Highly efficient iridium-catalyzed asymmetric hydrogenation of β-acylamino nitroolefins

Article abstract of DOI:10.1039/c4cc05815a

The first highly efficient Ir-catalyzed enantioselective hydrogenation of β-acylamino nitroolefins is reported. This reaction provides straightforward access to chiral β-amino nitroalkanes in high yields and excellent enantioselectivities (up to >99.9% ee) catalyzed by an Ir-(R,R)-f-spiroPhos complex. This journal is

Full text of DOI:10.1039/c4cc05815a

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Highly efficient iridium-catalyzed asymmetric
hydrogenation of b-acylamino nitroolefins†
Cite this: Chem. Commun., 2014,
0, 12870
5
Qiaozhi Yan,‡ Man Liu,‡ Duanyang Kong, Guofu Zi and Guohua Hou*
Received 26th July 2014,
Accepted 6th September 2014
DOI: 10.1039/c4cc05815a
www.rsc.org/chemcomm
10
11
12
The first highly efficient Ir-catalyzed enantioselective hydrogenation amino, carbonyl, and cyano groups have been hydrogenated in
of b-acylamino nitroolefins is reported. This reaction provides high enantioselectivities and efficiency. However, only one example
straightforward access to chiral b-amino nitroalkanes in high yields of asymmetric hydrogenation of b-amino nitroalkenes has been
and excellent enantioselectivities (up to 499.9% ee) catalyzed by an reported using the Rh–Tangphos complex as the catalyst, by Zhang
13
Ir-(R,R)-f-spiroPhos complex.
and co-workers; the best enantioselectivity was 93% ee for aryl
b-amino nitroalkenes, and a rather poor enantioselectivity (only
Enantiomerically pure b-amino nitroalkanes are valuable synthetic 8–22% ee) was observed for alkyl substrates. Thus, hydrogenation
intermediates that can be easily converted to useful compounds of b-amino nitroalkenes remains an active research area, and the
1
2
such as a-amino acids and diamines, and to various moieties development of new chiral catalyst systems is a desirable and
3
14
present in pharmaceuticals and biologically active molecules, such challenging goal. Herein, we report the first example of an
4
as, Tamiflu, which is used to treat influenza, and clopidogrel, a Ir-catalyzed asymmetric hydrogenation of b-acylamino nitroolefins
platelet aggregation inhibitor used to reduce the risk of strokes and to generate chiral b-amino nitroalkanes in high yields and excellent
5
heart attacks (Fig. 1).
enantioselectivities (up to 499.9% ee) using the novel chiral ligand
Because of the utility of chiral b-amino nitroalkanes in chemical (R,R)-f-spiroPhos (Scheme 1), which can be prepared from enantio-
0
15
0
synthesis, many methods have been developed for their enantio- merically pure (R)-1,1 -spirobiindane-7,7 -diol (SPINOL) by Zhou’s
selective synthesis, the main method being the asymmetric aza-Henry procedure (see ESI†).
6
reaction. In addition, asymmetric aza-Michael addition of amines to
The b-acylamino nitroolefin substrates were easily prepared
nitroalkenes is a useful approach. More recently, Sun and co-workers in two steps from readily accessible nitroalkenes 3 in good
7
reported the asymmetric hydrosilylation of b-amino nitroolefins as yields (Scheme 2). To evaluate various ligands and optimize the
8
another route to chiral b-amino nitroalkanes.
reaction conditions for the hydrogenation, we used (Z)-N-
Asymmetric catalytic hydrogenation is one of the most powerful (2-nitro-1-phenylvinyl)acetamide (1a) as a model substrate, and
approaches to chiral compounds, and great progress on its use has
9
been made. Many types of olefins bearing functional groups such as
Fig. 1 Key structural elements in chiral pharmaceuticals.
College of Chemistry, Beijing Normal University, 19 Xinjiekouwaidajie,
Beijing 100875, China. E-mail: ghhou@bnu.edu.cn
†
Electronic supplementary information (ESI) available: Details of experimental
procedures and characterization of the compounds, supplementary experimental
data and figures. See DOI: 10.1039/c4cc05815a
Scheme 1 Ir-catalyzed asymmetric hydrogenation of b-acylamino nitro-
olefins 1.
‡
These authors contributed equally to this work.
1
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conversions were obtained (r2%, Table 1, entries 1 and 2). Most of
the bidentate diphosphine ligands we evaluated, including Binap,
DuanPhos, SegPhos, and JosiPhos, also gave low conversions and
poor enantioselectivities (r43% ee, Table 1, entries 3–7), except for
f-spiroPhos, which afforded chiral b-acylamino nitroalkane 2a in
excellent enantioselectivity (99% ee), although the conversion was
low (Table 1, entry 8).
3 2
Scheme 2 Synthesis of b-acylamino nitroolefins. Conditions: (a) CH ONH –
HCl, BuOK, in DMF, 0 1C. (b) Ac O, DMAP, pyridine, in CH Cl .
2 2 2
t
In the evaluation of solvents in this catalytic transformation, poor
conversions (r22%) and moderate to high enantioselectivities
were observed in THF, toluene, DME, dioxane, ether, and MeOH
(Table 1, entries 9–14). The reaction temperature was crucial for this
transformation. Increasing the reaction temperature from room
temperature to 80 1C resulted in complete conversion in 12 h, albeit
with a slight loss in enantioselectivity (98% ee, Table 1, entry 15).
