The synthesis of a new nitrogen joined N-PEG-TsDPEN ligand and its application in asymmetric transfer hydrogenation of ketones in neat water

Article abstract of DOI:10.1016/j.jorganchem.2011.02.004

A new polyethylene glycol (PEG) supported ligand, with the PEG chain attached to the nitrogen of TsDPEN, was synthesized using a very simple procedure. The Ru-catalyzed asymmetric transfer hydrogenation of various aromatic ketones in water was investigated with this chiral ligand. High chemical yields and enantioselectivities were obtained under very mild conditions. In addition, the chiral ligand was easily recycled several times and this catalyst was especially suitable for the preparation of chiral tetrahydronaphthalen-1-ol and 2,3-dihydro-1H-inden-1-ol (up to 98% conversion with 99% ee). The latter product can be used as the key intermediate for the synthesis of neuroprotective and anti-AChE agents Rasagiline and Ladostigil.

Full text of DOI:10.1016/j.jorganchem.2011.02.004

Journal of Organometallic Chemistry 696 (2011) 1687e1690
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
The synthesis of a new nitrogen joined N-PEG-TsDPEN ligand and its application
in asymmetric transfer hydrogenation of ketones in neat water
*
Wenjun Shan, Fanchao Meng, Yinuo Wu, Fei Mao, Xingshu Li
Institute of Drug Synthesis and Pharmaceutical Processing, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new polyethylene glycol (PEG) supported ligand, with the PEG chain attached to the nitrogen of
TsDPEN, was synthesized using a very simple procedure. The Ru-catalyzed asymmetric transfer hydro-
genation of various aromatic ketones in water was investigated with this chiral ligand. High chemical
yields and enantioselectivities were obtained under very mild conditions. In addition, the chiral ligand
was easily recycled several times and this catalyst was especially suitable for the preparation of chiral
tetrahydronaphthalen-1-ol and 2,3-dihydro-1H-inden-1-ol (up to 98% conversion with 99% ee). The
latter product can be used as the key intermediate for the synthesis of neuroprotective and anti-AChE
agents Rasagiline and Ladostigil.
Received 17 November 2010
Received in revised form
2 February 2011
Accepted 8 February 2011
Keywords:
N-PEG-TsDPEN
PEG- supported
Asymmetric transfer hydrogenation
Ó 2011 Elsevier B.V. All rights reserved.
Water
Recycle
1. Introduction
reactivity and the enantioselectivity in asymmetric transfer hydro-
genation in water [13]. Ying et al. anchored TsDPEN onto siliceous
Since the important breakthrough made by Noyori et al. in 1995,
asymmetric transfer hydrogenation (ATH) has become one of the
best reduction systems for both academia and industry [1e4]. As
both the chiral ligands and metal in ATH are usually expensive and
cannot be easily separated from the products, some immobilized
ATH catalysts have been developed in recent years to match the
economic and environmental requirements (Fig. 1).
Tu et al. developed a highly efficient heterogeneous catalyst
through the immobilization of TsDPEN onto silica gel (2, Fig. 1),
which demonstrated excellent enantioselectivities and high reac-
tivities [5e7]. Xiao et al. prepared the polyethylene glycol (PEG)
supported ligand (PTsDPEN) (3, Fig. 1) and the related ruthenium
catalyst which represents one of the most efficient ligands for ATH
in water [8,9]. Ohta et al. presented a novel task-specific chiral ionic
ligand (4, Fig. 1) with an attached imidazolium salt, and demon-
strated its use in the recyclable catalytic ATH of ketones by an
HCO2HeEt3N azeotrope in Ils [10]. Deng designed and synthesized
tunable dendritic N-mono-sulfonyl ligands (2, Fig. 1) via direct
N-mono-sulfonylization of the chiral dendritic vicinal diamines
[11,12]. Itsuno developed polymer-supported chiral sulfonamides
containing a sulfonated pendant group (5, Fig. 1), in which the
quaternary ammonium salt acting as a pendant increased both the
mesocellular foam and obtained excellent reactivity, enantiose-
lectivity and reusability in ATH of an imine and ketones [14]. Liu
et al. reported a facile preparation of a mesoporous silica-supported
chiral catalyst by anchoring the Ru-DPEN-PPh2CH2CH2Si(OEt)3
complex onto mesoporous materials (SBA-15) through refluxing in
toluene for 24 h [15]. This material showed high catalytic activity
and excellent enantioselectivities for the ATH of various aromatic
ketones [15]. In this paper, we present the preparation of a new PEG
supported chiral ligand, N-PEG-TsDPEN and its application in ATH of
ketones (6, Fig. 1). Currently, this approach is the simplest method
for the preparation of immobilized ATH catalysts.
