Asymmetric hydrogenation of enamides with catalysts containing chiral thiourea ligands

Article abstract of DOI:10.1016/S0957-4166(00)00489-4

The asymmetric reduction of enamides with molecular hydrogen and catalytic amounts of rhodium, iridium or ruthenium complexes containing chiral N,S-ligands is reported. Various enantiomerically pure mono- and dithioureas were examined. The C₂-s

Full text of DOI:10.1016/S0957-4166(00)00489-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4835–4841
Asymmetric hydrogenation of enamides with catalysts
containing chiral thiourea ligands
M. Lorraine Tommasino, Magali Casalta, Je´re´my A. J. Breuzard and Marc Lemaire*
Laboratoire de Catalyse et Synthe`se Organique, CNRS: UMR 5622, CPE, Baˆt. 308, 43 bd. du 11 novembre 1918,
69622 Villeurbanne, France
Received 12 September 2000; accepted 8 December 2000
Abstract
The asymmetric reduction of enamides with molecular hydrogen and catalytic amounts of rhodium,
iridium or ruthenium complexes containing chiral N,S-ligands is reported. Various enantiomerically pure
mono- and dithioureas were examined. The C2-symmetry of the dithiourea ligands seems essential to the
enantioselectivity achieved. Ee values of up to 70% were observed. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Development of practical asymmetric hydrogenation of olefins was begun 30 years ago by
Knowles1 and Kagan,2 who focused on the enantioselective reduction of olefinic N-acyl-
aminoacrylic acids. Since then many catalytic rhodium and ruthenium systems containing chiral
diphosphine ligands have been reported to hydrogenate dehydroaminoacids3 and enamides4 with
more than 90% enantioselectivity. As enantiopure phosphines are often expensive to synthesize
and are additionally difficult to recycle, we are interested in replacing them by nitrogen
derivatives. Chiral N-ligands are now widely used in asymmetric catalysis5,6 and the reduction of
CꢀC bonds can be carried out by many different reducing agents, most commonly sodium
borohydride or molecular hydrogen. Nitrogen containing ligands such as semicorrins7 induced
high enantioselectivity when sodium borohydride was used, whilst in the case of olefin reduction
by molecular hydrogen, most of the chiral nitrogen ligands employed to date have been
N,P-ligands or chiral N-ligands linked to non-chiral phosphines.3,8–11 Some non-phosphorus
containing ligands for asymmetric CꢀC hydrogenations have been developed since Ogho et al.
proposed the bis(dimethylglyoximato)cobalt catalysts12,13 in 1970. Corma et al. studied proline
derived ligands and anchored their Rh complexes on modified USY zeolites allowing catalyst
* Corresponding author. E-mail: marc.lemaire@univ-lyon1.fr
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00489-4

