Homogeneous cobalt-catalyzed deoxygenative hydrogenation of amides to amines

Article abstract of DOI:10.1039/d0cy01078b

The first general and efficient cobalt-catalyzed deoxygenative hydrogenation of amides to amines is presented. The optimal catalytic system based on a combination of [Co(NTf2)2] and (p-anisyl)triphos (L3) in the presence of [Me3SiOTf] as acidic co-catalyst facilitates the direct hydrogenation of a broad range of amides to the corresponding amines under mild conditions. A set of control experiments indicate that, after the initial reduction of the amide carboxylic group to the well-known hemiaminal intermediate, the reaction mainly proceeds through C-O bond cleavage though other pathways might be also involved to a minor extent. This journal is

Full text of DOI:10.1039/d0cy01078b

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Homogeneous cobalt-catalyzed deoxygenative
hydrogenation of amides to amines†
Cite this: DOI: 10.1039/d0cy01078b
a
Jose R. Cabrero-Antonino, *ab Anke Spannenberg,
a
Veronica Papa,
Kathrin Junge
a
a
and Matthias Beller
*
The first general and efficient cobalt-catalyzed deoxygenative hydrogenation of amides to amines is
presented. The optimal catalytic system based on a combination of [CoIJNTf ] and (p-anisyl)triphos (L3) in
2 2
)
Received 10th March 2020,
Accepted 24th June 2020
the presence of [Me SiOTf] as acidic co-catalyst facilitates the direct hydrogenation of a broad range of
3
amides to the corresponding amines under mild conditions. A set of control experiments indicate that, after
the initial reduction of the amide carboxylic group to the well-known hemiaminal intermediate, the
reaction mainly proceeds through C–O bond cleavage though other pathways might be also involved to a
minor extent.
DOI: 10.1039/d0cy01078b
rsc.li/catalysis
6
e,g
hydrogenations represent a very difficult task.
More
Introduction
recently, catalytic protocols employing silanes or boranes
Amines are abundantly common in agrochemicals,
pharmaceuticals, and natural products. While aliphatic
have been developed showing excellent functional group
1
6a–c,10
tolerance.
Yet, all these methodologies suffer from the
amines are generally obtained industrially on a large scale via
generation of large amounts of waste-products and often
require complex and hazardous work-up procedures. To
overcome these drawbacks, the use of molecular hydrogen is
1d,e,g,2
reductive aminations,
primary aromatic and benzylic
3
4
amines are produced by nitroarene and/or nitrile group
reductions. In addition, reductive N-alkylations using readily
available and stable carboxylic acid derivatives were developed
6
highly desired. Unfortunately, given the low electrophilicity
of the carbonyl amide group and complex selectivity issues,
its environmental-friendly hydrogenation continues to be
5
in recent years. In principle, the direct hydrogenation of
6
e,g
carboxylic acid amides is highly attractive for the synthesis of
problematic.
In general, amide hydrogenations can occur via two
6
6e
a broad variety of amines. For instance, ammonia, as well as
11
primary and secondary amines can be easily transformed to
different pathways (C–O or C–N bond cleavage) after the initial
7
12
the corresponding amides. With subsequent hydrogenation,
hemiaminal formation (tetrahedral intermediate) (Scheme 1).
primary, secondary or tertiary amines with increased
molecular complexity may be afforded. However, performing
While the C–O cleavage (deoxygenative hydrogenation) gives the
N-alkylated amine and H O (Scheme 1, path A), the C–N
2
6
such reactions under mild conditions remains highly
cleavage (deaminative hydrogenation) produces the original
amine and the corresponding alcohol, or the aminoalcohol
6
e,g
challenging.
Compared to well-known stoichiometric reductions of
1
d,g,8,9
amides,
the straightforward catalytic hydrogenation of
such substrates is intrinsically greener as only water is
6
formed as
a
co-product.
However, owing to the
thermodynamic and kinetic stability of amides, such
a
Leibniz-Institut für Katalyse e.V, Albert-Einstein Str. 29a, 18059 Rostock,
Germany. E-mail: matthias.beller@catalysis.de
b
Instituto de Tecnología Química, Universitat Politécnica de València-Consejo
Superior Investigaciones Científicas (UPV-CSIC), Avda. de los Naranjos s/n, 46022
Valencia, Spain. E-mail: jcabrero@itq.upv.es
†
Electronic supplementary information (ESI) available: Detailed experimental
procedures, additional tables, schemes, figures, products characterization data
and NMR spectra of all the isolated products. CCDC 1972329. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0cy01078b
Scheme 1 Hydrogenation of amides: possible reaction pathways.
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Scheme 1, path B). From a synthetic and practical point of view,
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(
the synthesis of the higher amine by the deoxygenative
hydrogenation is the more desired transformation (Scheme 1,
8b
path A). Indeed, this process is considered as one of the three
most desirable transformations for future development by the
ACS Green Chemistry Institute and members of the
13
Pharmaceutical Roundtable.
