Efficient asymmetric transfer hydrogenation of ketones in ethanol with chiral iridium complexes of spiroPAP ligands as catalysts

Article abstract of DOI:10.1039/c5cc00479a

Highly efficient iridium catalyzed asymmetric transfer hydrogenation of simple ketones with ethanol as a hydrogen donor has been developed. By using chiral spiro iridium catalysts (S)-1a a series of alkyl aryl ketones were hydrogenated to chiral alcohols with up to 98% ee.

Full text of DOI:10.1039/c5cc00479a

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Efficient Asymmetric Transfer Hydrogenation of
Ketones in Ethanol with Chiral Iridium
Cite this: DOI: 10.1039/x0xx00000x
Complexes of SpiroPAP Ligands as Catalysts
WeiꢀPeng Liu, MingꢀLei Yuan, XiaoꢀHui Yang, Ke, Li, JianꢀHua Xie*, QiꢀLin Zhou*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
alcohols, we were therefore interested to the investigation of the
asymmetric transfer hydrogenation of simple ketones with chiral
spiro iridium catalysts Irꢀ(S)ꢀSpiroPAP ((S)ꢀ1) using ethanol as
hydrogen donor and solvent. The results showed that the catalysts
(S)ꢀ1 were also highly efficient for the asymmetric transfer
hydrogenation of simple ketones in ethanol, providing chiral
alcohols with up to 98% ee (Scheme 1).
A highly efficient iridium catalyzed asymmetric transfer
hydrogenation of simple ketones with ethanol as a hydrogen
donor has been developed. By using chiral spiro iridium
catalyst
(S)-1a a series of alkyl aryl ketones were
hydrogenated to chiral alcohols with up to 98% ee.
Optically pure alcohols are important chiral building blocks for the
preparation of fine chemicals, pharmaceuticals, agrochemicals,
bioactive natural products, as well as functional materials. Catalytic
asymmetric transfer hydrogenation of ketones is currently
recognized as one of the most powerful and valuable synthetic
methods for obtaining optically active chiral alcohols because of its
operational simplicity, easily availability of hydrogen sources, lower
cost and safety.1 By using 2ꢀpropanol or formate salts as hydrogen
donor and chiral transitionꢀmetal catalysts, a wide range of aromatic
ketones have been successfully reduced to chiral secondary alcohols
in high enantioselectivity.2 Recently, as a renewable resource,
feedstock for the chemical industry, as well as environmental and
humanꢀfriendly solvent, ethanol is also found to be efficient
hydrogen donor for transfer hydrogenation of ketones.3 However, the
catalytic asymmetric transfer hydrogenation of ketones with ethanol
as hydrogen donor is still a challenge. Grützmacher et al reported
that the chiral rhodium complexes of bis(olefin)amine ligands can
catalyze the transfer hydrogenation of acetophenone with ethanol as
hydrogen donor, however with only moderate enantioselectivities
(60% ee).4 The chiral ruthenium catalysts with hydroxylꢀamide
ligands reported by Lundberg and Adolfsson showed as high as 97%
ee for the reduction of alkyl aryl ketones in the mixed solvents of
ethanol and THF.5
Scheme 1. Asymmetric Transfer Hydrogenation of Ketones Catalyzed by (S)ꢀ1
The asymmetric transfer hydrogenation of acetophenone (2a) was
°
initially performed in ethanol at room temperature (25 C) with 0.1
mol% of catalyst (S)ꢀ1a. After reaction for 15 h the acetophenone
was converted in 93% and the hydrogenation product (R)ꢀ3a was
obtained with 98% ee (Table 1, entry 1). The reaction became faster
as the reaction temperature increased. When the transfer
hydrogenation was performed at 40 °C, the conversion of 2a
increased to 99% within 10 h and the enantioselectivity of reaction
remained (entry 2). Further increasing reaction temperature to 60 and
We recently developed a new type of chiral spiro iridium catalysts
containing
(SpiroPAP)
a
tridentate spiro pyridine aminophosphine ligand
and found they are extremely efficient for the
6
hydrogenation of simple ketones,7 α,βꢀunsaturated ketones,8
