Asymmetric transfer hydrogenation of acetophenone derivatives with novel chiral phosphinite based η6-p-cymene/ruthenium(II) catalysts

Article abstract of DOI:10.1016/j.jorganchem.2010.12.027

Enantioselective reduction of prochiral ketones to optically active secondary alcohols is an important subject in synthetic organic chemistry because the resulting chiral alcohols are extremely useful, biologically active compounds. The new chiral ligands (2R)-2-[benzyl{(2-((diphenylphosphanyl)oxy) ethyl)}amino]butyldiphenylphosphinite, 1 and (2R)-2-[benzyl{(2- ((dicyclohexylphosphanyl)oxy)ethyl)}amino]butyldicyclohexylphosphinite, 2 and the corresponding ruthenium(II) complexes 3 and 4 have been prepared. The structures of these complexes have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis. ³¹P-{¹H} NMR, DEPT, ¹H-¹³C HETCOR or ¹H-¹H COSY correlation experiments were used to confirm the spectral assignments. These ruthenium(II)-phosphinite complexes have been used as catalysts for the asymmetric transfer hydrogenation of acetophenone derivatives. Under optimized conditions, aromatic ketones were reduced in good conversions and in moderate to good enantioselectivities (up to 85% ee).

Full text of DOI:10.1016/j.jorganchem.2010.12.027

Journal of Organometallic Chemistry 696 (2011) 1541e1546
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Asymmetric transfer hydrogenation of acetophenone derivatives with novel chiral
phosphinite based h
6-p-cymene/ruthenium(II) catalysts
*
ꢀ
Murat Aydemir , Nermin Meric, Akin Baysal, Yilmaz Turgut, Cezmi Kayan, Sevil S¸ eker, Mahmut Togrul,
Bahattin Gümgüm
Dicle University, Department of Chemistry, TR-21280 Diyarbakır, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective reduction of prochiral ketones to optically active secondaryalcohols is an important subject
in synthetic organic chemistry because the resulting chiral alcohols are extremely useful, biologically active
compounds. The new chiral ligands (2R)-2-[benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]butyldi-
phenylphosphinite, 1 and (2R)-2-[benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}amino]butyldicyclohex-
ylphosphinite, 2 and the corresponding ruthenium(II) complexes 3 and 4 have beenprepared. The structures
of these complexes have been elucidated by a combination of multinuclear NMR spectroscopy, IR spec-
troscopy and elemental analysis. 31Pe{1H} NMR, DEPT, 1He13C HETCOR or 1He1H COSY correlation experi-
ments were used to confirm the spectral assignments. These ruthenium(II)ephosphinite complexes have
been used as catalysts for the asymmetric transfer hydrogenation of acetophenone derivatives. Under
optimized conditions, aromatic ketones were reduced in good conversions and in moderate to good enan-
tioselectivities (up to 85% ee).
Received 14 October 2010
Received in revised form
13 December 2010
Accepted 20 December 2010
Keywords:
Asymmetric transfer hydrogenation
Homogeneous catalysis
Chiral phosphinite ligands
Ruthenium(II) complexes
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
focus has been ruthenium(II). One reason is that the ruthenium(II)
catalysts have excellent performances [13,14]. Another reason is that
Hydrogen transfer reactions are mild methodologies for reduc-
tion of ketones and oxidation of alcohols in which a substrate-
selective catalyst transfers hydrogen between the substrate and
a hydrogen donor or acceptor, respectively. Furthermore, the donor
(e.g. 2-propanol) and the acceptor (e.g. a ketone) are environmen-
tally friendly and also easy to handle [1e3].
Asymmetric transfer hydrogenation of ketones has recently
emerged as an alternative method to asymmetric hydrogenation for
the production of chiral alcohols due to its operational simplicity and
easy availability of reductants [4e6]. Chiral alcohols are very
important building blocks and synthetic intermediates in organic
synthesis and the pharmaceutical industry [7,8]. Catalytic asym-
metric synthesis using chiral metal complexes as catalyst precursors
offers an ideal method for reducing ketones to chiral alcohols [9,10].
For the past ten years, a developed efficient method is the catalytic
transfer hydrogenation of ketones using chiral ruthenium(II),
rhodium(I), iridium(I), or lanthanoid complexes as catalyst precur-
sors and iso-PrOH/KOH or HCOOH/Et3N as hydride source [11,12]. In
general, asymmetric hydrogenation is mediated by a complex
bearing rhodium(I), ruthenium(II) or iridium(I), among which our
Ru enjoyed a cost advantage relative to other asymmetric hydroge-
nation metals such as rhodium(I) [15].
Phosphine ligands have found wide-spread applications in tran-
sition metal catalyzed asymmetric transformations [16,17]. Phos-
phinites provide different chemical, electronic and structural
properties compared to phosphines. The metalephosphorus bond is
often stronger for phosphinites compared to the related phosphine
due to the presence of electron-withdrawing PeOR group. In addi-
tion, the empty s
*-orbital of the phosphinite P(OR)R2 is stabilized
and it makes the phosphinite a better acceptor [18]. The most
important advantage of chiral phosphinite ligands over the corre-
sponding phosphine ligands is the easiness of preparation. From
a practical standpoint, it is a substantial interest to develop highly
effective chiral phosphinite ligands for asymmetric catalysis. The
excellent catalytic performance of phosphinite based transition
metal complexes [19,20] prompted us to develop new ruthenium(II)
complexes with well-designed ligands.
Recently, we reported the synthesis of new P,O-ligands [21,22]
and their application in ruthenium-catalyzed transfer hydrogena-
tion reactions [23e25]. As an extension of the ongoing research
program, we become interested in the synthesis of new unsymmetric
ligands: (2R)-2-[benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]
butyldiphenylphosphinite, 1 and (2R)-2-[benzyl{(2-((dicyclohexyl-
phosphanyl)oxy)ethyl)}amino]butyldicyclohexylphosphinite, 2. This
* Corresponding author. Tel.: þ90 412 248 8550; fax: þ90 412 248 8300.
