New ruthenium catalysts containing chiral Schiff bases for the asymmetric hydrogenation of acetophenone

Article abstract of DOI:10.1016/j.tetasy.2004.03.023

A series of new chiral N₄-Schiff bases, containing amine or sulfonamide functionalities has been synthesized. Coupled with ruthenium catalysts, these Schiff bases induce interesting results in the hydrogenation of acetophenone: complete conversion and 76% ee were obtained with the catalytic system Ru(PPh₃)₃Cl₂/(1R,2R)-N,N′-bis-(2- p-tosylaminobenzylidene)-1,2-diphenylethylenediamine. A very important phosphine co-ligand effect was observed on both activity and enantioselectivity of the catalysts. However, without the co-ligand, we obtained an enantioselectivity for the (R)-enantiomer, whereas with nonchiral co-ligand an enantioselectivity for the (S)-enantiomer was observed.

Full text of DOI:10.1016/j.tetasy.2004.03.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1569–1581
New ruthenium catalysts containing chiral Schiff bases for the
asymmetric hydrogenation of acetophenone
ꢀ
Iyad Karame, Mohamed Jahjah, Abdelhalim Messaoudi, M. Lorraine Tommasino and
Marc Lemaire*
Laboratoire de Catalyse et Synthꢁese Organique, UCLyon 1, UMR 5181, CPE- Bat 308, 43, Bd du 11 Novembre 1918,
69622 Villeurbanne cedex, France
Received 28 February 2004; accepted 15 March 2004
Abstract—A series of new chiral N4-Schiff bases, containing amine or sulfonamide functionalities has been synthesized. Coupled
with ruthenium catalysts, these Schiff bases induce interesting results in the hydrogenation of acetophenone: complete conversion
and 76% ee were obtained with the catalytic system Ru(PPh3)3Cl2/(1R,2R)-N,N0-bis-(2-p-tosylaminobenzylidene)-1,2-diphenyl-
ethylenediamine. A very important phosphine co-ligand effect was observed on both activity and enantioselectivity of the catalysts.
However, without the co-ligand, we obtained an enantioselectivity for the (R)-enantiomer, whereas with nonchiral co-ligand an
enantioselectivity for the (S)-enantiomer was observed.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
[(ꢀ)-TolBINAP]/(S,S)-DIPEN catalyzing the asymmet-
ric hydrogenation of 2,4,4-trimethyl-2-cyclohexanone to
the corresponding alcohol with 95% ee. Similar results
were obtained with enantiomerically pure (R)-
TolBINAP.5;6 The racemic catalysts could be used in
various strategies of asymmetric activation or deactiva-
tion of racemic complexes.7 The diphosphine/Ru/dia-
mine systems were found to be the most effective method
for asymmetric hydrogenation of aromatic ketones.
Asymmetric hydrogenation using molecular hydrogen
to reduce prochiral olefins, ketones, or imines has be-
come one of the most efficient methods for preparing
nonracemic chiral compounds. Knowles and Kagan
developed in the 1970s, chiral RhðIÞ–biphosphine com-
plexes for the enantioselective hydrogenation of ketones
and olefins with ee values up to 90%. Diphosphine
complexes of Rh and Ru have also been used success-
fully for the asymmetric hydrogenation of functional-
ized ketones.1;2 In 1995, Noyori reported the diamine/
Ru/BINAP catalysts for the asymmetric reduction of
various simple aromatic ketones.3 The synergetic effect
of the amine was noteworthy as the addition of a chiral
diamine considerably increased the activity, as well as
the enantioselectivity of BINAP–Ru catalysts for
asymmetric hydrogenation of ketones. trans-RuH(g1-
In our laboratory, C2-symmetric dithioureas and diam-
ines have been developed and complexed to rhodium,
iridium, or ruthenium precursors to form efficient cata-
lysts for the asymmetric hydrogenation of ketones. The
asymmetric reduction of acetophenone catalyzed by
chiral Irþ-diamine gave 1-phenylethanol in 63% ee.8 In
other studies, we pointed out that supported diimines
can be useful in the asymmetric transfer hydrogenation
of acetophenone (70% ee).9 Others diimines were tested
by Vinagradov for this reaction and gave up to 55% ee
in phenylethanol.10
BH4)(S-xylBINAP)(1S,2S-DIAPEN)
allowed
the
reduction of acetophenone to (S)-1-phenylethanol in
99% ee with very high TON (105). Without the diamine,
these catalysts alone were unable to hydrogenate simple
ketones.4 Noyori et al. performed the asymmetric acti-
vation of racemic TolBINAP by (1S,2S)-diphenylethy-
lenediamine (DIPEN) with the resulting system RuCl2
Until now, there are only a few reports on the use of
Schiff bases as chiral inductors for asymmetric hydro-
genation of ketones. We recently reported a new and
easy method for the preparation of chiral tetraaza Schiff
bases containing amine or sulfonamide functionalities,
which are promising ligands for a wide variety of tran-
sition metals.11 Other research groups are also currently
* Corresponding author. Tel.: +33-4-72-43-14-07; fax: +33-4-72-43-14-
08; e-mail: marc.lemaire@univ-lyon1.fr
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.03.023

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I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
interested in the synthesis of these compounds.12;13
Herein we report the synthesis of a new series of N4-
Schiff bases and report their first use in the asymmetric
hydrogenation of acetophenone with Ir, Rh, and Ru
precursors.
The Schiff base 2 was then transformed into several
functionalized compounds. (1R,2R)-N,N0-Bis-(2-triflu-
oromethylsulfonaminobenzylidene)-1,2-diaminocyclo-
hexane (1R,2R)-H2CyTf 3 (yield ¼ 73%) and (1R,2R)-
N,N0-bis(2-tosylamino-benzylidene)-1,2-diaminocyclo-
hexane (1R,2R)-H2CyTs 4 (yield ¼ 70%) were prepared
by N-sulfonation reactions of (1R,2R)-N,N0-bis(2-
aminobenzylidene)-1,2-diaminocyclohexane 2 with tri-
flic anhydride or tosyl chloride in presence of Et3N. An
anhydrous atmosphere and low temperature were nee-
ded to avoid the hydrolysis of the imine functions.11;14
2. Results and discusion
2.1. Synthesis of tetradentate Schiff bases
As we have previously reported, the synthesis of chiral
Schiff bases with sulfonamides functionalities is based
on the preparation of diimino–diamino ligands from
enantiomerically pure diamine and 2-nitrobenzalde-
hyde.11 The C2-symmetric diimino–diamino compound
formed was then transformed into various sulfonamide
derivatives (Fig. 1).
2.1.1.1. Synthesis of (1R,2R)-H2CyNphs 5. The reac-
tion of (1R,2R)-N,N0-bis(2-aminobenzylidene)-1,2-dia-
minocyclohexane 2 with 1-naphthalenesulfonic chloride
(NphSO2Cl), in the presence of Et3N at 0 ꢁC, gave
(1R,2R)-N,N0-bis(2-naphthylsulfonaminobenzylidene)-
1,2-diaminocyclohexane 5 in 40% yield.
2.1.1. Synthesis of Schiff bases with a (1R,2R)-diamino-
cyclohexane core. The condensation of (1R,2R)-diamino-
cyclohexane and 2-nitrobenzaldehyde was easily
performed in anhydrous THF to give dinitro compound
1 in good yield (91%). After selective reduction of 1
under an atmospheric pressure of hydrogen catalyzed by
Pd–C, the (1R,2R)-N,N0-bis(2-aminobenzylidene)-1,2-
diaminocyclohexane 2 was obtained in 65% yield.
2.1.1.2. Synthesis of (1R,2R)-(ꢁ)-N,N0-bis-(2-perfluo-
octanoylaminobenzylidene)-1,2-diaminocyclohexane
6.
Compound 2 could be transformed into either sulfon-
amide derivatives or compounds having amide functions.
(1R,2R)-N,N0-Bis-(2-perfluooctanoylamidobenzylidene)-
1,2-diaminocyclohexane 6 containing two perfluorinated
chains was obtained with a yield of 50%, via reaction of
2 with perfluorooctanoyle chloride at 0 ꢁC, in the pres-
N
N
OHC
THF
r.t.
+
2
NO2 O2N
O2N
H2N
NH2
1
yield= 91%
CH2Cl2
H2, Pd/C
N
N
N
N
N
Tf2O, Et3N
H
H
N
NH2 H2N
2
CH2Cl2, -78°C
SO2
CF3
SO2
CF3
yield= 65%
3
yield= 73%
RSO2Cl, Et3N CH2Cl2, 0°C
CF3(CF2)6COCl, Et3N
CH2Cl2, 0°C
N
N
N
N
NH
CO
HN
CO
NH
SO2
R
HN
SO2
(CF2)6 (CF2)6
R
4. R= p-Tol (yield= 70%)
CF3
CF3
6 (yield= 50%)
5. R= 1-Naphtyl (yield= 40%)
Figure 1. Synthesis of N4-Schiff bases 1–6.

