New C2-symmetric chiral phosphinite ligands based on amino alcohol scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones

Article abstract of DOI:10.1016/j.crci.2012.12.003

Asymmetric transfer hydrogenation processes of ketones with chiral molecular catalysts are attracting increasing interest from synthetic chemists due to their operational simplicity. C₂-symmetric catalysts have also received much attention and been used in many reactions. A series of new chiral C₂-symmetric bis(phosphinite) ligands has been prepared from corresponding amino acid derivated amino alcohols or (R)-2-amino-1-butanol through a three- or four-step procedure. Their structures have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis. ¹H-³¹P NMR, DEPT, ¹H-¹³C HETCOR or ¹H-¹H COSY correlation experiments were used to confirm the spectral assignments. In situ prepared ruthenium catalytic systems were successfully applied to ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives by iso-PrOH. Under optimized conditions, these chiral ruthenium catalyst systems serve as catalyst precursors for the asymmetric transfer hydrogenation of acetophenone derivatives in iso-PrOH and act as good catalysts, giving the corresponding optical secondary alcohols in 99% yield and up to 79% ee.

Full text of DOI:10.1016/j.crci.2012.12.003

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´
Full paper/Memoire
New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer
hydrogenation of aromatic ketones
*
Feyyaz Durap , Murat Aydemir, Duygu Elma, Akın Baysal, Yılmaz Turgut
Dicle University, Science and Art Faculty, Department of Chemistry, 21280 Diyarbakır, Turkey
A B S T R A C T
A R T I C L E I N F O
Article history:
Asymmetric transfer hydrogenation processes of ketones with chiral molecular catalysts
are attracting increasing interest from synthetic chemists due to their operational
simplicity. C2-symmetric catalysts have also received much attention and been used in
many reactions. A series of new chiral C2-symmetric bis(phosphinite) ligands has been
prepared from corresponding amino acid derivated amino alcohols or (R)-2-amino-1-
butanol through a three- or four-step procedure. Their structures have been elucidated by
a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis.
1H-31P NMR, DEPT, 1H-13C HETCOR or 1H-1H COSY correlation experiments were used to
confirm the spectral assignments. In situ prepared ruthenium catalytic systems were
successfully applied to ruthenium-catalyzed asymmetric transfer hydrogenation of
acetophenone derivatives by iso-PrOH. Under optimized conditions, these chiral
ruthenium catalyst systems serve as catalyst precursors for the asymmetric transfer
hydrogenation of acetophenone derivatives in iso-PrOH and act as good catalysts, giving
the corresponding optical secondary alcohols in 99% yield and up to 79% ee.
Received 30 April 2012
Accepted after revision 3 December 2012
Available online xxx
Keywords:
Homogeneous catalysis
Asymmetric transfer hydrogenation
Chiral phosphinite ligands
Ruthenium
C2-symmetry
´
ß 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
ment especially for large-scale reactions [4]. However, use
of a solvent that can donate hydrogen, such as 2-propanol,
The asymmetric hydrogenation of prochiral ketones
provides good opportunities for producing a range of chiral
alcohols. Chiral alcohols are very important building
blocks and synthetic intermediates in organic synthesis
and in the pharmaceutical industry [1].
Extensive efforts have been devoted to their reduction
into secondary alcohols especially via hydrogenation [2].
Noyori et al. provided an elegant solution for the
asymmetric catalytic molecular hydrogenation of simple
aryl ketones [3]. The use of hydrogen gas in the molecular
hydrogenation processes presents considerable safety
hazards and requires pressure vessels and other equip-
overcomes these difficulties. The volatile acetone by-
product can also be easily removed to shift unfavourable
equilibria. The most commonly used catalysts for this
reaction are ruthenium(II) complexes, but several rhodium
and iridium derivatives have also been used. Ru catalysts
have excellent performances [3a,5] and Ru enjoyed a cost
advantage relative to other asymmetric hydrogenation
metals such as Rh [6].
The use of organometallic complexes as catalysts for
asymmetric transfer hydrogenation from a suitable donor
(usually 2-propanol or formic acid) has been the subject of
ongoing researches for some decades. In particular, the
metals coordinated by one or more chiral phosphorus
ligands exhibit exciting enantioselectivity and reactivity [7].
Complexes of the type trans-RuCl2(diamine)(diphosphine)
with matching configurations of chiral diphosphine and
* Corresponding author.
E-mail address: fdurap@dicle.edu.tr (F. Durap).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.12.003
Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003

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Scheme 1.
