New functional chiral P-based ligands and application in ruthenium-catalyzed enantioselective transfer hydrogenation of ketones

Article abstract of DOI:10.1016/j.tetasy.2017.10.004

Metal-catalyzed asymmetric transfer hydrogenation is a powerful and practical method for the reduction of ketones to produce the corresponding secondary alcohols, which are valuable building blocks in the pharmaceutical, perfume, and agrochemical industries. Hence, a series of novel chiral β-amino alcohols were synthesized by chiral amines with regioselective ring opening of (S)-propylene oxide or reaction with (S)-(+)-2-hydroxypropyl p-toluenesulfonate by a straightforward method. The chiral ruthenium catalytic systems generated from [Ru(arene)(μ-Cl)Cl]₂ complexes and chiral phosphinite ligands based on amino alcohol derivatives were employed in asymmetric transfer hydrogenation of ketones to give the corresponding optically active alcohols; (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yldiphenylphosphinitobis[dichol-oro(η⁶-benzene)ruthenium(II)] acts an excellent catalyst in the reduction of α-naphthyl methyl ketone, giving the corresponding alcohol with up to 99% ee. The substituents on the backbone of the ligands were found to have a remarkable effect on both the conversion and enantioselectivity of the catalysts. Furthermore, this transfer hydrogenation is characterized by low reversibility under these conditions.

Full text of DOI:10.1016/j.tetasy.2017.10.004

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New functional chiral P-based ligands and application in
ruthenium-catalyzed enantioselective transfer hydrogenation of
ketones
a
a,
⇑
b
a
c
Nermin Meriç , Cezmi Kayan , Nevin Gürbüz , Mehmet Karakaplan , Nil Ertekin Binbay ,
a,
⇑
Murat Aydemir
a
Department of Chemistry, Faculty of Science, University of Dicle, TR-21280 Diyarbakir, Turkey
Department of Chemistry, Faculty of Science, University of Inönü, 44280 Malatya, Turkey
Dicle University, Vocational School, Department of Electronics 21280 Diyarbakir, Turkey
b
c
_
a r t i c l e i n f o
a b s t r a c t
Article history:
Metal-catalyzed asymmetric transfer hydrogenation is a powerful and practical method for the reduction
of ketones to produce the corresponding secondary alcohols, which are valuable building blocks in the
pharmaceutical, perfume, and agrochemical industries. Hence, a series of novel chiral b-amino alcohols
were synthesized by chiral amines with regioselective ring opening of (S)-propylene oxide or reaction
with (S)-(+)-2-hydroxypropyl p-toluenesulfonate by a straightforward method. The chiral ruthenium cat-
Received 26 August 2017
Accepted 6 October 2017
Available online xxxx
2
alytic systems generated from [Ru(arene)(l-Cl)Cl] complexes and chiral phosphinite ligands based on
amino alcohol derivatives were employed in asymmetric transfer hydrogenation of ketones to give the
corresponding optically active alcohols; (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phe-
6
nylethyl]amino}propan-2-yldiphenylphosphinitobis[dichol-oro(
excellent catalyst in the reduction of
g
-benzene)ruthenium(II)]
acts
an
a
-naphthyl methyl ketone, giving the corresponding alcohol with
up to 99% ee. The substituents on the backbone of the ligands were found to have a remarkable effect
on both the conversion and enantioselectivity of the catalysts. Furthermore, this transfer hydrogenation
is characterized by low reversibility under these conditions.
Ó 2017 Published by Elsevier Ltd.
1
. Introduction
the substrate and a hydrogen donor or acceptor, respectively. Fur-
thermore, the donor (e.g. 2-propanol) and the acceptor (e.g. a
Alcohols are very important building blocks for the pharmaceu-
ketone) are environmentally friendly and also easy to handle.6
For the past ten years, an efficient catalytic transfer hydrogena-
tion of ketones has been developed using chiral Rh(I), Ir(I) or Ru(II)
complexes as catalyst precursors and iso-PrOH/KOH as the hydride
tical and fine chemical industries.1 Although many applications
require racemic alcohols, the need for enantiomerically pure alco-
hols is growing because of their significance as intermediates for
2
7
the manufacture of pharmaceuticals and advanced materials. Cat-
source. There have been a large number of chiral ligands prepared
8
alytic asymmetric transfer hydrogenation of ketones has recently
for asymmetric transfer hydrogenations. Chiral b-amino alcohols
3
are useful building blocks for biologically active compounds9 as
well as important auxiliaries and ligands in asymmetric synthe-
emerged as a viable means of synthesizing chiral alcohols. Due
to the operational simplicity, the easy availability of reductants,
and the high enantioselectivities, the catalytic enantioselective
reduction of ketones has been extensively studied during the last
1
0
sis. Amino alcohols continue to be of importance in modern syn-
thetic chemistry, not only because of their biological properties,
4
11
decade. The asymmetric transfer hydrogenation of ketones has
but also because of their wide range of synthetic applications.
recently been developed as an alternative method to asymmetric
hydrogenation for the production of chiral alcohols.5 Hydrogen
transfer reactions are mild procedures for the reduction of ketones
in which a substrate-selective catalyst transfers hydrogen between
Hence, the asymmetric synthesis of enantiomerically enriched
amino alcohols has been extensively studied. In particular, amino
alcohols derivative catalysts have received much attention and
used in many asymmetric catalysis reactions, and they have shown
powerful utilities in the asymmetric reduction of prochiral
1
2
ketones.
⇑
Corresponding authors.
E-mail addresses: cezmik@dicle.edu.tr (C. Kayan), aydemir@dicle.edu.tr
We have had an ongoing interest in the synthesis and use of
optically active ligands in asymmetric catalysis, especially phos-
(
M. Aydemir).
https://doi.org/10.1016/j.tetasy.2017.10.004
957-4166/Ó 2017 Published by Elsevier Ltd.
0
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2
N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
phorus-based and related chiral modifiers.13 Many effective chiral
ligands, especially phosphinites, aminophosphines, and phosphine,
previously reported in the literature.16 The reaction of (S)-(+)-2-
hydroxypropyl p-toluenesulfonate with (R)- -phenylethylamine
was concluded with the product (S)-1-[N-(R)- -phenylethyl]
amino-2-propanole 1 with good yield. Since C -symmetric cata-
a
1
4
have been synthesized. In recent years, we have reported the
synthesis and applications of a number of modified Ru(II) catalysts
for asymmetric transfer hydrogenation, which contain well
designed groups formed by the reactions between chiral ligand
a
2
lysts generally enhance the enantioselectivity of the reaction by
reducing the number of competing diastereomeric pathways
because of the homotopic nature of the ring coordination sites of
the complexes formed by the catalysts, compound (2S)-1-{[(2S)-
2-hydroxypropyl][(1R)-phenylethyl]amino}propan-2-ol 2 was also
synthesized with the ring opening of enantiopure terminal (S)-
6
15
components and the
g -arene ring. Herein we report the synthe-
sis of novel phosphinite ligands and their application in the Ru(II)-
catalyzed asymmetric transfer hydrogenation of various ketones. A
comparison of the results obtained with the newly synthesized
ligands and those of the corresponding Ru(II) complexes is also dis-
cussed. The comparison concerns the structural features of ligands,
four of their ruthenium complexes, and the hydrogenation results.
Furthermore, a discussion concerning the role played by phos-
phinite coordination on the ruthenium center and the possible
mechanism of this transformation is also included.
1
7
propylene oxide with (R)-1-phenylethylamine (Scheme 1). It is
well-known that epoxides are versatile building blocks that have
been extensively used in the synthesis of complex organic com-
pounds. Their utility as valuable intermediates has been further
expanded upon with the advent of asymmetric catalytic methods
1
8
for their synthesis. The products were fully characterized by sev-
1
13
eral spectroscopic methods: LC-ESI-IT-TOF MS, H NMR, C NMR,
1
IR and elemental analysis. The assignment of the H chemical shifts
2
2
. Results and discussion
was derived from 2D HH-COSY spectra and the appropriate assign-
1
3
ment of the C chemical shifts from APT and 2D HMQC spectra.
The results were given in Section 4 with full details. Furthermore,
.1. Synthesis and characterization of the amino alcohols and
phosphinite ligands
1
13
H NMR, C NMR, IR and LC-ESI-IT-TOF MS spectra of amino alco-
hols also given in Supporting Information (SI).
