetero)aryl nitriles using
ammonium formate has been investigated in detail. In the presence
of commercially available Pd/C, a straightforward and selective
reduction is achieved without any additives under mild conditions.
carbon–nitrogen triple bond easily results in the formation of
the corresponding methyl group.23 Although the reduction of
benzonitriles has been achieved in the presence of RANEY®/Ni
using hydrazine as the transfer reagent,24–26 here, limited
chemoselectivity was demonstrated and the high toxicity of
hydrazine is a significant drawback.27–29 Moreover, hydrazine
is a highly reactive reducing agent which, in contact with some
metals such as copper or iron, can lead to fires and explo-
sions. Using the more favourable ammonium formate as the
transfer hydrogenation reagent, only one example is known for
the reduction of 2,4-dimethylbenzonitrile to the corresponding
benzyl amine.30 Owing to this fact and based on our general
interest in reductions of nitriles31 and transfer hydrogena-
tions,32 we started to investigate this reaction in more detail.
Initially, we explored the reduction of benzonitrile 1a as a
benchmark system in the presence of Pd/C (10% Pd) with
three different hydrogen donors: hydrazine hydrate, phosphinic
acid and formic acid–triethylamine.† Using H3PO2 or hydrazine
hydrate in the presence of 1 mol% of Pd/C at 70 °C in
THF as the solvent did not show any conversion. However,
in the case of HCOOH–NEt3 some reactivity was observed
and small amounts of benzylamine 2a were detected while
3a was formed as the main product (Table 1, entries 1–3).
Obviously, the formation of N-formylbenzylamine 3a proceeds
via benzylamine as the intermediate which reacts further with
formic acid. Such N-formylations have been described under
Amines are of importance as key intermediates for the
synthesis of polymers, dyes, pharmaceuticals, agro- and
water-chemicals, solvents as well as numerous fine chemicals.1
Among the different known routes to form aliphatic or
benzylic amines, the catalytic hydrogenation of the corre-
sponding nitriles with molecular hydrogen constitutes one of
the established processes.2 Here, typically Pd/C,3,4 Pd/black5
and Ni/RANEY®6 are used in liquid-phase hydrogenations.7
In addition to these classical heterogeneous catalysts, in
recent years homogeneous catalyst systems based on rhenium8
or ruthenium9 have been developed for this transformation.
Unfortunately, for the selective hydrogenation towards
primary amines, significant amounts of base are required to
prevent the formation of the (unwanted) secondary amines
as by-products.10,11
Complementary to catalytic hydrogenations with molecular
hydrogen, the use of transfer hydrogenation reagents allows
for reductions under ambient conditions without the need
for any special high pressure equipment.12 This is of special
interest to organic synthesis as well as fine chemical pro-
duction in batch processes. In general, different compounds
can be utilized as hydrogen donors, including phosphinic
acid salts,13 isopropanol,14 hydrazines,15 formic acid salts16
and the azeotropic mixture of formic acid–triethylamine.17
Depending on the catalyst and conditions, functional groups
such as ketones,18 esters,19 imines20 and nitro groups21,22 have
been successfully reduced. However, related transfer hydroge-
nations of nitriles have been much less studied. Notably, it
has been pointed out that transfer hydrogenation of the
different conditions for the protection of
a variety of
amines.33–35 Increasing the amount of the catalyst to 5 mol%
of Pd/C led to moderate conversion and 46% of the amide
3a was obtained (Table 1, entry 4). Notably, no traces of
dibenzylamine were detected. To reduce the amount of
formylation, we performed experiments at lower tempera-
ture (Table 1, entries 5 and 6). To our delight, benzylamine
was formed exclusively in only 40 min at 40 °C or in 1.5 h at
room temperature. At room temperature, no formylation of
benzylamine was observed even after 24 h. Furthermore, it
is known that different combinations of acids and bases
Leibniz-Institute for Catalysis e.V at the University Rostock, Albert-Einstein-Str. 29 a,
Germany. E-mail: matthias.beller@catalysis.de; Fax: +49 (381) 1281 51113
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Table 1 Benchmark reduction of benzonitrile: optimizationa
Entry
Hydrogen donor
Ratioc
T [°C]
t [h]
Conv.d [%]
Yield 2ad [%]
1b
2b
3b
4
5
6
7
8
9
10
11
12
13
14
H3PO2
N2H4·H2O
—
—
70
70
70
70
40
rt
40
40
40
40
40
40
40
40
20
20
20
20
40 min
1.5
2
2
2
2
2
2
2
n.r.
n.r.
