α-Amino-oximes based on optically pure limonene: A new ligands family for ruthenium-catalyzed asymmetric transfer hydrogenation

Article abstract of DOI:10.1002/chir.22073

A new family of bifunctional, optically pure α-amino-oxime ligands based on (R)-limonene has been synthesized and used as chiral inducers for enantioselective hydrogen transfer reactions on various ketones in the presence of ruthenium catalysts. The X-ray

Full text of DOI:10.1002/chir.22073

CHIRALITY (2012)
a-Amino-Oximes Based on Optically Pure Limonene: A New Ligands
Family for Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation
MOHAMMED SAMIR IBN EL ALAMI,1,2,3,4 MOHAMED AMIN EL AMRANI,1 ABDELAZIZ DAHDOUH,1 PASCAL ROUSSEL,2,3,4
2,3,4
ISABELLE SUISSE,2,3,4 AND ANDRÉ MORTREUX
*
1Laboratoire de Chimie Organique Appliquée, Faculté des Sciences, BP 2121, Université Abdelmalek Essaadi, Tétouan, Morocco
2Université Lille Nord de France, Villeneuve d’Ascq, France
3Unité de Catalyse et de Chimie du Solide, CNRS, UMR 8181, Lille, France
4Université Lille I, Sciences et Technologies, Villeneuve d’Ascq, France
ABSTRACT
A new family of bifunctional, optically pure a-amino-oxime ligands based on
(R)-limonene has been synthesized and used as chiral inducers for enantioselective hydrogen transfer
reactions on various ketones in the presence of ruthenium catalysts. The X-ray structures of Ru-amino-
oxime complexes are also described. Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: asymmetric transfer hydrogenation; limonene; amino-oxime; ruthenium
Optical rotations were measured on a ZUZ: Modelo 412 polarimeter
(Farmamundi, Valencia, Spain).
INTRODUCTION
The synthesis of chiral secondary alcohols by catalytic
transfer hydrogenation of the corresponding ketones is a
pivotal reaction in asymmetric synthesis because of its opera-
tional simplicity and its great potential for applications in the
fine chemical industries.1–3 As part of the development of
this chemistry, the design and synthesis of enantiomerically
pure ligands to produce chiral compounds with a maximal
selectivity remain one of the key challenges of today’s organic
chemistry.4–6 Among the different synthesis strategies of
asymmetric ligands, precursors from the chiral pool still
remain of interest because of their low cost and their avail-
ability in large quantities and as they avoid tedious resolution
processes of the racemates.7,8 As a former example in that
field, the pioneering Kagan’s DIOP synthesis started from
naturally occurring L-(+)-tartaric acid.9 Among naturally chiral
compounds used for optically pure ligands synthesis,
sugars,10–12 amino acids,13 or amino alcohols14 are largely
described. Terpenes such as limonene,15–17 a-pinene and
b-pinene,18–26 or carene27 as inexpensive available starting
materials were also widely used.
Recently, we converted a-pinene into chiral b-amino
alcohols and successfully used the corresponding ligands
in ruthenium-catalyzed asymmetric hydrogen transfer
reactions.28 On the other hand, a-amino-oxime derivatives
of terpenes have been described as “hemilabile” ligands of
ruthenium carbonyl complexes.29 In line with these former
studies, it seemed interesting to us to develop and synthesize
a series of ligands of this type, also bearing amino and hydroxyl
functions, and to use them in asymmetric hydrogen transfer
reactions in the presence of ruthenium arene complexes.
Herein, we report on the synthesis of a-amino-oximes in two
steps from optically pure limonene and their use in hydrogen
transfer on various ketones.
The X-ray intensity data were measured on an APEX II DUO system
equipped with
a
mirror monochromator and
a
MoKa ImuS
(l = 0.71073 Å).
Conversions and enantiomeric excesses were determined on the crude
mixture by gas chromatography (GC) analysis on a Chirasil-Dex CB
capillary column. The absolute configurations of the alcohols have been
assigned from comparison between the retention times observed using this
Chirasil-Dex column in this work versus those described in the literature
using the same stationary phase.33–36
Ligand 4c
A mixture of the nitrosochloride dimer 2 (2g, 4.95mmol) and iso
propylamine 3c (2 ml, 21.9 mmol) in ethanol (3 ml) was heated up to the
formation of a clear solution. This latter was cooled at ꢀ5 ꢁC, and HCl was
added slowly. A white solid precipitate of chlorhydrate was formed, which
was neutralized by the addition of Et3N (up to strongly basic pH). The solu-
tion was washed with water (2ꢂ 10ml) then dried over MgSO4. The solvent
was evaporated, and a yellow oil was obtained. Upon addition of petroleum
ether, the pure oxime 4c was obtained as a light yellow solid.
