Amino acid- and imidazolium-tagged chiral pyrrolidinodiphosphine ligands and their applications in catalytic asymmetric hydrogenations in ionic liquid systems

Article abstract of DOI:10.1016/j.tetasy.2012.07.008

Herein we report the synthesis of amino acid- and imidazolium-tagged chiral pyrrolidinodiphosphine ligands and the catalytic efficiency and reusability of their corresponding Rh-catalysts in the asymmetric hydrogenation of methyl (Z)-2-acetamidocinnamate

Full text of DOI:10.1016/j.tetasy.2012.07.008

Tetrahedron: Asymmetry 23 (2012) 1058–1067
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Amino acid- and imidazolium-tagged chiral pyrrolidinodiphosphine ligands
and their applications in catalytic asymmetric hydrogenations in ionic
liquid systems
⇑
Xin Jin , Xin-fu Xu, Kun Zhao
Department of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2012
Accepted 4 July 2012
Herein we report the synthesis of amino acid- and imidazolium-tagged chiral pyrrolidinodiphosphine
ligands and the catalytic efficiency and reusability of their corresponding Rh-catalysts in the asymmetric
hydrogenation of methyl (Z)-2-acetamidocinnamate in different reaction media, including classical organic
solvents, ionic liquid (IL) [bmim]BF4 (1-n-butyl-3-methyl-imidazolium tetrafluoroborate) and [bmim]BF4/
cosolvent systems. The effects of the ionic tag structures, IL, cosolvents, Rh precursors, and halide impurities
on catalytic activity and enantioselectivity were studied in detail. In the hydrogenation reaction, the amino
acid- and imidazolium modified ligands gave higher ee values than the classical pyrrolidinodiphosphine,
(2S,4S)-N-(tert-butoxycarbonyl)-4-(diphenylphosphino)-2-[(diphenylphosphino) methyl] pyrrolidine
(BPPM), both in pure methanol and in the [bmim]BF4/MeOH system. The catalyst recycling experiments
demonstrated that introducing the amino acid and imidazolium moieties into the pyrrolidinodiphosphine
backbone resulted in much better immobilization and reusability of the Rh-catalysts in [bmim]BF4, and
after several cycles there was no significant loss in activity, enantioselectivity, or Rh.
Keywords:
Asymmetric hydrogenation
Catalyst recycling
Homogeneous catalysis
Ionic liquids
Rhodium
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
a
-enamide esters,10 b-ketoesters,11 and aromatic ketones,12 signif-
icant limitations still remain. One limitation is that the chiral cat-
alyst tends to be lost into the product phase,10c,d and is prone to
oxidation after many cycles, thus resulting in reduced catalytic
activity and enantioselectivity.10b Another is that the activity and
enantioselectivity of asymmetric hydrogenation in ILs are often
unsatisfactory and inferior to those of the homogeneous reaction
in organic solvents.13 Therefore, a key concern in asymmetric
hydrogenations using ILs is the effective dissolution and immobili-
zation of the chiral catalyst in the ILs to avoid catalyst loss while
maintaining high catalytic activity and high stereoselectivity.
Ionic liquid supported (ILS) asymmetric catalysis offers a solu-
tion to this problem.14 In ILS asymmetric catalysis, the ionic liquid
molecules (imidazolium, pyridinium, guanidinium, etc.) are
embedded into the skeleton of the phosphine ligands to enhance
the stability and affinity of the chiral catalyst in, and to, the IL
phase.15 In addition, it is known that the introduction of a cosol-
vent into the ILs catalytic system can improve the activity and ste-
reoselectivity.16 However, to date, there are still very few numbers
of reported ILS chiral catalysts for the asymmetric hydrogenations.
Systematic research is necessary to explore the applicability of this
concept in other chiral ligands.14 The synergy between the ILs/
cosolvents and the chiral catalyst that affects the activity and
enantioselectivity has a very complex mechanism.16,17 It is theoret-
ically informative to interpret this mechanism and determine the
patterns in asymmetric hydrogenations using ILs.
Asymmetric hydrogenation was the first catalytic asymmetric
reaction that reached industrial scale application. It is currently
one of the most investigated areas in chemistry research and has
become the ideal method for preparing chiral compounds and
drugs, including amino acids, alcohols, and amines.1 A critical issue
in asymmetric hydrogenations is the successful design of chiral li-
gands that complex with noble metals such as Ru, Rh, and Ir to give
highly active and stereoselective chiral catalysts.2 Nevertheless, to
effectively recycle the expensive chiral catalysts from hydrogena-
tion products has remained a great challenge and a continuing re-
search focus in recent decades.3 Heterogeneous catalysis has
emerged as a solution to this problem, in which the chiral catalysts
can be immobilized on a polymer or inorganic matrix for easy sep-
aration.4 Alternatively, liquid-liquid biphasic catalytic systems
may be used, including aqueous-organic systems,5 fluorous-organ-
ic systems,6 supercritical fluids,7 ionic liquids (ILs),8 and so on. The
biphasic catalytic system using catalyst-supporting ILs has become
of great interest in recent years and is expected to show great po-
tential as a readily applicable system.9 Although some successful
use of ILs has been reported for the asymmetric hydrogenation of
⇑
Corresponding author. Tel./fax: +86 532 840 22719.
E-mail address: jinx1971@163.com (X. Jin).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.07.008

X. Jin et al. / Tetrahedron: Asymmetry 23 (2012) 1058–1067
1059
Herein, based on the ‘ILS asymmetric catalysis’ concept, we
have synthesized amino acid- and imidazolium-tagged chiral pyrr-
olidinodiphosphine ligands (Scheme 1) and tested their Rh com-
plexes in the enantioselective hydrogenation of methyl (Z)-2-
acetamidocinnamate (MAC). The hydrogenation reactions were
carried out in classical organic solvents, [bmim]BF4 and
[bmim]BF4/cosolvent systems. We aim to reveal the specific effects
of chiral catalyst structures, IL, and cosolvents on the catalytic
activity, enantioselectivity, and catalyst reusability.
backbone. The synthesis of amino acid- and imidazolium-tagged
chiral pyrrolidinodiphosphine ligands is shown in Scheme 2.
The amino acid-modified ligands 3a–e can be easily synthesized
in two steps from 2 (PPM). Firstly, the Boc and OtBu-protected
aspartic acid or glutamic acid was attached to the amino group
of the PPM by DIC-promoted amidation to obtain diphosphines
5a–e. Next, both the Boc and OtBu protecting groups were re-
moved in the presence of trifluoroacetic acid and triethylsilane to
give the trifluoroacetic acid salts of 3a–e. Similarly, 1-carboxy-
methyl-3-methylimidazolium tetrafluoroborate was attached to
the backbone of PPM by the same DIC-promoted amidation to give
ligand 4.
Table 1 systematically evaluates the catalytic performance of
amino acid- and imidazolium-tagged chiral pyrrolidinodiphos-
phine ligands in the Rh-catalyzed homogeneous asymmetric
hydrogenation of MAC. The effect of different rhodium precursors,
reaction solvents, ligand structures, reaction temperature, and
hydrogen pressure on the stereoselective hydrogenations was
determined.
Except for ligand 5a, all other ligands gave higher ee values
when using the cationic rhodium precursor [A: [Rh(COD)2]BF4]
than when using the non-ionic precursor [B: [Rh(COD)Cl]2]. The
observed effects of classical organic solvents on enantioselectivi-
ties were in agreement with literature.16c,23 For example, for li-
gands 5b and 3b (Table 1, entries 5, 7–9, 21, 23–25), the ee
values improved significantly with rising solvent polarity. Alcohols
were found to be the most suitable solvent, with methanol being
the best solvent, followed by ethanol and isopropanol. This is be-
cause the alcohols can coordinate to the metal center and partici-
pate in the catalytic cycle, thus promoting the catalytic
reaction.16a,b,23 The effect of different ionic tags on the enantiose-
lectivities showed obvious patterns. The best enantioselectivity
was achieved by the imidazolium-tagged ligand 4, which gave an
ee value of 95% in MeOH. For amino acid-tagged ligands, the posi-
tion of the stereogenic center in the amino acids had a significant
impact on the enantioselectivity. The ee values are obtained nota-
bly lower when the stereogenic center in the amino acid was closer
to the pyrrolidine ring (5a, 5d, 3aꢀCF3COOH, and 3dꢀCF3COOH) and
higher when the stereogenic center in the amino acid was more re-
Ph2P
Ph2P
PPh2
PPh2
N
Boc
N
H
(-)-BPPM 1
PPM 2
Ph2P
Ph2P
PPh2
PPh2
N
N
O
O
N
H2N
NH2-L-ASP(PPM)-OH 3b
Scheme 1. Studied ligands.