E-mail address: aydemir@dicle.edu.tr (M. Aydemir).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.12.027

1542
M. Aydemir et al. / Journal of Organometallic Chemistry 696 (2011) 1541e1546
study was completed with a synthesis and full characterization of
neutral p-cymeneeruthenium(II) complexes. Herein, we also report
that ruthenium complexes of these phosphinites form efficient
catalysts for the asymmetric transfer hydrogenation of acetophenone
derivatives with iso-PrOH under varying conditions.
available
a
-phellandrene
(5-isopropyl-2-methylcyclohexa-1,3-
6-p-cymene)(
-Cl)Cl]2
diene) with RuCl3 [34]. The reactions of [Ru(
h
m
with one equivalent of 1 or 2 in toluene at room temperature gave the
red compounds 3 and 4 in high conversions, respectively. The reac-
tions between ruthenium(II) precursor and bis(phosphinite) ligands,
1 and 2 are not affected by the molar ratio of [Ru(h m-Cl)
6-p-cymene)(
Cl]2 as well as the steric and electronic properties of the donor
phosphorus atoms. The initial color change, i.e., from clear orange to
deep red, attributed to the dimer cleavage most probably by the
2. Results and discussion
2.1. Synthesis of chiral ligands, 1 and 2 and their ruthenium(II)
complexes
bis(phosphinite) ligand [35].
phanyl)oxy)ethyl)}amino]butyldiphenylphosphinito-bis[dichloro
6-p-isopropyltoluene)ruthenium(II)], 3 and
-(2R)-2-[benzyl{(2-
((dicyclohexylphosphanyl) oxy)ethyl)}amino]butyldicyclohexyl-
phosphinito-bis[dichloro(
6-p-isopropyltoluene)ruthenium(II)],
were isolated as indicated by singlets in the 31Pe{1H} NMR spectra
at ( ) 110.87 and 113.48 ppm for 3 and at ( ) 144.25 and 144.78 ppm
m-(2R)-2-[benzyl{(2-((diphenylphos-
(h
m
Phosphinite ligands (2R)-2-[benzyl{(2-((diphenylphosphanyl)
oxy)ethyl)}amino]butyldiphenylphosphinite, 1 and (2R)-2-[benzyl
{(2-((dicyclohexylphosphanyl)oxy)ethyl)}amino]butyldicyclohexyl-
phosphinite, 2 were synthesized as outlined in Scheme 1. Ligands, 1
and 2 were synthesized by hydrogen abstraction from the described
chiral (2R)-2-[benzyl(2-hyroxyethyl)amino]butan-1-ol, by a base
(Et3N) and the subsequent reaction with two equivalents of chlor-
odiphenylphosphine or chlorodicyclohexylphosphine, respectively,
in anhydrous toluene or CH2Cl2 and under inert argon atmosphere.
The new ligands have been characterized by the 31P NMR spec-
troscopy. The 31P NMR spectra of 1 and 2 show no unexpected
features. Two singlets are observed in the 31P NMR spectrum of each
ligand due to the inequivalent phosphorus nuclei. The 31P NMR
spectra of the free ligands consist of two singlets at 112.95 and
114.05 ppm for 1 and at 147.25 and 148.63 ppm for 2 [26,27], in line
with the values previously observed for similar compounds,
respectively (see Supplementary material, Fig. 1) [28e31].
h
4
d
d
for 4, respectively in line with the values previously observed for
similar compounds (see Supplementary material, Fig. 2) [36]. It is
significant to remark that 31Pe{1H} NMR signals of ligands and
complexes do not differ significantly [37].
These complexes are highly soluble in CH2Cl2 and slightly in
hexane and they can be crystallized from CH2Cl2/hexane solutions.
The structure of the P-coordinated complexes 3 and 4 is supported
by spectroscopic data (1H and 13C NMR). 1H NMR spectral data of
complexes are consistent with the structures proposed. Analysis by
1H NMR reveals these compounds to be diamagnetic, exhibiting
signals corresponding to the aromatic rings. 1H NMR spectra of
complexes display signals of the h
6-p-cymene ligand together with
the resonances of the hydrogens of the P-coordinated ligands (for
details see experimental section). The arene signals are well
Solution of the ligands in CDCl3, prepared under anaerobic
condition, isunstableand decomposesgradually togiveoxideand the
hydrolysis product diphenylphosphinous acid, Ph2P(O)H [32].
Furthermore, the 31P NMR spectrum also displays formation of
resolved, as found in previously reported mononuclear h
6-p-cym-
ene complexes [38]. In the 13Ce{1H} NMR spectrum of compound 3,
J (31Pe13C) coupling constants of the carbons of the phenyl rings
were observed, which are in agreement consistent with the litera-
ture values [39,40]. In the compound 3, the coupling between i-
carbons and the phosphorus is relatively large, 1J(PC) 51.0 Hz, while
the coupling between o-carbon and the phosphorus relatively small
2J(PC) 11.06. In addition, the most relevant signals of 13Ce{1H} NMR
spectra of complex 4 are those corresponding to cyclohexyl moie-
ties. Carbon atoms of the cyclohexyl rings are observed as four
signals at 26.35, 27.20, 27.78 and 43.21 ppm in complex 4 (for details
see Experimental section). Furthermore, the structures of the 3 and
4 were further confirmed by IR spectroscopy and microanalysis, and
PPh2PPh2 and P(O)Ph2PPh2, as indicated by signals at about
d
ꢀ
15.6 ppm as singlet and
d
35.4 ppm and
d
ꢀ21.6 ppm as doublets with
1J(PP) 224 Hz, respectively [33]. Because of the compounds 1 and 2 are
not stable enough in solution, the ruthenium(II) complexes 3 and 4
were synthesized in-situ. Reactions of [Ru(h m-Cl)Cl]2
6-p-cymene)(
with phosphinite ligands (2R)-2-[benzyl{(2-((diphenylphosphanyl)
oxy)ethyl)}amino]butyldiphenylphosphinite, 1 and (2R)-2-[benzyl
{(2-((dicyclohexylphosphanyl)oxy)ethyl)}amino]butyldicyclohex-
ylphosphinite, 2 are depicted in Scheme 1.