Yield: 50% [a]2D0 = +12.41 (c = 0.4, CH3OH)
1H NMR (CDCl3): d = 8.75 (1H, OH); 4.76 (2H, CH2); 3.30 (1H,
J = 11.3 Hz); 2.86 (1H, t, J = 6.3 Hz, CH(CH3)2); 1.99 (1H, d, J = 11.9 Hz);
1.3–2.2 (m, 5H); 1.76 (3H, s, CH3-CHCH2); 1.28 (3H, s, CH3-CNH); 1.06
(3H, d, J = 6.3 Hz, (CH3)2CH); 0.99 (3H, d, J = 6.3 Hz, (CH3)2CH).
13C nuclear magnetic resonance (NMR) (CDCl3): d = 20.82 (CH3-C);
24.34 (CH3-CHNH); 25.02 (2 CH3); 25.57 (CH2); 26.19 (CH); 41.08
(CH2); 43.60 (CH-C); 44.68 (CH-(CH3)2); 56.85 (Cq-NH); 109.47 (CH2);
148.44 (Cq-CH2); d = 162.69 (CN).
Anal. calculated for C13H24N2O : C, 69.60; H, 10.78; N, 12.49. Found :
C, 69.48; H, 10.60; N, 12.21.
Ligand 4d
The same procedure as for 4c was applied using 2-picolylamine. Yield :
63% [a]2D0 = + 54.61 (c = 0.4, CH3OH)
Additional Supporting Information may be found in the online version of this
article.
EXPERIMENTAL
All manipulations were carried out under an inert nitrogen atmosphere
by using standard Schlenk techniques. All reagents were commercially
available and were used without further purification. Ligands 4a and 4b
were prepared according to the published methods.30–32 The different
1H and 13C NMR spectra were recorded on a Bruker AC 300 spectrome-
ter (Bruker BioSpin, Wissenbourg, France) and referenced to TMS.
*Correspondence to: Isabelle Suisse, UCCS, UMR CNRS 8181, Université de
Lille Nord de France.
E-mail: isabelle.suisse@ensc-lille.fr
Received for publication 03 February 2012; Accepted 17 April 2012
DOI: 10.1002/chir.22073
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

IBN EL ALAMI ET AL.
1H NMR (CDCl3) : d = 9.82 (1H, OH); 8.52 (1H, d, J= 4.5 Hz, C6H4N); 7.61
NMR 13C (APT, CDCl3) : d = 171.58 (CN); 142.85 (Cq-CH2); 135.25
(Cq-Ph); 129.17, 128.66, 128.21 (C6H5); 114.24 (Cq (p-cym); 109.89
(CH2); 96.46 (Cq (p-cym)); 87.46, 84.70, 81.36, 80.82 (4 CH (p-cym));
68.86 (Cq-NH); 55.04 (CH2-Ph); 39.22 (CH2-CH-CH2); 34.15 (CH2);
31.26 (CH(CH3)2); 29.41 (CH2); 24.36 (CH2); 23.47 (CH(CH3)2); 22.05
(CH3-CNH); 21.15 (CH3-C); 20.50 (CH(CH3)2); 18.98 (CH3 (p-cym)).
(1H, td, J = 1.1 Hz, C6H4N); 7.30 (1H, d, J = 7.8 Hz, C6H4N); 7.13 (1H, t, J = 5.8
Hz, C6H4N); 4.77 (2H, d, J = 8.1 Hz, CH2); 3,88 (1H, d, J = 14.2 Hz, CH2Py),
3.62 (1H, d, J = 14.3 Hz, CH2Py); 3.30 (1H, d, J = 13.1 Hz, CH2); 1.98
(1H, d, J = 12.3 Hz, CH2); 1.6–2.4 (m, 5H); 1,77 (s, 3H, CH3-CCH2); 1,34
(s, 3H, CH3-CNH).
13C NMR (CDCl3) : d =20.69 (CH3-C); 23.25 (CH3-CNH); 25.31 (CH2);
26.12 (CH2); 40.37 (CH2); 44.71 (CH-C); 47.86 (CH2NH); 56.49 (Cq-NH);
109.46 (CH2); 121.82, 122.38, 136.51, 148.60 (4 CH); 148.92 (Cq-CH); 159.91
(Cq (Py)); 162.19 (CN).