The strategy used herein was to prepare modularly designed,
highly active phosphinite ligands based on amino alcohol skele-
tons. Initially, (S)-(+)-2-hydroxypropyl p-toluenesulfonate was
To investigate the influence of the relative configuration of the
modular skeleton of ligands, the mono and C
2
-symmetric bidentate
phosphinites were prepared in accordance with the method
synthesized with the reaction of (R)-
+)-2-hydroxypropyl p-toluenesulfonate under an argon atmo-
sphere with the described procedure and the compound identified
a-phenylethylamine and (S)-
1
9
reported in the literature. The synthetic procedure for the prepa-
(
2
0
ration of the phosphinite ligands is shown in Scheme 1. Chiral
1
13
1
monodendate C -symmetric ligand 3 was synthesized by hydrogen
using H and C NMR, etc., which were consistent with the data
Ph
NH2
TsO
OTs
MeOH
O
Na2CO3
Ph
HO
OH
HO
OTs
Ph
N
N
H
OH
OH
OH
1
2
i
ii
Ph
Ph
N
Ph
N
H
OPPh2
OPPh2
OPPh2
N
Ph
3
4
N
v
H
iii
Ph2PO
Ru
Cl
OPPh2
Ru
Cl
OPPh2
Ru
Cl
vi
Cl
Cl
iv
Cl
7
5
Ph
Ph
N
H
N
OPPh2
Ru
Cl
6
Ph2PO
Ru
OPPh2
Ru
Cl
Cl
Cl
Cl
8
Cl
2 3 2
Scheme 1. Synthesis of aminoalcohols, phosphinites and their corresponding Ru(II)-arene complexes. (i) 1/2 equiv Ph PCl, 1/2 equiv Et N, THF; (ii) 1 equiv Ph PCl, 1 equiv
6
6
3 2 2
Et N, THF; (iii,v) 1 equiv [Ru(g -p-cymene)(l-Cl)Cl] , THF; (iv,vi) 1 equiv [Ru(g -benzene)(l-Cl)Cl] , THF.
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N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
abstraction from described chiral amino alcohols 1 by Et
the subsequent reaction with one equivalent of Ph
anhydrous CH Cl under inert argon atmosphere. To improve and
compare the catalytic activities of C and C -symmetric ligands, a
novel C -symmetric phosphinite ligand (2S)-1-{[(2S)-2-[(diphenyl-
3
N and
PCl in
[Ru(
g
6-p-cymene)(
l
-Cl)Cl]
2
was initially chosen as a starting
2
material, which was prepared from the reaction of the commer-
cially available -phellandrene(5-isoprophyl-2-methylcyclohexa-
1,3-diene) with RuCl
informative with respect to the symmetry of the three legged
fragment. Especially, one of the most available arene ligands in
ruthenium chemistry is p-cymene, whose NMR signals are very
2
2
a
2
8
1
2
3
.
The p-cymene ligand is particularly
2
2
9
phosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yl
diphenylphosphinite 4, which has a modular skeleton, was pre-
2
1
30
pared via hydrolysis. Typical spectra of these ligands are illus-
trated in Supporting information (SI) and for details see the
Section 4. It well known that phosphinites are generally unstable
and decompose gradually to give an oxide and the hydrolysis pro-
sensitive to the symmetry of organometallic compound. Thus,
when it is
6
0
g
-coordinated to a ML
2
L metal fragment (Cs symme-
1
13
try) the H and C NMR spectra are very different from that of
6
0
31
g
-coordinated to a ML L L fragment (C symmetry). In this
1 2 1
3
1
duct diphenylphosphinous acid, Ph
{
2
P(O)H. Furthermore, the P–
H} NMR spectrum also displays the formation of PPh PPh and
P(O)Ph PPh
, as indicated by signals at about d ꢀ15.8 ppm as sin-
glet and d 35.2 ppm and at d ꢀ21.4 ppm as doublets with
case, the steric hindrance of amino alcohol phosphinite ligands
seems to prevent free rotation of p-cymene ligand around the
1
2
2
3
2
2
2
arene-Ru axis. In most cases, the shape, chemical shifts and cou-
pling constants of NMR signals, together with the complete assign-
ment of signals (by using COSY and NOESY NMR techniques) of the
p-cymene group can give valuable information about the symme-
try of the complexes. In addition, the detailed analysis of NOE
interaction between p-cymene and other ligands can give valuable
information about the relative orientation of different groups in
the molecule and thus establish the stereochemistry of the
1
J
(PP)
2
2
2
24 Hz, respectively. However, a solution of these ligands in
CDCl , prepared under anaerobic conditions, is stable (up to 48 h)
and decomposes very slowly to give oxide and the hydrolysis pro-
duct diphenylphosphinous acid, Ph
P(O)H.23 These two com-
3
3
3
2
pounds are also very stable in air atmosphere for up to 24 h
because of the well-designed structures. The progress of this reac-
tion was conveniently followed by 31P–{ H} NMR spectroscopy.
1
complex (for details see the Section 4). After the preparation of
6
The signals of the starting materials PPh
2
Cl at d = 81.0 ppm disap-
the second precursor [Ru(
g
-benzene)(
in aqueous solution, we
synthesized (2S)-1-{[(1R)-1-phenylethyl]amino}propan-2-yl
2
l-Cl)Cl] by the reaction
peared and new singlets appeared downfield due to the phos-
of cyclo-1.3-hexadiene with RuCl
3
3
1
1
phinite ligands. The P–{ H} NMR spectra of the free ligands
2
4
6
are in line with the values previously observed for similar com-
diphenylphosphinito[dichloro(
(2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]
amino}propan-2-yldiphe-nyl phosphinitobis[dichloro(
zene)ruthenium (II)] 8 complexes with high yields. The reactions
of Ru(II) precursors with ligands are depicted in Scheme 1. The
poor solubility of the starting benzene derivative causes a decrease
in the yields of the complexes 6 and 8, which are more conve-
niently prepared by the reaction of the phosphinites with the
g -benzene) ruthenium (II)], 6 and
pounds, respectively. The 1H and C NMR spectra of these
2
5
13
6
ligands are also conclusive. The resonance assignments were made
g -ben-
1
1
1
13
on the basis of H– H COSY, NOESY, and H– C COSY experiments.
Typical spectra of these ligands are illustrated in Supporting infor-
mation (SI) and for details see the Section 4.
2
6
Following a similar procedure described by, Regadec et al.,
ruthenium(II) complexes of the phosphinite ligands, (S)-1-[N-(R)-
-phenylethyl]amino-2-propanol, 1 and (2S)-1-{[(2S)-2-hydrox-
3
4
a
monomeric adduct [RuCl
2
(C
6
H )(NCCH
6
3
)].
The initial color
ypropyl][(1R)-phenylethyl]amino}propan-2-ol 2 were readily pre-
change, i.e., from clear orange to deep red, was attributed to the
dimer cleavage most probably by the phosphinite or bis(phos-
pared in quantitative yields by reacting the appropriate
6
35
phosphorus ligands with either [Ru(
g
-p-cymene)(
l
-Cl)Cl]
2
or
phinite) ligand. All complexes were isolated as indicated by sin-
6
31
1
[
Ru(
The ability of dimers {[Ru(arene)(
uclear complexes of general formula [Ru(
g
-benzene)(
l
-Cl)Cl]
2
precursor as outlined in Scheme 1.
glets in their P–{ H} NMR spectra at approximately (d) 106–109
l
-Cl)Cl] } to form mono- or bin-
2
ppm, in line with the values previously observed for similar com-
6
36
31
1
g
-arene)Cl
2
L] is well-
pounds (Fig. 1). It is noteworthy that the P–{ H} NMR signals
2
7
37
known. For the synthesis of ruthenium(II) complexes 5 and 7,
of ligands and complexes do not differ significantly.
These
Figure 1. The 31P–{ H} NMR spectra of phosphinites 3 and 4 and their Ru(II)-complexes 5–8.
1
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4
N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
complexes are highly soluble in CH
2
Cl
2
, slightly in hexane, so they
et al.,44 who suggested that an NH moiety in the ligand may pro-
mote a cyclic transition state through hydrogen bonding to a
2 2
can be crystallized from CH Cl /hexane solutions. The structure of
4
5
P-coordinated complexes 5–8 is supported by spectroscopic data;
ketone substrate. It therefore appears that the formation of a
metal–ligand bifunctional catalyst can greatly increase the sub-
strate affinity to the catalyst active site and induce high enantios-
electivity. Earlier results from Noyori et al. and Lemaire et al. with
different ligands also showed a similar ‘NH’ effect (Fig. 1).46 Thus,
we expected that the new complexes would form a cyclic transi-
tion state similar to that suggested by Noyori, Backvall, Morris,
etc., and highly enantioselective transfer hydrogenation of simple
1
31
1
13
all H, P–{ H} NMR and C NMR spectra are given in the Sup-
1
porting Information (SI). The H NMR spectra data of complexes
are consistent with the proposed structures. The 1H NMR spectra
of these compounds clearly exhibit signals corresponding to the
aromatic rings. The arene resonances are well resolved, as found
in the previously reported for mononuclear or binuclear arene
1
3
1
31
13
complexes. In the C–{ H} NMR spectra of complexes, J( P– C)
coupling constants of the carbons of the phenyl rings were
observed, which are in agreement with the literature.38 In the com-
pounds, the coupling between i-carbons and the phosphorus is rel-
4
7
ketones might be realized.
