Iridium-Catalyzed Asymmetric Transfer Hydrogenation of Alkynyl Ketones Using Sodium Formate and Ethanol as Hydrogen Sources

Article abstract of DOI:10.1021/acs.orglett.8b01787

A green and efficient iridium-catalyzed asymmetric transfer hydrogenation of alkynyl ketones to chiral propargylic alcohols has been developed. By using sodium formate and ethanol as hydrogen sources, a series of alkynyl ketones were hydrogenated by chira

Full text of DOI:10.1021/acs.orglett.8b01787

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-Catalyzed Asymmetric Transfer Hydrogenation of Alkynyl
Ketones Using Sodium Formate and Ethanol as Hydrogen Sources
Yang-Ming Zhang,† Ming-Lei Yuan,† Wei-Peng Liu,† Jian-Hua Xie,*,† and Qi-Lin Zhou†,‡
†State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A green and efficient iridium-catalyzed asymmetric transfer hydrogenation of alkynyl ketones to chiral
propargylic alcohols has been developed. By using sodium formate and ethanol as hydrogen sources, a series of alkynyl ketones
were hydrogenated by chiral spiro iridium catalyst (S)-1b to provide optically active chiral propargylic alcohols with up to 98%
ee under base-free conditions. This protocol provides a practical and sustainable method for the preparation of optically active
propargylic alcohols.
ptically active propargylic alcohols are useful and
important chiral building blocks for the synthesis of
asymmetric transfer hydrogenation of simple ketones.9 With
ethanol as a hydrogen donor10 and tBuOK as a base, a series of
alkyl aryl ketones were reduced to their corresponding chiral
alcohols with good to excellent enantioselectivity. Considering
that ethanol is a renewable resource and a feedstock for the
chemical industry,11 as well as an environmental- and human-
friendly solvent, we were encouraged to evaluate this catalytic
system for the reduction of alkynyl ketones. This evaluation led
us to find that chiral spiro iridium catalysts 1 were also efficient
for the asymmetric transfer hydrogenation of alkynyl ketones
in the presence of both sodium formate and ethanol as
hydrogen sources without the addition of any base (Scheme
1).
The asymmetric transfer hydrogenation of 4-phenylbut-3-
yn-2-one (2a) was initially performed under our previous
reaction conditions, that is (S)-1b/EtOH/tBuOK at 40 °C,9
and no desired reduction product was obtained. Only the
Michael addition byproduct, formed by the ethoxide addition
to the CC bond of 2a, was observed (Table 1, entry 1). The
transfer hydrogenation of 2a also did not occur under the
conditions using HCO2H/NEt3 as a hydrogen donor (entries 2
and 3). To our delight when HCO2Na (2 equiv) is applied as a
hydrogen donor, the alkynyl ketone 2a was reduced to
propargylic alcohol (R)-3a in high enantioselectivity (97% ee,
entry 4). The reaction became faster when the reaction
temperature increased to 60 °C, and the reaction finished
O
various bioactive and structurally interesting compounds.1
Catalytic asymmetric hydrogenation of alkynyl ketones is
undoubtedly a direct and promising approach to chiral
propargylic alcohols. However, due to the reason that many
alkynyl ketones are labile to basic ketone hydrogenation
conditions,2 only limited catalytic systems documented were
efficient for the hydrogenation of alkynyl ketones.3 In contrast,
the catalytic asymmetric transfer hydrogenation, which can be
performed under mild reaction conditions, has been well-
developed for the reduction of alkynyl ketones to chiral
propargylic alcohols.4 In 1997, Noyori reported the asym-
metric transfer hydrogenation of alkynyl ketones by using
chiral Ru-TsDPEN catalysts with iPrOH/KOH as a hydrogen
donor.5 Since then, the asymmetric transfer hydrogenation of
alkynyl ketones to optically active chiral propargylic alcohols
has received intensive attention6 and has been successfully
applied in the enantioselective synthesis of bioactive natural
products.7 However, most of the reported asymmetric transfer
hydrogenations used Ru-TsDPEN or its analogs as catalysts
and iPrOH/KOH or HCO2H/NEt3 as hydrogen donors. In
this letter, we report an iridium-catalyzed asymmetric transfer
hydrogenation of alkynyl ketones to chiral propargylic alcohols
with sodium formate and ethanol as hydrogen sources under
base-free conditions, producing chiral propargylic alcohols in
high yield and enantioselectivity.