The starting ruthenium(II) complex was [Ru(
Cl]2, which was prepared from the reaction of the commercially
h m-Cl)
6-p-cymene)(
Scheme 1. Synthesis of the (2R)-2-[benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]butyldiphenylphosphinite, 1, (2R)-2-[benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}
amino]butyldicyclohexylphosphinite, 2, [C13H19N(OPPh2-Ru(
h
6-p-cymene)Cl2)2], 3 and [C13H19N(OPCy2-Ru(h6-p-cymene)Cl2)2], 4 compounds. (i) Ethylene oxide, MeOH, ꢀ20 ꢁC;
(ii)) 2 equiv. Ph2PCl, 2 equiv. Et3N, 1 h, toluene for 1 and 2 equiv. Cy2PCl, 2 equiv. Et3N, 48 h, CH2Cl2 for 2; (iii) 1 equiv. [Ru(h m-Cl)Cl]2, toluene, 6 h for 3 and 12 h for 4.
6-p-cymene)(

M. Aydemir et al. / Journal of Organometallic Chemistry 696 (2011) 1541e1546
1543
found to be in good agreement with the theoretical values (for
details see Experimental section).
2.2. Asymmetric transfer hydrogenation of acetophenone
derivatives
The excellent catalytic performance and the higher structural
permutability of phosphinite based transition metal complexes
[41,42] prompted us to develop new ruthenium(II) complexes with
well-shaped ligands. We paid particular attention to arene ligands
[43], because (i) the spectator ligands automatically occupy three
adjacent coordination sites of ruthenium(II) in an octahedral
coordination environment, leaving three facial sites for other
functions, (ii) arene ligands that are relatively weak electron donors
may provide a unique reactivity on the metallic center, and (iii) the
substitution pattern on the ring is flexible. Complexes 3 and 4 were
tested as catalysts in transfer hydrogenation of aromatic ketones in
an iso-PrOH solution. These complexes were then examined in the
asymmetric transfer hydrogenation of the acetophenone to the
corresponding alcohol by iso-PrOH/NaOH as a reducing system. Our
purpose here is to compare the coordinating abilities of various
functionalized phosphinites in ruthenium(II)earene complexes in
the catalytic asymmetric transfer hydrogenation. A comparison of
complexes 3 and 4 as precatalysts for the asymmetric hydrogena-
tion of acetophenone by 2-propanol in the presence of NaOH are
summarized in Table 1.
Scheme 2. Hydrogen transfer from iso-PrOH to acetophenone derivatives.
with high conversion and enantioselectivity (up to 82% ee). During
this period, the color changed from orange to deep red. In addition,
the ee’s do not vary with the time, as indicated by the catalytic
results collected with 3 and 4. Reduction of acetophenone into
1-phenylethanol could be achieved in high yield by increasing the
temperature up to 82 ꢁC. The negligible catalytic activity of [Ru(p-
cymene)Cl2]2 was observed under the applied experimental
conditions [45]. It should be also pointed out that complexes 3 and
4 are more active catalysts than the corresponding precursor: [Ru
(h m-Cl)Cl]2 (41% maximum yield in 24 h) [46]. When
6-p-cymene)(
the temperature was increased to 82 ꢁC smooth reduction of ace-
tophenone into 1-phenylethanol occurred with conversion
ranging from 66 to 51% after 30 min for 3 and 4. The catalytic
activities of 3 and 4 are comparable, with the TOF values referred
to 3 h of 22 hꢀ1 and 17 hꢀ1, respectively. These reactions were
carried out under Ar atmosphere at 82 ꢁC and reached the
maximum conversion within 6 h for 3 and 9 h for 4, respectively
(Table 1, entries 5 and 6). In these cases conversions higher than
30% have always been obtained (TOFs up to 25 hꢀ1), indicating that
the reactions start immediately after the addition of base without
any induction time. Furthermore, it is noteworthy that the catalytic
system, 3 and 4 display the differences in reactivity. Examination
of the results in Table 1 reveals that the reactions with the phos-
phiniteeruthenium(II), 4 catalytic system proceeded more slowly
than those of the phosphiniteeruthenium(II), 3. But, the catalyst
based on (2R)-2-[benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}
amino]butyldicyclohexylphosphinite, 2 is slightly more enantio-
selective than the (2R)-2-[benzyl{(2-((diphenylphosphanyl)oxy)
ethyl)}amino]butyl diphenylphosphinite, 1 counterpart, with ee
values of 78% and 67%, respectively (entries 5 and 6). Furthermore,
as can be inferred from the Table 1 (entries 7 and 8) the presence of
base is not necessary to observe appreciable conversions. The
choice of base, such as KOH and NaOH, had little influence on the
conversion and enantioselectivity. The base facilitates the forma-
tion of ruthenium alkoxide by abstracting proton of the alcohol
These complexes catalyzed the reduction of acetophenone to
corresponding alcohol ((R), (S)-1-phenylethanol) in the presence
NaOH as a promoter (Scheme 2). At room temperature, transfer
hydrogenation of acetophenone occurred very slowly [44] with
low conversion (5% after 1 h, entries 1 and 2) in all the reactions.