14
46
89
—
—
—
—
80
77
98
98
98
98
98
98
—
—
HCOOH–NEt3
HCOOH–NEt3
HCOOH–NEt3
HCOOH–NEt3
HCOOH–NEt3
HCOOH–NEt3
HCOOH–NEt3
HCOOH–NEt3
HCOOH–NEt3
HCOOH–NEt3
HCOOH
5 : 2
5 : 2
5 : 2
5 : 2
81
3.7 : 1
7.4 : 1
11.1 : 1
14.8 : 1
18.5 : 1
37 : 1
—
>99
>99
>99
>99
>99
>99
n.r.
n.r.
NEt3
—
2
a
b
c
Reaction conditions: benzonitrile (0.38 mmol), Pd/C (5 mol%), THF (1 mL), HCOOH/NEt3 (1 mL). 1 mol% Pd/C. Ratio of HCOOH/NEt3 is
based on molar ratio. d Determined by GC using hexadecane as an internal standard. n.r. = no reaction.
have a significant impact on the activity and selectivity in
transfer hydrogenations of ketones.36 Thus, we studied the
influence of the NEt3 concentration. For all HCOOH–NEt3
combinations, except for the commercially available mixture,
complete conversion was achieved (Table 1, entries 7–12). It is
worth noting that even a molar ratio of 37 : 1 (volume ratio of
10/1) for HCOOH–NEt3 afforded full conversion and 98% yield
(Table 1, entry 12), while in the absence of a base, no reaction
took place, demonstrating the importance of a small amount
of base.
yields of benzylamine. Obviously, these results might lead to
new alternative systems for the transfer hydrogenation of other
functional groups using formic acid as an H-donor, too.
Furthermore, we tested other commercially available
heterogeneous catalysts such as Ru/C, Pt/C or Pd/alumina.
Unfortunately, none of them was active in this model
reaction (Table 2). On the other hand, Pd/C (10% Pd) from
various suppliers (Merck, Sigma Aldrich) formed the desired
product in similar yields.
Finally, the reduction of several aromatic nitriles was
investigated. As shown in Table 3, 17 (hetero)aromatic nitriles
bearing electron-withdrawing as well as electron-donating
Next, we evaluated the effect of different bases with the same
acid/base molar ratios under the previously optimized condi-
tions (Fig. 1).
All tested additives, even the less basic amine, were suitable
for the reduction of benzonitrile and gave good to excellent
Table 2 Transfer hydrogenation of benzonitrile: screening of different
heterogeneous catalystsa
Entry
Catalyst
T [°C]
t [h]
Yield 2ab [%]
1
2
3
4
5
6
7
8
Ru/C
Ru/C
Pt/C
Pt/C
Pd/alumina
Pd/alumina
Pd/alumina
Pd/C
25
50
25
50
25
50
80
40
4
4
4
4
18
4
—
—
—
—
—
10
—
98
4
2
Fig. 1 Transfer hydrogenation of benzonitrile: screening of different
bases; reaction conditions: benzonitrile (0.38 mmol), Pd/C (5 mol%),
THF (1 mL), HCOOH–base (1 mL, 18.5 : 1). GC yields using hexadecane
as an internal standard. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Hünig base = N,N-diisopropylethylamine.
a
Reaction conditions: benzonitrile (0.38 mmol), THF (1 mL),
HCOOH–NEt3 (1 mL, 18.5 : 1 molar ratio), catalyst (5 mol%).
b
Determined by GC using hexadecane as an internal standard.
