Iridium-catalyzed asymmetric hydrogenation of β-ketophosphonates with chiral ferrocenyl P,N,N-ligands

Article abstract of DOI:10.1002/aoc.6283

The asymmetric hydrogenation of β-ketophosphonates with chiral Ir/P,N,N-ligands catalyst has been developed. A series of β-ketophosphonates were hydrogenated, and the corresponding β-hydroxyphosphonates were obtained in high yields with good or excellent

Full text of DOI:10.1002/aoc.6283

Received: 13 February 2021
DOI: 10.1002/aoc.6283
Revised: 12 April 2021
Accepted: 20 April 2021
F U L L P A P E R
Iridium-catalyzed asymmetric hydrogenation of
β-ketophosphonates with chiral ferrocenyl P,N,N-ligands
Yin-Feng Ma1
Ting-Ting Chu1
| Chuan-Jin Hou1,2
| Xiu-shuai Chen1,3
| De-Quan Wei1,3
| Xiang-Ping Hu3
| Xinwei He2
|
1School of Light Industry and Chemical
Engineering, Dalian Polytechnic
University, Dalian, China
The asymmetric hydrogenation of β-ketophosphonates with chiral Ir/P,N,N-
ligands catalyst has been developed. A series of β-ketophosphonates were
hydrogenated, and the corresponding β-hydroxyphosphonates were obtained
in high yields with good or excellent enantioselectivities under mild condition.
2The Key Laboratory of Functional
Molecular Solids, Ministry of Education,
Anhui Normal University, Wuhu, China
3Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, Dalian,
China
K E Y W O R D S
asymmetric hydrogenation, iridium, P,N,N-ligands, β-hydroxyphosphonates,
β-ketophosphonates
Correspondence
Chuan-Jin Hou and Ting-Ting Chu,
School of Light Industry and Chemical
Engineering, Dalian Polytechnic
University, Dalian 116034, China.
Email: houcj@dlpu.edu.cn; chutt@dlpu.
edu.cn
Xiang-Ping Hu, Dalian Institute of
Chemical Physics, Chinese Academy of
Sciences, Dalian 116023, China.
Email: xiangping@dicp.ac.cn
Funding information
NSFC, Grant/Award Numbers: 21772196,
22071240; The Key Laboratory of
Functional Molecular Solids, Ministry of
Education, Grant/Award Number:
FMS201906; Liaoning BaiQianWan
Talents Program, Grant/Award Number:
201892153; Natural Science Foundation of
Liaoning Province of China, Grant/Award
Number: 2019-MS-022
1 | INTRODUCTION
these reasons, several routes for the synthesis of chiral
β-hydroxyphosphonates have been developed,[3] which
Optical β-hydroxyphosphonates have received much
attention in the past decades due to their wide variety of
biological applications, such as antibacterial agents,
enzyme inhibitors, peptide analogues, and phosphonic
acid-based antibiotics.[1] Moreover, these compounds are
also useful intermediates for a variety of organophospho-
rus derivatives, such as β-aminophosphonates.[2] For
involved the resolution, asymmetric reduction of the
corresponding β-ketophosphonates, asymmetric C–C and
C–P bond formation reactions. For instance, they can be
prepared
by
resolution
with
MPA
((S)-
methoxyphenylacetic acid)[4] and enzymatic[5] and non-
enzymatic[6] kinetic resolutions. The asymmetric reduc-
tion of β-ketophosphonates for the preparation of chiral
Appl Organomet Chem. 2021;e6283.
wileyonlinelibrary.com/journal/aoc
© 2021 John Wiley & Sons, Ltd.
1 of 8
https://doi.org/10.1002/aoc.6283

2 of 8
MA ET AL.
β-hydroxyphosphonates has also been reported with chi-
ral modified metal hydrides[7] or biocatalysts.[8] In addi-
tion, the enantiomerically enriched α-substituted
β-hydroxyphosphonates derivatives have also been pre-
pared by stereoselective addition[9] of organophosphorous
esters with chiral aldehydes or organocatalyzed
enantioselective addition[10] of phosphonates with
aldehydes.
less explored, and there are very few successful examples
reported. In 1995, Noyori et al.[11] reported the first AH
of β-ketophosphonates using Ru/BINAP catalysts and
applied it to the preparation of fosfomycin (Scheme 1a).