I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
1571
Br
CHO
2
NH2
N
N
Br
7
THF, r.t.
Br
NH2 H2N
Br
H2N
NH2
Br
Br
8
CH2Cl2, 35°C
CHO
2
N
N
NH2
NH2 H2N
9
10
Figure 2. Synthesis of Schiff bases 8 and 10.
ence of Et3N (Fig. 1). This synthetic path enabled us to
prepare other perfluorinated chiral Schiff bases.
(1R,2R)-diaminocyclohexane in good yield (73%) (Fig.
2).
In order to prepare a Schiff base with tert-butyl sub-
stituents on the aromatic rings, we first used the method
described above (Section 2.1.1, Fig. 1) by preparing the
diimine–dinitro compound to be reduced further under
hydrogen pressure (1 bar). The 3,5-di-tert-butyl-2-
nitrobenzaldehyde 12, was prepared by the nitration of
3,5-di-tert-butylbenzaldehyde 11 (77% yield). This
aldehyde was obtained in two steps: Bromination of 3,5-
di-tert-butyltoluene with NBS in CCl4, followed by an
2.1.1.3. Synthesis of Schiff bases 8 and 10. Schiff bases,
with substituents on the aromatic rings were prepared
from (1R,2R)-diaminocyclohexane and aminocarboxal-
dehyde compounds 7 or 9, which are stable. Schiff base
(1R,2R)-N,N0-bis-(3,5-dibromo-2-aminobenzylidene)-1,2-
diaminocyclo hexane 8, which contains bromine atoms
on both aromatic rings, was synthesized by condensa-
tion of 2-amino-3,5-dibromobenzaldehyde
7
and
N
CHnBrm
CHO
N
N
NBS,
N
Ph-CO-O-O-CO-Ph
EtOH, H2O
CCl4, 12h
11
n=2, m=1 (25-45%)
n=1, m=2 (55-75%)
HNO3
H2SO4
CHO
NO2
N
N
H2N
NH2
NO2
O2N
THF, r.t.
12
13
H2, Pd-C(10%)
H2, Pd-C(10%)
CH2Cl2
CH2Cl2
CHO
OHC
N
N
14
+
H2N
NH2
Figure 3. Synthesis of 3,5-di-tert-butyl-2-nitrobenzaldehyde 12 and Schiff base 13.

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I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
oxidation/hydrolysis with hexamethylenetetraamine in
methanol/water (50/50) gave 95% yield of 3,5-di-tert-
butylbenzaldhyde 11 (Fig. 3).
reported by Kitaura and Mastuura,15 Gowda and co-
workers,16 and Khan et al.17 Thus, the diaza compound
14 could result from the reaction between 12 and the
amino-aldehyde 9. In order to avoid this reaction and
favor the formation of 3,5-di-tert-butyl-2-aminobenzal-
dehyde 9, we carried out the reduction of 12 under an
hydrogen pressure of 20 bar, at 50 ꢁC for 2 days: 9 was
the only product obtained in 95% yield (Fig. 4).
The Schiff base 13, (1R,2R)-N,N0-bis-(3,5-di-tert-butyl-
2-nitrobenzylidene)-1,2-diaminocyclohexane, was ob-
tained in an excellent yield (95%) via reaction of the 3,5-
di-tert-butyl-2-nitrobenzaldehyde 12 with (1R,2R)-di-
aminocyclohexane in THF.
The (1R,2R)-bis-(3,5-di-tert-butylamino-2-aminobenzyli-
dene)-1,2-diaminocyclohexane 10 was then prepared by
coupling 3,5-di-tert-butyl-2-aminobenzaldehyde 9 and
(1R,2R)-diaminocyclohexane and purified by precipita-
tion in methanol: 78% of pure product was obtained
(Fig. 4).
The reduction of the dinitro compound 13 under 1 bar
of hydrogen, did not allow the formation of diimine-
diamine derivative 10. Instead we observed the forma-
tion of diazo compound 14, which is a derivative of 3,5-
di-tert-butyl-2-nitrobenzaldehyde. The same secondary
product was obtained by reduction of 3,5-di-tert-butyl-
2-nitrobenzaldehyde under 1 bar of hydrogen (Fig. 3).
The use of hydride reageants such as NaBH4 or LiAlH4
gave a reduction of the imine groups, while the nitro
functions remained intact. Preparation of diaza com-
pounds from the nitrated products has already been
2.1.2. Synthesis of Schiff bases with a (1R,2R)-diphenyl-
ethylenediamine core. For the synthesis of (1R,2R)-N,N0-
bis-(2-amino-benzylidene)-1,2-diphenylethylenediamine,
we used the method described in Figure 1, based on the
coupling of the corresponding chiral diamine with 2-
nitrobenzaldehyde. The reaction between (1R,2R)-di-
phenylethylenediamine and 2-nitrobenzaldehyde in
THF, CH2Cl2, or methanol with molecular sieves, did
not allow the formation of compound 15 (Fig. 5). This
compound seemed unstable as when it appeared, it de-
graded rapidly.
CHO
CHO
NO2
NH2
H2 (20 bars), Pd-C (10%)
CH2Cl2, 50°C, 48h
9
12
(yield= 97%)
We next considered the synthesis of compound 16,
directly from 2-nitrobenzaldehyde in a one step reaction.
The (1R,2R)-diphenylethylenediamine and 2-nitrobenz-
aldehyde were dissolved in CH2Cl2 and mixed with
molecular sieves under 1 bar of hydrogen and catalytic
amounts of Pd–C (10%) at 0 ꢁC. The (1R,2R)-N,N0-bis-
(2-aminobenzylidene)-1,2-diphenylethylenediamine 16
crystallized in methanol and was obtained in 60% yield
(Fig. 5).
H2N
NH2
N
N
NH2 H2N
10 (yield= 78%)
Compound 17 was prepared from (1R,2R)-N,N0-bis-(2-
aminobenzylidene)-1,2-diphenylethylenediamine 16, by
Figure 4. Preparation of Schiff base 8.
OHC
N
N
+
2
T. A.
O2N
H2N
NH2
NO2 O2N
15
H2 (1 bar), Pd/C (10%)
CH2Cl2, 0°C
N
N
N
N
TsCl
NH
HN
SO2
p-Tol
17 (50%)
NH2 H2N
16 (60%)
Et3N, CH2Cl2
0°C
SO2
p-Tol
Figure 5. Synthesis of Schiff bases 16 and 17.

