A simple and efficient asymmetric hydrogenation of heteroaromatic ketones with iridium catalyst composed of chiral diamines and achiral phosphines

Article abstract of DOI:10.1016/j.tetlet.2020.152356

An efficient iridium catalyst composed of a simple and commercially available o-methoxytriphenylphosphine and 9-Amino (9-deoxy) epi-cinchonine was applied to the asymmetric hydrogenation of heteroaromatic ketones. A range of simple heteroaromatic ketones could be hydrogenated with good to excellent enantioselectivities and high activities. In particular, thiophene ketones and furyl ketones furnished 98.6% ee with up to 2.18 × 10⁴(1/h) TOF. This catalytic system can be of practical value.

Full text of DOI:10.1016/j.tetlet.2020.152356

Journal Pre-proofs
A simple and efficient asymmetric hydrogenation of heteroaromatic ketones
with iridium catalyst composed of chiral diamines and achiral phosphines
Chun Li, Xunhua Lu, Mengna Wang, Ling Zhang, Jian Jiang, Shunfa Yan,
Yuanyong Yang, Yonglong Zhao, Lin Zhang
PII:
S0040-4039(20)30834-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152356
TETL 152356
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 June 2020
8 August 2020
10 August 2020
Please cite this article as: Li, C., Lu, X., Wang, M., Zhang, L., Jiang, J., Yan, S., Yang, Y., Zhao, Y., Zhang, L.,
A simple and efficient asymmetric hydrogenation of heteroaromatic ketones with iridium catalyst composed of
chiral diamines and achiral phosphines, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152356
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
A simple and efficient asymmetric hydrogenation of heteroaromatic ketones with
iridium catalyst composed of chiral diamines and achiral phosphines
Chun Li, Xunhua Lu, Mengna Wang, Ling Zhang, Jian Jiang, Shunfa Yan, Yuanyong Yang, Yonglong
Zhao, Lin Zhang*
School of Pharmaceutical sciences, Guizhou Medical University, 550004, Guiyang, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient iridium catalyst composed of a simple and commercially available o-methoxytriphenylphosphine
and 9-Amino (9-deoxy) epi-cinchonine was applied to the asymmetric hydrogenation of heteroaromatic ketones.
A range of simple heteroaromatic ketones could be hydrogenated with good to excellent enantioselectivities and
high activities. In particular, thiophene ketones and furyl ketones furnished 98.6% ee with up to 2.18×104(1/h)
TOF. This catalytic system can be of practical value.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Heteroaromatic ketones
Asymmetric hydrogenation
Iridium
Chiral diamines
hydrogenation10-12. In 2010, Ohkuma13 reported the asymmetric
hydrogenation of aromatic heterocyclic ketones catalyzed by the
Introduction
Chiral heteroaryl alcohols containing nitrogen, oxygen or
sulfur in the heterocyclic ring are important intermediates in the
synthesis of biologically active molecules and chiral auxiliaries,
such as duloxetine, ricciocarpin A and (R)-5-(1-hydroxyethyl)-
catalyst Cp*Ir(OTf)(MsDPEN), affording the heterocyclic
alcohols in 93% to >99% ee. Wills and co-workers14 also
prepared a new type of Ru( Ⅱ)/TsDPEN catalyst containing an
ether-based linking tether for the asymmetric transfer
hydrogenation reactions of ketones, exhibiting excellent activity.
However, compared with the ruthenium, iridium catalyst was less
explored in the asymmetric hydrogenation of heteroaromatic
ketones, especially with H2 as hydrogen source. Zhang et al.15
developed tridentate ferrocene aminophosphoxazoline ligands
and successfully used in iridium-catalytic asymmetric
hydrogenation of simple ketones with up to 1000000 TON and
>99% ee. Recently, the Ir-catalyzed asymmetric hydrogenation
of simple aromatic ketones with chiral ferrocenyl P,N,N-ligands
has been developed by Hu and Hou16, and up to 98% ee obtained.