Later, Genet et al.[12] explored the AH reactions of
β-ketophosphonates and β-ketothiophosphonates using
Ru-MeO-Biphep catalysts (Scheme 1a). Zhang et al.[13]
reported
the
AH
reactions
of
α-substituted
The asymmetric hydrogenation (AH) has always been
one of the most important approach to synthesize many
chiral compounds because of its atom economy and
inherent efficiency. However, the AH reactions for the
synthesis of chiral β-hydroxyphosphonates still remain
β-ketothiophosphonates with Ru-SunPhos catalysts
(Scheme 1a). In addition, Pizzano et al.[14] reported the
AH of enol phosphonates for the synthesis of chiral
β-hydroxyphosphonates using Rh/phosphane-phosphite
ligands system (Scheme 1b). The Rh complex of chiral
SCHEME 1 Ru, Rh, or Ir-catalyzed
AH reactions for the preparation of
β-hydroxyphosphonates
TABLE 1 Screening of ligands in
asymmetric hydrogenation of 1a[a]
Entry
Ligand
Conv. (%)b
>99
Ee (%)c
92
1
2
3
4
5
6
(Sc,Rp,Rc)-L1
(Sc,Rp,Rc)-L2
(Sc,Rp,Rc)-L3
(Sc,Rp,Rc)-L4
(Sc,Rp,Rc)-L5
(Sc,Rp)-L6
>99
93
>99
95
>99
94
>99
94
16
90
aCarried out with 0.5 mol% of [Ir (cod)Cl]2, 1.1 mol% of P,N,N-ligands, and 5 mol% of t-BuOK under an H2
pressure of 20 bar for 24 h at room temperature.
bDetermined by 1HNMR analysis of crude products.
cDetermined by HPLC with chiral columns.

MA ET AL.
3 of 8
monodentate phosphoramidite ligands[15] had also been
proved to be efficient for the AH of enol phosphonates
(Scheme 1b). Despite these developments, the catalysts
used are based on chiral diphosphorus or
monophosphorus ligands combined with ruthenium
or rhodium as the transition metal. In contrast to chiral
ruthenium or rhodium catalysts, there are no reported
examples of AH of β-ketophosphonates with chiral irid-
ium catalysts, although the chiral iridium catalysts are
most commonly used in the AH of ketones, olefins, and
imines.[16] As a result, herein, we report our studies on
the iridium-catalyzed AH of β-ketophosphonates, which
provides the chiral β-hydroxyphosphonates with excellent
enantioselectivities under mild conditions (Scheme 1c).
2 | RESULTS AND DISCUSSION
Recently, our group developed an efficient Ir-catalyzed
AH of ketones and β-ketoesters with novel chiral
ferrocene-based P,N,N-ligands.[17] More importantly,
with the chiral Ir/P,N,N ligand system, a series of
α-alkyl-β-aryl-β-ketoesters could be easily hydrogenated,
and the corresponding chiral β-hydroxyesters were
obtained with excellent enantioselectivity and dia-
stereoselectivity.[18] Encouraged by the previous results,
we envisioned that this Ir/P,N,N ligand system should
also be suitable for the AH of β-ketophosphonates. Thus,
we evaluated the ligands' (L1–L6) efficiency in the AH of
dimethyl (2-oxo-2-phenylethyl) phosphonate (1a). The
TABLE 2 Optimization of base, solvent, and hydrogen pressure[a]
Entry
1
Base
P (bar)
20
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
Conv. (%)b
>99
>99
>99
>99
>99
>99
>99
>99
72
ee (%)c
95
93
90
91
91
90
88
89
84
_
t-BuOK
t-BuONa
t-BuOLi
KOH
2
20
3
20
4
20
5
NaOH
20
6
K2CO3
Na2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
20
7
20
8
20
9
20
i-PrOH
Toluene
THF
10
11
12
13
14
15
16
17d
18e
19f
20
NR
20
NR
_
20
Et2O
NR
_
20
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
NR
_
30
>99
>99
>99
57
91
90
90
87
87
_
40
50
20
20
21
20
<5
aCarried out with 0.5 mol% of [Ir (cod)Cl]2, 1.1 mol% of ligand (Sc,Rp,Rc)-L3 and 5 mol% of t-BuOK at room temperature for 24 h.
bDetermined by 1HNMR analysis of crude products.
cDetermined by HPLC with chiral columns.
dS/C = 1000.
eS/C = 2000.
fS/C = 5000.

4 of 8
MA ET AL.
reactions were carried out in methanol under an H2
atmosphere of 20 bar with 1.0 mol% iridium catalyst pre-
pared from [Ir (cod)Cl]2 and ligands L1–L6. To our
delight, as shown in Table 1, the Ir/P,N,N ligands catalyst
showed good performance and afforded the dimethyl (R)-
(2-hydroxy-2-phenylethyl)phosphonate (2a) with >99%
conversion and excellent enantioselectivities (entries 1–
5). The ligand (Sc,Rp,Rc)-L3 with 3-methyl phenyl substit-
uent at pyridinylmethyl position afforded the best result
of 95% ee (entry 3). In contrast, ligand (Sc,Rp)-L6 with
one chiral center showed disappointing reactivity (entry
6), which was similar as the AH of ketones and
β-ketoesters.[17,18] On the basis of above results, (Sc,Rp,
Rc)-L3 was selected as the ligand for further
optimization.