Complex 6b
To
a mixture of [Ru(p-cymene)Cl2]2 (76.5 mg, 0.125 mmol) and
benzylamino-oxime 4b ligand (68 mg, 0.25 mmol) in 10 ml of
dichloromethane, KOH (0.275 mmol) was added. After 4 h stirring at ambient
temperature, the orange solution was filtered, and KCl was eliminated. Upon
evaporation of the solvent, 6b was obtained as an orange powder. Yield: 70%
NMR 1H (CDCl3) : d = 7.2–7.6 (5H, m, C6H5); 6.11 (1H, d, J = 6 Hz, CH
(p-cym)); 5.92 (1H, d, J = 6 Hz, CH (p-cym)); 5.62 (1H, d, J = 6 Hz, CH
(p-cym); 5.44 (1H, d, J = 6 Hz, CH (p-cym)); 4.85 (2H, m, CH2NH); 4.66
(2H, d, J = 15 Hz, CH2); 4.03 (1H, s, NH); 3.61 (1H, d, J = 18Hz, CH2); 2.66
(1H, spt, CH(CH3)2); 2.39 (1H, m, CH); 2.17 (1H, dd, J = 6.1Hz, CH2);
2.00 (3H, s, CH3 (p-cym)); 1.2–1.9 (4H, m, 2 CH2); 1.58 (3H, s, CH3); 1.51
(3H, s, CH3); 1.09 (3H, d, J = 9 Hz, (CH3)2CH); 0.87 (3H, d, J = 9 Hz,
(CH3)2CH).
Anal. calculated for C16H23N3O: C, 70.30; H, 8.48; N, 15.37. Found:
C, 69.75; H, 8.85; N, 14.97.
Complex 5a
Phenylamino-oxime 4a ligand (136 mg; 0.527 mmol) and [RuCl2
(p-cymene)]2 (0.161 g; 0.263 mmol) were stirred for 30 min in 7 ml of
anhydrous dichloromethane. Diethyl ether (7ml) was then added drop by
drop, and the mixture was stirred overnight at ꢀ5 ꢁC. After filtration, the
crude product was concentrated under vacuum to give complex 5a as a
yellow powder. Yield: 65%.
1H NMR (CDCl3, 300 MHz): d = 12.46 (s, 1H, OH); 6.90–7.95 (m, 5H,
C6H5); 6.44 (d, J = 6Hz, 1H, CH (p-cym)); 6.31 (d, J= 6 Hz, 1H, CH
(p-cym)); 5.99 (d, J= 6 Hz, 1H, CH (p-cym)); 5.40 (s, 1H, NH); 4.74
(d, 1H, J=8 Hz, CH (p-cym)); 4.72 (s, 1H, CH2); 4.57 (s, 1H, CH2); 3.7
(d, J= 15Hz, 1H, CH2); 2.79 (st, 1H, CH(CH3)2); 2.49 (m, 1H, CH);
2.35–2.41 (m, 1H, CH2); 2.36 (s, 3H, CH3); 1.3–1.9 (m, 4H); 1,81 (s, 3H,
CH3); 1,56 (s, 3H, CH3); 1.07 (d, J=6Hz, 3H, (CH3)2CH); 0,57 (d, J=6Hz,
3H, (CH3)2CH).
NMR 13C (CDCl3) : d = 164.37 (CN); 143.79 (CqCH2); 136.01 (Cq-C6H5);
128.88, 128.42, 128.16 (CH(p-cym)); 113.49 (CH2); 108.32 (Cq(p-cym)); 96.37
(Cq(p-cym)); 87.74, 83.59, 81.79, 81.55 (CH(p-cym)); 68.45 (Cq-NH); 54.93
(CH2NH); 39.34 (CH); 34.33 (CH2); 31.10 (CH(CH3)2); 29.69 (CH2); 24.62
(CH2); 23.98 (CH(CH3)2); 22.20 (CH3); 21.18 (CH3); 20.10 (CH(CH3)2);
18.60 (CH3 (p-cym)).
X-ray crystallography, an irregular yellow plate-like specimen of
C54H74N4O2Ru2, approximate dimensions of 0.12 ꢂ 0.14 ꢂ 0.16 mm,
was used for the X-ray crystallographic analysis. The integration of the
data using an orthorhombic unit cell yielded a total of 14,148 reflections
to a maximum angle of 26.3ꢁ, of which 10,577 were independent
(completeness = 98.3%, Rint = 5.50%). The final cell constants of a = 8.8793
(11) Å, b = 22.171 (3) Å, c = 18.394 (2) Å, b = 90.627 (5)ꢁ, and volume =
3620.8 (8) Å3 are based upon the refinement of the XYZ centroids of
9823 reflections with 6ꢁ < 2 < 52ꢁ. Data were corrected for absorption
effects using the multiscan method (SADABS).
