Hydrogenation of β-N-substituted enaminoesters in the presence of ruthenium catalysts

Article abstract of DOI:10.1016/j.jorganchem.2010.01.008

β-Aminoesters were prepared in two simple steps from β-ketoesters derivatives and primary amines under mild conditions. Their hydrogenation was performed at 50 °C in the presence of several organometallic catalysts under acidic conditions. The new β-N-substituted aminoesters were isolated in moderate to good yields.

Full text of DOI:10.1016/j.jorganchem.2010.01.008

Journal of Organometallic Chemistry 695 (2010) 870–874
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Hydrogenation of b-N-substituted enaminoesters in the presence
of ruthenium catalysts
c,
Hania Hebbache a,b, Thomas Jerphagnon b, Zakia Hank a, Christian Bruneau b, , Jean-Luc Renaud
*
*
a Laboratoire d’électrochimie-corrosion, métallurgie et chimie minérale, Université des Sciences et Technologies Houari Boumedienne, Faculté de Chimie,
BP32 El Alia 16111 Bab-Ezzouar, Alger, Algeria
b CNRS-Université de Rennes 1, Sciences Chimiques de Rennes, Catalyse et Organométalliques, Campus de Beaulieu, UMR 6226, 35042 Rennes Cedex, France
c Laboratoire de Chimie Moléculaire et Thioorganique, UMR 6507, INC3M, FR 3038, ENSICAEN-Université de Caen, 14050 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
b-Aminoesters were prepared in two simple steps from b-ketoesters derivatives and primary amines
under mild conditions. Their hydrogenation was performed at 50 °C in the presence of several organome-
tallic catalysts under acidic conditions. The new b-N-substituted aminoesters were isolated in moderate
to good yields.
Received 14 December 2009
Received in revised form 4 January 2010
Accepted 5 January 2010
Available online 11 January 2010
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Catalysis
Hydrogenation
Ruthenium
b-Aminoesters
1. Introduction
functional building blocks for the synthesis of b-lactams, b-pep-
tides, antibiotics and drugs [12]. One of the most promising meth-
Hydrogenation of enamides and imines is a reaction of substan-
tial industrial interest and is widely used in the production of sev-
eral chemicals in the agricultural, pharmaceutical and fine
chemical industries [1–7]. However, imines and related C@N func-
tional groups have some chemical peculiarities that make their
reduction more complex than that of carbonyl derivatives and ole-
fins. The C@N compounds are often sensitive to hydrolysis and the
presence of syn/anti isomers as well as enamine tautomers can cre-
ate problems as demonstrated for the hydrogenation of imines and
oximes [8]. The nature of the N-substituents of the C@N function-
ality has more influence on the properties (basicity, reduction po-
tential, etc.) than the nature of the substituents at the carbon atom.
For example, it was found that the Ti-ebthi catalyst (ebthi = ethyl-
enebis(tetrahydroindenyl)) can hydrogenate only N-alkylimines
but not N-arylimines [9]. On the other hand, iridium catalysts have
recently shown high enantioselectivity in hydrogenation of quin-
oxalines and N-arylimines, but only low ee were obtained with
N-alkylimines [10]. Oximes and other C@N–X compounds show
even a more pronounced variations in their reactivity [11].
ods for a large scale preparation of optically pure b-amino-acids
appears to be the catalytic asymmetric hydrogenation of b-acetam-
idoacrylates, which involves clean atom economical reactions and
offers the preparation of both (R) and (S)-enantiomers [13], but
suffers from the ultimate deprotection step. With b-N-substituted
enaminoesters, the same observations, than those reported for imi-
nes, were also done. With acetyl substituent on the nitrogen atom,
the hydrogenation reactions occurred within 1 h under low pres-
sure of hydrogen in the presence of rhodium catalysts, whereas
with N-alkyl substituent no reaction was observed (vide infra).
Then, usually, the preparation of chiral b-amino esters from prochi-
ral b-keto esters was associated with the hydrogenation of b-ace-
tamidoacrylates using late transition metal catalysts bearing
chiral bidentate or monodentate phosphine ligands.
In our ongoing work on hydrogenation of b-acetamidoacrylates
catalyzed by chiral rhodium complexes [14], and on hydrogenation
of b-N-substituted and b-N,N-disubstituted enaminoesters cata-
lyzed by iridium(I) complexes [15], we report here the preparation
of b-aminoesters based on hydrogenation of b-N-substituted ena-
minoesters catalyzed by ruthenium(II) species in acidic medium.
