A modular design of ruthenium(II) catalysts with chiral C2-symmetric phosphinite ligands for effective asymmetric transfer hydrogenation of aromatic ketones

Article abstract of DOI:10.1016/j.tetasy.2010.04.002

Hydrogen-transfer reduction processes are attracting increasing interest from synthetic chemists in view of their operational simplicity. The new chiral C₂-symmetric ligands N,N′-bis-[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamid

Full text of DOI:10.1016/j.tetasy.2010.04.002

Tetrahedron: Asymmetry 21 (2010) 703–710
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A modular design of ruthenium(II) catalysts with chiral C2-symmetric
phosphinite ligands for effective asymmetric transfer hydrogenation
of aromatic ketones
*
Murat Aydemir , Nermin Meric, Akın Baysal, Bahattin Gümgüm, Mahmut Tog˘rul, Yılmaz Turgut
Department of Chemistry, Dicle University, TR-21280 Diyarbakır, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrogen-transfer reduction processes are attracting increasing interest from synthetic chemists in
view of their operational simplicity. The new chiral C2-symmetric ligands N,N0-bis-[(1S)-1-sec-butyl-2-O-
(diphenylphosphinite)ethyl]ethanediamide, 1 and N,N0-bis-[(1S)-1-phenyl-2-O-(diphenylphosphinite)-
ethyl]ethanediamide, 2 and the corresponding ruthenium complexes 3 and 4 have been prepared and
their structures have been elucidated by a combination of multi-nuclear NMR spectroscopy, IR spectros-
copy, and elemental analysis. 1H–31P NMR, DEPT, 1H–13C HETCOR, or 1H–1H COSY correlation experi-
ments were used to confirm the spectral assignments. The catalytic activity of complexes 3 and 4 in
transfer hydrogenation of acetophenone derivatives by iso-PrOH has also been studied. Under optimized
conditions, these chiral ruthenium complexes serve as catalyst precursors for the asymmetric transfer
hydrogenation of acetophenone derivatives in iso-PrOH and act as excellent catalysts, giving the corre-
sponding chiral alcohols in 99% yield and up to 75% ee. This transfer hydrogenation is characterized by
low reversibility under these conditions.
Received 2 March 2010
Accepted 6 April 2010
Available online 11 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
tivity. It has to be stressed that there are always examples where just
the opposite is true. A ligand is more likely to induce high enantiose-
Among the most spectacular recent developments in catalytic
asymmetric synthesis, asymmetric transfer hydrogenation is an
attractive method for the preparation of optically active alcohols.1
Chiral alcohols are very important building blocks and synthetic
intermediates in organic synthesis and the pharmaceutical indus-
try.2 Catalytic reduction is preferred to stoichiometric reduction
for large-scale industrial processes involving ketone hydrogena-
tions and they are well known.3 Hydrogen gas presents consider-
able safety hazards especially for large-scale reactions.4 The use
of a solvent that can donate hydrogen overcomes these difficulties.
2-propanol is a popular reactive solvent for transfer hydrogenation
reactions since it is easy to handle (bp 82 °C) and is relatively non-
toxic, environmentally benign, and inexpensive.
In general, the most successful chiral ligands used in asymmetric
hydrogenation reactions are rigid chelating diphosphines possess-
ing a C2-symmetry axis thus reducing the number of diastereomeric
transition states.5 In addition, most of them bear at least two aryl
substituents on their phosphorus atoms. If one analyzes the struc-
tures of these ligands,6 several design principles can be identified
which might lead to good enantiocontrol. Generally speaking, these
measures create the necessary flexibility of the ligand to give high
turnover rates and impart sufficient rigidity to control stereoselec-
lectivity if it has a C2 symmetry7 (first example: diop) or is very
strongly unsymmetrical8 (e.g., josiphos) in order to reduce the num-
ber of possible isomeric catalyst–substrate complexes.
Phosphine ligands have found wide-spread applications in tran-
sition metal-catalyzed asymmetric transformations.9 Phosphinites
provide different chemical, electronic, and structural properties
compared to phosphines. The metal–phosphorus bond is often
stronger for phosphinites compared to the related phosphine due
to the presence of electron-withdrawing P-OR group. In addition,
*
the empty
r -orbital of the phosphinite P(OR)R2 is stabilized and
it makes the phosphinite a better acceptor.10 The most important
advantage of chiral phosphinite ligands over the corresponding
phosphine ligands is the easiness of preparation. From a practical
standpoint, it is of substantial interest to develop highly effective
chiral phosphinite ligands for asymmetric catalysis. The excellent
catalytic performance of phosphinite-based transition metal com-
plexes11 prompted us to develop new Ru(II) complexes with
well-shaped ligands. On this subject, herein, we report the synthe-
sis and characterization of new C2-symmetric chiral phosphinite li-
gands N,N0-bis-[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]
ethanediamide, 1 and N,N0-bis-[(1S)-1-phenyl-2-O-(diphenylphos-
phinite)ethyl]ethanediamide, 2 and corresponding Ru(II) complexes
3 and 4. These compounds were also fully characterized by ele-
mental analysis, FT-IR, and multi-nuclear NMR spectroscopies. We
also report the catalytic activity of ruthenium(II) complexes as a
* Corresponding author.