2. Results and discussion
We first selected a medium sized molecular weight poly-
ethylene glycol (PEG750) and TsDPEN as starting materials for the
synthesis of the chiral ligand N-PEG-TsDPEN (Scheme 1). The
procedure was very simple. First, the reaction of MeO-PEG-OH,
oxalyl chloride and dimethyl sulfoxide in dichloromethane gave the
responding aldehyde in high yield. The aldehyde was then reacted
with TsDPEN and hydrogen in the presence of platinum/carbon to
give the N-PEG-TsDPEN in nearly quantitative yield. Other ligands
with different PEG chains (e.g., TsDPEN-PEG-200, TsDPEN-PEG-
300, TsDPEN-PEG-400, TsDPEN-PEG-1000, TsDPEN-PEG-2000)
(Scheme 1), ligands with N-methoxyethyl (9) and simple alkyl
* Corresponding author. Tel./fax: þ86 20 39943050.
E-mail address: lixsh@mail.sysu.edu.cn (X. Li).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.02.004

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W. Shan et al. / Journal of Organometallic Chemistry 696 (2011) 1687e1690
Table 1
O
Influence of chiral ligands on asymmetric transfer hydrogenation of acetophenone
in water.a
n
O
S
O
H
N
O
S
H
N
O
O
OH
H2N
NH2
Ru-L*
HCOONa, H O
TsHN
NH2
O
11
25,6,7,11,12,14
38,9
2
+
N
N
3
Conversion (%)b
E.e (%)c
O
O
Entry
Ligands
TsDPEN
NH
2CF3CO2
1
2
3
4
5
6
7
8
9
>99
>99
>99
>99
>99
>99
>99
65
94.8
94.6
94.5
94.8
94.0
94.0
94.0
95.2
93.6
93.0
O
S
S
N-PEG200-TsDPEN (6a)
N-PEG300-TsDPEN (6b)
N-PEG400-TsDPEN (6c)
N-PEG750-TsDPEN (6d)
N-PEG1000-TsDPEN (6e)
N-PEG2000-TsDPEN (6f)
N-methoxyethyl-TsDPEN (9)
N-propyl-TsDPEN (10)
N-heptyl-TsDPEN (11)
O
O
O
Ph
Ph
Ph
NHTs
NH
O
O2S
Ph
N
N
NH2
H
NH3
Ph
410
513
6
(N-PEG-TsDPEN)
Fig. 1. Some immobilized TsDPEN chiral ligands for ATH.
63
32
10
a
Reactions were carried out in 1 mmol scale at 40 ꢀC with an S/C ¼ 100 within
chains (10 and 11) instead of PEG were also prepared using the
same procedure to compare the effect of amino group modification.
Acetophenone was chosen as the model substrate, HCOONa as
the hydrogen donor, and PEG2000 as the additive for study of the
Ru-catalyzed asymmetric transfer hydrogenation using TsDPEN-
PEG as the chiral ligand. Full conversion with 94e95% ee was
obtained when the reaction was carried out at room temperature
overnight (Table 1). The results indicate the reactivity of the
nitrogen joined N-PEG-TsDPEN ligand was sufficiently active to
facilitate ATH. In comparison with the reaction rate of the Ru-PEG-
BsDPEN catalyst in water which we reported previously, the N-PEG-
TsDPEN ligand displayed a slightly slower rate; however, similar or
better enantioselectivities were observed. On the other hand,
ligands with N-methoxyethyl and simple N-alkyl chains seem not
favorable for the reaction rate of ATH although nearly the same
enantioselectivities were obtained (Table 1, entries 8e10).
Various other aromatic ketones were also examined with
N-PEG750-TsDPEN (6d) as chiral ligand under the optimized
conditions and the results are listed in Table 2. The electronic effect
of the substrates was important for the enantioselectivity of the
reaction. The electron-donating substituents appear to be favorable
for the enantioselectivities, for example, p-methylacetophenone
provided 99% ee with a quantitative conversion, whereas p-fluoro,
p-chloro and p-bromoacetophenone gave products with 95, 89 and
90% ee, respectively. Furthermore, p-nitroacetophenone only gave
84% ee using the same reaction conditions.
15 h.
b
c
The conversions were determined by 1H NMR.
The ees were determined by HPLC on chiral OD-H column.
including the neuroprotective and anti-AChE agents, Rasagiline [16]
and Ladostigil [17] (Fig. 2).