But, at 50 ꢁC (Table 1, entries 3 and 4), this reaction occurred slowly
Table 1
Transfer hydrogenation of acetophenone with iso-PrOH catalyzed by
[benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]butyldiphenylphosphinito-bis-
[dichloro( -(2R)-2-[benzyl{(2-((dicy-
6-p-isopropyltoluene)ruthenium(II)], 3 and
clohexylphosphanyl)oxy)ethyl)}amino]butyldicyclohexylphosphinito-bis[dichloro-
6-p-isopropyltoluene)ruthenium(II)], 4.
m-(2R)-2-
h
m
(
h
k
Entry Catalyst s/c
Time Conversion (%)h ee %i Configurationj TOF (hꢀ1
)
1
2
3
3a
4a
3b
100:1 1
100:1 1
100:1 32
(52)
100:1 32
(72)
<5
<5
71(98)
e
e
e
S
e
e
e
e
71
(69)
82
(80)
67
78
65
76
73
82
62
71
66
75
4
4b
40(99)
S
e
5
6
7
8
3c
4c
3d
4d
3e
4e
3f
100:1 6
100:1 9
96
97
94
95
98
99
98
99
97
98
S
S
S
S
S
S
S
S
S
S
e
e
and subsequently alkoxide undergoes
b-elimination to give
100:1 32
100:1 48
500:1 18
500:1 24
100:1 10
100:1 16
100:1 18
100:1 24
e
ruthenium hydride, which is an active species in this reaction. This
is the mechanism proposed by several workers on the studies of
ruthenium-catalyzed transfer hydrogenation reaction by metal
hydride intermediates [47,48]. In addition, optimization studies of
the catalytic reduction of acetophenone in iso-PrOH showed that
good activity was obtained with a base/cat. ratio of >5:1. Although
the conversions gradually decreased on increasing the mole ratios
of [acetophenone]/[ruthenium(II)] from 100/1 to 500/1, the
enantioselectivity was still high (Table 1, entries 9 and 10). That’s
to say, the ee remained unchanged when the molar ratio of
substrate to catalyst was increased.
For the transfer hydrogenation of acetophenone, the catalyst
system showed good activity and high selectivity even in the
presence of small amount of water (Table 1, Entries 11 and 12).
When we increased the amount of water in the reaction system, the
high conversion with the same enantioselectivity remained intact.
Performing the reaction in air slowed down the reaction but did not
affect enantioselectivity (66e75% ee, Table 1, Entries 13 and 14).
e
9
98
99
33
33
12
12
10
11
12
13
14
4f
3g
4g
a
At room temperature. Acetophenone/Ru/NaOH, 100:1:5.
At 50 ꢁC. Acetophenone/Ru/NaOH, 100:1:5.
Refluxing in iso-PrOH; acetophenone/Ru/NaOH, 100:1:5.
In the absence of base.
Refluxing in iso-PrOH; acetophenone/Ru/NaOH, 500:1:5.
Added 0.1 mL H2O.
Carried out (refluxing) the reaction in air.
Determined by GC (three independent catalytic experiments).
Determined by capillary GC analysis using a chiral cyclodex B (Agilent) capillary
b
c
d
e
f
g
h
i
column.
j
Determined by comparison of the retention times of the enantiomers on the GC
traces with literature values, (S) configuration was obtained in all experiments.
k
Referred at the reaction time indicated in footnotea; TOF ¼ (mol product/mol Ru
(II) Cat.) ꢂ hꢀ1
.

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M. Aydemir et al. / Journal of Organometallic Chemistry 696 (2011) 1541e1546
Table 2
Asymmetric Transfer Hydrogenation results for substituted acetophenones with the catalyst systems prepared from [Ru(h m-Cl)Cl]2 and (2R)-2-[benzyl{(2-
6-p-cymene)(
((diphenylphosphanyl)oxy)ethyl)}amino]butyldiphenylphosphinite, 1, and (2R)-2-[benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}amino]butyldicyclohexylphosphinite, 2.a
e
Entry
1
Catalyst
3
Substrate
Product
Conversion (%)b
98
ee (%)c
68
Configurationd
TOF (hꢀ1
16
)
S
O
OH
OH
OH
2
4
99
80
S
11
F
F
O
3
4
3
4
98
99
70
81
S
S
16
11
Cl
Br
Cl
Br
O
5
6
3
4
97
96
73
82
S
S
16
11
O
OMe
OMe
OH
7
8
9
3
4
3
4
95
94
92
90
76
87
65
74
S
S
S
S
16
10
15
10
O
OH
MeO
MeO
10
a
Catalyst (0.005 mmol), substrate (0.5 mmol), iso-PrOH (5 mL), NaOH (0.025 mmol %), 82 C, 6 h for 3 and 9 h for 4, the concentration of acetophenone is 0.1 M.
Purity of compounds is checked by NMR and GC (three independent catalytic experiments), yields are based on methyl aryl ketone.
b
c
Determined by capillary GC analysis using a chiral cyclodex B (Agilent) capillary column (30 m ꢂ 0.32 mm I.D. ꢂ 0.25
mm film thickness).
d
e
Determined by comparison of the retention times of the enantiomers on the GC traces with literature values.
Referred at the reaction time indicated in footnotea; TOF ¼ (mol product/mol Ru(II) Cat.) ꢂ hꢀ1
.
Table 3
Transfer hydrogenation of alkyl phenyl ketones with iso-PrOH catalyzed by
m-(2R)-2-[benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]butyldiphenylphosphinito-bis
[dichloro(
h
6-p-isopropyltoluene)ruthenium(II)],
3
and
m-(2R)-2-[benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}amino]butyldicyclohexylphosphinito-bis[dichloro(
h
6-p-
isopropyltoluene)ruthenium(II)], 4.
e
Entry
1
Catalyst
3
Time (h)
15
Substrate
Product
Conversion (%)b
97
ee (%)c
71
Configurationd
TOF (hꢀ1
)
S
<10
O
OH
2
4
23
98
77
S
<10
OH
O
3
4
3
4
18
26
92
94
70
77
S
S
<10
<10
5
6
3
4
24
30
96
95
68
75
S
S
<10
<10
O
O
OH
OH
7
8
3
4
32
32
56
42
66
70
S
S
<10
<10
a
Catalyst (0.005 mmol), substrate (0.5 mmol), iso-PrOH (5 mL), NaOH (0.025 mmol %), 82 C, the concentration of alkyl phenyl ketone is 0.1 M.