D- or L-valinol and (R)-2-amino-1-butanol derivatives of C2-symmetric chiral bis(phosphinite) ligands used in this study.
diamine, e.g. (S)-BINAP/(S,S)-DPEN, showhighreactivityand
enantioselectivity [8]. In general, the most successful chiral
ligands used in the asymmetric hydrogenation reactions are
rigid chelating diphosphines possessing a C2-symmetry axis
thus reducing the number of diastereomeric transition
states [9]. Phosphines and phosphinites are among the most
important phosphorus-based ligands with a wide range of
steric and electronic properties. Phosphine ligands have
found widespread applications in transition metalcatalyzed
asymmetric transformations [10], phoshinite-derived
ligands have also attracted a considerable attention for
catalytic hydrogenation [11–13]. The metal-phosphorus
bond is often stronger for phosphinites compared to the
related phosphine due to the presence of an electron-
withdrawing P-OR group. This feature of the phosphinites
provides different chemical, electronic and structural
propertiescomparedtophosphines.Additionally,theempty
isomeric metal complexes, as well as the number of
different substrate–catalyst arrangements and reaction
pathways, when compared with a nonsymmetrical ligand.
This consequence of C2-symmetry can have a beneficial
effect on enantioselectivity because the competing less-
selective pathways are possibly eliminated [20].
We began this study by preparing
D- or L-valinol from
the - or -valine which were reduced under standard
D
L
conditions using NaBH4-I2 in dry THF according to the
literature procedure [21] (Scheme 2).
We also prepared chiral C2-symmetric amino alcohols
from the D- or L-valinol, (R)-2-amino-1-butanol and (R)-N-
benzyl-2-amino-1-butanol according the procedures de-
scribed in the literature [22,23] as shown in Scheme 3. The
structures for these chiral amino alcohols are consistent
with the data obtained from 1H NMR, 13C NMR, IR spectra
and elemental analyses (for details see experimental
section).
s*-orbital of the phosphinite P(OR)R2 is stabilized, making
the phosphinite a better acceptor [14]. So, phosphinites
open many opportunities to design new improved ligands
for asymmetric catalysis. The most important advantage of
chiral phosphinite ligands over the corresponding phos-
phine ligands is the easiness of preparation [12c].
Chiral C2-symmetric bis(phosphinite) ligands were
prepared from the corresponding C2-symmetric amino
alcohols and two equivalents of chlorodiphenylphosphine
or chlorodiisopropylphosphine, in freshly distilled anhy-
drous toluene or CH2Cl2 respectively, under argon atmo-
sphere in the presence of Et3N as the base at room
temperature in high yield as outlined in Scheme 4.
The progress of this reaction was conveniently followed
by 31P-{1H} NMR spectroscopy. The signals of the starting
A ligand is more likely to induce high enantioselectivity
if it has C2-symmetry [1a,15] (first example: diop) or is
very strongly unsymmetrical [16] (e.g. josiphos) in order to
reduce the number of possible isomeric catalyst-substrate
complexes [12c]. So, C2-symmetric phosphinite derivated
catalysts have received much attention and have been used
in many asymmetric hydrogenation reactions and other
metal-catalyzed processes [17] and it is expected that
chiral amino alcohol based C2-symmetric phosphinite
ligands may result in unique properties for suitable
catalytic reactions. As part of our research program on
this subject, herein, we aim to synthesize new bis-
phosphinites based on C2-symmetric chiral amino alcohols
(Scheme 1) and use them with Ru(II) precursor as a catalyst
in the asymmetric transfer hydrogenation of acetophenone
derivatives with iso-PrOH under varying conditions.
materials Ph2PCl at
= 133.8 ppm disappeared and new singlets appeared in
d
= 81.0 ppm and iPr2PCl at
d
downfield due to the phosphinite ligands. The 31P-{1H}
NMR spectra of compounds 1, 2, 5, 7 show a single
resonance due to the diphenylphosphinite moiety at
114.78, 113.81, 113.84, 113.79 ppm (Fig. 1), respectively,
and compounds 3, 4, 6, 8 also exhibit a single resonance
due to the diisopropylphosphinite moiety at 150.93,
151.93, 151.98, 153.84 ppm (Fig. 2), respectively. These
spectra indicate that two phosphorus atoms in the each
molecule are equivalent [24].
The 31P-{H} NMR spectra also display formation of
PPh2PPh2 and P(O)Ph2PPh2, as indicated by signals
2. Results and discussion
2.1. Synthesis of chiral C2-symmetric ligands and their
corresponding Ru(II) complexes
C2-symmetric catalysts have received much attention
and have been used in many reactions [18,19]. We paid
particular attention to C2-symmetric phosphinite ligands,
because
a C2-symmetric ligand with two equivalent
Scheme 2. Synthesis of D- or L-valinol.
phosphorus atoms can reduce the number of possible
Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003

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3
Scheme 3. Synthesis of chiral C2-symmetric amino alcohols, i: 100 8C, 12 h; ii: CH3CN, 110 8C, 2 days.