In a first set of reactions, methyl-3-N-benzylaminobut-2-enoate
1a was selected as a model substrate for the hydrogenation of b-N-
substituted enaminoesters. Whatever the reaction conditions (rho-
dium complexes such as [Rh(diphosphine)(COD)]BF4 or ruthenium
complexes, such as [Ru(p-cymene)(diphosphine)Cl]Cl and CpRu
(diphosphine)Cl as precatalysts, hydrogen pressure, solvent. . .),
Among the amine-containing compounds, b-amino acids are
important targets in pharmaceutical industry as they are useful
* Corresponding authors. Tel.: +33 (0) 223236283; fax: +33 (0) 223236939
(C. Bruneau), tel.: +33 (0) 231452842; fax: +33 (0) 231452877 (J.-L. Renaud).
E-mail addresses: christian.bruneau@univ-rennes1.fr (C. Bruneau), jean-luc.
renaud@ensicaen.fr (J.-L. Renaud).
0022-328X/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.01.008

H. Hebbache et al. / Journal of Organometallic Chemistry 695 (2010) 870–874
871
[IrCl(COD)]2 (1 mol%)
H2
1) HBF4, Et2O (1 equiv.)
2) C2 (2 mol%), H2 (10 bar),
50°C, THF
3) NaHCO3 aq.
Bn
R1
Bn
R1
NH
NH
CO2R2
CO2R2
solvent, 50°C, 16 h
Ph
NH
O
Ph
NH
O
1a
2a
O
O
conv. 61%
1a
2a
Scheme 1.
Scheme 3.
N
C
H
-
R
R'
BF4
M(H2)
AgBF4, CH3CN
C4
Ph3P
Ru
Ru Cl
Ph3P
C1
DCM
NH
hydrogen
H2
Ph3P
proton
transfer
NCCH3
Ph3P
coordination
C
R
R'
H
M-H
M
-
BF4
AgBF4
N
C
Ph3P
Ph3P
Ru
N
C3
THF
R
R'
THF
C
H
R
R'
hydride transfer
Scheme 4.
Scheme 2.
As proposed by Norton in Scheme 2, a cationic intermediate
might be involved in the catalytic cycle. These cationic ruthenium
complexes would be more stable and easier to handle than the cor-
responding hydride species. Then, in order to improve the practical
aspect of this process, we synthesized two cationic ruthenium
complexes (C3 and C4) bearing either a THF or an acetonitrile li-
gand in nearly quantitative yields by halide abstraction in the pres-
ence of 1 equiv. of silver tetrafluoroborate at room temperature in
no reaction occurred. These results were in sharp contrast with
those obtained in the presence of the commercially available irid-
ium(I) dimer [Ir(COD)Cl]2 (Scheme 1) [15].
Recently, Norton reported the hydrogenation of iminium cat-
ions in the presence of CpRu(diphosphine)H complexes under
low pressure of hydrogen [16]. Following the proposed mecha-
nism, the ruthenium hydride may reduce the iminium via an hy-
dride transfer and liberate the amine. Dihydrogen might then
coordinate to the cationic ruthenium species to furnish the
[Ru(H2)]+ intermediate. A deprotonation step might regenerate
the catalyst and liberate the ammonium salt (Scheme 2).
THF or
a
mixture dichloromethane/acetonitrile, respectively
1) HBF4, Et2O (1 equiv.)
2) C1-4 (2 mol%), THF
3) aq. NaHCO3
Based on this work, we hypothesized that, in acidic medium, the
b-N-substituted enaminoesters might be isomerized and proton-
ated to the corresponding iminium salts (Fig. 1), and then be re-
duced in the presence of a ruthenium hydride catalyst. A similar
isomerization/hydrogenation was also proposed by the Merck
group during their studies on the hydrogenation of non protected
b-enaminoesters in the presence of rhodium complexes [6].