I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
1573
N-tosylation with tosyl chloride in anhydrous CH2Cl2,
in presence of Et3N at 0 ꢁC. After purification in meth-
anol,
hydrogen transfer reaction (t-BuOK, i-PrOH). When the
reaction mixture was stirred for 24 h without H2, no
reaction was observed. Only 5 equiv of t-BuOK are en-
ough for a complete conversion and a good enantiose-
lectivity.
(1R,2R)-N,N0-bis-(2p-tosyl-aminobenzylidene)-
1,2-diphenylethlenediamine 17 was obtained in 50%
yield (Fig. 5).
2.2. Asymmetric hydrogenation of acetophenone
2.2.2. Catalysts formed with [Ru(PPh3)3Cl2] and various
Schiff bases. The [Ru(PPh3)3Cl2] precursor was used
with various Schiff bases in the asymmetric hydrogena-
tion of acetophenone (Table 2). Results and reaction
conditions are summarized in Table 2.
The asymmetric hydrogenation reaction was carried out
under hydrogen pressure (30 bar) at room temperature
in the presence of the chiral catalyst prepared in situ.
The catalysts were prepared by the addition of the chiral
ligand to the metal precursor in an appropriate solvent.
The base was added to the reaction mixture just before
the addition of acetophenone (Fig. 6).
In the presence of Ru(PPh3)3Cl2, all the N4-Schiff bases
tested form active catalysts and only in two cases was
conversion not completed (ligands 3 and 7). Concerning
the enantioselection, (1R,2R)-N,N0-bis(2-aminobenzy-
lidene)-1,2-diaminocyclohexane 2 and its derivatives 3–6
and 10 led to moderate ee values (49–58%). The
replacement of NH2 by NHSO2R or NHCO(CF2)6CF3
in the Schiff bases with a diaminocyclohexane core did
not affect their activity nor their enantioselectivity, ex-
cept in the case of 3, which has NHSO2CF3 groups. Two
factors that could be responsible for the decreasing
activity: (i) the sulfonamide functions have particularly
acidic protons, which are easily removed with the
resulting R2Nꢁ groups coordinating to the metal as Xꢁ
ligands, thus blocking active sites on the catalyst, or (ii)
the conformation change, as shown by ORTEP views14
of 3 could affect the catalytic hydrogenation results. The
bromide substituents at the ortho- and para-positions on
the aromatic groups (ligand 8) strongly decrease the
enantioselectivity, whereas the tert-butyl groups (ligand
10) do not affect the activity or enantioselectivity of the
catalysts. In both cases, the catalyst appears to be sol-
uble. The Schiff base 16 with a (1R,2R)-diphenylethy-
lenediamine core also gave complete conversion and
54% ee. The (1R,2R)-N,N0-bis-(2-p-tosylaminobenzylid-
ene)-1,2-diphenylethylnediamine 17 with NHTs groups
led to 72% ee with complete conversion (Table 2). The
best enantiomeric excess (76% ee) was obtained by
preparing the catalyst directly in isopropanol from
Ru(PPh3)3Cl2 and 17.
O
OH
H2, 30 bars
MLnXm (1%), L* (1.2%)
i-PrOH, t-BuOK (10%)
r.t.
Figure 6. Asymmetric hydrogenation of acetophenone.
2.2.1. Catalysts formed with Schiff base 16. The
Schiff base (1R,2R)-N,N0-bis-(2-aminobenzylidene)-1,2-
diphenylethylenediamine 16 was used in the asymmetric
hydrogenation of acetophenone with several metallic
precursors of rhodium, iridium, and ruthenium. The
reaction conditions along with the main results are listed
in Table 1. When coupled with Schiff base 16, the cat-
ionic rhodium species did not allow any enantioselec-
tivity. In the case of iridium, the cationic precursor gave
moderate activity and enantioselectivity, whereas the
neutral one used in presence of base, led to almost
complete conversion but with disappointing ee. The
ruthenium complexes allowed complete acetophenone
hydrogenation. [Ru(COD)Cl2]x and [Ru(C6H6)Cl2]2
gave 41% and 20% ee, respectively and, in both cases,
the (R)-enantiomer was the major product. It is note-
worthy that the use of the phosphorus ruthenium pre-
cursor [Ru(PPh3)3Cl2] gave 54% ee of the opposite
enantiomer, (1S)-phenylethanol. This result was the best
obtained with Schiff base 16.
2.2.3. Role of the amine and sulfonamide functionalities.
All the tetradentate Schiff bases used herein, present an
amine or a sulfonamide group at the ortho-position of
The hydrogenation reaction with the ruthenium species
was carried under conditions close to those of the
Table 1. Asymmetric hydrogenation of acetophenone with catalysts containing 16
Metallic precursor
[Rh(COD)2]OTfa
Solvent
Base
Conversion (%)
Ee (%)
MeOH
MeOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
––
––
74
56
0
a
[Ir(COD)2]BF4
b
43 (S)
20 (S)
41 (R)
20 (R)
54 (S)
[Ir(COD)Cl]2
[Ru(COD)Cl2]x
t-BuOK
t-BuOK
t-BuOK
t-BuOK
99
c
100
100
100
c
[Ru(C6H6)Cl2]2
[Ru(PPh3)3Cl2]c
[S] ¼ 0.3 M and S/k-BuOK/Lꢂ/M ¼ 100/10/1/1; 30 bar of H2; 50 ꢁC; 16 h.
a [M]þ16þMeOH, 1 h at 50 ꢁC, then addition of acetophenone.
b [M]þ16þi-PrOH, 1 h at 50 ꢁC, then addition of t-BuOK and acetophenone.
c [M]þ16þtoluene, 1 h at rt, then evaporation of toluene and addition of i-PrOH and t-BuOK and acetophenone.

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I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
Table 2. Various Schiff bases in asymmetric hydrogenation of acetophenone
General structure
Ligand Lꢂ
Conversion (%)
100
Ee (%)
2. R1 ¼ R2 ¼ H
55 (S)
58a (S)
49 (S)
57 (S)
56 (S)
50 (S)
7 (R)
3. R1 ¼ H, R2 ¼ Tf
60
100
100
100
75
4. R1 ¼ H, R2 ¼ Ts
N
N
5. R1 ¼ H, R2 ¼ C10H7SO2
6. R1 ¼ H, R2 ¼ CF3 (CF2)6CO
8. R1 ¼ Br, R2 ¼ H
R1
NH
R2
HN
R1
R2
R1
R1
10. R1 ¼ t-Butyl, R2 ¼ H
100
50 (S)
16. R3 ¼ H
17. R3 ¼ Ts
100
100
54 (S)
72 (S)
76a (S)
N
N
NH
R3
HN
R3
[S] ¼ 0.3 M; L/M ¼ 1.2; S/metal ¼ 100; t-BuOK/metal ¼ 10; 30 bar of H2; t.a.; 16 h.
[M]þLꢂþtoluene, 1 h at rt, then evaporation of tolueneþi-PrOHþt-BuOKþacetophenone.
a [M]þ2 or 17þi-PrOH, then agitation 6–16 h at rt, then addition of t-BuOKþacetophenone.
benzylidene groups. In order to evaluate the role of
these functionalities, we tested phenyl diimines, which
we prepared according to reported procedures from
benzaldehyde and the corresponding chiral diamines
and then evaluated their chiral inductor properties in
acetophenone hydrogenation. The results of the cata-
lytic tests are summarized in Table 3. Contrary to
ligands 16 and 17, the (1R,2R)-N,N0-bis-(benzylidene)-
The (1R,2R)-N,N0-bis-(benzylidene)-1,2-diaminocyclo-
hexane 18 and (1R,2R)-N,N0-bis-(2-aminobenzylidene)-
1,2-diaminocyclohexane 2 tested with Ru(PPh3)3Cl2
gave identical results. The cyclohexyl skeleton can in-
duce a relative rigidity to ligand 18. Therefore, if we
used the [Ru(COD)Cl2]x without any phosphine, the
Schiff base 2 containing NH2 functions gave a better
result than ligand 18. The ligands with amine and sul-
fonamide groups contributed to the formation of the
rigid catalysts and constitute the N-donor ligands easily
replaced by phosphines.
1,2-diphenylethylenediamine
19
combined
with
Ru(PPh3)3Cl2 did not allow any chiral induction. In this
particular case, the cisoid conformation of 19 is less
stable than the transoid thanks to steric hindrance. In
the case of ligand 16, the amine–amine and amine–imine
interactions allow a rigidity of the Schiff base structure.
In the case of ligand 17, we can assume an increasing
rigidity due to the face to face p-stacking interaction
between the two tosyl groups. A p-stacking interaction
of that type has been noted in ligand 4 in our previous
study and also been reported by Bermejo and
co-workers.13
2.2.4. Phosphines as co-ligands. The metallic precursor
Ru(PPh3)3Cl2 has three triphenylphosphine ligands,
which can have a synergetic effect with diimine ligand. In
order to avoid this influence, we used [Ru(C6H6)Cl2]
with ligand 17 (Table 4): 44% conversion and 12% ee
(S) were then observed. The addition of 1, 2, and 3 equiv
of PPh3 to the [Ru(C6H6)Cl2]2/11 system, allowed
Table 3. Schiff base de 2, 16, 17, 18, and 19 in asymmetric hydrogenation of acetophenone
Lꢂ
X
Metallic precursor
Conversion (%)
Ee (%)
H (19)
NH2 (16)
NH-tosyle (17)
Ru(PPh3)3Cl2
Ru(PPh3)3Cl2
Ru(PPh3)3Cl2
100
100
100
0
54 (S)
76 (S)
N
X
N
X
H (18)
H (18)
Ru(PPh3)3Cl2
[Ru(COD)Cl2]x
[Ru(COD)Cl2]x
Ru(PPh3)3Cl2
100
37
56 (S)
0
N
X
N
X
NH2 (2)
NH2 (2)
100
100
37 (R)
55 (S)
[S] ¼ 0.3 M and S/t-BuOK/Lꢂ/M ¼ 100/10/1.2/1; 30 bar H2; rt; 16 h.