However, as is well known, the excellent enantioselectivity is a
result of the synergistic effect of the transition metal combining
chiral diphosphine and chiral diamine, which are often expensive
owing to difficulties in synthesis and instability17-19. In contrast,
much less effort has been dedicated to develop new iridium
catalysis system combining with commercially available chiral
diamine and simple achiral phosphine for the asymmetric
hydrogenation of heteroaromatic ketones. As part of our ongoing
studies toward the development of efficient catalysts for the
asymmetric hydrogenation of heteroaromatic ketones20, we
reported the catalytic performances of the iridium complex
combining with chiral diamines and achiral phosphines. To our
delight, the combination with chiral diamines and achiral
phosphine has proven to be high active and enantioselective for
the asymmetric hydrogenation of heteroaromatic ketones.
furan[2,3-c]
pyridine1-3
.
Homogeneous
asymmetric
hydrogenation of carbonyl compounds is a powerful alternative
for the synthesis of chiral alcohols in view of its easy handling,
high activity and low cost of reducing agents4. Therefore, a
number of efficient catalysts have been developed for the
asymmetric hydrogenation of ketones with chiral ligands. The
most famous example was the BINAP-ruthenium-diamine
catalyst system for the asymmetric hydrogenation of simple
aromatic ketones developed by Noyori and co-workers5 in 1995.
Furthermore, trans-RuCl2 [(R)-xylbinap][(R)-daipen] has been
reported by Noyori and co-workers6, which acted as an efficient
catalyst for asymmetric hydrogenation of hetero-aromatic
ketones with 100% ee and high yield. Meanwhile, Burk and
Zanotti-Gerosa7
developed
phanephos-ruthenium-diamine
complexes for the asymmetric hydrogenation of heteroaromatic
ketones with 99% ee obtained. Zhou et al.8 described the
synthesis of spiro diphosphines and their application in the
ruthenium-catalyzed asymmetric hydrogenation of simple
ketones with S/C up to 100000 and 99.5% ee. A series of
BINOL-derived ligands have been prepared and incorporated into
ruthenium( Ⅱ) complexes containing a diamine ligand by Wills
and co-workers9, giving reduction products with enantiomeric
excesses of up to 99%. Based on the study of Noyori, transition
metal ruthenium complexes are widely used not only in
asymmetric hydrogenation, but also in asymmetric transfer

2
Tetrahedron Letters
hours, equivalent conversion and enantioselectivity were
Results and Discussion
achieved (Table 1, entry 6). Meanwhile, m-MOTPP was also
examined just gave 63.8% conversion and 51.7%
enantioselectivity (Table 1, entry 8). Then we investigated the
effect of the other four chiral diamines combining with o-
MOTPP for the asymmetric hydrogenation of 2-acetylthiophene.
Contrary to chiral diamine A, just 39.0%-72.4% ee values were
obtained although excellent conversions shown (Table 1, entries
11-14).
With the goal of studying the steric and electronic properties of
the ligands, [Ir(COD)OCH3]2 combining with chiral diamines and
achiral phosphines (Figure 1) were evaluated for the asymmetric
hydrogenation of 2-acetylthiophene employed as a standard
substrate. The results were summarized in Table 1. In a
preliminary screen, just one single ligand was evaluated in the
asymmetric hydrogenation of 2-acetylthiophene, and neither
chiral diamine nor achiral phosphine examined here gave
satisfactory results (Table 1, entries 1, 2). Fortunately, excellent
conversion and higher enantioselectivity were obtained When
chiral diamine A and TPP were added in the same time (Table 1,
entry 3). Encouraged by this excellent result, a series of
triarylphosphine-bearing substituents on the benzene ring, such
as MOTPP, MTPP and TFTPP, were performed in the
asymmetric hydrogenation of 2-acetylthiophene. As can be seen,
conversion and enantioselectivity all decreased with the para-
substituted triarylphosphane, not only electron-withdonating
group but also electron-withdrawing group (Table 1, entries 7, 9
and 10).