Applying heterogeneous
hydrogenation, the specific C–O cleavage is commonly
catalysts
for
amide
6
e,14
observed.
After early work based on copper–chromium
oxide catalysts, bifunctional/bimetallic unsupported and
1
5
supported heterogeneous systems were developed. Notably,
in 2012 a general method for the hydrogenation of tertiary
and secondary amides to amines with excellent selectivity
using a bimetallic Pd–Re catalyst was reported by Breit and
1
5i
15e
co-workers. In addition, the groups of Kaneda, and later
Shimizu,
1
5d
reported in 2017 bimetallic heterogeneous
respectively) that are
systems (PtV/HAP and Re/TiO
2
,
compatible with aromatic groups which are likewise reduced
with most known heterogeneous systems. In spite of these
improvements, the search for
a general heterogeneous
catalyst system with high efficiency, broad functional group
selectivity and substrate scope is still ongoing.
Also most known homogeneous hydrogenation catalysts
1
1,16
react with amides via the C–N bond breaking route.
In
recent years, especially metal pincer complexes with metal–
ligand cooperation have proven to be suitable for such
1
1,16–17
deaminative C–N scissions.
So far, just a few examples
of organometallic complexes (mainly noble metal-based) have
been disclosed for the homogenously-catalyzed deoxygenative
hydrogenation of amides to amines (Scheme 2). Originally,
Scheme 2 Reported homogeneous metal-based catalytic systems for
the selective deoxygenative hydrogenation of amides to obtain higher
amines (cyclic amines are obtained from lactams).
1
8
investigations by Cole-Hamilton and co-workers,
extended by joint contributions with the groups of Leitner &
later
1
9
Klankermayer,
modified by 1,1,1-trisIJdiphenylphosphinomethyl)ethane L1
so-called triphos) as ligand, catalyze the deoxygenative
hydrogenation of amides. Both the in situ generated system
using [RuIJacac) ]/triphos, or the well-defined [(triphos)Ru-
IJtmm)] (tmm = trimethylenemethane) complex were used
have shown that ruthenium catalysts,
selective catalyst system for the deoxygenative amide
2
2
(
hydrogenation.
Notably, in all these [Ru/triphos]-based
catalysts the presence of an acidic co-catalyst is required for
catalytic performance. Usually, this additive provides a weakly
3
−
−
−
coordinating counter anion (CH
SO
3 3
, CF SO
3 3
2
or NTf ),
1
8,19
successfully for this transformation.
which is thought to stabilize the active complex fragment
2+ 19b,23
Furthermore, Klankermayer's group reported a related
[RuIJtriphos)] .
Furthermore, it creates the optimal
[
RuIJtriphos-xyl)IJtmm)] complex bearing a substituted triphos-
reaction medium pK
a
to benefit the hydrogenation events.
2
0
24
xylyl ligand. Interestingly, this novel ruthenium catalyst
showed superior activity for the hydrogenation of lactams.
Around the same time, we demonstrated that the [Ru/triphos
Recently,
ruthenium
four
novel
and manganese
been successively developed by the groups of Zhou, Saito,
well-defined
iridium,
1
6i,25
26
pincer complexes have
2
7
(
L1)] catalyst system, in combination with [YbIJOTf) ] as an
Ogata & Kayaki and Milstein, respectively (see Scheme 2).
3
additive, allows for improved amide hydrogenations which
follow the unusual hydrogenation pathway
see Scheme 1). In this case, the initially formed
Whilst the iridium- and manganese-based complexes show
remarkable catalytic activity for the deoxygenative
hydrogenation of a wide range of amides but stoichiometric
C
2
1
(
hemiaminal, generates the alcohol and the lower amine by
breaking the C–N bond (pathway B). Then, these compounds
amounts of the expensive Lewis acid [BIJC
with respect to the amide derivative) are required.
6 5 3
F ) ] (1 to 1.5 equiv.
2
4,26
On the
produce the higher amine via
autotransfer mechanism under acidic reaction conditions
pathway C). Moreover, a combination of a [RuIJH) IJCO)-
IJtriphos)] complex in the presence of catalytic amounts of
TsOH] and [BF ·Et O] was reported by Zhou's group as a
a
hydrogen borrowing/
other hand, the ruthenium pincer complex reported by Saito
was only applied for the deoxygenative hydrogenation of
ε-caprolactame, while the addition of catalytic amounts of
(
2
two different boron co-additives (NaBIJPh) and L-selectride)
4
1
6i
[
3
2
was needed. In particular, this bipyridyl-based ruthenium
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complex was preceded by a closely related system described
from the same group in 2013, which exhibited a similar
catalytic activity for the deoxygenative hydrogenation of
derivatives has attracted interest. Thus in 2015, the groups of de
Bruin and Elsevier originally reported the first 3d metal catalyst
4 2 2
able to hydrogenate carboxylic acids using [CoIJBF ) ·6H O/
1
6s
32
several lactams.