Purity of compounds is checked by NMR and GC (three independent catalytic experiments), yields are based on methyl aryl ketone.
b
c
Determined by capillary GC analysis using a chiral cyclodex B (Agilent) capillary column (30 m ꢂ 0.32 mm I.D. ꢂ 0.25
mm film thickness).
d
e
Determined by comparison of the retention times of the enantiomers on the GC traces with literature values.
Referred at the reaction time indicated in footnotea; TOF ¼ (mol product/mol Ru(II) Cat.) ꢂ hꢀ1
.

M. Aydemir et al. / Journal of Organometallic Chemistry 696 (2011) 1541e1546
1545
Encouraged by the enantioselectivities obtained in these pre-
liminary studies, we next extended our investigations to include
asymmetric hydrogenation of substituted acetophenone derivatives.
The results in Table 2 demonstrate that a range of acetophenone
derivatives can be hydrogenated with good to high enantioselectiv-
ities. The catalytic reduction of acetophenone derivatives was all
tested with the conditions optimized foracetophenone. Complexes 3
and 4 showed very high activity for the most of the ketones. The
introduction of electron-withdrawing substituents, such as F, Cl and
Br 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 easierhydrogenation [49,50]. An electron-withdrawing
group such as fluoro group to the p-position was helpful to obtain
good conversion and good enantioselectivity (up to 80% ee, Table 2,
Entry 1 and 2), while the introduction of an electron-donating
substituents such as methoxy group to the p-position tended to
lower enantioselectivity while maintaining satisfactory activity
(Entries 9 and 10). The position and electronic property of the ring
substituents also influenced hydrogenation results. The introduction
of an electron-donating group such as methoxy group to the p-
position decelerates the reaction, but that to the o-position increases
the rate however improves the enantioselectivity (Table 2, Entries
7e10). Among all selected ketones, the best result was obtained in
the reduction of o-methoxyacetophenone giving 87% ee (Entry 8).
The results (Table 2) indicated that strong electron-withdrawing
substituents, such as fluoro, chloro, were capable of higher conver-
sion but with slightly lower enantiomeric purity. Conversely, the
mostelectron-donating substituent (eOCH3) ledto lowerconversion
with higher ee. Additionally, we further extended our study from
acetophenone to other aryl alkyl ketones and the results are also
summarized in Table 3 (entries 1e8). It was found that the activity is
highly dependent on the steric bulkiness of the alkyl group [51].
When the size of alkygroup is increased, the activity was remarkable
decreased [52,53]. However, enantioselectivity was not significantly
influenced by increasing the bulkiness of the alkyl group.
(162.0 MHz) spectra were recorded on a Bruker Avance 400 spec-
trometer, with referenced to external TMS and 85% H3PO4
respectively. Elemental analysis was carried out on a Fisons EA 1108
CHNS-O instrument. Melting points were recorded by Gallenkamp
Model apparatus with open capillaries. GC analyses were performed
on an HP 6890 N Gas Chromatograph equipped with cyclodex B
d
(Agilent) capillary column (30 m ꢂ 0.32 mm I.D. ꢂ 0.25
mm film
thickness).
4.2. Procedure for the preparation of the chiral ligands and
ruthenium complexes
4.2.1. (2R)-2-[Benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]
butyldiphenylphosphinite, (1)
Chlorodiphenylphosphine (209 mg, 0.90 mmol) was added to
a stirred solution of (2R)-2-[benzyl(2-hyroxyethyl)amino]butan-1-ol
(100 mg, 0.45 mmol) and triethylamine (92 mg, 0.90 mmol) in
toluene (40 mL) at 0 ꢁC with vigorous stirring. The mixture was
stirred at room temperature for 1 h and the white precipitate (tri-
ethylammonium chloride) was filtered off under argon and dried in
vacuo to produce a white viscous oily compound 1 (Yield: 259 mg,
97%). 31Pe{1H} NMR (CDCl3)
114.05 (s, O-P0-(C6H5)2).
d(ppm): 112.95 (s, O-P-(C6H5)2) and
4.2.2. (2R)-2-[Benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}
amino]butyldicyclohexylphosphinite, (2)
Chlorodicyclohexylphosphine (216 mg, 0.90 mmol) was added
to a stirred solution (2R)-2-[benzyl(2-hyroxyethyl)amino]butan-1-
ol (100 mg, 0.45 mmol) and triethylamine (92 mg, 0.90 mmol) in
CH2Cl2 (40 mL) at 0 ꢁC 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
2 (Yield: 273 mg, 99%). 31Pe{1H} NMR (CDCl3)
P-(C6H5)2) and 148.63 (s, O-P0-(C6H5)2).
d(ppm): 147.25 (s, O-
3. Conclusions
4.2.3.
m-(2R)-2-[Benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}
In conclusion, we have developed efficient ruthenium(II)
complexes of inexpensive and easy-to-prepare based on (2R)-2-
[benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]butyl dipheny-
lphosphinite, 1 and (2R)-2-[benzyl{(2-((dicyclohexylphosphanyl)
oxy)ethyl)} amino]butyldicyclohexylphosphinite, 2 ligands. High
conversion and moderate to good enantioselectivity were obtained
in the catalytic reaction. Furthermore, the performance of these
catalysts quite surprising, since conversions and enantioselectivities
are not significantly affected in the absence of base. Amazingly, the
conversion of the reaction was also not affected in the air or with the
addition of water.
