Catalytic hydrogenation of amides to amines under mild conditions

Article abstract of DOI:10.1002/anie.201207803

Under (not so much) pressure: A general method for the hydrogenation of tertiary and secondary amides to amines with excellent selectivity using a bimetallic Pd-Re catalyst has been developed. The reaction proceeds under low pressure and comparatively low temperature. This method provides organic chemists with a simple and reliable tool for the synthesis of amines. Copyright

Full text of DOI:10.1002/anie.201207803

Angewandte
Chemie
DOI: 10.1002/anie.201207803
Amide Hydrogenation
Catalytic Hydrogenation of Amides to Amines under Mild
Conditions**
Mario Stein and Bernhard Breit*
In 2005, a round table of pharmaceutical companies and the
ACS Green Chemistry Institute generated a list of dream
reactions that would have an important impact to make the
future production of pharmaceuticals more economical, safe
and environmentally benign.[1] Among the top candidates in
this list was the catalytic hydrogenation of amides to furnish
amines, a functional group present in almost any drug or drug
candidate. In many cases, the amines are synthesized by the
reduction of the corresponding amides, which is typically
achieved by using a stoichiometric amount of a hydride
reagent such as LiAlH4, DIBAL, RedAl, borane, triethylsi-
lane, or polymethylhydroxysilane.[2] Reactions with these
reagents suffer from poor atom efficiency and issues regard-
ing both the safety of operation and the removal of
stoichiometric metal waste are not uncommon.[3] Conversely,
catalytic hydrogenation with molecular hydrogen as reducing
agent is ecologically and economically highly attractive with
water being the only byproduct (Scheme 1).
and high pressures of 100–990 bar, were required in all cases.
Significant improvements were reported by Dobson, who
employed a bimetallic catalyst of Pd and Re on high-surface-
area graphite (HSAG) for the hydrogenation of propiona-
mide at 2008C and 260 bar with good conversion, but with
poor chemoselectivity, furnishing mixtures of mono-, di-, and
tripropylamine.[8] The groups of Fuchikami[9a] and Why-
man[9b–d] have reported improved bimetallic catalysts based
on combinations of Rh/Re, Rh/Mo, Ru/Re, and Ru/Mo, which
allowed milder reaction conditions to be used. Intensive
screening of a large bi- and trimetallic catalyst library by
a research team from Avantium identified Pt/Re/In on silica
(or carbon) as the best catalyst; this enabled mild conditions
to be used in some cases, for example, 10 bar H2 and 1308C for
the hydrogenation of a single amide substrate (N-acetylpyr-
rolidine).[10] A drawback of this method is the requirement for
corrosive acetic acid as a solvent. A homogeneous catalyst
formed in situ from [Ru(acac)3] and triphos was reported by
Cole-Hamilton et al., which reduced amides at 1648C and
40 bar of hydrogen.[11] Recently, Thompson et al. reported the
catalytic hydrogenation of NMP with titania-supported Pt/Re
catalysts.[12] Almost complete conversion was achieved at
1208C and 20 bar H2, with a 100% selectivity for the desired
N-methylpyrrolidine. Unfortunately, the use of n-hexane as
solvent is crucial and, owing to the low solubility of amides in
this solvent, problems might occur with other substrates. DFT
calculations suggest that Re acts as a Lewis acid to render the
Unfortunately, the catalytic reduction of carboxylic acids
and their derivatives is highly challenging, with amides being
the least reactive motifs.[4] Early efforts towards catalytic
hydrogenation of amides with heterogeneous catalysts based
on copper chromite,[5] rhenium,[6] and Raney catalysts[7]
showed that the reaction is, in principle, feasible. However,
harsh reaction conditions, with temperatures of 175–2608C
=
C O more electrophilic, whereas Pt acts as the hydrogenation
catalyst.
Alternative catalytic reductions of amides employing
homogeneous Ru-catalysts have been developed by Mil-
stein,[13] Bergens,[14] and Ikariya.[15] With these catalysts,
amides are reduced under mild conditions with concomitant
À
C N bond cleavage to furnish an alcohol and an amine
component. Deoxygenation of amides by catalytic hydro-
silylation has been developed by the groups of Beller[16] and
Brookhart.[17]
Scheme 1. Hydrogenation of amides.
To date, there is no catalyst that is capable of hydro-
genating a diverse range of amides under mild conditions.