The structure was solved by Charge Flipping Method using Superflip
software37 and refined using the CRYSTALS Software Package38, using
the space group P21, with Z = 4 for the formula unit, C54H74N4O2Ru2.
In the final cycles of refinements, the contribution to electron density
suggested that part of solvent was highly disordered; attempts to model
this disorder were unsuccessful. In the final cycles of refinement, the
contribution to electron density corresponding to the disordered solvent
was removed from the observed data using the SQUEEZE option in
PLATON.39 The resulting data significantly improved the accurateness
of the geometric parameters for the remaining structure. The final
anisotropic full-matrix least-squares refinement on F with 578 variables
converged at R = 0.062 for the observed data and wR = 0.056 for all data.
The goodness-of-fit was 0.99.
13C NMR (CDCl3, 300 MHz) : d = 171.93 (CN); 167.25 (C6H5); 143.28
(C-NH); 142.70 (CCH2); 105.80 (p-cym); 124.00; 124.73; 127.89; 129.46;
130.15 (Ph); 113.83 (CH2); 105,8 (p-cym)); 97.56 (p-cym); 81.07; 84.81;
86.33; 86.55 (p-cym); 39.21 (CH); 34.60 (CH2); 30.48 (CH(CH3)2); 28.43
(CH2); 24.09 ((CH3)2CH); 23.94 (CH2); 22.86 (CH3); 22.07 (CH3); 18.79
(CH3); 18.41 ((CH3)2CH).
X-ray crystallography, a lustrous pale yellow plate-like specimen of
C28H38Cl8N2ORu, approximate dimensions of 0.07 ꢂ 0.23 ꢂ 0.27 mm,
was used for the X-ray crystallographic analysis. The integration of the
data using an orthorhombic unit cell yielded a total of 32,454 reflections
to a maximum angle of 23.46ꢁ, of which 5163 were independent
(completeness = 98.8%, Rint = 6.59%). The final cell constants of a = 9.5362
(15) Å, b = 15.604(3) Å, c = 23.905(4) Å, and volume = 3557.1(10) Å3 are
based upon the refinement of the XYZ centroids of 229 reflections above
20 s(I) with 4.338ꢁ < 2 < 30.68ꢁ. Data were corrected for absorption
effects by using the multiscan method (SADABS).
The structure was solved by Charge Flipping Method using Superflip
software37 and refined using the CRYSTALS Software Package,38 using
the space group P212121, with Z = 4 for the formula unit, C28H38Cl8N2ORu.
In the final cycles of refinements, the contribution to electron density
suggested that part of solvent was highly disordered; attempts to model this
disorder were unsuccessful. In the final cycles of refinement, the contribu-
tion to electron density corresponding to the disordered solvent was
removed from the observed data using the SQUEEZE option in PLATON.39
The resulting data significantly improved the accurateness of the geometric
parameters for the remaining structure. The final anisotropic full-matrix
least-squares refinement on F with 281 variables converged at R = 0.091
for the observed data and wR = 0.087 for all data. The goodness-of-fit
was 1.02.
Complexes 7b/7b 0
[Ru(p-cymene)Cl2]2 (76.5 mg; 0.125 mmol) and benzylamino-oxime 4b
ligand (68 mg; 0.25 mmol) in 5 ml isoPrOH were stirred for 30 min at
80 ꢁC. A solution of KOH in iPrOH (4.13 ml, 0.12 M) was added to the
reaction mixture. After stirring for 15 min, the solution was evaporated
under vacuum at 0 ꢁC to give a red powder. Yield: 91%.
NMR 1H (C6D6): d = 7.00–7.40 (5H, m, C6H5); 5.29, 5.02, 4.86, 4.64
(4H, 4d, J = 6 Hz, (p-cym)); 5.00 (1H, NH); 4.05–4.45 (4H, m, CH2Ph +
CH2); 2.46 (1H, spt, CH(CH3)2); 2.18 (1H, m, CH); 1.83 (3H, s, CH3
(p-cym); 1.15–1.65 (4H, m, 2 CH2); 1.48 (3H, dd, J = 1.5, 6 Hz, CH3); 1.14
(3H, d, J = 4.5 Hz (CH3)2CH)); 1.12 (3H, d, J = 4.5 Hz, (CH3)2CH));
ꢀ5.10 and ꢀ6.15 (Ru-H).