COOH
N
BF4
Me
4
2. Results and discussion
Chiral pyrrolidinodiphosphine ligands, such as BPPM and
PhCAPP, are versatile and efficient in Rh-catalyzed asymmetric
hydrogenation of
a a-keto-
-enamide esters,18 dehydro peptides,19
a
esters,20 dehydro
-aminophosphinic acids,21 and in asymmetric
hydroformylations.22 Moreover, the structure of the pyrrolidinodi-
phosphine ligand can be readily modifiable and various substitu-
ents can be introduced onto the N atom in the pyrrolidine
Ph2P
Ph2P
Me
-
BF4
-
N
COOH
BF4
N
N
N
Me
NH
N
DIC/CH2Cl2
O
Ph2P
Ph2P
(2S,4S)-PPM
2
4
O
*
DIC, HOBt/CH2Cl2
HO C (CH2)n CH (CH2)m CO2tBu
NHBoc
Ph2P
Ph2P
O
O
CF3COOH, (Et)3SiH
*
*
N C (CH2)n CH (CH2)m COOH
NH3+CF3COO-
N C (CH2)n CH (CH2)m CO2tBu
NHBoc
Ph2P
Ph2P
5a, n=0; m=1;
3a·CF3COOH, n=0; m=1;
Boc-L-Asp(OtBu)-PPM
CF3COO- NH3+-L-Asp-PPM
5b
, n=1; m=0;
3b·CF COOH,
n=1; m=0;
3
Boc-L-Asp(PPM)-OtBu
CF3COO- NH3+-L-Asp(PPM)-OH
n=1; m=0;
5c, n=1; m=0;
Boc-D-Asp(PPM)-OtBu
5d, n=0; m=2;
3c·CF COOH,
3
CF3COO- NH3+-D-Asp(PPM)-OH
n=0; m=2;
Boc-L-Glu(OtBu)-PPM
3d·CF COOH,
3
5e
, n=2; m=0;
CF3COO- NH3+-L-Glu-PPM
n=2; m=0;
Boc-L-Glu(PPM)-OtBu
3e·CF COOH,
3
CF3COO- NH3+-L-Glu(PPM)-OH
Scheme 2. Synthesis of amino acid- and imidazolium-tagged chiral pyrrolidinodiphosphine ligands.

1060
X. Jin et al. / Tetrahedron: Asymmetry 23 (2012) 1058–1067
Table 1
try 26). This resulted from the coordination of free amino groups to
Rh.18a,24 When two equivalent molar amounts of triethylamine or
the strongly basic IL [bmim]OH were added, the catalytic activity
and enantioselectivity decreased drastically (Table 1, entries 27
and 28). The reduced activity and enantioselectivity are likely to
be due to the complexation between Rh and the carboxylate anion,
which is formed in the presence of excess base.25 The enantioselec-
tivity decreased at a higher H2 pressure (Table 1, entries 17 and 18)
and slightly increased with rising reaction temperature (Table 1,
entry 19), which is in agreement with the results reported by Oji-
ma18b and indicates the same catalytic mechanism. Except for 5a
and 5d, all other ligands gave comparable or higher enantioselec-
tivity than BPPM (Table 1, entries 1 and 2).
Performance of amino acid- and imidazolium-tagged PPM ligands in the Rh-catalyzed
homogeneous asymmetric hydrogenation of MACa
H2
CO2Me
NHAc
CO2Me
NHAc
or Rh(B)-L*
Solvent
Rh(A)-L*
Entry
Ligand
BPPM
Solvent
Rh
ee (R) (%)
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
EtOAc
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
i-PrOH
EtOAc
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
i-PrOH
A
B
A
B
A
B
A
A
A
A
B
A
B
A
B
A
A
A
A
B
A
B
A
A
A
A
A
A
A
B
A
B
A
B
A
B
A
92
89
86
87
94
92
88
78
68
93
92
89
88
92
91
92
84
53
93
89
94
91
90
76
77
82
23
29
93
91
92
88
94
92
95
92
82
5a
5b
In the following experiments, we investigated the impact of li-
gand structure and solvents on the catalytic activity using BPPM as
the reference (Fig. 1). In methanol, Rh(A)-L4 showed the highest
catalytic activity with a TOF of 24,054 hꢁ1, whereas the activity
of Rh(B)-L4 declined drastically to a TOF of only 459 hꢁ1. This is
in contrast with the activity of BPPM (TOFRh(B)-BPPM > TOFRh(A)-BPPM
)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
5c
and for now cannot be well rationalized. For the amino acid-mod-
ified ligands, the position of the stereogenic center in the amino
acid has similar effects on both catalytic activity and enantioselec-
tivity. The amino acid stereogenic centers in Rh-L3bꢀCF3COOH and
Rh-L3eꢀCF3COOH are distant from the Rh, and thus have relatively
high catalytic activity and similar catalytic behavior to BPPM
(TOFRh(B)-L > TOFRh(A)-L). In contrast, the amino acid stereogenic
centers in Rh-L3aꢀCF3COOH and Rh-L3dꢀCF3COOH are closer to
5d
5e
3aꢀCF3COOH
the Rh, and their activity is relatively low. The
D
-aspartic acid mod-
-aspartic
3bꢀCF3COOH
ified Rh(A)-L3cꢀCF3COOH showed higher activity than
L
acid modified Rh(A)-L3bꢀCF3COOH, but its catalytic behavior
(TOFRh(B)-L3cꢀCF3COOH < TOFRh(A)-L3cꢀCF3COOH) was opposite to that of
BPPM. With other conditions being equal, using isopropanol as
the solvent gave much less catalytic activity than using methanol.
3b
3bꢀN(Et)3
3bꢀ[bmim]OH
3cꢀCF3COOH
3dꢀCF3COOH
3eꢀCF3COOH
4
a
Reaction conditions: A: Rh(COD)2]BF4, B: [Rh(COD)Cl]2, p(H2) = 1.5 atm,
T = 25 °C, t = 2.5 h, ligands/Rh = 1.1, substrate/Rh = 100, 2.0 mL solvent; entry 17:
p(H2) = 10 atm; entry 18: p(H2) = 50 atm; entry 19: T = 50 °C. Substrate conversion
rates are all 100% except entries 26–28. Entry 26: dissolve 3bꢀCF3COOH in MeOH
and add an equimolar amount of 10% NaHCO3; and the white precipitates are then
filtered and dried to give 3b, conversion 70%; entry 27: 3bꢀCF3COOH/N(Et)3 = 1/2,
conversion 17%; entry 28: 3bꢀCF3COOH/[bmim]OH = 1/2, conversion 8%.
Figure 1. Effect of ligand structure and reaction solvents on the catalytic activity.
Reaction conditions: p(H2) = 1.5 atm, T = 25 °C, t = 2 min, ligands/Rh = 1.1, sub-
strate/Rh = 1000, 2.0 mL solvent. 1: BPPM/MeOH; 2: 3aꢀCF3COOH/ MeOH; 3:
3bꢀCF3COOH/MeOH; 4: 3cꢀCF3COOH/MeOH; 5: 3dꢀCF3COOH/MeOH; 6:
3eꢀCF3COOH/MeOH; 7: 4/MeOH; 8: 3bꢀCF3COOH/i-PrOH; 9: 4/i-PrOH.
mote from the pyrrolidine ring (5b, 5c, 5e, 3bꢀCF3COOH,
3cꢀCF3COOH, and 3eꢀCF3COOH). This indicates that the stereogenic
center in the amino acid has a negative interaction with the metal
center of the stereogenic catalyst, and this negative interaction
weakens as the chiral center moves away from the metal center.
In addition, the stereochemistry of the amino acid tags had a rela-
tively small influence on the enantioselectivity. The ligands 5c and
Although the chiral pyrrolidinodiphosphine ligands bearing the
amino acid and imidazolium moieties showed high efficiency in
the Rh-catalyzed enantioselective hydrogenation of MAC in MeOH,
we were more interested in their performance in the ILs. Therefore,
we chose the most commonly used imidazole-based IL [bmim]BF4
(1-n-butyl-3-methylimidazolium tetrafluoroborate) as the chiral
catalyst carrier. We selected Rh-L3bꢀCF3COOH and Rh-L4 as the
model catalysts, both of which showed high activity and enantiose-
lectivity for the hydrogenation in methanol, and investigated their
catalytic performance in [bmim]BF4 and [bmim]BF4/cosolvent sys-
tems (Table 2).
3cꢀCF3COOH that were modified by
D-aspartic acid and the ligands
5b and 3bꢀCF3COOH that were modified by
L-aspartic acid showed
only a 1% difference in ee value.
Since the amino acid-tagged ligands are zwitterionic, we also
investigated the influence of alkaline additives on the ligand per-
formance. First, 3bꢀCF3COOH was neutralized with an equimolar
amount of NaHCO3 to give 3b. It was found that both the activity
and the enantioselectivity of Rh(A)-L3b decreased significantly,
giving a conversion rate of 70% and an ee value of 82% (Table 1, en-

X. Jin et al. / Tetrahedron: Asymmetry 23 (2012) 1058–1067
1061
Table 2
the retarded chloride dissociation resulted in the remarkable loss
of catalytic activity in [bmim]BF4. Fourthly, the minor amount of
chloride impurities in ILs may also poison the catalyst by coordi-
nating to Rh and consequently decrease the activity.10a,11b,13b,28 Fi-
nally, normal solvents assist in the catalytic cycle of transition
metal catalyzed reactions and thus effectively promote the cata-
lytic reaction.16,23 However, when ILs were employed as the sole
reaction medium, the lack of solvent involvement severely im-
pedes the catalytic activity and enantioselectivity.
