An effective aza-michael addition of aromatic amines to electron-deficient alkenes in alkaline Al2O3

Article abstract of DOI:10.1016/j.tet.2010.05.054

Aza-Michael addition of aromatic or aliphatic amines with various electron-deficient alkenes was performed using alkaline Al₂O ₃ as solid media at room temperature afforded the corresponding Michael addition products in good to excellent yields.The alkaline Al ₂O₃ can be easily recovered and reused.

Full text of DOI:10.1016/j.tet.2010.05.054

Tetrahedron 66 (2010) 5373e5377
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An effective aza-Michael addition of aromatic amines to electron-deficient
alkenes in alkaline Al2O3
,
y
,
*
y
*
Xin Ai, Xin Wang , Jin-ming Liu, Ze-mei Ge, Tie-ming Cheng, Run-tao Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Aza-Michael addition of aromatic or aliphatic amines with various electron-deficient alkenes was per-
formed using alkaline Al2O3 as solid media at room temperature afforded the corresponding Michael
addition products in good to excellent yields. The alkaline Al2O3 can be easily recovered and reused.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 March 2010
Received in revised form 10 May 2010
Accepted 14 May 2010
Available online 20 May 2010
Keywords:
Aza-Michael addition
Aromatic amines
Aliphatic amines
Alkaline Al2O3
Solvent-free
1. Introduction
report a simple and effective procedure for aza-Michael addition of
aromatic and aliphatic amines to electron-deficient alkenes in al-
kaline Al2O3 at room temperature (Scheme 1).
Owing to their wide range of biological activities1 and phar-
macological properties,2 the synthesis of
-amino carbonyl com-
b
pounds has become a field of increasing interest in organic
synthesis during the past few decades.3 The approach based on
conjugate addition of amines to
pounds (aza-Michael addition) is one of the simplest and most
effective methods for preparing -amino carbonyl compounds. In
a, b-unsaturated carbonyl com-
b
Scheme 1. Aza-Michael addition of aromatic and aliphatic amines to electron-de-
ficient alkenes in alkaline Al2O3.
recent years, a number of catalysts such as SmI2,4 Cu(OTf)2,5 Bi
(NO3),6 Bi(OTf)2,7 LiClO4,8 FeCl3$6H2O,9 TMSCl,10 boric acid11 and
clay12 have been developed for this reaction. However, most of
these catalytic systems are restricted to only aliphatic amines since
aromatic amines are poor nucleophiles.13 Therefore, the aza-Mi-
chael addition of aromatic amines encountered a big challenge
until the introduction of aqueous media with promoting agents,14
but the use of expensive and/or toxic catalysts, harsh reaction
conditions limited their application in organic synthesis. As a con-
sequence, several solvent-free or catalyst-free reaction conditions15
have been developed. But some methods still have the drawbacks
of low yields or finite scope of substrates. Hence, the requirement of
developing new aza-Michael addition with a broad scope of sub-
strates and mild reaction condition remains. In this paper, we
2. Results and discussion
Previously, we have developed an effective methodology for the
preparation of dithiocarbamic acid esters from Michael addition of
electron-deficient alkenes with aromatic amines and CS2 in alkaline
Al2O3 as solid media.16 During the course of investigating above reaction,
we noticed that aniline could react with acrylonitrile directly to produce
3-(phenylamino) propanenitrile in alkaline Al2O3. This unusual finding
aroused our interest to explore the possibility for aza-Michael addition of
aromatic amines to electron-deficient alkenes in solid media.
In this connection, our first experiments were performed by
reacting aniline and acrylonitrile in different solid media. As pre-
sented in Table 1, among the four screened solid media, namely
silica gel, bentonite, Celite and alkaline Al2O3, alkaline Al2O3 was
most effective for this reaction. Optimization for using amount of
the alkaline Al2O3 revealed that the best yield was obtained when
1 g alkaline Al2O3 was used under the experimental scale.
* Corresponding authors. Tel.: þ86 10 82 801 504; fax: þ86 10 82 716 956; e-mail
addresses: xinwang@bjmu.edu.cn (X. Wang), lirt@bjmu.edu.cn (R.-tao Li).
y
Present address: No.38 Xueyuan Road, Haidian District, Beijing100191, PR China
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.054

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X. Ai et al. / Tetrahedron 66 (2010) 5373e5377
Table 1
3. Conclusion
Aza-Michael addition of aniline to acrylonitrile under different reaction conditionsa
In conclusion, we have developed an effective aza-Michael ad-
dition of aromatic or aliphatic amines (primary or secondary) to
electron-deficient alkenes in alkaline Al2O3. The advantages of this
procedure include the wide scope of reaction substrates, the green
and reused solid reaction media, high yields and simple work-up
process. These remarkable advantages will make this approach
suitable not only for laboratory scale research but also for industrial
applications.
