Aza-Michael reaction promoted by aqueous sodium carbonate solution

Article abstract of DOI:10.1016/j.tetlet.2013.03.043

A general and efficient aza-Michael reaction promoted by aqueous sodium carbonate solution has been developed. The reaction has complete mono-alkylation selectivity and proceeds with complete chirality retention for chiral amino esters. With a broad substrate scope, a well-common catalyst and simple operation, the catalytic approach provides a facile, practicable, economical, and environmentally benign method for the synthesis of β-amino carbonyl compounds.

Full text of DOI:10.1016/j.tetlet.2013.03.043

Tetrahedron Letters 54 (2013) 2669–2673
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Tetrahedron Letters
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Aza-Michael reaction promoted by aqueous sodium carbonate solution
Xiao-Ji Tang, Zhao-Lei Yan, Wen-Liang Chen, Ya-Ru Gao, Shuai Mao, Yan-Lei Zhang,
⇑
Yong-Qiang Wang
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an
710069, PR China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient aza-Michael reaction promoted by aqueous sodium carbonate solution has been
developed. The reaction has complete mono-alkylation selectivity and proceeds with complete chirality
retention for chiral amino esters. With a broad substrate scope, a well-common catalyst and simple oper-
ation, the catalytic approach provides a facile, practicable, economical, and environmentally benign
method for the synthesis of b-amino carbonyl compounds.
Received 12 January 2013
Revised 25 February 2013
Accepted 8 March 2013
Available online 17 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aza-Michael reaction
Aqueous sodium carbonate solution
b-Amino carbonyl compounds
Mono-alkylation
b-Amino carbonyl structural motifs are embedded in a wide
range of natural products and biologically active compounds.1 b-
Amino carbonyl compounds also represent versatile building
blocks for the synthesis of b-amino acid derivatives, amino alco-
hols, diamines, many of which serve as important antibiotics or
other drugs.2 Classical synthetic approach to b-amino carbonyl unit
is the Mannich-type reaction.3 Alternatively, aza-Michael reaction
provides a promising method due to its simplicity and atom econ-
omy. Despite considerable efforts made for aza-Michael reaction in
the past decades,4–7 to date, the substrate scope is still limited as
follows: (1) Because of weak nucleophilicity compared with ali-
phatic amines, anilines especially bearing electron-withdrawing
substituent on the arene ring, such as 4-haloaniline, reacted with
methyl acrylate to give low conversions (620%).4e,4m,8 In 2006,
Rao reported an aza-Michael reaction promoted by b-cyclodextrin
(1 equiv),9 then Leadbeater and Varma separately presented micro-
wave assisted aza-Michael additions.10 Although the three meth-
ods were efficient for the conjugate addition of anilines onto
methyl acrylate, they are obviously hard to apply into mass pro-
duction. In 2008, Bhanage reported a Y(NO3)3Á6H2O (10 mol %) cat-
alyzed aza-Michael addition of aromatic amines in the absence of
solvents, but more hindered b-substituted Michael acceptors were
not suitable for the protocol (only 2–5% yields).11 (2) Amino acids,
as the largest amine sources, were less involved in the intermolec-
ular aza-Michael reaction as nucleophiles.12 Herein, we disclose a
general, efficient, and environmentally friendly aza-Michael reac-
tion promoted by aqueous sodium carbonate solution. This reac-
tion has complete mono-alkylation selectivity and
a broad
substrate scope, especially including poor nucleophilic anilines
and amino ester. Moreover, the aza-Michael reactions of chiral
amino esters as Michael donors are with complete chirality
retention.
Initially, we investigated the aza-Michael reaction with aniline
(1a) and ethyl acrylate (2a) as model substrates. Considering un-
ique reactivity of organic compounds in aqueous suspension and
Maryr’s findings that anilines react two times faster in water than
in acetonitrile for the reaction of anilines with benzhydrylium ion
[(dma)2CH+], as well as the ‘on water’ effect in rate acceleration
which has been evidently observed by Sharpless et al.,13 we chose
water as solvent. The reaction was found to proceed in low conver-
sion (<10%) in neat water at room temperature for 3 days (Table 1,
entry 1). When alkali hydroxides (0.1 equiv) as catalysts were
introduced, the conversion rose slightly (10–30% yields, Table 1,
entries 2–4). To our delight, sodium carbonate could markedly pro-
mote the aza-Michael reaction of aniline and ethyl acrylate and the
yield improved to 65%, while sodium bicarbonate was not effective
(Table 1, entries 5–6). According to the solvent screening experi-
ments, water did play an important role in the aza-Michael reac-
tion (Table 1, entry 7). In order to enhance the rate of the
reaction, we increased the reaction temperature to 50 °C. The yield
improved remarkably to 90%, furthermore, no double alkylation
product was observed (Table 1, entry 8). Nevertheless, higher tem-
perature led to a significant drop in the yield due to the decompo-
sition of product (Table 1, entries 9–10).
⇑
Corresponding author. Tel.: +86 29 88305966.
E-mail address: wangyq@nwu.edu.cn (Y.-Q. Wang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.043

