Ruthenium clay catalyzed reduction of α-iminoesters and α-iminoketones, and the reductive amination of α-ketoesters

Article abstract of DOI:10.1016/S0022-328X(99)00614-2

The reduction of α-iminoesters and α-iminoketones to the corresponding amino compounds was accomplished using ruthenium clay as the catalyst, at 75-100°C and 600-900 psi H₂. The same catalyst proved efficient for the reductive amination of α-ketoesters (100°C, 600 psi H₂). Diastereomeric excesses of up to 78% were obtained in the reductive amination reaction.

Full text of DOI:10.1016/S0022-328X(99)00614-2

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Journal of Organometallic Chemistry 593–594 (2000) 454–457
Ruthenium clay catalyzed reduction of a-iminoesters and
a-iminoketones, and the reductive amination of a-ketoesters
Raluca Aldea, Howard Alper *
Department of Chemistry, Uni6ersity of Ottawa, 10 Marie Curie, Ottawa, Ont., Canada K1N 6N5
Received 9 August 1999; accepted 4 October 1999
Dedicated to Professor Fausto Calderazzo, a wonderful person who has made outstanding contributions to science.
Abstract
The reduction of a-iminoesters and a-iminoketones to the corresponding amino compounds was accomplished using ruthenium
clay as the catalyst, at 75–100°C and 600–900 psi H2. The same catalyst proved efficient for the reductive amination of
a-ketoesters (100°C, 600 psi H2). Diastereomeric excesses of up to 78% were obtained in the reductive amination reaction. © 2000
Elsevier Science S.A. All rights reserved.
Keywords: Ruthenium; Iminoesters; Iminoketones; Ketoesters; Reductive amination
The catalytic hydrogenation of imines to amines has
attracted much interest in recent years, especially in
terms of diastereoselective and enantioselective reduc-
tion [1–6]. Complexes of transition metals (Ti, Ir, Rh,
Ru) have been used as catalyst precursors under homo-
geneous conditions [7–10]. Ruthenium complexes were
developed for the reduction of imines by hydrogen
transfer. Ba¨ckvall et al. demonstrated that imines are
reduced by hydrogen transfer in propan-2-ol, in the
presence of catalytic amounts of [RuCl2(PPh3)3] and a
base (K2CO3) [11]. [Ru3(CO)12] also proved active for
this process[8]. Significant progress was made by Noy-
ori’s group [12] in demonstrating that a ruthenium
based complex, in the presence of suitable chiral 1,2-di-
amines, efficiently catalyzes the asymmetric reduction
of imines with a formic acid–triethylamine mixture.
The number of heterogeneous systems reported for the
reduction of the imine group is less than those for the
corresponding homogeneous catalytic systems. Usually
palladium on carbon or Raney nickel is used under
heterogeneous conditions [13]. Recently, ruthenium clay
[14] (ruthenium anchored on Fluka K10 montmoril-
lonite through reaction of RuCl3·H2O with phosphi-
nated montmorillonite) was found to be of value for the
hydrogenation of unsaturated esters, epoxides, sulfones
and phosphonates [14]. We reasoned that Ru clay
should be capable of reducing the a-imine unit of
a-iminoesters and a-iminoketones. We now report the
results of this investigations and, as well, the reductive
amination of a-ketoesters. Several a-iminoesters were
prepared by the condensation reaction of an a-ketoester
with different amines [15,16]. The hydrogenation reac-
tions were carried out at 600 psi H2 and 75–80°C using
a 200/1 ratio of substrate/Ru (Eq. (1)).
(1)
The reactions are clean, and the only product formed
is the a-aminoester. For the a-iminoesters which are
derivatives of aniline, the conversion is almost complete
after 41 h (Table 1, entries 1, 2). In the case of the
N-butyl derivative, after the same reaction time, the
conversion to aminoester is 59% (Table 1, entry 3). The
N-phenyl iminoderivative of ethyl 3-methyl-2-oxo-bu-
tyrate was also considered as a possible starting mate-
rial. Hydrogenation of the a-iminoester 1 resulted in
incomplete conversion of the substrate after 64 h and
the reaction mixture contained the aminoalcohol to-
gether with the enamine 2.
* Corresponding author. Tel.: +1-613-564-6793.
E-mail address: halper@science.uottawa.ca (H. Alper)
0022-328X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00614-2

