Palladium-catalyzed asymmetric hydrogenation of α-acyloxy-1- arylethanones

Article abstract of DOI:10.1002/anie.201306231

First hand: The first example of a palladium-catalyzed asymmetric hydrogenation of α-acyloxy ketones (1) was accomplished to give the hydrogenated products 2 with by far the highest catalytic efficiency in up to quantitative conversions and excellent enantioselectivities. The hydrogenated products could serve as important intermediates for the preparation of many drug candidates. TFE=2,2,2-trifluoroethanol. Copyright

Full text of DOI:10.1002/anie.201306231

Angewandte
Chemie
DOI: 10.1002/anie.201306231
Homogeneous Catalysis
Palladium-Catalyzed Asymmetric Hydrogenation of a-Acyloxy-1-
arylethanones**
Jianzhong Chen, Delong Liu, Nicholas Butt, Chao Li, Dongyang Fan, Yangang Liu, and
Wanbin Zhang*
a-Acyloxy-1-arylethanols, especially those possessing chiral
centers, are a class of useful structural motifs commonly found
in natural products and drug candidates.[1] They can serve as
important intermediates for the preparation of many bioac-
tive and medicinal molecules (Figure 1).[2] However, little
often involve the migration of the acyl group by hydrolysis.
The asymmetric transfer hydrogenation of a-acyloxy-1-aryl-
ethanones has also been accomplished but with low yield and
enantioselectivity or limited substrate scope.[7] To the best of
our knowledge, a strategy using transition-metal-catalyzed
asymmetric hydrogenation of a-acyloxy-1-arylethanones
remains unexplored, despite it being one of the most powerful
methods for preparing chiral compounds.
Enantioselective hydrogenation reactions are of great
interest to the chemistry community because of their atom
efficiency and minimal environmental impact.[8] In particular,
palladium-catalyzed hydrogenations have gained increasing
interest, however the use of palladium catalysis in the
asymmetric hydrogenation of carbonyl compounds is rela-
tively unexplored and requires high catalyst loadings (usually
S/C = 50), the specific use of TFE as a solvent, and has limited
substrate scope.[9,10] Herein we present an efficient palladium-
catalyzed asymmetric hydrogenation of a variety of a-
acyloxy-1-arylethanones substrates for the preparation of
chiral a-acyloxy-1-arylethanols.
We first carried out the asymmetric hydrogenation of 2-
oxo-2-phenylethyl benzoate (1aa) using a catalytic system
of Pd(OCOCF3)2 (2.0 mol%) and C10-BridgePHOS (L1,
2.4 mol%), a novel chiral diphosphine ligand we recently
developed,[10e,h] under 30 bar H2 at room temperature in TFE.
As shown in Table 1, the reaction barely proceeded when
using C10-BridgePHOS (entry 1). Thus, commonly used
axially chiral diphosphine ligands (R)-binap (L2) and (R)-
SegPHOS (L3) were screened, and provided similar results
(entries 2 and 3). Finally, (R)-3,5-di-tBu-4-MeO-SegPHOS
(L4; (R)-DTBM-SegPHOS), which possesses a high electron
density and steric bulk, was examined. To our delight, almost
quantitative conversion was obtained with moderate enan-
tioselectivity (71% ee, entry 4).
Using L4 as the chiral ligand, our attention turned to the
effect the acyl group on 1a had on the reaction. A broad range
of substrates (1a) having different acyloxy groups (R1) were
investigated (Table 2). Aromatic groups were first examined
and up to 71% ee was obtained with Ph as a substituent
(entry 1). Both electron-withdrawing and electron-donating
groups at different positions of the aromatic ring delivered
somewhat poor enantioselectivity (entries 2–6). Aliphatic
groups were then examined. A methyl group could provide
quantitative conversion but low enantioselectivity (entry 7).
Increasing the steric hindrance of R1 increased the enantio-
selectivity. A tBu group, possessing the greatest steric bulk,
gave the highest ee value (76% ee, entries 7–11). Thus the
bulky aliphatic tBu group was selected for subsequent
reactions.
