Ruthenium-catalyzed hydrogenation of aromatic ketones using chiral diamine and monodentate achiral phosphine ligands

Article abstract of DOI:10.1016/j.catcom.2021.106303

The Ru-catalyzed asymmetric hydrogenation of ketones with chiral diamine and monodentate achiral phosphine has been developed. A wide range of ketones were hydrogenated to afford the corresponding chiral secondary alcohols in good to excellent enantioselectivities (up to 98.1% ee). In addition, an appropriate mechanism for the asymmetric hydrogenation was proposed and verified by NMR spectroscopy.

Full text of DOI:10.1016/j.catcom.2021.106303

Catalysis Communications 154 (2021) 106303
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Catalysis Communications
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Short communication
Ruthenium-catalyzed hydrogenation of aromatic ketones using chiral
diamine and monodentate achiral phosphine ligands
Mengna Wang1, Ling Zhang1, Hao Sun, Qian Chen, Jian Jiang, Linlin Li, Lin Zhang, Li Li,
Chun Li*
School of Pharmaceutical Sciences, Guizhou Medical University, 550004 Guiyang, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
The Ru-catalyzed asymmetric hydrogenation of ketones with chiral diamine and monodentate achiral phosphine
has been developed. A wide range of ketones were hydrogenated to afford the corresponding chiral secondary
alcohols in good to excellent enantioselectivities (up to 98.1% ee). In addition, an appropriate mechanism for the
asymmetric hydrogenation was proposed and verified by NMR spectroscopy.
Chiral diamines
Achiral phosphine
Ruthenium
Enantioselectivity
Ketones
1. Introduction
NN [13], NNN [14], SN [15], NO [16], PN [17,18], PNO [19], PNNP
[20,21], ferrocene-based ligands [22,23], macrocyclic ligands [24],
Enantiomerically pure alcohols, especially those bearing heterocy-
cles, are important building blocks and key intermediates for the pro-
duction of biologically active molecules and chiral auxiliaries such as
medicines, perfumes, and agrochemicals [1,2]. Undoubtedly, from the
view of green chemistry, asymmetric hydrogenation of prochiral ke-
tones represents a convenient approach towards enantiomerically
enriched alcohols in view of its atom economy, easy handling, high
activity, low catalyst loading and low cost of reducing agents on both
laboratory and industrial scales [3,4]. Based on the researches of Noyori
and co-workers [5,6], chiral diphosphine/diamine/transition metal
complexes were investigated to balance conversion, selectivity and atom
efficiency of asymmetric reduction of carbonyl compounds. Ru-BICP-
chiral-diamine-KOH and TunePhos/diamine-Ru(II) complex/t-BuOK
have been disclosed and proved to be efficient in the enantioselective
hydrogenation of aromatic ketones [7,8]. In 2000, Zanotti-Gerosa and
coworkers reported PhanePhos‑ruthenium-diamine complexes and
hemisalen type ligands [25] have been designed, synthesized and
applied successfully in asymmetric hydrogenation. As it can be seen, the
high enantioselectivity was imparted by the synergistic effect of the
chiral ligands, which are often expensive owing to difficulties in com-
plex structures constructed using multi-step reactions. In addition, it is
noteworthy that a variety of reactions still lack effective chiral ligands
and the enantioselectivities in many reactions are substrate dependent
[26]. Therefore, there is a continuing interest in the development of
simple, less expensive and more efficient catalysts for the asymmetric
hydrogenation of carbonyl compounds under mild conditions to access
chiral alcohols. Recently, we have reported the effective catalytic per-
formances of iridium combining with chiral diamine and achiral phos-
phine in the asymmetric hydrogenation of aryl, heteroaryl ketones and
enones [27–29]. Herein we reported a simple ruthenium complex co-
ordinated with o-MOTPP and chiral diamine as well as their activities
explored as catalysts for the asymmetric hydrogenation of simple aro-
matic and heteroaromatic ketones.
various aromatic, heteroaromatic and
α, β-unsaturated ketones were
effectively hydrogenated [9]. Chen et al. demonstrated asymmetric
hydrogenation of aromatic-heteroaromatic ketone using trans-
RuCl2[(R)-xylbinap][(R)-daipen] as a catalyst afforded secondary
alcohol with 99.4% ee [10]. Zhou and co-workers developed spiro
diphosphines that are highly efficient for the asymmetric hydrogenation
of ketones [11,12]. Moreover, a great deal of chiral compounds such as
2. Experimental part
2.1. General information
All reagents were commercially available or prepared according to
* Corresponding author.
