Chiral phosphoric acid catalyzed enantioselective aza-Michael addition of aromatic amines to nitroolefins

Article abstract of DOI:10.1016/S1872-2067(10)60261-6

Chiral phosphoric acid was found to be an effective organocatalyst in the enantioselective aza-Michael addition of aromatic amines to nitroolefins giving the corresponding β-nitroamine products in good yields (65-95) with moderate to good enantiomeric excess (16-70). This study represents the first example of a chiral phosphoric acid catalyzed asymmetric aza-Michael addition reaction.

Full text of DOI:10.1016/S1872-2067(10)60261-6

CHINESE JOURNAL OF CATALYSIS
Volume 32, Issue 10, 2011
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2011, 32: 1573–1576.
SHORT COMMUNICATION
Chiral Phosphoric Acid Catalyzed Enantioselective
Aza-Michael Addition of Aromatic Amines to Nitroolefins
YANG Lei, XIA Chungu, HUANG Hanmin*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sci-
ences, Lanzhou 730000, Gansu, China
Abstract: Chiral phosphoric acid was found to be an effective organocatalyst in the enantioselective aza-Michael addition of aromatic
amines to nitroolefins giving the corresponding ȕ-nitroamine products in good yields (65%–95%) with moderate to good enantiomeric
excess (16%–70%). This study represents the first example of a chiral phosphoric acid catalyzed asymmetric aza-Michael addition reaction.
Key words: chiral phosphoric acid; aromatic amine; nitroolefin; aza-Michael addition
ȕ-nitroamines are ubiquitous structural motifs found in
biologically important natural products and pharmaceutically
active compounds, and they are also useful synthetic building
blocks in organic synthesis especially for the synthesis of
nitrogen-containing compounds [1]. Using well-established
transformation chemistry, the ȕ-nitroamines can be easily
converted into Į-amino acids or other Į-aminocarbonyl com-
pounds and vicinal diamines through the Nef reaction by the
reduction of the nitro group [2]. Therefore, the development of
an efficient synthetic method leading to ȕ-nitroamines and their
derivatives has attracted much attention in organic synthesis.
Among the traditional methods used to generate ȕ-nitroamines,
the nucleophilic addition of nitroalkanes to imines and related
compounds (aza-Henry or nitro-Mannich reaction) [3,4] is a
powerful synthetic methodology that allows for the creation of
two vicinal stereogenic centers bearing nitro and amino func-
tional groups. Alternatively, because of its simplicity and atom
economy the 1,4-addition of nitrogen nucleophiles to nitroole-
fins (aza-Michael reaction) is a convenient way to introduce
this amine-based functionality to ȕ-carbons that are attached to
nitro groups (Scheme 1) [5–16]. Nevertheless, compared with
the former method for generating ȕ-nitroamines, only a few
reports of the corresponding aza-Michael addition of nitrogen
reagents to nitroolefins have been documented in the literature
wherein their asymmetric construction was achieved mainly
through the use of chiral substrates [17]. For example,
Mioskowski and co-workers recently described the first di-
astereoselective synthesis of
1,2-diamino-3,3,3-trifluoropropane using readily available
optically pure 4-phenyl-2-oxazolidinone as a nitrogen nu-
cleophile [18–20]. In contrast, only one very recent example
exists of the asymmetric catalytic aza-Michael addition of
aromatic amines to nitroolefins. Ooi and co-workers reported
the first highly enantioselective conjugate addition of
2,4-dimethoxyaniline to nitroolefins using chiral aminophos-
phonium cations as catalysts [21]. Obviously, the development
of the catalytic asymmetric aza-Michael addition for the syn-
thesis of chiral ȕ-nitroamines remains challenging and elusive.
Over the last few years, novel chiral Brönsted acids have
emerged as versatile enantioselective catalysts and their use in
a variety of enantioselective transformations has been widely
reported [22–26]. In this context, chiral phosphoric acids have
been shown to be excellent chiral organocatalysts for the
PG
NHPG
NO2
NO2
N
aza-Henry
aza-Michael
NH P
2 G
R'
+
R
+
R
R'
R'
R
NO2
NH2
R'
NH2
COOH
R
R
NH2
Scheme 1. Synthesis and transformation of ȕ-nitroamines.
Received 7 July 2011. Accepted 6 August 2011.
*Corresponding author. Tel: +86-931-4968326; Fax: +86-931-4968129; E-mail: hmhuang@licp.cas.cn
This work was supported by the National Natural Science Foundation of China (20802085).
Copyright © 2011, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(10)60261-6

