Screening of C2-symmetric chiral phosphinites as ligands for ruthenium(II)-catalyzed asymmetric transfer hydrogenation of prochiral aromatic ketones

Article abstract of DOI:10.1016/j.jorganchem.2013.01.012

Metal-catalyzed transfer hydrogenation processes provide a widely-used alternative to direct hydrogenation processes of ketones. As part of an ongoing program, we report enantioselective C₂-symmetric bis(phosphinite)- ruthenium(II) catalytic systems for the transfer hydrogenation of prochiral aromatic ketones. The new catalytic systems can readily be formed under in situ conditions from C₂-symmetric chiral bis(phosphinite) ligands and [Ru(η⁶-p-cymene)(μ-Cl)Cl]₂ in transfer hydrogenation reaction media. These chiral ruthenium catalytic systems serve as catalyst precursors for the asymmetric transfer hydrogenation of acetophenone derivatives in iso-PrOH and giving the corresponding optical active secondary alcohols up to 94% ee.

Full text of DOI:10.1016/j.jorganchem.2013.01.012

Journal of Organometallic Chemistry 729 (2013) 46e52
Contents lists available at SciVerse ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Screening of C2-symmetric chiral phosphinites as ligands for ruthenium(II)-
catalyzed asymmetric transfer hydrogenation of prochiral aromatic ketones
*
Duygu Elma, Feyyaz Durap, Murat Aydemir, Akin Baysal , Nermin Meric, Bünyamin Ak, Yılmaz Turgut,
Bahattin Gümgüm
Dicle University, Science Faculty, 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:
Metal-catalyzed transfer hydrogenation processes provide a widely-used alternative to direct hydroge-
nation processes of ketones. As part of an ongoing program, we report enantioselective C2-symmetric
bis(phosphinite)eruthenium(II) catalytic systems for the transfer hydrogenation of prochiral aromatic
ketones. The new catalytic systems can readily be formed under in situ conditions from C2-symmetric
Received 30 October 2012
Received in revised form
14 January 2013
Accepted 16 January 2013
chiral bis(phosphinite) ligands and [Ru(h m-Cl)Cl]2 in transfer hydrogenation reaction media.
6-p-cymene)(
These chiral ruthenium catalytic systems serve as catalyst precursors for the asymmetric transfer hy-
drogenation of acetophenone derivatives in iso-PrOH and giving the corresponding optical active sec-
ondary alcohols up to 94% ee.
Keywords:
Catalysis
Asymmetric transfer hydrogenation
Chiral phosphinite ligand
Ruthenium
Ó 2013 Elsevier B.V. All rights reserved.
C2-symmetry
1. Introduction
been considered as catalysts [2] in which ruthenium has been our
choice due to its superior performances and cost-effective avail-
Asymmetric catalysis is an important methodology for produc-
ing pure enantiomeric materials. Among the asymmetric catalytic
reactions, asymmetric hydrogenation is the most powerful one, as
it utilizes an inexpensive reagent (hydrogen) often with a relatively
inexpensive unsaturated substrate to yield a high value of a single
enantiomeric product [1]. In the last few decades, there has been
a widely increasing interest for suitable catalyst system for transfer
hydrogenation of ketones. Noyori and co-workers devoted much
effort for the asymmetric catalytic H2-hydrogenation [2e5] and
asymmetric transfer hydrogenation (iso-PrOH/KOH or HCOOH/Et3N
as hydride source) [6,7] of simple ketones [8e11]. The asymmetric
reduction of prochiral ketones is one of the most powerful pro-
cedures for the preparation of enantiomerically pure secondary
alcohols, which are considerably important because they exist in
a variety of pharmacologically active compounds and have proved
to be chiral resolution agents and chiral auxiliaries in asymmetric
synthesis [12,13]. Asymmetric synthesis using chiral transition
metal complexes as catalyst precursors offers an ideal method for
reducing ketones to chiral secondary alcohols [14,15]. Various types
of transition metals such as ruthenium, iridium, and rhodium have
ability as compared to other asymmetric hydrogenation metals
such as rhodium [16,17].