ketoesters,9 and esters10 in ethanol to chiral alcohols with excellent
activity and enantioselectivity. To address more “green”, sustainable,
safe, as well as highly efficient methods for preparing chiral
°
75 C continuously speeded the reaction, however slightly lowered
i
the enantioselectivity of reaction (entries 3 and 4). Using PrOH
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DOI: 10.1039/C5CC00479A
instead of EtOH as hydrogen donors and solvent led to a moderate catalyzed asymmetric transfer hydrogenation with ethanol as a
enantioselectivity (84% ee, entry 5). In addition to KOtBu, other
hydrogen donor. All the tested substrates gave high yields (93−99%)
and excellent enantioselectivities (90−98% ee) (Table 2). The
bases such as NaOtBu, KOH, and K2CO3 can also be used in the
transfer hydrogenation of 2a, providing (R)ꢀ3a with the same
enantioselectivity (entries 6−8). Although the use of HCO2Na as a
base afforded the highest enantioselectivity (99% ee), the conversion
of the reaction became very low (18%, 18 h, entry 9). Decreasing the
concentration of base from 0.04 mmol/mL to 0.02 mmol/mL resulted
in a lower conversion (83%, entry 10). In contrast, lowering the
concentration of substrate 2a led to a faster reaction (entry 12). The
catalysts (S)ꢀ1 with different substituents on the pyridine ring were
also compared in the asymmetric transfer hydrogenation of 2a. The
catalysts (S)ꢀ1b with a 3ꢀMe and (S)ꢀ1c with a 6ꢀMe on the pyridine
ring, respectively, afforded slightly lower enantioselectivity (entries
14 and 15). The catalyst (S)ꢀ1d with a 4ꢀtertꢀbutyl group on the
pyridine ring gave a comparable results to the catalyst (S)ꢀ1a which
has no substituent on the pyridine ring (entries 2 and 16). When the
loading of the catalyst 1a was reduced to be 0.05 mol% (S/C =
2000), the reaction still conducted very well and afforded (R)ꢀ3a in
97% conversion with 98% ee (entry 17). In addition, when the
transfer hydrogenation of 2a with catalyst (S)ꢀ1a was performed on a
gram scale (ca, 12.0 g, 0.1 mol), a comparable reactivity (99%
conversion, 96% isolated yield) and enantioselectivity (98% ee)
were also obtained within 16 h under similar reaction conditions
(entry 18). These results indicated that the iridium complex of the
tridentate SpiroPAP ligand are highly efficient chiral catalysts for
the asymmetric transfer hydrogenation of ketones with ethanol as a
hydrogen donor.
substituents on the phenyl ring of substrates have very little effect on
the yield and enantioselectivity of reaction. The transfer
hydrogenation of heteroarylꢀcontaining ketones such 3ꢀpyridinyl
methyl ketone (2q) also gave good yield and enantioselectivity
(entry 17). However, (S)ꢀ1a was less efficient for the transfer
hydrogenation of dialkyl ketones such as cyclohexyl methyl ketone
(2r) and tertꢀbutyl methyl ketones (2s), providing the corresponding
chiral aliphatic alcohols with moderate enantioselectivities (entries
18 and 19).
Table 2 Asymmetric transfer hydrogenation of 2 with (S)ꢀ1a.a
Entry
1
2
3
4
5
6
7
8
R1
C6H5
C6H5
R2
Me
Et
(R)ꢀ3
(R)ꢀ3a
(R)ꢀ3b
(R)ꢀ3c
(R)ꢀ3d
(R)ꢀ3e
(R)ꢀ3f
(R)ꢀ3g
(R)ꢀ3h
(R)ꢀ3i
(R)ꢀ3j
(R)ꢀ3k
(R)ꢀ3l
(R)ꢀ3m
(R)ꢀ3n
(R)ꢀ3o
(R)ꢀ3p
(R)ꢀ3q
(R)ꢀ3r
(R)ꢀ3s
Yield (%)b
99
Ee (%)c
98
97
96
91
90
95
96
93
96
97
98
96
98
96
93
95
95
95
95
98
93
93
96
98
95
99
94
96
99
98
99
87
4ꢀClC6H4
4ꢀBrC6H44
4ꢀMeC6H
4ꢀMeOC6H4
3ꢀClC6H4
3ꢀBrC6H4
3ꢀMeC6H4
3ꢀMeOC6H4
2ꢀClC6H4
2ꢀBrC6H4
2ꢀMeC6H4
2ꢀMeOC6H4
3,5ꢀ(CF3)2C6H3
2ꢀnaphthyl
3ꢀpyridinyl
cꢀHex
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
9
10
11
12
13
14
15
16
17d
18
19
Table 1 Optimization of reaction conditions for asymmetric transfer
hydrogenation of 2a.a
93
83
80
97
90
tBu
a Reaction conditions were the same as those listed in Table 1, entry 2. b
Isolated yield. c Determined by GC or HPLC by using chiral column, and the
configuration was determined as (R). d K2CO3 as a base.