Herein, we report the hydrogenation of various tertiary and
secondary amides at low temperatures and pressures using
a graphite-supported bimetallic Pd/Re catalyst.
At the start of our work, we screened 43 different catalysts
for activity in the catalytic hydrogenation of the model
substrate N-acetylpiperidine (Table 1).[18] This could be done
on a short timescale using a high pressure automation system
with four autoclave blocks each containing ten reaction
[*] Dipl.-Chem. M. Stein, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie und Biochemie, Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
[**] This work was supported by the DFG, the International Research
Training Group “Catalysts and Catalytic Reactions for Organic
Synthesis” (IRTG 1038) and the Krupp Foundation. We thank BASF
SE, Umicore, Chemtura, and Wacker for generous gifts of chem-
icals, especially BASF SE for the supply of catalysts. We thank Dr. M.
Keller, Dr. R. Thomann, Dr. J. Wçrth and C. Warth for analytical help,
and K. Wenz for assistance in functionalized amide synthesis and
catalysis.
vessels.
We
included
[Ru(CO)12]/[Mo(CO)6],
[Ru3(CO)12]/[Re2(CO)10] (Entries 11 and 12), and [Ru-
(acac)3]/triphos (Entry 7), which have been previously
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207803.
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Table 1: Catalytic hydrogenation of N-acetylpiperidine in the presence of
without any loss of conversion. In contrast to the observations
of Thompson et al.,[12] Pd/Re/graphite (catalyst A) showed
a higher activity than Pt/Re/graphite (catalyst B; for example,
Table 2, entries 3 and 8). Therefore, we decided to focus on
Pd/Re/graphite as the catalyst for further investigations. The
reactivity was independent of the substrate concentration in
the range of 0.07–1m (Table 2, entries 2, 10, and 11). For
practical reasons we used a concentration of 0.2m for further
experiments. Furthermore, it was found that molecular sieves
(MS) have a beneficial effect on the reactivity (Table 2,
entries 15–21). The hydrogenation of 1 occurred within 20 h
at 1208C and 10 bar H2 with 85% conversion, and with no
other byproducts observed (Table 2, entry 19). To the best of
our knowledge, these are the mildest conditions thus far
reported for amide hydrogenation. At 1608C and with
a higher catalyst loading, we were able to further reduce the
hydrogen pressure to 5 bar (Table 2, entry 21). Alternative
solvents were 1,4-dioxane, diglyme, and cyclohexane.[18]
Next, we examined the substrate scope and limitations for
the catalytic hydrogenation with Pd/Re/graphite. As general
conditions, we chose 1608C and 30 bar H2 for the hydro-
genation of 108 different amides.[18] A representative selec-
tion of the results is shown in Table 3. Out of the 108 amides
tested, 90 showed conversions of greater than 50%, and 69
showed more than 90%. In 79 examples, the selectivity for the
desired amine was 90% or higher. When the alkyl residue
next to the carbonyl function of the amide became longer, the
conversion slightly decreased, from 100% for methyl sub-
stitution to 60% for octyl substitution, whereas the selectivity
remained perfect (Table 3, entries 1–4). In many cases, the
different catalysts.[a]
Entry
Catalyst (mol%)[b]
Conversion[c] [%]
1
–
–
2
3
RuO2 (5.0)
4% Ru/C (5.0)
–
–
4
1% Ru/CDG (5.0)
–
5
[Ru2(CO)12] (5.0)
–
6
7
8
9
[Ru(NH3)5Cl]Cl2 (5.0)
[Ru(acac)3] (1.0)/triphos (2.0)
5% Rh/Al2O3 (5.0)
5% Rh/C (5.0)
–
1
–
–
10
11
12
13
14
15
[Rh(nbd)acac] (5.0)
[Ru3(CO)12] (1.6)/[Mo(CO)6] (2.5)
[Ru3(CO)12] (1.9)/[Re2(CO)10] (0.7)
Ni (5.0)/Al (5.0)
2% Pd (1.7)/10% Re (5.0)/C
1% Pt (0.5)/10% Re (5.0)/C
–
92
82
–
>99
>99
[a] Reaction conditions: N-acetyl piperidine (1.0 mmol), DME (15 mL),
20 h. [b] Mol% values are based on the amount of metal used.