at
d
d
–14.1 ppm as singlet and
d
37.0 ppm and
The outstanding catalytic performance of C2-symmetric
phosphinite based transition metal complexes [20,27]
prompted us to develop new Ru(II) complexes. In the scope
of the present study, new chiral bis(phosphinite) ligands
possessing C2-symmetry plane and having different alkyl
moieties were synthesized in several steps. Since the chiral
bis(phosphinite) ligands are substantially air and moisture
sensitive, Ru complexes used as catalyst in asymmetric
transfer hydrogenation reactions were prepared in situ
with chiral C2-symmetric bis(phosphinite) ligands and
1
–22.3 ppm as doublets with J(PP) 224 Hz, respectively
[25]. These by-products were easily eliminated by
washing the solid residue with freshly dried diethyl
ether. Our results agree with the chemical shifts for
other phosphinites reported in the literature [26]. The
solution of all phosphinite ligands prepared, in CDCl3,
under anaerobic conditions, is unstable and decompose
gradually to give oxide and bis(diphenylphosphino)
monoxide [Ph2P(O) PPh2] derivatives. The prepared
phosphinites are also unstable in the solid state and
decompose rapidly on exposure to air or moisture.
Transfer hydrogenation in which ruthenium complexes
are used as catalyst is a method which has been attracting
increasing attention. Rhodium and iridium transition
metals are frequently used in transfer hydrogenation
reactions as well [3a,5].
[Ru(h6-p-cymene)(
m-Cl)Cl]2 (molar ratio 2:1).
2.2. Asymmetric transfer hydrogenation of prochiral ketones
We examined the catalytic activity of in situ prepared
chiral C2-symmetric phosphinite Ru(II) catalayst system in
the transfer hydrogenation of aryl ketones with iso-PrOH
Scheme 4. Synthesis of chiral C2-symmetric bis(phosphinite) ligands, Et3N, rt, solvent (solvent: toluene for 1, 2, 5, 7; CH2Cl2 for 3, 4, 6, 8).
Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003

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Fig. 1. The 31P-{1H} NMR spectra of compounds 1, 2, 5, 7.
[28–30] to the corresponding alcohols (acetone is a by-
product), wherein iso-PrOH is the hydrogen source and
KOH presumably enhances catalysis by promoting forma-
tion of intermediates (possibly [Ru]-H from the [Ru]-Cl
precatalyst) [3c,31–33]. In a preliminary study, in situ
prepared Ru(II) catalayst systems 1-8 were used as
precatalayst, iso-PrOH/KOH as the reducing system, and
acetophenone as the model substrate (Scheme 5).
Fig. 2. The 31P-{1H} NMR spectra of compounds 3, 4, 6, 8.
Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003

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5
for the reduction of acetophenone by i-PrOH at 82 8C
within 30 minutes in the presence of KOH as a base [12c].
On the other hand, as mentioned above, we obtained high
catalytic activity (with 99% conversion) and a good ee
value (76%) in the reduction of acetophenone to (S)-1-
phenylethanol catalyzed by in situ prepared Ru(II)
catalytic system from ligand 1.
Encouraged by the enantioselectivities obtained in
these [Ru(h6-p-cymene)(
m-Cl)Cl]2-L (L:1-8) catalytic sys-
Scheme 5. Hydrogen transfer from iso-PrOH to acetophenone by in situ
prepared Ru (II) complexes 1-8.
tems, we next extended our investigations to include
asymmetric transfer hydrogenation of substituted acet-
ophenone derivatives. In a typical transfer hydrogenation
set up, the corresponding substrate (0.5 mmol), base (KOH,
Recently, iso-PrOH has received extensive attention as a
promising hydrogen source. This is a result of its many
appealing attributes, such as non-toxic, inexpensive,
having stability, environmentally benign, easy to handle
and soluble in many organic solvents [34]. The catalytic
systems were generated in situ from [Ru(h6-p-cymene)
0.025 mmol), [Ru(h6-p-cymene)(
m-Cl)Cl]2 (0.005 mmol)
and ligand 1-8 (2 eq. of Ru) were mixed in iso-PrOH
(5 mL). As shown in Fig. 3, a variety of pro-chiral aromatic
ketone derived from acetophenone (p-fluoroacetophe-
none, p-chloroacetophenone, p-methoxy acetophenone,
o-methoxy acetophenone) were reduced in short reaction
times (15 min–2 h) and led to the expected chiral alcohols
in very high yields (91%–99%) and with good enantiomeric
excesses (up to 79% ee). The examination of the results
indicates clearly that the best enantioselectivity was
achieved when (2S)-1, or (2R)-2-[(2-{[(2R)-1-[(diphenyl-
phosphanyl)oxy]-3-methylbutane-2-yl]amino}ethyl)
amino]-3-methylbutyl diphenylphosphinite 2 was used as
a ligand. The highest enantioselectivities (69–79%) were
reached with 1-2, it should also be noted that with the 3, 4,
5, 6 rather lower level of induction (15–62 ee %) and with 7
and 8 a racemic mixture was observed. The introduction of
electron withdrawing substituents, such as F and Cl, to the
p-position of the aryl ring of the ketone decreased the
electron density of the C O bond so that the activity was
improved, giving rise to easier hydrogenation [35,36]. An
electron-withdrawing group such as fluoro group to the p-
position was helpful to obtain excellent conversion (up to
99%) and moderate to good enantioselectivity (up to 72%
(m-Cl)Cl]2 by adding bis(phosphinite) 1-8 and the results
are collected in Table 1. All catalytic reactions were carried
out under argon atmosphere using standard Schlenk-tube
techniques.