YANG Lei et al. / Chinese Journal of Catalysis, 2011, 32: 1573–1576
asymmetric activation of various substrates through hydrogen
3H); 13C NMR (100 MHz, CDCl3) į 152.9, 148.4, 138.2, 129.7,
129.2, 128.5, 126.5, 112.0, 103.7, 99.3, 80.2, 57.4, 55.7, 55.6.
Our initial focus was on the optimization of the reaction
conditions (Table 1). Using toluene as the solvent and
4-methoxyaniline as the nitrogen nucleophile, a series of chiral
phosphoric acids with different substituents at the
3,3ƍ-positions of the binaphthyl scaffold were prepared and
screened to find the best catalyst (entries 1–9). The results
revealed that the chiral phosphoric acid 1a was superior in
terms of the observed selectivity of the aza-Michael addition
product of nitrostyrene and 4-methoxyaniline (entry 1). The
solvent also had a major effect on both the enantioselectivity
and reactivity of the product. The use of nonpolar and weakly
polar solvents gave promising results in terms of the product
yield (entries 10–12). The more polar solvent resulted in a
lower ee and a lower yield of the addition product compared
with the weakly polar solvents (entry 13). From the solvent
study, we determined that tetrahydrofuran (THF) was the best
choice (entry 10). Decreasing the reaction temperature to –20
bonding interactions and these include imines, enamides, ni-
troolefins as well as ketones [27–30]. Recently, we have
demonstrated that a cooperative catalytic system, produced by
the combination of an iron salt and a chiral phosphoric acid, is
able to catalyze the enantioselective Friedel-Crafts alkylation
of indoles with ȕ-aryl Įƍ-hydroxy enones [31]. Inspired by our
successful employment of chiral phosphoric acid catalysts [32]
and following our long-standing interest in aza-Michael reac-
tions [33–37], we envisioned that the synthesis of chiral
ȕ-nitroamines might be achievable by exploring the chiral
phosphoric acid catalyzed aza-Michael addition reaction of
aromatic amines to nitroolefins. Herein, we would like to re-
port our preliminary results on the chiral phosphoric acid
catalyzed enantioselective aza-Michael addition of aromatic
amines to nitroolefins.
The general procedure for the catalytic asymmetric
aza-Michael addition was as follows. To a flame-dried reaction
tube was added 2-nitrovinylbenzene (2a, 0.2 mmol), chiral
phosphoric acid (1a, 5 mol%), and a solvent (1 ml) at room
temperature and under Ar. After 20 min of stirring at the same
temperature the reactor was cooled to –20 °C and the aromatic
amine (3a, 0.3 mmol) was also added at the same temperature.