2670
X.-J. Tang et al. / Tetrahedron Letters 54 (2013) 2669–2673
Table 1
With the optimal reaction conditions in hand, we moved on to
Optimization of reaction conditionsa
explore the scope of the aza-Michael reaction promoted by aque-
ous sodium carbonate solution. Firstly, a variety of substituted ani-
lines were examined, and the results were summarized in Table 2.
Electron-rich anilines underwent conjugate addition to ethyl acry-
late giving the desired products in good yields (Table 2, entries 2–
4). For the more challenging electron-poor anilines, such as 4-chlo-
roaniline and 4-bromoaniline, in previous work, they gave poor
conversion (20%) and low yield (10%), respectively.8 Pleasingly,
they provided useful yields in this catalytic reaction system, albeit
the reactions required more reagents and higher reaction temper-
ature (Table 2, entries 5–7).
Then we turned our attention to aza-Michael reaction of various
amines with phenyl vinyl ketone under the catalytic reaction sys-
tem. The aza-Michael addition was found to be general with a wide
range of amines, and the reaction was fast at room temperature
without diaddition products being observed. Both electron-with-
drawing and electron-donating groups on the aromatic ring of ani-
lines were tolerated, yielding the desired products in excellent
yields (85–98%, Table 3, entries 1–9). 1-Naphthalenamine, ali-
phatic primary and secondary amine were suitable substrates for
this process (Table 3, entries 10–12). Particularly remarkable was
the participation of chiral amino esters in the aza-Michael reaction.
H
N
NH2
OEt
OEt
base
solvent
+
O
O
3aa
2a
1a
Entry
Base
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
—
LiOH
NaOH
KOH
Na2CO3
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
H2O
H2O
H2O
H2O
H2O
H2O
rt
rt
rt
rt
rt
rt
rt
50
80
100
<10
10
30
25
65c
20
6
7d
8
Solvents
H2O
610
90
82
9
10
H2O
H2O
80
a
Reaction conditions: aniline (1.0 mmol), ethyl acylate (1.2 mmol), and base
(0.1 mmol) in solvent (1 mL) at rt for 72 h.
b
Isolated yield.
The conversion was 72%.
c
d
Solvents: CH2Cl2, CH3CN, EtOAc, acetone, DMSO, toluene, Et2O, THF.
Table 2
Aza-Michael reaction of amines with ethyl acylatea
NH2
H
Na2CO3
( aq)
OEt
N
OEt
R
+
R
O
2a
O
1
3
Entry
1
Amine
Time (h)
Product
Yieldb (%)
90
NH2
1a
H
N
OEt
72
O
O
3aa
NH2
H
N
OEt
2
3
72
72
82
85
OMe
OMe
3ba
1b
NH2
Me
Me
H
N
Me
Me
OEt
OEt
O
1c
3ca
Me
Me
Me
NH2
1d
H
N
4
72
72
80
O
3da
Me
NH2
H
N
OEt
5c
75 (93)d
1e
O
3ea
Cl
Cl
Cl
Cl
NH2
H
N
OEt
OEt
6c
7c
72
72
62 (95)d
65 (92)d
1f
O
O
3fa
NH2
H
N
1g
Br
3ga
Br
a
b
c
Reaction conditions: ethyl acylate (1.2 mmol), amine (1 mmol), and Na2CO3 (0.1 M aq, 1 mL) at 50 °C.
Isolated yield.
Ethyl acylate (3 mmol), amine (1 mmol), and Na2CO3 (0.2 M aq, 1 mL) at 80 °C.
Yield in parentheses based on recovered starting material.
d