The development of suitable chiral ligands for a particular
application remains a tough task. There have been a great number
of chiral ligands prepared for asymmetric catalysis [12,18]. In par-
ticular, amino acids offer a specially convenient starting point for
the synthesis of chiral ligands. They are commercially available in
an enantiopure form. Also amino alcohols continue to be of
importance in modern synthetic chemistry because of wide range
of synthetic applications [19]. Phosphinites are among the most
important phosphorus based ligands with a wide range of steric
and electronic properties for example, the metalephosphorus
bonds are often strong in phosphinites due to the presence of the
electron withdrawing PeOR group [20e22]. Practically, it is a sub-
stantial interest to develop effective chiral phosphinite ligands for
asymmetric catalysis [23,24]. For these reasons, it is expected that
phosphinites based on C2-symmetric chiral amino alcohols may
result in suitable chiral ligands. C2-symmetric ligands [25,26] (first
example: diop) are more likely to induce high enantioselectivity
since they reduce the number of possible isomeric catalyste
substrate complexes [25]. Therefore, the design of effective C2-
symmetric chiral phosphorus ligands especially those having Oe
PR2 moiety, is still an important task for chemist. Hence, we high-
light our efforts to develop C2-symmetric chiral phosphinite ligands
* Corresponding author. Tel.: þ90 412 248 8550; fax: þ90 412 248 8300.
E-mail address: akinb@dicle.edu.tr (A. Baysal).
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.01.012

D. Elma et al. / Journal of Organometallic Chemistry 729 (2013) 46e52
47
with
L
-leucinol,
L
-isoleucinol,
L
-phenylglycinol and
L
-phenylalaninol
5e12 were synthesized by a hydrogen abstraction from the chiral
bis(aminoalcohol) 1e4 by a base (Et3N) and the subsequent reac-
and to apply them in ruthenium catalyzed asymmetric transfer
hydrogenation of prochiral aromatic ketones with iso-PrOH under
varying conditions.
tion with
2
equiv of chlorodiphenylphosphine or chlor-
odiisopropylphosphine, in freshly distilled anhydrous toluene or
CH2Cl2, respectively under inert atmosphere (Ar). The formed
ammonium salt was separated by filtration and the ligands were
obtained after removing the solvent under reduced pressure in
high yields (from 93% to 99%). The progress of this reaction was
followed by 31Pe{1H} NMR spectroscopy in which the signals of the
2. Results and discussion
2.1. Synthesis of chiral C2-symmetric ligands and their
ruthenium(II) catalyst systems
starting materials Ph2PCl at
d
¼ 81.0 ppm and iso-Pr2PCl at
d
¼ 133.8 ppm disappeared and new singlets appeared downfield
To design new chiral ligands with novel backbones, we became
interested in C2-symmetric chiral phosphinite ligands from amino
acid derivated amino alcohols. The reason why we especially
interested in C2-symmetric phosphinite ligands, is that C2-sym-
metric ligand with two equivalent phosphorus atoms can reduce
number of possible isomeric metal complexes, as well as the
number of different substrateecatalyst arrangements and reaction
pathways, when compared to a nonsymmetrical ligand [27]. This
consequence of C2-symmetry can have a positive effect on enan-
tioselectivity because the competing less-selective pathways are
possibly eliminated [28].
due to the equivalent phosphorus nuclei [34,35] of C2-symmetric
bis(phosphinite) ligands. The 31Pe{1H} NMR spectra of compounds
5e12 show single resonances due to diphenylphosphinite or dii-
sopropylphosphinite moiety at 114.00, 152.93, 113.81, 152.94,
114.81, 153.74, 114.20, 152.90 ppm, respectively, in line with the
values previously observed for similar compounds [34,36e38].