E-mail address: aydemir@dicle.edu.tr (M. Aydemir).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.002

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M. Aydemir et al. / Tetrahedron: Asymmetry 21 (2010) 703–710
pre-catalyst in asymmetric transfer hydrogenation reactions of ace-
tophenone derivatives with iso-PrOH.
o-, m-, and p-carbons of phenyl rings, consistent with the literature
data.14
The starting ruthenium(II) complex was [Ru(
Cl)Cl]2, which was prepared from the reaction of the commercially
available -phellandrene (5-isopropyl-2-methylcyclohexa-1,3-
diene) with RuCl3. The whole reactions with [Ru(
ne)( -Cl)Cl]2 with ligands 1 and 2 are depicted in Scheme 2. The
reactions of [Ru( -Cl)Cl]2 with 2 equiv of 1 and 2
6-p-cymene)(
g l-
6-p-cymene)(
2. Results and discussion
a
15
g
6-p-cyme-
2.1. Synthesis of chiral ligands, 1 and 2 and their corresponding
Ru(II) complexes
l
g
l
in toluene at room temperature gave the red compounds 3 and 4
The synthetic procedure for the preparation of the ligands is
shown in Scheme 1. Bis(phosphinite) ligands, N,N0-bis-[(1S)-1-
sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide, 1, and
N,N0-bis-[(1S)-1-phenyl-2-O,O0-(diphenylphosphinite)ethyl]ethane-
diamide, 2 were synthesized by hydrogen abstraction from the
described chiral bis(aminoalcohol) oxalamides N,N0-bis[(1S)-1-
sec-butyl-2-hydroxyethyl]ethanediamide and N,N0-bis[(1S)-1-phe-
nyl-2-hydroxyethyl]ethanediamide, respectively, by a base (Et3N)
and the subsequent reaction with 2 equiv of chlorodiphenylphos-
phine, in anhydrous toluene and inert atmosphere (Ar). The ammo-
nium salt was separated by filtration and the ligands were
obtained in high yields (91% 1 and 95% 2, respectively).
in high yields.
The reactions between Ru(II) precursor and bis(phosphinite) li-
gands, 1 and 2 are not affected by the molar ratio of [Ru(
ene)( -Cl)Cl]2 as well as the steric and electronic properties of the
g
6-p-cym-
l
donor phosphorus atoms. The initial color change, that is, from
clear orange to deep red, can be attributed to the dimer cleavage
most probably by the bis(phosphinite) ligand.16 [Ru(chloro(p-cym-
ene)(N,N0-bis[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]
ethanediamide))]chloride, 3 and [Ru(chloro(p-cymene)(N,N0-bis
[(1S)-1-phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide))]
chloride, 4 were isolated as indicated by singlets in the 31P–{1H}
NMR spectra at (d) 115.69 and 116.28 ppm, respectively, in line
with the values previously observed for similar compounds
(Fig. 1).17 It is significant to remark that 31P–{1H} NMR signals of
ligands and complexes do not differ significantly.18 These com-
plexes are highly soluble CH2Cl2 and slightly in hexane and they
can be crystallized from CH2Cl2/hexane solutions. The structure
of the P-coordinated complexes 3 and 4 is supported by elemental
analyses and spectroscopic data (IR and 1H and 13C NMR). 1H NMR
spectral data of complexes are consistent with the structures pro-
posed and their 1H NMR spectra differ from the spectra of com-
pounds 1 and 2. 1H NMR spectra of complexes display signals of
The air sensitivity of the free ligands 1 and 2 is a limitation. Both
compounds are unstable in air and decompose rapidly on exposure
to air or moisture. So, the synthesis and isolation of the products
must be carried out with rigorous exclusion of air, in order to avoid
oxidation of the phosphinite groups. The 31P–{1H} NMR spectra of
compounds 1 and 2 show single resonances due to phosphinite at
116.17 and 117.44 ppm, respectively, indicating the symmetric
nature of the molecules (Fig. 1). Our results agree with the chem-
ical shifts for other phosphinites reported in the literature12 The
31P–{1H} NMR spectra also display formation of PPh2PPh2 and
P(O)Ph2PPh2, as indicated by signals at about d ꢀ14.0 ppm as sin-
the
g
6-p-cymene ligand together with the resonances of the
1
glet and d 36.4 ppm and d ꢀ22.8 ppm as doublets with J(PP)
hydrogens of the P-coordinated ligands. The arene signals are well
resolved and show only H–H coupling, as found in the previously
226 Hz, respectively.13 1H NMR spectral data 1 and 2 are consistent
with the structures proposed. Furthermore, in the 13C NMR spectra
of all phosphinite ligands prepared showed characteristic J(31P-13C)
coupling constants of the carbons of the phenyl rings (including i-,
reported mononuclear
g
6-p-cymene compounds.19 Furthermore,
in the 1H NMR spectra, 3 and 4 are characterized by isopropyl
methyl doublets of p-cymene groups, at d 1.05 ppm (d, 6H,
O
N
O
H
N
H
PPh2Cl
toluene, rt
O
O
Ph2P
PPh2
1
H
H2N
MeOH, rt.
Ph
O
N
O
N
O
N
O
N
OH
OH
Ph
H
H
Ph
H
O
O
H2N
H
H
H
MeOH, rt.
MeO
OMe
OH
HO
OH
HO
O
H
O
H
N
Ph
Ph
PPh2Cl
N
toluene, rt
O
O
Ph2P
PPh2
2
Scheme 1. Synthesis of the N,N0-bis-[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide
ethanediamide 2.
1
and N,N0-bis-[(1S)-1-phenyl-2-O-(diphenylphosphinite)ethyl]

M. Aydemir et al. / Tetrahedron: Asymmetry 21 (2010) 703–710
705
Figure 1. The 31P–{1H} NMR spectra of complexes; (i) N,N0-bis-[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide; (ii) N,N0-bis-[(1S)-1-phenyl-2-O-(diphenyl-
phosphinite) ethyl]ethanediamide; (iii) [Ru(chloro(p-cymene)(N,N0-bis[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide))]chloride; (iv) [Ru(chloro(p-cym-
ene)(N,N0-bis[(1S)-1-phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide))]chloride.