I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
1575
with ruthenium dihydride.21;22 This mechanism carries
four steps. In the various mechanisms proposed for the
asymmetric hydrogenation reaction with ruthenium
(monohydride or dihydride), the presence of a base
proved essential for the exchange of the chloride ligand
by the hydride in the active species.23–25
Table 4. Co-ligand phosphines used in asymmetric hydrogenation of
acetophenone par 17/[Ru(C6H6)Cl2]
Co-ligand
Conversion (%) Ee (%)
None
PPh3
P(Cy)3
44
100
100
100
96
12 (S)
73 (S)
7 (S)
P(p-Tol)3
P(o-Tol)3
P(TMOPh)3
P(bTFMP)3
DPPE
67 (S)
10 (S)
5 (S)
Although the metal precursors [Ru(COD)Cl2]2 and
Ru(PPh3)3Cl2 are both ruthenium complexes, the first
with ligand 16 supported the majority formation of
(1R)-phenylethanol (41% ee), whereas the second sup-
ported the majority formation of (1S)-phenylethanol
(52% ee). This difference was also observed in the case of
ligand 2 (Table 5).
100
90
15 (S)
33 (S)
48 (S)
54 (S)
100
100
100
DPPP
DPPB
[S] ¼ 0.3 M; S/metal ¼ 100; t-BuOK/Ru ¼ 10; Lꢂ/M ¼ 1.2; phosphine/
Ru ¼ 1; 30 bar H2; rt; 16 h.
The complex formed from [Ru(COD)Cl2]x and chiral
ligand Lꢂ is undoubtedly different to that formed from
Ru(PPh3)3Cl2 and the same ligand Lꢂ. We can thus
consider that two different mechanisms occur during
acetophenone hydrogenation. In the case of
[Ru(COD)Cl2]x, the catalyst formed is probably of
Ru(Lꢂ)H2 21 type where the chiral ligand is coordinated
to the metal center by the four nitrogen atoms. A clear
difference in activity and enantioselectivity was observed
with [Ru(COD)Cl2]x when coordinated to ligand 2
(c ¼ 100%, ee ¼ 37%) or ligand 18 (c ¼ 37%, ee ¼ 0%).
This indicates the effective participation of amine groups
in the formation of catalysts. The dihydride complex
Ru(Lꢂ)H2 21 should be formed from the dichloride
complex Ru(Lꢂ)Cl2 20 in basic media (Fig. 8).
P
P
P
P
3
3
3
3
PPh3
P(p-Tol)3
P(o-Tol)3
P(Cy)3
CF3
MeO
P
Ph2P
PPh2
n
P
OMe
dppe n=2
dppp n=3
dppb n=4
3
3
CF3
P(bTFMP)3
MeO
P(TMOPh)3
Figure 7. Phosphines used as co-ligands for acetophenone hydro-
genation with Ru catalyst.
We suggest the mechanism (a) for the reduction carried
out with Ru(Lꢂ)H2 21 similar to that proposed by
Morris (Fig. 9). In this mechanism, the nitrogen atom
takes part not only in the coordination to metal, but also
to the hydrogen donation.
72–73% ee with complete conversion. This result was
identical to the one obtained for [Ru(PPh3)3Cl2]/17
(Table 2).
Several phosphines (Fig. 7) have also been used in order
to form a co-ligand with diimine (Table 4). Low
enantioselectivities (15%) were observed with P(Cy)3,
P(o-Tol)3, P(TMOPh)3, and P(bTFMP)3, which are
bulky phosphines. P(p-Tol)3 was the only phosphine
able to give results close to those obtained with PPh3.
The use of diphosphine co-ligands such as DPPE,
DPPP, and DPPB also decreased the enantioselectivity.
This effect was noticeable when the number of carbons
between the two phosphorus atoms decreased. This
could be explained by the low possibility of DPPB act-
ing as a mono phosphine due to the chelating effect.
The same results were obtained with ligand 2 or ligand
18 in the presence of Ru(PPh3)3Cl2 (55–56% ee); the
formation of two similar complexes can be assumed.
The presence of one or three triphenylphosphines
co-ligands gave identical results (Tables 1 and 5); the
active species should be dihydrides of a general formula
Ru(Lꢂ)(PPh3)H2 26, and should be formed from the
corresponding dichlorides Ru(Lꢂ)(PPh3)Cl2 25 in basic
media (Fig. 10).
We propose the mechanism (b), which is possible during
hydrogenation with the catalyst 26 and can be carried
out in four principal steps (Fig. 11): 1)––coordination of
substrate, 2)––migration 1–2 of the substrate, 3)––
reductive elimination and formation of Ru0 species, and
4)––oxidative addition and regeneration of catalyst.
2.2.5. Mechanism. Morris and co-workers18 have pro-
posed a mechanism for hydrogenation of simple ketones
catalyzed by BINAP–Ru–diamine system, in which the
dihydride complex reacts with a ketone to produce
the alcohol and novel amino–amido complex in the
unconventional second coordination sphere transfer of
dihydrogen. This transfer of dihydrogen as first pro-
posed by Noyori et al., was studied later by other
groups19 and our laboratory.20 Before the discovery of
Noyori catalysts, simple aromatic ketones such as the
acetophenone, were not hydrogenated by ruthenium
catalysts. Whereas Komiya and Yamamoto proposed in
1979, a mechanism for hydrogenation of olefins (C@C)
The amine or sulfonamides functionalities do not seem
to participate in coordination to the metal center during
the reaction. These functions can play a part in the
hindrance and stabilization of catalysts. With ligands 16
and 17, we observed better results than with 19 (Table
3).
The addition of 0.5 equiv of PPh3 to the catalytic system
[Ru(COD)2Cl2]x/2 allowed the formation of the two

1576
I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
Table 5. Selection results obtained with different catalytic system of ruthenium
Ligand (Lꢂ)
Metallic precursor (1%)
Co-ligand
Conversion (%)
Ee (%)
[Ru(COD)Cl2]x
Ru(PPh3)3Cl2
––
––
92
100
41 (R)
52 (S)
N
N
NH2 H2N
16
[Ru(COD)Cl2]x
[Ru(COD)Cl2]x
[Ru(COD)Cl2]x
Ru(PPh3)3Cl2
––
100
100
100
100
37 (R)
54 (S)
57 (S)
55 (S)
PPh3 (1.2%)
PPh3 (0.5%)
––
N
N
NH2 H2N
2
N
N
[Ru(COD)Cl2]x
Ru(PPh3)3Cl2
37
100
0
56 (S)
––
18
[S] ¼ 0.3 M; and S/t-BuOK/Lꢂ/M ¼ 100/10/1.2/1; 30 bar H2; rt; 18 h.
N
N
NH2
NH2
N
N
NH2
NH2
Cl
Ru
Cl
H
iPrOH
t-BuOK
2 ou 16 + [Ru(COD)Cl2]x
Ru
H
iPrOH, H2
21
20
Figure 8. Preparation of catalyst from chiral Schiff base Lꢂ and Ru(PPh3)3Cl2.
catalysts 21 and 26 in reaction mixture. As the results
obtained with 0.5 or 1 equiv of PPh3 are identical, we
assume that the rate of the reduction carried with 26 is
much larger than that of the reduction carried with 21.
N
N
NH2
NH2
H
O
Ru
H
O
H
21
3. Conclusion
H
This study is to the best of our knowledge the first report
on the use of Schiff bases as chiral inductors for aceto-
phenone hydrogenation. In the case of ruthenium species,
we have developed a new catalytic and enantioselective
system: the best result (100% conversion, 76% ee) was
obtained with (1R,2R)-N,N0-bis-(2-p-tosylaminobenzyl-
idene)-1,2-diphenylethylenediamine 17 coordinated to
H
N
N
NH
N
N
NH
H
Ru
Ru
H
NH2
H
NH2
24
22
[Ru(PPh3)3Cl2].
[Ru(COD)Cl2]/(1R,2R)-N,N0-bis-(2-
N
N
NH
H2
aminobenzylidene)-1,2-diphenylethylenediamine 16 led
to an encouraging enantiomeric excess (41%) with com-
plete conversion. This is one of the best results obtained
for asymmetric hydrogenation of acetophenone with a
nonphosphorus ruthenium catalyst. We have noticed a
synergetic co-ligand effect between some Schiff bases and
triphenylphosphine, increasing both the activity and
Ru
H
*
NH2
OH
23
Figure 9. Mechanism (a) proposed with catalyst Ru(Lꢂ)H2 21.