Results of the optimization of base, solvent, and
hydrogen pressure were summarized in Table 2. Some
bases were first screened for the AH of 1a with Ir-L3 cat-
alyst. All the tested bases such as t-BuONa, t-BuOK, t-
BuOLi, NaOH, KOH, K2CO3, and Na2CO3 gave good
results (entries 1–7), and t-BuOK was selected as the best
base with 95% ee (entry 1). The nature of the solvent dra-
matically affected the hydrogenation (entries 8–13). The
alcohol solvent was proved to be suitable solvent, provid-
ing complete conversion of 1a to 2a with good to excel-
enantioselectivity (entries 1 and 14–16). The conversions
and enantioselectivities decreased when the catalyst load-
ing was reduced to 0.1 mol% and less (entries 17–19).
Based on these results, we therefore set the optimized
conditions as follows: iridium complex of ligand (Sc,Rp,
Rc)-L3 as the catalyst (1 mol%), t-BuOK as the base
(5 mol%), MeOH as the solvent and 20 bar H2 at room
temperature for 24 h.
Under the optimized reaction conditions, the sub-
strates' scope of β-ketophosphonates for the AH reaction
was investigated, and results were summarized in
Scheme 2. It disclosed that
a
variety of
β-ketophosphonates could be hydrogenated smoothly
and afforded the chiral β-hydroxyphosphonates with
good or excellent enantioselectivities (2a–m). For the
β-ketophosphonates with an ortho substituent on the
phenyl ring, the results showed that the ee dropped dra-
matically for the substrate with electron-donating group
(2c, 88% ee) than that with an electron-withdrawing
group (2b, 96% ee). Substrates with different para substit-
uents on the phenyl ring were also investigated, and it
showed that electron density was important to the
enantioselectivity. Higher ee can be obtained for the sub-
strates having electron-donating substituents on the phe-
nyl ring (2e–f) than that having electron-withdrawing
groups (2g–h). Meanwhile, 2-naphthyl substrate also per-
formed well, giving the corresponding hydrogenation
product with 95% ee (2j). The heteroaryl group was also
tolerated and good enantioselectivity (91% ee) was
obtained (2k). Furthermore, aliphatic substrates 1l and
1m also reacted smoothly, affording the corresponding
products 2l and 2m with good enantioselectivity.
lent
enantioselectivities
(entries
1,
8–9).
Enantioselectivity in MeOH (entry 1) was superior to that
in EtOH (entry 8) and i-PrOH (entry 9). No reaction
occurred when toluene, THF, Et2O, and CH2Cl2 were
used as solvents (entries 10–13).[17b,19] The results
showed that the ee value was depended on the hydrogen
pressure, higher hydrogen pressure decreased the
SCHEME 2 Ir-catalyzed AH of β-ketophosphonates
1a–1m. Isolated yields are given; the ee values are
determined by HPLC with chiral columns and the
absolute configurations are determined by the
comparison of the specific rotations with reported data

MA ET AL.
5 of 8
Bruker 400 MHz spectrometer. Chemical shifts were
reported in δ value (ppm) with tetramethyl silane (TMS)
as the internal standard. HPLC analysis was performed
using Agilent 1260 series instrument with chiralcel
AD-H, chiralpak AS-H, or chiralcel OJ-H column. Copies
of NMR spectra and HPLC analysis were given in the
supporting information.
SCHEME 3 Ir-catalyzed AH of β-ketophosphine oxide 1n
4.2 | General procedure for the
asymmetric hydrogenation of
β-ketophosphonates
SCHEME 4 Gram-scale experiment of 1a
In a N2 filled glovebox, a stainless-steel autoclave was
charged with [Ir (COD)Cl]2 (1.7 mg, 0.005 mmol), L3
(3.2 mg, 0.11 mmol), and dry MeOH (1.0 ml). After the
solution was stirred for 1 h at room temperature, the
β-ketophosphonates 1 (0.5 mmol), t-BuOK (2.8 mg,
0.025 mmol), and MeOH (2.0 ml) were added. The reac-
tion was then performed under an H2 pressure of 20 bar
for 24 h at room temperature. The solvent was removed,
and the obtained crude product was then purified by
flash chromatography affording the corresponding prod-
uct β-hydroxyphosphonates.
