Synthesis of Primary Amines: First Homogeneously Catalyzed Reductive Amination with Ammonia

Article abstract of DOI:10.1021/ol0200605

(Matrix Presented) The synthesis of primary amines via reductive amination of the corresponding carbonyl compounds with aqueous ammonia is achieved for the first time with soluble transition metal complexes. Up to an 86% yield and a 97% selectivity for benzylamines were obtained in the case of various benzaldehydes by using a Rh-catalyst together with water-soluble phosphine and ammonium acetate. In the case of aliphatic aldehydes, a bimetallic catalyst based on Rh/Ir gave improved results.

Full text of DOI:10.1021/ol0200605

ORGANIC
LETTERS
2002
Vol. 4, No. 12
2055-2058
Synthesis of Primary Amines: First
Homogeneously Catalyzed Reductive
Amination with Ammonia
Thoralf Gross, Abdul Majeed Seayad, Moballigh Ahmad, and Matthias Beller*
Institut fu¨r Organische Katalyseforschung (IfOK) an der UniVersita¨t Rostock e.V.,
Buchbinderstrasse 5-6, D-18055 Rostock, Germany
matthias.beller@ifok.uni-rostock.de
Received March 19, 2002
ABSTRACT
The synthesis of primary amines via reductive amination of the corresponding carbonyl compounds with aqueous ammonia is achieved for
the first time with soluble transition metal complexes. Up to an 86% yield and a 97% selectivity for benzylamines were obtained in the case
of various benzaldehydes by using a Rh-catalyst together with water-soluble phosphine and ammonium acetate. In the case of aliphatic
aldehydes, a bimetallic catalyst based on Rh/Ir gave improved results.
Primary amines are of major importance in human life and
chemical industry. They are particularly useful as pharma-
ceutically active substances, dyes, and fine chemicals.
Various important methods for the synthesis of primary
amines include alkylation of organic halides with ammonia,
reductive amination of carbonyl compounds, hydrocyanation
of alkenes followed by reduction, hydroamination of olefins,
etc.1 Among them, the reductive amination of carbonyl
compounds constitutes one of the most convenient and
practical approaches. In general, the reductive amination of
carbonyl compounds is performed in the presence of
heterogeneous catalysts.2 The first elegant example of a
homogeneously catalyzed reductive amination using primary
and secondary amines was reported recently by Bo¨rner et
al.3 So far, no homogeneous catalytic reductive amination
has been described using ammonia. Such a reaction would
be of general interest for the synthesis of the industrially
most important primary amines. Unfortunately, the increased
nucleophilicity of the initially produced amine may lead to
the formation of a mixture of primary, secondary, and tertiary
amines, thereby making the control of the chemoselectivity
of the reaction difficult.
On the basis of our previous work on hydroaminomethy-
lation reactions of olefins,4 we envisioned that the use of
water-soluble hydrogenation catalysts in a biphasic medium5
might be a solution to this problem. This paper presents the
first procedure for the selective reductive amination of
aromatic and aliphatic carbonyl compounds to primary
amines using ammonia in the presence of water-soluble
transition metal complexes.6 The reaction of benzaldehyde
with ammonia served as a model reaction for studying the
influence of catalysts, ligands, cocatalysts, and critical
(1) For general references, see: (a) March, J. AdVanced Organic
Chemistry, 4th ed.; Wiley: New York, 1992; p 768 and references therein.
(b) Collman, J. P.; Trost, B. M.; Veroeven, T. R. In ComprehensiVe
Organometallic Chemistry, Wilkinson, G., Stone, F. G. A., Eds.; Pergamon
Press: Oxford, 1982; Vol. 8, p 892 and references therein. (c) Mu¨ller, T.
E.; Beller, M. Chem. ReV. 1998, 98, 675. (d) Gibson, M. S. In The Chemistry
of Amino Group; Patai, S., Ed.; Interscience: New York, 1968; p 61.
(2) (a) Rylander, P. N. Catalytic Hydrogenation in Organic Synthesis,
Academic Press: New York, 1979; p 165. (b) Rylander, P. N. Hydrogena-
tion oVer Platinum Metals; Academic Press: New York, 1967; p 292. (c)
Heinen, A. W.; Peters, J. A.; van Bekkum H. Eur. J. Org. Chem. 2000,
2501.
(3) Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Bo¨rner, A. Chem.
Commun. 2000, 1867.
(4) (a) Zimmermann, B.; Herwig, J.; Beller, M. Angew. Chem. 1999,
111, 2515; Angew. Chem., Int. Ed. 1999, 38, 2372. (b) Zimmermann, B.;
Herwig, J.; Beller, M. In Catalysis of Organic Reactions; Herkes, F., Ed.;
Marcel Dekker: 2000. (c) Review: Eilbracht, P.; Ba¨rfacker, L.; Buss, C.;
Hollmann, C.; Kitsos-Rzychon, B. E.; Kranemann, C. L.; Rische, T.;
Roggenbuck, R.; Schmidt, A. Chem. ReV. 1999, 99, 3329.
(5) Tafesh, A.; Beller, M. Tetrahedron Lett. 1995, 36, 9305.
(6) We have been informed that, parallel to our work, this goal has been
achieved by R. Kadyrov (Degussa AG). Kadyrov, R.; Riermeier, T. H.,
manuscript in preparation.
10.1021/ol0200605 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/22/2002

