Iridium-catalyzed asymmetric hydrogenation of β-keto esters with f-amphox ligands

Article abstract of DOI:10.1080/00397911.2017.1414267

The iridium-catalyzed asymmetric hydrogenation of β-keto esters with chiral tridentate P,N,N-ligands (f-amphox) has been developed. Under the optimized conditions, a wide range of β-keto esters can be hydrogenated smoothly, affording the corresponding β-hydroxy esters in good to excellent enantioselectivities (up to 95% ee).

Full text of DOI:10.1080/00397911.2017.1414267

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Iridium-catalyzed asymmetric hydrogenation of β-
keto esters with f-amphox ligands
Chao Qin, Xiu-Shuai Chen, Chuan-Jin Hou, Hongzhu Liu, Yan-Jun Liu, De-Zhi
Huang & Xiang-Ping Hu
To cite this article: Chao Qin, Xiu-Shuai Chen, Chuan-Jin Hou, Hongzhu Liu, Yan-Jun Liu, De-Zhi
Huang & Xiang-Ping Hu (2018): Iridium-catalyzed asymmetric hydrogenation of β-keto esters with f-
amphox ligands, Synthetic Communications, DOI: 10.1080/00397911.2017.1414267
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https://doi.org/10.1080/00397911.2017.1414267
Iridium-catalyzed asymmetric hydrogenation of β-keto
esters with f-amphox ligands
Chao Qina,b, Xiu-Shuai Chena,b, Chuan-Jin Houa,c, Hongzhu Liuc, Yan-Jun Liua,
De-Zhi Huanga, and Xiang-Ping Hub
aSchool of Light Industry and Chemical Enginerring, Dalian Polytechnic University, Dalian, China; bDalian
c
Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China; Post-Doctoral Research Station of
Dalian Zhenbang Fluorocarbon Paint Stock Co., Ltd., Dalian, China
ABSTRACT
ARTICLE HISTORY
Received 6 November 2017
The iridium-catalyzed asymmetric hydrogenation of β-keto esters with
chiral tridentate P,N,N-ligands (f-amphox) has been developed. Under
the optimized conditions, a wide range of β-keto esters can be
hydrogenated smoothly, affording the corresponding β-hydroxy
esters in good to excellent enantioselectivities (up to 95% ee).
KEYWORDS
Asymmetric hydrogenation;
f-amphox ligands; iridium;
β-keto esters
GRAPHICAL ABSTRACT
Introduction
Transition metal-catalyzed asymmetric hydrogenation represents one of the most
efficient strategies for the synthesis of optically pure compounds,[1] in which the
design and synthesis of chiral ligands is the key issue for obtaining high reactivity and
enantioselectivity. In the past decades, numerous chiral ligands have been developed
and successfully applied to the asymmetric hydrogenation. In 1987, Noyori et al.[2] reported
the first ruthenium-catalyzed enantioselective hydrogenation of β-keto esters using BINAP
(Fig. 1) as chiral ligand, yielding the chiral β-hydroxy esters, which are significant building
blocks for the synthesis of biologically active compounds. Since this pioneering work, a
large number of chiral diphosphine ligands such as synphos,[3] difluorphos,[4] tunephos,[5]
segphos,[6] solphos,[7] P-phos,[8] PQ-phos,[9] and MeO-naphephos[10] have been developed
and proved to efficient in the ruthenium-catalyzed asymmetric hydrogenation of
β-keto esters. Recently, Zhou[11] reported the chiral iridium catalysts with a tridentate
spiro P,N,N-ligands, SpiroPAP (Fig. 1), which showed excellent enantioselectivities and
extremely high turnover number (TON) for the hydrogenation of simple ketones and
CONTACT Chuan-Jin Hou
Polytechnic University, Dalian 116034, China; Xiang-Ping Hu
Physics, Chinese Academy of Sciences, Dalian 116023, China.
houcj@dlpu.edu.cn
School of Light Industry and Chemical Engineering, Dalian
xiangping@dicp.ac.cn
Dalian Institute of Chemical
Supplemental data (experimental details, characterization and copies of NMR spectra and HPLC analysis data for all
target compounds) can be accessed on the publisher’s website.
© 2018 Taylor & Francis