In a first series of experiments (entries 1–8), the
acetophenone/Ru/KOH (100:1:5 molar ratios) catalyst
system was used in transfer hydrogenation of acetophe-
none at room temperature but no appreciable formation of
(R) or (S)-1-phenylethanol was observed. In addition, it
should be noted that the base is quite necessary for these
reactions and we did not observe any conversion in the
absence of KOH or NaOH as a base. In the next step of
experiments, the acetophenone/Ru/KOH (100:1:5 molar
ratios) catalyst system was used at 82 8C and (R) or (S)-1-
phenylethanol was obtained in up to 76% ee (entry 9) with
quantitative conversions (94–99%, entries 9–14). Isolated
catalyst prepared from ruthenium precursor and C2-
symmetric phosphinite ligand, which is reported by
Aydemir et al., shows remarkable catalytic activity (with
98% conversion) and moderate stereoselectivity (63% ee)
Table 1
Transfer hydrogenation of acetophenone with iso-PrOH catalyzed by [Ru(h6-pcymene)(m-Cl)Cl]2-L (L: 1-8).
Entry
Catalyst
S/C/KOH
Time
Conversion (%)c
% eed
Configuratione
1
1a
2a
3a
4a
5a
6a
7a
8a
1b
2b
3b
4b
5b
6b
7b
8b
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
1/2 h
1/2 h
1/4 h
1/4 h
1 h
15
10
39
37
13
10
18
19
99
97
98
97
99
98
94
96
81
17
71
73
88
75
88
85
76
65
24
46
54
15
–
S
2
R
3
S
4
R
5
R
6
R
7
R
8
R
9
S
10
11
12
13
14
15
16
R
S
R
R
1/4 h
1 h
R
Racemic
Racemic
1 h
–
Reaction conditions:
a
At room temperature; acetophenone/Ru/KOH, 100:1:5.
Refluxing in iso-PrOH; acetophenone/Ru/KOH, 100:1:5.
Determined by GC (three independent catalytic experiments).
b
c
d
e
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 literature values.
Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003

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Fig. 3. Asymmetric Transfer Hydrogenation results for substituted acetophenones with the catalyst systems prepared from [Ru(h6-p-cymene)(
and C2-symmetric bis(phosphinites) ligands, (1-8).
m-Cl)Cl]2
ee) while the introduction of an electron-donating
substituent such as a methoxy group to the p-position
tended to lower activity while maintaining satisfactory
enantioselectivity. The position and electronic property of
the ring substituents also influenced hydrogenation
results. The introduction of an electron-donating group
such as a methoxy group to the p-position decelerates the
reaction, but addition to the o-position increases the rate
and improves the enantioselectivity (Fig. 3). So, these
results indicate that the position and electronic property of
the ring substituents also influenced hydrogenation
results.
[(2-{[(2S)-1-hydroxy-3-methylbutane-2-yl]amino}ethyl)
amino]-3-methylbutane-1-ol, (2R)-2-[(2-{[(2R)-1-hydro-
xybutane-2-yl]amino)ethyl)amino]butane-1-ol [22], (2R)-
2-[benzyl(2-{benzyl[(2R)-1-hydroxybutane-2-yl]ami-
no}ethyl)amino]butane-1-ol [22] were prepared according
to literature procedures. 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 recorded on a Bruker AV400
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 with a Gallenkamp Model apparatus with open
capillaries.
3. Experimental
3.2. GC analyses
3.1. Materials and method
GC analyses were performed on a Shimadzu GC 2010
Unless otherwise stated, all reactions were carried out
under an atmosphere of argon using conventional Schlenk
glass-ware, solvents were dried using established proce-
dures and distilled under argon immediately prior to use.
Analytical grade and deuterated solvents were purchased
Plus Gas Chromatograph equipped with cyclodex
(Agilent) capillary column (30 m  0.32 mm I.D.  0.25
B
m
m
mm film thickness). The GC parameters for asymmetric
transfer hydrogenation of ketones were as follows: initial
temperature, 50 8C; initial time 1.1 min; solvent delay,
4.48 min; temperature ramp 1.3 8C/min; final temperature,
150 8C; initial time 2.2 min; temperature ramp 2.15 8C/
min; final temperature, 250 8C; initial time 3.3 min; final
time, 44.33 min; injector port temperature, 200 8C; detec-
from Merck. The starting materials D- or L-valine, (R)-2-
amino-1-butanol, Ph2PCl, (iPr)2PCland Et3N werepurchased
from Fluka and were used as received. [Ru(h6-p-cyme-
ne)(m-Cl)Cl]2 [37], D- or L-valinol ([(2S)- or (2R)-2-(benzy-
lamino)-3-methylbutane-1-ol [21], (2S) or (2R)-2-
tor temperature, 200 8C, injection volume, 2.0 mL.
Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003

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7
3.3. General procedure for the transfer hydrogenation of
ketones
CH2OH (b)); 3.04 (br, 4H, NH + OH); 2.70 (m, 2H,
NCH2CH2N (a)); 2.59 (m, 2H, NCH2CH2N (b)); 2.28 (m,
2H, CH-N); 1.68 (m, 2H, CH(CH3)2; 0.85 (m, 6H, CH(CH3)2
A typical experimental procedure is described. A flame
dried Schlenk flask was charged with [Ru(h6-p-cyme-
(a)); 0.81 (m, 6H, CH(CH3)2 (b)); 13C-NMR (
d ppm, CDCl3):
64.55 (-CH2OH); 61.37 (-CH-N); 47.39 (NCH2CH2N); 29.04
ne)(m
-Cl)Cl]2 (0.005 mmol), bis(phosphinite) ligand
CH(CH3)2;19.31 (CH(CH3)2 (a)); 18.50 (CH(CH3)2 (b)); IR
(KBr pellet, cmS1
) y(OH): 3359; y(NH): 3243; y(CH): 2967,
(0.02 mmol) and a stir bar. To these components was
added iso-PrOH (5 mL, dried and degassed), and the
resultant solution was heated at 82 8C for 20 min, followed
by cooling to ambient temperature. A solution of the
desired ketone (0.5 mmol) in iso-PrOH (5 mL) was then
added to the catalyst mixture and the solution was heated
to the desired temperature (generally, 25 8C or 82 8C). The
reaction was initiated with the addition of a solution of
KOH (2.5 mL, 0.1 M iso-PrOH). Following the reaction
completion, an aliquot of the catalytic solution (1 mL) was
removed with a syringe and evaporated under reduced
pressure. The resultant oil was subjected to flash
chromatography (silica gel-60, Et2O) and subsequently
evaporated under reduced pressure to yield clear liquids in
each case. After this time, a sample of the reaction mixture
is taken off, diluted with acetone and analyzed immedi-
ately by GC, conversions obtained are related to the
residual unreacted ketone. Furthermore, 1H NMR spectral
data for the resultant products were consistent with
previously reported results.
2877; Anal. calcd for C12H28N2O2 (mw: 232 g/mol): C
62.03; H 12.15; N 12.06; found; 61.96; H 12.08; N 12.03.
3.4.3. (2R)-2-[(2-{[(2R)-1-hydroxybutane-2-
yl]amino)ethyl)amino]butane-1-ol
20
Yield; 2.65 g, 78%, [
a
]
+28.75 (c 0.5, MeOH), 1H-
D
NMR (
d
ppm, CDCl3): 0.96 (t, 6H, J = 7.2 Hz, CH3CH2), 1.63
(m, 4H, CH3CH2), 2.91 (m, 2H, CH-N); 3.05 (m, 2H,
NCH2CH2N (a)); 3.23 (m, 2H, NCH2CH2N (b)); 3.59 (m,
2H, CH2OH (a)); 3.82 (m, 2H, CH2OH (b)); 5.41 (br, 4H,
NH + OH); 13C-NMR (
d
ppm, CDCl3): 10.43 (CH3CH2);
22.75 (CH3CH2), 43.85 (NCH2CH2N), 60.85 (CH-N), 61.81
(CH2OH); IR (KBr pellet, cmS1
(OH): 3359; (NH): 3301;
(CH): 3082, 2967, 2838; Anal. calcd for C10H24N2O2 (mw:
)
y
y
y
204 g/mol): C 58.79; H 11.84; N 13.71; found; C 58.67; H
11.79; N 13.66.
3.5. Synthesis of (R)-N-benzyl-2-amino-1-butanol
(R)-2-Amino-1-butanol (71.2 g, 0.8 mol), benzyl chlo-
ride (25.3 g, 0.2 mol) and anhydrous Na2CO3 (20 g,
0.18 mol) were placed in a 250 mL two-necked round
bottomed flask. The mixture was stirred at 110 8C for 12 h
under dry Ar. The mixture was cooled to room temperature
and CHCl3 (150 mL) was then added to the mixture and
refluxed for 2 h. The CHCI3 layer was separated from the
solid phase. The solid residue was re-extracted with CHCI3
(3 Â 150 mL). The combined organic phase was dried over
anhydrous MgSO4, filtered and evaporated, The residue
3.4. General procedure for the preparation of the chiral C2-
symmetric amino alcohols
Corresponding chiral amino alcohol (100 mmol), 1,2-
dibromoethane, (16.67 mmol) and Na2CO3 (16.67 mmol)
were stirred at 110 8C for 12 h under Ar atmosphere. The
mixture was cooled to room temperature and CHCl3
(100 mL) was then added to the mixture and refluxed for
1 h. The CHCl3 layer was separated from the solid phase.