I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
1577
N
Cl
Ru
Cl
N
H
Ru
H
N
t-BuOK (10 éq)
iPrOH, H2
iPrOH
PPh3
+ Ru(PPh3)3Cl2
PPh3
N
N
N
25
26
L*
Figure 10. Preparation of catalyst from chiral Schiff base Lꢂ and [Ru(COD)Cl2]x.
of organometallic compounds were carried out under an
argon atmosphere. The metallic precursors were pur-
chased from STREM.
N
N
H
Ru
PPh3
O
H
26
H2
Melting points (mp), uncorrected, were determined with
€
O. A.
PPh3
R. E.
a Koffler Bench type WME (HeIZBANK). Elemental
analyses (C, H, N, S, O, F) were obtained from the
Service Central d’Analyse of the CNRS (Solaize). High
resolution mass spectra: HR LSIMS (Liquid Secondary
Ionization Mass Spectrometry: Thioglycerol), HR
CIMS (Isobutan), and HR EIMS were carried out on a
Finnegan MAT 95xL by the UCBL Centre de Spec-
troscopie de Masse. IR spectra (KBr plates) were
N
N
H
N
N
O
Ru
Ru
H
PPh3
29
27
recorded on a FT Nicolet impact spectrometer 410:
20
D
I.R.F.T. or on a FT Perkin–Elmer spectrometer. ½aꢃ
was determined with a Perkin–Elmer 241 polarimeter
(l ¼ 1 dm; 25 ꢁC; concentration c in g/mL). 1H, 13C, and
19F NMR spectra were recorded on a Bruker AC-200
(200.13 MHz for H, 50.32 MHz for 13C, 188.29 MHz
H
N
N
*
O
OH
Ru
H
1
PPh3
H
28
for 19F) or AC-300 FT (300.13 MHz for 1H,
75.46769 MHz for 13C, 282.4481 MHz for 19F) spec-
trometer; d values are given in ppm and J in hertz. The
ee values and conversion were determined by chiral GC
(Cyclodex b colum, 30 m).
O.A.: Oxidant addition; R.E.: Reducing elimination
Figure 11. Mechanism (b) proposed with catalyst Ru(Lꢂ)PPh3H2 26.
enantioselectivity of the ruthenium catalysts. In the case
of diimine–diamine ligands, the presence of phosphine
supported the majoritary formation of the opposite (S)-
enantiomer than the one formed without phosphine
(R)-1-phenylethanol. This difference suggests that two
different mechanisms of acetophenone hydrogenation
can occur with ruthenium complexes. The diimine/Ru/
phosphine system can be alternative catalysts to those
developed by Noyori. We are now focusing on the
development of these catalysts and on the study of the
complexes and the different effects, which can improve
better enantioselectivity.
4.2. Synthesis of ligands and organic compounds
4.2.1. (1R,2R)-N,N0-Bis-(2-naphthalene-sulfonaminobenz-
ylidene)-1,2-diaminocyclohexane, 5. (1R,2R)-N,N0-Bis-
(2-aminobenzylidene)-1,2-diaminocyclohexane (0.54 g,
1.68 mmol) was dissolved in dry dichloromethane
(10 mL), Et3N (490 lL, 3.53 mmol) then added and the
resulting solution cooled to ꢁ10 ꢁC under an argon
atmosphere. At this temperature, 1-naphthalenesulfonyl
chloride (0.8 mg, 3.53 mmol) was added and the result-
ing solution stirred overnight (the temperature was
allowed to rise at room temperature). The solvent was
then removed and ligand 5 (0.3 g) was obtained after a
flash chromatography as a yellow solid (silica, dichlo-
romethane/ethyl acetate, 99.5/0.5). Isolated yield ¼ 40%.
20
D
4. Experimental section
4.1. General remarks
MW ¼ 700.87; ½aꢃ ¼ ꢁ207 (c 11.35 · 10ꢁ3 g/mL;
CH2Cl2). Mp 140 ꢁC. 1H NMR (CDCl3, 300 MHz,
25 ꢁC), d (ppm) ¼ 13.73 (s, 2H, NHSO2), 8.74 (m, 2H,
Ar–H), 8.30 (s, 2H, Ar–H), 8.27 (m, 2H, Ar–H), 7.98 (m,
2H, Ar–H), 7.88 (m, 2H, Ar–H), 7.57 (m, 4H, Ar–H),
7.41 (m, 4H, Ar–H), 7.14 (m, 4H, Ar–H), 6.82 (m, 2H,
Ar–H), 3.49 (m, 2H, HC–N), 2–1.5 (m,8H, –CH2–). 13C
NMR (CDCl3, 300 MHz, 25 ꢁC): d (ppm) ¼ 164.9
(C4@N), 139.7 (Cq–Ar), 135.4 (Cq–Ar), 134.7 (C–Ar),
134.6 (Cq–Ar), 134.0 (C–Ar), 131.7 (C–Ar), 130.0 (C–
Ar), 129.4 (C–Ar), 128.6 (Cq–Ar), 128.48 (C–Ar), 127.1
All the organic and organometallic reagents used were
pure commercial products. The solvents from Carlo
Erba, anhydrous THF from Aldrich, dry CH2Cl2 were
prepared in the laboratory. Enantiomerically pure
diamines (1R,2R)-cyclohexanediamine and (1R,2R)-
diphenylethylenediamine were obtained from Fluka,
2-nitrobenzaldehyde from Avocado. All manipulations

