Rh-ImiFerroPhos complexes catalyzed asymmetric hydrogenation of β-substituted α,β-unsaturated hosphonates

Article abstract of DOI:10.1016/S1872-2067(12)60742-6

A series of chiral ferrocenyl diphosphine ligands (ImiFerroPhos ligands) has been applied to the hydrogenation of β-substituted α,β- unsaturated phosphonates to generate a range of optically active β-substituted alkylphosphonates in good yields with good

Full text of DOI:10.1016/S1872-2067(12)60742-6

Chinese Journal of Catalysis 35 (2014) 227–231
ava i l a b l e a t w w w. s c i e n c ed i r e c t . c o m
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Article
Rh‐ImiFerroPhos complexes catalyzed asymmetric hydrogenation
of β‐substituted α,β‐unsaturated phosphonates
Zhengchao Duana,*, Lianzhi Wanga, Xiaoyu Zuoa, Xiangping Hub,#, Zhuo Zhengb
a School of Chemical and Enviromental Engineering, Hubei University for Nationalities, Enshi 445000, Hubei, China
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of chiral ferrocenyl diphosphine ligands (ImiFerroPhos ligands) has been applied to the
hydrogenation of β‐substituted α,β‐unsaturated phosphonates to generate a range of optically ac‐
tive β‐substituted alkylphosphonates in good yields with good enantioselectivity (up to 92% ee)
under mild reaction conditions.
Received 11 September 2013
Accepted 23 October 2013
Published 20 February 2014
© 2014, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
β‐Substituted α,β‐unsaturated
phosphonate
Asymmetric catalytic hydrogenation
ImiFerroPhos ligands
Rhodium (II) complex
Chiral β‐substituted alkylphosphonate
1. Introduction
drogenation of β‐substituted α,β‐unsaturated phosphonates
[30,31] and β‐substituted β,γ‐unsaturated phosphonates
It is envisaged that chiral phosphonates will become in‐
creasingly useful chiral building blocks in organic synthesis
[1–8]. Furthermore, there has been considerable interest in the
biological properties of the phosphorus analogues of carboxylic
acids [9,10]. Although several efficient processes have been
developed during the past few decades for synthesis of chiral
1‐arylethylphosphonates [11–18], methods for the catalytic
enantioselective synthesis of chiral alkylphosphonates, espe‐
cially those bearing a β‐stereogenic center, remain scarce
[19–21]. Given its inherent efficiency and atom economy, it was
envisaged that catalytic asymmetric hydrogenation [22–29]
would provide an ideal approach for the preparation of chiral
phosphonate derivatives. We recently developed several new
synthetic methods involving the Rh‐catalyzed asymmetric hy‐
[32,33]. Although there have already been several reports in
the literature pertaining to the asymmetric hydrogenation of
unsaturated phosphonates, the number of effective catalysts
available for this transformation is limited, and the research
towards the development of new catalysts remains a great
challenge.
In our previous study, we developed a series of chiral
ImiFerroPhos ligands and used the rhodium complexes of the
ligand to affect the highly enantioselective hydrogenation of a
series of 3‐aryl‐substituted 2‐phosphonomethylpropenoates
[34]. The structure of the ImiFerroPhos ligands was similar to
that of the TaniaPhos ligand, which showed high levels of activ‐
ity towards the hydrogenation of β‐substituted α,β‐unsaturated
phosphonates but provided poor enantioselectivity. The
* Corresponding author. Tel/Fax: +86‐718‐8437531; E‐mail: dzhch168@163.com
# Corresponding author. Tel: +86‐411‐84379276; Fax: +86‐411‐84684746; E‐mail: xiangping@dicp.ac.cn
This work was supported by the National Natural Science Foundation of China (21262011).
DOI: 10.1016/S1872‐2067(12)60742‐6 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 35, No. 2, February 2014