Cl Ru
Cl
Cl
Ru Cl
O
N
O
H
N
O
N
O
H
N
Ph
H
Ph
H
O
Ph2P
O
PPh2
O
O
PPh2
Ph2P
1
2
O
O
O
O
Ph
H
H Ph
H
H
N
N
N
N
O
O
O
O
Ph2P
PPh2 Cl
Ph2P
PPh2
Cl
Ru
Ru
Cl
Cl
4
3
Scheme 2. Synthesis of the Ru{chloro(p-cymene)(N,N0-bis[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide)}] 3 and [Ru{chloro(p-cymene)(N,N0-bis[(1S)-1-
phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide)}] 4.

706
M. Aydemir et al. / Tetrahedron: Asymmetry 21 (2010) 703–710
J = 6.8 Hz) and 1.06 ppm (d, 6H, J = 7.2 Hz), respectively. In the 13C–
{1H} NMR spectra of compounds 3 and 4, J(31P–13C) coupling con-
stants of the carbons of the phenyl rings were observed, which are
consistent with the literature values.20 In the compounds 3 and 4,
the coupling between i-carbons and the phosphorus is relatively
large, 1J(PC) 49.3 and 50.3 Hz, while the coupling between o-car-
bon and the phosphorus is relatively small 2J(PC) 15.4; 22.0 and
12.1; 14.2 Hz, respectively. The most relevant signals of 13C–{1H}
NMR spectra of complexes 3 and 4 are those corresponding to
arene ligands (p-cymene). Carbon atoms of the arene rings in p-
cymene ligands are observed as four signals at 87.19, 88.30,
89.87, and 88.13 ppm in complex 3 and 87.68, 88.05, 89.81, and
90.30 ppm in complex 4.
Table 1
Transfer hydrogenation of acetophenone with iso-PrOH catalyzed by [Ru(chloro(p-
cymene)(N,N0-bis[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide))]
chloride, 3, and [Ru(chloro(p-cymene)(N,N0-bis[(1S)-1-phenyl-2-O-(diphenylphosph-
inite)ethyl]ethane diamide))] chloride, 4
Entry Catalyst s/c
Time
Conversion eej
Configurationk TOF1
(%)i
%
(hꢀ1
)
1
2
3
3a
4a
3b
100:1 1 h
100:1 1 h
100:1 48 h
(70 h)
100:1 48 h
(70 h)
<3
<3
—
—
—
—
S
—
—
<2
75 (98)
72
(73)
69
4
5
6
4b
3c
4c
74 (97)
S
S
S
<2
(72)
60
(62)
63
100:1 30 min 65 (98)
130
(98)
134
(99)
—
(1 h)
100:1 30 min 67 (99)
(1 h)
(64)
—
2.2. Asymmetric transfer hydrogenation of prochiral ketones
7
8
9
10
11
12
13
14
15
16
3d
4d
3e
4e
3f
100:1 1 h
100:1 1 h
500:1 5 h
500:1 5 h
1000:1 9 h
1000:1 9 h
100:1 3 h
100:1 3 h
100:1 8 h
100:1 8 h
—
—
—
S
—
—
—
98
In a preliminary study, the synthesized complexes 3 and 4 were
evaluated as a precursor for the catalytic transfer hydrogenation of
the acetophenone by iso-PrOH/KOH as a reducing system. In all the
reactions, these complexes catalyzed the reduction of acetophe-
none to the 1-phenylethanol via hydrogen transfer from iso-PrOH
(Scheme 3) and the results are summarized in Table 1.
98
99
99
98
98
99
97
98
73
71
74
75
71
70
66
63
S
99
S
S
S
110
109
33
4f
3g
4g
3h
4h
S
33
S
12
S
12
a
b
Reaction conditions: at room temperature; acetophenone/Ru/KOH, 100:1:5. At
c
O
OH
*
50 °C; acetophenone/Ru/KOH, 100:1:5. Refluxing in iso-PrOH; acetophenone/Ru/
KOH, 100:1:5. In the absence of base. Refluxing in iso-PrOH; acetophenone/Ru/
KOH, 500:1:5. Refluxing in iso-PrOH; acetophenone/Ru/KOH, 1000:1:5. Added
0.1 mL H2O. Carried out (refluxing) the reaction in air. Determined by GC (three
independent catalytic experiments). Determined by capillary GC analysis using a
chiral cyclodex B (Agilent) capillary column. Determined by comparison of the
retention times of the enantiomers on the GC traces with the literature values.
d
e
f
g
3 or 4 / KOH
iso-PrOH
h
i
R
R
j
k
l
R: H, 4-F, 4-Cl, 4-Br, 2-CH3O, 4-CH3O
Referred at the reaction time indicated in column; TOF = (mol product/mol Ru(II)
Cat.) ꢁ hꢀ1
.
Scheme 3. Hydrogen transfer from iso-PrOH to acetophenone derivatives.
Based on our results, these complexes catalyzed the reduction
of acetophenone to corresponding alcohol ((R)- or (S)-1-phenyleth-
anol) with KOH as a promoter. At room temperature, transfer
hydrogenation of acetophenone occurred very slowly21 with low
conversion (3% after 1 h, entries 1 and 2) in all the reactions. But,
at 50 °C (Table 1, entries 3 and 4), this reaction of acetophenone oc-
curred slowly with high conversion (<98% after 70 h) and high
enantioselectivity (up to 73% ee). In addition, the ees do not vary
with the time, as indicated by the catalytic results collected with
3 and 4. Reduction of acetophenone into 1-phenylethanol could
be achieved in high yield by increasing the temperature up to
82 °C. The negligible catalytic activity of [Ru(p-cymene)Cl2]2 was
observed under the applied experimental conditions.22 It should
be also pointed out that complexes 3 and 4 are more active catalyst
goes b-elimination to give ruthenium hydride, which is an active
species in this reaction. This is the mechanism proposed by several
workers on the studies of ruthenium-catalyzed transfer hydroge-
nation reaction by metal hydride intermediates.25 In addition, opti-
mization studies of the catalytic reduction of acetophenone in iso-
PrOH showed that good activity was obtained with a base/cat. ratio
of >5:1. Although the yields gradually decreased on increasing the
mole ratios of [acetophenone]/[Ru] from 100/1 to 500/1 or 1000/1,
the enantioselectivity was still high (Table 1, entries 9–12). That is
to say, the ee remained unchanged when the molar ratio of sub-
strate to catalyst was increased.