E-mail address: scuchunli@163.com (C. Li).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.catcom.2021.106303
Received 13 January 2021; Received in revised form 25 February 2021; Accepted 12 March 2021
Available online 13 March 2021
1566-7367/© 2021 The Authors.
Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

M. Wang et al.
Catalysis Communications 154 (2021) 106303
published procedures. The purity of hydrogen was over 99.99%. 1H
NMR and 13C NMR spectra were recorded on a Bruker NMR 400 MHz
spectrometer. The conversions and ee values were determined by GC-
9790 using a chiral capillary column (β-DEX120 column, 25 m × 0.25
mm). Optical rotations were taken on an IP-Digi 300 polarimeter.
investigated in the model reaction. As shown in Table 1, lower conver-
sion and enantioselectivity were obtained separately with phosphine or
diamine added alone (Table 1, entry 1–2). As expected, both triphe-
nylphosphine and 9-amino(9-deoxy) epi-cinchonine were used as li-
gands, the enantioselectivities increased dramatically (Table 1, entry 3).
Furthermore, more hindered triarylphosphine-bearing substituents on
the benzene ring, such as MOTPP, MTPP and TFTPP, were evaluated,
demonstrating higher efficiency than triphenylphosphine in asymmetric
hydrogenation (Table 1, entry 4–8). A more pronounced steric effect on
the catalytic efficiency was observed with o-MOTPP used, giving 1-phe-
nylethanol in excellent 90.2% ee value (Table 1, entry 4). These results
indicate that the sterically hindered monophosphines are effective for
the asymmetric hydrogenation of acetophenone. Next, a survey of chiral
diamines derived from cinchona alkaloid indicated that 9-amino(9-
deoxy) epi-cinchonine was better choice with respect to higher con-
versions and enantioselectivities (Table 1, entries 4, 9–12).
2.2. Typical procedure for asymmetric hydrogenation of ketones
Ruthenium precursor, ligands, solvent, base and ketones were added
to a 50 mL stainless autoclave with a magnetic stirrer. The autoclave is
then charged H2. After stirring for 2 h, the conversions and enantiose-
lectivity values were analyzed by GC. The ee values of chiral alcohols
were calculated from the equations enantioselectivity values (ee, %) = |
R - S| / |R + S|.
3. Results and discussion
To improve these results further, different molar ratios were tested.
The better molar ratios of chiral diamine 1/o-MOTPP/ruthenium was 2/
1/1. Additionally, the optimization studies exhibited that good catalytic
activity was gained with 1-PrOH and LiOH.
Our investigation was started with the asymmetric hydrogenation of
acetophenone as a model reaction. Initially, the activity of different
ruthenium precursors was evaluated in the presence of chiral diamine 1
and o-MOTPP. Most ruthenium precursors gave only low conversion.
Notably, benzylidene-bis(tricyclohexylphosphine)dichlororuthenium
showed 42.3% conversion and 90.2% ee. Since the steric and elec-
tronic properties of ligands are two critical factors for the asymmetric
hydrogenation [30,31], simple and commercially available mono-
dentate phosphine with different electronic and steric properties were
With standard conditions realized, we next extended the catalytic
system to involve asymmetric hydrogenation of substituted acetophe-
none and heteroaromatic ketones. As seen from Scheme 1, the substrates
bearing different ortho substitution patterns (F-, Cl-, Br-, CF3, CH3-,
OCH3-) at the phenyl group were hydrogenated smoothly in high
enantioselectivities (90.5–98.1% ee), regardless of their electronic
Table 1
The effect of chiral diamines and achiral phosphines for asymmetric hydrogenation of ketonesa.