[c] Determined by GC analysis. acac=acetylacetonate, CDG=chemi-
cally derived graphene, nbd=norbornadiene, triphos=bis(diphenyl-
phosphinoethyl)phenylphosphine.
reported to be active hydrogenation catalysts.[9,11] As
expected, most catalysts were inactive and no reaction
occurred. The results of Whyman and co-workers were
reproducible.[9] Unfortunately, the homogeneous Ru–triphos
catalyst was not active for our chosen substrate.[19] We were
delighted to observe that the bimetallic Pt/Re/graphite and
Pd/Re/graphite catalysts gave full conversion and excellent
selectivity for the desired amine (Entries 16 and 17).[18,20]
TEM images of the Pd/Re/graphite catalyst revealed
homogeneously dispersed nanoparticles of 2–6 nm deposited
on the graphite layers (Figure 1). The surface/volume ratio is
therefore rather high, which might be the cause of the high
reactivity of the catalyst.
Table 2: Screening of reaction conditions.[a]
Entry Cat.[b] Conc. [m] T [8C] p [bar] 4 ꢁ MS Conv. of 2[c] [%]
1
2
3
4
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21[d]
A
A
A
A
B
B
B
B
A
A
A
A
A
A
A
A
A
A
A
A
0.07
0.07
0.07
0.07
0.07
0.07
0.07
0.07
0.20
1.00
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.10
160
140
120
100
160
140
120
100
140
140
140
140
140
140
120
100
120
120
120
160
70
70
70
70
70
70
70
70
70
70
50
30
10
30
30
30
20
10
5
no
no
no
no
no
no
no
no
no
no
no
no
no
yes
yes
yes
yes
yes
yes
yes
>99
>99
59
Next we optimized the reaction parameters using both Pt/
Re/graphite and Pd/Re/graphite as catalysts (Tables 2 and 3).
The catalyst loading could be reduced to 4 mol% of Re
10
>99
>99
45
4
>99
>99
>99
81
59
>99
95
84
86
85
21
5
90
[a] Reaction conditions: N-acetylpiperidine (1.0 mmol), catalyst
(4 mol% Re), DME, 20 h. [b] Catalyst A: 2% Pd/10% Re/graphite,
catalyst B: 1% Pt/10% Re/graphite. [c] Determined by GC analysis.
[d] Loading of Re was 10 mol%. MS=molecular sieves.
Figure 1. TEM image of Pd/Re/graphite.
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Table 3: Representative examples of the substrate scope for catalytic hydrogenation with Pd/Re/graphite.[a]
Entry
Substrate
Conv.[b] [%]
Products
Selectivity [%][b] Entry
Substrate
Conv.[b] [%]
Products
Selectivity [%][b]
100
1
>99 (93)[c]
100
100
100
12
13
>99
2
3
>99 (95)[c]
>99
>99
>99
96
4
72
4
60
100
14
36
5
6
10
71
100
100
32
15
100
7
89
100
16
17
>99
>99
100
8
>99
100
63[f]
29[f]
100
9
>99 (88)[c]
9 (>99)[d]
100
10
100 (92)[c]
18
>99
11
21 (35)[e]
100
[a] Reaction conditions: substrate (1.0 mmol, 2% Pd/10% Re/graphite (4 mol% Re), DME (0.2m), 4 ꢁ MS, H2 (30 bar), 1608C, 20 h. [b] Determined
by GC, GC/MS, and/or 1H NMR analysis. [c] Values in parentheses are the yield of isolated product after precipitation as a hydrochloride salt.
[d] Values in parentheses are for reactions conducted at 2008C for 72 h. [e] 35% conversion was obtained when montmorillonite K-10 added. [f] Yield
of isolated product.
conversion dropped when the substituent on the amide
carbonyl was more sterically demanding, with N-pivaloylpi-
peridine giving only 10% conversion under the standard
conditions (Table 3, entry 5). Changes in the nitrogen sub-
stituents did not clearly affect the reactivity, as shown for
different caproic acid amides (Table 3, entries 6 and 7). The
reactivity trends were the same for both tertiary and
secondary amides.[18]
The effectiveness of the method on a 10 mmol scale was
demonstrated with N-acetylpiperidine and N-acetylpyrroli-
dine. In both cases the corresponding amines could be
isolated as hydrochloride salts with yields above 90%
(Table 3, entries 1 and 2).