Complexes 5–8 were selected as precatalysts, PrOH/KOH as a
reducing system, and acetophenone as model substrate
i
a
atively large, at approximately 1
J(PC) 50 Hz, while the coupling
(Scheme 3). Thus, in order to evaluate the effectiveness of our Ru
(II) complexes, we first deeply investigated the optimal conditions
starting with 2-acetophenone as a standard test reaction. Results
for the asymmetric transfer hydrogenation of ketones with cata-
lysts, 5–8 are collected in Table 1. Catalytic experiments were car-
ried out under argon using standard Schlenk-line techniques. To an
between o-carbon and the phosphorus relatively small, at approx-
2
imately
J(PC) 10 Compounds 5–8 were further confirmed by IR
spectroscopy as well as microanalysis, and found to be consistent
to expected to structures (for details see the Section 4).
i
2
.2. Catalytic transfer hydrogenation of ketones
PrOH solution of each complex, appropriate amounts of acetophe-
i
none and KOH/ PrOH solution were added at room temperature.
It is generally assumed that transition-metal-catalyzed hydro-
gen transfers involve metal hydrides as key intermediates. All
The solution was stirred, and the reaction was monitored by GC.
The reactions proceeded to give (R)- or (S)-1-phenylethanol in
10–20% conversion with 56–87% ee’s after stirring at room temper-
ature for 72 h. An increase in the reaction time to 120 h resulted in
17–43% conversion with 54–85% ee’s. Due to the reversibility at
room temperature, a prolonged reaction time led to a slight
decrease in enantioselectivity. However, when the reactions were
carried out at 82 °C for less than 1 h, all complexes showed satisfy-
ing catalytic activities (up to 396 TOF values) and enantioselectiv-
ities (Table 1, entries 9–12). Although the lower reaction
temperatures should have a beneficial effect on the enantioselec-
ruthenium complexes 5–8 most likely follow the well-established
3
9
mechanism via a metal alkoxide intermediate and b-elimination.
It is well-known that chlorides can be easily replaced by a
hydride with an alkoxide displacement/b-hydride elimination
4
0,41
sequence.
as a representative example. According to the literature, Ru(II)-
arenes are good precursors for catalytic transfer hydrogenation
This mechanism is depicted in Scheme 2 for catalyst
7
4
2
processes. Among the recently developed efficient transition-
4
3
metal-catalysts, is the Ru(II)-TsDPEN system reported by Noyori
Ph
N
H
1
R : Smaller group
OPPh2
Ru
2
R : Larger group
Cl
Cl
Ph
N
H
-
OH
H
δ
O
+
OPPh2
-
δ
+
δ
C
H3C
H3C
CH3
δ
R2
Ru
H
Baz
Cl−
R1
-
Cl
O
CH3
Transition state
Ph
Ph
N
H
N
H
OPPh2
Ru
OPPh2
Ru
Cl
H
Cl
R2
R1
R2
R1
H
O
HO
Scheme 2. Proposed concerted hydride transfer mechanism for the phosphinite catalysts.
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N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
O
OH
R2
complexes (2S)-1-{[(1R)-1-phenylethyl]amino}propan-2-yl
6
diphenylphosphinito[dichloro(g -benzene) ruthenium (II)], 6 and
R2
Ru(II) catalyst
CH3)2CHOH
R1
R1
(2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-pheny-
(
6
lethyl]amino}propan-2-yldiphe-nylphosphinitobis[dichloro(
g -
benzene)ruthenium (II)], 8 which have a benzene fragment are
more active than complexes 5 and 7 which include p-cymene frag-
ment. The good ee obtained for the initial reduction of acetophe-
none motivated us to keep employing Ru-benzene complexes.
These results clearly indicate that the skeleton of the ligands and
the fragment attached to the Ru(II) center are responsible for the
high conversion (up to 99%) and enantioselectivity (up to 93 ee
%), whatever the exact reaction mechanism. The best results were
obtained in the (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl]
Scheme 3. Hydrogen transfer from isoPrOH to acetophenone derivatives.
tivities, slightly higher asymmetric inductions (70–93% ee’s) were
observed at 82 °C, which may attributed to the shorter reaction
times. These results clearly indicate that the reaction temperature
plays an important role on the catalytic activity and
enantioselectivity.
The complexes were very active catalysts, leading to quantita-
tive conversions to (R)- or (S)-1-phenyl ethanol with a catalyst/
base ratio of 1:5 (Table 1, entries 13–16). A control experiment
in the absence of base did not lead to meaningful conversion
[(1R)-1-phenylethyl]amino}propan-2-yldiphenylpho-sphinitobis
6
[dichloro(
g
-benzene)ruthenium (II)] 8 catalytic system with up to
93% ee and 99% conversion.
(
Entries 5–8). Replacing KOH with NaOH slightly decreased both
Under the optimum conditions, aromatic ketones are hydro-
genated with high enantioselectivity and the same mode face
selection. Table 2 illustrates conversions of the reduction per-
formed in a 0.1 M of i-PrOH solution containing 5–8 and KOH
(Ketone/Cat./KOH = 100:1:5). One can easily see from the results
that a range of acetophenone derivatives can be hydrogenated with
high enantioselectivities. Substitution of the phenyl ring of the ace-
tophenone substrate led to a marked change in the catalytic activ-
ity and ee %, i.e., the electronic properties (the nature and position)
of the substituents on the phenyl ring of the ketone caused the
changes in the reduction rate and enantioselectivity. It is well-
known that the introduction of electron withdrawing substituents
of the aryl ring of the ketone decreases the electron density of the
[
e]
the reaction rate and enantioselectivity (Table 1, entries 9–12 ).
Increasing or decreasing the base:Cat. ratio from 5:1 to 9:1 or
3
tiomeric purity of the product (Table 1, entries 13–16). From the
results, it can be seen that generally, complexes 7 and 8, which
:1 slightly decreased the reaction rate with a slight loss of enan-
include C
alytic activity than complexes 5 and 6 which do not contain the
-symmetric phosphinite skeleton. It has been suggested that
the C -symmetric catalysts enhance the enantioselectivity of the
2
-symmetric phosphinite skeleton showed higher cat-
C
2
2
reaction by reducing the number of competing diastereomeric
pathways because of the homotopic nature of the ring coordination
sites of the complexes formed by the catalysts.19 Furthermore, the
Table 1
Transfer hydrogenation of acetophenone with 2-propanol catalyzed by (2S)-1-{[(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinito[dichloro(
(
phenylethyl]amino}propan-2-yl diphenylphosphinitobis[dichloro(
amino}propan-2-yldiphenylphosphinitobis[dichloro(
g
6-p-cymene) ruthenium
II)] 5, (2S)-1-{[(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinito[dichloro(g -benzene) ruthenium (II)] 6, (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-
6
6
g
-p-cymene)ruthenium(II)]
7
and (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]
6
g
-benzene)ruthenium(II)], 8
O
OH
OH
+
O
Cat.
*
+
Conversion (%)f
% eeg
Conf.h
TOF (h )i
ꢀ1
Entry
Complex
S/C/KOH
Time (h)
1
2
3
4
5a
100:1:5
100:1:5
100:1:5
100:1:5
72
72
72
72
10 (17)d
56 (54)d
(R)
(R)
(R)
(R)
<3
<3
<3
<3
a
14 (25)d
d
6
73 (74)
80 (77)
a
d
d
7
15 (27)
a
20 (43)d
87 (85)d
8
5
6
7
8
5b
100:1
100:1
100:1
100:1
1
1
1
1
<3
<3
<3
<3
. . ..
. . ..
. . ..
. . ..
. . ..
. . ..
. . ..
. . ..
. . ..
. . ..
. . ..
. . ..
b
6
b
7
b
8
e
70 (67)e
9
5c
100:1:5
100:1:5
100:1:5
100:1:5
1
1/2
1/2
1/4
99 (92)
98 (93)
97 (91)
99 (94)
(R)
(R)
(R)
(R)
99
196
194
396
c
e
e
1
1
1
0
1
2
6
76 (73)
c
e
e
7
84 (80)
c
e
e
8
93 (89)
k
k
k
k
13
14
15
16
8
8
8
8
100:1:3
100:1:5
100:1:7
100:1:9
1/4
1/4
1/4
1/4
93
99
92
89
88
93
89
87
(R)
(R)
(R)
(R)
372
396
368
356
Reaction conditions:
a
At room temperature; acetophenone/Cat./KOH, 100:1:5.
b
c
d
e
f
Refluxing in 2-propanol; acetophenone/Cat., 100:1, in the absence of base.
Refluxing in 2-propanol; acetophenone/Cat./KOH, 100:1:5.
