Rhodium-catalyzed asymmetric hydrogenation of β-acetylamino acrylosulfones: A practical approach to chiral β-amido sulfones

Article abstract of DOI:10.1021/cs500261k

The efficient and highly enantioselective catalytic asymmetric hydrogenation of β-acetylamino acrylosulfone has been achieved by employing Rhodium-TangPhos as catalyst. A series of β-amido sulfone products are obtained with excellent yields and good enantioselectivities.

Full text of DOI:10.1021/cs500261k

Letter
pubs.acs.org/acscatalysis
Rhodium-Catalyzed Asymmetric Hydrogenation of β‑Acetylamino
Acrylosulfones: A Practical Approach to Chiral β‑Amido Sulfones
Jun Jiang, Yan Wang,* and Xumu Zhang*
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072 People’s Republic of China
S
* Supporting Information
ABSTRACT: The efficient and highly enantioselective
catalytic asymmetric hydrogenation of β-acetylamino acryl-
osulfone has been achieved by employing Rhodium-TangPhos
as catalyst. A series of β-amido sulfone products are obtained
with excellent yields and good enantioselectivities.
KEYWORDS: asymmetric hydrogenation, enantioselectivity, rhodium, β-amido sulfones, diphosphine ligand
hiral β-amido sulfones are privileged scaffolds found in
chiral auxiliaries or afford low diasteroselectivities. The catalytic
enantioselective synthesis of β-amido sulfones is far less
established.
C
many natural products and biologically active compounds
(Figure 1).1 The β-amido sulfones can be readily transformed
Asymmetric hydrogenation represents one of the most
efficient approaches to generate chiral compounds through the
reduction of prochiral olefins, ketones, and imines9 utilizing
molecular hydrogen. The hydrogenation of enamides has been
widely used in the synthesis of chiral amines and their
derivatives;9,10 however, functionalized enamides, such as β-
amido sulfones, are rarely used in an asymmetric hydrogenation
reaction. In connection with our previous research on the chiral
phosphine ligands for asymmetric hydrogenation, herein, we
report the synthesis of chiral β-amido sulfones through the
asymmetric hydrogenation of enamide-possessing sulfone
groups.
So far, the preparation of β-acetylamino acrylosulfone
substrates relies on several known methods, such as a
rearrangement reaction,11 reduction of nitro alkenes12 or
ketoximes,13 the acylation of imines,14 and the direct
condensation of ketone with amide.15 We adopted the
condensation method because of the acceptable yields and
readily available starting materials. The condensation reaction
between a ketone and ammonia provided the N-unsubstituted
enamine16 as an intermediate, which reacted with acetyl
chloride to give the target product with Z and E isomers, as
shown in Table 1. Z isomers were, in most cases, a little more
numerous than E isomers, possibly because of the presence of
the stronger intramolecular N−H···O(S) hydrogen bonding
interaction (Table 1, entries 1−12). When R1 was cyclohexyl or
thienyl group, only the Z isomer was obtained (Table 1, entries
13−14). It might be attributed to the combination of a steric
and an electronic effect, which strengthen the intramolecular
N−H···O(S) hydrogen bonding interaction. The X-ray
structure of (E)-2a is shown in Figure 2.
Figure 1. Examples of natural products containing β-amido sulfone
scaffolds.