Entry
Solid media
Solid media amount (g)
Yieldb (%)
1
2
3
4
5
6
7
8
Silica gel
Diatomite
Bentonite
Alkaline Al2O3
Alkaline Al2O3
Alkaline Al2O3
Alkaline Al2O3
Alkaline Al2O3
1
1
1
0
0.5
0.75
1
Trace
23
54
0
82
85
98
95
4. Experimental
4.1. General experimental
1.5
a
Melting point data were recorded on an X-4 micro-melting
point instrument; NMR spectra were recorded on a Bruker ACF 300.
Column chromatography was performed on silica gel, Merck grade
60. Alkaline Al2O3 and other chemicals were purchased from LANYI.
The reaction was conducted with aniline (1 mmol), acrylonitrile (1.5 mmol) in
solid media at room temperature.
b
Isolated yields.
4.2. General procedure for the aza-Michael reaction
Subsequently, the structurally diverse aromatic amines were
chosen to react with acylonitrile under optimized conditions in
order to examine the versatility of the protocol and the results are
summarized in Table 2. All examined aryl amines could react with
acrylonitrile successfully to give corresponding aza-Michael addi-
tion products in moderate to excellent yields. Anilines bearing
para- or meta-electron donating substitutions (entries 2, 3, 5)
showed higher reactivity than their ortho-substituted analogues
(entries 4, 6) because the latter have higher steric hindrance. To our
pleasure, high yields could be provided in the cases of aniline
containing electron-withdrawing groups (entries 7e9), which is
reluctant to undergo Michael addition reaction according to pre-
vious literatures.17 It is noticeable that even 3-nitroaniline, which
has a strong electron-withdrawing group, still afforded the expec-
Amixtureofamine(1 mmol), alkene(1.5 mmol)andalkalineAl2O3
(1 g) was stirred at room temperature for the indicated time inTable 2
(monitored by TLC). Then, the solid mixture was washed with ethyl
acetate(10 mL)andthecrudeproductwasobtainedafterremovingoff
the ethyl acetate from washing solution. Further purification was
carried out by recrystallization from ethyl acetate/petroleum ether or
short column chromatography on silica gel (ethyl acetate/petroleum
ether¼1:6). The recovered alkaline Al2O3 could be reused.
4.2.1. 3-(Phenylamino)propanenitrile (Table 2, entry 1). Yellow
crystal; mp: 51e52 ꢀC (lit.21 51.5 ꢀC); 1H NMR (300 MHz, CDCl3)
d 2.57
(t, 2H, J¼2.2 Hz), 3.46(dd, 2H, J¼2.0,1.9 Hz),3.99(s,1H),6.58e7.22(m,
5H). NMR datawere identical with those described in the literature.21
ted compound in 46% yield (entry 10). Meanwhile, using a-naph-
thylamine as nucleophile, moderate yield was achieved (entry 11).
Furthermore, we applied the aza-Michael addition reaction to aryl
diamine since substituted diamines were an important class of
compounds for the preparation of hybrid materials18 and functional
nano-structured materials (entries 12, 13).19 The results demon-
strated that mono- or bis aza-Michael addition products of diamine
could be acquired selectively through adjusting the relative mole
ratio of the reactants.
4.2.2. 3-(p-Toluidino)propanenitrile (Table 2, entry 2). Yellow crys-
tal; mp: 102e103 ꢀC (lit.22 103e104 ꢀC); 1H NMR (300 MHz, CDCl3)
d
2.25 (s, 3H), 2.63 (t, 2H, J¼2.1 Hz), 3.51 (t, 2H, J¼2.1 Hz), 3.84 (s,
1H), 6.56 (d, 2H, J¼2.8 Hz), 7.03 (d, 2H, J¼2.7 Hz). NMR data were
identical with those described in the literature.22
4.2.3. 3-(m-Toluidino)propanenitrile (Table 2, entry 3). Yellow crys-
tal; mp: 50e51 ꢀC (lit.23 49.5e50.5 ꢀC); 1H NMR (300 MHz, CDCl3)
To determine the adaptability of this protocol, some examples of
aliphatic amines were investigated and satisfactory results were
also obtained (Table 2, entries 14e20). In the cases of conventional
aza-Michael addition, primary amine suffered from over-alkylation
produced a low yield of the mono- or di-substituted products.20
Whereas, in our cases, the ratios of mono- or di-substituted prod-
ucts were controllable by adding different proportions of acrylo-
nitrile and afforded satisfactory yields (entries 14e17). In addition,
N-hetero-aromatic amines were also effective and gave desired
adducts in 94e96% yields (entries 21e23).