The β-ketophosphine oxide 1n can also be hydroge-
nated with the Ir-L3 catalyst, giving the corresponding
chiral β-hydroxyphosphine oxide 2n with excellent
enantioselectivity (96% ee). In particular, the chiral
β-hydroxyphosphine oxides could be converted to opti-
cally active β-aminophosphines,[20] which are important
scaffolds for the construction of chiral ligands.
To further demonstrate the practicality of the meth-
odology, a scale-up experiment of 1a was carried out at
gram scale. To our delight, the desired product 2a was
obtained with 85% yield and 94% ee without noticeable
loss of reactivity and enantioselectivity (Scheme 4).
4.2.1 | Dimethyl (R)-(2-hydroxy-
2-phenylethyl)phosphonate (2a)
3 | CONCLUSION
The target compound was obtained as colorless oil in 96%
yield and 95% ee. The ee value was determined by HPLC
(chiralcel OJ-H, 10% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC,
210 nm): tR (minor) = 9.8 min, tR (major) = 10.6 min.
[α]D20 = À16.3 (c 1.13, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 7.43–7.32 (m, 4H), 7.31–7.26 (m, 1H), 5.17–5.08
(m, 1H), 3.77 (d, J = 11.0 Hz, 3H), 3.72 (d, J = 11.0 Hz,
3H), 2.33–2.13 (m, 2H).
In conclusion, we developed an efficient Ir-catalyzed AH
of β-ketophosphonates with chiral ferrocene-based P,N,
N-ligands. A wide range of β-ketophosphonates could be
hydrogenated
and
the
corresponding
β-hydroxyphosphonates were obtained in high yields and
with good or excellent enantioselectivities under mild
condition. This reaction can provide an important
method
for
the
preparation
of
chiral
β-hydroxyphosphonates.
4.2.2 | Dimethyl (R)-(2-(2-bromophenyl)-
2-hydroxyethyl)phosphonate (2b)
4 | EXPERIMENTAL SECTION
4.1 | General methods
The target compound was obtained as colorless oil in 95%
yield and 96% ee. The ee value was determined by HPLC
(chiralcel OJ-H, 10% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC,
210 nm): tR (minor) = 7.1 min, tR (major) = 8.1 min.
[α]D20 = À53.8 (c 1.02, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 7.65–7.58 (m, 1H), 7.45–7.38 (m, 1H), 7.30–7.23
(m, 1H), 7.09–7.00 (m, 1H), 5.42–5.24 (m, 1H), 4.50 (d,
J = 3.1 Hz, 1H), 3.71 (d, J = 11.0 Hz, 3H), 3.65 (d,
J = 11.0 Hz, 3H), 2.36–2.20 (m, 1H), 2.04–1.89 (m, 1H).
13C NMR (100 MHz, CDCl3) δ 142.7 (d, J = 17.1 Hz),
132.6, 129.0, 127.9, 127.2, 121.1, 67.7 (d, J = 4.8 Hz), 52.7
All the experiments were carried out under nitrogen (N2)
atmosphere. The asymmetric hydrogenation
(AH) reactions were carried out in glovebox with a
stainless-steel autoclave. All the solvents were purified
according to standard procedure. The other commercial
chemicals were used directly without any further purifi-
cation. 1H NMR and 13C NMR spectra were measured on

6 of 8
MA ET AL.
(d, J = 6.4 Hz), 52.6 (d, J = 6.7 Hz), 33.2 (d,
J = 136.0 Hz). HRMS cal. for C10H15BrO4P ([M + H]+):
308.9891, found: 308.9857.
(chiralcel OJ-H, 10% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC,
210 nm): tR (minor) = 16.8 min, tR (major) = 17.6 min.
[α]D20 = À10.3 (c 1.09, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 7.31 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz,
2H), 5.08 (t, J = 10.1 Hz, 1H), 3.80 (s, 3H), 3.77 (d,
J = 11.0 Hz, 3H), 3.74 (d, J = 11.0 Hz, 3H), 3.58 (br, 1H),
2.31–2.11 (m, 2H).
4.2.3 | Dimethyl (R)-(2-hydroxy-2-(o-
tolyl)ethyl)phosphonate (2c)
The target compound was obtained as colorless oil in 93%
yield and 88% ee. The ee value was determined by HPLC (chi-
ralcel OJ-H, 5% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC, 210 nm):
tR (minor) = 10.7 min, tR (major) = 14.1 min. [α]D20 = À35.0
4.2.7 | Dimethyl (R)-(2-hydroxy-
2-(4-chlorophenyl)ethyl)phosphonate (2g)
1
(c 1.11, CH2Cl2). H NMR (400 MHz, CDCl3) δ 7.55 (d,
The target compound was obtained as colorless oil in 94%
yield and 90% ee. The ee value was determined by HPLC
(chiralcel OJ-H, 10% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC,
210 nm): tR (minor) = 9.4 min, tR (major) = 10.2 min.