Rh-catalyzed asymmetric hydrogenation of MAC using amino acid- and imidazolium-
tagged chiral pyrrolidinodiphosphine ligands in [bmim]BF4 and [bmim]BF4/cosolvent
systemsa
Entry Ligand
Reaction medium
Rh Conversion
(%)
ee (R) (%)
1
2
3
4
5
6
7
3bꢀCF3COOH [bmim]BF4
A
B
A
B
A
B
A
60
36
100
46
100
66
100
19
45
21
33
47
55
66
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
b
b
c
To address these issues, we employed four sets of experiments
in order to investigate how the catalytic activity and enantioselec-
tivity of the asymmetric hydrogenation of MAC was influenced by
chloride impurities, cosolvents, and so on. As can be seen in Table 2,
a notable increase in catalytic activity could be observed when
high purity [bmim]BF4 (<10 ppm chloride) was used in the place
of normal [bmim]BF4 (<150 ppm chloride), but the ee value did
not improve and even decreased (Table 2, entries 3, 4, 13, and
14), for which no explanation could be put forward. We found that
if the chiral catalyst was prepared in situ in the homogeneous
[bmim]BF4/MeOH system and the hydrogenation was carried out
after removal of methanol under reduced pressure, both the cata-
lytic activity and enantioselectivity improved greatly compared
with using [bmim]BF4 alone (Table 2, entries 5, 6, 15, and 16). This
result indicates that although most of the methanol was removed,
the residual methanol in the IL still assisted in the catalytic cycle
and enhanced the catalytic performance. Furthermore, when using
[Rh(COD)Cl]2 as the Rh precursor, the methanol molecules may
more effectively solvate the chloride dissociated from the Rh, thus
enhancing the catalytic cycle.27 Moreover, after the in situ catalyst
generation and removal of methanol under reduced pressure, we
introduced the immiscible isopropanol to carry out the hydrogena-
tion reaction in the [bmim]BF4/i-PrOH biphasic system, and
achieved complete substrate conversion in the same reaction time
with an improved ee value. This could be attributed to; (1) higher
H2 solubility in [bmim]BF4/i-PrOH that accelerated the hydrogena-
tion; (2) participation of i-PrOH in the catalytic cycle; and (3) de-
creased viscosity of the [bmim]BF4 phase due to partial
dissolution of i-PrOH, which improved the enantioselectivity. In
the subsequent experiments, we replaced i-PrOH with MeOH and
carried out the hydrogenation in the homogeneous [bmim]BF4/
MeOH system. As expected, when using [Rh(COD)2]BF4 as the pre-
cursor in the [bmim]BF4/MeOH system, the ee value obtained was
slightly lower than using methanol (Table 2, entries 9 and 19).
However, when using [Rh(COD)Cl]2 as the precursor, the obtained
ee value was closely parallel to the results in MeOH (Table 2, entry
20) and was even higher than using methanol (Table 2, entry 10).
Moreover, in both cases, better enantioselectivity was achieved
than using BPPM (entries 23 and 24). We believe that this observed
‘homogeneous-like catalytic performance’ should be accounted for,
not only by the higher H2 solubility and MeOH involvement in the
catalytic cycle,16b but also by the drastically decreased viscosity of
the [bmim]BF4/MeOH system.
c
[bmim]BF4
[bmim]BF4/i-
PrOHc
8
[bmim]BF4/i-
PrOHc
[bmim]BF4/MeOH
[bmim]BF4/MeOH
[bmim]BF4
B
100
68
9
10
11
12
13
14
15
16
17
A
B
A
B
A
B
A
B
A
100
100
100
59
100
91
100
84
100
91
92
19
50
16
32
46
56
71
4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
b
b
c
c
[bmim]BF4
[bmim]BF4/i-
PrOHc
18
[bmim]BF4/i-
PrOHc
[bmim]BF4/MeOH
[bmim]BF4/MeOH
[bmim]BF4/
MeOHb
B
100
72
19
20
21
A
B
A
100
100
100
91
92
91
22
[bmim]BF4/
B
100
89
MeOHb
23
24
BPPM
[bmim]BF4/MeOH
[bmim]BF4/MeOH
A
B
100
100
88
89
a
Reaction conditions: p(H2) = 1.5 atm, T = 25 °C, t = 2.5 h, ligands/Rh = 1.1, sub-
strate/Rh = 100, 1 g IL, 1 mL i-PrOH or 5 mL MeOH, the IL contained <150 ppm
chloride unless otherwise noted.
b
Use a high-purity ionic liquid that contained <10 ppm chloride.
The chiral catalysts were formed in situ in the presence of both methanol and IL,
c
then MeOH was removed at 50 °C under reduced pressure.
As expected, compared with using MeOH as the solvent, using
[bmim]BF4 greatly reduced the catalytic activity and enantioselec-
tivity of Rh-L3bꢀCF3COOH and Rh-L4, which is in agreement with
the literature.10d,e,13,16b In particular, compared with Rh(A)-
L3bꢀCF3COOH, the Rh(B)-L3bꢀCF3COOH had a higher activity in
methanol but lower activity in [bmim]BF4 (Table 2, entries 1 and 2).
These observations can be rationalized as follows. Firstly, the ILs
have high viscosity and low H2 solubility;26 therefore the low H2
concentration in [bmim]BF4, due to inadequate mass transfer, is a
major cause of decreased catalytic activity.10c,d,16c,17d Secondly,
the chiral pyrrolidinodiphosphine ligands are a typical class of
1,4-diphosphine ligands with no C2 axis, and they form rather flux-
ional seven-membered ring chelate structures with Rh (I). Ojima
et al. argued that such a fluxional structure favors an ‘induced-fit’
in the coordination between the chiral rhodium catalyst and the
substrate to form a preferred conformation.18b However, in highly
viscous [bmim]BF4, the chiral catalyst and the substrate have to
consume more energy to realize ‘induced-fit’ through bond rota-
tion and bond angle adjustment, which can be thermodynamically
disfavored and leads to significantly lower ee values. Thirdly, dur-
ing their studies on the hydrogenation of styrene in [bmim][CF3-
SO3], Dyson et al. found it very difficult to dissociate the chloride
anion from the Ru-complex, which completely inhibited the activ-
ity of the catalyst precursor. They attributed this observation to the
low solvation enthalpy of chloride in the imidazolium-based ILs.27
Similarly for us, the chloride dissociation from the Rh complex is a
vital step to form a catalytically active species when using
[Rh(COD)Cl]2 as the Rh precursor,18b and it can be argued that
The effects of chloride impurities on the enantioselectivity is
insignificant in [Bmim]BF4/MeOH, since using high purity
[bmim]BF4 did not increase (entry 21) or even decrease the ee value
(entry 22). In contrast, the chloride impurities had a greater impact
onthe catalytic activity. In the case of ligand 3bꢀCF3COOH (Fig. 2), the
TOF declined sharply when [bmim]BF4 was introduced to MeOH.
However, the TOF recovered when high purity [bmim]BF4 was used.
In particular, when using [Rh(COD)Cl]2 with high purity [bmim]BF4,
the TOF was approximately 75% of that of using MeOH.
Finally, we evaluated the recycling and reuse of the Rh chiral cat-
alyst for the asymmetric hydrogenation of MAC with ligands
3bꢀCF3COOH, 4, and the reference ligand BPPM (Table 3). The recy-
cling experiments were carried out in [bmim]BF4/MeOH in which
the best catalytic activity and stereoselectivity were observed com-

1062
X. Jin et al. / Tetrahedron: Asymmetry 23 (2012) 1058–1067
creased rapidly afterward, whereas the ee value showed a steady
slight decrease in all four cycles when using [Rh(COD)Cl]2. When
BPPM was used, the conversion rate significantly decreased after
three cycles and the ee value declined sharply in all four cycles.
ICP-AES analysis showed that the loss of Rh into the i-PrOH extrac-
tion phase was more than 3% in the first cycle when using BPPM. In
contrast, when using 3bꢀCF3COOH, the Rh loss after the first cycle
was 0.3% and 1.4% for the [Rh(COD)2]BF4 precursor and
[Rh(COD)Cl]2 precursor, respectively. BPPM is hydrophobic and
has inadequate affinity with the polar [bmim]BF4, and thus leading
to a partial loss of the chiral rhodium catalyst into the i-PrOH
phase. On the contrary, the polar 3bꢀCF3COOH exists in the form
of an ammonium salt and has a high affinity to [bmim]BF4. In par-
ticular, the doubly charged Rh(A)-L3bꢀCF3COOH has an even higher
affinity to an IL than the singly charged Rh(B)-L3bꢀCF3COOH and is
thus much less susceptible to catalyst loss. The Rh-L4 was found to
have high catalytic activity and enantioselectivity over an even
longer term, i.e., high catalytic activity and enantioselectivity was
maintained after 8 and 6 cycles for the [Rh(COD)2]BF4 precursor
and the [Rh(COD)Cl]2 precursor, respectively. The variation of
enantioselectivity showed a similar trend to that of 3bꢀCF3COOH.