X.-J. Tang et al. / Tetrahedron Letters 54 (2013) 2669–2673
2671
Table 3
Aza-Michael reaction of amines with phenyl vinyl ketonea
O
O
Na2CO3
R'
R'
N
R
(0.1 M aq)
+
NH
R
rt
1
2b
3
Entry
1
Amine
Time (h)
0.5
Product
Yieldb (%)
98
NH2
H
N
Ph
1a
O
3ab
NH2
H
N
Ph
2
3
0.5
0.5
94
92
OMe
O
OMe
1b
3bb
Me
Me
NH2
H
Me
Me
N
Ph
Ph
1c
O
O
3cb
Me
Me
Me
NH2
H
N
4
5
0.5
94
92
1d
3db
Me
NH2
H
N
Ph
1
1e
O
3eb
Cl
Cl
Cl
NH2
1f
H
N
Ph
6
7
8
1
1
1
94
85
90
Cl
Br
O
3fb
NH2
1g
H
N
Ph
O
3gb
Br
NH2
Cl
H
N
Ph
O
1h
Cl
3hb
NH2
H
N
Ph
9
1
2
90
86
1i
Me
O
3ib
Me
Cl
Cl
NH2
O
HN
Ph
10
3jb
1j
H
N
NH2
Ph
1k
n
-Bu
11
12
2
3
78
85
3kb
O
H
N
1l
Et
N
Ph
Et
3lb
O
(continued on next page)

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X.-J. Tang et al. / Tetrahedron Letters 54 (2013) 2669–2673
Table 3 (continued)
Entry
Amine
Time (h)
2
Product
Yieldb (%)
H
NH2
H
O
13
Me
CO2Me
Me
MeO2C
83 (>99% ee)
N
H
Ph
O
1m
3mb
H
NH2
H
14
3
87 (>99% ee)
CO2Me
N
Ph
1n
MeO2C
H
3nb
a
Reaction conditions: phenyl vinyl ketone (1 mmol), amine (1.2 mmol), and Na2CO3 (0.1 M aq, 1 mL) at rt.
Isolated yield.
b
Table 4
Aza-Michael reaction of anilines with enonea
H
N
R2
Na2CO3
NH2
O
(0.1 M aq)
R
R
R1
R2
+
R1
O
rt
1
2
3
Entry
1
Acceptor
Time (h)
2
Product
Yieldb (%)
94
O
H
N
Et
2c
O
O
3ac
O
H
N
Et
2
3
4
6
86
88
Me
3ad
2d
O
H
N
O
3ae
2e
O
H
N
Ph
4
5
4
3
80
87
Me
Me
3af
O
2f
O
OMe
I
H
N
Ph
Ph
2g
3ag
MeO
O
O
H
N
6
7
3
86
72
2h
3ah
I
O
H
N
CN
2i
CN
20
3ai
O
H
Me
Cl
N
Et
Et
8
9
2
3
91c
93d
O
2c
3cc
Me
O
H
N
O
2c
3fc
a
b
c
Reaction conditions: amine (1 mmol), Michael acceptors (1.2 mmol), and Na2CO3 (0.1 M aq, 1 mL) at rt.
Isolated yield.
Reacted with 1c.
Reacted with 1f.
d
To our knowledge, amino esters were scarcely involved in the
intermolecular aza-Michael reaction as nucleophiles, though they,
as masked amino acids, are the largest amine sources. Under the
standard reaction conditions, -alanine and -phenylalanine under-
L
L