At room temperature; acetophenone/Cat./KOH, 100:1:5, (120 h).
Refluxing in 2-propanol; acetophenone/Cat./NaOH, 100:1:5.
Determined by GC (three independent catalytic experiments).
g
h
i
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).
Determined by comparison of the retention times of the enantiomers on the GC traces with the literature values, (S)- or (R)-configuration was obtained in all experiments.
ꢀ1
TOF = (mol product/mol Cat.) ꢁ h
.
k
Refluxing in 2-propanol; acetophenone/Cat.,100:1.
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6
N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 2
Transfer hydrogenation results for substituted acetophenones with the catalyst systems prepared from (2S)-1-{[(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinito
6
6
[
[
dichloro(
g
-p-cymene) ruthenium (II)] 5, (2S)-1-{[(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinito[dichloro(
g
-benzene) ruthenium (II)] 6, (2S)-1-{[(2S)-2-
6
(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinitobis [dichloro(
phanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yldiphenylphosphinitobis[dichloro(
g
-p-cymene)ruthenium(II)] 7 and (2S)-1-{[(2S)-2-[(diphenylphos-
6
a
g
-benzene)ruthenium(II)], 8
O
OH
OH
O
*
Cat.
R
+
R
+
Conv. (%)b
% eec
TOF (h )d
ꢀ1
Config.e
Entry
Cat.
Substrate
Product
Time
1
2
3
4
5
6
7
8
O
OH
30 min
10 min
10 min
5 min
98
99
97
98
68
75
83
91
196
596
582
(R)
(R)
(R)
(R)
O2N
O2N
1176
5
6
5
6
CF3
O
CF3 OH
45 min
20 min
99
98
70
77
132
294
(R)
(R)
7
8
7
8
20 min
10 min
98
99
84
91
294
596
(R)
(R)
9
5
6
7
8
O
OH
OH
30 min
10 min
10 min
5 min
98
98
99
98
68
73
80
87
196
588
596
594
(R)
(R)
(R)
(R)
10
11
12
F3C
F3C
1
1
3
4
5
6
O
15 min
5 min
98
99
65
71
198
396
(R)
(R)
1
1
5
6
7
8
5 min
3 min
98
99
78
85
388
1188
(R)
(R)
F3C
F3C
1
1
7
8
5
6
7
8
O
OH
9 h
6 h
6 h
3 h
98
98
99
98
78
83
91
96
11
16
17
33
(R)
(R)
(R)
(R)
H3CO
H3CO
1
2
9
0
2
2
1
2
5
6
O
OH
6 h
4 h
99
99
59
65
17
25
(R)
(R)
2
2
3
4
7
8
4 h
2 h
97
99
72
78
24
45
(R)
(R)
H3CO
CH3
H3CO
CH3
O
OH
2
5
5
7 h
98
73
14
(R)
26
27
28
6
7
8
5 h
5 h
3 h
99
99
99
77
83
88
20
20
33
(R)
(R)
(R)
2
3
9
0
5
6
7
8
O
OH
5 h
3 h
3 h
2 h
98
99
99
98
68
74
79
84
20
33
33
49
(R)
(R)
(R)
(R)
H3C
H3C
H3C
H3C
3
3
1
2
3
3
3
4
5
6
7
8
O
OH
4 h
2 h
2 h
1 h
99
99
99
98
62
68
67
81
25
45
45
98
(R)
(R)
(R)
(R)
3
3
5
6
Reaction conditions:
a
Catalyst (0.005 mmol), substrate (0.5 mmol), 2-propanol (5 mL), KOH (0.025 mmol %), 82 °C, the concentration of acetophenone derivatives are 0.1 M.
Purity of compounds is checked by NMR and GC (three independent catalytic experiments), yields are based on aryl ketone.
b
c
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
e
-1
TOF = (mol product/mol Cat.) ꢁ h
.
Determined by comparison of the retention times of the enantiomers on the GC traces with literature values, (S) or (R) configuration was obtained in all experiments.
C@O bond so that the activity is improved, thus resulting in easier
to acetophenones have a detrimental effect. As expected, the low-
est enantioselectivity was observed in case of p-methoxyacetophe-
none, whereas the highest one was found in case of o-
methoxyacetophenone (96% ee). Overall, the chiral efficiency
attains a very high level in the asymmetric reduction of aromatic
ketones and compares well with the recently discovered catalyst
4
8
hydrogenation. Thus, the introduction of electron-withdrawing
substituents, such as CF or NO , of the aryl ring of the ketone,
3
2
resulted in improved activity with good enantioselectivity (Table 2,
entries 1–16). On the contrary, the introduction of an electron-
donating group, such as a methyl or methoxy group, decelerates
the reaction with similar enantioselectivities, whatever the posi-
tion of substitution (Table 3, entries 17–36). It can be seen from
Table 2, that ortho-substituted acetophenones can dramatically
increase the enantioselectivity, while meta- and para-substitution
4
9
systems.
Due to their efficiency in the transfer hydrogenation of ace-
tophenone derivatives, complexes 5–8 was further investigated
in the transfer hydrogenation of a variety of ketones to converted
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N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
Table 3
Asymmetric transfer hydrogenation results for various ketones catalyzed by (2S)-1-{[(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinito[dichloro(
g
6-p-cymene)
6
ruthenium (II)]
5
(2S)-1-{[(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinito[dichloro(
g
-benzene) ruthenium (II)]
6 (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]
6
propyl][(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinitobis [dichloro(
g
-p-cymene)ruthenium(II)] 7 and (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-
6
a
phenylethyl]amino}propan-2-yldiphenylphosphinitobis[dichloro(
g
-benzene)ruthenium(II)] 8
O
OH
OH
O
Cat.
+
+
R
1
R
2
R
1
*
R
2
Conv. (%)b
ee (%)c
TOF (h )d
ꢀ1
Conf.e
Entry
Cat.
R
1
R
2
Time
1
2
3
4
5
6
7
8
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
CH
2
CH
3
2
2 h
1 h
1 h
98
98
97
98
71
75
88
92
196
98
97
(R)
(R)
(R)
(R)
1/2 h
196
5
6
7
8
5
6
7
8
CH
2
CH
C
6
H
5
3 h
2 h
2 h
1 h
99
99
99
99
68
78
84
90
33
45
45
99
(R)
(R)
(R)
(R)
9
5
6
7
8
CH(CH
3
)
2
5 h
3 h
3 h
2 h
98
98
98
99
64
71
78
82
20
33
33
45
(R)
(R)
(R)
(R)
10
11
12
13
14
15
16
5
6
7
8
CH
2
CH(CH
3
)
2
3 h
2 h
2 h
97
98
96
98
61
68
77
80
32
49
48
(R)
(R)
(R)
(R)
3/2 h
147
17
18
19
20
5
6
7
8
1-Naphthyl
1 h
1/2 h
1/2 h
1/4 h
99
98
98
99
74
79
93
99
198
196
196
396
(R)
(R)
(R)
(R)
21
22
23
24
5
6
7
8
n-C
4
H
9
4 h
2 h
2 h
1 h
97
99
97
99
60
67
78
81
25
49
48
99
(R)
(R)
(R)
(R)
25
26
27
28
5
6
7
8
C
C
6
H
H
11
11
3 h
1 h
1 h
98
99
99
98
53
58
70
73
33
99
99
(R)
(R)
(R)
(R)
30 min
196
29
30
31
32
5
6
7
8
C
6
H
5
6
5 h
3 h
3 h
2 h
98
97
98
99
57
60
72
76
20
32
33
45
(R)
(R)
(R)
(R)
Reaction conditions:
a
Catalyst (0.005 mmol), substrate (0.5 mmol), 2-propanol (5 mL), KOH (0.025 mmol %), 82 °C, the concentration of acetophenone derivatives are 0.1 M.
Purity of compounds is checked by NMR and GC (three independent catalytic experiments), yields are based on aryl ketone.
b
c
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
e
ꢀ1
TOF = (mol product/mol Cat.) ꢁ h
.
Determined by comparison of the retention times of the enantiomers on the GC traces with literature values, (S) or (R) configuration was obtained in all experiments.
into the corresponding chiral alcohols under the optimization con-
ditions. Table 1 shows several examples of the asymmetric reduc-
tions tried using this method. The reaction of methyl/alkyl and
methyl/aryl ketones gave the chiral alcohol products in acceptable
chemical yields and enantiomeric purity. We carried out further
experiments to study the influence of bulkiness of the alkyl groups
on the catalytic activity and selectivity (Table 3, entries 1–16). A
variety of simple aryl/alkyl ketones were transformed into the cor-
responding secondary alcohols, and it was found that the activity
and selectivity were highly dependent on the steric hindrance of
the alkyl group. Reaction of methyl/alkyl ketones possessing a
bulky alkyl substituent proceeded rather sluggish and led to a
decrease in enantioselectivity. As the bulkiness of the alkyl group
increases from ethyl to sec-butyl, the enantioselectivity decreases.