amino]butyldiphenylphosphinito-bis[dichloro(h
6-p-isopropyl-
toluene)ruthenium(II)], (3)
[Ru(h m-Cl)Cl]2 (270 mg, 0.44 mmol) and (2R)-2-
6-p-cymene)(
[benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]butyldiphenyl-
phosphinite, 1 (259 mg, 0.44 mmol) were dissolved in 25 mL of
toluene and stirred for 6 h at room temperature. The volume was
concentrated to ca. 1e2 mL under reduced pressure and addition of
petroleum ether (15 mL) gave 3 a clear red solid. The product was
collected by filtration and dried in vacuum. (Yield: 456 mg, 86%); mp:
25
160e162 ꢁC [
a]
D
¼ ꢀ25.36 (c 0.08, EtOH). [C57H67NO2P2Ru2Cl4]
(mw: 1204.06 g/mol); Calcd. C, 56.86; H 5.61; N 1.16; Anal. found: C,
56.56; H 5.58; N 1.13%. Selected IR,
(cmꢀ1): 3054, 2973 (aromatic-
H), 2929, 2895 (aliphatic-H), 1100 (CeO), 1031 (PeO). 1H NMR
(CDCl3) (ppm): 0.97 (m, 3H, eCH2CH3 and 12H, (CH3)2CHPh of p-
y
4. Experimental
d
4.1. Materials and methods
cymene), 1.13 (m, 2H, eCH2CH3), 1.72 (s, 6H, CH3ePh of p-cymene),
2.64e2.79 (m, 2H, eCHCH3e of p-cymene; 1H eCHNe and 2H,
eCHCH2OP), 3.47e3.75 (m, 2H, CH2CH2OP; 2H, CH2CH2OP and 2H,
CH2ePh), 5.16 (br, 8H, aromatic CH protons of p-cymene), 7.24e7.86
Unless otherwise stated, all reactions were carried out under an
atmosphere of argon using conventional Schlenk glassware, solvents
were dried using established procedures and distilled under argon
immediately prior to use. Analytical grade and deuterated solvents
were purchased from Merck. The starting materials PPh2Cl, PCy2Cl
and Et3N are purchased from Fluka and were used as received. [Ru
(m, 5H, CH2ePh and 20H, eOPePh). 13Ce{1H} NMR (CDCl3)
d(ppm):
11.78 (eCH2CH3),15.29 (eCH2CH3),17.53 (CH3Ph of p-cymene), 21.80
((CH3)2CHPh of p-cymene), 30.10 (eCHe of p-cymene), 51.20
(eCHCH2OP), 54.92 (CH2ePh) 62.20 (eCHNe), 65.85 (CH2CH2OP)
66.35 (CH2CH2OP), 87.55, 90.37, 90.54,111.48 (aromatic carbons of p-
cymene), 127.83, 128.14, 128.57, 140.61 (aromatic carbons of
eCH2ePh), 127.87 (d, 3J ¼ 10:12 Hz, m-carbons of phenyls), 132.31
(d, 2J ¼ 11:06 Hz, o-carbons of phenyls), 133.12 (s, p-carbons of
phenyls),136.82 (d, 1J ¼ 51:0 Hz, i-carbons of phenyls): assignment
(h
6-p-cymene)(
(2R)-2-[benzyl(2-hyroxyethyl)amino]butan-1-ol
m
-Cl)Cl]2 [54], (2R)-2-(benzylamino)butan-1-ol and
[55,56] 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 31Pe{1H} NMR

1546
M. Aydemir et al. / Journal of Organometallic Chemistry 696 (2011) 1541e1546
was based on the 1He13C HETCOR and 1He1H COSY spectra. 31Pe
[17] H.B. Kagan, M. Sasaki, Transition Metals for Organic Synthesis. Wiley-VCH,
Weinheim, 1998.
{1H} NMR (CDCl3)
d(ppm): 110.87 (s, O-P-(C6H5)2) and 113.48 (s, O-
[18] P.W. Galka, H.-B. Kraatz, J. Organomet. Chem. 674 (2003) 24e31.
[19] G. Venkatachalam, R. Ramesh, Inorg. Chem. Commun. 8 (2005) 1009e1013.
[20] C. Claver, O. Pamies, M. Dieguez, in: A. Börner (Ed.), Chiral Diphosphinites,
Diphosphonites, Diphosphites and Mixed PeO Ligands in Phosphorus Ligands
in Asymmetric Catalysis, Wiley, Weinheim, 2008, pp. 506e528.
[21] M. Aydemir, A. Baysal, N. Meric, B. Gümgüm, J. Organomet. Chem. 694 (2009)
2488e2492.
P0-(C6H5)2).
4.2.4.
m-(2R)-2-[Benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}
amino]butyldicyclohexylphos phinito-bis[dichloro(h
6-p-isopropyl-
toluene)ruthenium(II)], 4
[Ru(h m-Cl)Cl]2 (270 mg, 0.44 mmol) and (2R)-2-
6-p-cymene)(
ꢀ
[22] M. Aydemir, A. Baysal, N. Meric, C. Kayan, M. Togrul, B. Gümgüm, Appl.
Organomet. Chem. 24 (2010) 215e221.
[23] M. Aydemir, N. Meric, F. Durap, A. Baysal, M. Togrul, J. Organomet. Chem. 695
[benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}amino]butyldicycl-
ohexylphosphinite, 2 (273 mg, 0.44 mmol) were dissolved in 25 mL of
toluene and stirred for 12 h at room temperature. The volume was
concentrated to ca. 1e2 mL under reduced pressure and addition of
petroleum ether (15 mL) gave 3 a clear red solid. The product was
ꢀ
(2010) 1392e1398.
ꢀ
[24] M. Aydemir, F. Durap, A. Baysal, N. Meric, A. Buldag, B. Gümgüm, S. Özkar,
L.T. Yildirim, J. Mol. Catal. A: Chem. 326 (2010) 75e81.
ꢀ
[25] M. Aydemir, N. Meric, A. Baysal, B. Gümgüm, M. Togrul, Y. Turgut, Tetrahe-
dron: Asymmetry 21 (2010) 703e710.
[26] E. Hauptman, R. Shapiro, W. Marshall, Organometallics 17 (1998) 4976e4982.