[α]D20 = À14.8 (c 1.02, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 7.33 (s, 4H), 5.10 (t, J = 10.0 Hz, 1H), 3.91 (d,
J = 2.3 Hz, 1H), 3.77 (d, J = 11.0 Hz, 3H), 3.73 (d,
J = 11.0 Hz, 3H), 2.25–2.10 (m, 2H).
J = 7.6 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.3 Hz,
1H), 7.13 (d, J = 7.4 Hz, 1H), 5.33 (t, J = 10.0 Hz, 1H), 3.80 (d,
J = 11.0 Hz, 3H), 3.76 (d, J = 11.0 Hz, 3H), 3.62 (br, 1H), 2.34
(s, 3H), 2.24–2.07 (m, 2H).
4.2.4 | Dimethyl (R)-(2-hydroxy-2-(m-
tolyl)ethyl)phosphonate (2d)
The target compound was obtained as colorless oil in 94%
yield and 95% ee. The ee value was determined by HPLC
(chiralcel OJ-H, 5% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC,
210 nm): tR (minor) = 12.7 min, tR (major) = 13.8 min.
[α]D20 = À15.5 (c 1.01, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 7.26–7.19 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.08
(d, J = 7.3 Hz, 1H), 5.07 (td, J = 10.2, 2.8 Hz, 1H), 3.94
(br, 1H), 3.74 (d, J = 7.2 Hz, 3H), 3.71 (d, J = 7.2 Hz,
3H), 2.34 (s, 3H), 2.31–2.10 (m, 2H).
4.2.8 | Dimethyl (R)-(2-hydroxy-
2-(4-bromophenyl)ethyl)phosphonate (2h)
The target compound was obtained as colorless oil in 98%
yield and 92% ee. The ee value was determined by HPLC
(chiralcel OJ-H, 10% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC,
210 nm): tR (minor) = 10.2 min, tR (major) = 11.2 min.
[α]D20 = À13.6 (c 1.01, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H),
5.09 (t, J = 9.1 Hz, 1H), 3.93 (br, 1H), 3.79 (d, J = 10.8 Hz,
3H), 3.74 (d, J = 10.8 Hz, 3H), 2.30–2.08 (m, 2H).
4.2.5 | Dimethyl (R)-(2-hydroxy-2-(p-
tolyl)ethyl)phosphonate (2e)
4.2.9 | Dimethyl (R)-(2-hydroxy-
2-(3,4,5-trimethoxyphenyl)ethyl)
phosphonate (2i)
The target compound was obtained as colorless oil in 96%
yield and 97% ee. The ee value was determined by HPLC
(chiralcel OJ-H, 5% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC,
210 nm): tR (minor) = 15.8 min, tR (major) = 16.2 min.
[α]D20 = À16.6 (c 1.0, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 7.28 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 7.8 Hz,
2H), 5.09 (t, J = 10.2 Hz, 1H), 3.77 (d, J = 11.0 Hz, 3H),
3.73 (d, J = 11.0 Hz, 3H), 3.57 (d, J = 2.5 Hz, 1H), 2.34 (s,
3H), 2.29–2.12 (m, 2H).
The target compound was obtained as colorless oil in 92%
yield and 94% ee. The ee value was determined by HPLC
(chiralcel OJ-H, 15% i-PrOH/n-hexane, 0.8 ml/min, 40ꢀC,
210 nm): tR (minor) = 12.2 min, tR (major) = 13.6 min.
[α]D20 = À14.2 (c 1.05, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 6.62 (s, 2H), 5.11–5.01 (m, 1H), 3.87 (s, 6H),
3.79 (dd, J = 21.0, 9.8 Hz, 9H), 2.31–2.11 (m, 2H).
4.2.6 | Dimethyl (R)-(2-hydroxy-
2-(4-methoxyphenyl)ethyl)phosphonate
(2f)
4.2.10 | Dimethyl (R)-(2-hydroxy-
2-(naphthalen-2-yl)ethyl)phosphonate (2j)
The target compound was obtained as colorless oil in 95%
yield and 96% ee. The ee value was determined by HPLC
The target compound was obtained as colorless oil in 89%
yield and 95% ee. The ee value was determined by HPLC

MA ET AL.