Lower activity and enantioselectivity were obtained in the case of
thyl methyl ketone (up to 97% ee, entries 17–20). In that case, a
high TOF value (TOF: 396) and the highest enantioselectivity, up
to 99% ee, were obtained for catalyst (2S)-1-{[(2S)-2-
[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}
6
propan-2-yldiphenylphosphinitobis[dichloro(
g
-benzene)ruthe-
nium (II)] 8. Furthermore, hydrogenation of the ketones including
cyclohexyl group was very slow and the enantioselectivities were
remarkably low (Table 3, entries 25–32).
3
. Conclusions
Herein we have reported new chiral phosphinite ligands, which
form highly efficient and practical catalysts with ruthenium pre-
cursor for asymmetric transfer hydrogenation of aryl/alkyl ketones.
High conversion and enantioselectivity were obtained in the cat-
alytic reaction. We believe that for ligands 1 and 2, the NH moiety
of the coordinated ligand may behave as suggested in Noyoriꞌs
system, in which hydrogen bonding exists between ketone sub-
strates and ligands. The high catalytic activity and enantioselectiv-
5
0,51
methyl sec-butyl ketone (Entries 13–16, 61–80% ee),
as
expected. When the size of alkyl group increased, the activity
and selectivity decreased.5
2,53
In addition, as can be seen from
Table 3, the highest enantioselectivity was observed with 1-naph-
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8
N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
ity for this kind of ligands show great potential for further explor-
ing similar system and achieving outstanding stereoselectivity for
a wider scope of ketone substrates. The simplicity and efficiency
make it an excellent choice as a catalyst for the practical prepara-
tion of highly valued alcohols via catalytic asymmetric transfer
hydrogenation of ketones.
and water, respectively. The organic phase was dried over MgSO
4
and filtered and the solvent was removed under reduced pressure.
The residue was purified by chromatography over silica gel using
toluene/EtOAc (5/1) to give product (1.70 g, 56%) as white crystals.
2
5
1
M.p: 33–35 °C, [
a]
D
= ꢀ12.05 (c 1, CHCl
3 3
). H NMR (CDCI , ppm): d
7.80 (d, 2H, J = 8.0 Hz, of OTs), 7.36 (d, 2H, J = 8.0 Hz, of OTs), 3.97–
4
3 2 2
.05 (m, 2H, –CHCH – + CH OTs (a)), 3.83–3.88 (m, 1H, CH OTs
(
b)), 2.45 (s, 3H, –CH
H, –CHCH
H– H COSY spectra.
3
of OTs), 2.39 (s, 1H, OH), 1.15 (d, J = 6.4 Hz,
), assignment was based on the H– C HETCOR and
4
4
. Experimental
1
13
3
3
1
1
.1. Materials and method
4
.4.2. (S)-1-[N-(R)-
R)- -Phenylethylamine (2.11 g, 17.37 mmol), (S)-(+)-2-
hydroxypropyl p-toluenesulfonate (1.00 g, 4.34 mmol) and Na CO
0.53 g, 4.99 mmol) were stirred at 110 °C for 12 h under argon.
a-Phenylethyl]amino-2-propanole 1
All manipulations were carried out under an atmosphere of
(
a
argon using conventional Schlenk glassware, solvents were dried
using established procedures and distilled under argon immedi-
ately prior to use. Analytical grade and deuterated solvents were
2
3
(
3
The mixture was cooled after which 10 mL of CHCl were added
to the mixture and refluxed for further 2 h. The organic phase
was separated from the solid phase. The remaining solid was re-
extracted with CHCl
dried with Na SO
reduced pressure. The excess (R)-
tilled at 90–95 °C/1 mmHg and the product was distilled at 140–
purchased from Merck. The starting materials
D
-glycine,
D-alanine,
i
PPh
2
Cl, P Pr
2
Cl and Et
3
N are purchased from Fluka and were used
6
54
6
as received. [Ru(
g
-p-cymene)(
l
-Cl)Cl]
2
,
[Ru(g -benzene)(l-Cl)
3
(3 ꢁ 5 mL). The combined CHCl
and the organic phase was removed under
-phenyl ethylamine was dis-
3
layers were
5
5
56
Cl]
2
and (S)-(+)-2-hydroxypropyl p-toluenesulfonate, were pre-
2
4
pared according to the literature procedures. IR spectra were
recorded on a Mattson 1000 ATI UNICAM FT-IR spectrometer as
a
1
13
31
1
KBr pellets. H (400.1 MHz), C NMR (100.6 MHz) and P–{ H}
NMR (162.0 MHz) spectra were recorded on a Bruker AV400 spec-
1
5
7
1
1
45 °C/1 mmHg to give 1 (0.56 g, 72% as white solid). M.p: 53–
20
1
4 °C, [
.38 (m, 5H, Ar-H), 3.80–3.84 (m, 2H, –CHOH + –CHPh), 2.62 (m,
H, –CH N (a)), 2.52 (br, 2H, NH+OH), 2.27 (m, 1H, –CH N, (b)),
.40 (d, J = 6.8 Hz, 3H, CH CHPh), 1.11 (d, J = 6.0 Hz, 3H, CH CHOH);
, ppm): d 20.46 (CH CHPh), 24.41 (CH CHOH),
N), 57.68 (–CHPh), 65.79 (HOCHCH ), 126.54, 127.09,
128.56 (o-, m-, p-carbons of phenyl), 144.98 (i-carbon of phenyl)
D 3 3
a] = +83.4 (c 1, CHCl ). H NMR (CDCI , ppm): d 7.25–
3 4
trometer, with d referenced to external TMS and 85% H PO respec-
tively. Elemental analysis was carried out on a Fisons EA 1108
CHNS-O instrument. Melting points were recorded by a Gal-
lenkamp Model apparatus with open capillaries.
2
2
3
3
13
C NMR (CDCI
4.40 (–CH
3
3
3
5
2
3
4
.2. GC analyses
1
13
1
1
assignment was based on the H– C HETCOR and H– H COSY
spectra; IR (cm ): m 3157 (NH+OH), 3086, 3026 (aromatic C–H),
2967, 2917, 2884 (aliphatic C–H) cm ; Anal. Calc. for C11H17NO
(179.26 g/mol): C 73.70, H 9.56, N 7.81; found C 73.62, H 9.46, N
ꢀ1
GC analyses were carried out on a Shimadzu GC 2010 Plus Gas
ꢀ1
Chromatograph equipped with cyclodex B (Agilent) capillary col-
m film thickness). The GC
umn (30 m ꢁ 0.32 mm I.D. ꢁ 0.25
l
+
parameters for asymmetric transfer hydrogenation of ketones were
as follows; initial temperature, 50 °C; initial time 1.1 min; solvent
delay, 4.48 min; temperature ramp 1.3 °C/min; final temperature,
7.73; IT-TOF MS ([M+H] ): 180.14 g/mol.
4.4.3. (2S)-1-{[(2S)-2-Hydroxypropyl][(1R)-phenylethyl]amino}
propan-2-ol 2
1
50 °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;
injector port temperature, 200 °C; detector temperature, 200 °C,
injection volume, 2.0 lL.
To an ice-cold solution of (R)-1-phenylethylamine (1.04 g, 8.61
mmol) in 3 mL methanol, (S)-propylene oxide (1.00 g, 17.21 mmol)
in 3 mL methanol was added at 0 °C and stirred for 1 h. It was then
refluxed for 3 h. After the completion of the reaction, the solvent
was removed and amino alcohol was distillated at 140–145 °C,
while the product was distillated at 158–160 °C (1.43 g, 70% as vis-
4
.3. General procedure for the transfer hydrogenation of
ketones
2
0
1
D 3 3
cous). [a] = +65.8 (c 1, CHCl ). H NMR (CDCI , ppm): d 7.36–7.26
Typical procedure for the catalytic hydrogen-transfer reaction:
(m, 5H, Ar-H), 4.01 (m, 1H, –CHPh), 3.77–3.85 (m, 2H, –CHCH3),
a solution of the ruthenium complexes 5–8 (0.005 mmol), KOH
3.21 (br, 2H, –OH), 2.40–2.43 (m, 4H, –CH N), 1.49 (d, J = 7.0 Hz,
3H, CH CHPh), 1.12 (d, J = 6.2 Hz, 6H, CH CHOH); C NMR (CDCI3,
3 3
2
1
3
(
0.025 mmol) and the corresponding ketone (0.5 mmol) in
degassed isoPrOH (5 mL) was refluxed until the reaction was com-
pleted. After this time, a sample of the reaction mixture was taken
off, diluted with acetone and analyzed immediately by GC, conver-
sions obtained are related to the residual unreacted ketone. Fur-
3 3 2
ppm): d 18.74 (CH CHPh), 20.38 (CH CHOH), 58.78 (–CH N), 60.05
(CHPh), 64.18 (HOCHCH ), 127.36, 128.11, 128.29 (o-, m-, p-car-
3
bons of phenyl), 141.04 (i-carbon of phenyl) assignment was based
1
13
1
1
ꢀ1
on the H– C HETCOR and H– H COSY spectra; IR (cm ):
m 3365
1
ꢀ1
thermore, H NMR spectral data for the resultant products were
(OH), 3028 (aromatic C–H), 2968, 2932 (aliphatic C–H) cm ; Anal.
consistent with previously reported results.