Complex 5b
Similar procedure as 5a using benzylamino-oxime 4b. Yield : 81%
1H NMR (CDCl3) : d = 12.19 (s, 1H, OH); 7.2–7.6 (m, 5H, C6H5), 5.96
(d, 1H, J = 5.9 Hz, p-cym); 5.86 (d, 1H, J = 5.7 Hz, p-cym); 5.76 (d, 1H,
J = 6.5 Hz, p-cym); 5.39 (d, 1H, J = 5.97 Hz, p-cym); 4.68 (m, 2H, CH2-);
4.58 (m, 2H, CH2-NH); 4.05 (singlet large, 1H, NH); 3.64 (d, 1H1,
J = 16.6 Hz, CH2); 2.67 (spt, 1H, J = 7.2 Hz, CH(CH3)2); 2.41 (singlet
large, 1H, CH-CH2); 2.29 (dd, 1H1, J = 6 Hz, CH2); 2.7 (s, 3H, CH3
(p-cym)); 1.30–2.01 (m, 4H, CH2); 1.59 (s, 3H, CH3-CCH2); 1.51 (s, 3H,
CH3-C-NH); 1.16 (d, 3H, J = 7 Hz, (CH3)2-CH (p-cym); 0.90 (d, 3H, J = 6.9
Hz, (CH3)2-CH).
Typical Transfer Hydrogenation Procedure
The catalysts were generated in situ prior to catalysis by heating a
mixture of the [RuCl2(arene)2]2 complex (0.01 mmol) with the desired
amino-oxime (0.04 mmol, 2 eq per Ru) at 80 ꢁC for 20 min in dry propan-
2-ol (5 ml). Then, a solution of the substrate (2 mmol) in propan-2-ol was
Chirality DOI 10.1002/chir

A NEW LIGANDS FAMILY FOR RUTHENIUM-CATALYZED ASYMMETRIC TRANSFER HYDROGENATION
added, immediately followed by 0.33 ml of a 0.12-M solution of KOH in
iPrOH, and the mixture was heated at the desired temperature. The reac-
tion course was monitored versus time using GC analysis of aliquots on a
Chirasil-Dex column to assess conversions and enantioselectivities.
RESULTS AND DISCUSSION
Synthesis of Chiral Ligands and Complexes
As described previously,30–32 the synthesis of a-amino-
oximes derived from (R)-limonene proceeds via the
(1S,2S,4R)-nitroso chloride intermediate formation followed
by the addition of amines (Scheme 1). Thus, (R)-limonene 1
was reacted with isopentylnitrite in a hydrochloric acid solution
to form the nitrosochloride dimer 2. The amines 3a–d were
then reacted into methanol with 2 at 50ꢁC to afford the desired
a-amino-oximes 4a–d, from which series 4c and 4d are new
compounds. These latter were obtained respectively in 50%
and 63% yield and were fully characterized. As described in
the literature,30–32 the configurations of these compounds were
assumed to be (1S,4R) and confirmed by NMR analysis.
Reaction of the a-amino-oxime 4a with the [RuCl2
(p-cymene)]2 precursor leads to the clean formation of com-
plex 5a in 65% yield. Single crystals were isolated as brown
needles after recrystallization by slow diffusion of chloroform
in an ether solution (Scheme 2). The electrospray ionization
mass spectrum of 5a in MeOH solution showed an isotope
cluster at m/z = 529. The mass peaks observed for this cluster
and the intensity ratio of the various isotope peaks were in
excellent agreement with the calculated pattern for the
expected molecule C26H36ClN2ORu. X-ray analysis of this
complex (Figure 1) confirms the (1S,4R) configuration onto
the amino-oxime.
Fig. 1. Molecular structure of the ruthenium complex 5a, 2CHCl3 (the
solvate molecules and hydrogen atoms have been omitted for clarity).
TABLE 1. Selected bond lengths (Å) and angles (ꢁ) for 5a
Bond lengths
Angles
Ru-N3
Ru-Noxime
Ru-Cl
N3-C10
oxime-C11
2.192
2.103
2.405
1.517
1.207
1.498
Noxime-Ru-N3
Cl-Ru-N3
Noxime-Ru-Cl
C4-N3-C10
74.0
79.2
85.7
119.0
117.2
N
C10-C11-Noxime
C10-C11
The main bond lengths and bond angles are given in
Table 1. This cationic complex has a highly distorted octahedral
coordination environment. A cationic complex of the type [Ru
(arene)Cl(neutral amino-amino)]+ had already been crystallo-
graphically described.40
The ruthenium atom has the characteristic of a three-legged
“piano-stool” arrangement. The amino-oxime is coordinated by
the two nitrogen atoms that are involved in a five-membered
chelated ring displaying an envelope conformation with C10
and C11. A chloride anion and the arene complete the coordi-
nation sphere on ruthenium. A second chloride anion is pres-
ent as a non coordinating counterion. Both the Ru-Noxime
[2.103Å] and Ru-N3 [2.192Å] as well as the Ru-Cl [2.405Å]
and the Ru-(C)arene distances (range 2.17–2.23Å) are compara-
ble with those reported in the literature.41
The same procedure was used with the amino-oxime 4b and
[RuCl2(p-cymene)]2, but suitable crystals for X-Ray analysis of
the cationic complex 5b could not be obtained. A description
of the NMR data of the two complexes 5a and 5b are given
in the Experimental section. The presence of the OH hydroxy
moieties is clearly identified at 12.46 and 12.19 ppm
(respectively, for 5a and 5b complexes).