N
N
H2N
H2N
N
H2N
O
N
N
N
2
3
1
9-Amino(9-deoxy)epi-cinchonine
9-Amino(9-deoxy)epi-cinchonidine
9-Amino-(9-deoxy)epi-quinine
N
N
H2N
H2N
P
3
R
O
O
N
N
R = H, o-OCH3, m-OCH3, p-OCH3, p-CH3, p-CF3
4
5
9-Amino-(9-deoxy)epi-dihydroquinine
9-Amino-(9-deoxy)epi-dihydroquinidine
Entry
Chiral diamine
Achiral phosphine
Con(%)
Ee(%)
Config.
1
1
–
–
<3
–
–
–
S
S
S
S
S
S
R
R
R
S
2
o-MOTPP
TPP
<3
–
3
1
1
1
1
1
1
2
3
4
5
4.1
70.4
90.2
79.7
75.6
77.7
85.3
57.8
84.2
51.0
56.5
4
o-MOTPP
m-MOTPP
p-MOTPP
p-MTPP
p-TFTPP
o-MOTPP
o-MOTPP
o-MOTPP
o-MOTPP
42.3
18.7
8.9
5
6
7
26.0
12,4
13.5
33.7
18.1
38.3
8
9
10
11
12
a
Substrate/Ru/chiral diamine/achiral phosphine = 400/1/1/2, acetophenone: 0.857 mol/L, LiOH: 0.1 mol/L, EtOH: 2 ml, 25 ◦C, 6 MPa, 2 h.
2

M. Wang et al.
Catalysis Communications 154 (2021) 106303
O
Ru/chiral diamine 1/o-MOTPP, LiOH
OH
R1
R2
R1
R2
H2 , 30 , 1-PrOH
1
2
OH
Cl
OH
OH
F
OH
Br
OH
CF3
2-5b
35.0% Conv.
98.1% ee
2-1
2-3
2-2
98.8% Conv.
94.9% ee
2-4
49.6% Conv.
94.2% ee
>99% Conv.
94.7% ee
93.6% Conv.
97.9% ee
OH
OH
OH
OH
OH
S
O
O
2-6b
68.8% Conv.
96.8% ee
2-8
2-10c
28.5% Conv.
88.5% ee
2-7
2-9
72.6% Conv.
92.6% ee
71.7% Conv.
90.5% ee
92.5% Conv.
88.1% ee
OH
S
OH
Cl
OH
S
S
Br
OH
S
OH
S
Cl
2-12
48.1% Conv.
96.5% ee
2-11b
31.8% Conv.
97.3% ee
2-15d
38.6% Conv.
87.5% ee
2-13b
80.5% Conv.
83.3% ee
2-14
47.2% Conv.
86.3% ee
OH
S
OH
O
OH
O
OH
OH
O
O
2-16c
26.5% Conv.
89.0% ee
2-17
2-18d
68.1% Conv.
88.7% ee
2-19d
53.0% Conv.
81.5% ee
2-20d
25.0% Conv.
87.3% ee
60.3% Conv.
84.5% ee
OH
HO
N
N
2-21c
2-22c
53.0% Conv.
83.9% ee
83.7% Conv.
80.1% ee
Scheme 1. Scope of the asymmetric hydrogenation of ketones. (substrate/Ru/chiral diamine 1/o-MOTPP = 200/1/2/1, ketones: 0.428 mol/L, LiOH: 0.1 mol/L, 1-
PrOH: 2 mL. 30 ◦C, 6 MPa, 2 h; b 40 ◦C, c substrate/Ru = 100/1, d substrate/Ru = 50/1)
properties and steric effect. It is worth noting that the steric effect of the
group on the phenyl ring had an important influence on the conversion.