Figure 1. Chiral a-acyloxy-1-arylethanols. Bz=benzoyl, Piv=pivaloyl.
attention has been focused on their synthesis and the general
approaches to prepare them often involve the selective
acylation of the corresponding chiral diol species.[3] Strategies
to directly obtain the chiral a-acyloxy-1-arylethanols from a-
acyloxy-1-arylethanones are relatively unknown. The initial
study on the asymmetric reduction of a-acyloxy ketones was
achieved in 1985 by utilizing the mixed reducing agent of
a chiral diamine and SnCl2.[4] Although moderate yields and
good enantioselectivities were obtained, 3 equivalents of the
reducing agent were required. Santaniello and co-workers,
Fujisawa and co-workers, and Ema et al. reported asymmetric
reductions of prochiral a-acyloxy ketones, using either
bakerꢀs yeast or similar enzymes, with excellent enantiose-
lectivity but moderate regioselectivity.[5] Kambourakis and
co-workers developed an efficient ketoreductase-catalyzed
asymmetric synthesis of chiral a-acyloxy-1-alkylethanols.[6]
These enzyme regulated asymmetric syntheses require harsh
reaction conditions, often have limited substrate scope, and
[*] J. Chen, Dr. N. Butt, Prof. W. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
E-mail: wanbin@sjtu.edu.cn
Homepage: http://wanbin.sjtu.edu.cn
Prof. D. Liu, C. Li, D. Fan, Prof. Y. Liu, Prof. W. Zhang
School of Pharmacy, Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
[**] This work was partly supported by the National Nature Science
Foundation of China (No. 21172143, 21172145 and 21232004),
Science and Technology Commission of Shanghai Municipality (No.
09JC1407800), Nippon Chemical Industrial Co. Ltd, Shanghai Jiao
Tong University (SJTU), and the Instrumental Analysis Center of
SJTU. We thank Prof. Tsuneo Imamoto and Dr. Masashi Sugiya for
helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306231.
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Table 1: The effect of ligand on the reaction.[a]
Table 3: Optimization of the reaction conditions.[a]
Entry Solvent (v/v)
H2 (bar) Conv. [%][b] ee [%][c] By-pro-
Entry
Ligand
Conv. [%][b]
ee [%][c,d]
duct [%][d]
1
2
3
4
L1
L2
L3
L4
<5
<5
<5
–
–
–
1
TFE
30
30
30
30
30
30
30
60
60
10
10
30
30
30
>99
>99
>99
27
>99
<5
76
87
88
88
88
–
0
11
13
8
0
–
–
0
17
0
10
8
2
3
4
5
MeOH
EtOH
iPrOH
CH2Cl2
DME
>99
71
[a] Reaction conditions: 1aa (0.1 mmol), Pd(OCOCF3)2 (2.0 mol%),
ligands (2.4 mol%), TFE (1 mL), RT, 24 h. [b] Determined by H NMR
analysis. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] The absolute configuration of product was determined as R by
comparison of the specific rotations with the literature data.[7a]
TFE=2,2,2-trifluoroethanol.
1
6
7
8
9
10
11
toluene
CH2Cl2
EtOH
CH2Cl2
EtOH
<5
–
>99
>99
>99
>99
>99
<5
89
89
87
86
93
–
12[e] EtOH
13[e] CH2Cl2
14[f] EtOH
–
10
–
51
93
–
15[e] EtOH/CH2Cl2 (10:1) 30
<5
16[e] EtOH/TFE (10:1)
17[e] EtOH/TFE (20:1)
18[e] EtOH/TFE (8:1)
19[e] EtOH/TFE (4:1)
20[g] EtOH/TFE (4:1)
21[h] EtOH/TFE (4:1)
30
30
30
30
30
30
>99
>99
>99
>99
>99
>99
92
92
92
92
92
92
3
5
2
<1
<1
<1
Table 2: The effect of R1 group on the reaction.[a]
[a] Reaction conditions: 1ak (0.1 mmol), Pd(OCOCF3)2 (2.0 mol%), L4
1
(2.4 mol%), solvent (1 mL), RT, 24 h. [b] Determined by H NMR
analysis. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] The by-product was determined to be acetophenone by 1H NMR
analysis. [e] At 08C. [f] At À108C. [g] S/C=2000, (0.66 g 1ak), 3 days.
[h] S/C=5000, (1.66 g 1ak), 5 days. DME=dimethoxyethane.