R. Aldea, H. Alper / Journal of Organometallic Chemistry 593–594 (2000) 454–457
455
Table 2
The tautomerization of the imine 1 to enamine 2 prob-
Reductive amination of a-ketoesters in the presence of Ru claya
ably takes place under the reaction conditions and
reduction of the tetrasubstituted double bond is more
difficult to accomplish with the present catalytic system.
This fact is in agreement with our previous observa-
tions that a fully substituted alkene was not hydro-
genated using the Ru clay [14].
The a-ketoimines used in the hydrogenation reac-
tions were synthesized by direct condensation between
benzil and aniline or an aniline derivative using the
conditions described by Knoevenagel [17]. The main
difference in reactivity of a-ketoimines in comparison
with a-iminoesters is that more severe conditions are
necessary: increase of pressure to 900 psi H2 and an
increase of temperature to 100°C. The reaction of the
aniline derivative (Table 1, entry 4) afforded the corre-
sponding a-aminoketone as the only product in 95%
yield. The reaction of the p-tolyl derivative gave com-
plete conversion of the starting material (42 h) but
diastereomeric a-aminoalcohols (40%) are formed in
addition to the aminoketone. The yield of the a-
aminoketone was only 60%.
Table 1
Hydrogenation of a-iminoesters and a-iminoketones catalyzed by Ru
clay a,b
a Reaction conditions: 1 mmol substrate; 1.1 mmol amine; 0.005
mmol Ru; 0.6 g molecular sieves; 600 psi H2; 100°C; 24 h.
The good activity of Ru clay for the reduction of the
imine bond of a-iminoesters suggested that direct for-
mation of the a-aminoesters without isolation of the
imine derivative may be possible. Reductive amination
has previously been studied using heterogeneous cata-
lytic systems based on palladium and nickel. The pro-
cess is envisioned to proceed via the formation of an
iminium ion which is then rapidly reduced to the amine
[2] (Eq. (2)).
(2)
The possibility that ruthenium clay catalyzes this pro-
cess was first investigated using achiral amines. The
reaction of ethyl 2-oxo-4-phenylbutyrate with n-buty-
lamine at 600 psi H2 and 100°C, in the presence of
ruthenium clay, gives the a-aminoester in 65% yield
(Table 2, entry 1). The reaction was carried out in the
presence of molecular sieves as drying agents. No hy-
drogenation product is formed if the reaction proceeds
only in the presence of molecular sieves, without Ru
clay. The conversion of the a-ketoester is complete. The
reaction mixture also contains the excess of the amine
a Reaction conditions: 1 mmol substrate; 0.005 mmol Ru; 8 ml dry
benzene.
b Diastereomeric a-aminoalcohols were also formed.