Cl
RHN
NO
N
OH
a
2
b
3a-d
1
2
4a-d
a (H3C)2CH(CH2)2ONO, HCl, MeOH
b R-NH2 3a : R=Ph, 3b : R = CH2Ph, 3c : R = iPr, 3d : R = H2C
N
Results of Catalysis
The four synthezised a-amino-oximes were applied in the
ruthenium-catalyzed transfer hydrogenation of acetophenone
(Scheme 3). We used the in situ technique to check the
catalytic performance of each ligand on different precursors
by varying the arene moiety on ruthenium from p-cymene to
benzene and hexamethylbenzene.
These catalysts were formed by mixing [RuCl2(arene)]2
with one or two equivalents of the desired amino-oxime in
isopropanol in the presence of potassium hydroxide; the
substrate was then added and the mixture heated up to 80 ꢁC.
As shown in Table 2, hydrogen transfer is effective because
all the conversions are rather high, up to 97% after at most
24 h. The best activity is obtained using [RuCl2(benzene)]2
Chirality DOI 10.1002/chir
Scheme 1. Synthesis of a-amino-oxime ligands from (R)-limonene.
+
H
O
N
Cl
Ru
[RuCl2(p-cymene)]2
4a
, Cl-
NH
Ph
Scheme 2. Synthesis of the cationic ruthenium complex 5a.

IBN EL ALAMI ET AL.
OH
O
In the case of substituted aromatic ketones (substrates
[Ru(Arene)Cl2]2
6–14), for a given catalytic system, the reaction rate is gener-
ally sensitive to the electronic properties of the phenyl ring
substituent. By using 4a as ligand, reaction rates of substrates
with electrodonating substituents (-CH3: 6, 7 and -OCH3:
8 and 9) are similar to those observed with acetophenone;
90% conversions were reached after 20h (entries 13, 15, 17,
Table 3 versus entry 5, Table 2). On the other hand, by using
electron-withdrawing groups as -Cl or -NO2, the reactions
proceed at much higher rate (up to 99% conversion after only
1–10 h, entries 21–34). These differences in reactivity of
various substrates were already described by Gladiali with
the same trend.43 The extent of the enantioselectivity appears
to be also strongly dependent on the aromatic ring substitu-
ents. Enantioselectivities between 6% and 75% were obtained,
and it is more difficult to rationalize these ee values. The best
result is observed with the m-chloroacetophenone (74–75% ee,
entries 23 and 24, Table 3) The same observation has already
been reported by Noyori who found that the best activity and
enantioselectivity were also reached with this substrate.44 In
the case of trifluoroacetophenone 15, the result was rather
disappointing with a maximal ee of 46% (entries 31–32). The
asymmetric reduction of 2-acetonaphtone 16 led to the best
result in terms of activity (90% yield after 2 h) and enantioselec-
tivity (78% ee) with the catalytic system [Ru(benzene)Cl2]2/
4b/KOH (entry 34).
4a-d
KOH/iPrOH
Scheme 3. Hydrogen transfer of acetophenone using Ru catalysts.
as precursor coordinated by the picolylamino-oxime 4d with
94% conversion after only 7 h. (entry 8, Table 2) On the other
hand, for all these reactions, the selectivities are very
variable, with a maximal ee of 80%. In that latter case, the
ligand used was 4b with a 92% conversion after 19 h. (entry
6, Table 2). Comparing the different results in Table 2 also
tells us that the benzene ruthenium complexes are the most
active, as shown earlier41 within this series, and that ligands
4a and 4b lead to the best enantioselectivities.