[27] K. Ruhlan, P. Gigler, E. Herdweck, J. Organomet. Chem. 693 (2008) 874e893.
[28] M. Hariharasarma, C.H. Lake, C.L. Watkins, M.G. Gray, J. Organomet. Chem. 580
(1999) 328e338.
[29] A. Baysal, M. Aydemir, F. Durap, B. Gümgüm, S. Özkar, L.T. Yildirim, Poly-
hedron 26 (2007) 3373e3378.
[30] R. Ceron-Camacho, V. Gomez-Benitez, R. Le, J. Mol. Catal. A: Chem. 247 (2006)
124e129.
[31] E.A. Broger, W. Burkart, M. Hennig, M. Scalone, R. Schmid, Tetrahedron:
Asymmetry 9 (1998) 4043e4054.
[32] Z. Fei, R. Scopelliti, P.J. Dyson, Inorg. Chem. 42 (2003) 2125e2130.
[33] Z. Fei, R. Scopelliti, P.J. Dyson, Eur. J. Inorg. Chem. (2004) 530e537.
[34] M.A. Bennet, G.B. Robertson, A.K. Smith, J. Organomet. Chem. 43 (1972) C41.
[35] A.M. Maj, K.M. Michal, I. Suisse, F. Agbossou, A. Mortreux, Tetrahedron:
Asymmetry 10 (1999) 831e835.
[36] M.S. Balakrishna, P.P. George, S.M. Mobin, Polyhedron 24 (2005) 475e480.
[37] I.D. Kostas, B.R. Steele, A. Trezis, S.V. Amosova, Tetrahedron 59 (2003)
3467e3473.
[38] I. Moldes, E. de la. Encarnacion, J. Ros, A. Alvarez-Larena, J.F. Piniella,
J. Organomet. Chem. 566 (1998) 165e174.
[39] P. Le Gendre, M. Offenbecher, C. Bruneau, P.H. Dixneuf, Tetrahedron: Asym-
metry 9 (1998) 2279e2284.
collected by filtration and dried in vacuum. (Yield: 437 mg, 81%); mp:
25
137e139 ꢁC [
a
]
¼ ꢀ22.55 (c 0.08, EtOH). [C57H91NO2P2Ru2Cl4] (mw:
D
1228.25 g/mol); Calcd. C, 55.74; H 7.47; N 1.14; Anal. found: C, 55.65;
H 7.39; N 1.11%. Selected IR,
(cmꢀ1): 3045, 2975 (aromatic-H), 2925,
2906 (aliphatic-H), 1116 (CeO), 1031 (PeO). 1H NMR (CDCl3)
(ppm):
y
d
0.90e2.11 (m, 3H, eCH2CH3; m, 2H, eCH2CH3; 12H, (CH3)2CHPh of p-
cymene; 6H, CH3ePh of p-cymene and 44H, hydrogens of cyclohexyls
{(C6H11)4}), 2.43e2.88 (m, 2H, eCHCH3e of p-cymene; 1H eCHNe
and 2H, eCHCH2OP), 3.77e4.24 (m, 2H, CH2ePh; 2H, CH2CH2OP and
2H, CH2CH2OP), 5.35 (br, 4H, aromatic CH protons of p-cymene), 5.52
(br, 4H, aromatic CH protons of p-cymene), 7.28e7.36 (m, 5H,
CH2ePh). 13Ce{1H} NMR (CDCl3)
d(ppm): 11.97 (eCH2CH3), 17.94
(CH3Ph of p-cymene), 18.80 (eCH2CH3), 22.39 ((CH3)2CHPh of p-
cymene), 26.35, 27.20, 27.78, 43.21 (carbons of cyclohexyls {C6H11)4}),
30.41 (eCHe of p-cymene), 51.60 (eCHCH2OP), 56.25 (CH2ePh)
63.69 (eCHNe), 67.07 (CH2CH2OP), 69.10 (CH2CH2OP), 87.43, 89.05,
96.18, 108.53 (aromatic carbons of p-cymene), 126.91, 128.21, 128.64,
140.94 (aromatic carbons of eCH2ePh): assignment was based on
the 1He13C HETCOR and 1He1H COSY spectra. 31Pe{1H} NMR (CDCl3)
[40] Q. Zhang, G. Hua, P. Bhattacharrya, A.M.Z. Slawin, J.D. Woollins, J. Chem. Soc.
Dalton Trans. (2003) 3250e3257.
[41] M. Alvarez, N. Lugan, R. Mathieu, J. Chem. Soc. Dalton Trans. (1994) 2755e2760.
[42] H. Yang, M. Alvarez, N. Lugan, R. Mathieu, J. Chem. Soc. Chem. Commun.
(1995) 1721e1722.
d
(ppm): 144.25 (s, O-P-(C6H5)2) and 144.78 (s, O-P0-(C6H5)2).
[43] E.L. Muetterties, J.R. Bleeke, E.J. Wucherer, T.A. Albright, Chem. Rev. 82 (1982)
499e525.
Acknowledgments
[44] J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya, R. Noyori, J. Chem. Soc.
Chem. Commun. (1996) 233e234.
[45] P. Palegatti, M. Carcelli, F. Calbiani, C. Cassi, L. Elviri, C. Pelizzi, U. Rizzotti,
D. Rogolino, Organometallics 24 (2005) 5836e5844.
Partial support from Dicle University (Project number: DÜBAP-
07-01-22) is gratefully acknowledged.
[46] R. Tribo, S. Munoz, J. Pons, R. Yanez, A. Alvarez-Larena, J.F. Piniella, J. Ros,
J. Organomet. Chem. 690 (2005) 4072e4079.
Appendix. Supplementary material
[47] J. Hannedouche, G.J. Clarkson, M. Wills, J. Am. Chem. Soc. 126 (2004) 986e987.