At last, we studied the reactions of aniline with different elec-
tron-deficient alkenes under our reaction conditions to test the
generality of Michael acceptors. The three chosen Michael accep-
tors afforded the mono aza-Michael products in comparable yields
(entries 24e26).
d
2.29(s, 3H), 2.63(t, 2H, J¼2.2 Hz), 3.51 (dd, 2H, J¼2.2, 2.1 Hz), 3.92(s,
1H), 6.43 (d, 2H, J¼2.2 Hz), 6.60 (d,1H, J¼2.1 Hz), 7.10 (t,1H, J¼2.2 Hz).
NMR data were identical with those described in the literature.23
4.2.4. 3-(o-Toluidino)propanenitrile (Table 2, entry 4). Yellow oil; 1H
NMR (300 MHz, CDCl3)
d
2.16 (s, 3H), 2.07 (t, 2H, J¼2.2 Hz), 3.57 (dd,
2H, J¼2.2, 2.1 Hz), 3.85 (s, 1H), 6.55e7.24 (m, 5H). NMR data were
identical with those described in the literature.23
4.2.5. 3-(4-Methoxyphenylamino)propanenitrile (Table 2, entry 5).
Yellow crystal; mp: 63e64 ꢀC (lit.23 62e64 ꢀC); 1H NMR (300 MHz,
CDCl3)
d
2.52 (t, 4H, J¼2.2 Hz), 3.59 (t, 4H, J¼2.2 Hz), 3.79 (s, 3H),
6.81e6.91 (m, 5H). NMR data were identical with those described in
the literature.23
It is noteworthy that all cases were carried out just by mixing all
reactants together and stirring at room temperature for 4e18 h. The
products can be isolated from the reaction system by simply
washing with ethyl acetate, and the alkaline Al2O3 can be easily
recovered and reused for at least three times without any signifi-
cant loss of activity. Pure products could be readily obtained by
recrystallization from petroleum ether/ethyl acetate in most cases.
4.2.6. 3-(2-Methoxyphenylamino)propanenitrile (Table 2, entry 6).
Yellow crystal; mp: 70e71 ꢀC (lit.24 70e71 ꢀC); 1H NMR (300 MHz,
CDCl3)
d
2.63 (t, 2H, J¼2.2 Hz), 3.53 (dd, 2H, J¼2.2, 2.1 Hz), 3.84 (s,
3H), 4.55 (s, 1H), 6.55e6.90 (m, 5H).
4.2.7. 3-(4-Chlorophenylamino)propanenitrile (Table 2, entry 7).
Yellow crystal; mp: 75e76 ꢀC (lit.23 75e76 ꢀC); 1H NMR (300 MHz,

X. Ai et al. / Tetrahedron 66 (2010) 5373e5377
5375
Table 2
Aza-Michael addition of diverse nitrogen nucleophiles with Michael acceptors in alkaline Al2O3
a
Entry
Nucleophile
Acceptor
Product
Time (h)
Yieldb (%)
1
2
PhNH2
8
8
98
98
p-CH3PhNH2
3
m-CH3PhNH2
o-CH3PhNH2
p-CH3OPhNH2
o-CH3OPhNH2
p-ClPhNH2
8
8
8
8
8
8
8
8
95
75
98
83
88
84
86
46
4
5
6
7
8
m-ClPhNH2
9
p-BrPhNH2
10
m-NO2PhNH2
11
12
8
8
75
53
13c
14
18
4
76
74
90
80
15c
16
4
4
(continued on next page)

5376
Table 2 (continued)
X. Ai et al. / Tetrahedron 66 (2010) 5373e5377
Entry
Nucleophile
Acceptor
Product
Time (h)
4
Yieldb (%)
88
17c
18
4
98
19
20
21
22
23
24
25
4
4
8
8
8
8
8
95
96
95
96
94
63
64
PhNH2
PhNH2
26
PhNH2
8
84
a
Unless specified, the reaction was carried out with amines (1 mmol) and Michael acceptors (1.5 mmol) in the presence of alkaline Al2O3 (1 g).
Isolated yields.