Typical spectra of these ligands are given in supplementary
material (Figs. S1 and S2). The phosphinites are unstable in the
solid state and decompose rapidly on exposure to air or moisture.
So, the synthesis and isolation of the products must be carried out
with rigorous exclusion of air, in order to avoid oxidation of the
phosphinite groups. Solution of the ligands in CDCl3, prepared
under anaerobic condition, is unstable and decomposes gradually
to give oxide and the hydrolysis product diphenylphosphinous acid,
Ph2P(O)H [39]. Because compounds 5e12 are not stable enough in
common solvents, the corresponding ruthenium(II) complexes
were prepared in situ with chiral C2-symmetric bis(phosphinite)
First, we began this study by preparing
-phenylglycinol and -phenylalaninol in one step from the corre-
sponding amino acids namely, -leucine, -isoleucine, -phenyl-
glycine and -phenylalanine, respectively, which were reduced
under standard conditions using NaBH4eI2 in dry THF [29]. Then
chiral C2-symmetric amino alcohols were prepared from the
leucinol, -isoleucinol, -phenylglycinol and -,phenylalaninol ac-
cording to the literature procedure [30e33].
L-leucinol, L-isoleucinol,
L
L
L
L
L
L
L-
L
L
L
ligands and [Ru(h m-Cl)Cl]2 (molar ratio 2:1) and they
6-p-cymene)(
were used as catalysts in asymmetric transfer hydrogenation
reactions.
The synthetic procedure for the preparation of chiral C2-sym-
metric bis(phosphinite) ligands is depicted in Scheme 1. The ligands
Scheme 1. Synthesis of chiral C2-symmetric amino alcohols and bis(phosphinite) ligands.

48
D. Elma et al. / Journal of Organometallic Chemistry 729 (2013) 46e52
catalytic systems were generated in situ from [Ru(h m-
6-p-cymene)(
Cl)Cl]2 by adding chiral bis(phosphinite) ligands 5e12. In all the
reactions, these catalyst systems catalyzed the reduction of aceto-
phenone to the 1-phenylethanol via hydrogen transfer from iso-
PrOH (Scheme 2) and the results are summarized in Table 1.
Initially, to an iso-PrOH solution of chiral bis(phosphinite) ligand
and [Ru(h m-Cl)Cl]2, an appropriate amount of aceto-
6-p-cymene)(
phenone and KOH/iso-PrOH solutions were added, respectively, at
room temperature (acetophenone/Ru/KOH; 100:1:5 molar ratios).
The solution was stirred for 24 h, and then examined with capillary
GC analysis. At room temperature, transfer hydrogenation of ace-
tophenone occurred very slowly and formation of (S)-1-
phenylethanol was observed with low conversion (up to 42%) and
moderatetohighenantioselectivity (upto82%ee)in all thereactions
(Table 1, entries 1e8). Furthermore, as can be inferred from Table 1
(entries 9e16), the presence of base is absolutely necessary to
observe appreciable conversions because KOH presumably facilitate
catalysis by promoting formation of intermediates (possibly [Ru]eH
from the [Ru]eClprecatalyst) [46]. The choice of base, suchas KOH or
NaOH, had little influence on the conversion and enantioselectivity
(entries 17e24). In the next step of experiments acetophenone/Ru/
KOH (100:1:5 molar ratios) catalyst system was used at 50 ꢀC and
82 ꢀC. (S)-1-Phenylethanol was obtained up to 88% ee at 50 ꢀC in 24 h
(entry 3) and in upto84% ee at 82 ꢀC in 30 min (entry 19) with high to
quantitative conversions (97e99%, entries 17e24).
Scheme 2. Hydrogen transfer from iso-PrOH to acetophenone by in situ prepared
Ru(II) catalyst 5e12.