Table 1. Reductive Amination of Benzaldehydea
yield, %b
primary
selectivity:
primary amine
vs alcohol, %
TPPTS,
NH4OAc,
mol %
temperature,
°C
organic
solvent
entry
catalyst, mol %
[Ir(cod)Cl]2, 0.1c
[Ir(cod)Cl]2, 0.1
[Ir(cod)Cl]2,0.1/[Rh(cod)Cl]2,
0.025
mol %
amine
alcohol
1
2
3
5.2
2.6
5.2
0
5
5
135
135
135
MTBE
MTBE
MTBE
6
42
67
66
44
14
8
49
83
4
5
6
7
8
[Rh(cod)Cl]2, 0.025
[Rh(cod)Cl]2, 0.1
[Rh(cod)Cl]2, 0.025
[Rh(cod)Cl]2, 0.025
[Rh(cod)Cl]2, 0.05
[Rh(cod)Cl]2, 0.05
[Rh(cod)Cl]2, 0.05
[Rh(cod)Cl]2, 0.05
[Rh(cod)Cl]2, 0.05
[Rh (cod )Cl]2, 0.05
[Rh(cod)Cl]2, 0.05
2.6
2.6
5.2
2.6
2.6
2.6
2.6
2.6
2.6
1.3
2.6
5
5
50
5
5
5
5
5
5d
50
0
135
135
115
95
135
135
135
135
135
135
135
MTBE
MTBE
MTBE
MTBE
MTBE
toluene
methanol
THF
74
76
64
48
80
73
72
86
85
86
19
10
12
4
8
11
9
4
8
8
3
88
86
94
86
88
89
95
90
91
97
37
9
11
11
12
13
14
THF
THF
THF
33
a Reaction conditions: benzaldehyde (0.034 mol), 25% aqueous ammonia (20 mL), NH3/benzaldehyde (8:1), org/aq solution (1:1), H2 (65 bar), time (2
h). b Yields are determined by GC analysis with bis(methoxyethyl) ether as an internal standard. c Time ) 10 h. d Octanoic acid was used instead of NH4OAc.
reaction parameters (solvent, temperature, concentration of
starting materials) (Scheme 1 and Table 1).
Cl]2 and [Rh(cod)Cl]2, which gave superior results in
domino-hydroformylation-reductive amination reactions,
benzylamine is obtained in 67% yield. Interestingly, the use
of [Rh(cod)Cl]2 alone as a precatalyst under similar reaction
conditions facilitates smooth reductive amination10 with
complete conversion improving significantly the selectivity
for benzylamine (76%, Table 1, entries 4-5). This result is
in contrast to our previous hydroaminomethylation reactions,
in which the in situ reductive amination was realized only
in the presence of the bimetallic catalyst system consisting
of Rh and Ir complexes.
Scheme 1
On the basis of the successful demonstration of iridium
as a hydrogenation catalyst for the reduction of isolated
imines,7 we initially explored the applicability of iridium
complexes as precatalysts for the reductive amination of
benzaldehyde with ammonia for the synthesis of primary
amines. Unfortunately, low selectivity (8%) for the primary
amine is observed with [Ir(cod)Cl]2 as a catalyst precursor
in the presence of TPPTS8 (TPPTS ) tris sodium salt of
meta trisulfonated triphenylphosphine) as the ligand in a
biphasic medium comprised of MTBE (methyl tert-butyl
ether) and 25% aqueous ammonia at 135 °C and 65 bar of
hydrogen (Table 1, entry 1). Hydrogenation of the aldehyde
to the alcohol is found to be the major reaction. Although