Calc. for C14H23NO (237.34 g/mol): C 70.85, H 9.77, N 5.90; found
C 70.78, H 9.71, N 5.79; IT-TOF MS ([M+H] ): 238.14 g/mol.
2
+
4
4
.4. Synthesis and characterization of amino alcohols
4
.5. Synthesis and characterization of phosphinite ligands and
.4.1. (S)-(+)-2-Hydroxypropyl p-toluenesulfonate
their ruthenium complexes
To a stirred solution of (S)-2-propanediol (1.00 g, 13.14 mmol)
in dichloromethane/pyridine (10:10 V/V) at ꢀ25 °C under argon
4.5.1. (2S)-1-{[(1R)-1-Phenylethyl]amino}propan-2-yl
diphenylphosphinite 3
was added dropwise p-toluenesulfonyl chloride (2.51 g, 13.14
mmol) dissolved in 10 mL of CH
ture was stirred at ꢀ25 °C for 4 h and then at room temperature for
further 2 h. After the reaction was completed, 30 mL of CH Cl
were added and the mixture was shaken successively with ice-cold
water, 1 M 10 mL aqueous HCl, 15 mL water, saturated NaHCO
2
Cl
2
over a period of 2 h. The mix-
(S)-1-[N-(R)-
a-Phenylethyl]amino-2-propanole 1 (0.100 g, 0.56
mmol) and Et N (0.057 g, 0.56 mmol) were dissolved in dry CH Cl
3
2
2
2
2
(30 mL) under an argon atmosphere. Next Ph PCl (0.13 g, 0.56
mmol) was added dropwise with a syringe to this solution. The
mixture was stirred at room temperature for 30 min, and the sol-
2
3
,
Please cite this article in press as: Meriç, N.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.004

N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
vent was removed under reduced pressure. After addition of dry
THF, the white precipitate (triethylammonium chloride) was fil-
tered under argon and dried in vacuo to produce a white viscous
p-cymene), 126.95, 127.73, 128.42 (o-, m-, p-carbons of phenyl),
(not observed i-carbons of phenyl), 127.91 (d, J = 10.1 Hz, m-car-
bons of OPPh
10.1 Hz, o-carbons of OPPh
OPPh
); assignment was based on the H– C HETCOR and 1H– H
2
COSY spectra; P–{ H} NMR (CDCl );
2
), 130.75 (s, p-carbons of OPPh
2
), 133.90 (d, J =
20
oily compound 3 (Yield: 0.19 g, 93.8%). [
a
]
D
= +28.3 (c 1, CH
, ppm): d 7.19–7.62 (m, 15H, Ar-H), 4.24–4.31 (m,
H, CHOP), 3.69 (q, J = 6.5 Hz, 1H, CHPh), 2.60 (d, J = 5.4 Hz, 2H,
2
Cl
2
).
2
), 138.72 (d, J = 50.3 Hz, i-carbons of
1
1
13
1
H NMR (CDCI
3
2
3
1
1
1
3
, ppm): d 109.28 (s, O–PPh
3057 (aromatic C–H), 2962, 2928, 2877 (aliphatic C–
H), 1435 (P–Ph), 965 (O–P), 531 (Ru–P); Anal. Calc. for C33
NOPRuCl (669.64 g/mol): C 59.19, H 6.02, N 2.09; found C 58.98,
ꢀ
1
CH
CH
2
N), 1.28 (d, J = 6.3 Hz, 3H, CH
3
CHOP), 1.17 (d, J = 6.6 Hz, 3H,
, ppm): d 20.38 (d, J = 5.0 Hz, CH CHOP),
CHPh), 53.92 (d, J = 5.0 Hz, –CH N), 57.44 (–CHPh), 76.60
CHOP), 126.58, 126.85, 128.40 (o-, m-, p-carbons of phenyl),
29.67 (d, J = 10.1 Hz, m-carbons of OPPh ), 129.93 (s, p-carbons
of OPPh ), 131.04 (d, J = 23.1 Hz, o-carbons of OPPh ), 142.81 (d,
J = 36.2 Hz, i-carbons of OPPh ), 145.25 (i-carbon of phenyl),
IR (cm ): m
1
3
3
CHPh); C NMR (CDCI
3
3
40
H -
2
4.32 (CH
3
2
2
(
1
H 5.91, N 1.93.
2
2
2
4.5.4. (2S)-1-{[(1R)-1-Phenylethyl]amino}propan-2-yl
6
2
1
diphenylphosphinito[dichloro(
g
-benzene) ruthenium (II)] 6
assignment was based on the H– C HETCOR and 1H– H COSY
13
1
[Ru(g
6
-benzene)(m-Cl)Cl]
(0.07 g, 0.14 mmol) and (2S)-1-
2
3
1
1
spectra; P–{ H} NMR (CDCl
3
, ppm): d 109.35 (s, O-PPh
3292 (N–H), 3057 (aromatic C–H), 2968 (aliphatic C–
H), 1438 (P–Ph), 973 (O–P); Anal. Calc. for C23 26NOP (363.44
g/mol): C 76.01, H 7.21, N 3.85; found C 75.93, H 7.15, N 3.79.
2
); IR
{[(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinite 3
ꢀ1
(
cm ):
m
(0.10 g, 0.28 mmol) were dissolved in 30 mL of THF under an argon
atmosphere and stirred for 1h at room temperature. The volume
was concentrated to ca. 1–2 mL under reduced pressure and addi-
tion of petroleum ether (25 mL) gave 6 as a red solid. The product
was collected by filtration and dried in vacuo (yield: 0.14 g, 82.9%;
H
4
.5.2. (2S)-1-{[(2S)-2-[(Diphenylphosphanyl)oxy]propyl][(1R)-1-
phenylethyl]amino}pro-pan2-yl diphenylphosphinite 4
2S)-1-{[(2S)-2-Hydroxypropyl][(1R)-phenylethyl]amino}pro-
pan-2-ol 2 (0.100 g, 0.42 mmol) and Et N (0.086 g, 0.84 mmol)
were dissolved in dry CH Cl (30 mL) under an argon atmosphere.
Next, Ph PCl (0.190 g, 0.84 mmol) was added dropwise with a syr-
2
5
1
D 2 2 3
mp:125–126 °C); [a] = +10° (c 1, CH Cl ). H NMR (CDCI , ppm): d
(
7.88–7.98 (m, 4H, Ar-H), 7.25–7.47 (m, 11H, Ar-H), 5.44 (s, 6H, aro-
matic protons of benzene), 4.72 (br, 1H, –CHOP), 3.63 (br, 1H,
3
2
2
CHPh), 2.50 (br, 2H, –CH
2
N), 1.34 (br, 3H, CH
3
CHPh), 1.01 (d, J =
5.9 Hz, 3H, CH , ppm): d 20.09 (CH CHOP),
2
24.27 (CH CHPh), 53.55 (–CH N), 58.45 (–CHPh), 76.21 (CHOP),
1
3
2
3
CHOP); C NMR (CDCI
3
3
inge to this solution. The mixture was stirred at room temperature
for 30 min, and the solvent was removed under reduced pressure.