Recently, we found that the chiral iridium catalysts Ir-
SpiroPAP (1) with a tridentate spiro pyridine-aminophosphine
ligand developed in our group8 were highly efficient for the
Received: June 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituted groups on the pyridine ring were also tested. The
catalysts having no substituent or having a methyl group
exhibited high activity and high enantioselectivity; however,
the catalyst (S)-1c containing a 4-tBu group gave low
conversion and enantioselectivity (entries 5 and 15−17).
The reaction can also be performed by using 0.5 mol % of
catalyst (S)-1b (entry 18).
Scheme 1. Iridium Catalyzed Asymmetric Transfer
Hydrogenation of Alkynyl Ketones
Under the optimal reaction conditions, a range of aryl
alkynyl ketones 2 were evaluated, and the results are
summarized in Table 2. The electronic property of the R
Table 2. Asymmetric Transfer Hydrogenation of Alkynyl
a
Ketones 2 with (S)-1b
time
(h)
yield
b
c
entry
Ar
C6H5
C6H5
C6H5
C6H5
R
3
(%)
ee (%)
1
2
3
4
5
6
7
8
Me
Et
iPr
CF3
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
99
99
90
99
86
93
95
99
92
96
98
99
95
96
96 (R)
96 (R)
84 (R)
98 (S)
96
11
40
4
Table 1. Asymmetric Transfer Hydrogenation of 2a.
a
Optimizing Reaction Conditions
C6H5
C6H5
(CH2)2CO2Et
(CH2)3CO2Et
4
hydrogen
donor
temp
time conv
ee
12
24
30
7
7
10
8
95
b
c
entry
(S)-1
solvent
EtOH
(°C)
(h)
(%)
(%)
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
3-MeC6H4
3-ClC6H4
2-MeOC6H4
2-ClC6H4
Me
Me
Me
Me
Me
Me
Me
Me
95 (R)
96 (R)
96 (R)
97
d
1
(S)-1b EtOH/
tBuOK
40
40
40
20
−
ND
ND
ND
9
e
2
(S)-1b HCO2H/
CH2Cl2
EtOH
20
20
−
−
10
11
12
13
14
NEt3
e
97
96
86
91
3
(S)-1b HCO2H/
NEt3
4
5
6
7
8
(S)-1b HCO2Na
(S)-1b HCO2Na
(S)-1b HCO2Na
(S)-1b HCO2Na
(S)-1b HCO2Na
(S)-1b HCO2Na
(S)-1b HCO2Li
(S)-1b HCO2K
(S)-1b HCO2Cs
(S)-1b HCO2Na
(S)-1b HCO2Na
(S)-1a HCO2Na
(S)-1c HCO2Na
(S)-1d HCO2Na
(S)-1b HCO2Na
EtOH
EtOH
EtOH
EtOH
MeOH
iPrOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
40
60
80
60
60
60
60
60
60
60
60
60
60
60
60
20
8
6
20
8
8
20
7
5
12
20
8
20
10
20
97
99
99
78
40
52
60
99
99
94
95
97
47
94
95
97
96
90
89
75
72
94
96
96
95
95
94
78
93
95
48
10
a
Reaction conditions were the same as those listed in Table 1, entry 5.
Isolated yield. Determined by HPLC using a chiral column.
f
b
c
9
10
11
12
13
14
15
16
17
group in the substrates had no effect on the yield and
enantioselectivity of the reaction, although the substrate 2d,
which has an electron-withdrawing group (R = CF3), gave a
faster reaction rate (entries 1, 2, and 4). However, when the R
group is a bulky isopropyl (2c), the reaction became sluggish,
and both the yield and enantioselectivity decreased (entry 3).
The ester group in the substrates 2e and 2f was tolerated under
the reaction conditions (entries 5 and 6). The substituent at
the para- or meta-position of the phenyl ring of the aryl alkynyl
group of ketones 2 had little impact on the yield and
enantioselectivity of the reaction (entries 7−12). For steric
reasons the substitution at the ortho-position lowered the
enantioselectivity of the reaction (entries 13 and 14).