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M. L. Tommasino et al. / Tetrahedron: Asymmetry 11 (2000) 4835–4841
recovery.14 Recently, other N-ligands such as symmetric diamines were reported,15 but there are
also S-ligands which are efficient: Claver et al. showed that sugar dithioethers16 can induce up
to 62% enantioselectivity in the asymmetric hydrogenation of acrylic acid derivatives. The
promising enantioselectivities observed with various chiral diamines for CꢀO hydrogenation
reactions17 prompted us to test them in CꢀC hydrogenations, but no significant asymmetric
induction was then observed. We recently developed a new series of chiral N,S-ligands with and
without C2-symmetry: some of those monothiourea and dithiourea ligands have previously
afforded good enantioselectivities in the hydroformylation of styrene18 and in the hydrogen
transfer reactions of ketones.19 Herein we report the use of optically pure mono- and dithioureas
in Rh, Ir and Ru catalyzed asymmetric enamide hydrogenation reactions.
2. Results and discussion
Interactions between thiourea ligands and transition metals in catalytic species are under
investigation in our laboratory and theoretical studies are on course.20 As we have not yet
obtained suitable crystals for X-ray studies, the types and number of interactions between the
metal center and the functional thiourea group have not been completely established. This
encouraged us to study and compare monothiourea ligands with their dithiourea equivalents as
chiral catalysts in the hydrogenation of enamides.
2.1. Monothiourea ligands
Optically pure monothioureas 1–4 (Scheme 1) are easily obtained in more than 70% yield
from the corresponding chiral amines and isothiocyanates (see Section 4). The prepared
monothioureas were examined in the hydrogenation of both enamides with Rh, Ir or Ru in a 2:1
molar ratio, but despite complete conversion, no significant enantioselectivity was observed (ee
<6%). The metallic particles formed during the reactions suggest that monothioureas do not
coordinate even if used in large excess (5 equivalents per metal atom).
2.2. Dithiourea ligands
Ligands 5–7 (Scheme 2) were obtained from the corresponding optically pure diamines in the
presence of two equivalents of phenylisothiocyanate. These dithiourea compounds are very
stable and therefore easy to handle and store but most of all, they appear to be more promising
than their diamine precursors as chiral inducers for the enamide hydrogenations studied here.
Scheme 1. Chiral monothioureas used in hydrogenation reactions

M. L. Tommasino et al. / Tetrahedron: Asymmetry 11 (2000) 4835–4841
4837
Scheme 2. Chiral dithioureas used in hydrogenation reactions
The reduction of methyl-2-acetamido acrylate and a-acetamidocinnamic methyl ester was
carried out under hydrogen catalyzed by Rh, Ir or Ru complexes of thioureas 5–7. The
N,S-ligands were combined in various ligand to metal molar ratios in MeOH solutions of the
metallic precursors (unless otherwise stated) before their use in the hydrogenation reactions. The
results obtained with iridium are not reported here since the observed enantioselectivity was
poor (ee <15%) when iridium was combined with any of the chiral ligands studied. In order to
compare ligand effects, we gathered the results in two tables depending on the nature of the
substrate. The first results with DIOP are also listed to allow comparisons. Table 1 concerns the
hydrogenation of methyl-2-acetamido acrylate and Table 2 shows the results obtained from
studies on the hydrogenation of a-acetamidocinnamic methyl ester hydrogenation.
Table 1
Dithioureas as chiral catalytic ligands for the hydrogenation of methyl-2-acetamido acrylate
Entry
L*
Metal
% Yield
% Ee (R)
0
1
2
3
4
5
6
7
8
DIOPa
[RhCl(COD)2]2
96a
65
73a
17
26
2b
5
5
6
6
7
7
7
7
[Rh(COD)2]BF4
Ru(COD)(h3-C4H7)2
[Rh(COD)2]BF4
71
100b
96b
67
Ru(COD)(h3-C4H7)2
[Rh(COD)2]BF4
3b
30
38
48c
61c
Ru(COD)(h3-C4H7)2
Ru(COD)(h3-C4H7)2
Ru(COD)(COT)
70
75c
92c
a From Ref. 2: Sub/Rh=150; 1.1 atm H2, ex situ prepared Rh/DIOP complex.
b Grey particles formed in the reaction mixture.
c In THF instead of MeOH.