To validate this approach, we prepared a ruthenium hydride
complex and the iminium salt. Following the procedure described
by Demerseman et al., the complex [CpRu(PPh3)2H] C2 was ob-
tained in 96% yield from [CpRu(PPh3)2Cl] C1 in refluxing methanol
in the presence of 1.1 equiv. of K2CO3 [17]. The iminium salt was
generated in situ by adding 1 equiv. of HBF4ÁOEt2 to an ethereal
solution of methyl 3-N-benzylaminobut-2-enoate 1a. Then, in the
presence of 2 mol% of the ruthenium complex C2, in THF at 50 °C
for 50 h under 15 bar of hydrogen, we were pleased to observe
the reduction of 1a and the compound 2a was obtained in a mod-
erate but encouraging conversion (61%, Scheme 3). Without the
addition of the acid, no hydrogenation occurred. The use of basic
conditions also did not provide any reaction. In a protic solvent,
such as methanol, the hydrogenation of the iminium salt led to
the corresponding N-substituted aminoester but the deprotected
methyl 3-aminobutanoate resulting from hydrogenolysis of the
N-benzyl group was also formed.
Ph
NH
O
Ph
NH
O
O
O
1a
2a
Table 1
Hydrogenation of methyl b-benzylaminoacrylate 1a.a
Entry
Catalyst
t (h)
Conv. (%)b
1
2
3
C2
C3
C4
C1
C1
C1
C1
C1
50
16
50
2
2
4
61
42
2
4c
5d
6d
7e
8
50f
50
65
80
76
2
2
a
The hydrogenation reactions were carried out with 0.5 mmol of enaminoester
1a, 0.5 mmol of HBF4 and 2% of ruthenium precatalyst C1–4 in 5 mL of THF under
10 bar of hydrogen at 50 °C.
b
As determined by 1H NMR spectroscopy.
1 mol% of catalyst in methanol.
2 mol% of catalyst in methanol.
1 mol% of catalyst in methanol under 20 bar of H2.
c
d
e
f
Debenzylation was observed.
R3HN
R1
R3HN
R1
R3HN
[Ru]-H
HX
CO2R2
CO2R2
CO2R2
R1
Norton mechanism
Fig. 1. Work hypothesis for the hydrogenation of b-N-substituted enaminoesters.

872
H. Hebbache et al. / Journal of Organometallic Chemistry 695 (2010) 870–874
(Scheme 4). Complexes C3 and C4 were isolated in 93% and 97%,
respectively.
1) HBF4, Et2O (1 equiv.)
2) cat C11 (1 mol%), THF,
10 bar H2, 50°C
R1
R1
As shown in Table 1, when the complex C3 was used in the
reduction of the in situ generated iminium salt, an improved con-
version was noticed (42% within 16 h with C3 vs. 61% within
50 h with C2). On the other hand, using complex C4, almost no con-
version was observed after 50 h of reaction time. The lack of reac-
tivity might be explained by the strong coordination of the
acetonitrile ligand to the ruthenium center avoiding coordination
of hydrogen and generation of hydride species. Our initial hypoth-
esis based on reduction of an iminium salt was validated by these
results. However, despite the greater reactivity of C3, this complex
was not very stable and not easy to handle, and we finally tested C1
as stable precursor of complexes C2–4, as precatalyst. We were
pleased to observe the formation of the b-aminoester 2a in various
solvents such as methanol or THF, but sometimes accompanied by
the debenzylated derivative when the hydrogenation was carried
out in methanol (Table 1). It is worth noting that the hydrogena-
tion rate in the presence of [CpRu(PPh3)2Cl] C1 was higher than
in the presence of catalysts C2–4, and that C1 was completely air
stable and moisture insensitive.
We then explored the catalytic activity of various ruthenium
precursors in this hydrogenation reaction (Table 2). Ruthe-
nium(arene) precursors are well-known precatalysts for the reduc-
tion of carbonyl functions [18]; they might then be also active in
the hydrogenation of iminium derivatives [16]. The first attempt
with ruthenium bidentate bipyridine complex [RuCl(bipyri-
dine)(p-cymene)]Cl C5 in THF at 50 °C under 10 bar of hydrogen
gave no conversion. However, the use of complexes bearing phos-
phine ligands provided better results (Table 2, entries 2–10). Under
the same reaction conditions, moderate conversions (up to 39%)
were obtained with bidentate dppe, dppp and dppb as ligands.