attributed that the formation of the C–O cleavage product is
the result of hydrogenation/C–N cleavage/hydrogen
In this case, the authors tentatively
triphos (L1)]. Later on, the reductive alkoxylation of cyclic
imides with alcohols to the corresponding alkoxy substituted
33
a
derivatives applying the same catalyst was reported. Beyond
34
borrowing sequence of the secondary lactam. This
assumption is in agreement with the more recent findings
this, CO hydrogenation to methanol or dialkoxymethane
2
3
5
36
ethers,
and the reductive C-alkylation of indoles
and
2
1
37
with the [Ru/triphosIJL1)/YbIJOTf)
3
] system vide supra. Finally,
N-alkylation of amines with carboxylic acids was realized
using modified related cobalt catalysts making use of triphos-
type ligands.
2
5
Ogata & Kayaki presented a ruthenium pincer catalyst that
enables the formal deoxygenative hydrogenation of
benzofused and non-fused lactams, including a wide range of
unprotected substrates. Interestingly, in this contribution the
authors prove that the observed C–O selectivity is actually
Encouraged by these previous findings, and taking into
account the unique activity revealed by Ru/triphos related
1
8–22
catalysts for amide hydrogenation (see Scheme 2),
we
attributed to
mechanism (see Scheme 1, pathway C).
a
C–N hydrogenolysis/hydrogen borrowing
envisaged the development of related cobalt catalysts. Herein,
we report for the first time, the selective deoxygenative
hydrogenation of amides to amines, catalyzed by a non-noble
metal under relatively mild conditions. Advantageously,
(over)stoichiometric amounts of acid additives are not
required in these transformations. In addition, the cobalt
catalytic system is remarkably stable and can be handled
even under air.
Despite all these recent efforts for homogeneous
deoxygenative amide hydrogenations, the development of
more economically viable and environmental-friendly general
catalytic systems in this area is highly desirable.
The replacement of precious metals with earth abundant
and bio-relevant non-noble metals is real goal in
homogeneous catalysis and in organometallic chemistry.
6
b–g
a
17d,28
28b,29
17,29,30
In this direction, elegant examples of iron-,
and even manganese-based
cobalt-
Results and discussion
17b,d,31
homogeneous hydrogenation
catalysts have been successfully reported in the last years.
Additionally, the use of molecular cobalt/triphos complexes for
reductive processes involving carboxylic acids and related
As a starting point of our present investigation we chose the
hydrogenation of benzanilide (1) as a benchmark reaction
(Table 1). Inspired by the previously described cobalt-based
Table 1 Cobalt-catalysed hydrogenation of benzanilide (1a): initial screening of the reaction conditions
a
b
b
b
b
Entry
[Co] precursor
Conv. (%)
2 (%)
3 (%)
4 (%)
c
1
CoIJBF
CoIJBF
CoIJNTf
4
)
)
2
·6H
·6H
2
O
O
<10
83
95
50
52
15
31
77
—
<5
67
—
—
—
2
7
7
2
3
4
4
2
2
32
46
15
14
7
51
49
35
34
7
51
49
35
33
7
2
)
2
c
CoIJNTf )
2
2
5
6
7
8
9
CoIJacac)
CoIJF -acac)
CoIJacac)
CoIJOAc)
CoIJNO
CoIJClO
CoF
CoCl
CoBr
2
6
2
3
9
20
49
—
—
35
—
—
—
—
—
61
51
54
20
50
—
—
35
—
—
—
—
—
61
51
54
2
·4H
·6H
·6H
2
O
23
—
—
29
—
—
—
—
—
38
39
23
3
)
2
2
O
10
11
12
13
14
15
16
17
18
19
4
)
2
2
O
2
2
2
·6H
2
O
d
c,d
e
CoIJNTf
CoIJNTf
—
CoIJNTf
CoIJNTf
CoIJNTf
2
)
)
2
2
2
—
—
>99
91
78
f
2
2
2
)
2
)
2
)
2
g
h
a
Standard reaction conditions: benzanilide (1) (50.3 mg, 0.25 mmol), Co precatalyst (0.01 mmol, 4 mol%), triphos (L1) (0.02 mmol, 8 mol%, 2
b
equiv. to Co), [HNTf
2 2 2
] (0.025 mmol, 10 mol%, 2.5 equiv. to Co), n-Bu O (2 mL) and H (20 bar) at 145 °C during 18 h. Conversion of 1 and
yield of products 2, 3 and 4 were determined by gas chromatography using flame ionization detector (GC-FID) and n-hexadecane as an internal
c
d
e
f
g
h
standard. Run without [HNTf
C and 10 bar of H
2
]. Run without ligand L1. Run without [CoIJNTf
2
)
2
]. Run at 40 bar of H
2
.