For the transfer hydrogenation of acetophenone, the catalyst sys-
tem showed high activity and moderate selectivity even in the pres-
ence of small amount of water. When we increased the amount of
water in the reaction system, the high conversion with the same
enantioselectivity remained intact (Table 1, entries 13 and 14).
Performing the reaction in air slowed down the reaction but did
not affect enantioselectivity (65–70% ee, Table 1, entries 15 and
16). Under identical conditions, the differences in enantioselectivi-
ties between the Ru(chloro(p-cymene)(N,N0-bis[(1S)-1-sec-butyl-
2-O-(diphenylphosphinite)ethyl]ethanediamide))]chloride, 3 and
[Ru(chloro(p-cymene)(N,N0-bis[(1S)-1-phenyl-2-O-(diphenylphosph-
inite)ethyl]ethanediamide))]chloride, 4 were quite small and (S)
configuration was obtained in all experiments.
than the corresponding precursor: [Ru(g l-Cl)Cl]2
6-p-cymene)(
(41% maximum yield in 24 h) with a 1/14 complex/NaOH ratio.23
When the temperature was increased to 82 °C smooth reduction
of acetophenone into 1-phenylethanol occurred with conversion
ranging from 65% to 67% after 30 min for 3 and 4. The catalytic
activities of 3 and 4 are comparable, with the TOF values referred
to 30 min of 130 hꢀ1 and 134 hꢀ1, respectively. These reactions
were carried out under Ar atmosphere at 82 °C and reached the
maximum conversion within 1 h (Table 1, entries 5 and 6). In these
cases conversions higher than 30% have always been obtained
(TOFs up to 120 h-1), indicating that the reactions start immedi-
ately after the addition of base without any induction time. Fur-
thermore, as can be inferred from Table 1 (entries 7 and 8), the
precatalysts and the presence of base are necessary to observe
appreciable conversions and the absence of base leads to the deac-
tivation of the catalysts.24 The choice of base, such as KOH and
NaOH, had little influence on the conversion or enantioselectivity.
The base facilitates the formation of ruthenium alkoxide by
abstracting proton of the alcohol and subsequently alkoxide under-
With the cationic ruthenium complexes, [Ru{chloro(p-cym-
ene)(N,N0-bis[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]
ethanediamide)}]chloride,
3
and [Ru{chloro(p-cymene)(N,N0-bis
[(1S)-1-phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide)}]
chloride, 4, a variety of aromatic ketones were transformed to the
corresponding secondary alcohols and it is noteworthy that 3 and 4
complexes display the same catalytic activities and selectivities in
the transfer hydrogenation of acetophenone derivatives (Table 2).

M. Aydemir et al. / Tetrahedron: Asymmetry 21 (2010) 703–710
707
Table 2
Asymmetric transfer hydrogenation results for substituted acetophenones with the catalyst systems prepared from [Ru(
O-(diphenylphosphinite)ethyl]ethanediamide, 3, and N,N0-bis-[(1S)-1-phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide, 4a
g
6-p-cymene)(
l
-Cl)Cl]2 and N,N0-bis-[(1S)-1-sec-butyl-2-
Entry
Catalyst
Substrate
Product
Conversionb (%)
eec (%)
Configurationd
1
2
3
4
99
98
62
64
S
S
O
OH
F
F
3
4
3
4
98
98
58
60
S
S
O
OH
Cl
Br
Cl
Br
5
6
3
4
96
97
61
58
S
S
O
OH
7
8
3
4
93
94
77
75
S
S
O
OMe OH
OMe
9
10
3
4
90
91
68
70
S
S
O
OH
MeO
MeO
a
b
c
Catalyst (0.005 mmol), substrate (0.5 mmol), iso-PrOH (5 mL), KOH (0.025 mmol %), 82 °C, 1.0 h for 3 and 4, the concentration of acetophenone is 0.1 M.
Purity of compounds is checked by NMR and GC (three independent catalytic experiments), yields are based on methyl aryl ketone.
Determined by capillary GC analysis using a chiral cyclodex B (Agilent) capillary column (30 m ꢁ 0.32 mm I.D. ꢁ 0.25
lm film thickness).
d
Determined by comparison of the retention times of the enantiomers on the GC traces with the literature values.
Replacing a sec-butyl moiety by a phenyl group induced no signif-
icant increase of the conversion and enantioselectivity.
the electron density of the C@O bond so that the activity was im-
proved giving rise to easier hydrogenation.26 An electron-with-
drawing group such as fluoro group to the para-position was
helpful to obtain excellent conversion and good enantioselectivity
(up to 65% ee, Table 2, entries 1 and 2), while the introduction of an
electron-donating substituents such as methoxy group to the para-
position tended to higher enantioselectivity while maintaining sat-
The catalytic reductions of acetophenone derivatives were all
tested with the conditions optimized for acetophenone. Complexes
3 and 4 showed very high activity for most of the ketones. The
introduction of electron-withdrawing substituents, such as F, Cl,
and Br to the para-position of the aryl ring of the ketone decreased
Figure 2. The 31P–{1H} NMR spectrum of the hydrolysis product diphenylphosphinous acid, Ph2P(O)H.