X.-J. Tang et al. / Tetrahedron Letters 54 (2013) 2669–2673
2673
O
References and notes
H
H
O
R'
O
O
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Interscience: New York, 2005; 4.
H
O
H
O
2-
R'
2-
CO3
O
O
H
-CO3
-H2O
R'
N
R
RHN
H
RNH2
Scheme 1. Plausible mechanism for the aza-Michael addition.
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products in 83% and 87% yields, respectively, with the chirality of
amino ester moiety intact (both products ee >99%, see Supplemen-
tary data) (Table 3, entries 13 and 14).
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W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633; (b) Yamagiwa, N.; Qin, H.;
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C.-E.; Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63, 904; (h) Xu, J.-M.; Wu, Q.;
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C.; Blue, E. D.; Gunnoe, T. B. J. Am. Chem. Soc. 2006, 128, 1446; (b) Fetterly, B. M.;
Jana, N. K.; Verkade, J. G. Tetrahedron 2006, 62, 440; (c) Munro-Leighton, C.;
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D.-H.; Jiang, J.; Xu, X.-P.; Chen, T.; Ji, S.-J. Tetrahedron 2011, 67, 3631.
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C.; Spencer, J. B. Org. Lett. 2003, 5, 2141; (b) Yang, L.; Xu, L.-W.; Xia, C.-G.
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Dong, D.-W. Tetrahedron 2008, 64, 4959.
Finally, we studied the effect of electronic and structural varia-
tions to the enone by using aniline as Michael donor (Table 4).
Gratifyingly, enones with various electronic properties and struc-
tural formations (cyclic or linear, terminal or internal) could pro-
ceed efficiently to produce the corresponding aza-Michael
addition products at room temperature in good to excellent yields
(80–94%) (Table 4, entries 1–6). Acrylonitrile also participated in
the conjugate addition (Table 4, entry 7). Anilines substituted by
electron-withdrawing group or electron-donating group reacted
smoothly with EVK (2c) to give the corresponding addition prod-
ucts in 91% and 93% yields, respectively (Table 4, entries 8 and 9).
Our current understanding of the catalytic aza-Michael reaction
is illustrated in Scheme 1. Initially, the amine adds to the Michael
acceptor and carbonate ion in the transformation acts as a proton
shuttle, using hydrogen bonding to facilitate transfer of the proton
from nitrogen to oxygen.5b Water plays an important role here by
pre-associating with the carbonyl group, and consequently acceler-
ates the addition step.
In summary, we have developed an effective aza-Michael reac-
tion promoted by aqueous sodium carbonate solution. The reaction
shows complete mono-alkylation selectivity and complete chiral-
ity retention for chiral amino esters. With a broad substrate scope,
a well-common catalyst and simple operation, the catalytic ap-
proach provides a facile, practicable, economical, and environmen-
tally benign method for the synthesis of b-amino carbonyl
compounds which are ubiquitous in nature. The method should
have many applications in organic and medical chemistry. Detailed
mechanistic investigations and applications to the synthesis of bio-
logically active molecular complexes are currently underway.
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Acknowledgments
11. Bhanushali, M. J.; Nandurkar, N. S.; Jagtap, S. R.; Bhanage, B. M. Catal. Commun.
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This research was supported by the National Natural Science
Foundation of China (NSFC-20872183, 20972126, 21272185), the
Program for New Century Excellent Talents in University of the
Ministry of Education China (NCET-10-0937), and the Education
Department of Shaanxi Provincial Government (09JK776).
12. (a) Sham, H. L.; Betebenner, D. A.; Herrin, T.; Kumar, G.; Saldivar, A.;
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
043.