Run at 15 bar of H
2
.
Run at 130
°
2
.
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catalytic systems for reductive processes involving carboxylic
compared to [CoIJNTf ) ]. As expected, in the absence of L1 or
2
2
acid and related derivatives vide supra, initially [CoIJBF4)2
a cobalt precursor no conversion was observed (Table 1,
entries 14–16). Both higher (40 bar) and lower (15 bar)
hydrogen pressure and/or temperature were detrimental for
the yield of 2 (Table 1, entries 17–19). For example, at 130 °C
lower conversion was obtained with decreased selectivity,
which shows that the different reaction pathways
2
·6H O] (4 mol% Co), in combination with ligand L1 (2 equiv.
to Co), was tested under H (20 bar) at 145 °C using n-butyl
2
ether as solvent over 18 h (Table 1, entry 1). Unfortunately,
only low conversion was reached and the undesired C–N
cleavage products aniline (3) and benzyl alcohol (4) were
mainly detected, along with traces of the desired product
N-benzylaniline (2) (Table 1, entry 1).
(hydrogenolysis versus hydrogenation) have
a different
temperature influence. In case of pressure, the effects are less
pronounced.
Previous hydrogenation studies involving carboxylic acid
derivatives or CO revealed the crucial requirement of an acid
To improve the selectivity towards 2, we studied the
2
1
9–23,34–36,38
additive for catalytic activity.
For instance, we
2 2 2
catalytic activity of the [CoIJNTf ) /HNTf ]
system in
recently disclosed that for the [Co/triphos (L1)]-catalyzed CO2
combination with a series of mono- and multi-dentate
phosphine ligands (Table S1†). Among the >20 different
phosphine ligands tested, only triphos (L1) and related
tridentate derivatives (L2, L3, L4 and L7) afforded significant
activity (Table 2), while all the other ligands remained
inactive. Compared to the parent triphos, L2 (p-tolyl) and L3
(p-anisyl) slightly improved the amide conversion and yield of
the desired higher amine (Table 2, entries 2 and 3); however,
L4 (p-aminodimethylphenyl), L5 (m-xylyl), and L6 (1-naphthyl)
were shown to be as inactive for the hydrogenation of the
benchmark amide 1 under the same conditions (Table 2,
entries 4–6, respectively). When the most active ligands L2
and L3 were compared under milder reaction conditions for
hydrogenation to methanol, small amounts of triflimidic acid
3
4a
2
[HNTf ] are required to form the active catalyst species.
Therefore, we decided to explore the hydrogenation of 1 in
the presence of [HNTf ] (2.5 equiv. to Co) as an acid additive.
2
4 2 2
Beneficially, the combination of [CoIJBF ) ·6H O/L1] and
HNTf enhanced the conversion of 1, affording 32% yield of
2
the desired amine 2 (Table 1, entry 2). Taking into account
that this improved activity might be attributed to the in situ
formation of [CoIJNTf ) ], we tested this pre-catalyst. Indeed,
2
2
2 2 2
[CoIJNTf ) /L1] in combination of HNTf afforded almost
quantitative conversion of 1, with 46% yield of 2 (Table 1,
entry 3). As observed for [CoIJBF ) ·6H O/L1], worse results
4
2
2
2 2
were obtained using [CoIJNTf ) /L1] in the absence of [HNTf
2
]
benzanilide (1) hydrogenation (135 °C and 10 bar of H
2
), L3
(
Table 1, entry 4). Next, other cobalt salts featuring different
was noticed to be superior to L2 (55% yield of 2, Table 2,
3
7b
counteranions (Table 1, entries 5–13) were tested in
combination with triphos under the same conditions;
however, all catalyst systems afforded poorer results
entries 8 and 9).
Due to the crucial role of the acid additive (Lewis or
19–23,34–36,38
Brønsted),
further acid additives were employed for
Table 2 Cobalt-catalysed hydrogenation of benzanilide (1): study with different triphos-type ligands
a
b
b
b
b
Entry
Triphos ligand
Conv. (%)
2 (%)
3 (%)
4 (%)
1
2
3
4
5
6
7
(L1)
(L2)
(L3)
(L4)
(L5)
(L6)
(L7)
(L2)
(L3)
95
46
52
52
—
2
—
44
48
55
49
48
48
—
3
—
55
21
45
49
48
48
—
3
—
55
20
44
>99
>99
—
<5
—
>99
69
>99
c
8
c
9
a
Standard reaction conditions: benzanilide (1) (50.3 mg, 0.25 mmol), [CoIJNTf
mol%, 2 equiv. to Co), [HNTf ] (0.025 mmol, 10 mol%, 2.5 equiv. to Co), n-Bu
of 1 and yield of products 2, 3 and 4 were determined by gas chromatography using flame ionization detector (GC-FID) and n-hexadecane as an
2 2
) ] precatalyst (0.01 mmol, 4 mol%), triphos ligand (0.02 mmol,
O (2 mL) and H (20 bar) at 145 °C during 18 h. Conversion
2 2
b
8
2
c
2
internal standard. Run at H (10 bar) and 135 °C.