the addition of acids,9 e.g., acetic acid, octanoic acid, or
ammonium acetate, significantly enhances the formation of
benzylamine (42% yield), formation of the alcohol is found
to occur to a considerable degree (44% yield) as shown in
Table 1 (entry 2). In the presence of a mixture of [Ir(cod)-
Next, the effect of cocatalysts and reaction parameters on
the selective formation of benzylamine using the Rh/TPPTS
catalyst system was examined (Table 1, entries 6-14). In
general, chemoselectivities in the range of 85-90% are
observed for benzylamine using the biphasic system consist-
ing of aqueous ammonia and MTBE at 135 °C and 65 bar
of hydrogen (Table 1, entries 3-5). In addition to benzyl
alcohol, a very small amount (2-3%) of dibenzylamine is
also observed as a side product. Apart from these, no other
side products are detected.
(10) General Procedure. In a typical experiment (Table 1, entry 12),
benzaldehyde (34 mmol), [Rh(cod)Cl]2 (0.05 mol %), TPPTS (1.3 mol %),
ammonium acetate (50 mol %), 25% aqueous NH3 (20 mL), and freshly
distilled THF (20 mL) were charged under an argon atmosphere into a 160
mL stainless steel autoclave equipped with a magnetic stirrer and temper-
ature-controlled heating. The autoclave was closed, flushed once with
hydrogen gas, and pressurized to 65 bar of H2, and the reaction was carried
out for 2 h at a temperature of 135 °C (total pressure at 135 °C was ca. 100
bar). After the reaction, the autoclave was cooled to rt and slowly
depressurized. The organic layer was collected, and the aqueous phase was
treated with NaOH (0.5 g) and extracted with THF (2 × 10 mL). Bis-
(methoxyethyl) ether (5 mL) was added to the combined organic phases,
and the mixture was analyzed by gas chromatography. All aldehydes as
well as synthesized amines and corresponding alcohols are commercially
available. Therefore, benzaldehyde and products were identified by
comparison with authentic samples by GC (column: cross-linked 5% PH
ME Siloxane, 30 m × 0.25 mm × 0.25 µm). In addition, all products were
confirmed by GC-MS.
(7) (a) Togni, A.; Breutel, C.; Schnyder, A.; Spindler F.; Landert, H.;
Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062. (b) Blaser, H.-U.; Buser, H.
P.; Coers, K.; Hanreich, R.; Jalett, H.-P.; Jelsch, E.; Pugin, B.; Schneider,
H.-D.; Spindler F.; Wegmann, A. Chimia 1999, 53, 275. (c) Blaser, H.-U.;
Buser, H. P.; Jalett, H.-P.; Pugin, B.; Spindler F. Synlett 1999, 867.
(8) Herrmann, W. A.; Kohlpaintner, C. W. Angew. Chem. 1993, 105,
1588; Angew. Chem., Int. Ed. Engl. 1993, 32, 1524.
(9) Satory, Y.; Makoto, H.; Yuzuru, T. Nippon Kagaku Kaishi 1998, 8,
525.
2056
Org. Lett., Vol. 4, No. 12, 2002