2.2. Asymmetric transfer hydrogenation of prochiral ketones
The outstanding catalytic performance of C2-symmetric phos-
phinite based transition metal complexes [28,40e42] stimulated us
to develop new ruthenium(II) complexes. In earlier studies, we
reported the catalytic activity of various ruthenium(II) complexes
with C2-symmetric bis(phosphinite) ligands for asymmetric transfer
hydrogenation acetophenone derivatives. The poor to good ee %
despite the high catalytic performance and the higher structural
permutability of phosphinite based transition metal catalysts
prompted us to develop new Ru(II) catalytic systems [25,35,43]. In
the present report, we described a series of ligand containing dif-
ferent synthetic routes and the skeleton contrast to previous studies.
In addition, the substituents bound to the P-atom were changed
(isopropyl insteadofphenyl) andtheresults were compared indetail.
So, we examined the catalytic activity of in situ prepared chiral
C2-symmetric phosphinite Ru(II) catalyst system in the transfer
hydrogenation of aryl ketones with iso-PrOH [10,44,45] to the cor-
responding alcohols (acetone is a byproduct), wherein iso-PrOH is
the hydrogen source. In a preliminary study, in situ prepared Ru(II)
catalyst systems 5e12 were used as precatalaysts, iso-PrOH/KOH as
the reducing system, and acetophenone as the model substrate. The
Encouraged by the enantioselectivities obtained in these [Ru(h6
p-cymene)( -Cl)Cl]2eL (L: 5e12) catalytic systems, we next
-
m
extended our investigations to include asymmetric transfer hy-
drogenation of substituted acetophenone derivatives. In a typical
transfer hydrogenation setup, the corresponding substrate
(0.5 mmol), base (KOH, 0.025 mmol), [Ru(h m-Cl)Cl]2
6-p-cymene)(
(0.005 mmol) and ligand 5e12 (4 equiv of Ru) were mixed in iso-
PrOH (5 mL). Under the optimized conditions, reaction of prochiral
Table 1
Transfer hydrogenation of acetophenone with iso-PrOH catalyzed by [Ru(
h
6-p-cymene)(
Conversion (%)e
m-Cl)Cl]2eL (L: 5e12).
h
Entry
L (ligand)
S/C/KOH
Time
% eef
Configurationg
TOF (hꢁ1
)
1
2
3
4
5
6
7
8
5a
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1
100:1
100:1
100:1
100:1
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
45 min
10 min
30 min
10 min
1 h
35 (86)
31 (93)
33 (94)
31 (67)
42 (91)
25 (61)
37 (78)
22 (64)
Trace
Trace
Trace
Trace
Trace
80 (78)
69 (71)
82 (88)
54 (56)
60 (63)
55 (60)
70 (68)
65 (67)
e
S
S
S
S
S
S
S
S
e
e
e
e
e
e
e
e
S
S
S
S
S
e
6a
e
7a
e
8a
e
9a
e
10a
11a
12a
5b
e
e
e
9
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
6b
e
e
7b
e
e
8b
e
e
9b
e
e
10b
11b
12b
5c
100:1
100:1
100:1
Trace
Trace
Trace
e
e
e
e
e
e
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
100:1:5
99 (97)d
97 (98)d
99 (98)d
96 (97)d
97 (95)d
99 (98)d
98 (99)d
97 (95)d
78 (76)d
42 (45)d
84 (82)d
54 (55)d
63 (62)d
60 (61)d
71 (71)d
67 (68)d
132
582
188
576
97
33
98
32
6c
7c
8c
9c
10c
11c
12c
3 h
1 h
3 h
S
S
S
a
Reaction conditions: at room temperature (at 50 ꢀC); acetophenone/Ru/KOH, 100:1:5.
Reaction conditions: refluxing in iso-PrOH; acetophenone/Ru, 100:1, in the absence of base.
Reaction conditions: refluxing in iso-PrOH; acetophenone/Ru/KOH, 100:1:5.
Reaction conditions: refluxing in iso-PrOH; acetophenone/Ru/NaOH, 100:1:5 (in parenthesis).