1578
I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
(C–Ar), 124.9 (C–Ar), 124.5 (C–Ar), 122.2 (C–Ar),
119.9 (Cq–Ar), 116.3 (C–Ar), 73.6 (CH–N), 33.5 (CH2),
24.7 (CH2). IR (KBr), m (cmꢁ1) ¼ 2857–2928 (NH), 1629
(C@N), 1134–1160 (SO2). HR LSIMS calcd for
C40H36N4O4S2ÆHþ ¼ 701.2178; found ¼ 701.2247.
4.2.4. 3,5-Di-tert-butyl-2-amino-benzaldehyde 9. 3,5-Di-
tert-butyl-2-nitrobenzaldehyde (1 g, 0.0038 mmol) was
dissolved in 75 mL of CH2Cl2. To this solution 1 g of
Pd–C (10%) was added and the resulting mixture stirred
under hydrogen pressure (20 bar) at 50 ꢁC. After 48 h the
mixture was filtered on Celite, the solvent removed by
evaporation to give 0.859 g of 3,5-di-tert-butyl-2-
aminobenzaldehyde 9 as a yellow solid. Isolated
yield ¼ 97%. FW ¼ 233.35; Mp ¼ 95 ꢁC. 1H NMR
(CDCl3, 300 MHz, 25 ꢁC) d (ppm) ¼ 9.9 (s, 1H, CHO),
7.5 (d, 4JH;H ¼ 2:08 Hz, 1H, Ar–H), 7.33 (d,
4JH;H ¼ 2:08 Hz, 1H, Ar–H), 6.6 (br s, 2H, Ar–NH2),
1.45 (s, 9H, tert-butyl), 1.3 (9H, s, tert-butyl). 13C NMR
(CDCl3, 300 MHz, 25 ꢁC) d (ppm) ¼ 194.9 (C@O), 146.9
(Cq–Ar), 138.2 (Cq–Ar), 133.4 (Cq–Ar), 130.5 (C–Ar),
118.8 (Cq–Ar), 34.5 (Cq, C(CH3)3), 34 (Cq, C(CH3)3),
31.3 (CH3, t-Bu), 29.6 (CH3, t-Bu). IR (KBr) m
(cmꢁ1) ¼ 1662 (CHO), 3319 (NH2). HR EIMS calcd for
C15H23NO ¼ 233.177964; found ¼ 233.17768.
4.2.2. (1R,2R)-N,N0-Bis-(2-perfluooctanoylsulfonamino-
benzylidene)-1,2-diaminocyclohexane 6. The (1R,2R)-
N,N0-bis-(2-aminobenzylidene)-1,2-diaminocyclohexane
(0.26 g, 0.8 mmol) was dissolved in dry CH2Cl2 (10 mL),
before addition of Et3N (0.27 mL, 1.9 mmol). The
resulting solution was cooled to ꢁ10 ꢁC, and
CF3(CF2)6Cl (750 mg, 1.9 mmol) was then added drop-
wise. The solution was stirred overnight (the tempera-
ture was allowed to rise at room temperature) and
washed with 4 · 10 mL of a saturated solution of NaCl.
After separation, the organic layer was dried over
Na2SO4, and the solvent evaporated. Ligand 6 was ob-
tained as a yellow oil and dried under vacuum
(P ¼ 0:1 mmHg). Isolated yield ¼ 50%. FW ¼ 1169.46;
4.2.5. (1R,2R)-(ꢁ)-N,N0-Bis-(3,5-di-tert-butyl-2-amino-
benzylidene)-1,2-diaminocyclohexane 10. To a solution
of 3,5-di-tert-butyl-2-aminobenzaldehyde (0.437 g, 18.7 ·
10ꢁ4 mmol) in 10 mL of dichloromethane, 0.107 g
(9.35 · 10ꢁ4 mmol) of (1R,2R)-diaminocyclohexane and
20
1
½aꢃ ¼ ꢁ283 (c 0.01 g/mL, CH2Cl2). H NMR (CDCl3,
D
300 MHz, 25 ꢁC): d (ppm) ¼ 14.2 (s large, 2H, NH), 8.63
(m, 2H, Ar–H), 8.23 (s, 2H, HC@N), 7.4 (m, 2H, Ar–H),
7.26 (m, 2H, Ar–H), 7.18 (m, 2H, Ar–H), 3.37 (m, 2H,
CH–N), 1.9 (m, 4H, –CH2–), 1.7 (m, 2H, –CH2–), 1.5
(m, 2H, –CH2–). 13C NMR (CDCl3, 300 MHz, 25 ꢁC): d
(ppm) ¼ 164 (C@N), 156 (C@O), 138 (Cq–Ar), 133.6
(C–Ar), 132 (C–Ar), 125 (C–Ar), 121.7 (Cq–Ar), 120.5
(C–Ar), 74.8 (C–N), 33.5 (–CH2), 24.56 (–CH2–). 19F
NMR (CDCl3, 300MHz, 25ꢁC): d (ppm) ¼ ꢁ81.2 (m, 6F,
CF3), ꢁ119.4 (m, 4F, –CF2–), ꢁ121.8 (m, 4F, –CF2–),
ꢁ122.3 (m, 4F, –CF2–), ꢁ122.6 (m, 4F, –CF2–), ꢁ123.1
(m, 4F, –CF2–), ꢁ126.5 (m, 4F, –CF2–CO). IR (NaCl) m
(cmꢁ1) ¼ 1150–1330 (CF2, CF3), 1636 (C@N), 1724
(CHO). HR LSIMS calcd for C36H22F30N4O2ÆHþ ¼
1113.1340; found ¼ 1113.13378.
ꢂ
4 A molecular sieves were added. The resulting mixture
was stirred overnight at 35 ꢁC. After the mixture was
filtered through Celite and the solvent removed by
evaporation, the residue was washed with methanol and
filtered through a Millipore filter (vv type, pore size
0.10 lm). Finally, it was dried under vacuum to give 0.4 g
of ligand 10 as a white solid. Isolated yield ¼ 78%.
20
FW ¼ 544.86. Mp ¼ 194 ꢁC. ½aꢃ ¼ ꢁ313 (c 0.001 g/mL,
D
CH2Cl2). 1H NMR (CDCl3, 300 MHz, 25 ꢁC)
d
4
(ppm) ¼ 8.3 (s, 2H, HC@N), 7.26 (d, JH;H ¼ 2:16 Hz,
2H, Ar–H), 7.0 (d, 4JH;H ¼ 2:16 Hz, 2H, Ar–H), 6.76 (br
s, 4H, Ar–NH2), 3.22 (m, 2H, CH–N), 1.9–1.5 (m, 8H,
–CH2–), 1.35 (s, 18H, C(CH3)3), 1.22 (s, 18H, C(CH3)3).
13C NMR (CDCl3, 200 MHz, 25 ꢁC) d (ppm) ¼ 164.6
(C@N), 145 (Cq–Ar), 137.2 (Cq–Ar), 132.5 (Cq–Ar),
128.5 (C–Ar), 125.5 (C–Ar), 117.8 (Cq–Ar), 74.4 (CH–
N), 34.5 (Cq–C(CH3)3), 33.8 (Cq–C(CH3)3), 33.6
(–CH2), 31.5 (CH3–C(CH3)3), 29.7 (CH3–C(CH3)3), 24.6
(–CH2). IR (KBr) m (cmꢁ1) ¼ 1633.49 (C@N), 3139–3515
(NH2). Anal. Calcd (%) for C36H56N4: C, 79.36; H, 10.36;
N, 10.28. Found (%): C, 79.15; H, 10.32; N, 10.11. HR
LSIMS calcd for C36H56N4ÆHþ ¼ 545.4584; found ¼
545.4590.
4.2.3. (1R,2R)-(ꢁ)-N,N0-Bis-(2-amino-3,5-dibromobenzyl-
idene)-1,2-diaminocylohexane 8. To
a solution of
(1R,2R)-(ꢁ)-diaminocyclohexane (0.564 g, 4.94 mmol)
in anhydrous THF (10 mL), 2-amino-3,5 dibromobenz-
ꢂ
aldehyde (2.755 g, 9.88 mmol) and molecular sieves 4 A
were added. After stirring for 17 h under an argon
atmosphere at room temperature, the mixture was fil-
tered through silica (CH2Cl2). The solvents were evap-
orated to give 2.28 g of ligand 7 as a yellow solid.
Isolated yield ¼ 73%. FW ¼ 632.4; Mp ¼ 174 ꢁC.
20
1
½aꢃ ¼ ꢁ244 (c 0.01 g/mL, CH2Cl2). H NMR (CDCl3,
D
300 MHz, 25 ꢁC) d (ppm) ¼ 8.27 (s, 2H, CH@N), 7.5
4.2.6. 3,5-Di-tert-butylbenzaldehyde 11. A solution of
3,5-di-tert-butyltoluene (5 g, 24.46 mmol) of N-bromo-
succinimide (9 g, 50.56 mmol) and 40 mg of benzoyl
peroxide in 80 mL of CCl4 was heated at reflux for 15 h.
When the reaction was finished (CG control) the reac-
tion mixture was filtered through Celite and the CCl4
was removed on a rotary evaporator to give an oily
mixture of 3,5-di-tert-butylbenzylbromide (38%) and
3,5-di-tert-butylbenzyldibromide (62%). 1H NMR for
4
(d, 2H, JH;H ¼ 2:15 Hz, Ar–H), 7.16 (d, 2H,
4JH;H ¼ 2:16 Hz, Ar–H), 7 (br s, 4H, NH2), 3.26 (m, 2H,
CH–N), 1.5–2 (m, 8H, –CH2–). 13C NMR (CDCl3,
300 MHz, 25 ꢁC) d (ppm) ¼ 161.6 (C@N), 145 (Cq–Ar),
135.8 (C–Ar), 135.1 (C–Ar), 119.7 (Cq–Ar), 110.3 (Cq–
Ar), 106.5 (Cq–Ar), 74.8 (CH–N), 33.6 (–CH2–), 24.7
(–CH2–). IR (KBr), m (cmꢁ1) ¼ 3231–3464 (NH2), 1627
(C@N). HR LSIMS calcd for C20H20N4-Br4ÆHþ ¼
632.8500; found ¼ 632.84993. Anal. Calcd (%) for
C20H20N4Br4 (632.4 g molꢁ1): C, 37.985; H, 3.187; N,
8.86. Found: C, 37.85; H, 3.00; N, 8.08.
3,5-di-tert-butylbenzylbromide
(CDCl3,
300 MHz,
25 ꢁC) d (ppm) ¼ 7.4–7.25 (m, 3H, Ar–H), 4.53 (s, 2H,
CH2Br), 1.37 (s, 18H, C(CH3)3). For 3,5-di-tert-butyl-