Entry
R1
2a
Conv. [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
Ph
2aa
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
71
59
62
70
67
58
32
39
44
51
76
2-ClC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
1-naphthyl
Me
Et
Cy
iPr
tBu
Increasing H2 pressure from 30 to 60 bar in both CH2Cl2
and EtOH resulted in a slight increase in enantiomeric excess
(Table 3, entries 8 and 9). Similarly, a slight decrease in
enantiomeric excess was observed by reducing the H2
pressure from 30 to 10 bar (entries 10 and 11). Unlike the
effects of H2 pressure, reaction temperature had a significant
effect on the asymmetric catalysis. Decreasing the reaction
temperature to 08C under 30 bar H2, provided the desired
product with 93% ee in EtOH, while only a trace amount of
product was obtained in CH2Cl2 (entries 12 and 13). Further
lowering the temperature to À108C in EtOH also gave
excellent enantioselectivity, but a significant decrease in
reaction activity was observed (entry 14).
9
10
11
2aj
2ak
[a] Reaction conditions: 1a (0.1 mmol), Pd(OCOCF3)2 (2.0 mol%), L4
(2.4 mol%), TFE (1 mL), RT, 24 h. [b] Determined by H NMR analysis.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] The
absolute configuration of product was determined as R by comparison
with 2aa.
1
Solvent had an obvious effect on the reaction outcome
with the substrate 1ak (Table 3). Compared with the initial
result in TFE, both MeOH and EtOH gave full conversions
and better enantioselectivities (entries 1–3). However, a by-
product also appeared, thus resulting in a lower yield. Only
27% conversion was obtained with iPrOH as the solvent
(entry 4). The use of the aprotic solvent CH2Cl2 provided the
desired product exclusively with good enantiomeric excess
(entry 5). Other low-polarity solvents, such as DME and
toluene, were used but reactivity was poor (entries 6 and 7).
Considering both CH2Cl2 and EtOH showed promising
results, these two were chosen to examine the effect of
pressure and temperature on the reaction.
Although excellent enantioselectivity was obtained by
using EtOH as the solvent, a by-product was always
produced. Therefore, a mixed solvent system was examined
by addition of either CH2Cl2 or TFE to EtOH. The reaction
was unsuccessful in a mixed solvent system of EtOH/CH2Cl2
(10:1) at 08C (Table 3, entry 15). To our delight, when CH2Cl2
was replaced by TFE, the reaction proceeded smoothly with
excellent enantioselectivity and formation of the by-product
was significantly suppressed (entry 16). The ratio of TFE in
the mixed solvent affects the production of the by-product. A
higher ratio of TFE decreased the formation of the by-
product, as well as the enantioselectivity of the desired
product (entries 16–19). Taking into account these results,
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a mixed solvent system (EtOH/TFE, ratio 4:1) was consid-
ered suitable for the reaction (entry 19).
transforming 2i into its corresponding O-acyl thiourea species
(4), a novel and promising analgesic and antiinflammatory
agent (Scheme 1).[1h] The compound 2i was prepared from the
a-acyloxy-1-arylethanone 1i with quantitative conversion and
To examine the efficiency of our current catalytic system,
the hydrogenation of 1ak was tested with a relatively low
catalyst loading (S/C = 2000 and 5000; Table 3, entries 20 and
21). To our delight, the reaction proceeded smoothly with
quantitative conversion of the substrate and 92% ee, albeit
with a long reaction time. The example represents by far the
lowest catalyst loading for the palladium-catalyzed asymmet-
ric hydrogenation.[11]
Finally, substrate scope was explored based on the
optimized reaction conditions (Table 4). The influence of
the electronic and steric effects of the substituents on the
aromatic ring were first examined. Substrates with a substitu-
Table 4: Asymmetric hydrogenation of a-acyloxy-1-arylethanones.[a]
Entry
R2
2
Conv. [%][b]
ee [%][c,d]
Scheme 1. Reagents and conditions: a) L4 (2.4 mol%) and Pd-
(OCOCF3)2 (2.0 mol%), H2 (30 bar), EtOH/TFE (>99% conversions
and 96%, 97% ee); b) DPPA, DBU, toluene (71% and 77% yield, 95%
and 92% ee for 3 and 5, respectively). DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DPPA=diphenylphosphoryl azide.