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the hydrogenation of 1 using the optimal [CoIJNTf ) /L3] system
results obtained in previous studies with [Ru/triphosIJL1)]
system.
2
2
21
(Fig. 1). This survey of more than 35 commercially available acid
additives included Brønsted (acetic, trifluoroacetic, triflic,
methanesulfonic, p-toluenesulfonic and tetrafluoroboric acid,
marked in red) and Lewis acid additives comprising boron-
Next, the influence of critical parameters (solvent,
hydrogen pressure, temperature, and the relative amounts of
[CoIJNTf ) ], ligand L3 and [Me SiOTf] additive) on the model
2
2
3
based species [BCl
triflimidates [X (NTf ) ; X = Mn , Ag , Li , marked in green]
3
, BIJC
6
F
5
)
3
, BF
3
·Et
2
O, marked in orange],
reaction was investigated systematically in the presence of
n+
n+
+
+
+
the best additive (Me SiOTf) and [CoIJNTf ) /L3]. Testing
2
n
3
2 2
n+
n+
+
+
+
2+
2+
as well as triflates [X (OTf) ; X = Li , Me Si , Me , Zn , Ga ,
different solvents (ethers, arenes, halogen-containing,
n
3+
3
2
+
2+
2+
3+
3+
3+
3+
3+
3+
3+
Fe , Mg , Ni , Tb , Ce , Yb , Al , Mn , Fe , Sc , Sn ,
alkanes, and alcohols) revealed a positive influence of
3+
3+
3+
3+
3+
3+
3+
4+
16h,39
In , Ho , Sm , Eu , Dy , Pr , La and Hf , marked in
blue]. In general, Brønsted acids presented moderate activities
nonpolar reaction media,
with n-heptane leading to the
best results (Fig. S1†). As shown in Fig. S2,† a high yield of
the desired amine 2 was obtained using 5 mol% of cobalt
4 2 2
(HOTf, MSA, HBF ·Et O, HNTf ), while triflate-based derivatives
such as [Me SiOTf], [MeOTf], [AlIJOTf) ], [FeIJOTf) ], [SnIJOTf) ],
precursor and a 1/1.2 molar ratio of [CoIJNTf ) /L3] at 10 bar
3
3
3
3
2 2
[
InIJOTf) ] and [DyIJOTf) ] showed superior performance than
pressure and 125 °C. Applying slightly higher temperature
3
3
the other additives (Fig. 1). The best yield (69%) of the desired
2
and lower pressure (135 °C and 5 bar of H ) gave similar
amine 2 was obtained in the presence of [Me SiOTf] (TMSOTf),
results. Variation of the relative amount of additive was
detrimental for the yield of 2. Hence, under optimal
conditions, full conversion of 1 and an 80% yield of 2 were
achieved.
3
which to the best of our knowledge wasn't previously reported
as suitable additive in this transformation. In contrast, boron
.
3
Lewis acid additives such as [BCl ], [BIJC F ) ] and [BF Et O]
3
6
5 3
2
produced lower yields of 2. Surprisingly, the [CoIJNTf
system in combination with [YbIJOTf)
amounts of amine 2 (Fig. 1, <10%), which is in contrast to the
2
)
2
/L3]
Remarkably, the selective hydrogenation preceded with
3
] generated only small
good yield and selectivity even using only 1 bar of H
2
. To the
best of our knowledge no homogeneous catalyst system has
Fig. 1 Evaluation of the catalytic activity of different acid additives in the hydrogenation of benzanilide (1) with the [CoIJNTf
amine 2 in the presence of each acid additive. Standard reaction conditions: benzanilide (1) (50.3 mg, 0.25 mmol), [CoIJNTf
ligand L3 (0.02 mmol, 8 mol%, 2 equiv. to Co), acid additive (0.025 mmol, 10 mol%, 2.5 equiv. to Co), n-Bu O (2 mL) and H
2
)
2
/L3] system: yield of
] (0.01 mmol, 4 mol%),
(10 bar) at 135 °C
2 2
)
2
2
during 18 h. Yield of product 2 was determined by gas chromatography using flame ionization detector (GC-FID) and n-hexadecane as an internal
standard. In all cases, only the alcohol and amine arising from the C–N bond cleavage were detected as by-product.
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a
Scheme
3
Control experiments (a–e).