The amount of acrylonitrile was twice as much as that used in the corresponding mono-substituted cases.
b
c
CDCl3)
d
2.64 (t, 2H, J¼2.2 Hz), 3.50 (t, 2H, J¼2.2 Hz), 4.00 (s, 1H),
CDCl3)
6.90e7.92 (m, 5H).
d
2.71 (t, 2H, J¼2.2 Hz), 3.59 (t, 2H, J¼2.2 Hz), 4.38 (s, 1H),
6.53e7.18 (m, 5H). NMR data were identical with those described in the
literature.23
4.2.11. 3-(Naphthalen-2-ylamino)propanenitrile (Table 2, entry 11).
Pink powder; mp: 70e71 ꢀC (lit.26 69e70 ꢀC); 1H NMR (300 MHz,
4.2.8. 3-(3-Chlorophenylamino)propanenitrile (Table 2, entry 8).
Yellow crystal; mp: 46e47 ꢀC (lit.21 44e47 ꢀC); 1H NMR (300 MHz,
CDCl3)
d
2.65 (t, 2H, J¼2.2 Hz), 3.58 (t, 2H, J¼2.2 Hz), 4.59 (s, 1H),
6.51e7.80 (m, 5H).
CDCl3)
d
2.64 (t, 2H, J¼2.2 Hz), 3.50 (t, 2H, J¼2.2 Hz), 4.00 (s, 1H),
6.53e7.18 (m, 5H).
4.2.12. 3-(2-Aminophenylamino)propanenitrile (Table 2, entry 12).
Red crystal; mp: 117e119 ꢀC (lit.27 116e118 ꢀC); 1H NMR (300 MHz,
4.2.9. 3-(4-Bromophenylamino)propanenitrile (Table 2, entry 9).
Yellow crystal; mp: 96.5 ꢀC (lit.25 96.5e97.5 ꢀC); 1H NMR (300 MHz,
CDCl3)
d
2.66 (t, 2H, J¼2.2 Hz), 3.48 (t, 2H, J¼2.2 Hz), 6.63e6.85
(m, 4H).
CDCl3)
d
2.64 (t, 2H, J¼2.2 Hz), 3.50 (s, 2H), 4.01 (s,1H), 6.49e7.32 (m, 5H).
4.2.10. 3-(3-Nitrophenylamino)propanenitrile (Table 2, entry 10).
4.2.13. N,N0-o-Phenylene-di-alanine dinitrile (Table 2, entry 13).
Yellow crystal; mp: 97e98 ꢀC (lit.25 95e96 ꢀC); 1H NMR (300 MHz,
Dark red crystal; mp: 117e118 ꢀC (lit.28 116e118 ꢀC); 1H NMR

X. Ai et al. / Tetrahedron 66 (2010) 5373e5377
5377
(300 MHz, CDCl3)
6.70e6.89 (m, 4H).
d
2.66 (t, 4H, J¼2.2 Hz), 3.46 (t, 4H, J¼2.2 Hz),
4.55 (s, 1H), 5.00 (s, 1H), 6.55e7.92 (m, 15H). NMR data were
identical with those described in the literature.38
4.2.14. 3-(Butylamino)propanenitrile (Table 2, entry 14). Yellow oil;
1H NMR (300 MHz, CDCl3)
4H), 2.54 (t, 2H, J¼2.2 Hz), 2.64 (t, 2H, J¼2.2 Hz), 2.94 (t, 2H,
J¼2.2 Hz). NMR data were identical with those described in the
literature.29
Acknowledgements
d
0.92 (t, 3H, J¼2.4 Hz), 1.31e1.53 (m,
This work was supported by the funds of Natural Science
Foundation of China (NSFC20772009).
4.2.15. 3,30-Butylimino-di-propionitrile (Table 2, entry 15). White
oil; 1H NMR (300 MHz, CDCl3)
J¼2.2 Hz), 7.03 (s, 1H), 7.12 (s, 1H), 7.57 (s, 1H).