Para-OCH3 substituted substrate and 1-phenyl-1-butanone also per-
formed well, giving the corresponding hydrogenation product with
92.6% and 88.1% ee, respectively. Encouraged by the excellent
enantioselectivities attained in these initial studies, we next extended
our researches to involve asymmetric hydrogenation of heteroaromatic
ketones. 2-acetylthiophene proceeded efficiently with 88.5% ee. Ace-
tylthiophene derivates bearing substituted groups such as methyl,
chloro, bromo at ortho or meta positions, also reacted to afford the
3

M. Wang et al.
Catalysis Communications 154 (2021) 106303
desired corresponding secondary alcohol in high ee values. In particular,
in the case of hydrogenation of 2-acetyl-5- methylthiophene, 97.3% ee
were obtained. Due to the steric hindrance, both 2-propionyl thiophene
and 2-butyryl thiophene were reduced in lower conversion. Further-
more, other heteroaromatic ketones, such as 2-acetylfuran, 2-butyr-
ylfuran, 2-methyl-5-propionyl-furan and 2-acetyl-5-methylfuran were
also reduced with good enantioselectivities under mild conditions,
furnishing 81.5–88.7% ee. As is well known, acetyl pyridines were more
difficult to hydrogenate due to the strong coordination ability of nitro-
gen atom in previous studies [32]. To our delight, 3-acetyl pyridines and
4-acetyl pyridines were hydrogenated well under reducing S/C to 100/
1, 83.9 and 80.1% ee obtained with moderate to good conversion,
respectively. The results disclosed that a wide range of aromatic and
heteroaromatic ketones can be hydrogenated to afford various chiral
alcohols with good to excellent enantioselectivities. (See Scheme 1).
We proposed a mechanism, similar to the mechanism described by
Morris and co-workers for asymmetric hydrogenation with Ru complex,
chiral diamine and achiral phosphine ligand, in which the ultimate
catalyst that reacted with the ketones may be a ruthenium dihydride
(structure C in Scheme 2) [33–35]. First, the chiral diamine 1 and o-
MOTPP reacted with complex A to form complex B. Under the influence
of base and hydrogen, the ruthenium complex B lost two chlorine atoms
to transform into ruthenium dihydride complex C. Then, the ruthenium
dihydride C transferred a hydridic Ru-H and a protic N-H unit to the
carbonyl group of the ketones through the transition state TS to generate
chiral alcohol. And the ruthenium complex lost one molecule of H2
produce to the ruthenium complex D. Finally, the ruthenium dihydride
C was regenerated under hydrogen atmosphere. The mechanism was
verified by 1H and 31P NMR spectroscopy. Fig. 1 show 1H spectra taken
without H2 to the solution of in situ generated complex B in 1-PrOH and
1H spectra of the complex A and chiral diamine 1. The 1H NMR spectrum
exhibits single peak at δ = 19.91 ppm, which belong to Phenyl vinyl
group of the complex A disappeared in the beginning. At the same time,
a new single peak at δ = 5.49 ppm appeared, which maybe the signal of
coordination between chiral diamine 1 and ruthenium. These indicated
the formation of ruthenium complex B. In addition, the 31P NMR spectra
of the ruthenium complex A, chiral diamine 1 and o-MOTPP taken
without H2 to the solution and 31P NMR spectra of the complex A were
collected (Fig. 2). The 31P NMR spectrum of ruthenium complex A ex-
hibits one singlet at δ = 35.71 ppm (s). After the complex A, chiral
diamine 1 and o-MOTPP mixed without H2 to the solution, the singlet of
ruthenium complex A disappeared and the 31P NMR spectrum exhibits
two new singlets at δ = 33.27 ppm (s, major) and 33.45 ppm (s, minor).
These may indicate the phosphine ligands coordinate to form the com-
plex B. Fig. 3 and Fig. 4 show 1H and 31P NMR spectra taken at 2 min to
2 h after introducing H2 to the solution of in situ generated ruthenium
hydride in 1-PrOH. After treatment with H2 for 2 min at ambient at-
mosphere, the 1H NMR spectrum exhibits signal at δ = ꢀ 12.45 ppm, and
the 31P NMR spectrum exhibits two singlets at δ = 53.27 ppm (s, major)
and 31.14 ppm (s, minor). These may indicate the formation of ruthe-
nium dihydride complexes C. After 30 min, some weak signals appeared
at δ = ꢀ 16.50 ppm in the 1H NMR spectrum, and at δ = 73.17 ppm in the
31P NMR spectrum, showing the formation of ruthenium monohydride
complexes D. In addition, signals for the early formed ruthenium dihy-
dride complexes D became weak in the 1H NMR spectrum with the in-
crease of reaction time. Furthermore, the new generated minor signals in
both the 1H NMR spectrum and 31P NMR spectrum show the formation
of other ruthenium hydride complexes.