Standard reaction conditions: benzyl alcohol (4), benzaldehyde (5), benzanilide (1) and
N-phenylbenzylimine (6) (0.25 mmol), [CoIJNTf
mmol, 10 mol%, 2 equiv. to Co), n-heptane (2 mL) and H
products were determined by gas chromatography using flame ionization detector (GC-FID) and n-hexadecane as an internal standard.
2
)
2
] (0.0125 mmol, 5 mol%), ligand L3 (0.015 mmol, 6 mol%, 1.2 equiv. to Co), [Me
3
SiOTf] (0.025
b
2
or N (5 bar) at 135 °C during 14 h. Conversion of starting material and yield of
2
Scheme 4 Proposed reaction mechanism for the [CoIJNTf
2
)
2
/L3/Me
3
SiOTf]-catalyzed deoxygenative hydrogenation of amides to amines.
been described for amide reduction with molecular hydrogen
under such mild conditions and it seems that these
conditions aren't compatible with the well-known Ru/triphos
system previously used for this reaction (Table 4).
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Thus, to better understand this improved homogeneous
cobalt-catalyzed deoxygenative hydrogenation of amides, a set
of control experiments were carried out (Scheme 3). Firstly, we
performed an experiment using aniline (3) and benzyl alcohol
(4) as starting materials (Scheme 3a) to provide evidence of a
C–N breaking/hydrogen borrowing sequence similar to the one
21
reported for [Ru/triphosIJL1)/Yb]. Remarkably, N-alkylation of
with 4 only gave very small amounts of the alkylated amine 2
under 5 bar pressure of H or N
3
2
2
.
Similar results were obtained starting from benzaldehyde
in the presence of a slight excess of aniline (3) (Scheme 3b).
Both experiments exclude an initial C–N hydrogenolysis, with
the formation of benzaldehyde (5) or benzyl alcohol (4) and
aniline (3) as the major reaction pathway. Interestingly,
employing aldimine (6) as a starting material, both with and
without Me SiOTf (Scheme 3c), gave amine 2 in 75% and
3
6
9% yield, respectively.
This shows the importance of the acidic additive in the
first reduction step of the amide and not in the final
hydrogenation. Moreover, a competition experiment under
our standard reaction conditions was carried out by reacting
benzanilide (1) in the presence of 1 equiv. of 4-methylbenzyl
alcohol (7) (Scheme 3d). As expected, benzanilide (1) was
almost fully converted and the major product observed was
N-benzyl aniline (2). At the same time, the N-alkylated amine
8
and the imine 9, both products arising of the alkylation of
4
-methylbenzyl alcohol, were detected to a minor extent.
Evidently, 8 and 9 are not formed via direct N-alkylation
Scheme 3a), but instead apparently the aldimine or the
aminal underwent alkylation in the presence of 1 equiv. of
-methylbenzyl alcohol (7) to give 8 and 9. Indeed, reacting 6
(
4
with 7 yielded 8 in a similar quantity as above (Scheme 3e).
Based on these experiments, we believe that the aldimine
6
is a likely intermediate of this cobalt-catalyzed amide
hydrogenation (Scheme 4). Nevertheless, other reaction
pathways cannot be excluded.
Next, to characterize potential catalytically active species,
CoIJNTf ) ] and ligand L3 were mixed in a 1/1.2 molar ratio
2 2
in toluene and stirred at room temperature overnight (see
ESI†). Subsequently a dark brown powder was formed which
Fig. 2 (Top) In situ formation of [CoIJL3)F]
2
IJBF
4
)
2
and crystal structure.
[
(
Bottom) Evaluation of the catalytic activity of [CoIJL3)F]
hydrogenation of benzanilide (1). Molecular structure of the cation of
[CoIJL3)F] IJBF drawn with thermal ellipsoids at the 30% probability
2 4 2
IJBF ) in the
2
4 2
)
level. Hydrogen atoms and minor occupancy atoms are omitted for
2
could be assigned to [Co/(L3)/F]NTf according to HR-MS.
a
clarity. Standard reaction conditions: benzanilide (1) (50.3 mg, 0.25
Unfortunately, many crystallization attempts failed and we
were unable to get a crystal structure due to the high level
of disorder of the triflimide anion. Fortunately, using
mmol), [CoIJL3)F]
2 4 2
IJBF ) precatalyst (0.0125 mmol, 5 mol%), n-heptane
b
(
2 mL) and H (5 bar) at 135 °C during 14 h. Conversion of 1 and yield
2
of products 2, 3 and 4 were determined by gas chromatography using
flame ionization detector (GC-FID) and n-hexadecane as an internal
standard.
[
4 2 2
CoIJBF ) ·6H O] as a precursor showed similar catalytic
activity compared to [CoIJNTf ) ] and we were successful in
2
2
obtaining crystals appropriate for X-ray analysis. As shown
in Fig. 2, a fluoride-bridged dimeric species [CoIJL3)F] IJBF )
2 4 2
is formed.