I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
1579
benzyldibromide d (ppm) ¼ 7.4–7.25 (m, 3H, Ar–H), 6.7
(s, 1H, CHBr2), 1.37 (s, 18H, C(CH3)3). The mixture of
3,5-di-tert-butylbenzylbromide and 3,5-di-tert-butyl-
benzyldibromide was added to a solution of 9.45 g of
hexamethylenetetramine in 7 mL of water and 7 mL of
ethanol. This solution was refluxed for 4 h. After liquid–
liquid extraction with a mixture of Et2O/toluene (50/50),
the organic layer was washed with 3 · 20 mL of brine,
and dried with Na2SO4. The solvents were evaporated to
give 4 g of 11 as a white solid. Isolated yield ¼ 75%.
FW ¼ 218.33. Mp ¼ 86 ꢁC. 1H NMR (CDCl3, 300 MHz,
25 ꢁC) d (ppm) ¼ 10.02 (s, 1H, CHO), 7.73 (m, 3H, Ar–
H), 1.37 (s, 18, C(CH3)3). 13C NMR (CDCl3, 200 MHz,
25 ꢁC) d (ppm) ¼ 193.24 (CHO), 151.9 (Cq–Ar), 136.3
(Cq–Ar), 129.9 (C–Ar), 124.2 (C–Ar), 35 (Cq, C(CH3)3),
31.4 (3CH3, C(CH3)3). IR (KBr) m (cmꢁ1) ¼ 1693
(CHO). HR EIMS calcd for C15H22O ¼ 218.1671;
found ¼ 218.16749.
127.9 (Cq–Ar), 127.2 (C–Ar), 123.3 (C–Ar), 74.33 (CH–
N), 36 (Cq, C(CH3)3), 35.11 (Cq, C(CH3)3), 32.5 (–CH2–),
31.05 (3CH3, C(CH3)3), 30.9 (3CH3, C(CH3)3), 24.3
(–CH2–). IR (KBr) m (cmꢁ1) ¼ 1530 (NO2), 1644 (C@N).
HR LSIMS calcd for C36H52N4O4ÆHþ ¼ 605.4068;
found ¼ 605.40775.
4.2.9. 3,5-Di-tert-butyl-2-azobenzaldehyde 14. A brown
oil was obtained by reduction of 3,5-di-tert-butyl-2-
aminobenzaldehyde, in dichloromethane under one
atmosphere of hydrogen at 50 ꢁC. Compound 14 was
also obtained as a secondary product, if the reduction of
3,5-di-tert-butyl-2-nitrobenzaldehyde did not go to
completion. In this case 14 and 9 were separated by flash
1
chromatography on silica (eluent: CH2Cl2). H NMR
(CDCl3, 300 MHz, 25 ꢁC) d (ppm) ¼ 9.03 (s, 2H, CHO),
7.26 (d, 4JH;H ¼ 1:5 Hz, 2H, Ar–H), 7.22 (d,
4JH;H ¼ 1:5 Hz, 2H, Ar–H), 1.56 (s, 18H, C(CH3)3), 1.35
(s, 18H, C(CH3)3). 13C NMR (CDCl3, 300 MHz, 25 ꢁC)
d (ppm) ¼ 154.57 (Cq–Ar), 153.3 (C@O), 146.9 (Cq–Ar),
138.1 (Cq–Ar), 125.3 (C–Ar), 119.8 (Cq–Ar), 110.5 (Cq–
Ar), 35.8 (Cq–C(CH3)3), 35 (Cq–C(CH3)3), 30.5 (3CH3,
4.2.7. Compound 12: 3,5-di-tert-butyl-2-nitro-benzalde-
(4 g,
hyde.
The
3,5-di-tert-butylbenzaldehyde
18.32 mmol) was dissolved in 12 mL of concentrated
solution of H2SO4. After the mixture was cooled at 0 ꢁC,
0.9 mL of concentrated solution of HNO3 was added
drop by drop. The mixture was stirred for 30 min at 0 ꢁC
and then poured into 50 mL of water containing chop-
ped ice. The organic product was separated by extrac-
tion with 3 · 50 mL of CH2Cl2, the organic layer was
washed with water, dried with Na2SO4, and evaporated
on a rotary evaporator to give 4.1 g of 12 as a yellow
solid. Isolated yield ¼ 85%. FW ¼ 263.33. Mp ¼ 90 ꢁC.
1H NMR (CDCl3, 300 MHz, 25 ꢁC) d (ppm) ¼ 9.82 (s,
1H, CHO), 7.83 (d, 4JH;H ¼ 2:07 Hz, 1H, Ar–H), 7.82 (d,
4JH;H ¼ 2:07 Hz, 1H, Ar–H), 1.45 (s, 9H, C(CH3)3), 1.34
(s, 9H, C(CH3)3). 13C NMR (CDCl3, 200 MHz, 25 ꢁC) d
(ppm) ¼ 187.5 (CHO), 153.56 (Cq–Ar), 140.8 (Cq–Ar),
135 (Cq–Ar), 127.35 (Cq–Ar), 125.63 (C–Ar), 36.3 (Cq,
C(CH3)3), 35.35 (Cq, C(CH3)3, 31.08 (3CH3, C(CH3)3),
30.85 (3CH3, C(CH3)3). IR (KBr) m (cmꢁ1) ¼ 1701
(CHO), 1541 (NO2). HR EIMS calcd for
C15H21NO2ÆHþ ¼ 263.1521; found ¼ 263.1599.
C(CH3)3), 29.8 (3CH3, C(CH3)3). IR (NaCl)
(cmꢁ1) ¼ 1636 (CHO), 1532–1557 (N@N).
m
4.2.10. (1R,2R)-N,N0-Bis-(2-aminobenzylidene)-1,2-diph-
enylethlenediamine 16. To a solution of (1R,2R)-1,2-
diphenylethlenediamine (0.4 g, 1.088 mmol) in anhy-
drous dichloromethane (8 mL), 2-nitrobenzaldehyde
(0.56 g, 3.74 mmol), 0.1 g of Pd–C (10%) and molecular
ꢂ
sieves (4 A) were added and the resulting mixture stirred
under one atmosphere of hydrogen at 0 ꢁC. After con-
sumption of the required volume of H2 (275 mL), the
mixture was filtered on Celite and the solvent removed.
The resulting residue was washed with methanol, filtered
through a Millipore filter and dried under vacuum
(P ¼ 0:1 mmHg) to give ligand 16 (0.47 g) as a grey
solid. Isolated yield: 60%. FW ¼ 418.54; Mp ¼ 200 ꢁC.
20
1
½aꢃ ¼ ꢁ37 (c 10ꢁ3 g/mL, CH2Cl2). H NMR (CDCl3,
D
300 MHz, 25 ꢁC): d (ppm) ¼ 8.27 (s, 2H, HC@N), 7.20
(m, 10H, Ar–H), 7.09 (m, 4H, Ar–H), 6.63 (m, 4H, Ar–
H), 6.47 (s large, 4H, NH2), 4.67 (s, 2H, CH–N). 13C
NMR (CDCl3, 300 MHz, 25 ꢁC): d (ppm) ¼ 165.0
(C6@N), 148.9 (Cq–Ar), 141.6 (Cq–Ar), 134.0 (C–Ar),
131.3 (C–Ar), 128.7 (C–Ar), 128.3 (C–Ar), 127.4 (C–
Ar), 118.1 (Cq–Ar), 116.3 (C–Ar), 115.9 (C–Ar), 82.5
(C5–N). IR (KBr) m (cmꢁ1) ¼ 3256–3460 (Ar–NH2) 1626
(C@N). HR CIMS calcd for C28H26N4Hþ ¼ 419.22364;
found ¼ 419.2240. C28H26N4 (418.54 g molꢁ1): Anal.
Calcd: C, 79.04; H, 6.53; N, 13.17. Found: C, 78.99; H,
6.22; N, 13.29.
4.2.8. (1R,2R)-(ꢁ)-N,N0-Bis-(3,5-di-tert-butyl-2-nitrobenz-
ylidene)-1,2-diaminocyclohexane 13. To a solution of 1 g
of (1R,2R)-1,2-diaminocyclohexane (8.75 mmol) in
15 mL of anhydrous THF, 4.612 g of 3,5-di-tert-butyl-2-
ꢂ
nitrobenzaldehyde (17.514 mmol) and 4 A molecular
sieves were added. The mixture was stirred overnight at
room temperature under an argon atmosphere. Di-
chloromethane (15 mL) were added and the resulting
mixture filtered through silica (CH2Cl2), the solvents
evaporated and the residual oil dried under vacuum to
give 3.44 g of product 13 as a yellow solid. Isolated
20
D
yield ¼ 65%. FW ¼ 604.82. Mp ¼ 98 ꢁC. ½aꢃ ¼ ꢁ58 (c
4.2.11.
(1R,2R)-N,N0-Bis-(2p-tosylaminobenzylidene)-
0.001 g/mL, CH2Cl2). 1H NMR (CDCl3, 300 MHz,
1,2-diphenylethlenediamine 17. (1R,2R)-N,N0-Bis-(2-
aminobenzylidene)-1,2-diphenylethlenediamine (0.36 g,
0.86 mmol) was dissolved in 4 mL of dry CH2Cl2, Et3N
(250 lL, 1.8 mmol) was added and the solution cooled at
ꢁ10 ꢁC under an argon atmosphere. At this tempera-
ture, p-toluenesulfonyle chloride (0.34 g, 1.8 mmol) was
added and the resulting mixture stirred overnight (the
25 ꢁC)
d
(ppm) ¼ 8 (s, 2H, HC@N), 7.68 (d,
4
4JH;H ¼ 2:2 Hz, 2H, Ar–H), 7.5 (d, JH;H ¼ 2:2 Hz, 2H,
Ar–H), 3.4 (m, 2H, CH–N), 1.8–1.4 (m, 8H, –CH2–),
1.37 (s, 18H, C(CH3)3), 1.26 (s, 18H, C(CH3)3). 13C
NMR (CDCl3, 200 MHz, 25 ꢁC) d (ppm) ¼ 155.27
(CHO), 162.65 (Cq–Ar), 148.5 (Cq–Ar), 139.6 (Cq–Ar),