The recycling of the Ru-catalyst with different length of PEG
moiety ligands (N-PEG200-TsDPEN (6a), N-PEG750-TsDPEN (6d)
and N-PEG2000-TsDPEN (6f)) were investigated with acetophenone
as the substrate and HCOONa as the hydrogen donor in water. The
procedure was simple. After each catalytic cycle, hexane was added
to extract the product and the residue containing the catalyst was
reused by adding 1.0 equivalent of formic acid to regenerate sodium
formate for the next cycle. The results in Table 3 indicated that the
length of PEG moiety has an effect on the activity of the catalyst. For
example, the conversion of ATH remained 99% at the eighth run
with N-PEG2000-TsDPEN as the chiral ligand, whereas N-PEG750-
TsDPEN and N-PEG200-TsDPEN kept the same conversion at the
fifth and the third run at the same reaction conditions, respectively.
Some Ru complex may be extracted to n-hexanes phase when short
Table 2
Asymmetric transfer hydrogenation of various ketones in water.a
O
OH
Ru-L*
HCOONa, H2O
It is interesting that 1-tetralone, 1-indanone and 2-acetylnaph-
thalene all gave 99% ee with the N-PEG750-TsDPEN (6d) as the chiral
ligand (Scheme 2 and Table 2, entry 10), which was higher than that
found using other ligands such as PTsDPEN [8] or TsDPEN with
HCOONa as the hydrogen donor. The results indicated that the N-
PEG-TsDPEN ligand was favorable for particular steric substrates.
The excellent ee values for these substrates, for example, 2,3-dihy-
dro-1H-inden-1-ol or its derivatives, provide an alternative method
for the preparation of key intermediates of several important drugs,
Ar
Ar
Entry
Substrates
Conversion (%)b
E.e (%)c
1
2
3
4
5
6
7
8
Phenyl
>99
>99
>99
>99
>99
86
94
95
89
90
99
94
84
93
92
4-fluorophenyl
4-chlorophenyl
4-bromophenyl
4-methylphenyl
4-methoxyphenyl
4-nitrophenyl
Furan-2-yl
Propiophenone
Naphthalen-2-yl
Ferrocenyl
(COCl)2
>99
>99
>99
90
O
R1
O
CHO
RO
OH
n
DMSO, CH2Cl2
n
9
10
11
7 (R = H or CH3; n = 4 - 50)
8 (R1 = CHO or CH2OCH3)
>99
98
6a: R = H
TsDPEN-PEG-200
Ph
Ph
90d
Ph
Ph
8
, H2
6b
: R = H
TsDPEN-PEG-300
TsDPEN-PEG-400
6c: R = H
a
O
R
Reactions were carried out in 1 mmol scale at room temperature with an
TsHN
N
H
TsHN
NH2
n
O
Pt /C
6d: R= CH3 TsDPEN-PEG-750
S/C ¼ 100.
6e
: R= H
TsDPEN-PEG-1000
TsDPEN-PEG-2000
b
c
TsDPEN
6f: R = H
The conversions were determined by 1H NMR.
The ees were determined by HPLC on chiral OD-H column.
Isolated yield.
d
Scheme 1. The synthesis of chiral ligand N-PEGTsDPEN.

W. Shan et al. / Journal of Organometallic Chemistry 696 (2011) 1687e1690
1689
Table 3
O
OH
Results of Catalyst Recycling in the Asymmetric Transfer Hydrogenation in Watera.
Ru-L*
Conversion (%)b
E.e (%)d
98% conversion
99% ee
Run
Ligands
Substrates
Time (h)
HCOONa, H2O
1e8
9
10
1e5
6
7
1e3
4
1
2
3
4
6f
6f
6f
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
acetyl ferrocene
acetyl ferrocene
acetyl ferrocene
acetyl ferrocene
acetyl ferrocene
6
6
6
6
6
12
6
6
24
24
24
48
48
>99
97
85
>99
98
80
94
93.8
94
93.7
93
92.5
94
O
OH
6d
6d
6d
6a
6a
6d
6d
6d
6d
6d
Ru-L*
97% conversion
99% ee
HCOONa, H2O
99
87
93
Scheme 2. Asymmetric transfer hydrogenation of tetralone and indanone.
90c
90c
86c
78c
65c
97.5
97.7
97.5
97.0
96.5
N-PEG chain DPEN were used as the ligand. Therefore, longer chain
might be more suitable for the catalyst recycle.
5
Extraction and separation of the products from particular polar
substrates in the recycling process of the catalyst with TsDPEN as
the chiral ligand was challenging in either non-polar solvents such
as hexane or polar solvents such as ether (e.g., acetyl ferrocene).