d
2.83 (t, 2H, J¼2.2 Hz), 4.27 (t, 2H,
Supplementary data
The original data of 1H NMR of all products are supplied. The
supplementary data files are to be used as an aid for the referring of
the paper only. Supplementary data for this article can be found in
the online version, at doi:10.1016/j.tet.2010.05.054. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
4.2.16. 3-(Benzylamino)propanenitrile (Table 2, entry 16). Yellow
oil; 1H NMR (300 MHz, CDCl3)
d
2.52 (t, 2H, J¼2.2 Hz), 2.83 (t, 2H,
J¼2.2 Hz), 3.83 (s, 2H), 7.26e7.34 (m, 5H). NMR data were identical
with those described in the literature.22
4.2.17. 3,30-[(Phenylmethyl)imino]bis(propanenitrile) (Table 2, entry
17). Yellow oil; 1H NMR (300 MHz, CDCl3)
d
2.42 (t, 2H, J¼2.3 Hz),
2.84 (t, 2H, J¼2.3 Hz), 3.67 (s, 2H), 7.26e7.34 (m, 5H). NMR data
References and notes
were identical with those described in the literature.31
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4.2.18. 3-(Dibutylamino)propanenitrile (Table 2, entry 18). Yellow
oil; 1H NMR (300 MHz, CDCl3)
d
0.91 (t, 6H, J¼2.3 Hz), 1.26e1.46 (m,
8H), 2.39e2.45 (m, 6H), 2.77 (t, 2H, J¼2.3 Hz). NMR data were
identical with those described in the literature.29
3. (a) For review: Juaristi, E.; Soloshonok, V. A. Enantioseloctive Synthesis of
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Amino Acids, 2nd ed;; John Wiley & Sons: New York, NY, 2005; Reboule, I.; Gil,
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d
2.50e2.55 (m, 6H), 2.65e2.70 (m, 2H), 3.69e3.72 (m, 4H). NMR
data were identical with those described in the literature.30
4.2.20. 3-(4-Methylpiperazin-1-yl)propanenitrile (Table 2, entry
20). White crystal; mp: 97e98 ꢀC (lit.32 96e100 ꢀC); 1H NMR
(300 MHz, CDCl3)
d
2.26 (t, 3H, J¼2.7 Hz), 2.48 (s, 8H, J¼2.2 Hz), 2.67
(s, 2H), 8.22 (s, 1H). NMR data were identical with those described
in the literature.32
4.2.21. 3-(1H-1,2,4-Triazol-1-yl)propanenitrile (Table 2, entry 21).
White oil; 1H NMR (300 MHz, CDCl3)
d
3.01 (t, 2H, J¼2.2 Hz), 4.48 (t,
2H, J¼2.2 Hz), 8.02 (s, 1H), 8.22 (s, 1H). NMR data were identical
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4.2.22. 3-(1H-Imidazol-1-yl)propanenitrile (Table 2, entry 22).
White crystal; mp: 35e36 ꢀC (lit.34 33e35 ꢀC); 1H NMR (300 MHz,
CDCl3)
d
2.83 (t, 2H, J¼2.2 Hz), 4.27 (t, 2H, J¼2. 2 Hz), 7.03 (s, 1H),
7.12 (s, 1H), 7.57 (s, 1H). NMR data were identical with those de-
scribed in the literature.34
4.2.23. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)propanenitrile (Table 2,
entry 23). White crystal; mp: 83e84 ꢀC (lit.35 83e85 ꢀC); 1H NMR
(300 MHz, CDCl3)
d
3.15 (t, 2H, J¼2.2 Hz), 4.94 (t, 2H, J¼2.2 Hz),
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7.41e8.12 (m, 5H). NMR data were identical with those described in
the literature.35
25. Bauer, L.; Cymerman, J.; Sheldon, W. J. J. Chem. Soc. 1951, 3311e3315.
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4.2.24. Methyl 3-(phenylamino)propanoate (Table 2, entry 24).
White crystal; mp: 49e50 ꢀC (lit.36 50 ꢀC); 1H NMR (300 MHz,
27. Braunholtz, J. T.; Mann, F. G. J. Chem. Soc. 1953, 1817e1824.
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CDCl3):
d
2.57 (t, 2H, J¼2.2 Hz), 3.46 (dd, 2H, J¼2.0, 1.9 Hz), 3.70 (s,
3H), 3.99 (s, 1H), 6.58e7.22 (m, 5H). NMR data were identical with
those described in the literature.36
31. Verma, A. K.; Kumar, R.; Chaudhary, P.; Saxena, A.; Shankar, R.; Mozumdar, S.;
4.2.25. N-(1-Nitrobutan-2-yl)benzenamine (Table 2, entry 25). Yel-
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32. Zhang, Y.; Chu, T.; Gao, X.; Liu, X.; Yang, Z.; Guo, Z.; Wang, X. Bio. Med. Chem.
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low oil; 1H NMR (300 MHz, CDCl3)
d
1.06 (t, 2H, J¼2.4 Hz),1.56e1.80
(m, 2H), 3.67 (d, 1H, J¼3.0 Hz), 4.01 (d, 1H, J¼1.8 Hz), 4.41e4.59 (m,
2H), 6.66e7.26 (m, 5H). NMR data were identical with those
described in the literature.37
4.2.26. 1,3-Diphenyl-3-(phenylamino)propan-1-one (Table 2, entry
26). Yellow oil; 1H NMR (300 MHz, CDCl3)
d 3.38e3.55 (m, 2H),