Ph
Cl
Cl
Ru
Cl
o-MOTPP
N
N
PAr
PAr
1-PrOH
3
3
P
Ru P
+
+
Chiral diamine 1
Cl
H H
B
H
Base
A
2
-2Cl
H
Ru
H
N
N
PAr
PAr
3
3
O
R
H H
C
H
Ru
H
N
PAr
PAr
3
3
H H
N
PAr
PAr
3
N
H
Ru
H
H
N
H
3
TS
O
E
R
N
PAr
PAr
3
Ru
H
HO
R
H
N
H
3
D
Scheme 2. Proposed mechanism for the asymmetric hydrogenation.
4

M. Wang et al.
Catalysis Communications 154 (2021) 106303
Fig. 1. 1H spectra taken without H2 to the solution and 1H spectra of the complex A and chiral diamine 1.
Fig. 2. 31P NMR spectra of the complex A, chiral diamine 1 and o-MOTPP taken without H2 to the solution and 31P NMR spectra of the complex A.
Fig. 3. 1H NMR spectra taken at 2 min to 2 h after introducing H2 to the solution.
5

M. Wang et al.
Catalysis Communications 154 (2021) 106303
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.catcom.2021.106303.
References
[1] K. Abdur-Rashid, R. Guo, A.J. Lough, R.H. Morris, D. Song, Adv. Synth. Catal. 347
(2005) 571.
[2] R. Guo, R.H. Morris, D. Song, J. Am. Chem. Soc. 127 (2005) 516.
[3] Y. Xu, N.W. Alcock, G.J. Clarkson, G. Docherty, G. Woodward, M. Wills, Org. Lett.
6 (2004) 4105.
[4] Y. Xu, G.C. Clarkson, G. Docherty, C.L. North, G. Woodward, M. Wills,
J. Organomet. Chem. 70 (2005) 8079.
[5] T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 117
(1995) 2675.
[6] T. Ohkuma, D. Ishii, H. Takeno, R. Noyori, J. Am. Chem. Soc. 122 (2000) 6510.
[7] P. Cao, X. Zhang, J. Organomet. Chem. 64 (1999) 2127.
[8] W. Li, X. Sun, L. Zhou, G. Hou, S. Yu, X. Zhang, J. Organomet. Chem. 74 (2009)
1397.
[9] M.J. Burk, W. Hems, D. Herzberg, C. Malan, A. Zanotti-Gerosa, Org. Lett. 2 (2000)
4173.
Fig. 4. 31P NMR spectra taken at 2 min to 2 h after introducing H2 to
[10] C. Chen, R.A. Reamer, J.R. Chilenski, C.J. McWilliams, Org. Lett. 5 (2003) 5039.
[11] J.H. Xie, L.X. Wang, Y. Fu, S.F. Zhu, B.M. Fan, H.F. Duan, Q.L. Zhou, J. Am. Chem.
Soc. 125 (2003) 4404.
the solution.
[12] J.B. Xie, J.H. Xie, X.Y. Liu, W.L. Kong, S. Li, Q.L. Zhou, J. Am. Chem. Soc. 132
(2010) 4538.
4. Conclusion
[13] Y. Ma, H. Liu, L. Chen, X. Cui, J. Zhu, J. Deng, Org. Lett. 5 (2003) 2103.
[14] K. Junge, K. Mçller, B. Wendt, S. Das, D. Gçrdes, K. Thurow, M. Beller, Chem. Asian
J. 7 (2012) 314.
In conclusion, we have successfully developed a ruthenium catalyst
bearing chiral diamine and inexpensive achiral phosphine that are
highly efficient for the asymmetric hydrogenation of various ketones.
The reaction provides a readily accessible method for the synthesis of
chiral secondary alcohols in excellent enantioselectivities and makes
this asymmetric hydrogenation highly practical. In addition, the pro-
posed mechanism for the asymmetric hydrogenation was verified by 1H
and 31P NMR spectroscopy.