The use of monodentate PMe3 or P(OMe)3 as ligand improved this
procedure and conversions of 58% and 48%, respectively, were ob-
tained (Table 2, entries 6–7). Finally, the neutral complex C11 con-
taining the monophosphine PPh3 led to the best results as the
hydrogenation of 1a in the presence of this precursor provided
the aminoester 2a in 78% conversion within 2 h (Table 2, entry
NH
O
NH
O
3) aq. NaHCO3
R2
R2
O
O
1
2
Table 3
Hydrogenation of alkyl b-N-substituted aminoacrylate 1.a
Entry
R1
R2
Aminoester 2
t (h)
Yield (%)b
1
2
3
Bn
Bn
Ph
Ph
Ph
Ph
Bu
i-Pr
Me
Et
Me
Me
Et
t-Bu
Me
Me
2a
2b
2c
2c
2d
2f
6
96
70
98
100
100
100
95
16
16
16
16
16
12
4c
5c
6c
7
2d
2e
8
90
a
The hydrogenation reactions were carried out with 0.5 mmol of enaminoester 1,
0.5 mmol of HBF4 and 1% of ruthenium precatalyst C11 in 5 mL of THF under 10 bar
of hydrogen at 50 °C.
b
Isolated yield after purification on silica gel.
In a 2:1 mixture of CH2Cl2:THF.
c
8). Increasing the reaction time to 6 h enhanced the conversion and
the aminoester 2a was obtained in almost quantitative yield (Ta-
ble 2, entry 10).
With this optimized catalytic system in hand, we explored the
scope of the hydrogenation reaction by using a variety of b-N-
substituted-enaminoesters (Table 3). In all reactions, whatever
the N-alkyl or N-aryl substituent, the conversions were complete
and isolated yields were excellent. The hydrogenation occurred
usually within 16 h. As compared to our previous studies in irid-
ium-catalyzed hydrogenation under neutral conditions, there is
no difference of reactivity between the N-aryl and N-alkyl substi-
tuted enaminoesters in terms of yields and reaction rate.
In conclusion, we have found a new general procedure for the
synthesis of a range of b-N-substituted aminoesters via catalytic
hydrogenation of b-N-substituted enaminoesters in acidic condi-
tions in the presence of ruthenium complexes. Further efforts are
now devoted to the asymmetric version of this transformation.
1) HBF4, Et2O (1 equiv.)
2) cat C5-11 (1 mol%), THF,
10 bar H2, 50°C
Ph
NH
O
Ph
NH
O
3) aq. NaHCO3
2. Experimental section
O
O
2.1. General
1a
2a
Purifications by column chromatography were performed with
70–230 mesh silica gel. TLC analysis were carried out on alumina
sheets precoated with silica gel (60 F254) and visualized with UV
light; NMR spectra were recorded with a Bruker Avance DRX 500
FT spectrometer [200.13 MHz (1H) and 50.33 MHz (13C)] or a Bru-
ker AH 300 FT spectrometer [300.13 MHz (1H) and 75.45 MHz
Table 2
Hydrogenation of methyl b-benzylaminoacrylate 1a with various ruthenium
precatalyst.a
Entry
Catalyst
t (h)
Conv. (%)b
(
13C)]. Chemical shifts are expressed in ppm downfield from TMS.
1
2
3
[RuCl(bipy)(p-cymene)]Cl C5
[RuCl(dppe)(p-cymene)]Cl C6
[RuCl(dppe)(p-cymene)]Cl C6
[RuCl(dppp)(p-cymene)]Cl C7
[RuCl(dppb)(p-cymene)]Cl C8
RuCl2(PMe3)(p-cymene) C9
RuCl2(P(OMe)3)(p-cymene) C10
RuCl2(PPh3)(p-cymene) C11
RuCl2(PPh3)(p-cymene) C11
RuCl2(PPh3)(p-cymene) C11
16
2
4
2
2
4
4
2
4
0
22
33
32
39
58
48
78
85
96
High-resolution mass spectra were obtained with a Varian Mat
311 double focussing instrument at the CRMPO ‘‘Centre de Me-
sures Physiques de l’Ouest” with a source temperature of 170 °C.
An ion accelerating potential of 3 kV and ionising electrons of
70 eV were used. All commercially available reagents were used
as supplied. Solvents were freshly distilled and kept under argon
flush.
4c
5c
6
7
8
9
10
6
a
The hydrogenation reactions were carried out with 0.5 mmol of enaminoester
2.2. General procedure for the preparation of b-aminoesters
1a, 0.5 mmol of HBF4 and 1% of ruthenium precatalyst C5–11 in 5 mL of THF under
10 bar of hydrogen at 50 °C.
b
As determined by 1H NMR spectroscopy.