Attempts were made to improve the selectivity upon chang-
ing the L/Ru ratio. In all cases, when the ratio was decreased
to 1, the activity was improved with conversion ranging from
85% to 100% after 4–6 h. Nevertheless, the enantioselectivity
generally dropped drastically. For example, in the case of
[RuCl2(benzene)]2 coordinated by 4a, an 81% conversion and
a 43% ee were observed after 21h, whereas at L/Ru = 1, the
conversion was 88% after 6 h but to the detriment of the
enantioselectivity (17%). The same trend was observed with
ligand 4b, but to a much less extent, as using a Ligand/Ru
ratio of 1, the ee remained much more stable (84% and 80% ee
after 4 h and 9 h at 82% and 93% conversion, respectively). This
racemization process has already been reported, because of
the reversibility of the reaction, and found to be subtantially
ketone and ligand dependent.42 Conversely, when the ratio
L/Ru was increased to 4, the activity largely decreases as
expected with no change in the ee.
As these ligands are bearing both NH and OH moieties,
attempts were made to look at the mechanism of the hydro-
gen transfer, which may occur via pathways involving
a ruthenium hydride as already described for amino
alcohols.42,45
To confirm this hypothesis, we followed Noyori’s procedure,
that is, via stoichiometric reactions step by step from the
Lowering the temperature to 60ꢁC using standard condi-
tions with 4a led to a decrease in the reaction rate but did
not improve the enantioselectivity (80% ee at 50% conversion
after 2 h, 74% ee at 94% conversion after 16h).
Generalization of this reaction to other ketones was next
performed. Considering the above results on acetophenone,
the [RuCl2(benzene)]2/4a and 4b catalysts were then
applied on substrates 6–16 (Scheme 4), at a ligand/ruthenium
ratio of 2 to avoid or limit the racemization process. The results
are reported in Table 3.
R = o-Me : 6
R = p-Me : 7
O
O
O
8
R = o-MeO :
CF3
15
R =p-MeO : 9
R =o-Cl : 10
R = m-Cl :
16
11
R
R = p-Cl : 12
R = m-NO2 : 13
14
R = p-NO2
:
Scheme 4. Aromatic ketones used for asymmetric transfer hydrogenation.
TABLE 2. Transfer hydrogenation of acetophenone using ruthenium complexes [RuCl2(arene)]2 of amino-oxime ligands 4a–da
Entry
Arene
Ligand
T (h)
Conversion (%)
Ee (%)
Configuration
1
2
3
4
5
6
7
8
p-cymene
4a
4b
4c
4d
4a
4b
4c
4d
4a
4b
4c
4d
21
21
22
22
21
19
23
7
20
21
23
24
97
93
64
96
84
92
93
94
85
97
93
26
24
12
5
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
35
43
80
28
20
53
40
28
39
Benzene
HMB
9
10
11
12
HMB, hexamethylbenzene.
aAll reactions were performed using 2 mmol of acetophenone in 20 ml of iPrOH. S/Ru = 100, Ligand/Ru = 2, Base/Ru = 2, T = 80 ꢁC.
Chirality DOI 10.1002/chir

A NEW LIGANDS FAMILY FOR RUTHENIUM-CATALYZED ASYMMETRIC TRANSFER HYDROGENATION
TABLE 3. Transfer hydrogenation of various ketones using ruthenium complexes of amino-oxime ligands 4a and 4ba
Entry
Substrate
Ligand
T (h)
Conversion (%)b
Ee (%)b
Configurationc
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
6
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
22
23
22
23
22
5
7
18
8
2
23
3
6
2
24
1
24
0.5
10
3
98
99
96
97
84
88
94
84
71
95
87
97
93
92
59
99
27
95
99
99
92
90
6
24
12
55
28
66
6
39
30
56
74
75
17
65
47
66
34
64
37
46
59
78
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(S)
(S)
7
8
9
10
11
12
13
14
15
16
8
2
aAll reactions were performed by using 2 mmol of ketone in 20 ml of iPrOH. S/Ru = 100, Ligand/Ru = 2, Base/Ru = 2, T = 80ꢁC.
bDetermined using chiral gas chromatography with a Chirasil-Dex CB column.
cDetermined by comparison of the retention times of the enantiomers on the gas chromatography traces with literature values.
ruthenium precursor and the amino-oxime 4b. Next are the
observations made during these reactions, allowing to support
the mechanism and intermediates described in Figures 2 and 4.
depicted in Figure 3, which shows the nitrogen coordi-
nation with a pendent Oꢀ moiety as already described
by Pandey.46 In the asymmetric unit of 6b, there are
two independent molecules that are almost identical.
As previously for 5a complex, the Ru-N (2.171 Å), Ru-
Noxime (2.066Å), and Ru-Cl (2.401Å) distances and N-
Ru-Noxime, Noxime-Ru-Cl, and N-Ru-Cl angles (respec-
tively, 74.8, 82.45, and 82.62ꢁ) support a three-legged “pi-
ano-stool” arrangement. Noteworthy is also the absence
of OH proton in the 1H NMR spectrum, confirming the
abstraction of the oxime proton by the base.
i. To a mixture of [Ru(p-cymene)Cl2]2 and 4b (1:2) in
dichloromethane, 2.2 equivalents of KOH were added.