The effect of molar ratios of iridium/chiral diamine A/o-
MOTPP were investigated for the asymmetric hydrogenation of
2-acetylthiophene. The optimum molar ratio of iridium/chiral
diamine A/o-MOTPP was 1/2/3.5. Increasing or decreasing the
ratio was unfavorable for the activity and enantioselectivity.
It was reported that base was crucial and played a very
important role for the asymmetric hydrogenation in our previous
work. Herein, the influence of bases on the asymmetric
hydrogenation of 2-acetylthiophene was also examined. Typical
results are listed in Table 2. In the presence of LiOH, the
enantioselective reduction of 2-acetylthiophene proceeded
smoothly to give chiral alcohols with the best 90.9% conversion
and 90.5% enantioselectivity (Table 2, entry 1). With NaOH
added, enantioselectivity was equivalent to the best data, but
lower activity achieved (Table 2, entry 2). With other bases
added, such as KOH and t-BuOK, both conversion and
enantioselectivity significantly decreased (Table 2, entries 3 and
5). Only less than 1% conversion was achieved under the same
reaction conditions with Ba(OH)2 and K2CO3 as the base (Table
2, entries 4 and 6).
N
N
H
N
H N
2
N
2
H
N
2
O
N
N
N
B
C
A
9-Amino(9-deoxy)epi-cinchonine
9-Amino(9-deoxy)epi-cinchonidine
9-Amino-(9-deoxy)epi-quinine
N
N
H N
2
H N
2
P
Table 2. The effect of bases for asymmetric hydrogenation of
2-acetylthiophene catalyzed by [Ir(COD)OMe]2/chiral
diamine A/o-MOTPP.a
3
R
O
O
N
N
R = H, o-OCH , m-OCH , p-OCH , p-CH , p-CF
3
3
3
3
3
D
E
9-Amino-(9-deoxy)epi-dihydroquinine
9-Amino-(9-deoxy)epi-dihydroquinidine
Entry
Base
Con.(%)
Ee(%)
Config.
Figure 1. Chiral diamines and achiral phosphines.
LiOH
NaOH
KOH
Ba(OH)2
t-BuOK
K2CO3
90.9
74.4
16.4
<1
90.5
91.6
84.0
-
S
S
S
-
1
2
3
4
5
6
Table 1. The effect of chiral diamines and achiral phosphines
for asymmetric hydrogenation of 2-acetylthiophene catalyzed
by [Ir(COD)OMe]2.a
6.0
80.1
-
S
-
Chiral
diamine
Achiral
phosphine
Entry
Con.(%)
Ee(%)
Config.
<1
a
substrate/Ir/chiral amine A/o-MOTPP = 2000/1/2/3.5, 2-acetylthiophene:
1.149mol/L, Base: 0.1 mol/L, CH3CH2OH: 2 ml, 25℃, 6 MPa, 5 min.
>99
5.2
42.4
5.4
S
S
S
S
S
S
S
S
S
S
R
R
R
S
1
2
A
-
-
o-MOTPP
TPP
>99
72.9
>99
97.4
44.5
63.8
81.7
93.9
>99
>99
>99
>99
70.4
63.6
87.3
82.6
56.8
51.7
61.8
57.5
61.8
39.0
52.1
72.4
3
A
A
A
A
A
A
A
A
B
C
D
E
Since the choice of solvent, especially alcohols, had great
influence on the conversion and enantioselectivity of asymmetric
hydrogenation, five different alcohols were investigated in this
reaction with results collected in Table 3. Excellent
enantioselectivities (82.2-90.5% ee) were obtained in all of
alcohols except i-PrOH, although quite different conversions
4
TPP
5
o-MOTPP
o-MOTPP
p-MOTPP
m-MOTPP
p-MTPP
p-TFTPP
o-MOTPP
o-MOTPP
o-MOTPP
o-MOTPP
6
7
8
9
Table 3. The effect of solvent for asymmetric hydrogenation
of 2-acetylthiophene catalyzed by [Ir(COD)OMe]2/chiral
diamine A/o-MOTPP.a
10
11 b
12 b
13 b
14 b
Entry
Solvent
Con.(%)
Ee(%)
Config.