Encouraged by the success in the deoxygenative
hydrogenation of the benchmark substrate 1 (vide supra), we
explored the reactivity of different amides under the
preselected reaction conditions; all these reactions were run
This complex performed the hydrogenation of 1 under the
optimized conditions similar to the in situ system. In fact,
the desired product 2 was obtained in 70% yield and even
better selectivity (86%). Reaction of this dimeric complex
2
in heptane at 125 or 135 °C with 10 bar H for a standard
[
CoIJL3)F]
afforded a cobalt complex which could be assigned to [Co/
L3)/OTf]OTf according to HR-MS.
2
IJBF
4
)
2
with 4 equiv. of [Me
3
SiOTf] in THF at 70 °C
reaction time of 14 hours (see Table 3). For poorly reacting
substrates the reaction time was extended to improve both
conversions and selectivities in the desired amines. In
(
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Table 3 Substrate scope for the cobalt-catalysed deoxygenative hydrogenation of amides
a
b
b
b
Entry
Amide 1a
Conv. (%)
Amine 2a
Yield (%)
Sel. (%)
1
>99
80
42
26
80
45
87
c
2
88
c
3
30
c
4
97
97
92
83
61
65
43
40
63
67
47
48
5
6
7
8
70
96
84
40
82
36
57
85
43
d
9
10
c
1
1
1
74
70
30
66
40
94
2
1
1
3
4
89
70
20
79
20
e
>99
f
1
1
5
6
60
48
80
—
—
—
g
1
7
8
32
36
31
36
>99
>99
g
1
a
Standard reaction conditions: amide or imide (0.25 mmol), [CoIJNTf
2 2
) ] (0.0125 mmol, 5 mol%), ligand L3 (0.015 mmol, 6 mol%, 1.2 equiv. to
b
Co), [Me
3
SiOTf] (0.025 mmol, 10 mol%, 2 equiv. to Co), n-heptane (2 mL) and H (10 bar) at 125 °C during 14 h. Conversion of amides, yields
2
of amines and product selectivity were determined by gas chromatography using flame ionization detector (GC-FID) and n-hexadecane as an
c
internal standard. In all cases, only the alcohols and amines arising from the C–N bond cleavage were detected as by-products. Run at 135 °C
d
e
and 18 h. Isolated yield of the product after purification with column chromatography is given. Run with [Me
3
SiOTf] (0.03 mmol, 12.5
mol%, 2.5 equiv. to Co) at 145 °C and H (15 bar) over 24 h. 4-Trifluoromethyldibenzylamine was also detected as by-product in a 50% yield.
2
f
g
Run at 24 h, 1H-indoline was detected in <10% yield. Run at 18 h.
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Table 4 Cobalt vs. ruthenium system in the hydrogenation of benzanilide (1)
a
b
b
Entry
[M (mol%)]/L (mol%)/additive (mol%)]
Conv. (%)
2 (%)
1
2
[CoIJNTf
2
)
2
3
3
3
3
3
(5)/L3 (6)/Me
(5)/L3 (6)/Me
(2)/L3 (4)/YbIJOTf)
(2)/L1 (4)/YbIJOTf)
3
SiOTf (10)]
3
SiOTf (10)]
>99
—
—
46
25
80
99
37
80
—
—
4
[RuIJacac)
[RuIJacac)
[RuIJacac)
[RuIJacac)
[RuIJacac)
c
3
3
(4)]
(4)]
c
4
3
c
5
(5)/L3 (4)/Me
(2)/L1 (4)/Me
3
SiOTf (4)]
SiOTf (4)]
1
c
6
3
17
70
19
d
7
[CoIJNTf
2
)
2
(5)/L3 (6)/Me
(2)/L1 (4)/Me
3
SiOTf (10)]
3
SiOTf (4)]
d
8
[RuIJacac)
3
a
Standard reaction conditions: benzanilide (1) (50.3 mg, 0.25 mmol), [M] = [CoIJNTf
SiOTf] or [YbIJOTf) ] (4 or 10 mol%, 0.8 or 2 equiv. to metal), n-heptane (2 mL) and H
during 14 h. Conversion of 1 and yield of product 2 was determined by gas chromatography using flame ionization detector (GC-FID) and
2
)
2
] or [RuIJacac)
3
] (2 or 5 mol%), ligand L1 or L3 (4 or 6
mol%, 1.2 or 2 equiv. to metal), [Me
3
3
2
(5 bar) at 135 °C
b
c
d
2
n-hexadecane as an internal standard. Run using THF as solvent. Run at H (1 bar) during 36 h.
general, high conversions and moderate to good selectivities
Notably, the presented protocol can be applied to the
hydrogenation of cyclic imides, too. In particular
were obtained for both N-aryl acet- and benzamides
Table 3, entries 1–12) except for 2-chloro acetanilide,
4
0
(
phthalimides are an important type of carboxylic acid
derivative and several of these compounds show interesting
whose amine yield was only 26% (Table 3, entry 3). In
some cases, small amounts of alcohol and amine by-
products were detected, arising from C–N hydrogenolysis of
the amide. Overall, para-substituted acetanilides afforded
higher yields than the corresponding meta- and ortho-
substituted substrates, and no direct correlation between
the electronic nature of the substituents and the amine
yield became evident. Apparently, an increased steric
hindrance seems to have a negative effect on the reactivity.