Determined by GC (three independent catalytic experiments).
b
c
d
e
f
Determined by capillary GC analysis using a chiral cyclodex B (Agilent)capillary column.
g
h
Determined by comparison of the retention times of the enantiomers on the GC traces with the literature values, (S) configuration was obtained in all experiments.
Referred the reaction time indicated in column; TOF ¼ (mol product/mol Ru(II) cat.) ꢂ hꢁ1
.

D. Elma et al. / Journal of Organometallic Chemistry 729 (2013) 46e52
49
aromatic ketone derived from acetophenone, such as p-fluo-
roacetophenone, p-chloroacetophenone, p-methoxyaceto-phe-
none, o-methoxyacetophenone with iso-PrOH gave high yields
(89%e99%) in short reaction times (10 min to 3 h) and with high
enantiomeric excesses (up to 94% ee) without any induction time
periods in the presence of 5e12 as seen in Table 2. The examination
of the results indicates clearly that the highest enantioselectivities
(92e94%) were reached with 5 and 7. It should also be noted that
with the 6, 8, 9, 10, 11 and 12 rather lower level of induction (53e84
ee %) was observed. Compared with our previous bis(phosphinite)
ligands, compounds 5 and 7 provide higher enantioselectivity or
TOF values in ruthenium(II)-catalyzed asymmetric transfer hydro-
genation of acetophenone derivatives [25,35,43,47,48]. It is note-
(L: 5e12), display the differences in reactivity. The results demon-
strate that the enantioselectivity of the reaction is sensitive to the
structure of the ligands. Although, increasing the bulkiness of the
substituent on the chiral carbon, generally, induces an increase in
the enantioselectivity [49], our experimental results show that the
phenyl or benzyl group on the chiral center did not benefit the
enantioselectivity process. The aliphatic groups such as
or -isoleucinol near the chiral center on C2-symmetric backbone
increased enantioselectivity, while substitution of phenyl groups
such as -phenylalaninol or -phenylglycinol caused a decrease in
L-leucinol
L
L
L
enantioselectivity as seen in Table 1 or Table 2. Furthermore, the
reaction rate could be enhanced by changing the nature of the
substituents on the phosphorus atom. Thus, replacing an isopropyl
moiety by a phenyl group induced an increase in the conversion
worthy that the catalytic systems, [Ru(h m-Cl)Cl]2eL
6-p-cymene)(
Table 2
Asymmetric transfer hydrogenation results for substituted acetophenones with the catalyst systems prepared from [Ru(
h
6-p-cymene)(
m
-Cl)Cl]2 and C2-symmetric
bis(phosphinite) ligands (5e12).a
e
Entry
1
L (ligand)
5
Substrate
Product
Time
3/4 h
Conv. (%)b
98
ee (%)c
79
Configurationd
TOF (hꢁ1
)
S
130
2
3
4
5
6
7
8
6
7
8
1/6 h
1/2 h
1/6 h
1/2 h
2 h
99
98
99
97
98
98
98
71
83
73
59
58
72
65
S
S
S
S
S
S
S
594
196
594
196
50
9
10
11
12
1/2 h
2 h
196
50
9
5
3/4 h
95
83
S
127
10
11
12
13
14
15
16
6
7
8
1/6 h
1/2 h
1/6 h
1 h
3 h
1 h
96
98
97
92
90
98
99
75
86
75
58
53
73
69
S
S
S
S
S
S
S
576
196
582
92
30
98
9
10
11
12
3 h
33
17
5
3/4 h
92
94
S
123
18
19
20
21
22
23
24
6
7
8
1/6 h
1/2 h
1/6 h
3 h
7 h
3 h
92
94
91
95
94
92
90
80
92
84
66
61
74
70
S
S
S
S
S
S
S
552
188
546
32
13
31
9
10
11
12
7 h
13
25
5
3/4 h
91
91
S
121
26
27
28
29
30
31
32
6
7
8
1/6 h
1/2 h
1/6 h
2 h
4 h
2 h
90
91
89
97
96
95
94
70
90
83
64
55
71
65
S
S
S
S
S
S
S
540
182
534
49
24
48
9
10
11
12
5 h
19
a
Catalyst (0.005 mmol), substrate (0.5 mmol), iso-PrOH (5 mL), KOH (0.025 mmol %), 82 ꢀC, 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 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 the reaction time indicated in column; TOF ¼ ꢂ (mol product/mol Ru(II) cat.) ꢂ hꢁ1
.

