On the reductive amination of aldehydes and ketones catalyzed by homogeneous Rh(I) complexes

Article abstract of DOI:10.1039/b005777k

The homogeneously catalyzed reductive amination of aldehydes and ketones under smooth conditions is reported, showing for the first time, that Rh(I) catalysts based on chelating diphosphines and diphosphinites can be advantageously employed for this reaction, even for the production of chiral amino acid derivatives.

Full text of DOI:10.1039/b005777k

On the reductive amination of aldehydes and ketones catalyzed by
homogeneous Rh( ) complexes
I
Vitali I. Tararov,a,b Renat Kadyrov,a,c Thomas H. Riermeierc and Armin Börner*a
a Institut für Organische Katalyseforschung an der Universität Rostock e.V., Buchbinderstr. 5/6, D-18055 Rostock,
Germany. E-mail: armin.boerner@ifok.uni-rostock.de
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova 28, 117813
Moscow, Russian Federation
c
Aventis Research & Technologies GmbH Industriepark Höchst, G 830, D-65926 Frankfurt/Main, Germany
Received (in Cambridge, UK) 18th July 2000, Accepted 15th August 2000
First published as an Advance Article on the web 15th September 2000
The homogeneously catalyzed reductive amination of alde-
hydes and ketones under smooth conditions is reported,
showing for the first time, that Rh( ) catalysts based on
I
chelating diphosphines and diphosphinites can be ad-
vantageously employed for this reaction, even for the
production of chiral amino acid derivatives.
Scheme 1 Reductive amination of aldehydes and ketones with Rh(I)
catalysts.
One-stage (or direct) reductive amination of aldehydes and
ketones with amines affording higher alkylated amines is an
interesting target in modern organic chemistry with great
synthetic potential for application in academia and industry.
Hitherto several chemical reducing agents, in particular borohy-
drides, have been shown to be valuable for this reaction giving
rise to the alkylated amines in good yield.1 However, from the
ecological point of view and taking into account the demand for
atom economy, more promising is the use of molecular
hydrogen as a reducing agent. Indeed it was shown that
reductive amination with hydrogen can be mediated by
heterogeneous platinum, palladium, nickel or ruthenium metal
catalysts.2 Several amines have been prepared by this method-
ology even on an industrial scale.
starting carbonyl compound and selectivity in terms of
produced amine/alcohol ratio in the final reaction mixtures were
determined by 1H NMR spectroscopy. As shown, cationic
precatalysts 1 and 2 are efficient for reductive amination. It is of
note that in all trials the desired amine and the corresponding
alcohol were exclusively formed. Both complexes were more
effective and selective than Wilkinson’s complex Rh(PPh3)3Cl
(run 1, cf. runs 3 and 6; run 9, cf. runs 11 and 14). Also the
hydroformylation precatalyst Rh(PPh3)2(CO)Cl (run 10), fre-
quently applied in hydroaminomethylation,8 is inferior. Similar
behavior was observed for the in situ prepared neutral complex
[Rh(dppb)Cl]2 (run 2). Although the conversion measured after
20 h was similar to that for precatalyst 1 the hydrogen uptake
proceeded significantly more slowly.
Interestingly, only a few preliminary studies on the homoge-
neous version of this reaction can be found in the literature in
spite of the tremendous progress which homogeneous catalysis
has seen over the last decades.3 For example, typical hydro-
formylation catalysts such as rhodium and cobalt carbonyls
were tested, but were found to require rather severe reaction
conditions (100–300 atm H2, 100–200 °C).4 The selectivity and
efficiency of some glyoxyme Rh and Co complexes were
studied in the reductive amination of cyclohexanone with
ammonia.5 A related cyanocobalt catalyst afforded only
moderate yields of product amines.6 More noteworthy is the
unique reaction of a sterically hindered aniline with methox-
yacetone in the presence of a chiral Ir–diphosphine catalyst.7
Tandem hydroformylation–amination reactions (hydroamino-
methylation) also contain a reductive amination step, however
the range of products is limited owing to the use of olefins as
starting material.8
Increasing concentrations of the amine had no pronounced
effect on the selectivity, this applying for PhCHO (runs 3 and 4)
as well as for PhCHMeCHO (runs 11 and 12) as substrate when
precatalyst 1 was used. Application of precatalyst 2 in the
Table 1 Reductive amination of aldehydes with piperidine as the aminea
Ratio
Molar ratio Conv.
produced
piperidine/
aldehyde
aldehyde amine/
Run
Catalyst
(%)b
alcohol
PhCHO
1
2
3
4
5
6
7
8
Rh(PPh3)3Cl
[Rh(dppb)Cl]2
1
1
1c
2
2
2c
1+1
1+1
1+1
2+1
1+1
1+1
2+1
1+1
94
> 99
> 99
> 99
> 99
> 99
> 99
> 99
0.1
1.0
1.5
1.5
1.3
1.8
1.2
1.4
Recently, we reported that cationic rhodium( ) complexes
I
[Rh(dppb)(cod)]BF4 1 [dppb = 1,4-bis(diphenylphosphino)bu-
tane, cod = cycloocta-1,5-diene] and [Rh(dpoe)(cod)]BF4 2
[dpoe = 1,2-bis(diphenylphosphinito)ethane] are highly effi-
cient precatalysts in the hydrogenation of imines9 and enam-
ines10 under mild conditions (room temperature, 1–50 bar H2
pressure). Usually these substrates are considered to be
intermediates in some direct reductive amination reactions.11
Herein we demonstrate that complexes 1 and 2 are also useful
for reductive amination (Scheme 1). For this reaction, besides
the activity of the catalyst the selectivity for the formation of the
desired amine is important. The production of the relevant
alcohol by the competitive reduction of the carbonyl compound
should be minimized.
PhCHMeCHO
9
Rh(PPh3)3Cl
Rh(PPh3)2(CO)Cl 1+1
1
1+1
70
4
0.4
n.d.
1.7
1.9
4.8
6.1
3.2
10
11
12
13
14
15
1+1
2+1
1+1
1+1
1+1
> 99
> 99
> 99
> 99
> 99
1
1c
2
2c
a Reaction conditions: 5 mmol aldehyde, 0.2 mol% precatalyst, 10 ml
MeOH, 50 bar initial pressure of H2, room temp. b Measured after 20 h.
c TsOH·xH2O added (TsOH·xH2O/Rh = 20).
Our results obtained with selected aldehydes and piperidine
as the amine are listed in Table 1. Conversion with respect to the
DOI: 10.1039/b005777k
Chem. Commun., 2000, 1867–1868
This journal is © The Royal Society of Chemistry 2000
1867