MeOH
EtOH
17.3
90.9
48.1
7.2
82.2
90.5
90.5
88.8
-
S
S
S
S
-
1
2
3
4
5
a substrate/Ir/chiral diamine/achiral phosphine = 500/1/2/1, 2-acetylthiophene:
0.287mol/L, LiOH: 0.1 mol/L, CH3CH2OH: 2 ml, 25℃, 6 MPa, 3 h.
b 2 h.
n-PrOH
n-Butanol
i-PrOH
<1
Excitedly, conversion and enantioselectivity all increased
when the methoxy group of triarylphosphane changed from the
para position to the ortho position (Table 1, entry 5). The best
results, >99% conversion and 87.3% enantioselectivity, were
obtained with 3 hours. When the reaction time reduced to 2
a
substrate/Ir/chiral amine A/o-MOTPP = 2000/1/2/3.5, 2-acetylthiophene:
1.149mol/L, solvent: 2 ml, LiOH: 0.1 mol/L, 25℃, 6 MPa, 5 min.
achieved (Table 3, entries 1-4). The catalyst system showed the
best performance in ethanol, up to 90.5% ee and 90.9% of

3
conversion were achieved (Table 3, entry 2). And the catalysis
system showed the worst performance, only less than 1%
conversion being achieved, with i-PrOH as the solvent (Table 3,
entry 5).
The effect of hydrogen pressure for asymmetric hydrogenation
of heteroaromatic ketones was also evaluated (Table 4). As can
be seen, increasing the hydrogen pressure from 4-7 MPa limits
the conversion but no influence on the enantioselectivity of
asymmetric hydrogenation. This indicates that an appropriate
hydrogen pressure is crucial for obtaining high activity of the
catalytic system. When the reactions were run at 6 MPa hydrogen
pressure, the highest 90.9% conversion and 90.5% ee were
maintained (Table 4, entry 4).
iridium in the catalytic transition state more strongly than a
sulfur atom or an oxygen atom, which would result in a
deterioration of the induced activity and enantioselectivities11.
When reducing S/C to 50/1, medium conversions and
enantioselectivities were achieved (Table 5, entries 12-14). From
these experiment data, we can conclude that the different
activities and enantioselectivities were affected by the kind of
heteroatom in the heterocyclic of the ketones and the steric
effects of the substrates.
Table 5. Asymmetric hydrogenation of heteroaromatic
ketones catalyzed by [Ir(COD)OMe]2/chiral diamine A/o-
MOTPP.a
Entry
Substrate
S/C
Con.(%)
Ee(%)
Config.
Table 4. The effect of hydrogen pressure for asymmetric
O
S
S
hydrogenation
of
2-acetylthiophene
catalyzed
by
1
1500/1
>99
88.4
S
[Ir(COD)OMe]2/chiral diamine A/o-MOTPP.a
Con.
(%)
Ee
2
3
500/1
500/1
95.3
96.9
90.9
84.8
S
S
Entry
Pressure(MPa)
Config.
(%)
91.8
91.7
90.5
92.1
O
4
5
6
7
55.5
58.5
90.9
80.8
S
S
S
S
1
2
3
4
S
O
S
4
5
6
500/1
500/1
500/1
67.6
94.7
59.9
98.6
84.7
76.9
S
S
S
O
a
substrate/Ir/chiral amine A/o-MOTPP = 2000/1/2/3.5, 2-acetylthiophene:
1.149mol/L, LiOH: 0.1 mol/L, CH3CH2OH: 2 ml, 25℃, 5 min.
b TOF = 2.18×104(1/h).
O
S
Cl
Br
O
S
Subsequently, having established the optimal reaction
condition, we explored various heteroaromatic ketones to
evaluate the substrate scope as shown in Table 5. The catalysis
system showed the best activity when 2-acetylthiophene was
hydrogenated. A conversion of >99% was obtained after just 5
min and the enantioselectivity was 88.4% (Table 5, entry 1).