Temp
(oC)
25
40
60
75
40
40
40
40
40
40
40
40
40
40
40
40
40
40
Time
(h)
15
10
8
Conv.
(%)b
93
99
99
100
98
99
97
97
18
83
99
99
99
99
99
99
Ee
(%)c
98
98
96
95
84
98
98
98
99
98
98
98
98
96
93
98
98
98
Entry
(S)ꢀ1
Base
1
2
3
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1a
(S)ꢀ1b
(S)ꢀ1c
(S)ꢀ1d
(S)ꢀ1a
(S)ꢀ1a
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuONa
KOH
K2CO3
HCO2Na
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
To understand this iridiumꢀcatalyzed asymmetric transfer
hydrogenation of ketone with ethanol as a hydrogen donor, we
studied the transfer hydrogenation of 2a in situ by using a ReactIR
spectrometer. As the reaction progresses, the peak at 1680 cmꢀ1 (2a)
disappeared within 1.5 h, and a new peak at 1743 cmꢀ1 (ethyl acetate)
appeared and increased quickly in the beginning and kept nearly
unchanged after 1.5 h (Figure 1, a and b). This result indicated that
the ethanol was converted to ethyl acetate11 and provided hydride,
which reduced ketone 2a to alcohol (R)ꢀ3a. The detection of the
reaction by using GC also showed the same phenomenon (Figure 1,
c). The conversion of 2a reached to 97% within 1.5 h. Extending
reaction time to 3 h slowly increased the conversion of 2a to 99%.
The ee value of the product (R)ꢀ3a was 98.6 % in the beginning and
slowly decreased to 98% ee when the conversion reached 99%. The
reason for slow decrease of ee value of product in the reaction was
ascribed to the slow decomposition of the catalyst.
In conclusion, we developed a highly efficient asymmetric
transfer hydrogenation of ketones with ethanol as a hydrogen
donor. With chiral spiro iridium catalyst (S)ꢀ1a a variety of
alkyl aryl ketones were hydrogenated to chiral alcohols in high
yields and excellent enantioselectivities. This reaction provided
a practical and “greener” method for the synthesis of optically
active alcohols.
4
5
5d
6
10
10
12
12
20
15
10
7
12
7
12
10
15
16
7
8
9
10e
11f
12g
13h
14
15
16
17i
18j
97
99 (96)
a Reaction conditions: 2.0 mmol scale, [2a] = 0.4 mmol/mL, 0.1 mol% of
catalyst, [base] = 0.04 mmol/mL, EtOH (5.0 mL). b Determined by 1H NMR.
c Determined by GC or HPLC by using chiral column, and the configuration
was determined as (R). d Using iPrOH instead of EtOH. e [tBuOK] = 0.02
mmol/mL. f [tBuOK] = 0.06 mmol/mL. g [2a] = 0.2 mmol/mL. h [2a] = 0.6
mmol/mL. i 0.05 mol% catalyst (S/C = 2000). j 12.0 g (0.1 mol), 0.05 mol%
catalyst. The data in parenthese is isolate yield.
Under the optimal reaction conditions, a variety of alkyl aryl
ketones were tested to examine the substrate scope of (S)ꢀ1aꢀ
2 | J. Name., 2012, 00, 1-3
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