1580
I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
temperature was allowed to rise at room temperature).
The solvent was removed and methanol (5 mL) was
added to the yellow residual oil. A yellow precipitate
was formed, collected by filtration through a Millipore
filter, and dried under vacuum (P ¼ 0:1 mmHg) to give
1 mL of isopropanol. After stirring 7–12 h under an
argon atmosphere at room temperature, 3.7 mg
(33 lmol) of t-BuOK and 40 mg (0.33 mol) of acetophe-
none were added. The resulting solution was stirred un-
der hydrogen pressure (30 bar) in a stainless-steel reactor.
ligand 17 (0.32 g) as a yellow solid. Isolated yield: 50%.
20
FW ¼ 726.91; Mp 205 ꢁC. ½aꢃ ¼ ꢁ67 (c 16.75 · 10ꢁ3 g/
D
mL; CH2Cl2). 1H NMR (CDCl3, 300 MHz, 25 ꢁC): d
(ppm) ¼ 13.17 (s, 2H, NHSO2), 8.43 (s, 2H, HC@N),
7.45 (m, 6H, Ar–H), 7.26 (m,14H, Ar–H), 6.88 (m, 2H,
Ar–H), 6.73 (m, 4H, Ar–H), 4.88 (s, 2H, HC–N), 2.1 (s,
3H, Ar–CH3). 13C NMR (CDCl3, 300 MHz, 25 ꢁC): d
(ppm) ¼ 166 (C6@N), 143.7 (Cq–Ar), 140.2 (Cq–Ar),
139.7 (Cq–Ar), 136.9 (Cq–Ar), 134.5 (C–Ar), 132 (C–
Ar), 129.8 (C–Ar), 128.9 (C–Ar), 128.5 (C–Ar), 128 (C–
Ar), 127.5 (C–Ar), 122.7 (C–Ar), 120.5 (C–Ar), 117.2
4.3.3. Hydrogenation of acetophenone with chiral ligand
and [Ru(COD)Cl2]x or [Ru(C6H6)Cl2]2. In a Schlenk
tube, 3.33 lmol of [Ru(COD)Cl2]x (or [Ru(C6H6)Cl2]2),
and 4 lmol of desired chiral ligand were mixed in 1 mL
of isopropanol. After stirring for 7–12 h under an argon
atmosphere at room temperature, 33 lmol of t-BuOK
and 40 mg (0.33 mol) of acetophenone were added. The
resulting solution was stirred under hydrogen pressure
(30 bar) in a stainless-steel reactor.
(C–Ar), 81.4 (CH–N), 21.7 (CH3). IR (KBr)
(cmꢁ1) ¼ 2870–3100 (NH), 1634 (C@N), 1167 (SO2). HR
m
LSIMS calcd for C42H38N4O4S2Hþ ¼ 727.24135;
C42H38N4O4S2 (726.91 g molꢁ1): Anal. Calcd: C, 69.4; H,
5.27; N, 7.71; O, 8.8; S, 8.82. Found: C, 69.27; H, 5.54;
N, 7.93; O, 8.5; S, 8.6.
found ¼ 727.24123.
Elementary
analysis
for
Acknowledgements
ꢁ
We thank Genevieve Heraud for valuable advice con-
cerning chiral GC analysis.
4.3. Typical procedures for catalytic hydrogenation tests
References and notes
All hydrogenation tests were carried out in stainless-
steel reactors, previously degassed three times with
argon and twice with hydrogen. It was then pressurized
to 30 bar at room temperature and stirred for the reac-
tion time (7–16 h). At the end of the reaction time, the
reactor was degassed and the reaction mixture filtered
throught Celite before chiral GC analysis (Cyclodextrin
b column, 30 m).
1. Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3069.
2. Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
Chem. Rev. 2000, 100, 2159–2231.
3. Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 2675–2676.
~
4. Ohkuma, T.; Koizumi, M.; Muniz, K.; Hilt, G.; Kabuto,
C.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508–6509.
5. Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.; Kore-
naga, T.; Terada, M.; Noyori, R. J. Am. Chem. Soc. 1998,
120, 1086–1087.
4.3.1. Hydrogenation of acetophenone with the system
Ru(PPh3)3Cl2/chiral ligand. Method 1: In a Schlenk tube,
3.2 mg (3.3 lmol) of [Ru(PPh3)Cl2] and 4 lmol of the
desired ligand were mixed in 1 mL of toluene. After 1 h
stirring under an argon atmosphere at room tempera-
ture, the solvent was removed and 1 mL of isopropanol
added. Then, 3.7 mg (33 lmol) of t-BuOK and 40 mg
(0.33 mol) of acetophenone were introduced and the
resulting solution stirred under hydrogen pressure
(30 bar) in a stainless-steel reactor.
6. Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.;
Kozawa, M.; Katayama, E.; England, A. F.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703–1707.
7. Mikami, K.; Korenaga, T.; Yusa, Y.; Yamanka, M. Adv.
Synth. Catal. 2003, 345, 246–254.
8. (a) Ferrand, A.; Bruno, M.; Tommasino, M. L.; Lemaire,
M. Tetrehedron: Asymmetry 2002, 1379–1384; (b) Tom-
masino, M. L.; Thomazeau, C.; Touchard, F.; Lemaire,
M. Tetrehedron: Asymmetry 1999, 10, 1813–1819; (c)
Tommasino, M. L.; Casalta, M.; Breuzard, J. A. J.;
Lemaire, M. Tetrahedron: Asymmetry 2000, 11, 4835–
4841.
Method 2: In a Schlenk tube, 3.2 mg (3.33 lmol) of
Ru(PPh3)3Cl2 and 4 lmol of the desired ligand were
mixed in 1 mL of isopropanol. After 7–12 h stirring
under an argon atmosphere at room temperature,
3.7 mg (33 lmol) of t-BuOK and 40 mg (0.33 mol) of
acetophenone were added. The resulting solution was
stirred under hydrogen pressure (30 bar) in a stainless-
steel reactor.
9. Breysse, E.; Pinel, C.; Lemaire, M. Tetrahedron: Asymme-
try 1998, 897–900.
10. Pavlov, V. A.; Vinogradov, M. G.; Starodubtseva, E. V.;
Chel’tsova, G. V.; Ferapontov, V. A.; Malyshev, O. R.;
Heise, G. L. Russ. Chem. Bull., Int. Ed. 2001, 50, 734–735.
11. Karame, I.; Tommasino, M. L.; Faure, R.; Lemaire, M.
Eur. J. Org. Chem. 2003, 1271–1276.
€
12. Fonseca, M. H.; Eibler, E.; Zabel, M.; Konig, B. Tetra-
hedron: Asymmetry 2003, 14, 1989–1994.
ꢀ
13. Vazquez, M.; Bermejo, M. R.; Sanmartın, J.; Garcıa-
Deibe, A. M.; Lodeiro, C.; Mahıa, J. J. Chem. Soc.,
ꢀ
ꢀ
ꢀ
4.3.2. Hydrogenation of acetophenone with chiral ligand,
phosphines and [Ru(COD)Cl2]x or [Ru(C6H6)Cl2]2. In a
Schlenk tube, (3.33) lmol of [Ru(COD)Cl2]x (or
[Ru(C6H6)Cl2]2), 4 lmol of desired chiral ligand and
x lmol (x ¼ 4, 8, or 12 lmol) of phosphine were mixed in
Dalton Trans. 2002, 870–877.
14. Karame, I.; Tommasino, M. L.; Faure, R.; Fenet, B.;
Lemaire, M. Chem. Lett. 2004, 33, 178–179.
15. Kitaura, Y.; Mastuura, T. Tetrahedron 1971, 27, 1583–
1595.

I. Karamꢀe et al. / Tetrahedron: Asymmetry 15 (2004) 1569–1581
1581
16. Srinivasa, G. R.; Abiraj, K.; Channe Gowda, D. Tetra-
hedron Lett. 2003, 44, 5835–5837.
Mr.; Anderson, P. G. J. Am. Chem. Ploughshare. 1999,
121, 9580–9588.
17. Khan, F. A.; Dash, J.; Sudheer, C.; Kumar Gupta, R.
Tetrahedron Lett. 2003, 44, 7783–7787.
20. Bernard, Mr.; Delbecq, F.; Sautet, P.; Fache, F.; Lemaire,
Mr. Organometallics 2000, 19, 5715–5722.
18. (a) Ohkuma, T.; Noyori, R. Angew. Chem., Int. Ed. 2001,
40, 41–73; (b) Abdur-Rachid, K.; Faatz, M.; Lough, A. J.;
Morris, R. H. J. Am. Chem. Soc. 2001, 123, 7473–7474; (c)
Abdur-Rachid, K.; Clapham, S. E.; Hadzovic, A.; Harvey,
J. N.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2002,
124, 15104–15118; (d) Rautenstrauch, V.; Hoang-Cong,
X.; Churlaud, R.; Abdur-Rachid, K.; Morris, R. H. Chem.
Eur. J. 2003, 9, 4954–4967; (e) Sandoval, C. A.; Ohkuma,
21. Komiya, S.; Yamamoto, A. J. Mol. Catal. 1979, 5, 279–292.
22. James, B. R. In Comprehensive Organometallic Chemistry
I; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.;
Pergamon Press: Oxford, 1982; Vol. 8, pp 285–370.
€
~
23. Arguello, E.; Bolanos, A.; Cuenu, F.; Navaro, Mr.;
Herrera, V.; Fuentes, A.; Sanchez-Dalgado, R. A. Poly-
hedron 1996, 15, 909–915.
24. Bennet, Mr. A.; Matheson, T. W. In Understanding
Organometallic Chemistry I; Wilkinson, G., Stone, F. G.
A., Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 4, pp
931–966.
25. Thomas, C. A.; Bonilla, R. J.; Huang, Y.; Jessop, P. G.
Can. J. Chem. 2001, 79, 719–724.
~
T.; Muniz, K.; Noyori, R. J. Am. Chem. Soc. 2003,
125(44), 13490–13503.
19. (a) Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R.
K.; Kavana, Mr. J. Am. Chem. Ploughshare. 2001, 123,
1090–1100; (b) Alonso, D. A.; Brandt, P.; Nordin, S. J.