1
2
3
4
5
6
7
8
Ph
2ak
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99[e]
>99
>99
>99
>99
>99
>99
37
92
86
92
96
83
90
94
92
96
96
94
96
94
94
90
95
96
93
97
95
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-MeC6H4
4-tBuC6H4
4-PhC6H4
4-HOC6H4
4-EtOC6H4
4-BrC6H4
96% ee (Table 4, entry 9). The azide species 3 was prepared
from 2i in 71% yield and 95% ee, and then converted into 4
according to a literature procedure.[1h] Similarly, the chiral 1,6-
dihydro-2H-pyridin-3-one 6 (an intermediate which can be
used to prepare chiral pyridine-3-ones and pyridines species)
was prepared from the intermediate 2s via 5 (Scheme 1).[2f]
X-ray crystallography studies confirmed the absolute
configuration of the products. X-ray crystal analysis of 2i
showed that the aforementioned product could be assigned
with the R configuration,[12] which is consistent with that of
previously reported results.[7a]
9
10
11
12
13
14
15
16
17
18[e]
19
20[f]
4-FC6H4
4-CF3C6H4
3,4-OCH2OC6H3
3,4-(MeO)2C6H3
2-naphthyl
2-furyl
2s
2t
2-thienyl
To conclude, we have developed the first efficient
palladium-catalyzed asymmetric hydrogenation of a-acy-
loxy-1-arylethanones, thus providing the hydrogenated prod-
ucts in up to quantitative conversions and excellent enantio-
selectivities (up to 97% ee). This procedure utilizes the lowest
reported catalyst loadings (S/C = 5000) for the palladium-
catalyzed hydrogenation. The absolute configuration of the
products was confirmed to be in accordance with reported
results and further confirmed by X-ray crystallography
studies. The hydrogenated products could subsequently be
transformed into natural products and drug candidates. This
simple and convenient methodology is suitable for the
synthesis of a wide range of chiral a-acyloxy-1-arylethanols,
important intermediates for the preparation of many kinds of
drug candidates.
[a] Reaction conditions: 1 (0.1 mmol), Pd(OCOCF3)2 (2.0 mol%), L4
(2.4 mol%), EtOH/TFE (4/1, 1 mL), 08C, 24 h. [b] Determined by
1H NMR analysis with less than 1% by-product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] The absolute configuration of
products was deduced as R by comparison with 2aa. [e] 48 h. [f] 72 h.
ent at the 4-position gave the best results for both electron-
donating and electron-withdrawing species (entries 1–7).
Therefore, a series of substrates with a substituents at the 4-
position were examined and all gave excellent results
(entries 8–15). 3,4-Disubstituted a-acyloxy ketones were
also subjected to the hydrogenation. The reaction proceeded
smoothly and gave the desired products in quantitative
conversion and excellent ee values (entries 16 and 17).
When the phenyl ring was replaced by either a naphthalene,
furan, or thiophene ring, excellent enantioselectivities (up to
97% ee) were also observed, albeit with a low reaction
activity for the thiophene species (entries 18–20).
Received: July 17, 2013
Published online: && &&, &&&&
The reduced products 2 have the potential to participate
in a variety of transformations. An illustration is provided by
Keywords: homogeneous catalysis · hydrogenation · palladium ·
reduction · synthetic methods
.
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Angewandte
Chemie
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[11] To the best of our knowledge, the ratio of S/C was 50:1 for most
cases of palladium-catalyzed asymmetric hydrogenation and
only one example of higher S/C ratio (1000:1) was reported.[9c,k,l]
[12] CCDC 943698 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif. The single-crystal structure could be
found in the Supporting Information.
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.
Angewandte
Communications
Communications
Homogeneous Catalysis
J. Chen, D. Liu, N. Butt, C. Li, D. Fan,
Y. Liu, W. Zhang*
&&&& — &&&&
Palladium-Catalyzed Asymmetric
Hydrogenation of a-Acyloxy-1-
arylethanones
First hand: The first example of a palla-
dium-catalyzed asymmetric hydrogena-
tion of a-acyloxy ketones (1) was accom-
plished to give the hydrogenated prod-
ucts 2 with by far the highest catalytic
efficiency in up to quantitative conver-
sions and excellent enantioselectivities.
The hydrogenated products could serve
as important intermediates for the prep-
aration of many drug candidates. TFE=
2,2,2-trifluoroethanol.
6
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!