708
M. Aydemir et al. / Tetrahedron: Asymmetry 21 (2010) 703–710
isfactory activity (entries 9 and 10). The position and electronic
property of the ring substituents also influenced hydrogenation re-
sults. The introduction of an electron-donating group methoxy
group to the para-position decelerates the reaction, but that to
the ortho-position increases the rate, however, improves the
enantioselectivity (Table 2, entries 7–10). Among all the selected
ketones, the best result was obtained in the reduction of ortho-
methoxyacetophenone giving 75% and 77% ee (entries 7 and 8).
The results (Table 2) indicated that a strong electron-withdrawing
substituent, such as fluoro or chloro, was capable of higher conver-
sion but with slightly lower enantiomeric purity. Conversely, the
most electron-donating substituent (–OCH3) led to lower conver-
sion with higher ee. In order to investigate the evolution of the cat-
alyst, 3 or 4, 31P–{1H} NMR spectrum was recorded immediately
after the catalytic reaction. The observed singlet at 21.6 ppm
(Fig. 2) in the spectrum is corresponding to hydrolysis product
diphenylphosphinous acid, Ph2P(O)H.27
injector port temperature, 200 °C; detector temperature, 200 °C,
injection volume, 2.0 L.
l
4.4. General procedure for the transfer hydrogenation of
ketones
Typical procedure for the catalytic hydrogen-transfer reaction:
a
solution of the ruthenium complexes [Ru{chloro(p-cym-
ene)(N,N0-bis[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]
ethanediamide)}]chloride,
or [Ru{chloro(p-cymene)(N,N0-bis
3
[(1S)-1-phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide)}]
chloride, 4 (0.005 mmol), KOH (0.025 mmol), and the correspond-
ing ketone (0.5 mmol) in degassed iso-PrOH (5 mL) was refluxed
for one hour. After this time a sample of the reaction mixture is ta-
ken off, diluted with acetone, and analyzed immediately by GC,
yields obtained are related to the residual unreacted ketone.
4.5. Procedure for the preparation of the chiral ligands and
ruthenium complexes
3. Conclusions
4.5.1. Synthesis of N,N0-bis-[(1S)-1-sec-butyl-2-O-
(diphenylphosphinite)ethyl]ethanediamide, 1
In conclusion, we have developed an effective, modular cata-
lytic system for the asymmetric transfer hydrogenation of ketones.
High conversion and moderate to good enantioselectivity were ob-
tained in the catalytic reaction. Amazingly, the reaction was not af-
fected in the air or with the addition of water. This may imply
industrial applications. Future work will focus on finding the struc-
ture of the real catalyst and improving the enantioselectivity of the
catalytic system.
PPh2Cl (0.16 g, 0.70 mmol) was slowly added to a solution of
N,N0-bis[(1S)-1-sec-butyl-2-hydroxyethyl]ethanediamide (0.10 g,
0.35 mmol) and triethylamine (0.07 g, 0.70 mmol) in 25 mL of tol-
uene at room temperature. The mixture was stirred for 2 h and tri-
ethylammonium chloride was filtered off. Evaporation of the
solvent in vacuo gave N,N0-bis-[(1S)-1-sec-butyl-2-O-(diphenyl-
phosphinite)ethyl]ethanediamide,
1
as
a white solid. (Yield:
0.21 g, 91%); mp: 83–85 °C. ½a D25
ꢂ
¼ þ33:6 (c 1.0, DMSO). [C38H46N2
O4P2] (mw: 656.74 g/mol); Anal. Calcd: C, 69.49; H, 7.06; N, 4.27.
4. Experimental
Found: C, 69.35; H 7.01; N 4.22%. Selected IR,
m
(cmꢀ1): 3325 (N–
H), 2967, 2934 (Ar-H), 1658 (C@O, first amide band), 1510 (C@O,
second amide band), 1074 (C–O), 1041 (P–O). 1H NMR (CDCl3) d
(ppm): 0.91 (t, 6H, J = 7.4 Hz, –CH2CH3), 0.96 (d, 6H, J = 6.8 Hz, –
CHCH3), 1.14 ((m, 2H, –CH2CH3), (a)), 1.43 ((m, 2H, –CH2CH3),
(b)), 1.78 (m, 2H, CHCH3), 3.92 ((m, 2H, –CH2O–P, (a)), 3.98 ((m,
2H, –CH–N and 2H, –CH2O–, (b)), 7.36–7.52 (m, 20H, o-, m- and
p-protons of phenyls), 8.61 (b, 2H, NH). 13C–{1H} NMR (CDCl3) d
(ppm): 11.26 (–CH2CH3), 15.47 (–CHCH3), 24.16 (–CH2CH3), 34.37
4.1. Materials and methods
Unless otherwise stated, all reactions were carried out under an
atmosphere of argon using conventional Schlenk glass-ware, sol-
vents were dried using established procedures and distilled under
argon immediately prior to use. Analytical grade and deuterated
solvents were purchased from Merck. The starting materials PPh2Cl
and Et3N are purchased from Fluka and were used as received.
3
2
(–CHCH3), 55.08 (d, J31P–13C = 8.0 Hz, –CH–N), 68.96 (d, J31P–13C
=
15
[Ru(g
6-p-cymene)(
l-Cl)Cl]2
and N,N0-bis[(1S)-1-sec-butyl-2-
3
18.0 Hz, –CH2O–P), 128.43 (d, J31P–13C = 8.4 Hz, m-carbons of
hydroxyethyl]ethanediamide28 were prepared according to the lit-
erature procedures.
2
phenyls), 129.54 (s, p-carbons of phenyls), 130.50 (d, J31P–13C
=
22.0 Hz, o-carbons of phenyls), 140.26 (d, 1J31P–13C = 18.1 Hz, i-car-
bons of phenyls), 158.39 (s, C@O), assignment was based on the
1H–13C HETCOR and 1H–1H COSY spectra. 31P–{1H} NMR (CDCl3)
d (ppm): 116.17 (s, O–P–(C6H5)2).