reductive amination of benzaldehyde led to a slight decrease in
selectivity (runs 6 and 7). The absence of a significant
dependence of the selectivity on the amine concentration is
noteworthy. Obviously, the rate limiting step in the overall
process is the reduction of the corresponding intermediates but
not their formation. This assumption is also confirmed by the
fact that preliminary heating of a mixture of PhCHO and
piperidine in methanol had no effect on the selectivity.
It is interesting that both precatalysts exhibited approx-
imately the same selectivity with PhCHO as carbonyl compo-
nent (runs 3 and 6) while the selectivity observed in the
reductive amination of PhCHMeCHO with 1 as a precatalyst
was lower than with 2 (runs 11 and 14).
The effect of TsOH·xH2O as additive is less clear. Thus, this
additive slightly diminished the selectivity of precatalysts 1 and
2 in the reaction of benzaldehyde with piperidine (runs 3/5, 6/8).
However, in the reaction with PhCHMeCHO the effect of the
additive was dependent upon the precatalyst used (runs 11/13,
14/15). In general, in the presence of TsOH·xH2O, the rate of the
hydrogen uptake was lowered.
We next investigated the reductive amination of aldehydes
with a two-fold excess of piperidine as a function of the
substitution pattern of the aldehyde using precatalyst 1 (Table
2). In the series of substituted benzaldehydes (runs 1–5) the
beneficial effect of electron-withdrawing groups upon the
selectivity is evident. The presence of a methyl group in an
ortho position exhibited no steric effect on the selectivity (run
3). Unfortunately, NO2- and CN-groups did not survive under
the reaction conditions. An alkyl substituent a to the carbonyl
group strongly affected the selectivity of amination (runs 6–8).
The highest selectivity was observed with n-octanal (run 8).
Scheme 2 Preparation of racemic and enantiomerically enriched
N-benzylphenylalanine.
piperidine but is sterically more hindered, only traces of the
desired amine were formed (run 5).
In contrast to the reductive amination of PhCHO with
piperidine, the reaction with PhCH2NH2 using precatalyst 1 was
slow. After 20 h only 39% conversion was observed. However
the high observed amine/alcohol ratio of 11 is remarkable.
Unexpectedly, reductive alkylation with a-keto acid deriva-
tives afforded good yields of the desired amino acids. Thus, the
industrially relevant reductive amination of PhCH2COCOH
with benzyl amine gave N-benzylphenylalanine in a yield of
71% (Scheme 2). The product precipitated from the reaction
mixture and the analytically pure compound could simply be
isolated by filtration and subsequent washing with ethanol. In a
preliminary investigation the reaction was also run with a
catalyst bearing the chiral diphosphine 3.12 (R)-N-Benzylphe-
nylalanine was obtained in 59% isolated yield and 38% ee.
In conclusion, Rh( ) complexes represent efficient homoge-
I
Table 2 Comparison of the selectivity and the rate of amination of various
aldehydes with piperidine using [Rh(dppb)(cod)]BF4 1 as a precatalysta