Generally, an electron-withdrawing substitution at the
arylalkynyl group of the ketones 2 accelerated the reaction
rate (entries 9, 10, 12, and 14).
g
h
i
18
a
Reaction conditions: 0.2 mmol of 2a (0.04 M), 0.4 mmol of
HCO2Na, 1 mol % catalyst, EtOH (5.0 mL). Determined by H
NMR. NR means no reaction. Determined by HPLC using chiral
column. The configuration is (R). ND means not determined.
Adding 0.02 mmol of tBuOK. 0.4 mmol of HCO2H, HCO2H/NEt3
= 2/5 (v/v). 0.2 mmol of HCO2Na. [2a] = 0.08 M. [2a] = 0.1 M.
0.5 mol % catalyst (S/C = 200).
b
1
c
d
e
f
g
h
i
within 8 h (entry 5). However, further increasing the reaction
temperature to 80 °C resulted in lower enantioselectivity (90%
ee, entry 6). Reducing the amount of HCO2Na to 1 equiv
lowered both the conversion and enantioselectivity of the
reaction (entry 7). Solvent experiments showed that EtOH was
the best solvent. The reactions in MeOH and iPrOH gave low
conversion and low enantioselectivity (entries 8 and 9). Other
alkali metal formates can also be used as hydrogen sources
although the HCO2Li gave a lower reaction rate and
conversion (entries 10−12). Increasing the concentration of
the substrate resulted in comparable enantioselectivity, but
longer reaction times were required to complete the reaction
(entries 13 and 14). The catalysts (S)-1 containing different
The asymmetric transfer hydrogenation of alkynyl ketone 2d
with HCO2Cs12 was tracked by in situ IR spectroscopy. We
found that the HCO2Cs was converted to cesium ethyl
carbonate (EtOCO2Cs) after providing hydrogen (Figure 1).
In the reaction of 2d (1704 cm−1) with 1.2 equiv of HCO2Cs
(1602 cm−1) catalyzed by (S)-1b (2 mol %) at 60 °C, the
peaks at 1704 and 1602 cm−1 decreased rapidly at the first
stage and a new peak at 1640 cm−1, which belongs to
EtOCO2Cs, increased. After reaction for 3 h, the peaks at 1704
and 1602 cm−1 disappeared, and the peak at 1640 cm−1 was a
single major peak in the spectrum. In addition, no obvious
peak at 1743 cm−1, which belongs to ethyl acetate,13 was
observed in the reaction. These results indicate that the
B
DOI: 10.1021/acs.orglett.8b01787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
which was obtained from the extraction of the final residue
with hexane still has catalytic activity for asymmetric
hydrogenation of alkynyl ketone 2a under the same reaction
conditions (see Supporting Information). This result indicates
that the catalyst (S)-1b was stable and robust under the
reaction conditions and easily recycled. The low turnover
numbers (e.g., 190, Table 1, entry 18) of the hydrogenation of
2a is likely due to the fact that the propargylic alcohol product
inhibits the activity of the catalyst (S)-1b.
In conclusion, we have developed a green and efficient
iridium-catalyzed asymmetric transfer hydrogenation of alkynyl
ketones to chiral propargyl alcohols. With sodium formate and
ethanol as hydrogen sources under base-free conditions, a
variety of alkynyl ketones were hydrogenated by chiral spiro
iridium catalyst (S)-1b to provide chiral propargyl alcohols in
high yield and enantioselectivity. This protocol provides a
practical and sustainable method for the preparation of
optically active propargyl alcohols.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01787.
Experimental procedures and the characterizations of the
substrates and products (PDF)
Figure 1. Plots of asymmetric transfer hydrogenation of 2d
(monitored by a ReactIR spectrometer).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jhxie@nankai.edu.cn.
ORCID
formate salt and EtOH served as the hydride and proton
sources, respectively, in the reaction (Scheme 2).
Scheme 2. Asymmetric Transfer Hydrogenation of 2d with
HCO2Cs in EtOH and in Gram Scale
Jian-Hua Xie: 0000-0003-3907-2530
Qi-Lin Zhou: 0000-0002-4700-3765
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21325207, 21532003, and 21421062) and the “111”
project (B06005) of the Ministry of Education of China for
financial support.
REFERENCES
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DOI: 10.1021/acs.orglett.8b01787
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