Then, 2-Propionyl thiophene, 2-isobutyryl thiophene and 2-
butyryl thiophene were also used as hydrogenation substrate to
study the influence of the alkyl group of heteroaromatic ketones
on activity and enantioselectivity. Obviously, the alkyl group
deactivated the reaction activity due to the steric hindrance, low
conversion was obtained for the asymmetric hydrogenation of 2-
Propionyl thiophene under the same condition. When reducing
S/C to 500/1, both 2-Propionyl thiophene and 2-isobutyryl
thiophene were hydrogenated with 95.3% and 96.9% conversion,
giving 90.9% and 84.8% ee, respectively (Table 5, entries 2-3).
The hydrogenation of 2-butyryl thiophene gave the highest
98.6% ee with 67.6% conversion (Table 5, entry 4). In addition
to the reduction of 5-methyl-2-acetylthiophene was also
examined and was smoothly converted into the corresponding
alcohol with 84.7% ee and 94.7% conversion under 500/1 (Table
5, entry 5). Considering the electron-withdrawing substituent
effect, halogenated 2-acetylthiophene was hydrogenated. It seems
that the electron-withdrawing group decreased both activity and
selectivity (Table 5, entries 6-7). Two furyl ketones were used to
test the catalyst. It is shown that not only 2-acetylfuran but also
5-methyl-2-acetylfuran were hydrogenated with excellent
conversion (92.9->99%) and enantioselectivity (85.6-87.9%)
with just 5min reaction time and S/C = 1500/1 (Table 5, entries 8,
9). Encouraged by these excellent results, 2-acetylpyrrole was
also investigated. Unfortunately, no reaction took place (Table 5,
entry 10), which may owe to the hydrogen atom on the
acetylfuran ring. When 1-methyl-2-acetylpyrrole was reduced to
prove the guess, 6.7% conversion and 11.0% ee were gave (Table
5, entry 11) with the same conditions. In addition, the ortho-,
meta- and para-acetyl pyridines were investigated. Compared to
thiophene ketones and furyl ketones, low conversions were
achieved under the same conditions. The reason is probably that
the nitrogen atom of the heteroaromatic ring coordinates to the
O
S
7
500/1
46.5
78.1
S
O
8
9
1500/1
1500/1
>99
85.6
87.9
S
S
O
O
92.9
O
H
N
10
11
500/1
500/1
-
-
-
O
O
N
6.7
11.0
S
12
13
50/1
50/1
73.6
47.1
62.7
50.4
S
S
N
O
O
N
O
14
50/1
47.4
40.1
S
N
a Ir/chiral diamine A/o-MOTPP = 1/2/3.5, LiOH: 0.1 mol/L, CH3CH2OH: 2
ml, 25℃, 6 MPa, 5 min.
A likely catalytic mechanism involving a “metal-ligand-
substrate” interaction for the hydrogenation of heteroaromatic
ketones catalyzed by [Ir(COD)OMe]2/chiral diamine A/o-
MOTPP was proposed (Scheme 1)12, 21-23. In the first step, the
chiral diamine A and o-MOTPP reacted with [Ir(COD)OMe]2 to
form complex 1. Then the iridium complex was transformed into
iridium dihydride complex 2 under hydrogen atmosphere. Under
the influence of base, the iridium dihydride complex 2 lost one
molecule of CH3OH to produce an Ir-amide complex 3. This step
maybe explains the fact that the catalysis system showed poor
reactivity with CH3OH as solvent. The Ir-amide complex 3 was
further hydrogenated to iridium trihydride complex 4. This
iridium trihydride complex transferred a hydridic Ir-H and a
protic N-H unit to the carbonyl group of the heteroaromatic

4
Tetrahedron Letters
2. S.W. Krabbe, M.A. Hatcher, R.K. Bowman, M.B. Mitchell, M.S.
ketones through the transition state 5 to generate chiral alcohol,
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Biotechnol. Biochem. 2003, 67, 809.
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of phosphines with larger substituents on the P-phenyl ring is
Scheme 1. Proposed Mechanism for the Asymmetric
Hydrogenation.