2
C. QIN ET AL.
Figure 1. Examples of efficient chiral ligands in asymmetric hydrogenation.
β-keto esters. The exceptionally high reactivity and enantioselectivity due to the
metal–ligand bifunctional mechanism involve “NH effect,” similar to the Noyori’s
diphoshpine–ruthenium–diamine catalyst system. Utilizing the strategy of “NH effect,”
Zhang[12] has successfully developed a novel ferrocenyl tridentate P,N,N-ligands
(f-amphox, Fig. 1) and applied them in the Ir-catalyzed asymmetric hydrogenation of
various ketones with excellent enantioselectivities. Based on our research in the synthesis
of chiral tridentate P,N,N-ligands and their application in asymmetric hydrogenation,[13]
we envisioned that the f-amphox ligands should also be efficient in the asymmetric
hydrogenation of β-keto esters. As a result, herein, we report our studies in the
iridium-catalyzed asymmetric hydrogenation of β-keto esters with the f-amphox ligands,
which provides the corresponding chiral β-hydroxy esters with good to excellent
enantioselctivity (up to 95% ee) under mild conditions.
Results and discussion
The f-amphox ligands L1–L5 were prepared from (Sc, Rp)-PPFNH2 as literature reported.
With these ligands on hand, we then evaluated them in the iridium-catalyzed asymmetric
hydrogenation of methyl 3-oxo-3-phenylpropanoate (1a) as the model substrate with the
catalyst generated in situ by mixing [Ir(cod)Cl]2 with f-amphox ligands L1–L5 in MeOH.
As shown in Table 1, the f-amphox ligands displayed moderate to excellent enantioselec-
tivity (entries 1–5). The ligand screening results demonstrated that the substituent on the
oxazoline had a significant effect on the enantioselectivity. Ligand L3 with t-Bu substituent
afforded the best result with 95% ee (entry 3). Subsequently, different bases were screened
for this transformation catalyzed by Ir-L3 in MeOH. All the bases tested such as t-BuOK,
t-BuONa, KOH, NaOH, and K2CO3 showed good to excellent results (entries 6–9), and
t-BuOK was identified as the best choice in terms of reactivity and enantioselectivity.
Encouraged by this initial result, we explored the hydrogenation of various β-keto esters
to evaluate the scope and limitation of the reaction, and the results are summarized in
Table 2. The results indicated that a wide range of β-keto esters 1 can be hydrogenated
affording the corresponding chiral β-hydroxy esters 2 with good to excellent enantioselec-
tivities (entries 1–8). The substrates containing different substitution patterns (ortho-, meta-,
para-) at the phenyl ring were hydrogenated smoothly, regardless of the electronic
properties (electron donating or electron withdrawing). In addition, 2-naphthyl substrate
1i proceeded efficiently with 88% ee (entry 9). Meanwhile, the heterocyclic substrates 1j
and 1k also served well, giving the corresponding hydrogenation products with both 92%
ee (entries 10–11). To our delight, the i-Pr substrate 1l also reacted smoothly to produce
the corresponding β-hydroxy esters with 76% ee (entry 12). However, low enantioselectivity
(32% ee) was obtained when Me substrate 1m was applied in the reaction (entry 13).