After the reaction was complete the crude product was purified
directly by flash chromatography using ethyl acetate/petroleum
ether (1:10) to afford the desired pure addition product. The
enantiomeric excess (ee) was determined by chiral HPLC on
Chiralpak IA, AS-H or OD-H columns. The spectral data of
some representative products are given below. 4aa: yellow oil.
(Chiral HPLC was performed on a HP series 1200 and
Table 1 Optimization of the aza-Michael addition
OMe
NH2
HN
NO2
NO2
5 mol% (R)-1
*
+
solvent, rt
OMe
3a
4aa
2a
Ar
1a: 2-naphthyl
1b: phenyl
O
O
O
1c: SiPh3
P
1d: 9-phenanthryl
OH
Chiralpak AS-H column. hexane/2-propanol = 9, 1.0 ml/min,
1e: 2,4,6-(i-Pr)3C6H2
1f: 3,5-(CF3)2C6H3
1g: 4-(2-naphthyl)C6H4
1h: 9-anthryl
20
210 nm) tminor: 47.56 min, tmajor: 39.33 min, 26% ee; [Į]D
=
Ar
–3.4 (c 0.21, CH2Cl2). 1H NMR (400 MHz, CDCl3) į 7.31–7.29
(m, 5H), 6.66–6.64 (m, 2H), 6.52–6.49 (m, 2H), 5.00 (m, 1H),
4.61 (d, 2H, J = 6.4 Hz), 4.09 (s, 1H), 3.65 (s, 3H); 13C NMR
(100 MHz, CDCl3) į 152.1, 138.6, 137.0, 128.2, 127.6, 125.5,
113.9, 113.8, 79.1, 56.7, 54.6. 4af: yellow oil. (Chiral HPLC
was performed on a HP series 1200 and Chiralpak IA column.
(R)-1
1i: 1-naphthyl
Entry
1
Catalyst
1a
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
Time (h) Yield (%)
ee/%
14
9
24
24
24
24
24
24
24
24
24
24
24
24
24
48
48
80
95
70
85
85
92
87
90
90
85
80
95
60
86
89
2
1b
1c
3
0
hexane/2-propanol = 9, 1.0 ml/min, 210 nm) tminor: 15.33 min,
4
1d
1e
7
1
t
major: 16.74 min, 54% ee; [Į]D20= –9.2 (c 0.54, CH2Cl2). H
5
10
8
6
1f
NMR (400 MHz, CDCl3) į 7.40–7.30 (m, 5H), 7.23–7.18 (m,
2H), 6.49–6.45 (m, 2H), 5.14–5.09 (m, 1H), 4.73–4.64 (m,
2H), 4.48 (d, 1H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) į
144.7, 137.2, 132.1, 129.4, 128.9, 126.4, 115.6, 110.8, 80.0,
56.7. 4ah: yellow viscous oil. (Chiral HPLC was performed on
a HP series 1200 and Chiralpak AS-H column. hex-
7
1g
4
8
1h
1i
0
9
9
10
11
12
13
14a
15a,b
1a
20
8
1a
CHCl3
xylene
1,4-dioxane
THF
1a
11
0
ane/2-propanol = 9, 1.0 ml/min, 210 nm) tminor: 22.70 min, tmajor
:
1a
25.25 min, 16% ee; [Į]D20= –3.6 (c 0.11, CH2Cl2). The absolute
configuration was assigned as (R) by comparison of the optical
rotation with the reported value[21]: [Į]D29= 10.8 (c 1.77,
CHCl3), 95% ee for (S)-isomer. 1H NMR (400 MHz, CDCl3) į
7.38–7.31 (m, 5H), 6.44–6.42 (m, 2H), 6.29 (1H, dd, J = 8.8,
2.4 Hz), 5.11 (s, 1H), 4.76–4.66 (m, 2H), 3.82 (s, 3H), 3.71 (s,
1a
23
26
1a
THF
Reaction conditions: 5 mol% 1, 0.2 mmol 2a, 0.3 mmol 3a, 1 ml solvent,
under Ar.
aThe reaction was run at –20 °C.
b0.3 nm molecular sieves (100 mg) were added.