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helpful for hydrogenation process. Considering the
heteroaromatic ketones containing nitrogen, oxygen or sulfur in
the heterocyclic ring, which would result in coordination with
iridium, the hydrogenation process showed much difference in
activity and enantioselectivities.
General experimental procedure: All reagents were of analytical
grade and used as purchased. The purity of hydrogen was over 99.99%.
1H NMR and 13C NMR spectra were recorded on Bruker NMR 400
MHz spectrometer with reference to TMS as the internal standard.
Product were determined by GC-9790 with a β-DEX120 column (25 m
× 0.25 mm). Optical rotation was measured on the Rudolph Autopol Ⅰ
with [ α]D25 values reported in degrees at 25 ℃; concentration (c) is in
g/100 ml. Iridium precursor, chiral diamine, achiral phosphine, solvent,
base and heteroaromatic ketones were added to a 50 ml stainless
autoclave with a magnetic stirrer, followed by a purge with hydrogen
three times, and then, the hydrogen pressure was raised to desired level.
The mixture was stirred at a predetermined temperature for preset time.
After hydrogenation, the conversion and enantioselectivity values were
analyzed by GC. The ee values of heteroaryl alcohols were calculated
from the equations enantioselectivity values (ee, %) = |R - S| / |R + S|.
Conclusion
In summary, we have demonstrated that asymmetric
hydrogenation of heteroaromatic ketones to chiral heteroaryl
alcohols is feasible. The reaction was catalyzed by an iridium
catalyst combined a simple achiral phosphine and a chiral
diamine, which exhibited high enantioselectivities (98.6% ee)
and high activities (up to 2.18×104(1/h) TOF). These
experimental results provide another attractive method for
obtaining very useful chiral heteroaromatic alcohols.
Acknowledgment
Research reported in this publication was supported by the
National Natural Science Foundation of China (21601039,
21562010).
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References and notes
1. E. Buitrago, H. Lundberg, H. Andersson, P. Ryberg, H. Adolfsson,
ChemCatChem. 2012, 4, 2082.
☒The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
Declaration of interests
☒ 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.

5
O
[I
We declare that we have no financial and personal relationships with other people or organizations that can
inappropriately influence our work, there is no professional or other personal interest of any nature or kind
in any product, service and/or company that could be construed as influencing the position presented in, or
the review of, the manuscript entitled “A simple and efficient asymmetric hydrogenation of
R
R
2
1
1: R1 = 2-thienyl,
2: R1 = 2-thienyl,
3: R1 = 2-thienyl,
4: R1 = 2-thienyl,
5: R1 = 5-methyl-
6: R1 = 5-chloro-2
7: R1 = 5-bromo-2
8: R1 = 2-furyl, R
9: R1 = 5-methyl-
10: R1 = 2-pyrroly
11: R1 = 1-methyl
12: R1 = 2-pyridy
13: R1 = 3-pyridy
14: R1 = 4-pyridy
heteroaromatic ketones with iridium catalyst composed of chiral diamines and achiral phosphines”.
Graphic Abstract
A simple and efficient asymmetric
hydrogenation of heteroaromatic ketones with
iridium catalyst composed of chiral diamines
and achiral phosphines
Chun Li, Xunhua Lu, Mengna Wang, Ling Zhang,
Highlights：
Jian Jiang, Shunfa Yan, Yuanyong Yang, Yonglong
Zhao, Lin Zhang*
1. An Iridium catalyst was used for heteroaromatic
ketones asymmetric hydrogenation;
2. Cheap phosphine ligands and cinchona alkaloids
An efficient iridium catalyst composed of a
simple and commercially available o-
methoxytriphenylphosphine and 9-Amino (9-
deoxy) epi-cinchonine was applied to the
asymmetric hydrogenation of heteroaromatic
ketones.
derivatives were used;
3. A series of heteroaromatic ketones has been well
asymmetric hydrogenated;
4. 98.6% ee and high up to 2.18×104(1/h) TOF
were obtained under mild conditions.