After addition of dry THF, the white precipitate (triethylammo-
nium chloride) was filtered under argon and dried in vacuo to pro-
3
90.16 (aromatic carbons of benzene), 126.81, 127.81, 128.47 (o-,
m-, p-carbons of phenyl), (not observed i-carbons of phenyl),
128.08 (d, J = 10.1 Hz, m-carbons of OPPh
of OPPh ), 133.46 (d, J = 12.1 Hz, o-carbons of OPPh
); assignment was based on the
2
), 130.95 (s, p-carbons
2
0
duce a white viscous oily compound 4 (Yield: 0.23 g, 90.1%). [
a]
D
2
2
), 138.96 (d,
1
=
ꢀ8.2 (c 1, CH
Ar-H), 4.06 (m, 2H, CHCH
CH N (a)), 2.43 (m, 2H, –CH
CHPh), 1.15 (d, J = 6.1 Hz, 6H, CH
d 12.68 (CH CHPh), 20.75 (d, J = 5.0 Hz, CH
N), 58.96 (CHPh), 76.30 (d, J = 19.1 Hz, CHCH
27.82, 128.16, 128.25 (o-, m-, p-carbons of phenyl), 128.21 (d, J
5.0 Hz, p-carbons of OPPh ), 129.08 (d, J = 15.1 Hz m-carbons of
), 130.53 (d, J = 21.1 Hz, o-carbons of OPPh ), 142.75 (d, J =
3.2 Hz, i-carbons of OPPh ), 143.30 (i-carbon of phenyl), assign-
2
Cl
2
). H NMR (CDCI
), 3.93 (m, 1H, CHPh), 2.84 (m, 2H, –
N (b)), 1.29 (d, J = 5.1 Hz, 3H, CH
CHOP); 13C NMR (CDCI
, ppm):
CHOP), 58.01 (d, J =
),
3
, ppm): d 7.62–7.27 (m, 25H,
J = 48.3 Hz, i-carbons of OPPh
H– C HETCOR and H– H COSY spectra; P–{ H} NMR (CDCl ,
3
ppm): d 106.91 (s, O–PPh ); IR (cm ): m 3056 (aromatic C–H),
2
2
1
13
1
1
31
1
3
ꢀ1
2
2
3
-
3
3
2972, 2928 (aliphatic C–H), 1435 (P–Ph), 965 (O–P), 530 (Ru–P);
3
3
Anal. Calc. for C29 32NOPRuCl (613.53 g/mol): C 56.77, H 5.26, N
H
2
5
1
=
.0 Hz, CH
2
3
2.28; found C 56.59, H 5.21, N 2.21.
2
4.5.5. (2S)-1-{[(2S)-2-[(Diphenylphosphanyl)oxy]propyl][(1R)-1-
OPPh
2
2
phenylethyl]amino} propan-2-yl diphenylphosphinitobis
6
3
2
[dichloro(
g
-p-cymene)ruthenium(II)] 7
(0.10 g, 0.17 mmol) and (2S)-1-
1
13
1
1
6
ment was based on the H– C HETCOR and H– H COSY spectra;
[Ru(g
-p-cymene)(m-Cl)Cl]
2
3
1
1
ꢀ1
P–{ H} NMR (CDCl
056 (aromatic C–H), 2971, 2929 (aliphatic C–H), 1438 (P–Ph),
70 (O–P); Anal. Calc. for C38 (605.70 g/mol): C 75.35, H
3
, ppm): d 106.47 (s, O-PPh
2
); IR (cm ):
m
{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]
amino}propan-2-yl diphenylphosphinite 4 (0.10 g, 0.17 mmol)
were dissolved in 30 mL of THF under an argon atmosphere and
stirred for 1h at room temperature. The volume was concentrated
to ca. 1–2 mL under reduced pressure and the addition of petro-
leum ether (25 mL) gave 7 as a red solid. The product was collected
by filtration and dried in vacuo (yield: 0.18 g, 90.5%; mp:145–147
3
9
6
H
2 2
41NO P
.82, N 2.31; found C 75.28, H 6.77, N 2.27.
4
.5.3. (2S)-1-{[(1R)-1-Phenylethyl]amino}propan-2-yl
6
diphenylphosphinito[dichloro (
g
-p-cymene) ruthenium (II)] 5
6
25
1
[
Ru(
[(1R)-1-phenylethyl]amino}propan-2-yl diphenylphosphinite
0.10 g, 0.28 mmol) were dissolved in 30 mL of THF under an argon
g
-p-cymene)(m-Cl)Cl]
2
(0.08 g, 0.14 mmol) and (2S)-1-
°C); [
a
]
D
= ꢀ42 (c 1, CH
2 2 3
Cl ). H NMR (CDCI , ppm): d 7.84–7.91
{
(
3
(m, 8H, Ar-H), 7.37 (m, 12H, Ar-H), 7.05–7.20 (m, 5H, Ar-H), 5.31
(d, J = 6.1 Hz, 2H, aromatic protons of p-cymene), 5.13 (m, 4H, aro-
matic protons of p-cymene), 5.02 (d, J = 5.9 Hz, 2H, aromatic pro-
atmosphere and stirred for 1h at room temperature. The volume
was concentrated to ca. 1–2 mL under reduced pressure and addi-
tion of petroleum ether (25 mL) gave 5 as a red solid. The product
was collected by filtration and dried in vacuo (yield: 0.15 g, 82.0%;
tons of p-cymene), 4.24 (br, 2H, CHCH
CHPh), 2.63 (m, 2H, –CH of p-cymene), 2.21 (d, J = 10.4 Hz, 2H, –
CH N (a)), 1.84 (m, 8H, CH Ph’ı of p-cymene + –CH N (b)), 1.15
(d, J = 6.9 Hz, 6H, (CH CHPh of p-cymene), 1.07 (d, J = 6.9 Hz,
6H, (CH CHPh of p-cymene), 0.90 (d, J = 6.4 Hz, 3H, CH CHPh),
0.84 (d, J = 5.3 Hz, 6H, CH , ppm): d 8.98
(CH CHPh), 17.57 (CH Ph of p-cymene), 20.17 (CH CHOP), 21.93,
21.98 ((CH CHPh of p-cymene), 30.04 (–CH of p-cymene), 55.19
(CH N), 56.85 (CHPh), 73.93 (d, J = 8.0 Hz, CHCH ), 87.39 (d, J =
3
), 3.25 (q, J = 6.7 Hz, 1H,
2
3
2
2
5
1
mp: 101–103 °C); [
a
]
D
= +23.0 (c 1, CH
2
Cl
2
). H NMR (CDCI
3
, ppm):
3 2
)
d 7.85–7.99 (m, 4H, Ar-H), 7.22–7.44 (m, 11H, Ar-H), 5.25–5.30 (m,
Hz, 3H, aromatic protons of p-cymene), 5.11 (br, 1H, aromatic pro-
ton of p-cymene), 4.53 (br, 1H, –CHOP), 3.55 (br, 1H, CHPh), 2.64
3
)
2
3
1
3
3
CHOP); C NMR (CDCI
3
3
3
3
(
m, 1H, –CH– of p-cymene), 2.39 (br, 2H, –CH
Ph of p-cymene), 1.34 (br, 3H, CH CHPh), 1.07 (m, 9H, CH
CH , ppm): d 17.34 (CH
CHPh of p-cymene); 13C NMR (CDCI
of p-cymene), 20.20 (CH CHOP), 22.10 ((CH CHPh of p-cymene),
4.20 (CH CHPh), 30.03 (–CH of p-cymene), 53.03 (–CH N), 58.33
–CHPh), 75.45 (CHOP), 86.68, 88.30, 90.12, 91.59 (aromatic
carbons of p-cymene), 96.67, 111.01 (quaternary carbons of
2
N), 1.84 (s, 3H, CH
CHOP +
Ph
3
-
3 2
)
3
3
2
3
(
3
)
2
3
3
5.0 Hz, aromatic carbons of p-cymene), 88.49 (d, J = 7.0 Hz, aro-
matic carbons of p-cymene), 89.45 (d, J = 4.0 Hz, aromatic carbons
of p-cymene), 90.36 (s, aromatic carbons of p-cymene), 97.71,
111.35 (quaternary carbons of p-cymene), 127.48, 127.57, 128.26
(o-, m-, p-carbons of phenyl), 127.78 (d, J = 10.1 Hz, m-carbons of
3
3 2
)
2
(
3
2
Please cite this article in press as: Meriç, N.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.004

1
0
N. Meriç et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
OPPh
1
2
), 130.81 (d, J = 4.0 Hz, p-carbons of OPPh
1.1 Hz, o-carbons of OPPh ), 137.73 (d, J = 49.3 Hz, i-carbons of
), 143.31 (i-carbon of phenyl); assignment was based on
2
), 132.71 (d, J =
8. (a) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed., 2nd ed.; Wiley-VCH: New York, 2000; pp 1–110; (b) Brown, J. M.
In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. I, pp 121–182; (c) Tang, W.; Zhang, X. Chem.
Rev. 2003, 103, 3029–3069.
2
OPPh
2
the H– C HETCOR and 1H– H COSY spectra; P–{ H} NMR
1
13
1
31
1
ꢀ1
9. Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576.
(
CDCl
3 2
, ppm): d 109.29 (s, O-PPh ); IR (cm ): m 3056 (aromatic
10. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–876.
C–H), 2963, 2922, 2867 (aliphatic C–H), 1435 (P–Ph), 966 (O–P),
11. Corey, E. H.; Helal, C. J. Angew. Chem., Int. Ed. Eng. 1998, 37, 1986–2102.
5
5
29 (Ru–P); Anal. Calc. for C58
7.19, H 5.71, N 1.15; found C 56.98, H 5.67, N 1.11.
H
69NO
2
P
2
Ru
2
Cl
4
(1218.09 g/mol): C
12. (a) Korey, E. J.; Shibata, S.; Bakshi, R.-K. J. Am. Chem. Soc. 1987, 109, 7925–7926;
b) Kagan, H. Chem. Rev. 1992, 92, 1007–1019.