YANG Lei et al. / Chinese Journal of Catalysis, 2011, 32: 1573–1576
Table 2 Chiral phosphoric acid 1a catalyzed asymmetric aza-Michael
Table 3 Scope of the enantioselective aza-Michael addition catalyzed
addition of aromatic amines to 2-nitrovinylbenzene
by chiral phosphoric acid 1a
R1
R1
NH2
HN
*
NH2
HN
*
NO2
NO2
NO2
NO2
5 mol% 1a
ꢀ
5 mol% 1a
20 oC, THF
R1
R1
+
+
ꢀ
20 oC, THF
3
4
2a
3
4
2a
Entry
R1 in 3
H 3b
Time (h)
4
Yield (%)
ee/%
40
Entry
R in 2
Ar in 3
4
Yield (%)
ee/%
1
2
3
4
5
6
7
36
36
48
48
48
48
36
4ab
4ac
4ad
4ae
4af
4ag
4ah
80
85
—
65
70
80
76
1
2
4-Br 2b
4-Cl 2c
4-BrC6H4 3f
4-BrC6H4 3f
4-BrC6H4 3f
4-BrC6H4 3f
4-BrC6H4 3f
4-BrC6H4 3f
Ph 3b
4bf
4cf
4df
4ef
4ff
82
81
65
—
85
85
70
75
70
64
19
30
44
—
45
70
30
30
42
48
4-Me 3c
4-CF3 3d
4-Cl 3e
30
—
3
2-OMe 2d
4-OMe 2e
2-Br 2f
43
4
4-Br 3f
54
5
4-F 3g
43
6
2,3-(OMe)2 2g
4-Me 2h
4gf
4hb
2,4-(OMe)2 3h
16
7
Reaction conditions: 5 mol% 1a, 0.2 mmol 2a, 0.3 mmol 3, 1 ml THF,
0.3 nm molecular sieves (100 mg), at –20 °C, in Ar.
aThe absolute configuration of 4ah was assigned as (R) by comparison of
8
4-Me 2h
4-MeC6H4 3c 4hc
4-FC6H4 3g 4hg
2-Naphthyl 3i 4hi
9
4-Me 2h
10
4-Me 2h
the optical rotation with the reported value [21].
Reaction conditions: 5 mol% 1a, 0.2 mmol 2, 0.3 mmol 3, 1 ml THF, 0.3
nm molecular sieves (100 mg), –20 °C, 48 h, in Ar.
aAt –20 °C for 36 h.
°C resulted in increased ee of the addition product (entry 14).
Further optimization of the reaction conditions revealed that
the addition of 0.3 nm molecular sieves could improve the ee of
the addition product (entry 15).
also investigated in the aza-Michael addition reaction with
4-methylnitrostyrene 2h as the substrate. The electronic and
steric effects of the aromatic amines were all important for the
enantioselectivities of the addition products (entries 7–10).
Although the exact mechanism of this addition reaction is not
clear at current stage, on the basis of the results that we ob-
tained here and previously [32], a plausible transition state
model which involves the acidic proton of phosphoric acid for
activation the nitro moiety and the phosphoryl oxygen atom
activation the aromatic amine N–H moiety through the hy-
drogen bond is the most likely involved.
With the optimized reaction conditions in hand, we turned
our attention to the effect of substituent groups on the various
aromatic amines (Table 2). A variety of amines were investi-
gated for the generality of this reaction under the optimized
reaction conditions. As shown in Table 2, amine 3b, which had
no substituent on the phenyl ring (entry 1) and the amines
containing electron-withdrawing groups on the phenyl ring
(entries 4–6) were good substrates. They provided the addition
products in good yields with high ee values. In contrast, a slight
decrease in ee was observed for the amine bearing elec-
tron-donating group on the phenyl ring (entry 2). Along with
the electronic effect, the steric effect was also obvious in this
reaction (entry 7). It should be noted that when the phenyl ring
of the aromatic amines had more electron-withdrawing groups
such as CF3 the aza-Michael reaction did not occur at all (entry
3).
To demonstrate the synthetic use of the current methodology
for the synthesis of vicinal diamine derivatives, the reduction
of the nitroamine derivative was evaluated. As shown in
Scheme 2, after a work-up of the reaction of nitroamine 4af
(54% ee) with LiAlH4, the desired diamine derivative 5 was
obtained in 74% yield with 34% ee, which indicated a slight
racemization during the reduction process.
In conclusion, we developed an efficient method for the
enantioselective aza-Michael addition reaction between aro-
matic amines and nitroolefins using chiral phosphoric acids as
catalyst for the first time. The aza-Michael addition products
were generally obtained in good yields (65%–95%) with
moderate to good enantiomeric excesses (16%–70%). Further
Further exploration of this novel chiral phosphoric acid
catalyzed asymmetric aza-Michael addition of 4-bromoaniline
3f was conducted using various substituted nitroolefins. As
listed in Table 3, the halogenated nitroolefins gave the corre-
sponding products in good yields with moderate ee values
(entries 1–2). An increase in ee values was observed when the
steric hindrance of the aromatic ring in the nitroolefin was
increased (entry 5). To our delight moderate to good product
yields and ee values were obtained when election-donating
groups such as OMe were present on the phenyl ring of the
nitroolefins (entries 3 and 6). It was surprising that no product
was observed when 4-methoxynitrostyrene 2e was employed
(entry 4). Finally, various substituted aromatic amines were
Br
Br
HN
*
HN
*
NH2
NO2
LiAlH4
0-25 oC,
THF
5
4af
Scheme 2. Reduction of the ȕ-nitroamine product.

YANG Lei et al. / Chinese Journal of Catalysis, 2011, 32: 1573–1576
Tetrahedron: Asymmetry, 2008, 19: 2149
studies into improving the selectivity and the scope of this
reaction and related aza-Michael reactions catalyzed by chiral
Brönsted acids are ongoing in our lab and will be reported in
due course.
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