4.2. Spectroscopic analyses
The IR spectra were recorded on a Mattson 1000 ATI UNICAM
FT-IR spectrometer as KBr pellets. 1H (400.1 MHz), 13C NMR,
(100.6 MHz) and 31P–{1H} NMR (162.0 MHz) spectra were re-
corded on a Bruker Avance 400 spectrometer, with d referenced
to external TMS and 85% H3PO4, respectively. Elemental analysis
was carried out on a Fisons EA 1108 CHNS-O instrument. Melting
points were recorded by Gallenkamp Model apparatus with open
capillaries.
4.5.2. Synthesis of N,N0-bis-[(1S)-1-phenyl-2-O-
(diphenylphosphinite)ethyl]ethanediamide, 2
PPh2Cl (0.14 g, 0.60 mmol) was slowly added to a solution of
N,N0-bis[(1S)-1-phenyl-2-hydroxyethyl]ethanediamide29 (0.10 g,
0.30 mmol) and triethylamine (0.06 g, 0.60 mmol) in 25 mL of
toluene at room temperature. The mixture was stirred for 3 h
and triethylammonium chloride was filtered off. Evaporation of
the solvent in vacuo gave N,N0-bis-[(1S)-1-phenyl-2-O-(diphenyl-
4.3. GC analyses
phosphinite)ethyl]ethanediamide,
2
as
a white solid. (Yield:
0.20 g, 95%); ½a 2D5
ꢂ
¼ ꢀ35:2 (c 1.0, DMSO). [C42H38N2O4P2] (mw:
GC analyses were performed on a HP 6890N Gas Chromato-
graph equipped with cyclodex
696.72 g/mol); Anal. Calcd: C, 72.41; H, 5.50; N, 4.02. Found: C,
B
(Agilent) capillary column
72.29; H, 5.43; N, 3.94. Selected IR, m
(cmꢀ1): 3293 (N–H), 3050,
(30 m ꢁ 0.32 mm I.D. ꢁ 0.25 m film thickness). The GC parame-
l
2966 (Ar-H), 1688 (C@O, first amide band), 1515 (C@O, second
amide band), 1099 (C–O), 1029 (P–O). 1H NMR (CDCl3) d (ppm):
4.12 (m, 4H, –CH2O–P), 5.18 (m, 2H, –CH–N), 7.25–7.58 (m, 20H,
o-, m- and p-protons of phenyls and 10 protons of CH(C6H5)),
8.03 (d, 2H, J = 8.0 Hz, NH). 13C–{1H} NMR (CDCl3) d (ppm): 54.72
ters for asymmetric transfer hydrogenation of ketones were as fol-
lows; initial temperature, 50 °C; initial time 1, 1 min; solvent
delay, 4.48 min; temperature ramp 1, 3 °C/min; final temperature,
150 °C; initial time 2, 2 min; temperature ramp 2, 15 °C/min; final
temperature, 250 °C; initial time 3, 3 min; final time, 44.33 min;
3
2
(d, J31P–13C = 9.0 Hz, –CH–N), 71.62 (d, J31P–13C = 18.0 Hz, –CH2O–

M. Aydemir et al. / Tetrahedron: Asymmetry 21 (2010) 703–710
709
2
P), 126.95, 127.99, 128.68, 137.83 (carbons of CH(C6H5)), 128.36 (d,
(–CH–N), 69.29 (–CH2O–P), (87.68 (d, J31P–13C = 6.0 Hz), 88.05
(d, 2J31P–13C = 6.0 Hz), 89.81 (d, 2J31P–13C = 3.0 Hz), 90.30 (d, 2J31P–13C
=
4
3J31P–13C = 7.6 Hz, m-carbons of phenyls), 129.54 (d, J31P–13C
=
2
3.0 Hz, p-carbons of phenyls), 130.47 (d, J31P–13C = 22.0 Hz, o-car-
bons of phenyls), 140.04 (d, J31P–13C = 17.6 Hz, i-carbons of phen-
4.0 Hz), aromatics carbons of p-cymene), 97.84, 112.10 (quaternary
carbons of p-cymene), 126.92, 127.98, 128.65, 137.85 (carbons of
CH(C6H5)), 128.10 (d, J31P–13C = 10.0 Hz, m-carbons of phenyls),
1
yls), 158.04 (s, C@O), assignment was based on the 1H–13
HETCOR and 1H–1H COSY spectra. 31P–{1H} NMR (CDCl3)
(ppm): 117.44 (s, O–P–(C6H5)2).
C
d
3
4
131.16 (d, p-carbons of phenyls), 132.48 (dd, J31P–13C
=
2
12.1 and J31P–13C = 14.2 Hz, o-carbons of phenyls), 136.00 (d,
1J31P–13C = 50.3 Hz, i-carbons of phenyls), 159.15 (s, C@O), assign-
ment was based on the 1H–13C HETCOR and 1H–1H COSY spectra.
31P–{1H} NMR (CDCl3) d (ppm): 116.26 (s, O–P–(C6H5)2).
4.5.3. Synthesis of [Ru{chloro(p-cymene)(N,N0-bis[(1S)-1-sec-
butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide)}]
chloride, 3
[Ru(g
6-p-cymene)(
l
-Cl)Cl]2 (0.05 g, 0.08 mmol) and N,N0-bis-
Acknowledgment
[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide,
1 (0.10 g, 0.15 mmol) were dissolved in 25 mL of toluene and stir-
red for 4 h at room temperature. The volume was concentrated to
ca. 1–2 mL under reduced pressure and addition of diethyl ether
(20 mL) gave 3 as a clear red solid. The product was collected by
filtration and dried in vacuum. (Yield: 0.13 g, 86%); mp: 202–
Partial support from Dicle University (Project number: DÜBAP-
07-01-22) is gratefully acknowledged.