Figure 2. Effects of IL and chloride impurities on the catalytic activity of ligand
3bꢀCF3COOH. The reaction conditions are the same as those in Figure 1, using 1 g of
IL and 5 mL of MeOH.
The imidazolium-tagged ligand
4 had a higher affinity to
Table 3
[bmim]BF4 due to its structural resemblance, and only 0.1–0.2%
Rh was lost in extraction.
Recycling and reuse of the chiral catalyst in the asymmetric hydrogenation of MAC in
[bmim]BF4/MeOH systema
According to the catalyst recycling results, we believe that the
rapid loss of catalytic activity and enantioselectivity in
[bmim]BF4/MeOH with Rh-BPPM was because of both Rh loss and
catalyst deactivation due to ligand oxidation. When the amino acid
cation and imidazolium cation were introduced to the PPM mole-
cule, the affinity of the chiral catalyst to IL improved greatly, which
effectively reduced Rh loss. The improved affinity enabled the IL to
more effectively protect the chiral catalyst and avoid aerobic oxida-
tion,15a,d thus enhancing the recyclability of the chiral catalysts.
Entry Ligand
Rh Cycle Conversion
(%)
ee (R)
(%)
Rh leachingb
(%)
1
2
3bꢀCF3COOH
A
A
A
A
B
B
B
B
A
A
A
A
A
B
B
B
B
B
B
A
A
A
B
B
B
B
1
2
3
4
1
2
3
4
1
3
5
7
8
1
2
3
4
5
6
1
2
3
1
2
3
4
100
100
100
78
100
100
100
95
100
100
100
100
98
100
100
100
100
91
91
91
82
78
92
91
89
87
91
90
82
84
84
92
90
90
89
86
87
88
85
80
89
86
85
76
0.3
—
—
—
1.4
—
—
—
0.1
—
—
—
—
0.2
—
—
—
—
—
3.1
—
3
4
5
6
7
8
9
4
3. Conclusion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
In conclusion, we have synthesized chiral pyrrolidinodiphos-
phine ligands bearing amino acid and imidazolium tags and applied
them to the Rh catalyzed asymmetric hydrogenations of a-enamide
esters in classical organic solvents, [bmim]BF4 and [bmim]BF4/
cosolvent systems. Methanol was found to be the best solvent in
the homogeneous catalysis. The imidazolium-tagged chiral pyrroli-
dinodiphosphine ligands showed the best activity and enantiose-
lectivity in methanol, giving a TOF of 24,054 hꢁ1 and an ee value
of 95%, which well exceeded the performance of the classical pyrr-
olidinodiphosphine BPPM. For ligands bearing amino acid tags, the
position of the stereogenic center in the amino acid had a critical
impact on the catalytic efficiency. The catalytic activity and enanti-
oselectivity declined as the stereogenic center in the amino acid ap-
proached the pyrrolidine ring, which may be due to the negative
interaction between the stereogenic center in the amino acid and
Rh. When using the IL systems, the H2 solubility, type of Rh precur-
sor, viscosity of the IL, chloride impurities, and cosolvent were ma-
jor factors that affected the catalytic activity and enantioselectivity,
among which the cosolvent is the most influential factor. In the case
of the homogeneous [bmim]BF4/MeOH system, the introduction of
MeOH not only promoted the catalytic cycle and increased H2 sol-
ubility, but also effectively decreased the IL viscosity; the enanti-
oselectivity obtained closely paralleled and even exceeded that of
using methanol alone. The catalyst recycling experiments using
[bmim]BF4/MeOH showed that introducing amino acid and imi-
dazolium tags to the PPM molecule can effectively enhance the
affinity of the chiral catalyst to the IL, which reduced the Rh loss
and improved the catalyst stability, and after several cycles no sig-
nificant loss of activity and enantioselectivity was observed.
85
BPPM
100
100
94
100
100
100
67
—
3.2
—
—
—
a
Reaction conditions: p(H2) = 1.5 atm, T = 25 °C, t = 2.5 h, ligands/Rh = 1.1, sub-
strate/Rh = 100, 1 g IL, 5 mL MeOH. The [bmim]BF4 contained <150 ppm chloride.
b
Percentage of leached Rh in the total Rh, determined by ICP-AES analysis.
pared with using [bmim]BF4 alone or using [bmim]BF4/i-PrOH. The
hydrogenation was allowed to proceed in the homogeneous
[bmim]BF4/MeOH. Upon completion of reaction, the volatile metha-
nol was removed under reduced pressure and the non-volatile
hydrogenated product was extracted using i-PrOH. Subsequently,
new substrates were replenished into the IL for the next catalysis
cycle.
It can be seen in Table 3 that Rh-L3bꢀCF3COOH maintained high
catalytic activity in the first three cycles and the conversion de-
clined slightly in the fourth cycle. It should be noted that when
using [Rh(COD)2]BF4 as the precursor, the enantioselectivity re-
mained the same in the first two cycles but the ee value then de-

X. Jin et al. / Tetrahedron: Asymmetry 23 (2012) 1058–1067
1063
4.5. General procedure for the Rh-catalyzed monophasic
4. Experimental
asymmetric hydrogenation of MAC in a [bmim]BF4/MeOH
System and for catalyst recycling
4.1. General details
PPM 2 was synthesized according to literature methods.18b
BPPM 1 was purchased from Merck. All other reagents and ionic
liquids (ILs) were obtained commercially and were used as re-
ceived, except as noted. The ILs contained <0.2 wt % water and
<150 ppm halide, and no precipitate formed upon addition of
aqueous AgNO3. The high-purity [bmim]BF4 contained <10 ppm
halide. The ionic liquid [bmim]OH was prepared using standard lit-
erature methods.29 All reactions were carried out under an argon
atmosphere using standard Schlenk techniques. The solvents and
reagents used were rigorously deoxygenated prior to use. The
hydrogenation reactions were performed in a home-made 60 ml
stainless steel autoclave. The conversions and enantioselectivity
were determined by GC on a CP-Chirasil-L-Val (25 m ꢂ 0.25 mm)
chiral column. NMR spectra were recorded on a Bruker 500 MB
instrument. High resolution mass spectra (HRMS) were obtained
by electrospray technique using a Q-Tof Ultima Global mass spec-
trometry. ICP-AES data were measured on an IRIS IstrepidIIXSP
apparatus.
Typically, 1.1 mg of [Rh(COD)2]BF4 (0.0027 mmol), chiral ligand
(0.0030 mmol), and 1 g of [bmim]BF4 was dissolved in 3.0 mL of
degassed MeOH under an argon atmosphere, and the solution
was stirred for 20 min at room temperature. Next, the catalyst
solution was transferred to a 60 mL autoclave. The solution of
MAC (0.27 mmol) in 2.0 mL of MeOH was added via a syringe.
The hydrogenation was carried out under 1.5 atm pressure of
hydrogen at 25 °C for 2.5 h. After releasing the hydrogen, the reac-
tion mixture was transferred to a Schlenk tube under an argon
atmosphere. Next, the MeOH was removed under reduced pressure
and i-PrOH was added to extract the product (2 mL ꢂ 2). The top
solvent layer was removed by a syringe for GC analysis, and the
new substrate and MeOH was added to the IL for the next catalyst
recycling.
4.6. Preparation and characterization of 5a
At first, 5a was synthesized by a DIC-promoted condensation of
PPM with both Boc and tBu protected aspartic acid. Typically, a
mixture of PPM (2.06 g, 0.0045 mol), Boc-L-Asp(OtBu)-OH (1.32 g,
4.2. General procedure for the homogeneous Rh-catalyzed
asymmetric hydrogenation of MAC in organic solvents
0.0045 mol), DIC (0.58 g, 0.0045 mol), and HOBt (0.62 g,
0.0045 mol) in 70 mL of degassed CH2Cl2 and 0.4 mL of DMF was
stirred at room temperature for 4 h under an argon atmosphere.
The completion of the reaction was monitored by TLC analysis.