[48] A. Bacchi, M. Balordi, R. Cammi, L. Elviri, C. Pelizzi, F. Picchioni, V. Verdolino,
K. Goubitz, R. Peschar, P. Pelagatti, Eur. J. Inorg. Chem. (2008) 4462e4473.
[49] J.W. Faller, A.R. Lavoie, Organometallics 20 (2001) 5245e5247.
Supplementary data related to this article can be found online at
doi:10.1016/j.jorganchem.2010.12.027.
_
[50] I Özdemir, S. Yas¸ ar, Trans. Met. Chem. 30 (2005) 831e835.
[51] J.-X. Gao, X.-D. Yi, P.-P. Xu, C.-L. Tang, H.-L. Wan, T. Ikariya, J. Organomet.
Chem. 592 (1999) 290e295.
References
[52] J.-X. Gao, H. Zhang, X.-D. Yi, P.-P. Xu, C.-L. Tang, H.-L. Wan, K.-R. Tsai, T. Ikariya,
Chirality 12 (2000) 383e388.
[53] J.-S. Chen, Y.-Y. Li, Z.-R. Dong, B.-Z. Li, J.-X. Gao, Tetrahedron Lett. 45 (2004)
8415e8418.
[54] M.A. Bennet, A.K. Smith, J. Chem. Soc. Dalton Trans. (1974) 233e241.
[55] M. Togrul, Y. Turgut, H. Hosgoren, Chirality 16 (2004) 351e355.
[56] Preparation of (R)-(e)-N-benzyl-4-hydroxymethyl-3-azahexzane-1-ol: A solu-
tion of 0.47 g (2.6 mmol) of (R)-(ꢀ)-N-benzyl-2-amino-1-butanol in 10 mL of
methanol was cooled to ꢀ20 ꢁC in a 25 mL of flask; 0.12 g (2.6 mmol) of ethylene
oxide in 5 mL of methanol was added dropwise to the solution at the same
temperature. The mixture was stirred for 12 h at ꢀ20 ꢁC and then 24 h at 4 ꢁC.
The mixture was kept for one day at room temperature. Methanol was evapo-
[1] J.S.M. Samec, J.-E. Backwall, P.G. Andersson, P. Brandt, Chem. Soc. Rev. 35
(2006) 237e248.
[2] S. Gladiali, E. Alberico, in: M. Beller, C. Bolm (Eds.), Transition Metals for
Organic Synthesis, vol. 2, Wiley-WCH, Weinheim, 2004, pp. 145e166.
[3] S.E. Clapham, A. Hadzovic, R.H. Morris, Coord. Chem. Rev. 248 (2004) 2201e2237.
[4] X. Li, X. Wu, W. Chen, F.E. Hancock, F. King, J. Xiao, Org. Lett. 19 (6) (2004)
3321e3324.
[5] K. Everaere, A. Mortreux, J.-F. Carpentier, Adv. Synth. Catal. 345 (2003) 67e77.
[6] Q.H. Fan, Y.M. Li, A.S.C. Chan, Chem. Rev. 102 (2002) 3385e3446.
[7] H.U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer, Adv. Synth.
Catal. 345 (2003) 103e151.
rated in vacuo. The product was purified by distillation under reduced pressure
[8] R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed. Engl. 40 (2001) 40e73.
[9] H. Takaha, T. Ohta, R. Noyori, Catalytic asymmetric synthesis. in: I. Ojima (Ed.),
Asymmetric Hydrogenation. VCH, Berlin, 1993, pp. 20e31.
[10] R. Noyori, Asymmetric Catalysis in Organic Synthesis. John Wiley, New York,
1994, pp. 1e82.
[11] M.J. Palmer, M. Wills, Tetrahedron: Asymmetry 10 (1999) 2045e2061.
[12] N. Noyori, S. Hashiguchi, Acc. Chem. Res. 30 (1997) 97e102.
[13] R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H. Kumobayashi,
S. Akutagawa, J. Am. Chem. Soc. 109 (1987) 5856e5858.
[14] T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 117
(1995) 2675e2676.
[15] H. Shimizu, I. Nagasaki, T. Satio, Tetrahedron 61 (2005) 5405e5432.
[16] R.H. Crabtree, The Organometallic Chemistry of the Transition Metals. Wiley-
Interscience, New York, 2001.
25
at 155 ꢁC/0.1 mmHg to give 0.56 g (94%). [
a
]
¼ ꢀ14.89 (c 0.08, EtOH).
D
[C13H21NO2] (mw: 223.3 g/mol); Calcd. C, 66.90; H 9.07; N 6.00; Anal. found: C,
66.76; H 9.04; N 6.08%. Selected IR,
(cmꢀ1): 3368, 3085, 3061, 3026, 2957, 2876,
(ppm): 0.92 (3H,
y
1602, 1494, 1453, 1372, 1115, 1054, 729, 698. 1H NMR (CDCl3)
d
t, 3J 8.20, CH2CH3), 1.24 (1H, m, CH2CH3, (a)), 1.65 (1H, m, CH2CH3, (b)), 2.62 (1H,
m, NCH2OH, (a)), 2.71 (1H, m, CHNe), 2.80 (1H, m, NCH2OH, (b)), 3.40e3.56 (m,
2H, CH2CH2OH and 2H, CH2CH2OH), 3.62 (d, 1H, 3J 14.00 Hz, CH2ePh (a)), 3.69
(br, 2H, CH2CH2OH and NCH2OH), 3.83 (d, 1H, 3J 13.60 Hz, CH2ePh (b)),
7.22e7.36 (m, 5H, aromatic protons of phenyls). 13Ce{1H} NMR (CDCl3)
d(ppm):
11.87 (CH2CH3), 19.20 (CH2CH3), 51.37 (NCH2OH), 54.87 (CH2ePh), 60.12
(CH2CH2OH), 61.46 (CH2CH2OH), 62.92 (CHN), 127.09, 128.44, 128.82, 140.07
(aromatic carbons of phenyls): assignment was based on the 1He13C HETCOR
and 1He1H COSY spectra.