Zhengchao Duan et al. / Chinese Journal of Catalysis 35 (2014) 227–231
ImiFerroPhos ligands, which contain a heterocycle, are more
distilled to dryness in vacuo to give the crude product as a res‐
idue, which was purified by column chromatography (silica gel,
EtOAc:hexane = 1:1).
amenable to asymmetric catalysis than other chiral ligands
because they can be readily constructed and derivatized, and
possess unique electronic and steric properties. In the current
study, we investigated the application of ImiFerroPhos ligands
to the Rh‐catalyzed asymmetric hydrogenation of β‐substituted
α,β‐unsaturated phosphonates. The ImiFerroPhos ligands per‐
formed effectively in this regard to give the corresponding chi‐
ral phosphonates in good to high enantioselectivity under mild
hydrogenation condition.
2.4. General procedure for asymmetric hydrogenation of
α,β‐unsaturated phosphonates
In a nitrogen‐filled glove box, [Rh(COD)2]BF4 (1.0 mg,
0.0025 mmol) and (Rc,SFc)‐ImiFerroPhos (0.0028 mmol) were
dissolved in degassed CH2Cl2 (1 ml) in a 5 ml vial. Following a
15‐min period of stirring at room temperature, a solution of
α,β‐unsaturated phosphonate (1, 0.25 mmol, S/C = 100) in
degassed CH2Cl2 (1 ml) was added to the reaction vial, and the
resulting mixture was transferred to an autoclave. The auto‐
clave was then charged with H2 (≈ 1 MPa), and the reaction
mixture was hydrogenated at room temperature for 24 h. The
H2 gas was carefully released from the autoclave, and the reac‐
tion mixture was passed through a plug of silica gel (eluting
with a mixture of hexanes/EtOAc) to afford β‐substituted al‐
kylphosphonates (2). The enantiomeric excess was determined
by HPLC on a chiral stationary phase.
2. Experimental
2.1. General methods
All of the reactions and manipulations were performed in a
nitrogen‐filled glove box or under a nitrogen atmosphere using
Schlenk techniques unless otherwise noted. All of the solvents
were distilled under argon in the presence of the following
desiccants: sodium and benzophenone for toluene and tetra‐
hydrofuran (THF), and CaH2 for dichloromethane (CH2Cl2). The
NMR spectra were obtained on a Bruker DRX 400 spectrome‐
ter. 31P NMR shifts were referenced to external 85% H3PO4,
3. Results and discussion
1
while 13C and H NMR shifts were referenced to the residual
signals of deuterated solvents.
Diethyl (E)‐(2‐phenyl‐1‐propene) phosphonate (E)‐1a was
initially selected as a model substrate for the ligand screening
and optimization experiments for the Rh‐catalyzed asymmetric
hydrogenation reaction. The reactions were typically conduct‐
ed at room temperature for 24 h in CH2Cl2 under 1 MPa of H2
pressure using 1% of [Rh(COD)2]BF4 and 1.1% of ligand. The
results are summarized in Table 1. When (Rc,SFc)‐ImiFerroPhos
La (Fig. 1) bearing a methyl substituent in the ferrocenylmethyl
position was used as the ligand, 1a was hydrogenated to give
2a in 82% ee (Table 1, entry 2). This result showed that
ImiFerroPhos, which contained a heterocycle, was more effi‐
cient than TaniaPhos (Table 1, entry 2 vs entry 1). The intro‐
2.2. Preparation of ligands
All of the ligands used in the current study were prepared
according to previously reported procedures [34].
1‐{(R)‐1‐[(S)‐2‐(diphenylphosphino)ferrocenyl]lpropyl}‐2‐(
diphenylphosphino)benzimidazole (Le). Orange crystals; 1H
NMR (400 MHz, CDCl3): δ 0.63 (t, J = 8.0 Hz, 3H), 2.35 (m, 1H),
2.54 (m, 1H), 3.87 (s, 1H), 4.07 (m, 4H), 4.12 (s, 1H), 4.43 (s,
1H), 4.90 (s, 1H), 5.82 (m, 2H), 6.39 (m, 2H), 6.70 (m, 1H), 6.87
(m, 1H), 7.04 (m, 2H), 7.25 (m, 8H), 7.32 (m, 3H), 7.43 (m, 2H),
7.65 (m, 2H), 7.75 (m, 2H); 13C NMR (100 MHz CDCl3): δ 11.3,
28.9, 60.8 (d, J = 20 Hz), 68.3, 69.4, 70.1, 71.5, 74.4, 91.9, 111.7,
118.6, 120.0, 120.8, 125.3, 125.6, 126.2, 126.9, 127.0, 127.7,
128.2, 129.8, 133.1, 134.6, 135.6, 136.3, 136.8, 137.8; 31P NMR
(162 MHz, CDCl3): δ 25.5 (d, J = 59.9 Hz), 34.5 (d, J = 55.1 Hz);
HRMS (ESI): calcd for C44H38FeN2P2 [M+H]+, 713.1938; found,
713.1922.
Table 1
Asymmetric hydrogenation of diethyl (E)‐(2‐phenyl‐1‐propenyl)
phosphonate (1a).
[Rh(COD) ]BF (1%)
2
4
O
P
O
P
chiral ligand
OEt
OEt
OEt
OEt
*
Ph
Ph
H
2
(1 MPa), solvent, RT, 24 h
(E)-1a
2a
Entry
Ligand
TaniaPhos
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
i‐PrOH
THF
Conversiona (%)
eeb (%)
54 (R)
82 (S)
83 (S)
81 (S)
75 (S)
90 (S)
1
2
3
4
5
6
7
8
9
10
100
100
100
100
100
100
45
100
61
5
2.3. General procedure for the preparation of β‐substituted
α,β‐unsaturated phosphonates
La
Lb
Lc
Ld
Le
Le
Le
Le
Le
A solution of (EtO)2P(O)CH2P(O)(OEt)2 (1.44 g, 5 mmol) in
THF (2 ml) was slowly added to a slurry of NaH (0.19 g, 5.5
mmol, 70% in oil) in THF (10 ml) at 0 °C, and the resulting
mixture was stirred at room temperature for 30 min. A solution
of ketone (4.25 mmol) in THF (3 ml) was then added to the
reaction, and the resulting mixture was stirred at room tem‐
perature until the ketone could no longer be detected by TLC.
The mixture was then diluted with ether and washed sequen‐
tially with an aqueous solution of saturated NH4Cl (25 ml) and
brine (25 ml) before being dried over anhydrous Na2SO4 and
c
—
89 (S)
77 (S)
c
Toluene
—
The reactions were carried out with 0.25 mmol of substrate at room
temperature under H2 pressure of 1 MPa in 2 ml of the indicated sol‐
vent for 24 h.
a Determined by GC.
b Determined by HPLC on a chiral column.
c Not determined because of low conversion.