50
D. Elma et al. / Journal of Organometallic Chemistry 729 (2013) 46e52
(but in longer time) and an increase in enantioselectivity was
observed as well (Table 1 or Table 2). The introduction of electron
withdrawing substituents, such as F and Cl to the p-position of the
aryl ring of the ketone decreased the electron density of the C]O
bond so that the activity was improved giving rise to easier hy-
drogenation [50,51]. An electron-withdrawing group such as fluoro
group to the p-position was helpful to obtain excellent conversion
(up to 99%) and moderate to good enantioselectivity (up to 83% ee),
whereas the introduction of an electron-donating substituents such
as methoxy group to the p-position tended to lower activity while
maintaining satisfactory enantioselectivity. The position and elec-
tronic property of the ring substituents also influenced hydroge-
nation results. The introduction of an electron-donating group such
as methoxy group to the p-position decelerates the reaction (for
example TOF 121 hꢁ1, Table 2 entry 25), but that to the o-position
increases the rate (for example TOF 123 hꢁ1, Table 2 entry 17) and
improves the enantioselectivity (94% ee) as seen in Table 2 [25].
temperature. A solution of ketone (0.5 mmol) in iso-PrOH (5 mL)
was then added to catalyst mixture and the solution was heated to
the desired temperature (generally, 25 ꢀC, 50 ꢀC or 82 ꢀC). The re-
action was initiated with the addition of a solution of KOH (2.5 mL,
0.1 M iso-PrOH). As soon as the reaction completed, an aliquot of
the catalytic solution (1 mL) was removed via syringe and evapo-
rated under reduced pressure. The resultant oil was subjected to
flash chromatography (silica gel-60, Et2O) and subsequent evapo-
ration under reduced pressure to yield clear liquids in each case.
After this time a sample of the reaction mixture was taken off,
diluted with acetone and analyzed immediately by GC, conversions
obtained are related to the residual unreacted ketone.
3.4. General procedure for the preparation of the chiral C2-
symmetric amino alcohols
Corresponding chiral amino alcohol (100 mmol), 1,2-
dibromoethane, (16.67 mmol) and Na2CO3 (16.67 mmol) were
stirred at 110 ꢀC for 12 h under Ar atmosphere. Then the mixture
was cooled and CHCl3 (100 mL) was added to the mixture and
refluxed for 1 h. The CHCl3 layer was separated from the solid
phase. The remaining solid was re-extracted with CHCl3
(3 ꢂ 25 mL). The combined CHCl3 layers were dried (Na2SO4) and
evaporated. After the excess amino alcohol was distilled, the
product was purified by flash column chromatography on silica gel
(eluent: ethyl acetate/n-hexane; 1/2).