The solvent was then partially removed under reduced pressure,
and the resulting white precipitate was filtered off. The filtrate
was concentrated and the residue was purified by column chroma-
tography (degassed SiO2, petroleum ether/EtOAc = 5/1) under ar-
gon to afford pure product 5a as a white solid; yield: 2.5 g
The cationic or neutral Rh-catalysts were prepared in situ. Typ-
ically, 1.1 mg of cationic rhodium precursor [Rh(COD)2]BF4
(0.0027 mmol) and chiral ligand (0.0030 mmol) was dissolved in
1.0 mL of degassed solvent under an argon atmosphere. The solu-
tion was stirred for 15 min at room temperature. To the solution
of catalyst, a solution of MAC (0.27 mmol) in 1.0 mL of solvent
was added. Next, the reaction mixture was transferred to a
60 mL autoclave. The hydrogenation was carried out under
1.5 atm pressure of hydrogen at 25 °C for 2.5 h. The conversions
and ee values were determined by GC on a CP-Chirasil-L-Val
(25 m ꢂ 0.25 mm) chiral column.
(75.5%). mp: 66–68 °C; ½a D20
ꢃ
¼ ꢁ27:0 (c 0.5, CH2Cl2); 1H NMR
(500.0 MHz, CDCl3): d = 7.61–7.30 (m, 20H, Ph-H), 5.32 (d,
J = 9.0 Hz, 1H, Hb), 4.63 (td, J = 9.0, 7.0 Hz, 1H, Ha), 4.13 (overlapped
0
m, 1H, Hd), 4.08 (overlapped m, 1H, He ), 3.46 (dt,
e
0
Jee0 ¼ JPCCH ¼ 10:8 Hz, Jeh = 8.0 Hz, 1H, He), 3.18 (td, Jgg = 13.0 Hz,
Jgd ¼ JgPCH ¼ 3:0 Hz, 1H, Hg), 2.82 (m, 1H, Hh), 2.62 (dd, J = 15.5,
0
7.0 Hz, 1H, Hc), 2.39 (dd, J = 15.5, 7.0 Hz, 1H, Hc ), 2.23 (m, 1H,
4.3. General procedure for the Rh-catalyzed monophasic
asymmetric hydrogenation of MAC in a [bmim]BF4
0
0
Hf), 1.87 (overlapped m, 1H, Hg ), 1.84 (overlapped m, 1H, Hf ),
1.41 (s, 9H, Boc-Me or OtBu-Me), 1.35 (s, 9H, OtBu-Me or Boc-
Me); 13C NMR (125.7 MHz, CDCl3): d = 169.2, 168.9, 154.9, 139.1,
136.6, 136.4, 136.2, 133.3, 133.0, 132.8, 132.5, 129.1, 128.7,
128.6, 128.5, 128.5, 128.3, 81.1, 79.7, 56.4, 50.9, 49.2, 38.7, 36.3,
36.0, 33.1, 28.3, 27.9; 31P NMR (202.4 MHz, CDCl3): d = ꢁ7.5,
Typically, 1.1 mg of [Rh(COD)2]BF4 (0.0027 mmol) and chiral li-
gand (0.0030 mmol) was dissolved in 1 g of [bmim]BF4 under an
argon atmosphere, and the solution was stirred for 20 min at room
temperature. MAC (0.27 mmol) was added, and the solution was
stirred for 1 h. Next, the solution was transferred to a 60 mL auto-
clave. The hydrogenation was carried out under 1.5 atm pressure of
hydrogen at 25 °C for 2.5 h. After releasing the hydrogen, i-PrOH
(1 mL ꢂ 2) was added to extract the organic product. The top sol-
vent layer was separated for GC analysis.
ꢁ8.4, ꢁ21.8, ꢁ22.9 (two peaks P and Pb due to the two conforma-
a
tions of the RCO group at room temperature); HRMS (Q-Tof MS,
ES+): m/z = 725.3248, calcd for C42H51N2O5P2 [M+1]+: 725.3273.
Ph2P g,g'
b
a
H
BocHN
f,f
CH2
COOtBu
CH2 c,c'
H
H d
H
4.4. General procedure for Rh-catalyzed biphasic asymmetric
hydrogenation of MAC in a [bmim]BF4/i-PrOH system
N
O
Ph2P
Typically, 1.1 mg of [Rh(COD)2]BF4 (0.0027 mmol), chiral ligand
(0.0030 mmol), and 1 g of [bmim]BF4 was dissolved in 2.0 mL of
degassed MeOH under an argon atmosphere, and the solution
was stirred for 20 min at room temperature. Next, the catalyst
solution was transferred to a 60 mL autoclave. The MeOH was re-
moved under reduced pressure. The solution of MAC (0.27 mmol)
in 1.0 mL of i-PrOH was added via a syringe. The hydrogenation
was carried out under 1.5 atm. pressure of hydrogen at 25 °C for
2.5 h. After releasing the hydrogen, the i-PrOH phase was removed
for GC analysis.
H
H
H
h
e,e'
4.7. Preparation and characterization of 5b
Compound 5b was synthesized by a DIC-promoted condensa-
tion of PPM with Boc-L-Asp-OtBu as described for ligand 5a. Col-
umn chromatography (degassed SiO2, petroleum ether/EtOAc = 3/
1) under argon afforded the pure product 5b as a white solid; yield:

1064
X. Jin et al. / Tetrahedron: Asymmetry 23 (2012) 1058–1067
94.0%. mp: 189–191 °C; ½a D20
ꢃ
¼ ꢁ10:3 (c 0.5, CH2Cl2); 1H NMR
1H NMR (500.0 MHz, CDCl3): d = 7.27–7.60 (m, 20H, Ph-H), 5.37
(d, J = 8.5 Hz, 1H, Hb), 4.36 (dt, J = 8.5, 4.5 Hz, 1H, Ha), 4.16 (m,
(500.0 MHz, CDCl3): d = 7.28–7.59 (m, 20H, Ph-H), 5.70 (d,
J = 9.5 Hz, 1H, Hb), 4.32 (td, J = 9.5, 4.5 Hz, 1H, Ha), 4.19 (m, 1H,
0
0
0
1H, Hi), 3.96 (dd, Je e = 10.6 Hz, Je h = 7.6 Hz, 1H, He ), 3.45 (dt,
e
0
0
0
0
Hd), 3.52 (dd, Je e = 10.7 Hz, Je h = 7.2 Hz, 1H, He ), 3.29 (dt,
Jee0 ¼ JPCCH ¼ 10:6 Hz, Jeh = 8.3 Hz, 1H, He), 3.15 (td, Jgg = 13.0 Hz,
Jee0 ¼ JPCCH ¼ 10:7 Hz, Jeh = 8.2 Hz, 1H, He), 3.08 (td, Jgg = 13.0 Hz,
Jgi ¼ JgPCH ¼ 3:6 Hz, 1H, Hg), 2.82 (m, 1H, Hh), 2.17–2.31 (overlapped
e
0
Jgd ¼ JgPCH ¼ 3:0 Hz, 1H, Hg), 2.86 (dd, J = 16.5, 4.5 Hz, 1H, Hc), 2.79
m, 3H, Hd and Hf), 1.91–1.96 (overlapped m, 2H, Hg and Hc), 1.83
0
0
0
0
(m, 1H, Hh), 2.26 (dd, J = 16.5, 4.5 Hz, 1H, Hc ), 2.24 (overlapped
(m, 1H, Hf ), 1.65 (m, 1H, Hc ), 1.42 (s, 9H, OtBu-Me or Boc-Me),
1.40 (s, 9H, OtBu-Me or Boc-Me); 13C NMR (125.7 MHz, CDCl3):
d = 172.0, 170.0, 155.5, 139.0, 136.7, 136.4, 136.0, 133.4, 133.3,
133.1, 132.9, 132.7, 132.5, 129.2, 128.7, 128.5, 128.4, 128.4, 80.4,
79.4, 56.5, 51.5, 51.2, 36.4, 36.1, 33.4, 30.9, 28.3, 28.1; 31P NMR
0
0
0
m, 1H, Hf), 2.19 (dd, Jg g = 13.0 Hz, Jg d = 10.0 Hz, 1H, Hg ), 1.92 (m,
1H, Hf ), 1.44 (s, 18H, Boc-Me and OtBu-Me); 13C NMR
0
(125.7 MHz, CDCl3): d = 170.8, 168.4, 155.7, 138.9, 137.2, 136.5,
136.1, 133.1, 132.9, 132.8, 129.2, 128.7, 128.5, 128.4, 81.5, 79.4,
56.4, 51.3, 50.6, 37.2, 36.2, 35.8, 33.2, 28.3, 27.9; 31P NMR
(202.4 MHz, CDCl3): d = ꢁ6.8, ꢁ8.0, ꢁ22.1, ꢁ22.5 (two peaks P
a
(202.4 MHz, CDCl3): d = ꢁ6.1, ꢁ9.1, ꢁ22.2, ꢁ22.7 (two peaks P
and Pb due to the two conformations of the RCO group at room
a
and Pb due to the two conformations of the RCO group at room
temperature); HRMS (Q-Tof MS, ES+): m/z = 739.3409, calcd for
temperature); HRMS (Q-Tof MS, ES+): m/z = 725.3253, calcd for
C
43H53N2O5P2 [M+H]+: 739.3430.
C
42H51N2O5P2 [M+H]+: 725.3273.