to chiral amino acids,2 amino alcohols,3 alkaloids,4 carbohydrate
derivatives,5 and other functionalized chiral amines.6 For
example, the Julia−Lythgoe olefination of β-amido sulfones
can be utilized to generate various kinds of chiral allylic amines
(Scheme 1). Therefore, the synthesis of β-amido sulfones has
Scheme 1. Synthesis of Chiral β-Amido Sulfones through
Hydrogenation of Enamides and Their Derivatizations
received considerable attention. The most applied approach to
β-amido sulfones is multistep transformations of amino acids;
in addition, several other interesting methodologies, including
stereoselective additions of sulfonyl carbanions to chiral N-
sulfinyl imines7 and aza-Michael additions to α,β-unsaturated
sulfones.8 However, most of these approaches require expensive
Received: February 27, 2014
Revised: April 6, 2014
Published: April 8, 2014
© 2014 American Chemical Society
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ACS Catalysis
Letter
Table 1. Preparation of β-Acetylamino Acrylosulfones
a
b
c
d
entry
ketone
R1
R2
enamide
Z/E
Z/E (%)
combined yield (%)
1
2
1a
1b
1c
1d
1e
1f
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2a
2b
2c
2d
2e
2f
55:45
47:53
60:40
56:44
52:48
41:59
50:50
50:50
63:37
67:33
75:25
56:44
100:0
100:0
40/33
29/32
35/23
33/26
32/29
23/32
34/33
26/26
41/25
47/24
55/18
30/23
46/0
73
61
58
59
61
55
67
52
66
71
73
53
46
41
m-MePh
p-MePh
p-MeOPh
p-FPh
3
4
5
6
m-FPh
7
1g
1h
1i
p-ClPh
m-ClPh
p-BrPh
p-tBuPh
Ph
2g
2h
2i
8
9
10
11
12
13
14
1j
2J
1k
1l
2k
2l
p-CF3Ph
cyclohexyl
2-thienyl
Me
Me
Me
1m
1n
2m
2n
41/0
a
b
1
See the Supporting Information for their preparation. The Z/E ratios of the crude reaction mixture were estimated by H NMR spectroscopy
c
d
analysis. Isolated yields of Z and E isomers by silica gel column chromatography, respectively. Combined yield of isolated Z and E isomers.
Table 2. Solvent and Ligand Screening for Rh-Catalyzed
a
Asymmetric Hydrogenation of (Z)-2a and (E)-2a
b
c
entry
subtrate
ligand
solvent
conv (%)
ee (%)
1
2
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(Z)-2a
(E)-2a
(E)-2a
(E)-2a
(E)-2a
(E)-2a
(E/Z)-2a
L1
L2
L3
L4
L5
L6
L7
L8
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOAc
EtOH
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
trace
58
92
63
57
74
81
31
25
34
92
89
88
3
4
5
6
7
Figure 2. X-ray crystal structure of (E)-2a.
8
9
10
11
12
13
14
15
16
17
After the synthesis of β-acetylamino acrylosulfones (Z)-2 and
(E)-2, they were used as the substrates for the hydrogenation
reaction to screen the reaction conditions; the results are
summarized in Table 2. A variety of diphosphine ligands
developed by our group and some commercially available chiral
ligands were examined (Figure 3).
dioxane
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
−27
−29
−19
−70
−43
31
12
31
37
Although all these ligands can efficiently promote the
hydrogenation of (Z)-2a with almost quantitative conversion,
only electron-rich, rigid TangPhos affored good ee values
(Table 2, entries 1−8). Solvent screening shows that methanol
was the best solvent we chose(Table 2, entries 1, 9−12). The
reactions of (E)-2a with different ligands resulted in only low to
moderate conversions and opposite enantioselectivities (Table
2, entries 13−17), which indicated that the configuration of the
double bond in substrates 2 played a critical role.17 When the
mixture of Z and E isomers ((E)-2a/(Z)-2a = 1:1) was used for
the hydrogenation, it afforded only β-amido sulfone with 33%
ee (Table 2, entry 18).
24
d
18
99
a
All reactions were carried out with a substrate/catalyst ratio of 100:1
b
at room temperature under 50 atm hydrogen pressure for 12 h. L1 =
(1S,1S′,2R,2R′)-TangPhos, L2 = (Sc,Rp)-DuanPhos, L3 = (S)-
Binapine, L4 = (S)-SegPhos, L5 = (S)-BINAP, L6 = WalPhos, L7 =
(R,S)-JosiPhos, L8 = (R)-QuinoxP*. The ee value was determined by
HPLC on a chiral phase. The ratio of (E)-2a/(Z)-2a was 1:1.