Zhengchao Duan et al. / Chinese Journal of Catalysis 35 (2014) 227–231
were successfully hydrogenated under the optimized condi‐
Ph2P
Ph2P
Ph2P
Fe
N
N
tions to give the corresponding 2‐arylpropylphosphonates in
good yields and good to high enantioselectivity (up to 92% ee).
These results indicated that the current catalytic system was
tolerant to the electronic properties of the substituents on the
phenyl ring of the substrate in terms of the impact of these
properties on the reactivity and enantioselectivity of the trans‐
formation. The position of the substituent on the phenyl ring
appeared to have very little impact on the outcome of the reac‐
tion. Three substrates bearing a methoxy group at the ortho,
meta, or para position of the phenyl ring were hydrogenated in
good enantioselectivity (Table 2, entries 2–4). The electronic
properties of the substituents at the para position of the phenyl
ring also appeared to have very little impact on the enantiose‐
lectivity, with electron withdrawing and electron donating
groups at this position providing similar results. Diethyl
(E)‐[2‐(2‐naphthyl)‐1‐propenyl] phosphonate (1g) and the
(S)‐heteroaromatic substrate 1h were also successfully hydro‐
genated under the optimized conditions to give the desired
products in 84% and 86% ee, respectively (Table 2, entries 7
and 8).
To expand the synthetic scope and application of this enan‐
tioselective procedure, we also applied the optimized condi‐
tions to a variety of other α,β‐unsaturated phosphonates (Fig.
2). As shown in Table 3, the β‐alkyl substituted α,β‐unsaturated
phosphonate (E)‐1i provided the hydrogenation product in
good yield with 75% ee (Table 3, entry 1). In contrast, the hy‐
drogenation of the corresponding (Z)‐isomer ((Z)‐1i), gave the
opposite enantiomer with a lower ee value (Table 3, entry 2).
The enantioselectivity results for substrates (E)‐1j and (E)‐1k
were lower than that of their methyl analogue (E)‐1a.
N
N
Ph2P
Ph2P
Ph2P
Fe
Fe
R
ImiFerroPhos
ImiFerroPhos
TaniaPhos
Le
La: R = Me
Lb: R = Et
Lc: R = Ph
Ld: R = i-Pr
Fig. 1. Structure of the ligands used for the asymmetric hydrogenation.
duction of an ethyl group, as in (Rc,SFc)‐ImiFerroPhos Lb, in‐
creased the enantioselectivity of the transformation very
slightly to 83% ee (Table 1, entry 3). Further increases in the
size of the substituent at the ferrocenyl position to a phenyl
(Lc) or i‐Pr (Ld) group, however, resulted in a reduction in the
enantioselectivity to 81% and 75% ee (Table 1, entries 4 and
5), respectively. The conversion of the imidazole heterocycle in
Lb to a benzimidazole (ligand Le) led to an increase in the ee
value to 90% (Table 1, entry 6).
It is noteworthy that both the catalytic activity and enanti‐
oselectivity of the Rh/(Rc,SFc)‐ImiFerroPhos Le complex were
sensitive to the solvent used. The use of protonic solvents such
as MeOH and i‐PrOH provided mixed results. For example, the
MeOH provided a much lower conversion (Table 1, entry 7),
whereas the i‐PrOH gave complete conversion, albeit with a
slightly lower enantioselectivity (Table 1, entry 8). THF and
toluene proved to be inferior solvents and gave lower conver‐
sions, with toluene providing the lowest conversion of all of the
solvents tested in the current study (Table 1, entries 9 and 10).
Encouraged by the positive results obtained for the hydro‐
genation of (E)‐1a, we proceeded to investigate the scope of
this transformation towards a variety of different β‐substituted
α,β‐unsaturated phosphonates 1a–1k, using (Rc,SFc)‐ImiFerro‐
Phos Le as the ligand and CH2Cl2 as the solvent under H2 pres‐
sure of 1 MPa at room temperature for 24 h. As shown in Table
2, a range of β‐aryl‐α,β‐unsaturated phosphonates (E)‐1a–1h
P(O)(OEt)2
(EtO)2(O)P
(E)-1i
P(O)(OEt)2
(Z)-1i
P(O)(OEt)2
Table 2
Asymmetric hydrogenation of diethyl (E)‐(2‐aryl‐1‐propene) phos‐
phonates (1a–1h).
Rh(COD)2BF4 (1%)
(Rc,SFc)-Le (1.1%)
O
(E)-1k
Fig. 2. Substrates for the asymmetric hydrogenation.
O
(E)-1j
OEt
OEt
OEt
OEt
*
P
P
Ar
Ar
H2 (1 MPa), CH2Cl2, RT
2
(E)-1
Table 3
Entry
Substrate
1a
Ar
Ph
Yielda (%)
eeb (%)
90 (S)
90 ()
90 ()
86 ()
92 ()
91 ()
84 ()
86 ()
Asymmetric hydrogenation of α,β‐unsaturated phosphonates 1i–1k.
1
2
3
4
5
6
7
8
98
94
95
96
97
96
94
95
Rh(COD)2BF4 (1%)
(Rc,SFc)-Le (1.1%)
R2
*
O
P
R2
O
P
1b
1c
1d
1e
1f
1g
1h
2‐MeOC6H4
3‐MeOC6H4
4‐MeOC6H4
4‐FC6H4
4‐ClC6H4
2‐naphthyl
2‐thiophenyl
OEt
OEt
OEt
OEt
R1
R1
H
2 (1MPa), CH2Cl2, RT
2
1
Entry
Substrate
(E)‐1i
Yielda (%)
eeb (%)
75 ()
64 (+)
69 ()
72 ()
1
2
3
4
97
98
96
97
(Z)‐1i
(E)‐1j
All reactions were carried out with 0.25 mmol of substrate at room
temperature under H2 pressure of 1 MPa in 2 ml of CH2Cl2 for 24 h with
substrate:Rh(COD)2BF4:ligand = 1:0.01:0.011.
(E)‐1k
All reactions were carried out with 0.25 mmol of substrate at room
temperature under H2 pressure of 1 MPa in 2 ml of CH2Cl2 for 24 h with
substrate:Rh(COD)2BF4:ligand = 1:0.01:0.011.
a Isolated yield.
b Determined by HPLC on a chiral column (Chiralpak AD‐H or OJ‐H), and
the absolute configurations were determined by comparing the optical
rotation data with those reported in the literature.
a Isolated yield.
b Determined by HPLC on a chiral column (Chiralpak AD‐H or OJ‐H).