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Table 2
Dithioureas as chiral catalytic ligands for the hydrogenation of a-acetamidocinnamic methyl ester
Entry
L*
Metal
% Yield
% Ee (R)
0
1
2
3
4
5
6
7
8
DIOPa
[RhCl(COD)2]2
90a
90
55a
19
37
4b
5
5
6
6
7
7
7
7
[Rh(COD)2]BF4
Ru(COD)(h3-C4H7)2
[Rh(COD)2]BF4
84
30b
28b
86
Ru(COD)(h3-C4H7)2
[Rh(COD)2]BF4
5b
39
42
58c
70c
Ru(COD)(h3-C4H7)2
Ru(COD)(h3-C4H7)2
Ru(COD)(COT)
96
99c
100c
a From Ref. 2: Sub/Rh=150; 1.1 atm H2, ex situ prepared Rh/DIOP complex.
b Grey particles formed in the reaction mixture. Conversions are complete, the by-product being
C6H10CH2C(CO2CH3)COCH3.
c In THF instead of MeOH.
For Rh as well as for Ru, the presence of a Me group (ligand 6) instead of a H atom (ligand
5) on the nitrogen atoms of the central chiral core leads to poor enantioselectivity, and metallic
particles were observed in the reaction mixtures.21 This may be due to the fact that 6 is not
coordinated strongly enough to Rh or Ru and the metallic particles formed led to high racemic
hydrogenation rates. In fact, Cauzzi et al. showed that even if the thiourea group is mainly
coordinated through the sulfur atom to a Rh center, a H atom on the neighbouring nitrogen
helps to stabilize the active hydridic species and, in one of the rare X-ray structures of a thiourea
rhodium complex, [Rh(COD)(Hbztu)Cl], an intramolecular hydrogen bond was determined.22
We have observed that for both metals, Rh and Ru, the presence of the central cyclohexyl
group allows better asymmetric induction than the diethylene diphenyl central group, while
activity remains the same (entries 5 versus 1).
For ligands 5 and 7, ruthenium species are more enantioselective than rhodium catalysts
(entries 1 versus 2 and 5 versus 6). As the neutral ruthenium precursors employed have little
solubility in MeOH, we used various common solvents (CH2Cl2, toluene, pentane), the most
suitable was found to be dried THF, which may stabilize the intermediate complexes by
coordinating to the ruthenium center. It is notable that the replacement of the methylallyl
groups (entry 7) by a cyclooctatriene (COT) ligand (entry 8) in the ruthenium precursor
improves both activity and enantioselectivity. The active species thus seems easily formed after
one COT hydrogenation rather than two h3-C4H7 hydrogenations. The 61% ee value obtained
for methyl-2-acetamido acrylate hydrogenation is moderate but it prompted us to test an
activated substrate such as a-acetamidocinnamic methyl ester (see Table 2).
The same trends are seen for a-acetamidocinnamic methyl ester as those in the hydrogenation
of methyl-2-acetamido acrylate. A hydrogen atom is needed on the central nitrogen atoms to