c
d
hydrogen pressure increased from 4 to 30 atm (Table 3, entries
1−3), but with a further increase in the pressure, there was no
positive effect on the ee value (Table 3, entries 3−5). Lowering
the reaction temperature to 0 °C resulted in a dramatic
decrease in the reactivity, and and increase in the temperature
Inspired by these promising results of the hydrogenation of
(Z)-2a catalyzed by Rh(COD)2BF4−TangPhos, the hydrogen
pressure and reaction temperature were examined as shown in
Table 3. The enantioselectivities gradually improved when the
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Table 4. Rh-Catalyzed Asymmetric Hydrogenation of β-
a
Acetylamino Acrylosulfones (Z)-2
b
c
entry substrate
R1
R2
product conv (%)
ee (%)
1
2
(Z)-2a
(Z)-2b
(Z)-2c
(Z)-2d
(Z)-2e
(Z)-2f
(Z)-2g
(Z)-2h
(Z)-2i
(Z)-2j
(Z)-2k
(Z)-2l
(Z)-2m
(Z)-2n
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
3a
3b
3c
3d
3e
3f
>99 (95)
92
90
89
87
84
94
94
94
95
87
97
96
23
91
m-MePh
p-MePh
p-MeOPh
p-FPh
>99 (96)
>99 (96)
>99 (95)
>99 (95)
>99 (94)
>99 (94)
>99 (95)
>99 (94)
>99 (95)
>99 (95)
>99 (96)
>99 (96)
>99 (95)
3
4
5
6
m-FPh
Figure 3. Structures of the phosphine ligands for hydrogenation of
(Z)-2a and (E)-2a.
7
p-ClPh
m-ClPh
p-BrPh
p-tBuPh
Ph
3g
3h
3i
8
9
Table 3. Pressure and Temperature Screening for Rh-
a
10
11
12
13
14
3j
Catalyzed Asymmetric Hydrogenation of (Z)-2a
3k
3l
entry
pressure (atm)
temp (°C)
conv (%)
ee (%)
p-CF3Ph
cyclohexyl
2-thienyl
Me
Me
Me
1
2
3
4
5
6
7
8
4
10
30
50
80
50
50
50
25
25
25
25
25
0
>99
>99
>99
>99
>99
21
80
86
91
92
91
93
86
75
3m
3n
a
Unless mentioned otherwise, all reactions were carried out with a
substrate/catalyst ratio of 100:1 in MeOH at room temperature under
b
50 atm hydrogen pressure for 12 h. Determined by 1H NMR; data in
parentheses are the yields of the isolated product based on consumed
starting material. Determined by chiral HPLC analysis.
c
50
100
>99
>99
a
All reactions were carried out with a substrate/Rh-TangPhos catalyst
ratio of 100:1 in MeOH for 12 h.
led to a decrease in the enantioselectivity (Table 3, entries 4,
6−8).
Under the optimized conditions, a variety of β-acetylamino
acrylosulfones (Z)-2 were examined, and the results are
summarized in Table 4. Excellent yields and good to excellent
enantioselectivities were achieved when R1 was different
substituted aryl groups (84−94% ee; Table 4, entries 1−12).
When R2 was changed from alkyl to aryl, a better
enantioselectivity was obtained (97% ee; Table 4, entry 11).
This might be attributed to the steric hindrance of an aryl
group, which can enhance the enantioselectivity. Good
enantioselectivity was also achieved when R1 was a heteroaryl
group (91% ee; Table 4, entry 14); however, when both R1 and
R2 are alkyl groups, it did not give satisfactory results (Table 4,
entry 13). The absolute configuration of product 3a was
confirmed to be S by X-ray crystal structure analysis, as
illustrated in Figure 4.18
In summary, we have developed a novel asymmetric
hydrogenation approach for the generation of chiral β-amido
sulfones from β-acetylamino acrylosulfones. The hydrogenation
of substrates with Z configuration gave the the desired products
in excellent yields with good to excellent enantioselectivities. It
is believed that this strategy will provide a novel way for the
development of synthetic strategies for chiral β-amido sulfones.
Further investigations to improve the enantioselectivity and
extending the substrate scope of this reaction are underway in
our laboratory.
Figure 4. X-ray crystal structure of (S)-3a
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*Fax: (+)86 27-68755925. E-mail: ywang@whu.edu.cn.
*E-mail: xumu@whu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for a grant from Wuhan University
(203273463) and the “111” Project of the Ministry of
Education of China for financial support.
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ACS Catalysis
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