neous catalysts for reductive amination of aldehydes and
ketones. The successful employment of chelating phosphorus
ligands for this reaction opens up a broad field of modifications,
whereby asymmetric reductive amination is one of the most
challenging goals.
Financial support from Aventis Research & Technologies
GmbH (Frankfurt, Germany) and the Fonds der Chemischen
Industrie is gratefully acknowledged.
Ratio produced
Run
Aldehyde
amine/alcoholb
1
2
3
4
5
6
7
8
4-HOC6H4CHO
4-MeOC6H4CHO
2-MeC6H4CHO
PhCHO
4-ClC6H4CHO
PhCHMeCHO
EtCHMeCHO
n-C7H15CHO
0.8
0.9
1.0
1.5
1.9
1.9
2.4
12.0
Notes and references
1 A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and
R. D. Shah, J. Org. Chem., 1996, 61, 3849 and references therein; D.
Dubé and A. A. Scholt, Tetrahedron Lett., 1999, 40, 2295; I. Saxena, R.
Borah and J. C. Sharma, J. Chem. Soc., Perkin Trans. 1, 2000, 503.
2 P. N. Rylander, Catalytic Hydrogenation in Organic Synthesis,
Academic Press, New York, 1979, p. 165; P. N. Rylander, Catalytic
Hydrogenation over Platinum Metals, Academic Press, New York,
1967, p. 292.
3 Applied Homogenous Catalysis with Organometallic Compounds, ed.
B. Cornils and W. A. Herrmann, VCH, Weinheim, 1996, vol. 1 and 2;
Transition Metals for Organic Synthesis, ed. M. Beller and C. Bolm,
Wiley-VCH, Weinheim, 1998, vol. 1 and 2.
4 L. Markó and J. Bakos, J. Organomet. Chem., 1974, 81, 411.
5 M. V. Klyuev and M. L. Khidekel, Transition Met. Chem., 1980, 5,
134.
6 M. Murakami and J.-W. Kang, Bull. Chem. Soc. Jpn., 1963, 36, 763.
7 H.-U. Blaser, H.-P. Buser, H.-P. Jalett, B. Pugin and F. Spindler, Synlett,
1999, 867.
a For reaction conditions see Table 1. b After 20 h full conversion was
observed in all reactions.
The results of reductive amination of PhCHO with various
amines are summarized in Table 3. In general, good correlation
between the selectivity of the reaction and the basicity of the
amine was observed (runs 1–4). Apparently, steric effects can
exert a strong influence. Thus, with 2-methylpiperidine as
substrate, which has approximately the same basicity as
Table 3 Comparison of reductive amination of PhCHO with various amines
employing [Rh(dppb)(cod)]BF4 1 as a precatalysta
Ratio produced
Run
Amine
pKa (amine)
amine/alcoholb
8 P. Eilbracht, L. Bärfacker, C. Buss, C. Hollmann, B. E. Kitsos-Rzychon,
C. L. Kranemann, T. Rische and R. Roggenbuck and A. Schmidt, Chem.
Rev., 1999, 99, 3329.
9 V. I. Tararov, R. Kadyrov, T. H. Riermeier, J. Holz and A. Börner,
Tetrahedron: Asymmetry, 1999, 10, 4009.
1
2
3
4
5
Pyrrolidine
Piperidine
Me2NH
11.27
11.02
10.73
10.49
2.30
1.50
0.43
0.07
< 0.05
Et2NH
10 V. I. Tararov, R. Kadyrov, T. H. Riermeier, J. Holz and A. Börner,
Tetrahedron Lett., 2000, 41, 2351.
2-Methylpiperidine 10.99
11 W. S. Emerson, Org. React., 1948, 4, 174; K. A. Schellenberg, J. Org.
Chem., 1963, 28, 3259.
12 U. Berens, D. Leckel and S. C. Oepen, J. Org. Chem., 1995, 60,
8294.
a Reaction conditions: 5 mmol aldehyde, 10 mmol amine, for other
conditions see Table 1. b After 20 h full conversion was observed in all
reactions.
1868
Chem. Commun., 2000, 1867–1868