7 of 8
(chiralpak AS-H, 10% i-PrOH/n-hexane, 0.8 ml/min,
40ꢀC, 210 nm): tR (minor) = 21.9 min, tR (major)
4.2.14 | (R)-(2-Hydroxy-2-phenylethyl)
diphenylphosphine oxide (2n)
1
= 24.0 min. [α]D20 = À11.5 (c 1.02, CH2Cl2). H NMR
(400 MHz, CDCl3) δ 7.83–7.65 (m, 4H), 7.46–7.29 (m,
3H), 5.19 (td, J = 10.4, 2.9 Hz, 1H), 4.08 (br, 1H), 3.63 (t,
J = 10.4 Hz, 6H), 2.32–2.11 (m, 2H).
The target compound was obtained as colorless oil in 92%
yield and 96% ee. The ee value was determined by HPLC
(chiralpak AD-H, 10% i-PrOH/n-hexane, 0.8 ml/min,
40ꢀC, 210 nm): tR (minor) = 32.9 min, tR (major)
1
= 35.0 min. [α]D20 = À15.9 (c 1.10, CH2Cl2). H NMR
4.2.11 | Dimethyl (R)-(2-(furan-2-yl)-
2-hydroxyethyl)phosphonate (2k)
(400 MHz, CDCl3) δ 7.88–7.78 (m, 2H), 7.78–7.68 (m,
2H), 7.65–7.50 (m, 4H), 7.50–7.44 (m, 2H), 7.39–7.29
(m, 4H), 7.28–7.23 (m, 1H), 5.18 (t, J = 8.0 Hz, 1H), 5.03
(s, 1H), 2.86–2.72 (m, 1H), 2.66–2.55 (m, 1H).
The target compound was obtained as colorless oil in 93%
yield and 91% ee. The ee value was determined by HPLC
(chiralpak OJ-H, 10% i-PrOH/n-hexane, 0.8 ml/min,
40ꢀC, 210 nm): tR (minor) = 23.6 min, tR (major)
= 24.4 min. [α]D20 = À8.8 (c 1.11, CH2Cl2). 1H NMR
(400 MHz, CDCl3) δ 7.37 (s, 1H), 6.31 (d, J = 10.9 Hz,
2H), 5.19–5.03 (m, 1H), 4.39 (br, 1H), 3.72 (s, 3H), 3.70 (s,
3H), 2.49–2.25 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
155.2 (d, J = 17.0 Hz), 142.2, 110.3, 106.2, 62.8 (d,
J = 4.1 Hz), 52.7 (d, J = 6.3 Hz), 52.5 (d, J = 6.6 Hz), 31.5
(d, J = 139.6 Hz). HRMS cal. for C8H13NaO5P ([M
+ Na]+): 243.0367, found: 243.0365.
ACKNOWLEDGMENTS
This work was supported by the Natural Science Founda-
tion of Liaoning Province of China (2019-MS-022), Liao-
ning BaiQianWan Talents Program (201892153), The Key
Laboratory of Functional Molecular Solids, Ministry of
Education (FMS201906), and NSFC (nos. 21772196 and
22071240).
AUTHOR CONTRIBUTIONS
Yin-Feng Ma: Data curation; investigation; methodol-
ogy. Chuan-Jin Hou: Conceptualization; supervision.
De-Quan wei: Data curation; investigation; methodol-
ogy; validation. Ting-Ting Chu: Formal analysis; super-
vision. Xiu-Shuai Chen: Data curation; investigation;
methodology; validation. Xiang-Ping Hu: Conceptuali-
zation; supervision.
4.2.12 | Dimethyl (R)-(2-cyclohexyl-
2-hydroxyethyl)phosphonate (2l)
The target compound was obtained as colorless oil in 95%
yield and 88% ee. The ee value was determined after con-
verting to the corresponding p-nitrobenzoyl derivative by
HPLC (chiralcel AD-H, 10% i-PrOH/n-hexane,
0.8 ml/min, 40ꢀC, 210 nm): tR (major) = 18.0 min, tR
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are avail-
able in the supporting information of this article.
1
(minor) = 20.1 min. [α]D20 = À9.8 (c 1.03, CH2Cl2). H
NMR (400 MHz, CDCl3) δ 3.77 (d, J = 2.6 Hz, 3H), 3.74
(d, J = 2.6 Hz, 3H), 3.10 (s, 1H), 2.04–1.80 (m, 3H), 1.79–
1.71 (m, 2H), 1.70–1.60 (m, 2H), 1.44–1.32 (m, 1H), 1.30–
1.12 (m, 3H), 1.10–0.95 (m, 2H).