The reaction also proceeds below 100 °C though the best
results are obtained at 135 °C. At higher temperatures, ligand
stability is considerably reduced, thereby making the catalyst
recycle questionable. Increasing the amount of acid cocatalyst
to 50 mol % almost completely suppressed the reduction of
the carbonyl group, thereby achieving a selectivity of 97%
for benzylamine (Table 1, entry 13). Similar to the Ir catalyst
system, the Rh catalyst also leads to low yields and selectivity
for benzylamine without any acid cocatalyst (Table 1, entry
14). Typically, the reactions were performed in the presence
of 0.05 mol % Rh catalyst, thereby leading to catalyst
turnover numbers (TON) of up to 1720. Nevertheless, further
decrease in the amount of catalyst seems to be feasible as
shown by Table 1, entry 4.
Table 2. Reductive Amination of Substituted Benzaldehydesa
It is important in a biphasic reaction to check whether the
catalyst is reusable after the reaction. For this purpose, the
catalyst phase is recycled, after phase separation, in a typical
experiment of benzaldehyde (Table 1, entry 13). The
comparable yields of benzylamine observed in both runs
suggest negligible catalyst deactivation.
Further, the reductive amination of different substituted
aromatic aldehydes (Scheme 2) was studied. In all cases,
Scheme 2
a Reaction conditions: substrate (0.034 mol), [Rh(cod)Cl]2 (0.05 mol
%), TPPTS (1.3 mol %), NH4OAc (50 mol %), THF (20 mL), 25% aqueous
ammonia (20 mL), NH3/substrate (8:1), org/aq (1:1), H2 (65 bar) temperature
(135 °C), time (2 h).
the corresponding primary amines are observed as main
products with high selectivities. Only small amounts of the
corresponding benzylic alcohols are produced as side prod-
ucts. In general, benzylic aldehydes with electron-donating
groups (CH3, CH3O) give good yields of primary amines
(65-85%), while those with electron-withdrawing groups
(Cl, F, CF3) give lower yields (33-78%).
Apart from the reductive amination of aromatic aldehydes
with ammonia, we are also interested in similar reactions of
other carbonyl compounds. Some preliminary studies dem-
onstrate the feasibility of our method for the synthesis of
aliphatic primary amines from the corresponding aldehydes
with ammonia as shown in Scheme 3. The reaction of
hexanal with aqueous ammonia under standard conditions
of benzaldehyde resulted in up to 33% yield of hexylamine.
The yield of hexylamine is further improved to 45% by using
a temperature of 145 °C and toluene as the solvent.11 Under
similar conditions, 47% yield of pentylamine is obtained by
using n-pentanal as the substrate. In the case of octanal,
octylamine is formed in 47% yield by using the bimetallic
Rh/Ir catalyst. In all cases, the formation of alcohol by the
reduction of aldehyde is found to be negligible under these
conditions. However, secondary amine as well as aldol
condensation products are formed in considerable amounts.
Nevertheless, these studies show that a homogeneously
catalyzed reductive amination of aliphatic aldehydes with
ammonia is possible. Further studies are in progress to
improve the yield of primary amines from aliphatic alde-
hydes.
In summary, we have shown for the first time that
reductive amination of carbonyl compounds with ammonia
can be performed in the presence of soluble transition metal
Scheme 3
(11) In a typical experiment, aldehyde (16 mmol), [Rh(cod)Cl]2 (0.05
mol %), TPPTS (2.6 mol %), ammonium acetate (50 mol %), 25% aqueous
NH3 (20 mL), and freshly distilled toluene (10 mL) were charged under an
argon atmosphere into a 100 mL stainless steel Parr autoclave equipped
with an overhead stirrer and temperature-controlled heating, and the reaction
was carried out at 145 °C and 65 bar of hydrogen for 10 h. After the reaction,
the organic layer was collected; the aqueous layer was washed twice (5
mL) with toluene, and the combined organic layers were analyzed by GC
(column: cross-linked 5% PH ME Siloxane, 30 m × 0.25 mm × 0.25 µm).
The products were also confirmed by GC-MS.
Org. Lett., Vol. 4, No. 12, 2002
2057

complex catalysts. Up to 97% selectivity for benzylamine
is achieved using water-soluble Rh catalysts. High selectivi-
ties are also obtained in the case of substituted benzalde-
hydes. The procedure is environmentally friendly (i.e., water
is the only byproduct), and the starting materials are both
inexpensive and readily available. Remarkable are the low
quantities of catalyst required (0.025-0.05 mol %) for
successful reactions.
Acknowledgment. A.S. thanks the Alexander-von-Hum-
boldt-Stiftung for an AvH-grant. This work has been
supported by the State of Mecklenburg-Western Pommerania,
the “Fonds der Chemischen Industrie”, and the “Bundesmin-
isterium fu¨r Bildung und Forschung” (BMBF).
OL0200605
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Org. Lett., Vol. 4, No. 12, 2002