The remaining solid was re-extracted with CHCl3
(3 Â 25 mL). The combined CHCl3 layers were dried
(Na2SO4) and evaporated. After the excess amino alcohol
was distilled at 165–175 8C/0.8 mmHg, the product was
purified by flash column chromatography on silica gel
(eluent: ethyl acetate/n-hexane 1/2).
was then distilled under reduced pressure to give 29.0 g of
20
the desired product (81%); [
NMR (
(m, 2H), 2.62–2.66 (m, 1H), 3.33–3.83 (ddd, 2H), 3.72–3.84
(dd, 2H), 7.26–7.38 (m, 5H); 13C-NMR (
ppm, CDCl3):
10.62, 24.61, 51.33, 60.11, 62.87, 127.12, 127.78, 140.33;
IR (KBr pellet, cmS1
(OH): 3295; (CH): 3033, 2915,
a]
D +54.9 (c 0.5, MeOH); 1H-
d
ppm, CDCl3): 1,01 (t, 3H, J = 7.48 Hz), 1.47–1.64
d
)
y
y
3.4.1. (2S)-2-[(2-{[(2S)-1-hydroxy-3-methylbutane-2-
yl]amino}ethyl)amino]-3-methylbutane-1-ol
2838. Anal. calcd for C11H17NO (mw: 179 g/mol): C 73.70;
H 9.56; N 7.80; found; C 73.18; H 9.47; N 7.29.
Yield; 3.29 g, 85%, [
ppm, CDCl3): 3.60 (m, 2H, CH2OH (a)); 3.36 (m, 2H,
a]
20 +25.5 (c 1.0, CHCl3), 1H-NMR
D
(
d
3.6. Synthesis of (2R)-2-[benzyl(2-{benzyl[(2R)-1-
hydroxybutane-2-yl]amino}ethyl)-amino]butane-1-ol
CH2OH (b)); 2.90 (m, 4H, NH + OH); 2.81 (m, 2H,
NCH2CH2N (a)); 2.66 (m, 2H, NCH2CH2N (b)); 2.36 (m,
2H, CH-N); 1.76 (m, 2H, CH(CH3)2; 0.93 (m, 6H, CH(CH3)2
(a)); 0.87 (m, 6H, CH(CH3)2 (b)); 13C-NMR (
d ppm, CDCl3):
64.59 (-CH2OH); 61.69 (-CH-N); 47.40 (NCH2CH2N); 29.26
CH(CH3)2;19.44 (CH(CH3)2 (a)); 18.59(CH(CH3)2 (b)); IR
(KBr pellet, cmS1
) y(OH): 3357; y(NH): 3240; y(CH): 2967,
(R)-N-benzyl-2-amino-1-butanol (3.0 g, 0.017 mol),
ethylene glycol ditosylate (2.97 g, 0.008 mol), Na2CO3
(1.80 g, 0.017 mol) and CH3CN (10 mL) were stirred at
110 8C for 2 days under Ar atmosphere. Then the mixture
was cooled to rt and solved in CH2Cl2 (50 mL). The obtained
solution was extracted with Na2CO3 (1 M, 3 Â 25 mL) and
water (2 Â 25 mL) respectively. The combined CH2Cl2
extracts were dried (Na2SO4) and evaporated. The desired
product was purified by flash column chromatography on
silica gel (eluent: toluene/ethyl acetate 5/3) to give 1.59 g
2864; Anal. calcd for C12H28N2O2 (mw: 232 g/mol): C
62.03; H 12.15; N 12.06; found; C 61.98; H 12.03; N 12.01.
3.4.2. (2R)-2-[(2-{[(2S)-1-hydroxy-3-methylbutane-2-
yl]amino}ethyl)amino]-3-methylbutane-1-ol
20
Yield; 3.17 g, 82%, [
a
]
D
-25.5 (c 1.0, CHCl3), 1H-NMR
(52%). [
CDCl3): 0.87 (m, 6H, J = 7.60 Hz, CH3CH2), 1.12 (m, 2H,
a] d ppm,
20: –13.8 (c 1.0, CHCl3); 1H-NMR (
D
(d ppm, CDCl3): 3.51 (m, 2H, CH2OH (a)); 3.29 (m, 2H,
Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003

G Model
CRAS2C-3665; No. of Pages 9
8
F. Durap et al. / C. R. Chimie xxx (2013) xxx–xxx
CH3CH2, (a)), 1.62 (m, 2H, CH3CH2, (a)), 2.60 (m, 2H, CH-N);
2.38 (m, 2H, NCH2CH2N (a)); 2.67 (m, 2H, NCH2CH2N (b));
3.36 (m, 2H, CH2Ph (a)); 3.52 (m, 2H, CH2Ph (b)); 3.28 (m,
2H, CH2OH (a)); 3.69 (m, 2H, CH2OH (b)); 7.12-7.31 (m,
a white viscous oily compound 5 (Yield: 0.198 g, 71%). 31P-
{1H} NMR (CDCl3)
(ppm): 113.84 (s, O-P-(C6H5)2).