Ph2P
b
g, g'
CH2
d
BocHN
f, f'
H2C
COOtBu
H
Ph2P
f'
H
O
C
H
f,
H
H
g, g'
CH2
CH2
OtBu
H a
c, c'
H
d
H
H2C
N
N
NHBoc
b
O
Ph2P
H
H
O
h H
Ph2P
H
h
H
H
e,e'
4.10. Preparation and characterization of 5e
4.8. Preparation and characterization of 5c
Compound 5e was synthesized by a DIC-promoted condensa-
tion of PPM with Boc-L-Glu-OtBu as described for ligand 5a. Col-
Compound 5c was synthesized by a DIC-promoted condensa-
umn chromatography (degassed SiO2, petroleum ether/EtOAc = 3/
tion of PPM with Boc-D-Asp-OtBu as described for ligand 5a. Col-
1) under argon afforded the pure product 5e as a white solid; yield:
umn chromatography (degassed SiO2, petroleum ether/EtOAc = 3/
92.0%. mp: 175–176 °C; ½a D20
ꢃ
¼ ꢁ8:7 (c 0.5, CH2Cl2); 1H NMR
1) under argon afforded the pure product 5c as a white solid; yield:
94.3%. mp: 190–192 °C; ½a D20
ꢃ
¼ ꢁ37:2 (c 0.1, CH2Cl2); 1H NMR
(500.0 MHz, CDCl3): d = 7.27–7.60 (m, 20H, Ph-H), 5.24 (d,
J = 8.0 Hz, 1H, Hb), 4.17(m, 1H, Hi), 4.06 (dt, J = 8.0, 4.5 Hz,1H, Ha),
(500.0 MHz, CDCl3): d = 7.27–7.57 (m, 20H, Ph-H), 5.85 (d,
J = 9.5 Hz, 1H, Hb), 4.37 (ddd, J = 9.5, 4.0, 3.0 Hz, 1H, Ha), 4.11 (m,
0
0
0
3.52 (dd, Je e = 10.5 Hz, Je h = 7.0 Hz, 1H, He ), 3.30 (dt,
e
0
0
0
0
Jee0 ¼ JPCCH ¼ 10:5 Hz, Jeh = 8.4 Hz, 1H, He), 3.14 (td, Jgg = 13.5 Hz,
1H, Hd), 3.49 (t, Je e = Je h = 9.5 Hz, 1H, He ), 3.32 (q,
Jgi ¼ JgPCH ¼ 3:0 Hz, 1H, Hg), 2.82 (m, 1H, Hh), 2.29 (m, 1H, Hf),
Jee0 ¼ JePCCH ¼ 9:5 Hz,
1H,
He),
3.28
(td,
Jgg = 12.5 Hz,
0
Jgd ¼ JgPCH ¼ 2:5 Hz, 1H, Hg), 2.83 (dd, J = 16.5, 4.0 Hz, 1H, Hc), 2.78
0
2.23 (m, 1H, Hd), 2.11 (overlapped m, 1H, Hg ), 2.06 (overlapped
0
0
m, 1H, Hc), 2.02 (overlapped m, 1H, Hd ), 1.96 (overlapped m, 1H,
(m, 1H, Hh), 2.56 (dd, J = 16.5, 3.0 Hz, 1H, Hc ), 2.22 (m, 1H, Hf),
0
0
0
0
0
0
Hf ), 1.79 (m, 1H, Hc ), 1.42 (s, 9H, Boc-Me or OtBu-Me), 1.39 (s,
9H, OtBu-Me or Boc-Me); 13C NMR (125.7 MHz, CDCl3): d = 171.5,
170.1, 155.5, 138.9, 137.0, 136.6, 136.1, 133.3–132.7 (overlapped
m, Ph-C), 129.3–128.3 (overlapped m, Ph-C), 81.8, 79.5, 56.3,
53.8, 51.1, 36.2, 35.7, 33.3, 31.5, 28.3, 27.9, 27.6; 31P NMR
1.89 (t, Jg g = Jg d = 12.5 Hz, 1H, Hg ), 1.74 (m, 1H, Hf ), 1.43 (s, 9H,
Boc-Me or OtBu-Me), 1.40 (s, 9H, OtBu-Me or Boc-Me); 13C NMR
(125.7 MHz, CDCl3): d = 170.6, 168.6, 155.8, 139.0, 137.0, 136.3,
136.0, 132.7–133.1 (overlapped m, Ph-C), 128.3–129.4 (overlapped
m, Ph-C), 81.6, 79.4, 56.5, 50.8, 50.6, 37.7, 36.6, 35.8, 33.7, 28.3,
27.9; 31P NMR (202.4 MHz, CDCl3): d = ꢁ6.4, ꢁ8.6, ꢁ22.2, ꢁ22.4
(202.4 MHz, CDCl3): d = ꢁ6.6, ꢁ8.9, ꢁ22.7, ꢁ22.8 (two peaks P
a
and Pb due to the two conformations of the RCO group at room
(two peaks P and Pb due to the two conformations of the RCO
a
temperature); HRMS (Q-Tof MS, ES+): m/z = 739.3402, calcd for
C
group at room temperature); HRMS (Q-Tof MS, ES+): m/
43H53N2O5P2 [M+H]+: 739.3430.
z = 725.3257, calcd for C42H51N2O5P2 [M+H]+: 725.3273.
Ph2P
f, f'
H
O
C
b
a
H
Ph2P
g, g'
BocHN
g, g'
CH2
OtBu
f, f'
c,c'
CH2
COOtBu
H
H
H
NHBoc
H2C
d, d'
H
d
H
H2C
O
CH2
c, c'
b
a
i
N
H
N
O
Ph2P
H
h
H
e,e'
Ph2P
H
H
h
H
H
e,e'
4.9. Preparation and characterization of 5d
4.11. Preparation and characterization of 3aꢀCF3COOH
Typically, Schlenk flask was charged with 5a (2.3 g,
Compound 5d was synthesized by a DIC-promoted condensa-
tion of PPM with Boc-L-Glu(OtBu)-OH as described for ligand 5a.
a
Column chromatography (degassed SiO2, petroleum ether/
0.0032 mol), Et3SiH (0.92 g, 0.0079 mol), and 10 mL of trifluoroace-
tic acid under an argon atmosphere, and the solution was stirred for
5 h at room temperature. Then, trifluoroacetic acid was evaporated
EtOAc = 3/1) under argon afforded the pure product 5d as a white
solid; yield: 92.7%. mp: 137–139 °C; ½a D20
¼ ꢁ14:2 (c 0.5, CH2Cl2);
ꢃ

X. Jin et al. / Tetrahedron: Asymmetry 23 (2012) 1058–1067
1065
under reduced pressure to give a trifluoroacetic acid salt of 3a. The
salt was submitted to column chromatography (degassed SiO2,
EtOAc/MeOH/H2O = 15:3:2) under argon to give the pure product
3aꢀCF3COOH as a white solid; yield: 2.1 g (98.0%). mp: 203–
Jgd ¼ JgPCH ¼ 3:0 Hz, 1H, Hg), 3.02 (m, 1H, Hc), 2.97 (dd, J = 17.5,
0
0
3.5 Hz, 1H, Hb), 2.68 (dd, J = 17.5, 7.5 Hz, 1H,Hb ), 2.14 (m, 2H, Hg
and Hf ), 1.74 (m, 1H, Hf); 31P NMR (202.4 MHz, CD3OD): d = ꢁ6.5,
0
ꢁ7.5, ꢁ20.8, ꢁ21.8 (two peaks P and Pb due to the two conforma-
a
205 °C; ½a 2D0
ꢃ
¼ ꢁ37:5 (c 0.24, EtOH); 1H NMR (500.0 MHz, CD3OD):
tions of the RCO group at room temperature); HRMS (Q-Tof MS,
d = 7.35–7.58 (m, 20H, Ph-H), 4.43 (dd, J = 8.6, 4.2 Hz, 1H, Ha), 4.26
ES+): m/z = 569.2139, calcd for C33H35N2O3P2 [M+H]+: 569.2123.
0
0
0
(m, 1H, Hd), 3.80 (dd, Je e = 10.5 Hz, Je c = 7.5 Hz, 1H, He ), 3.47 (dt,
Jee0 ¼ JePCCH ¼ 10:5 Hz, Jec = 8.0 Hz, 1H, He), 2.96 (overlapped m, 2H,
Ph2P
g, g'
CH2
f, f'
COOH
0
Hc and Hg), 2.80 (dd, J = 17.6, 4.2 Hz, 1H, Hb ), 2.63 (dd, J = 17.6,
H
b,b'
H
d
H
H2C
0
0
0
+
8.6 Hz, 1H, Hb), 2.29 (dd, Jg g = 13.5 Hz, Jg d = 9.7 Hz, 1H, Hg ), 2.12
NH3 CF3COO-
(m, 1H, Hf ), 1.74 (m, 1H, Hf); 13C NMR (125.7 MHz, CD3CN, 50
lL
0
N
H
a
of HBF4): d = 172.1, 168.8, 135.9, 135.7, 134.7, 134.6, 134.3, 133.6,
O
131.2 (overlapped m), 54.9, 50.5, 49.4, 35.1, 33.8, 31.7, 27.5; 31P
Ph2P
H
c
H
H
NMR (202.4 MHz, CD3OD, 50
l
L of CF3COOD): d = ꢁ5.7, ꢁ8.2,
e,e'
ꢁ21.5, ꢁ22.5 (two peaks P and Pb due to the two conformations
a
of the RCO group at room temperature); HRMS (Q-Tof MS, ES+):
4.14. Preparation and characterization of 3dꢀCF3COOH
m/z = 569.2141, calcd for C33H35N2O3P2 [M+H]+: 569.2123.