ORCID
Yin-Feng Ma https://orcid.org/0000-0003-4385-7592
Chuan-Jin Hou https://orcid.org/0000-0002-1871-4648
De-Quan Wei https://orcid.org/0000-0002-0359-521X
Xinwei He https://orcid.org/0000-0002-1974-2464
Ting-Ting Chu https://orcid.org/0000-0002-2736-5996
Xiu-shuai Chen https://orcid.org/0000-0003-2350-9865
Xiang-Ping Hu https://orcid.org/0000-0002-8214-1338
4.2.13 | Dimethyl (R)-(2-hydroxybutyl)
phosphonate (2m)
The target compound was obtained as colorless oil in 88%
yield and 72% ee. The ee value was determined after con-
verting to the corresponding p-nitrobenzoyl derivative by
HPLC (chiralcel AD-H, 10% i-PrOH/n-hexane,
0.8 ml/min, 40ꢀC, 210 nm): tR (minor) = 20.1 min, tR
REFERENCES
[1] a) M. Hashimoto, K. Hemmi, H. Takeno, T. Kamiya, Tetrahe-
dron Lett. 1980, 21, 99; b) J. F. Dellaria Jr., R. G. Maki,
Tetrahedron Lett. 1986, 27, 2337; c) J. F. Dellaria Jr., R. G. Maki,
H. H. Stein, J. Cohen, D. Whittern, K. Marsh, D. J. Hoffman,
J. J. Plattner, T. J. Perun, J. Med. Chem. 1990, 33, 534.
[2] F. Palacios, C. Alonso, J. M. de los Santos, Chem. Rev. 2005,
105, 899.
1
(major) = 21.6 min. [α]D20 = À14.7 (c 1.12, CH2Cl2). H
NMR (400 MHz, CDCl3) δ 4.01–3.92 (m, 1H), 3.82 (d,
J = 4.4 Hz, 3H), 3.79 (d, J = 4.5 Hz, 3H), 2.53 (br, 1H),
2.06–1.89 (m, 2H), 1.69–1.51 (m, 2H), 0.99 (t,
J = 7.4 Hz, 3H).
[3] For some reviews, seea)O. I. Kolodiazhnyi, Phosphorus, Sulfur
Silicon Relat. Elem. 2014, 189, 1102. b)O. I. Kolodiazhnyi, V. P.

8 of 8
MA ET AL.
Kukhar, A. O. Kolodiazhna, Tetrahedron: Asymmetry 2014,
25, 865.
V. Ratovelomanana-Vidal, J.-P. Genet, N. Champion, G.
Deschaux, P. Dellis, Org. Process Res. Dev. 2003, 7, 399.
[13] a) X. Tao, W. Li, X. Ma, X. Li, W. Fan, L. Zhu, X. Xie, Z.
Zhang, J. Org. Chem. 2012, 77, 8401; b) X. Tao, W. Li, X. Li, X.
Xie, Z. Zhang, Org. Lett. 2013, 15, 72.
[14] a) S. Vargas, A. Suarez, E. Alvarez, A. Pizzano, Chem. A Eur. J.
2008, 14, 9856; b) M. A. Chavez, S. Vargas, A. Suarez, E.
Alvarez, A. Pizzano, Adv. Synth. Catal. 2011, 353, 2775.
[15] J. Zhang, K. Dong, Z. Wang, K. Ding, Org. Biomol. Chem.
2012, 10, 1598.
[16] For some reviews in Ir-catalyzed asymmetric hydrogenation,
seea)A. Pfaltz, J. Blankenstein, R. Hilgraf, E. Hormann, S.
McIntyre, F. Menges, M. Schonleber, S. P. Smidt, B.
Wustenberg, N. Zimmermann, Adv. Synth. Catal. 2003, 345,
33; b) K. Kallstrom, I. Munslow, P. G. Andersson, Chem. A
Eur. J. 2006, 12, 3194; c) S. Roseblade, A. Pfaltz, Acc. Chem.
Res. 2007, 40, 1402; d) Z. Zhang, N. Butt, W. Zhang, Chem.
Rev. 2016, 116, 14769; e) Q. Yuan, W. Zhang, Chin. J. Org.
Chem. 2016, 36, 274.
[17] a) X.-S. Chen, C.-J. Hou, C. Qin, H. Liu, Y.-J. Liu, D.-Z.
Huang, X.-P. Hu, RSC Adv. 2017, 7, 12871. b)C. Qin, C.-J. Hou,
H. Liu, Y.-J. Liu, D.-Z. Huang, X.-P. Hu, Tetrahedron Lett.
2018, 59, 719.
[4] a) M. Ordonez, A. Gonzalez-Morales, C. Ruiz, R. De la Cruz-
Cordero, M. Fernandez-Zertuche, Tetrahedron: Asymmetry
2003, 14, 1775. b)H. Rojas-Cabrera, M. Fernandez-Zertuche,
O. Garcia-Barradas, O. Munoz-Muniz, M. Ordonez, Tetrahe-
dron: Asymmetry 2007, 18, 142.