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R. Aldea, H. Alper / Journal of Organometallic Chemistry 593–594 (2000) 454–457
(0.1 M excess), small amounts of a-hydroxyester and
traces of another product which was not identified. For
substrates in which the a-carbonyl moiety is bound
directly to the phenyl ring a competitive process-reduc-
tion of the keto unit-occurs more quickly. Methyl man-
delate is formed in 72% yield, while the aminoester is
the minor product (Table 2, entry 2). In the reaction of
ketopantolactone with n-butylamine, the amino deriva-
tive of pantolactone was obtained in 51% isolated yield
as the major product of the reaction (Table 2, entry 3).
No ketopantolactone was recovered from the reaction
mixture. If ketopantolactone is reacting with an aro-
matic amine (e.g. aniline), the products obtained in-
clude that resulting from a simultaneous reduction of
the phenyl ring (Eq. (3)).
hydrogenation of Schiff bases prepared from benzyl
esters of pyruvic acid and amino acid esters [18,19].
It can be concluded that the ruthenium based cata-
lytic system represents a new alternative for the reduc-
tion of iminoesters and iminoketones, even if it requires
more severe reaction conditions than the Pd based
system. The new catalytic system is, to our knowledge,
the first which uses ruthenium on clays for the reductive
amination process. The results obtained have similar,
and in several cases, higher values in terms of yield and
diastereomeric excess compared to previously reported
systems (palladium or nickel) for reductive amination.
1. Experimental
1.1. General procedure for the Ru clay catalyzed
hydrogenation of h-iminoesters and h-iminoketones
A mixture of the substrate (1 mmol) and ruthenium
clay (0.005 mmol Ru) in dry benzene (8 ml) was placed
in a 45 ml autoclave equipped with a glass liner and a
magnetic stirrer. The autoclave was purged three times
with hydrogen and then pressurized to the desired level
(600–900 psi H2). The reactor was placed in an oil bath
and maintained at constant temperature (75 or 100°C)
for 40–44 h. The autoclave was cooled to room temper-
ature (r.t.), the excess hydrogen gas was released, and
the reaction mixture was filtered through Celite. The
filtrate was concentrated by rotary evaporation. Purifi-
cation of the products was effected by silica gel column
chromatography using different ratios of hexane and
ethyl acetate as eluant.
(3)
The presence of N-cyclohexylamine in the mixture sug-
gests that the hydrogenation of the aromatic ring may
occur before the reaction with ketopantolactone. No
hydrogenation occurs in the aromatic moiety once the
imine bond is formed, as shown by the reduction of the
N-phenyl-imino-derivative of ketopantolactone.
Reductive aminations are often utilized in organic
synthesis in conjunction with the use of chiral amines.
In reactions carried out using Pd/C, the diastereomeric
excess was postulated to arise from interaction of the
Schiff base with the catalyst-adsorption onto the cata-
lyst from the less bulky face of the molecule [18]. In
order to examine if any diastereoselectivity would be
obtained using Ru clay, methyl pyruvate was reacted
with (R)-(+)-a-methyl benzylamine and (R)-(+)-1-(1-
naphthyl) ethylamine. We were concerned that the use
of chiral aromatic amines could be problematic as
reduction of the aromatic ring may occur giving a
complex mixture of products. Contrary to the result
obtained with ketopantolactone and aniline, the reac-
tion between methyl pyruvate and the chiral amines
proceeded with very good selectivity affording N-ary-
laminoesters as the major product of the reactions.
The reaction of methyl pyruvate with either a phenyl
1.2. General procedure for the reducti6e amination of
h-ketoesters in the presence of Ru clay
A mixture of the a-ketoester (1 mmol), amine (1.1
mmol), ruthenium clay (0.005 mmol Ru) and molecular
,
sieves (4 A, 0.6 g), in dry benzene (8 ml), was placed in
a 45 ml autoclave equipped with a glass liner and a
magnetic stirrer. The autoclave was purged three times
with hydrogen and then pressurized to 600 psi H2. The
reactor was placed in an oil bath and maintained at
100°C. The decrease of the hydrogen pressure was
observed on the gauge. The autoclave was cooled to
r.t., excess hydrogen gas was released and the reaction
mixture was filtered through Celite. The filtered mate-
rial was washed with benzene, and the filtrate was
concentrated by rotary evaporation. Purification of the
products was effected by silica gel column chromatog-
raphy using different ratios of hexane/ethyl acetate as
eluant, or by preparative HPLC.
or
a
naphthyl amino derivative produced two
diastereoisomers. In the case of (R)-(+)-a-methyl ben-
zylamine the diastereomeric mixture was isolated in
76% yield and in 75% diastereomeric excess (determined
1
by H-NMR, Table 2, entry 4). Using (R)-(+)-1-(1-
naphthyl) ethylamine the yield of aminoester was 81%
and the diastereomeric excess was 78% (Table 2, entry
5). It was reported that the hydrogenation of Schiff
bases of i-butyl pyruvate with (R) or (S) alanine, over
palladium on charcoal, gave products in 71–81% d.e.,
and the same catalyst afforded 40–70% de in the
The physical and spectroscopic data for the com-
pounds obtained were compared to the data reported in
the literature [18–22]. Diastereomeric excesses were de-
1
termined by H-NMR.

R. Aldea, H. Alper / Journal of Organometallic Chemistry 593–594 (2000) 454–457
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