SYNTHETIC COMMUNICATIONS®
3
Table 1. Asymmetric hydrogenation of methyl 3-oxo-3-phenylpropanoate (1a): Optimizing reaction
conditions.a
Entry
Ligand
Base
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L3
L3
L3
L3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
KOH
95
95
95
95
95
95
90
85
95
52
88
95
72
71
87
94
95
87
NaOH
K2CO3
aHydrogenation was performed with 0.5 mol% of [Ir(cod)Cl]2, 1.1 mol% of f-amphox ligands, and 5 mol% of bases under
10 bar of H2 at room temperature for 12 h, unless otherwise stated.
bIsolated yield.
cEnantiomeric excesses were determined by HPLC using a chiral stationary phase.
Table 2. Asymmetric hydrogenation of β-keto esters 1 with Ir/L3.a
Entry
Substrate
R
Yield (%)b
ee (%)c
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
95
96
91
90
94
90
90
91
94
88
93
80
82
95
83
71
75
80
86
92
92
88
92
92
76
32
2
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-MeC6H4
4-MeOC6H4
2-Naphthyl
2-Furyl
3
4
5
6
7
8
9
10
11
12
13
1j
1k
1l
2-Thienyl
i-Pr
Me
1m
aHydrogenation was performed with 0.5 mol% of [Ir(cod)Cl]2, 1.1 mol% of f-amphox ligands L3, and 5 mol% of t-BuOK under
10 bar of H2 at room temperature for 12 h, unless otherwise stated.
bIsolated yield.
cEnantiomeric excesses were determined by HPLC using a chiral stationary phase.
Conclusion
In conclusion, we have developed a highly efficient iridium-catalyzed asymmetric
hydrogenation of β-keto esters with chiral tridentate P,N,N-ligands f-amphox. The results

4
C. QIN ET AL.
suggest that a wide range of β-keto esters can be hydrogenated with good to excellent
enantioselectivities under the optimized conditions.
Experimental
The hydrogenation reaction was performed in glove box by use of a stainless steel
autoclave. Solvents were purified by standard procedure and commercial reagents were
1
used without further purification. HNMR spectra were recorded on a Bruker 400 MHz
spectrometer. Chemical shifts are expressed in δ value (ppm) using tetramethylsilane as
an internal standard. HPLC analysis was performed on an Agilent 1100 series instrument
with a chiralpak AS-H, chiralcel OD-H, chiralcel AD-H, or chiralcel OJ-H column. Optical
rotations were recorded on a JASCO P-1020 polarimeter. The absolute configurations of
the products were determined by comparing optical rotation with the reported data.
General procedure for asymmetric hydrogenation
In a nitrogen-filled glove box, a stainless steel autoclave was charged with [Ir(cod)Cl]2
(3.4 mg, 0.05 mmol) and (Sc, Rp, Sc)-L3 (6.1 mg, 0.11 mmol) in 1.0 mL of dry MeOH. After
stirring for 1 h at room temperature, a solution of the substrates 1 (1.0 mmol) and t-BuOK
(5.6 mg, 0.05 mmol) in 2.0 mL of MeOH was added to the reaction mixture, and then the
hydrogenation was performed at room temperature under the H2 pressure of 10 bar for
12 h. The solvent was then evaporated and the residue was purified by flash column
chromatography to give the corresponding hydrogenation product, which was analyzed
by chiral HPLC to determine the enantiomeric excesses.
(R)-methyl 3-hydroxy-3-phenylpropanoate 2a
Colorless oil was obtained in 95% yield. 95% ee was determined by chiral HPLC (chiralcel
OD-H, n-hexane/i-PrOH ¼ 90/10, 0.8 mL/min, 210 nm, 40 °C): tR (minor) ¼ 11.3 min,
tR (major) ¼ 16.3 min. ½a�D20 ¼ þ 45.5 (c 1.10, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ
7.39–7.29 (m, 5H), 5.14 (dd, J ¼ 8.8, 4.0 Hz, 1H), 3.72 (s, 3H), 2.81–2.69 (m, 3H).[13b]
Funding
The authors are grateful for the financial support from the National Natural Science Foundation of
China (Nos. 21403022, 21572226, and 21772196), Natural Science Foundation of Liaoning Province
of China (No. 2015020194), and program of Star of Dalian Youth Science and Technology
(No. 2016RQ062).
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