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Table 3 Transfer hydrogenation of (hetero)aromatic nitriles: scope
and limitationsa
Entry Substrate
1
Pd/C [mol%] T [°C] t [h] Yield 2b [%]
5
5
5
40
40
40
2
1
2
98
98
98
Scheme 1 Reduction of cinnamonitrile under standard reaction conditions.
2
3
groups were smoothly hydrogenated to the corresponding
primary amines under mild conditions (rt-40 °C) using 5 or
10 mol% of Pd/C. Compared to the state-of-the-art system
RANEY®/Ni and hydrazinium monoformate,25 benzonitrile
was reduced more efficiently giving 98% yield with our catalyst
system (Table 3, entry 1). Nitriles with a methoxy group
(Table 3, entries 2 and 6) showed high reactivity. The reaction
with the methoxy group in the para-position was faster
(1 h reaction time) than in the ortho-position (12 h), demon-
strating that steric hindrance plays a role in the reduction.
In general, no side-products were detected and mostly
excellent yields of amines were obtained. In the case of
para-phenyl-benzonitrile and 4-cyano-indole (Table 3, entries
8 and 9) the yield did not improve even with prolonged
reaction time. Interestingly, high chemoselectivity is achieved
for nitriles containing ester and amide functionalities (Table 3,
entries 12–14). Heterocycles such as pyridines were also
suitable substrates for our reaction, although a molar ratio of
3.7 : 1 of formic acid–triethylamine had to be used for optimal
results (Table 3, entries 15–17). Clearly, the yields were
only moderate (Table 3, entries 15 and 16), but such types of
substrates are known to be difficult for reduction reactions.
Unfortunately, attempts to hydrogenate aliphatic nitriles
under the presented reaction conditions failed. For example,
phenylacetonitrile did not show any reaction at all. When
cinnamonitrile was used as a substrate, full conversion was
achieved but a complex mixture of products was obtained.
Among them, 3-phenylpropanenitrile (23%), 3-phenyl-2-en-1-amine
(12%), and 3-phenylpropan-1-amine (5%) were identified
(Scheme 1). These results suggest that conjugation with the triple
bond of the cyano group plays a significant role in the reduction.
4
5
5
5
40
40
2
1
94
98
6
5
40
12
92
7
8
10
10
40
40
2
98
52
12
9
10
10
40
40
2
4
83
95
10
11
10
40
3
98
12
13
10
10
40
40
3
2
98
98
14
10
40
3
98
Conclusions
A general procedure for the catalytic transfer hydrogenation
of aromatic nitriles to the corresponding primary amines is
described. Applying commercially available Pd/C (10%) as a
heterogeneous catalyst, a variety of different (hetero)aromatic
nitriles is reduced smoothly. The procedure is attractive for
organic synthesis because the protocol can be easily performed
using standard equipment. Advantageously, no additives are
needed and the reaction proceeds with good to excellent
yields under mild conditions. Related functional groups such
as amides and esters were not affected under the optimized
conditions allowing the synthesis of interesting bifunctional
building blocks.
15c
16c
17c
10
10
10
rt
rt
rt
3
3
3
51
72
98
a
Reaction conditions: nitrile (0.38 mmol), Pd/C (5 or 10 mol%),
THF (1 mL) and HCOOH–NEt3 (1 mL, 18.5 : 1) at 40 °C or rt.
b
Determined by GC using hexadecane as an internal standard.
Ratio of HCOOH/base is based on molar ratio (3.7/1).
c
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† General procedure: to a solution of benzonitrile (0.38 mmol) in tetrahydrofuran
(1.0 mL), a mixture of formic acid and triethylamine (1.0 mL) was added
under an argon atmosphere. After the addition of Pd/C (10%; 5 or 10 mol%)
gas evolution is observed and the mixture is stirred for 1 h at the given
temperature (rt or 40 °C). Then, the reaction mixture was filtered through a
short plug of silica gel and hexadecane was added as an internal standard.
The yield was measured by GC (30 m HP Agilent Technologies column, 50–300 °C;
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