Remarkably, the hydrogenation could also be achieved at a much
lower pressure of H
of 1a was complete in 12 h and afforded 2a in 99% ee (Table 1,
entry 16). Upon lowering the H pressure further, to 10 atm, the
2 2
: under 20 atm of H pressure, hydrogenation
2
excellent enantioselectivity remained, although the conversion
slightly decreased (92%; Table 1, entry 17).
Encouraged by the promising result obtained in the hydro-
genation of the substrate 1a, we next subjected a variety of
b-acylamino nitroolefins substrates (1b–1t) to the hydrogenation
Fig. 2 Structures of phosphine ligands evaluated in the hydrogenation of
Z)-N-(2-nitro-1-phenylvinyl) acetamide (1a).
(
the hydrogenation was initially performed under 100 atm of H
in CH Cl at room temperature with an iridium catalyst generated f-spiroPhos in CH
in situ from 0.5 mol% [Ir(COD)Cl] and various chiral phosphorus (Table 2). We found that hydrogenation of all the substrates
2
reaction under the optimized conditions: [Ir(COD)Cl]
2
/(R,R)-
2
2
2
Cl at 80 1C under 20 atm of H pressure
2
2
2
ligands (Fig. 2 and Table 1). Of the ligands available in our provide the desired b-amino nitroalkanes with high conversions
laboratory, monodentate phosphorus ligands, such as MonoPhos
and SIPHOS, were inefficient for this transformation, and very low
Table 2 Ir-catalyzed asymmetric hydrogenation of b-acylamino nitro-
olefins 1
a
Table 1 Optimization of conditions for Ir-catalyzed asymmetric hydro-
a
genation of b-acylamino nitroolefin 1a
b
c
Entry
R
C
Product
Con. (%)
ee (%)
1
2
3
4
5
6
7
8
6
H
5
(1a)
(1b)
4-ClC H (1c)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
499 (98)
499 (99)
499 (97)
499 (98)
499 (96)
499 (97)
499 (99)
499 (99)
499 (98)
499 (95)
499 (98)
499 (97)
499 (96)
499 (96)
499 (98)
499 (99)
499 (99)
499 (99)
499 (96)
499 (93)
99
99
499.9
499.9
99.3
99
99.6
99
99.2
99
99
98
99
99.3
97
6 4
4-FC H
b
c
Entry Ligand
Solvent T (1C) PH
2
(atm) Con. (%) ee (%)
6
4
4-BrC
4-MeOC H (1e)
4-MeC H (1f)
6 4
4-CF C H (1g)
3-FC H (1h)
6 4
3-ClC H (1i)
3-MeC H (1j)
3-MeOC H (1k)
2-FC H (1l)
2-ClC H (1m)
2-MeC H (1n)
1-Napthyl (1o)
2-Napthyl (1p)
1-Furyl (1q)
n-Butyl (1r)
Isopropyl (1s)
Cyclohexyl (1t)
6 4
H (1d)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
(S)-MonoPhos
(R)-SIPHOS
(S)-Binap
(R)-DM-SegPhos CH
(S,R)-DuanPhos CH
(R)-JosiPhos-1
(R)-JosiPhos-2
CH
CH
CH
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
rt
rt
rt
rt
rt
rt
rt
rt
rt
100
o1
2
6
ND
ND
15
39
43
19
28
99
91
66
91
90
82
83
98
99
99
6
4
100
100
100
100
100
100
100
100
100
100
100
100
100
100
20
3
6
4
15
12
23
61
37
17
22
18
14
8
9
6
4
CH
CH
10
11
12
13
14
15
16
17
18
19
20
6
4
6
4
(R,R)-f-spiroPhos CH
(R,R)-f-spiroPhos THF
6
4
6
4
0
1
2
3
4
5
6
7
(R,R)-f-spiroPhos Toluene rt
(R,R)-f-spiroPhos DME rt
(R,R)-f-spiroPhos Dioxane rt
(R,R)-f-spiroPhos Et rt
(R,R)-f-spiroPhos MeOH rt
(R,R)-f-spiroPhos CH
(R,R)-f-spiroPhos CH
(R,R)-f-spiroPhos CH
6
4
99
97
91
96
2
O
7
d
d
d
2
2
2
Cl
2
Cl
2
Cl
2
80
80
80
499
499
92
2s
2t
98
10
a
Unless otherwise mentioned, all reactions were carried out at a
a
Reaction conditions: [Ir(COD)Cl] /phosphine/substrate ratio = 0.5 : 2 : 100, [Ir(COD)Cl] /(R,R)-f-spiroPhos/substrate ratio of 0.5 : 1 : 100 in CH Cl
2
2
2
2
b
c
b
1
2
2
100 atm H , 24 h. Conversion, determined by GC analysis. Determined at 20 atm H and 80 1C for 12 h. Conversion, determined by H NMR
by chiral GC using a Supelco Gamma-Dex 225 column (30 m ꢀ 0.25 mm ꢀ spectroscopy or GC analysis; data in parentheses are isolated yields.
d
c
0
.25 mm). 12 h.
Determined by chiral GC or HPLC analysis.
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Notes and references
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3
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Cl, or Me substituent at the ortho position of the phenyl group
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full conversions (Table 2, entries 15 and 16). A slightly decreased
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In summary, we developed a highly enantioselective Ir-catalyzed
1
hydrogenation of b-acylamino nitroolefins for direct synthesis of
enantiomerically pure b-amino nitroalkanes, which are versatile
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(
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1
We are grateful for the financial support from the National
Natural Science Foundation of China (grant no. 21272026, 14 For the hydrogenation of nitroalkenes see: (a) S. Li, K. Huang, B. Cao,
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21172022 and 21472013), the Fundamental Research Funds for
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the Central Universities, Specialized Research Fund for the Doctoral
Program of Higher Education of China and Beijing Municipal
Commission of Education for generous financial support. We also
thank Professors Qi-Lin Zhou and Xumu Zhang for providing chiral
SPINOL and for helpful discussions.
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1
2872 | Chem. Commun., 2014, 50, 12870--12872
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