d
3.10. (2R)-2-[(2-{[(2R)-1-{[bis(propane-2-
yl)phosphanyl]oxy}butane-2-yl]amino}ethyl)-amino]butyl
bis(propane-2-yl)phosphinite 6
10H, ArH); 13C-NMR (
d ppm, CDCl3): 11.80 (CH3CH2);
17.74 (CH3CH2), 47.80 (NCH2CH2N), 60.81 (CH2Ph), 54.39
(CH2OH), 62.51 (CH-N), 127.14, 128.45, 129.24,
139.21(CH2Ph); IR (KBr pellet, cmS1):
y
(OH): 3378;
(iPr)2PCl (0.16 g, 9.8 Â 10À4 mol) was added to a stirred
solution of (2R)-2-[(2-{[(2R)-1-hydroxybutane-2-yl]ami-
no)ethyl)amino]butane-1-ol (0.10 g, 4.9 Â 10À4 mol) and
triethylamine (0.1 g, 9.8 Â 10À4 mol) in CH2Cl2 (25 mL) at
room temperature with vigorous stirring. The mixture was
stirred at room temperature for 48 h and the white
precipitate (triethylammonium chloride) was filtered off
under argon and dried in vacuo to produce a white viscous
oily compound 6 (Yield: 0.201 g, 94%). 31P-{1H} NMR
y(CH): 3064, 3031; 2973; y(C C): 1485, 1459, 1417; Anal.
calcd for C24H36N2O2 (mw: 384 g/mol): C 74.96; H 9.43; N
7.28; found; C 74.90; H 9.38; N 7.21.
3.7. (2S)- 1 or 2(R)-2-[(2-{[(2S)-1-
[(diphenylphosphanyl)oxy]-3-methylbutane-2-yl]-
aminoethyl)amino]-3-methylbutyl diphenylphosphinite 2
Chlorodiphenylphosphine (0.20 g, 8.6 Â 10À4 mol) was
added to a stirred solution of (2S)- or (2R)-2-[(2-{[(2S)-1-
hydroxy-3-methylbutane-2-yl]amino}ethyl)amino]-3-
methylbutane-1-ol, (0.1 g, 4.3 Â 10À4 mol) and triethyla-
mine (0.09 g, 8.6 Â 10À4mol) in toluene (25 mL) at room
temperature with vigorous stirring. The mixture was
stirred at room temperature for 1 h and the white
precipitate (triethylammonium chloride) was filtered off
under argon and the remaining solution dried in vacuo to
produce a white viscous oily compound 1 or 2, respective-
(CDCl3) d
(ppm): 151.98 (s, O-P-(iPr)2).
3.11. (2R)-2-[benzyl(2-{benzyl[(2R)-1-
[(diphenylphosphanyl)oxy]butane-2-yl]amino}-
ethyl)amino]butyldiphenylphosphinite 7
Chlorodiphenylphosphine (0.121 g, 5.2 Â 10À4 mol)
was added to a stirred solution of (2R)-2-[benzyl(2-
{benzyl[(2R)-1-hydroxybutane-2-yl]amino}ethyl)amino]-
butane-1-ol (0.100 g, 2.6 Â 10À4 mol) and triethylamine
(0.053 g, 5.2 Â 10À4 mol) in toluene (25 mL) at room
temperature with vigorous stirring. The mixture was
stirred at room temperature for 1 h and the white
precipitate (triethylammonium chloride) was filtered off
under argon and dried in vacuo to produce a white viscous
oily compound 7 (Yield: 0.181 g, 92%). 31P-{1H} NMR
ly. (Yield: 0.243 g, 94%, 0.248 g 96%, for
1 and 2,
respectively). 31P-{1H} NMR (CDCl3)
d(ppm): 114.78,
113.81 (s, O-P-(C6H5)2) for 1 and 2, respectively.
3.8. (2S)- 3 or (2R)-2-[(2-{[(2S)-1-{[bis(propane-2-
yl)phosphanyl]oxy}-3-methylbutane-2-
yl]amino}ethyl)amino]-3-methylbutyl bis(propane-2-
yl)phosphinite 4
(CDCl3) d(ppm): 113.79 (s, O-P-(C6H5)2).