The trifluoroacetic acid salt of 3d was synthesized as described
for ligand 3aꢀCF3COOH. Column chromatography (degassed SiO2,
EtOAc/MeOH/H2O = 15:3:2) under argon afforded the pure trifluo-
roacetic acid salt of 3d as a white solid; yield: 82.7%. mp: 97–99 °C;
Ph2P
CF3COO-
+H3N
g, g'
CH2
a
H
f, f'
COOH
CH2
H
H
H
d
a 2D0
¼ ꢁ12:0 (c 0.25, MeOH); 1H NMR (500.0 MHz, CD3OD):
b,b'
½ ꢃ
N
d = 7.27–7.55 (m, 20H, Ph-H), 4.21 (m, 1H, Hd), 4.10 (dd, J = 7.9,
O
0
0
0
3.5 Hz, 1H, Ha), 3.78 (dd, Je e = 10.5 Hz, Je h = 7.0 Hz, 1H, He ), 3.44
Ph2P
H
c
H
(dt, Jee0 ¼ JePCCH ¼ 10:5 Hz, Jeh = 8.0 Hz, 1H, He), 3.02 (td,
H
e,e'
g
0
Jgg = 13.0 Hz, Jgd ¼ JPCH ¼ 3:3 Hz, 1H, Hg), 2.93 (m, 1H, Hh), 2.34
4.12. Preparation and characterization of 3bꢀCF3COOH
0
0
0
(m, 2H, Hc), 2.22 (dd, Jg g = 13.0 Hz, Jg d = 10.3 Hz, 1H, Hg ), 2.07
0
0
(m, 1H, Hf ), 1.94 (m, 1H, Hb), 1.86 (m, 1H, Hb ), 1.70 (m, 1H, Hf);
13C NMR (125.7 MHz, CD3CN, 50
L of HBF4): d = 175.2, 169.8,
135.8, 134.7, 134.3, 133.8, 131.1, 130.8, 55.2, 53.2, 50.3, 36.0,
32.9, 29.8, 27.4, 25.8; 31P NMR (202.4 MHz, CD3OD, 50
L of
The trifluoroacetic acid salt of 3b was synthesized as described
for ligand 3aꢀCF3COOH. Column chromatography (degassed SiO2,
EtOAc/MeOH/H2O = 15:3:2) under argon afforded the pure trifluo-
roacetic acid salt of 3b as a white solid; yield: 98.7%. mp: 128–
l
l
CF3COOD): d = ꢁ5.3, ꢁ8.7, ꢁ22.2, ꢁ22.5 (two peaks P and Pb due
a
131 °C; ½a 2D0
ꢃ
¼ ꢁ7:8 (c 0.25, MeOH); 1H NMR (500.0 MHz, CD3OD):
to the two conformations of the RCO group at room temperature);
HRMS (Q-Tof MS, ES+): m/z = 583.2266, calcd for C34H37N2O3P2
[M+H]+: 583.2279.
d = 7.32–7.50 (m, 20H, Ph-H), 4.23 (m, 1H, Hd), 4.07 (dd, J = 7.5,
0
0
0
3.5 Hz, 1H, Ha), 3.67 (t, Je e = Je c = 10.0 Hz, 1H, He ), 3.36 (q,
Jee0 ¼ JecJe
¼ 10:0 Hz, 1H, He), 3.01 (overlapped m, 2H, Hc and
PCCH
-
g, g'
CH2
CF3COO
c
Hg), 2.91 (dd, J = 17.6, 7.5 Hz, 1H, Hb), 2.68 (dd, J = 17.6, 3.5 Hz,
Ph2P
f, f'
a
+H3N
H
H2C
COOH
0
0
0
0
1H, Hb ), 2.41 (dd, Jg g = 13.5 Hz, Jg d = 9.4 Hz, 1H, Hg ), 2.18 (m, 1H,
H
H
Hf ), 1.87 (m, 1H, Hf); 13C NMR (125.7 MHz, CD3OD, 50
l
L of
0
CH2
b, b'
H
CF3COOD): d = 171.0, 168.9, 140.1, 139.0, 138.2, 137.7, 134.5,
N
134.1, 133.8, 130.4, 129.9, 129.7, 129.6, 58.2, 52.3, 50.9, 36.8,
O
36.5, 35.1, 34.2; 31P NMR (202.4 MHz, CD3OD, 50
lL of CF3COOD):
Ph2P
H
h
H
d = ꢁ6.1, ꢁ7.6, ꢁ21.0, ꢁ21.8 (two peaks P and Pb due to the two
H
a
e,e'
conformations of the RCO group at room temperature); HRMS
(Q-Tof MS, ES+): m/z = 569.2144, calcd for C33H35N2O3P2 [M+H]+:
569.2123.
4.15. Preparation and characterization of 3eꢀCF3COOH
The trifluoroacetic acid salt of 3e was synthesized as described
for ligand 3aꢀCF3COOH. Column chromatography (degassed SiO2,
EtOAc/MeOH/H2O = 15:3:2) under argon afforded the pure trifluo-
roacetic acid salt of 3e as a white solid; yield: 75.2%. mp: 70–72 °C;
Ph2P
g, g'
CH2
f, f'
COOH
H
b,b'
H
d
H
H2C
a
H
+CF3COO-
N
NH3
½
a 2D0
ꢃ
¼ ꢁ7:8 (c 0.25, MeOH); 1H NMR (500.0 MHz, CD3OD):
O
d = 7.28–7.56 (m, 20H, Ph-H), 4.22 (m, 1H, Hd), 3.69 (t,
Ph2P
H
c
H
0
0
0
0
Je e = Je h = 10.0 Hz, 1H, He ), 3.55 (t, Jab = Jab = 5.6 Hz, 1H, Ha), 3.34
H
(q, Jee0 ¼ Jeh ¼ JePCCH ¼ 10 Hz, 1H, He), 3.00 (m, 1H, Hh), 2.93 (td,
e,e'
g
0
0
Jgg = 13.5 Hz, Jgd ¼ JPCH ¼ 3:0 Hz, 1H, Hg), 2.46 (td, Jcc = 17.0 Hz,
4.13. Preparation and characterization of 3cꢀCF3COOH
0
0
0
Jcb = Jcb = 7.0 Hz, 1H, Hc), 2.38 (dd, Jg g = 13.5 Hz, Jg d = 9.5 Hz, 1H,
0
0
0
0
0
0
Hg ), 2.23 (td, Jc c = 17.0 Hz, Jc b = Jc b = 7.0 Hz, 1H, Hc ), 2.14 (m,
1H, Hf), 2.00 (m, 2H, Hb, Hb ), 1.85 (m, 1H, Hf ); 13C NMR
(125.7 MHz, CD3OD, 50 L of CF3COOD): d = 171.9, 171.6, 139.8,
The trifluoroacetic acid salt of 3c was synthesized as described
for ligand 3aꢀCF3COOH. Column chromatography (degassed SiO2,
EtOAc/MeOH/H2O = 15:3:2) under argon afforded the pure trifluo-
roacetic acid salt of 3c as a white solid; yield: 95.0%. mp: 88–91 °C;
0
0
l
138.8, 138.2, 137.8, 133.8–134.5 (overlapped m, Ph-C), 129.6–
130.4 (overlapped m, Ph-C), 58.1, 53.3, 52.5, 36.8, 36.3, 34.1,
31.7, 26.5; 31P NMR (202.4 MHz, CD3OD, 50
lL of CF3COOD):
½
a 2D0
ꢃ
¼ ꢁ15:0 (c 0.1, MeOH); 1H NMR (500.0 MHz, CD3OD):
d = 7.27–7.55 (m, 20H, Ph-H), 4.16 (m, 1H, Hd), 3.86 (dd, J = 7.5,
d = ꢁ6.4, ꢁ7.7, ꢁ22.1 (two peaks P and Pb due to the two confor-
a
0
0
0
3.5 Hz, 1H, Ha), 3.71 (t, Je e = Je c = 10.0 Hz, 1H, He ), 3.36 (q,
mations of the RCO group at room temperature); HRMS (Q-Tof MS,
Jee0 ¼ JecJe
¼ 10:0 Hz, 1H, He), 3.15 (td, Jgg = 13.0 Hz,
ES+): m/z = 583.2261, calcd for C34H37N2O3P2 [M+H]+: 583.2279.