In a 25 mL stainless steel autoclave were placed under an argon
atmosphere, the N-substituted b-amino acrylates (0.5 mmol,
c
Only one phosphine was coordinated to the ruthenium center.

H. Hebbache et al. / Journal of Organometallic Chemistry 695 (2010) 870–874
873
1 equiv.), the ruthenium precatalyst (0.005 mmol, 1% mol). The
2.9. Methyl 3-(iso-propylamin)-butanoate (2g)
mixture was degassed by three vacuum-filling with argon cycles
before adding 5 mL of degassed and distilled CH2Cl2. Then, the
autoclave was purged three times by hydrogen and the vessel
was pressurized to 10 bar of hydrogen. At the end of the reaction
(see text) at 50 °C, the autoclave was carefully opened; the solvent
was removed under reduced pressure. Conversion was determined
by 1H NMR analysis of the crude mixture. Subsequently, the resi-
due was purified by purification on silica gel, eluted with a 1:1
mixture of heptane and AcOEt.
1H NMR (300.13 MHz, CDCl3), d ppm: 0.98 (dd, J = 6 Hz, 12 Hz,
6H), 1.04 (d, J = 6 Hz, 3H), 2.32 (ABX, JAB = 15 Hz, JAX = 7.5 Hz,
JBX = 9 Hz, 2H), 2.83 (m, 1H), 3.12 (m, 1H), 3.61 (s, 3H). 13C
NMR (75.03 MHz, CDCl3), d ppm: 20.9, 22.9, 23.5, 41.7, 45.2,
47.1, 51.3, 172.7. HRMS Calc. for C8H17NO2: 159.1259. Found:
159.1271.
Acknowledgements
2.3. Methyl 3-(benzylamino)-butanoate (2a)
The authors wish to warmly acknowledge the Ministry of Edu-
cation and Research of the Algerian government for a doctoral
grant to H.H. The authors are grateful to SEAC-Chimie Fine for a
PhD grant to T.J.
1H NMR (300.13 MHz, CDCl3), d ppm: 1.15 (d, J = 6 Hz, 3H), 2.44
(ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2H), 3.16 (m, 1H), 3.66 (s,
3H), 3.79 (AB, JAB = 12 Hz, 2H), 7.20-7.34 (m, 5H). 13C NMR
(75.03 MHz, CDCl3), d ppm: 20.5, 41.4, 49.7, 51.2, 51.5, 126.9,
128.1, 128.4, 140.4, 172.8. HRMS Calc. for C11H14NO2 [M–CH3]+:
192.1024. Found: 192.1013.
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2.5. Methyl 3-(phenylamino)-butanoate (2c)
1H NMR (300.13 MHz, CDCl3), d ppm: 1.30 (d, J = 6 Hz, 3H), 2.56
(ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2H), 3.70 (s, 3H), 3.97 (m,
1H), 6.64–6.76 (m, 3H), 7.09-7.37 (m, 2H). 13C NMR (75.03 MHz,
CDCl3), d ppm: 20.7, 40.8, 46.0, 51.6, 113.6, 117.7, 129.4, 146.8,
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(t, J = 4.5 Hz, 3H), 2.54 (ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2H),
3.96 (m, 1H), 4.16 (q, J = 7 Hz, 2H), 6.62–6.75 (m, 3H), 7.15–7.23
(m, 2H). 13C NMR (75.03 MHz, CDCl3), d ppm: 14.3, 20.6, 41.1,
46.0, 60.5, 113.6, 117.6, 129.4, 146.9, 171.8.
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N.R. Rivera, T. Rosner, S.W. Krska, E. Njolito, F. Wang, Y. Sun, J.D. Armstrong
III, E.J.J. Grabowski, R.D. Tillyer, F. Spindler, C. Malan, J. Am. Chem. Soc. 126
(2004) 9918;
2.7. Tert-butyl 3-(phenylamino)butanoate (2e)
1H NMR (300.13 MHz, CDCl3), d ppm: 1.29 (d, J = 6 Hz, 3H), 1.47
(s, 9H), 2.46 (ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2H), 3.92 (m,
1H), 6.61–6.75 (m, 3H), 7.16–7.23 (m, 2H). 13C NMR (75.03 MHz,
CDCl3), d ppm: 20.5, 28.1, 42.3, 46.2, 80.7, 113.5, 117.5, 129.3,
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