3. Experimental
3.1. Materials and method
Unless otherwise stated, all reactions were carried out under an
atmosphere of argon using conventional Schlenk glass-ware, sol-
vents were dried using established procedures and distilled under
argon immediately prior to use. Analytical grade and deuterated
solvents were purchased from Merck. The starting materials
leucine, -isoleucine, -phenylglycine, -phenylalanine, Ph2PCl, (iso-
Pr)2PCl and Et3N are purchased from Fluka and were used as
L-
L
L
L
3.4.1. (2S)-2-[(2-{[(2S)-1-Hydroxy-4-methylpentan-2-yl]amino}
ethyl)amino]-4-methylpentan-1-ol, 1
20
received. [Ru(
h
6-p-cymene)(
m-Cl)Cl]2 [52],
L-leucinol ((2S)-2-
Yield: 3.3 g, 76%, [
a]
þ33.5 (c 1.0, CHCl3), 1H NMR (
d ppm,
D
amino-4-methylpentan-1-ol),
L-isoleucinol ((2S,3S)-2-amino-3-
CDCl3): 3.62 (m, 2H, CH2OH (a)); 3.32 (m, 2H, CH2OH (b)); 2.83 (m,
2H, NCH2CH2N (a)); 2.70 (m, 2H, NCH2CH2N (b) and 2H, CHeN) 1.67
(m, 2H, CH2CH(CH3)2); 1.34 (m, 2H, CH2CH(CH3)2 (a)); 1.31 (m, 2H,
CH2CH(CH3)2 (b)); 0.92 (m, 6H, CH2CH(CH3)2 (a)); 0.89 (m, 6H,
methylpentan-1-ol),
L-phenylglycinol
([(2S)-2-amino-2-
phenylethan-1-ol]), and
L-phenylalaninol ([(2S)-2-amino-3-
phenylpropan-1-ol]) [29,53] were prepared according to the liter-
ature procedures. We prepared the known compounds 1e4 by
a slightly modified procedure [31e33]. The IR spectra were recor-
ded 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
(162.0 MHz) spectra were recorded on a Bruker AV 400 spec-
CH2CH(CH3)2 (b)); 13C NMR (
d ppm, CDCl3): 64.29 (eCH2OH); 57.05
(eCHeN); 46.99 (NCH2CH2N); 41.23 (CH2CH(CH3)2); 24.96
(CH2CH(CH3)2); 23.27 (CH2CH(CH3)2 (a)); 22.97(CH2CH(CH3)2 (b));
IR (KBr pellet, cmꢁ1
) n(OH): 3356; n(NH): 3281; n(CH): 2955, 2834.
Anal. Calcd for C14H32N2O2 (mw: 260 g/mol): C, 64.57; H, 12.38; N,
10.76. Found; C, 64.50; H, 12.28; N, 10.71.
trometer, with
d referenced to external TMS and 85% H3PO4
respectively. Elemental analysis was carried out on a Fisons EA 1108
CHNS-O instrument. Melting points were recorded by Gallenkamp
Model apparatus with open capillaries.
3.4.2. (2S)-2-[(2-{[(2S)-1-Hydroxy-3-methylpentan-2-yl]amino}
ethyl)amino]-3-methylpentan-1-ol, 2
20
Yield: 3.4 g, 79%, [
a
]
D
þ31.1 (c 1.0, CHCl3), 1H NMR (
d ppm,
3.2. GC analyses
CDCl3): 3.56 (m, 2H, CH2OH (a)); 3.31 (m, 2H, CH2OH (b)); 2.75 (m,
2H, NCH2CH2N (a)); 2.61 (m, 2H, NCH2CH2N (b)); 2.43 (m, 2H, CHe
N); 1.51 (m, 2H, CHCH2CH3); 1.38 (m, 2H, CHCH2CH3 (a)); 1.14 (m,
2H, CHCH2CH3 (b)); 0.86 (t, 6H, J ¼ 8.0 Hz, CHCH2CH3 (a)); 0.82 (d,
GC analyses were performed on a Shimadzu GC 2010 Plus Gas
Chromatograph equipped with cyclodex B (Agilent) capillary col-
umn (30 m ꢂ 0.32 mm I.D. ꢂ 0.25
m
m film thickness). The GC pa-
6H, J ¼ 8.4 Hz, CHCH2CH3 (b)); 13C NMR (
d ppm, CDCl3): 61.20 (e
rameters 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,
150 ꢀC; initial time 2.2 min; temperature ramp 2.15 ꢀC/min; final
temperature, 250 ꢀC; initial time 3.3 min; final time, 44.33 min;
injector port temperature, 200 ꢀC; detector temperature, 200 ꢀC,
CH2OH); 62.94 (eCHeN); 47.25 (NCH2CH2N); 35.70 (CHCH2CH3);
26.27 (CHCH2CH3); 14.48 (CHCH2CH3 (a)); 11.81 (CHCH2CH3 (b)); IR
(KBr pellet, cmꢁ1
) n(OH): 3344; n(NH): 3265; n(CH): 2962, 2885.