0
PCCH

1066
X. Jin et al. / Tetrahedron: Asymmetry 23 (2012) 1058–1067
3. (a) Frohning, C. D.; Kohlpainter, C. W. In Applied Homogeneous Catalysis with
a
CF3COO-
Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH:
Weinheim, 1996; p 29; (b) Pu, L. Chem. Rev. 1998, 98, 2405–2494; (c) Fan, Q. H.;
Li, Y. M.; Chan, A. S. C. Chem. Rev. 2002, 102, 3385–3466.
H
g, g'
CH2
Ph2P
+H3N
f, f'
COOH
H
H
c, c'
H2C
4. (a) Berthod, B.; Mignani, G.; Woodward, G.; Lemaire, M. C. Chem. Rev. 2005, 105,
1801–1836; (b) Heitbaum, M.; Glorius, F.; Escher, I. Angew. Chem., Int. Ed. 2006,
45, 4732–4762; (c) Nielsen, M.; Thomsen, A. H.; Jensen, T. R.; Jakobsen, H. J.;
Skibsted, J.; Gothelf, K. V. Eur. J. Org. Chem. 2005, 342–347; (d) Saluzzo, C.;
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Synth. Catal. 2002, 344, 239–260.
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Science 1997, 275, 823–826; (b) Horvth, I. T. Acc. Chem. Res. 1998, 31, 641–650.
7. Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. Rev. 1999, 99, 475–493.
8. Welton, T. Chem. Rev. 1999, 99, 2071–2083.
H
d
CH2
b, b'
N
O
Ph2P
H
h
H
H
e,e'
4.16. Preparation and characterization of 4
Compound 4 was synthesized by a DIC-promoted condensation
of PPM with 1-carboxymethyl-3-methylimidazolium tetrafluoro-
9. (a) Dupont, J.; de Souza, R. F. Chem. Rev. 2002, 102, 3667–3691; (b) Baudequin,
C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumont, A. C.; Plaquevent, J. C.
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R. Chimie 2007, 10, 152–177.
borate.
A
mixture of PPM (0.56 g, 0.0012 mmol), 1-carboxy-
tetrafluoroborate (0.28 g,
methyl-3-methyl-imidazolium
10. (a) Chauvin, Y.; Mussmann, L.; Olivier, H. Angew. Chem., Int. Ed. Engl. 1995, 34,
2698–2700; (b) Guernik, S.; Wolfson, A.; Herskowitz, M.; Greenspoon, N.;
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Delgado, M. R.; Dupont, J. Tetrahedron: Asymmetry 2001, 12, 1825–1828; (d)
Frater, T.; Gubicza, L.; Szollosy, A.; Bakos, J. Inorg. Chim. Acta. 2006, 359, 2756–
2759; (e) Boyle, K. L.; Lipsky, E. B.; Kalberg, C. S. Tetrahedron Lett. 2006, 47,
1311–1313.
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2004, 15, 2219–2221; (c) Hu, A.; Ngo, H. L.; Lin, W. Angew. Chem., Int. Ed. 2004,
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2459–2477.
0.0012 mmol) and DIC (0.16 g, 0.0012 mmol) in 10 mL of degassed
CH2Cl2 was stirred at room temperature for 10 h under an argon
atmosphere. The completion of the reaction was monitored by
TLC analysis. Then, the solvent was partially removed under re-
duced pressure, and the residue was purified by column chroma-
tography (degassed SiO2, EtOAc/MeOH/ H2O = 15/6/2) under
argon to afford the pure product 4 as a white solid; yield: 0.48 g
(58.5%). mp: 149–150 °C; ½a D20
ꢃ
¼ ꢁ34:8 (c 0.25, MeOH); 1H NMR
(500.0 MHz, CD3CN): d = 8.30 (s, 1H, Hb), 7.32–7.54 (m, 21H, Ph-
H and Hc or Hd), 7.21 (t, J = 1.6 Hz, 1H, Hd or Hc), 4.89 (d,
0
0
0
Jee = 16.8 Hz, 1H, He), 4.61 (d, Je e = 16.8 Hz, 1H, He ), 4.11 (m,
j
0
0
Jjg = 3.3 Hz, Jjg ¼ Jjh ¼ Jjh ¼ JPCCH ¼ 8:0 Hz, 1H, Hj), 3.85 (s, 3H, Ha),
f0
0
0
0
3.67 (t,
J
f f = Jf i = 10.0 Hz, JPCCH ¼ 0 Hz 1H, Hf ), 3.39 (q,
Jff ¼ Jfi ¼ JPCCH ¼ 10:0 Hz, 1H, Hf), 3.08 (m, Ji ¼ 17 Hz, 1H, Hi),
f
0
PCH
g0
0
0
2.97 (td, Jg g = 13.4 Hz, Jg0j ¼ JPCH ¼ 3:3 Hz, 1H, Hg ), 2.22–2.26 (over-
14. (a) Ni, B.; Headley, A. D. Chem. Eur. J. 2010, 16, 4426–4436; (b) Lombardo, M.;
Trombini, C. ChemCatChem 2010, 2, 135–145; (c) Šebesta, R.; Kmentová, I.;
Toma, Š. Green Chem. 2008, 10, 484–496.
lapped m, 2H, Hg and Hh), 1.88 (m, 1H, Hh ); 13C NMR (125.7 MHz,
0
CD3CN): d = 163.4, 139.9, 138.6, 138.1, 138.0, 137.5, 134.3, 133.7,
133.6, 130.3, 129.7, 129.5, 124.8, 123.9, 58.0, 51.8, 51.0, 37.0,
36.3, 35.8, 33.5; 31P NMR (202.4 MHz, CD3OD): d = ꢁ6.7, ꢁ7.9,
15. (a) Lee, S.-G.; Zhang, Y. J.; Piao, J. Y.; Yoon, H.; Song, C. E.; Choi, J. H.; Hong, J.
Chem. Commun. 2003, 2624–2625; (b) Geldbach, T. J.; Dyson, P. J. J. Am. Chem.
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T.; Shibuta, H.; Uchida, N.; Yamashita, M.; Ohta, S. Chem. Commun. 2005, 2134–
2136; (d) Feng, X.; Pugin, B.; Küsters, E.; Sedelmeier, G.; Blaser, H.-U. Adv.
Synth. Catal. 2007, 349, 1803–1807; (e) Gadenne, B.; Hesemann, P.; Moreau, J. J.
E. Tetrahedron Lett. 2004, 45, 8157–8160; (f) Gadenne, B.; Hesemann, P.;
Moreau, J. J. E. Tetrahedron: Asymmetry 2005, 16, 2001–2006; (g) Baleizão, C.;
Gigante, B.; García, H.; Corma, A. Tetrahedron 2004, 60, 10461–10468; (h)
Doherty, S.; Goodrich, P.; Hardacre, C.; Knight, J. G.; Nguyen, M. T.; Pârvulescu,
V.; Paun, C. Adv. Synth. Catal. 2007, 349, 951–963; (i) Doherty, S.; Goodrich, P.;
Hardacre, C.; Pârvulescu, V.; Paun, C. Adv. Synth. Catal. 2008, 350, 295–302; (j)
Gavrilov, K. N.; Lyubimov, S. E.; Bondarev, O. G.; Maksimova, M. G.; Zheglov, S.
V.; Petrovskii, P. V.; Davankov, V. A.; Reetz, M. T. Adv. Synth. Catal. 2007, 349,
609–616; (k) Yang, S.-D.; Shi, Y.; Sun, Z.-H.; Zhao, Y.-B.; Liang, Y.-M.
ꢁ21.5, ꢁ22.3 (two peaks P and Pb due to the two conformations
a
of the RCO group at room temperature); HRMS (Q-Tof MS, ES+):
m/z = 576.2329, calcd for C35H36N3OP2 [M]+: 576.2334.
b
H
Ph2P
h, h'
a
g, g'
CH2
CH3
BF4
N
H
e, e'
H2C
H
H
j
N
N
ˇ
Tetrahedron: Asymmetry 2006, 17, 1895–1900; (l) Šebesta, R.; Bilcík, F.
H c
ˇ
Tetrahedron: Asymmetry 2009, 20, 1892–1896; (m) Šebesta, R.; Meciarová,
M.; Polácková, V.; Veverková, E.; Kmentová, I.; Gajdošiková, E.; Cvengroš, J.;
O
d
H
ˇ
Ph2P
Buffa, R.; Gajda, V. Coll. Czech. Chem. Commun. 2007, 72, 1057–1068; (n) Pugin,
B.; Groehn, V.; Moser, R.; Blaser, H. U. Tetrahedron: Asymmetry 2006, 17, 544–
549.
H
i
H
H
f, f'
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Acknowledgments
We gratefully thank the support of this investigation by the Na-
tional Natural Science Foundation of China (Nos. 20606019 and
20976086) and Natural Science Foundation of Qingdao, China
(No. 12-1-4-3-(6)-jch).
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