(
1
3. (a) Aydemir, M.; Meric, N.; Baysal, A.; Gümgüm, B.; To g˘ rul, M.; Turgut, Y.
Tetrahedron: Asymmetry 2010, 21, 703–710; (b) Ak, B.; Aydemir, M.; Ocak, Y. S.;
Durap, F.; Kayan, C.; Baysal, A.; Temel, H. Inorg. Chim. Acta 2014, 409, 244–253;
4
.5.6. (2S)-1-{[(2S)-2-[(Diphenylphosphanyl)oxy]propyl][(1R)-1-
(
c) Meriç, N.; Durap, F.; Aydemir, M.; Baysal, A. Appl. Organometal. Chem. 2014,
28, 803–808; (d) Meriç, N.; Aydemir, M. J. Organometal. Chem. 2016, 819, 120–
28.
phenylethyl]amino}pro-pan-2-yldiphenylphosphinitobis
6
[
dichloro(
g
-benzene)ruthenium(II)] 8
-benzene)(m-Cl)Cl] (0.08 g, 0.17 mmol) and (2S)-1-
[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]
1
6
[
Ru(
g
2
14. (a) Aydemir, M.; Baysal, A.; Meric, N.; Kayan, C.; To g˘ rul, M.; Gümgüm, B. Appl.
Organomet. Chem. 2010, 24, 215–221; (b) Aydemir, M.; Meric, N.; Durap, F.;
Baysal, A.; To g˘ rul, M. J. Organomet. Chem. 2010, 695, 1392–1398; (c) Aydemir,
M.; Durap, F.; Baysal, A.; Meric, N.; Bulda g˘ , A.; Gümgüm, B.; Özkar, S.; Yıldırım,
L. T. J. Mol. Catal. A: Chem. 2010, 326, 75–81.
15. (a) Ak, B.; Elma, D.; Meriç, N.; Kayan, C.; I sß ık, U.; Aydemir, M.; Durap, F.
Tetrahedron: Asymmetry 2013, 24, 1257–1264; (b) Aydemir, M.; Baysal, A.;
Sß ahin, E.; Gümgüm, B.; Özkar, S. Inorg. Chim. Acta 2011, 378, 10–18; (c) Durap,
F.; Karaka ßs , D. E.; Ak, B.; Baysal, A.; Aydemir, M. J. Organomet. Chem. 2016, 818,
92–97; (d) Ak, B.; Durap, F.; Aydemir, M.; Baysal, A. Appl. Organomet. Chem.
2015, 29, 764–770.
{
amino}propan-2-yl diphenyl phosphinite 4 (0.10 g, 0.17 mmol)
were dissolved in 30 mL of THF under an argon atmosphere and
stirred for 1h at room temperature. The volume was concentrated
to ca. 1–2 mL under reduced pressure and addition of petroleum
ether (25 mL) gave 8 as a red solid. The product was collected by
filtration and dried in vacuo (yield: 0.16 g, 88.5%; mp:159–160
2
5
1
°C); [
a]
D
= ꢀ53 (c 1, CH
2 2 3
Cl ). H NMR (CDCI , ppm): d 7.87–7.95
1
6. Turgut, Y.; Aral, T.; Karakaplan, M.; Deniz, P.; Ho sß gören, H. Synth. Commun.
010, 40, 3365–3370.
17. (a) Kitaori, K.; Furukawa, Y.; Yoshimoto, H.; Ctera, J. Tetrahedron 1999, 55,
4381–14390; (b) Chen, J.; Shum, W. Tetrahedron Lett. 1995, 36, 2379–2382.
(
m, 8H, Ar-H), 7.36–7.44 (m, 12H, Ar-H), 7.10–7.21 (m, 5H, Ar-H),
2
5
3
1
3
.38 (s, 12H, aromatic protons of benzene), 4.47 (br, 2H, CHCH ),
1
.33 (q, J = 6.4 Hz 1H, CHPh), 2.17 (d, J = 10.7 Hz 2H, –CH N (a)),
.96 (dd (pseudo t), J = 11.4 Hz, J = 11.2 Hz, 2H, –CH N (b)), 0.89
2
1
8. (a) Jacopsen, E. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH:
New York, 1993; p 287; (b) Sun, J.; Yuan, F.; Yang, M.; Pan, Y.; Zhu, C.
Tetrahedron Lett. 2009, 50, 548–549.
2
(
d, J = 4.7 Hz, 6H, CH
3
CHOP), 0.83 (d, J = 6.6 Hz, 3H, CH
3
CHPh);
CHOP),
1
3
19. (a) Galka, P. W.; Kraatz, H. B. J. Organomet. Chem. 2003, 674, 24–31; (b)
Gilbertson, S.; Collibee, S. E.; Agarkov, A. J. Am. Chem. Soc. 2000, 122, 6522–
C NMR (CDCI
5.14 (CH
aromatic carbons of benzene), 127.57, 127.99, 128.09 (o-, m-, p-
carbons of phenyl), 127.74 (d, J = 10.1 Hz, m-carbons of OPPh ),
), 132.20 (d, J = 11.1 Hz, o-carbons
3
, ppm): d 9.04 (CH
3
CHPh), 19.92 (CH
3
5
2 3
N), 56.80 (CHPh), 73.82 (CHCH ), 90.17 (d, J = 4.0 Hz,
6523.
20. Tribo, A.; Munoz, S.; Pons, J.; Yanez, R.; Alvarez-Larena, A.; Piniella, J. F.; Ros, J. J.
Organomet. Chem. 2005, 690, 4072–4079.
2
21. Baysal, A.; Aydemir, M.; Durap, F.; Gümgüm, B.; Özkar, S.; Yıldırım, L. T.
1
31.09 (s, p-carbons of OPPh
2
Polyhedron 2007, 25, 3373–3378.
of OPPh
2
), 137.95 (d, J = 53.3 Hz, i-carbons of OPPh
2
), 143.12 (i-car-
22. Fei, Z.; Scopelliti, R.; Dyson, P. J. Eur. J. Inorg. Chem. 2004, 530–537.
23. Fei, Z.; Scopelliti, R.; Dyson, P. J. Inorg. Chem. 2003, 42, 2125–2130.
24. (a) Hauptman, E.; Shapiro, R.; Marshall, W. Organometallics 1998, 17, 4976–
1
13
bon of phenyl); assignment was based on the H– C HETCOR and
1
1
31
1
H– H COSY spectra; P–{ H} NMR (CDCl
3
, ppm): d 106.80 (s, O-
4
8
982; (b) Ruhlan, K.; Gigler, P.; Herdweck, E. J. Organomet. Chem. 2008, 693,
74–893.
ꢀ
1
PPh
2
); IR (cm ):
m
3057 (aromatic C–H), 2976, 2928 (aliphatic
C–H), 1435 (P–Ph), 966 (O–P), 529 (Ru–P); Anal. Calc. for C50
NO Ru Cl (1105.87 g/mol): C 54.31, H 4.83, N 1.27; found C
4.10, H 4.78, N 1.21.
H
53
-
25. (a) Hariharasarma, M.; Lake, C. H.; Watkins, C. L.; Gray, M. G. J. Organomet.
Chem. 1999, 580, 328–338; (b) Broger, E. A.; Burkart, W.; Hennig, M.; Scalone,
M. Tetrahedron: Asymmetry 1998, 9, 4043–4054.
P
2 2
2
4
5
2
6. (a) Iwai, T.; Akiyama, Y.; Tsunoda, K. Tetrahedron: Asymmetry 2015, 26, 1245–
250; (b) Ceron-Camacho, R.; Gomez-Benitez, V.; Le Lagadec, R.; Morales-
Morales, D.; Toscano, R. A. J. Mol. Catal. A: Chem. 2006, 247, 124–129.
27. Le Bozec, H.; Touchard, D.; Dixneuf, P. H. Adv. Organomet. Chem. 1989, 29, 163–
47.
1
Acknowledgement
2
2
8. Bennet, M. A.; Robertson, G. B.; Smith, A. K. J. Organomet. Chem. 1972, 43, C41–
Partial support from TUBITAK (Project number: 113Z297) is
gratefully acknowledged.
C43.
29. de la Encarnacion, E.; Pons, J.; Yanez, R.; Ros, J. Inorg. Chim. Acta 2005, 358,
272–3276.
3
3
3
3
0. Moldes, I.; de la Encarnacion, E.; Ros, J.; Alvarez-Larena, A.; Piniella, J. F. J.
A. Supplementary data
Organomet. Chem. 1998, 566, 165–174.
1. Caballero, A.; Jalon, F. J.; Manzano, B.; Espino, G.; Perez-Manrique, M.;
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Supplementary data associated with this article can be found, in
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