References
204 °C. ½a 2D5
¼ þ38:2 (c 1.0, DMSO). [C48H60N2O4P2RuCl2] (mw:
ꢂ
1. (a) Hannedouche, J.; Clarksom, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986–
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962.94 g/mol); Anal. Calcd: C, 59.87; H, 6.28; N, 2.91. Found: C,
59.78; H, 6.23; N, 2.86. Selected IR,
m
(cmꢀ1): 3396 (N–H), 3057,
2973 (Ar-H), 1666 (C@O, first amide band), 1504 (C@O, second
amide band), 1097 (C–O), 1026 (P–O). 1H NMR (CDCl3) d (ppm):
0.76 (m, 6H, –CHCH3 and 6H, –CH2CH3), 1.05 (d, 6H, J = 6.8 Hz,
(CH3)2CHPh of p-cymene), 1.30 ((m, 2H, –CH2CH3), (a)), 1.40 ((m,
2H, –CH2CH3), (b)), 1.62 (m, 2H, –CHCH3), 1.76 (s, 3H, CH3-Ph of
p-cymene), 2.55 (m, 1H, –CHCH3– of p-cymene), 3.79 (m, 4H,
–CH2O–P and 2H, –CH–N), 5.04, 5.08, 5.16, 5.23 (4s, 4H, aromatic
CH protons of p-cymene), 7.32–7.84 (m, 20H, o-, m- and p-protons
of phenyls), 8.73 (br, 2H, NH). 13C–{1H} NMR (CDCl3) d (ppm):
11.32 (–CH2CH3), 15.41 (–CHCH3), 17.60 (CH3Ph of p-cymene),
22.01 ((CH3)2CHPh of p-cymene), 25.07 ((–CH2CH3), 35.63
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124–129; (c) Broger, E. A.; Burkart, W.; Hennig, M.; Scalone, M.; Schmid, R.
Tetrahedron: Asymmetry 1998, 9, 4043–4054.
3
(–CHCH3), 54.79 (d, J31P–13C = 8.0 Hz –CH–N), 67.11 (–CH2O–P),
2
2
(87.19 (d, J31P–13C = 5.0 Hz), 88.30 (d, J31P–13C = 6.0 Hz), 89.87
(d, 2J31P–13C = 4.5 Hz), 91.31 (d, 2J31P–13C = 4.0 Hz), aromatic carbons
of p-cymene), 97.26, 111.97 (quaternary carbons of p-cymene),
3
128.19 (t, J31P–13C = 10.1 Hz, m-carbons of phenyls), 131.30 (d,
4
4J31P–13C = 6.6 Hz, p-carbons of phenyls), 132.81 (dd, J31P–13C
=
2
15.4 Hz and J31P–13C = 22.0 Hz, o-carbons of phenyls), 136.22 (d,
1J31P–13C = 49.3 Hz, i-carbons of phenyls), 159.41 (s, C@O), assign-
ment was based on the 1H–13C HETCOR and 1H–1H COSY spectra.
31P–{1H} NMR (CDCl3) d (ppm): 115.69 (s, O–P–(C6H5)2).
4.5.4. Synthesis of [Ru{chloro(p-cymene)(N,N0-bis[(1S)-1-
phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide)}]
chloride, 4
[Ru(
[(1S)-1-phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide,
13. Fei, Z.; Scopelliti, R.; Dyson, P. J. Eur. J. Org. Chem. 2004, 530–537.
14. (a) Majoumo, F.; Lönnecke, P.; Kühl, O.; Hey-Hawkins, E. Z. Anorg. Allg. Chem.
2004, 630, 305–308; (b) Aydemir, M.; Baysal, A.; Öztürk, G.; Gümgüm, B. Appl.
Organomet. Chem. 2009, 23, 108–113; (c) Aydemir, M.; Baysal, A.; Gümgüm, B.
J. Organomet. Chem. 2008, 693, 3810–3814; (d) Morales-Morales, D.; Redon, R.;
Yung, C.; Jensen, C. M. Chem. Commun. 2000, 1619–1620.
15. Bennet, M. A.; Robertson, G. B.; Smith, A. K. J. Organomet. Chem. 1972, 43, C41.
16. Maj, A. M.; Michal, K. M.; Suisse, I.; Agbossou, F.; Mortreux, A. Tetrahedron:
Asymmetry 1999, 10, 831–835.
17. Balakrishna, M. S.; George, P. P.; Mobin, S. M. Polyhedron 2005, 24, 475–480.
18. Kostas, I. D.; Steele, B. R.; Trezis, A.; Amosova, S. V. Tetrahedron 2003, 59, 3467–
3473.
19. (a) Yang, H.; Lugan, N.; Mathieu, R. An. Quim. 1997, 93, 28–38; (b) Moldes, I.; de
la Encarnacion, E.; Ros, J.; Alvarez-Larena, A.; Piniella, J. F. J. Organomet. Chem.
1998, 566, 165–174.
20. (a) Gendre, P. L.; Offenbecher, M.; Bruneau, C.; Dixneuf, P. H. Tetrahedron:
Asymmetry 1998, 9, 2279–2284; (b) Zhang, Q.; Hua, G.; Bhattacharrya, P.;
Slawin, A. M. Z.; Woollins, J. D. J. Chem. Soc., Dalton Trans. 2003, 3250–3257.
21. Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya, T.; Noyori, R. J. Chem.
Soc., Chem. Commun. 1996, 233–234.
22. Palegatti, P.; Carcelli, M.; Calbiani, F.; Cassi, C.; Elviri, L.; Pelizzi, C.; Rizzotti, U.;
Rogolino, D. Organometallics 2005, 24, 5836–5844.