However, when Ru-N-PEG-TsDPEN was used as the chiral ligand of
the ATH of acetyl ferrocene, the recycling of the catalyst proceeded
smoothly. Table 3 summarized the results of the recycling of the
catalyst. The results indicated good chemical yields were obtained
following four cycles, and the enantioselectivity was consistent in
all five cycles.
a
Reaction conditions were the same as used in Table 1, 1.0 equiv of HCOOH was
added to regenerate HCOONa after each run.
b
The conversions were determined by 1H NMR.
Isolated yuield.
The ees were determined by HPLC on chiral OD-H column.
c
d
chromatography (silica gel, methanol/ethyl acetate 1:10). 1H NMR
(CDCl3)
d
: 7.59 (d, J ¼ 7.6 Hz, 1H), 7.15e7.30 (m, 12H), 6.95 (d,
J ¼ 6.8 Hz, 2H), 5.03 (s, 1H), 4.51 (d, J ¼ 5.2 Hz, 1H), 4.30 (d,
J ¼ 5.2 Hz, 1H), 2.40 (s, 3H) ppm. The mass spectrum of N-PEG-
TsDPEN was measured by APCI-MS, and compared with starting
material PEG750.
3. Experimental
3.1. General methods
3.2.2. General procedure of catalyst recycling in asymmetric
transfer hydrogenation of acetophenone in water
NMR spectra were recorded with TMS as the internal standard on
a Bruker 400 MHz spectrometer. Coupling constants were given in
Hz. Enantiomeric excess was determined by HPLC on Chiralcel OD-H
columns (4.6 mm ꢁ 250 mm). MS spectra were recorded on an Agi-
lent LC-MS 6120 with APCI. Purification of the products was per-
formed by column chromatography on silica gel (200e300 mesh).
A suspension of [RuCl2(p-cymene)]2 (3.1 mg, 0.005 mmol),
PEG2000 (1.0 g) and N-PEG-TsDPEN ligand 6d (13.5 mg,
0.012 mmol) in H2O (1 ml) was purged with argon and stirred at
40 ꢀC for 1 h. HCOONa (340 mg, 5.0 mmol) and acetophenone
(120 mg, 1.0 mmol) were then introduced to the catalyst solution.
The mixture was degassed three times, and stirred at 45 ꢀC under
an argon atmosphere. After 6 h, the product was extracted with n-
hexane (2 ml) three times. The conversion was determined by 1H
NMR and the enantioselectivity was determined by chiral HPLC
analysis.
3.2. Experimental procedures
3.2.1. The preparation of ligand 6d (general procedure)
A solution of dimethyl sulfoxide (1.4 ml, 20 mmol) in CH2Cl2
(10 ml) was added dropwise over 3 min to a stirred solution of oxalyl
chloride (1 ml, 22.6 mmol) in CH2Cl2 (50 ml) at ꢂ78 ꢀC. After 5 min of
stirring, a solution of MeO-PEG-OH (7.50g, 10 mmol) in CH2Cl2
(25 ml) was added dropwise over 30 min. After a further 30 min
stirring, triethylamine (5.6 ml, 40mmol)wasadded. The mixturewas
stirred at ꢂ78 ꢀC for 1 h and then 2 h at room temperature. Water
(40 ml) was added and the aqueous layer was extracted with CH2Cl2
(3 ꢁ 40 ml). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to yield PEG-aldehyde (6.15g, 91%). The
structure of the PEG-aldehyde was proved by the 1H NMR analysis
and 9.5 ppm indicated the presence of the hydrogen of aldehyde.
To a solution of (S,S)-TsDPEN (2 mmol) in CH3OH (15 ml),
PEG-aldehyde, 0.215g Pt/C and Na2SO4 (6 mmol) were added
successively. The system was charged with hydrogen and stirred at
room temperature for 24h. After the reaction was finished, the
mixture was filtered to remove Pt/C and the filtrate was evaporated
in vacuo to afford the crude product, which was purified by flash
The aqueous solution containing the catalyst was used for the
subsequent transfer hydrogenation run: HCOOH (0.039 ml,1 equiv.)
was added to regenerate sodium formate and then acetophenone
(120 mg, 1.0 mmol) was added into the aqueous solution for a new
reaction cycle.
Acknowledgements
We thank the Natural Science Foundation of China (20972198)
and the Ministry of Science and Technology of China (No.
2009ZX09501-017) for financial support of this study.
Appendix. Supplementary material
Supplementary data related to this article can be found online at
doi:10.1016/j.jorganchem.2011.02.004.
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