M. L. Tommasino et al. / Tetrahedron: Asymmetry 11 (2000) 4835–4841
4839
allow effective ligand coordination (entries 1 and 2 versus 3 and 4), the presence of a chiral
cyclohexyl core enhances enantioselectivity (entries 1 and 5 and 2 and 6) and Ru species are
more active and enantioselective than Rh complexes (entry 5 versus entry 6). The presence of the
phenyl group on the enamide substrate increased both activity and enantioselectivity. This has
already been observed with Rh/DIOP and various asymmetric hydrogenation catalysts.2–5
Dithiourea 7 thus led to 70% ee in the hydrogenation of a-acetamidocinnamic methyl ester.
Even if this enantioselection is far from the >99% ee obtained with MeDUPHOS23 or BINAP24
chiral diphosphines, it is one of the first examples of significant asymmetric enamide hydrogena-
tion by non-phosphorus ligands. The N,S-ligands we have developed also offer a potentially
good alternative to phosphorus ligands since they are easier to obtain, and handle, than chiral
diphosphines.
A common point observed in P- and N,S-ligands used in asymmetric enamide hydrogenation
is the general need for C2-symmetry of the chiral inducers. This symmetry reduces the number
of complexes which can be formed by coordination of the ligand to the metal center. The
formation of C2-symmetric complexes is then favoured when chelating dithiourea ligands are
used instead of monothioureas, enhancing the enantioselection of the active species. Finally, we
can point out that the more strained dithiourea 7 is a better asymmetric inducer than its analog
5. The rigidity of the ligand backbone has been recently reported25 to be related to enantioselec-
tion improvements for bis(phospholano)ethane ligands.
3. Conclusion
Asymmetric enamide hydrogenation was carried out with N,S-ligands and rhodium or
ruthenium catalysts giving enantioselectivities up to 70%. Two types of enantiomerically pure
ligands, monothioureas and dithioureas have been tested, but only dithioureas provided
significant enantioselection. This suggests that for enamide hydrogenation the C2-symmetry of
the dithiourea ligands is a key factor in the degree of control observed. Even if more active and
enantioselective catalysts are formed with bidentate P-ligands, the easy to obtain and stable
dithioureas 5 and 7 are interesting alternatives for asymmetric enamide hydrogenation. This is
important since enantiomerically pure ligand availability is directly related to the price of a
chiral catalyst. The robustness of these new chiral inducers may facilitate the identification of the
active species and aid catalyst recovery. Thus, we focus on the ex situ preparation and
characterization of the ruthenium–dithiourea 7 species. We are also interested in the polymeriza-
tion of the dithiourea ligands in order to obtain reusable catalysts.
4. Experimental
4.1. General
Solvents were degassed before use by prolonged argon bubbling for MeOH, cyclooctadiene
and pentane or by distillation under a nitrogen atmosphere for THF. Ethyl-2-acetamido
acrylate, a-acetamidocinnamic methyl ester from Aldrich® and RuCl3·7H2O, [Rh(COD)Cl]2 and
Ru(COD)(h3-C4H7)2 from Strem Chemicals were used. Gas chromatography analyses were
carried out with a JW DB-1701 (non-chiral) or a Lipodex A (chiral) 25 m column on Shimadzu
GC-14A chromatographs using flame-ionization detector and Shimadzu C-R6A integrators.

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M. L. Tommasino et al. / Tetrahedron: Asymmetry 11 (2000) 4835–4841
4.2. Catalytic precursors
[Rh(COD)2]BF4 was prepared from [Rh(COD)Cl]2 and AgBF4 as already described.26
Ru(COD)(h3-C4H7)2 was used as received and Ru(COD)(COT) was prepared according to the
published procedure.27
4.3. Monothioureas 1–4
The enantiomerically pure amine was added to a stoichiometric amount of desired isothio-
cyanate in CH2Cl2 and the solution was stirred overnight at room temperature. The reaction
mixture was then poured into a large excess of cold pentane to allow monothiourea precipita-
tion. The product was filtered and washed before drying under vacuum. Spectroscopic data were
compared to those already published.18
4.4. Dihioureas 5–7
Dithioureas were prepared following the same experimental procedure as that for mono-
thiouras, except that two isothiocyanate equivalents are needed per amine molecule. Enan-
tiomerically pure diamines used were (1R,2R) cyclohexanediamine from Aldrich® and (1R,2R)-
(+)-N,N%-dimethyl-1,2-diphenyl-1,2-ethylenediamine prepared according to recently published
procedures.28 Spectroscopic data of obtained dithioureas 5–7 were compared to those we have
already published.17,19,29
4.5. Enamide hydrogenations
A typical enamide hydrogenation test was carried out as follows: the metallic precursor was
added under an argon atmosphere to a degassed and dried MeOH (or THF) solution of the
chiral ligand. After stirring for 30 minutes, the substrate was added and the resulting solution
was transferred to a purged stainless steel autoclave and pressurized with H2. After stirring
overnight at 50°C the autoclave was cooled and degassed. The reaction mixtures were then
filtered through Celite and analyzed by chiral gas chromatography (60 m bdex 225 column) for
the hydrogenation of methyl-2-acetamido acrylate or by gas chromatography (25 m JW-DB-
1701 column) and chiral HPLC (25 m Chiralcel OD column) for the hydrogenation of
a-acetamidocinnamic methyl ester.
Acknowledgements
We thank Genevie`ve He´raud for chiral HPLC analysis.
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