Zhengchao Duan et al. / Chinese Journal of Catalysis 35 (2014) 227–231
Graphical Abstract
Chin. J. Catal., 2014, 35: 227–231 doi: 10.1016/S1872‐2067(12)60742‐6
Rh‐ImiFerroPhos complexes catalyzed asymmetric hydrogenation of β‐substituted α,β‐unsaturated phosphonates
Zhengchao Duan*, Lianzhi Wang, Xiaoyu Zuo, Xiangping Hu*, Zhuo Zheng
Hubei University for Nationalities; Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Ph2P
N
Rh(COD)2BF4 (1%)
ImiFerroPhos (1.1%)
O
P
O
P
N
OEt
OEt
OEt
OEt
*
Ph2P
Fe
Ar
Ar
H2 (1 MPa), CH2Cl2, RT
ImiFerroPhos
A range of optically active β‐substituted alkylphosphonates have been prepared in good yields and good enantioselectivity under mild
conditions via the Rh‐catalyzed asymmetric hydrogenation of β‐substituted α,β‐unsaturated phosphonates using chiral ImiFerroPhos
ligands.
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4. Conclusions
We have demonstrated that (Rc,SFc)‐ImiFerroPhos Le is a
suitable ligand for the Rh‐catalyzed asymmetric hydrogenation
of β‐substituted α,β‐unsaturated phosphonates, with good yield
and ee value of up to 92% being obtained for a range of sub‐
strates under mild hydrogenation conditions (i.e., 1 MPa of H2
pressure and room temperature). This catalytic system could
therefore be used in a practical sense for the synthesis of opti‐
cally active β‐substituted alkylphosphonates. The development
of new catalytic methods for the synthesis of chiral al‐
kylphosphonates is currently underway in our laboratory.
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