[5] a) Y. Zhang, Z. Li, C. Yuan, Tetrahedron Lett. 2002, 43, 3247;
b) Y. Zhang, C. Yuan, Z. Li, Tetrahedron 2002, 58, 2973. c) M.
Mikolajczyk, J. Luczak, P. Kielbasinski, J. Org. Chem. 2002, 67,
7872; d) O. Pamies, J.-E. Backvall, J. Org. Chem. 2003, 68,
4815; e) G. Guanti, M. T. Zannetti, L. Banfi, R. Riva, Adv.
Synth. Catal. 2001, 343, 682.
[6] a) A. Moriyama, S. Matsumura, M. Kuriyama, O. Onomura,
Tetrahedron: Asymmetry 2010, 21, 810. b)L. Mesas-Sanchez,
A. E. Diaz-Alvarez, P. Koukal, P. Diner, Tetrahedron 2014, 70,
3807.
[7] a)C. Meier, W. H. G. Laux, Tetrahedron 1996, 52, 589. b)V. V.
Nesterov, O. I. Kolodiazhnyi, Tetrahedron 2007, 63, 6720. c)
E. V. Gryshkun, V. Nesterov, O. I. Kolodyazhnyi, ARKIVOC
2012, 2012, 100.
[8] a) E. Zymanczyk-Duda, B. Lejczak, P. Kafarski, J. Grimaud, P.
Fischer, Tetrahedron 1995, 51, 11809; b) R. Zurawinski, K.
Nakamura, J. Drabowicz, P. Kielbasinski, M. Mikolajczyk, Tet-
rahedron: Asymmetry 2001, 12, 3139; c) C. P. Marocco, E. V.
Davis, J. E. Finnell, P. H. Nguyen, S. C. Mateer, I. Ghiviriga,
C. W. Padgett, B. D. Feske, Tetrahedron: Asymmetry 2011, 22,
1784.
[9] a) E. Bandini, G. Martelli, G. Spunta, M. Panunzio, Tetrahe-
dron: Asymmetry 1995, 6, 2127; b) A. Bongini, R. Camerini, M.
Panunzio, E. Bandini, G. Martelli, G. Spunta, Tetrahedron:
Asymmetry 1996, 7, 3485.
[18] C.-J. Hou, X.-P. Hu, Org. Lett. 2016, 18, 5592.
[19] a) G. Gu, T. Yang, J. Liu, J. Wen, L. Dang, X. Zhang, Org.
Chem. Front. 2018, 5, 1209; b) Y. Hu, W. Wu, X.-Q. Dong, X.
Zhang, Org. Chem. Front. 2017, 4, 1499; c) Z. Liang, T. Yang,
G. Gu, L. Dang, X. Zhang, Chin. J. Chem. 2018, 36, 851.
[20] a) C. Xu, C. Yuan, Eur. J. Org. Chem. 2004, 4410; b) H.-Q. Du,
X.-P. Hu, Org. Lett. 2019, 21, 8921.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[10] a) W.-Y. Han, J.-Q. Zhao, Z.-J. Wu, X.-M. Zhang, W.-C. Yuan,
J. Org. Chem. 2013, 78, 10541. b)Y.-M. Gao, F.-F. Shen, F.-T.
Zhang, J.-L. Zhang, R. Wang, Angew. Chem. Int. Ed. 2014, 53,
1862.
[11] a) M. Kitamura, M. Tokunaga, R. Noyori, J. Am. Chem. Soc.
1995, 117, 2931. b)M. Kitamura, M. Tokunaga, T. Pham, W. D.
Lubell, R. Noyori, Tetrahedron Lett. 1995, 36, 5769.
[12] a) I. Gautier, V. Ratovelomanana-Vidal, P. Savignac, J.-P.
Genet, Tetrahedron Lett. 1996, 37, 7721. b)J. Madec, X. Pfister,
P. Phansavath, V. Ratovelomanana-Vidal, J.-P. Genet, Tetrahe-
dron 2001, 57, 2563. c)S. D. de Paule, S. Jeulin, V.
Ratovelomanana-Vidal, J.-P. Genet, N. Champion, P. Dellis,
Eur. J. Org. Chem. 1931-1941, 2003. d)S. D. de Paule, S. Jeulin,
How to cite this article: Ma Y-F, Hou C-J,
Wei D-Q, et al. Iridium-catalyzed asymmetric
hydrogenation of β-ketophosphonates with chiral
ferrocenyl P,N,N-ligands. Appl Organomet Chem.
2021;e6283. https://doi.org/10.1002/aoc.6283