Anal. Calcd for C14H32N2O2 (mw: 260 g/mol): C, 64.57; H, 12.38; N,
10.76. Found: C, 64.48; H, 12.34; N, 10.71.
injection volume, 2.0
m
L.
3.4.3. [(2S)-2-[(2-{[(1S)-2-Hydroxy-1-phenylethyl]amino}ethyl)
amino]-2-phenylethan-1-ol, 3
3.3. General procedure for the transfer hydrogenation of ketones
Yield: 4.12 g, 82%, [
a
]
20 þ59.75 (c 0.5, MeOH); 1H NMR (
d ppm,
D
CDCl3): 7.28e7.36 (m, 10H, ArH); 3.92 (m, 2H, CH2OH (a) and 2H,
CHeN); 3.75 (m, 2H, CH2OH (b)); 2.70 (m, 2H, NCH2CH2N (a)); 2.57
A typical experimental procedure is described. A flame dried
Schlenk flask was charged with [Ru(
h
6-p-cymene)(
m-Cl)Cl]2
(m, 2H, NCH2CH2N (b)); 13C NMR (
d
ppm, CDCl3): 139.89, 128.68,
127.73, 127.45, (C6H5); 66.59 (eCH2OH); 64.63 (eCHeN); 46.19
(NCH2CH2N); IR (KBr pellet, cmꢁ1
(OH): 3450; (NH): 3314; (CH):
(0.005 mmol), bis(phosphinite) ligand (0.02 mmol) and a stir bar.
To these components was added iso-PrOH (5 mL, dried and
degassed), and the resultant solution was heated at 82 ꢀC until the
reaction was completed, followed by cooling to ambient
)
n
n
n
3060, 3023, 2915. Anal. Calcd for C18H24N2O2 (mw: 300.4 g/mol): C,
71.97; H, 8.05; N, 9.33. Found: C, 71.92; H, 8.01; N, 9.29.

D. Elma et al. / Journal of Organometallic Chemistry 729 (2013) 46e52
51
3.4.4. [(2S)-2-[(2-{[(2S)-1-Hydroxy-3-phenylpropan-2-yl]amino}
ethyl)amino]-3-phenylpropan-1-ol], 4
Appendix A. Supplementary material
20
Yield: 4.31 g, 78.8%; [
a
]
e9.6 (c 0.5, MeOH). 1H NMR (
d
ppm,
Supplementary material associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/j.
jorganchem.2013.01.012.
D
CDCl3): 7.18e7.34 (m, 10H, ArH); 3.62 (m, 2H, CH2OH (a)); 3.38 (m,
2H, CH2OH (b)); 2.89 (m, 2H, CHeN); 2.73 (m, 4H, NCH2CH2N and 2H
CH2Ph (a)); 2.63 (m, 2H, CH2Ph (b)); 2.19 (br, 4H, -NH and eOH); 13
C
NMR (
(eCH2OH); 60.32 (eCHeN); 46.89 (CH2Ph); 38.24 (NCH2CH2N); IR
(KBr pellet, cmꢁ1
(OH): 3498; (NH): 3280; (CH): 3089, 3025,
2912, 2869. Anal. Calcd for C20H28N2O2 (mw: 328.5 g/mol): C, 73.14;
H, 8.59; N, 8.53. Found: C, 73.11; H, 8.51; N, 8.48.
d ppm, CDCl3): 138.58, 129.14, 128.57, 126.42, (eC6H5); 63.49
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