3.12. (2R)-2-[benzyl(2-{benzyl[(2R)-1-{[bis(propane-2-
yl)phosphanyl]oxy}butane-2-yl]-amino}ethyl)amino]butyl
bis(propane-2-yl)phosphinite 8
(iPr)2PCl (0.14 g, 8.6 Â 10À4 mol) was added to a stirred
solution of (2S)- or (2R)-2-[(2-{[(2S)-1-hydroxy-3-
methylbutane-2-yl]amino}ethyl)amino]-3-methylbu-
tane-1-ol (0.1 g, 4.3 Â 10À4 mol) and triethylamine
(0.09 g, 8.6 Â 10À4 mol) in CH2Cl2 (25 mL) at room
temperature with vigorous stirring. The mixture was
stirred at room temperature for 48 h, and the solvent was
removed under reduced pressure. After addition of dry
toluene, the white precipitate (triethylammonium chlo-
ride) was filtered off under argon and dried in vacuo to
produce a white viscous oily compounds 3 and 4. (Yield:
0.185 g, 92.5%, 0.178 g, 89% for 3 and 4, respectively). 31P-
(iPr)2PCl (0.083 g, 5.2 Â 10À4 mol) was added to a
stirred solution (2R)-2-[benzyl(2-{benzyl[(2R)-1-hydro-
xybutane-2-yl]amino}ethyl)amino]butane-1-ol (0.100 g,
2.6 Â 10À4 mol)
and
triethylamine
(0.053 g,
5.2 Â 10À4 mol) in CH2Cl2 (25 mL) at room temperature
with vigorous stirring. The mixture was stirred at room
temperature for 48 h, and the solvent was removed
under reduced pressure. After addition of dry toluene,
the white precipitate (triethylammonium chloride) was
filtered off under argon and dried in vacuo to produce a
white viscous oily compound 8 (yield: 0.152 g, 95%). 31P-
{1H} NMR (CDCl3) (ppm): 150.93, 151.93 (s, O-P-(iPr)2)
d
for 3 and 4, respectively.
{1H} NMR (CDCl3)
d
(ppm): 151.84 (s, O-P-(iPr)2).
3.9. (2R)-2-[(2-{[(2R)-1-[(diphenylphosphanyl)oxy]butane-
2-yl]amino}ethyl)amino]butyl-diphenyl phosphinite 5
4. Conclusions
Chlorodiphenylphosphine (0.23 g, 9.8 Â 10À4 mol) was
added to a stirred solution of (2R)-2-[(2-{[(2R)-1-hydro-
In summary, we have synthesized new catalysts for
asymmetric transfer hydrogenation of aromatic ketones
and our study has led to the following conclusions and
insights:
xybutane-2-yl]amino)ethyl)amino]butane-1-ol
(0.10 g,
4.9 Â 10À4 mol) and triethylamine (0.1 g, 9.8 Â 10À4 mol)
in toluene (25 mL) at room temperature with vigorous
stirring. The mixture was stirred at room temperature for
1 h and the white precipitate (triethylammonium chloride)
was filtered off under argon and dried in vacuo to produce
ꢀ
we synthesized new C2-symmetric chiral bis(phosphi-
nite) ligands based on amino alcohol scaffolds and used
Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003

G Model
CRAS2C-3665; No. of Pages 9
F. Durap et al. / C. R. Chimie xxx (2013) xxx–xxx
9
(b) M. Aydemir, A. Baysal, N. Meric¸, C. Kayan, M. Tog˘rul, B. Gu¨ mgu¨m,
Appl. Organomet. Chem. 24 (2010) 215 ;
(c) M. Aydemir, N. Meric¸, A. Baysal, B. Gu¨ mgu¨m, M. Tog˘rul, Y. Turgut,
Tetrahedron Asymmetr. 21 (2010) 703.
them with ruthenium(II) precursor as a catalyst in the
asymmetric transfer hydrogenation of acetophenone
derivatives;
[13] D. Hobuß, J. Hasenjager, B. Driessen-Ho¨lscher, A. Baro, K.V. Axenov, S.
Laschat, W. Frey, Inorg. Chim. Acta 374 (2011) 94.
ꢀ
ꢀ
using in situ prepared Ru(II) catalytic systems in the
asymmetric transfer hydrogenation reactions gives high
yields (90%–99%, from ligand 1-8) and short reaction
times;
catalytic experiments show that in situ prepared Ru(II)
catalytic systems from ligand 1-6 give moderate to high
enantioselectivity and from ligand 7-8 give racemic
mixture.
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[22] Y. Turgut, N. Demirel, H. Hos¸ go
Financial support from TUBITAK (Project number:
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Please cite this article in press as: Durap F, et al. New C2-symmetric chiral phosphinite ligands based on amino alcohol
scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. C. R. Chimie
(2013), http://dx.doi.org/10.1016/j.crci.2012.12.003