[15] M. Ito, Y. Shibata, A. Watanabe, T. Ikariya, Synlett 10 (2009) 1621.
[16] M.L. Han, X.P. Hu, J.D. Huang, L.G. Chen, Z. Zheng, Tetrahedron Asymmetry 22
(2011) 222.
´
[17] C.A. Madrigal, A. García-Fernandez, J. Gimeno, E. Lastra, J. Organomet. Chem.
693 (2008) 2535.
[18] L. Zeng, F. Wu, Y.Y. Li, Z.R. Dong, J.X. Gao, J. Organomet. Chem. 762 (2014) 34.
[19] O. Altan, M.K. Yılmaz, J. Organomet. Chem. 861 (2018) 252.
[20] Z.R. Dong, Y.Y. Li, J.S. Chen, B.Z. Li, Y. Xing, J.X. Gao, Org. Lett. 7 (2005) 1043.
[21] H. Zhang, C.B. Yang, Y.Y. Li, Z.R. Dong, J.X. Gao, H. Nakamura, K. Murata,
T. Ikariya, Chem. Commun. 34 (2003) 142.
Credit author statement
[22] W. Wu, S. Liu, M. Duan, X. Tan, C. Chen, Y. Xie, Y. Lan, X.Q. Dong, X. Zhang, Org.
Lett. 12 (2016) 2938.
[23] C. Qin, C.J. Hou, H. Liu, Y.J. Liu, D.Z. Huang, X.P. Hu, Tetrahedron Lett. 59 (2018)
719.
Chun Li: Conceptualization; Funding acquisition; Writing - review &
editing; Project administration; Mengna Wang and Ling Zhang:
Investigation; Data curation; Formal analysis; Writing - original draft;
Hao Sun, Qian Chen and Jian Jiang: Software; Supervision; Valida-
tion; Lin Zhang: Methodology; Li Li and Linlin Li: Visualization;
Resources.
[24] W.J. Zhang, S.H. Ruan, W.Y. Shen, Z. Wang, D.L. An, Y.Y. Li, J.X. Gao, Catal.
Commun. 119 (2018) 153.
[25] M. Boukachabia, L. Aribi-Zouioueche, O. Riant, J. Organomet. Chem. 868 (2018)
95.
[26] R. H, Crabtree in the Organometallic Chemistry of the Transition Metals,
WileyIinterscience, New York, 2001.
[27] C. Li, L. Zhang, Y. Du, X.L. Zheng, H.Y. Fu, H. Chen, R.X. Li, Catal. Commun. 28
(2012) 5.
Declaration of Competing Interest
[28] X. Lu, M. Wang, L. Zhang, J. Jiang, L. Li, X. Gao, L. Zhang, C. Li, Tetrahedron Lett.
61 (2020) 151661.
[29] C. Li, X. Lu, M. Wang, L. Zhang, J. Jiang, S. Yan, Y. Yang, Y. Zhao, L. Zhang,
Tetrahedron Lett. 61 (2020) 152356.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
[30] H. Zhou, H. Huang, ChemCatChem 5 (2013) 2253.
[31] S. Takebayashi, N. Dabral, M. Miskolzie, S.H. Bergens, J. Am. Chem. Soc. 133
(2011) 9666.
[32] W.Y. Shen, Y.Y. Li, Z.R. Dong, J.X. Gao, Synthesis 14 (2009) 2413.
[33] K. Abdur-Rashid, S.E. Clapham, A. Hadzovic, J.N. Harvey, A.J. Lough, R.H. Morris,
J. Am. Chem. Soc. 124 (2002) 15104.
Acknowledgements
Research reported in this publication was supported by the National
Natural Science Foundation of China (21601039, 21562010).
[34] R. Abbel, K. Abdur-Rashid, M. Faatz, A. Hadzovic, A.J. Lough, R.H. Morris, J. Am.
Chem. Soc. 127 (2005) 1870.
[35] M. Zimmer-De Iuliis, R.H. Morris, J. Am. Chem. Soc. 131 (2009) 11263.
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