Thus, the hydrogenation of 4-, 3-, and 2-methylacetanalide
4
1
biological activities. Among the possible products obtained
6
g,40
40,42
from the reduction of phthalimides,
and substituted derivatives
isoindolinones
3
3,38c,40,42a
are the most desired as
they are valuable scaffolds in pharmaceuticals and
agrochemicals, as well as relevant building blocks in organic
4
3
synthesis;
our protocol also enables the reduction of
phthalimides in modest yield, but excellent selectivity to give
isoindolinones (Table 3, entries 17 and 18). It is noteworthy
to point out that homogeneous catalysts with the ability to
perform this transformation in a regioselective fashion using
(Table 3, entries 5, 6 and 7) afforded 65%, 43%, and 40%
4
0,42
yield of amine products, respectively. Also, in case of N-1-
naphthalenyl acetanilide the desired product yield was only
molecular hydrogen are rare.
Finally, we were interested comparing the catalytic
activity of the [CoIJNTf /L3/Me SiOTf] system with the
previous state-of-the-art [Ru/triphosIJL1)/YbIJOTf)3]
3
6% (Table 3, entry 10).
)
2 2
3
21
In addition to acet- and benzanilides, 2-phenylacetanilide
catalyst
was hydrogenated in 70% yield with very good selectivity
for the hydrogenation of amides 1. Other homogeneous
catalyst systems e.g. based on manganese have not been
included because of the drastic reaction conditions
necessary for such systems. As shown in Table 4, the
current cobalt system performed the hydrogenation of
benzanilide (1) with better yields of the desired higher
amine 2 in comparison with the ruthenium system under
identical conditions.
(Table 3, entry 13).
Similarly, to previously known homogeneous Ru-
1
8,19,21,22
based catalysts,
the hydrogenation of both
primary and tertiary amides is more challenging. In
fact, the hydrogenation of 4-trifluoromethylbenzamide
resulted in quantitative conversion but generated only
a
low yield of the desired primary amine (20%,
Table 3, entry 14).
Obviously, this does not proof that the presented catalyst
system always shows improved performance. However, also
applying different combinations of [RuIJacac) ] with L3 and/or
3
As a special case, the hydrogenation of oxindole gave
mainly 3H-indole 48% yield (Table 3, entry 15) due to the
aromatic stabilization and 1H-indoline was observed only in
minor amounts (<10%). On the other hand, unfortunately an
aliphatic cyclic amide substrates such as ε-caprolactame did
not afford any conversion to the desired product (Table 3,
entry 16).
[Me SiOTf] as additive, did not improve the results. This
3
behavior might be attributed to the fact that in the case of
Ru as a catalyst, in situ N-alkylation with the alcohol takes
2
1
place, which is not the case in this novel cobalt-based
process.
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Experimental details
General procedure for the hydrogenation of benzanilide (1)
Germany (BMBF) for financial support. V. P. thanks the
Ermenegildo Zegna Founder's Scholarship for financial
support. J. R. C.-A. thanks the Spanish Minister of Science
and Innovation for a Ramón y Cajal contract and Generalitat
Valenciana for SEJI program funding. We also thank D. K.
Leonard (LIKAT) for the assistance in manuscript
preparation.
A 4 mL glass vial containing a stirring bar was sequentially
charged with [CoIJNTf
ligand L3 (12 mg, 0.015 mmol, 6 mol%), amide (0.25 mmol),
Me SiOTf] (10–12.5 mol%) as additive and n-heptane (2.0
2 2
) ] (7.7 mg, 0.0125 mmol, 5 mol%),
[
3
mL) as solvent. Afterwards, the reaction vial was capped with
a septum equipped with a syringe and set in an alloy plate,
which was then placed into a 300 mL autoclave. Once sealed,
the autoclave was purged three times with 30 bar of
hydrogen, then pressurized to 5–10 bar and placed into an
aluminum block, which was preheated at 125–135 °C. After
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(
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Conclusions
The first cobalt-catalyzed protocol for the deoxygenative
hydrogenation of amides to amines is described. The
combination of [CoIJNTf ) ] or [CoIJBF ) ·6H O] with (p-
2
2
4 2
2
1
975, 255, 28–33.
anisyl)triphos (L3) as a ligand, in the presence of [Me SiOTf]
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2
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2
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1
0 For general reviews about catalytic reduction of amides with
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