23. Tribo, R.; Munoz, S.; Pons, J.; Yanez, R.; Alvarez-Larena, A.; Piniella, J. F.; Ros,
J. Organomet. Chem. 2005, 690, 4072–4079.
g l
6-p-cymene)( -Cl)Cl]2 (0.04 g, 0.07 mmol) and N,N0-bis-
2
(0.10 g, 0.14 mmol) were dissolved in 20 mL of toluene and stirred
for 2 h at room temperature. The volume was concentrated to ca.
1–2 mL under reduced pressure and addition of diethyl ether
(20 mL) gave 4 as a clear red solid. The product was collected by
filtration and dried in vacuum. (Yield: 0.12 g, 85%); mp: 193–
195 °C. ½a 2D5
¼ ꢀ38:0 (c 1.0, DMSO) [C55H52N2O4P2RuCl2] (mw:
ꢂ
1002.92 g/mol); Anal. Calcd: C, 62.28; H, 5.23; N, 2.79. Found: C,
62.14; H, 5.16; N, 2.68. Selected IR,
m
(cmꢀ1): 3415 (N–H), 3057,
2966 (Ar-H), 1670 (C@O, first amide band), 1496 (C@O, second
amide band), 1099 (C–O), 1036 (P–O). 1H NMR (CDCl3) d (ppm):
1.06 (d, 6H, J = 7.2 Hz, (CH3)2CHPh of p-cymene), 1.78 (s, 3H, CH3-
Ph of p-cymene), 2.60 (m, 1H, –CH– of p-cymene), 4.05 (m, 4H,
–CH2O–P), 5.03 (d, 2H, J = 5.6 Hz, aromatic CH protons of p-cymene,
(a)), 5.18 (m, 2H, aromatic CH protons of p-cymene, (a) and 2H,
–CH–N), 7.25–7.38 (m, 20H, o-, m- and p-protons of phenyls and
10 protons of CH(C6H5)), 8.29 (d, 2H, J = 8.0 Hz, NH). 13C-{1H}
24. Pamies, O.; Backvall, J.-E. Chem. Eur. J. 2001, 7, 5052–5058.
25. (a) Zhang, H.; Yang, B. C.; Li, Y. Y.; Donga, Z. R.; Gao, J. X.; Nakamura, H.; Murata,
K.; Ikariya, T. J. Chem. Soc., Chem. Commun. 2003, 142–143; (b) Hannedouche, J.;
Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986–987; (c) Bacchi, A.;
Balordi, M.; Cammi, R.; Elviri, L.; Pelizzi, C.; Picchioni, F.; Verdolino, V.; Goubitz,
K.; Peschar, R.; Pelagatti, P. Eur. J. Inorg. Chem. 2008, 4462–4473.
NMR (CDCl3)
d (ppm): 17.49 (CH3Ph of p-cymene), 21.88
((CH3)2CHPh of p-cymene), 30.08 (–CH– of p-cymene), 54.39

710
M. Aydemir et al. / Tetrahedron: Asymmetry 21 (2010) 703–710
26. (a) Chen, J.-S.; Li, Y.-Y.; Dong, Z.-R.; Li, B.-Z.; Gao, J.-X. Tetrahedron Lett. 2004, 45,
8415–8418; (b) Faller, J. W.; Lavoie, A. R. Organometallics 2001, 20, 5245–5247;
stirred for further 5 min and the resulting white solid precipitates were
collected and washed with small portion of diethyl ether to give a white solid.
(Yield: 1.65 g, 56%); ½a D25
¼ ꢀ35:2 (c 1.0, DMSO). [C18H20N2O4] (mw: 328.37 g/
ꢂ
_
(c) Özdemir, I.; Yasßar, S. Transition Met. Chem. 2005, 30, 831–835.
27. (a) Fei, Z.; Scopelliti, R.; Dyson, P. J. Inorg. Chem. 2003, 42, 2125; (b) Fei, Z.;
Scopelliti, R.; Dyson, P. J. Eur. J. Inorg. Chem. 2004, 530–537; (c) Berger, S.;
Braun, S.; Kolinowski, H.-O. NMR-Spektroskopie von Nichtmetallen Band 3, 31P
NMR-Spektroskopie; Georg Theime Verlag: Stuttgart, New York, 1993.
28. Sunkur, M.; Baris, D.; Hosgoren, H.; Togrul, M. J. Org. Chem. 2008, 73, 2570–
2575.
mol); Anal. Calcd: C, 65.84; H, 6.09; N, 8.53. Found: C, 65.65; H, 6.04; N, 8.44%.
Selected IR,
m
(cmꢀ1): 3420 (O–H), 3296 (N–H), 3070, 3043 (Ar-H), 1654 (C@O,
first amide band), 1515 (C@O, second amide band), 1042 (C–O). 1H NMR
(CDCl3) d (ppm): 3.50 (br, 2H, CH2OH), 3.63 (m, 2H, –CH2–OH, (a)), 3.73 (m, 2H,
–CH2–OH, (b)), 4.88 (m, 2H, –CH–N), 7.21–7.42 (m, 10 protons of CH(C6H5)),
9.00 (d, 2H, J = 8.8 Hz, NH). 13C–{1H} NMR (CDCl3) d (ppm): 56.71 (–CH–N),
64.41 (–CH2–OH), 127.48, 127.53, 128.64, 140.72 (carbons of CH(C6H5)), 160.22
(s, C@O), assignment was based on the 1H–13C HETCOR and 1H–1H COSY
spectra.
29. Preparation of N,N0-bis[(1S)-1-phenyl-2-hydroxyethyl]ethanediamide:
solution of -glisinol (2.5 g, 0.0182 mol) in MeOH (25 mL) was slowly added
dropwise over 30-min period to solution of dimethyloxalate (1.07 g,
0.009 mol) in MeOH (30 mL) at room temperature. The reaction mixture was
A
L
a
a