After stirring for 4 h at ambient temperature, the orange
solution was filtered, and KCl was eliminated. Evapora-
1
tion of solvent led to an orange powder. The H NMR
analysis of this complex shows the complete disappear-
ance of the OH signal, which is due to the more acidic
character of the hydrogen of the oxime than that of
the amine. Thereafter, two coordination modes could
be envisaged, either via the oxygen moiety to form an
oximato complex or with the nitrogen atom. The molec-
ular structure of this complex 6b has been determined
by single crystal X-ray diffraction analysis and is
ii. In the presence of a second equivalent of base, HCl
should be eliminated to form the active 16-electrons
species. In spite of numerous attempts, no clean
complex suitable for NMR analysis could be
obtained. The use of three or four equivalents of
NaOH or NaH as bases led to untractable results
as well.
iii. The same procedure was then performed in iPrOH
instead of CH2Cl2. After addition of two equivalents of
KOH, the solution turned rapidly red. After 15 min stir-
ring at room temperature, the solvent was evaporated,
+
-
Cl
Ru
O
N
N
H
R = CH2Ph
1
R
and a red powder was obtained and analyzed by H
NMR. Two resonances at ꢀ5.10 and ꢀ6.15 ppm in a
1:2 ratio were observed, which would correspond to
Ru-H units according to the literature.41,47 These two
signals could be assigned to the presence of the
expected two ruthenium diastereoisomers 7b and 7b'
as already observed by Sirlin and Pfeffer.47
6b
+
+
-
-
H
O
N
O
Ru
Ru
N
N
H
N
H
R
R
H
These data are in line with the hypothesis that from a
mechanistic point of view, the amino-oxime ligands behave
similarly as amino alcohols in these transfer reactions.
We then propose the following mechanism (Figure 4).
Chirality DOI 10.1002/chir
7b'
7b
Fig. 2. Proposed intermediates for 3b amino-oxime-based hydrogen
transfer.

IBN EL ALAMI ET AL.
Fig. 3. Molecular structure of the ruthenium complex 6b (the hydrogen atoms have been omitted for clarity).
R
NH
[Ru(p-cymene)Cl2]2
+
*
N
OH
+
R
, Cl-
Ru
NH
Cl
18e-
N
*
O-
2eq KOH
OH
R'
+
R
OH
Ru
N
16e-
R
H
N
*
O-
R
R'
O
H
O
+
H
R
H
Ru
N
+
H
R
Ru
N
N
18e-
O-
*
N
18e-
*
O-
O
H
H
O
+
R
R'
Ru
R
N
N
*
O-
Fig. 4. Proposed mechanism for the asymmetric transfer reaction of ketones over Ru(arene)(aminooxime)-based catalysts.
Chirality DOI 10.1002/chir

A NEW LIGANDS FAMILY FOR RUTHENIUM-CATALYZED ASYMMETRIC TRANSFER HYDROGENATION
15. Cimarelli C, Fratoni D, Palmieri G. A convenient synthesis of new
CONCLUSION
diamine, amino alcohol and aminophosphines chiral auxiliaries based on
Although their propensity to induce asymmetric induction
is by far lower than that of amino alcohols, the use of amino-
oxime as ligands for hydrogen transfer reactions using ruthe-
nium catalysts is here proposed for the first time and been
shown to probably occur via an outer sphere, six-membered
ring catalytic mechanism.
The main advantage that may be found in this chemistry is
the straightforward synthesis of these ligands from natural,
enantiomerically pure compounds, especially when, as in the
present case, both enantiomeric forms are available from the
chiral pool, resulting in the possibility to synthesize both
enriched enantiomeric mixtures of a desired alcohol at will.
Keeping in mind that the chiral terpene sources are renewable
and both in large varieties and quantities, these results may
open the way to the synthesis of new chiral ligands that may
be used in this reaction and many others in asymmetric
catalysis.
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ACKNOWLEDGMENTS
We are grateful to the “Ministère des Affaires Etrangères”
(programme Volubilis, AI nꢁ012/SM/07), the CNRS, the
“Ministère de l’Enseignement Supérieur et de la Recherche”
and the “Ministère de l’Education Nationale, de l’Enseignement
Supérieur et de la Recherche Scientifique du Maroc” for their
financial support.
24. Krzeminski MP, Wojtczak A. Chiral terpene auxiliaries. Part 1: highly
enantioselective reduction of ketones with borane catalyzed by an oxa-
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