To our delight, secondary and tertiary lactams were
readily hydrogenated with high selectivities for the desired
cyclic amines. (Table 3, entries 8 and 9). For e-caprolactam,
the reaction performed on a 10 mmol scale produced
quantitative conversion, and the corresponding hydrochloride
salt of the azepan was isolated in 88% yield.[18]
For very bulky carboxylic acid amides the conversion was
rather low in most cases, with N-tert-butyl-isobutyramide
giving only 9% conversion (Table 3, entry 10). At a temper-
ature of 1808C and with a longer reaction time, the conversion
increased to 55%, whereas at 2008C the bulky amide was
hydrogenated with full conversion and 92% yield. This
demonstrates that it is possible to reduce very unreactive
amides simply by increasing the temperature and reaction
time.
Unfortunately, the hydrogenation of primary amides was
problematic. In these cases, secondary amines were obtained
as the major products (Table 3, entry 11).
As expected, alkene and alkyne functions were rapidly
hydrogenated (Table 3, entries 12–15 and 17). Even a trisub-
stituted double bond does not withstand the active hydro-
genation catalyst and is readily converted into the corre-
sponding alkane (Table 3, entry 13). Also, aromatic rings were
hydrogenated prior to amide reduction (Table 3, entries 16
and 17). Various attempts were made to suppress this without
success. However, amides with ether substituents were
hydrogenated without problems (Table 3, entry 18).
We were also interested in the recyclability of the Pd/Re/
graphite catalyst, the heterogeneous nature of which makes it
easy to separate by simple filtration. After the reduction of
N-acetyl piperidine to N-ethyl piperidine, we filtered the
catalyst and directly submitted the residue to another hydro-
genation under the same reaction conditions. With this
procedure, we obtained 80% conversion from the second
run and 70% from the third run. Other recycling techniques,
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the addition of new substrate after the reaction, did not
improve the results.
In conclusion, we have developed the first general
catalytic hydrogenation of secondary and tertiary amides to
secondary and tertiary amines employing a highly reactive
bimetallic Pd/Re/graphite catalyst. This catalyst displays the
highest activity reported to date. The generality of this
method was demonstrated by the hydrogenation of 108
different amides. Depending on the steric hindrance of the
substrate, the reaction rate can be adjusted by varying the
temperature, thus allowing even very hindered substrates to
be hydrogenated in high yields. Simple filtration liberates the
desired amine without significant impurities and allows
reisolation of the catalyst, which could be recycled and used
in two subsequent runs. This makes this method an environ-
mentally benign, easy, and reliable tool for the preparation of
amines from amides.
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Experimental Section
General procedure for the hydrogenation of amides: A 30 mL
headspace vial containing a stir bar was charged with 2% Pd/
10% Re/graphite (74 mg, 4 mol% Re, 1.4 mol% Pd). The amide
(1 mmol) was dissolved in 1,2-dimethoxyethane (DME; 5 mL) and
added. The vial was closed with a septum and transferred under argon
atmosphere to a parallel autoclave block capable of performing ten
reactions in parallel. After purging with argon, the parallel autoclave
was pressurized with H2 (30 bar). The mixture was stirred for 20 h at
1608C. After cooling to room temperature, the pressure was released
and the reaction mixture was filtered. The conversion and yield was
determined from the clear filtrate by GC analysis by comparison with
representative samples.
Received: September 27, 2012
Published online: December 6, 2012
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Keywords: amides · amines · hydrogenation · nanoparticles ·
sustainable chemistry
.
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[18] See the Supporting Information for details.
[19] We also applied the exact conditions originally reported by Cole-
Hamilton et al.,[11] but we were unable to reproduce their results.
Cole-Hamilton et al. provided modified reaction conditions
which have subsequently been published: D. L. Dodds, J.
Coetzee, S. Brosinski, J. Klankermeyer, W. Leitner, D. J. Cole-
Hamilton, Chem. Commun., 2007, 3154 – 3156; amendment
published in 2011. Using these modified conditions, we obtained
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the corresponding amide.
[20] Pt/Re/graphite and Pd/Re/graphite were provided by BASF SE.
For catalyst preparation, see the Supporting Information and: H.
Urtel, M. Rçsch, A. Haunert, M. Schubert (BASF Aktienge-
sellschaft), WO-2005077871, 2005.
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