Functionalized ionic liquid promoted aza-michael addition of aromatic amines

Article abstract of DOI:10.1002/jccs.201000180

A functionalized ionic liquid, 3-(N,N-dimethyldodecylammonium) propanesulfonic acid hydrogen sulphate ([DDPA][HSO₄]) has been used as catalyst for the aza-Michael reactions of aromatic amines with α,β-unsaturated compounds at room temperature to produce β-amino compounds in good yields. The catalyst can be reused for several times without obvious loss of the catalytic activity.

Full text of DOI:10.1002/jccs.201000180

Journal of the Chinese Chemical Society, 2010, 57, 1221-1226
1221
Communication
Functionalized Ionic Liquid Promoted Aza-Michael Addition of Aromatic
Amines
Xiao-Bing Liu (
Ting-Ting Lu (
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing 210094, P. R. China
), Ming Lu* (
),
) and Guo-Liang Gu (
)
A functionalized ionic liquid, 3-(N,N-dimethyldodecylammonium) propanesulfonic acid hydrogen
sulphate ([DDPA][HSO4]) has been used as catalyst for the aza-Michael reactions of aromatic amines with
a,b-unsaturated compounds at room temperature to produce b-amino compounds in good yields. The cat-
alyst can be reused for several times without obvious loss of the catalytic activity.
Keywords: Aza-Michael reaction; Aromatic amines; b-Amino carbonyl compounds; Ionic liquid;
Catalyst.
INTRODUCTION
The aza-Michael reaction is an important reaction in
pounds is well known; in contrast, aromatic amines being
weakly nucleophilic do not undergo such additions easily.
Y(NO3)3·6H2O 30 and alkaline Al2O3 31 were used as effi-
cient catalysts for promoting the aza-Michael addition of
aromatic amines to a,b-unsaturated compounds. However,
the search for the new readily available and green catalysts
is still being actively pursued.
organic chemistry especially for the synthesis of hetero-
cycles containing a b-amino carbonyl unit. b-Amino car-
bonyl compounds are useful building blocks for the mole-
cules with applications in pharmaceuticals and fine chemi-
cals.1-7 They are versatile intermediates for the synthesis of
biologically important natural products and antibiotics.
The most common method for the construction of this func-
tionality is the Mannich reaction;8-11 however, the reaction
is associated with disadvantages like drastic reaction con-
ditions and longer reaction times.12 Alternatively, the con-
jugate addition of amines to a,b-unsaturated compounds
(aza-Michael reaction) is an attractive route for the synthe-
sis of b-amino carbonyl compounds due to its simplicity
and atom economy.
Ionic liquids have attracted extensive interest as ex-
cellent alternatives to organic solvents, due to their favor-
able properties. Recently, there were reports of aza-Mi-
chael reactions conducted in ionic liquids,32 Cu(acac)2/
ionic liquid,33 ionic liquid/quaternary ammonium salt in
water,34 and boric acid in water.35 However, these reactions
were unsuccessful in water alone, without using acid or
base catalyst. Combining the useful characteristics of solid
acids and mineral acids, Brønsted acidic task-specific ionic
liquids (TSILs) are designed to replace traditional mineral
liquid acid catalysts, such as sulfuric acid and hydrochloric
acid in chemical processes. However, TSILs with imida-
zole as the cation are relatively expensive, which hinders
their industrial applications. Furthermore, typical ionic liq-
uids consist of halogen containing anions (such as [PF6]-,
[BF4]-, [CF3SO3]- and [(CF3SO2)2N]-) which in some re-
gard limit their “greenness”.36-38 Therefore, it is necessary
to synthesize less expensive and halogen-free TSILs. Some
SO3H-functional halogen-free acidic ionic liquids have
been prepared and their catalytic activities for acid-cata-
lyzed reactions have also been investigated.39-44
The aza-Michael reactions are usually carried out un-
der acid and base catalysis.13-16 Recently, many synthetic
methods for preparing the b-amino carbonyl compounds
have been reported to improve and modify this reaction. A
variety of reagents such as InCl3, supported CeCl3·7H2O-
NaI, Yb(OTf)2, Bi(NO3)2, clay, silica gel, FeCl3, palladium,
RuCl3/PEG and KF/alumina have been reported as promot-
ers for this reaction.17-26 Heterogeneous solid acids have
also been employed for this reaction.27,28 Further, the use of
microwave technique using stoichiometric amount of ace-
tic acid at high temperature has been reported.29 The Mi-
chael addition of aliphatic amines to a,b-unsaturated com-
* Corresponding author. E-mail: lumingnj302@126.com

1222 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Liu et al.
Recently, a novel SO3H-functional halogen-free
Brønsted acidic ionic liquid 3-(N,N-dimethyldodecyl-
ammonium) propanesulfonic acid hydrogen sulphate
([DDPA][HSO4]) has been successfully applied to catalyze
the Mannich reaction.45 The remarkable activity and reus-
ability of this ionic liquid encouraged us to study its utility
for aza-Machael reaction. To the best of our knowledge in
the open literature, the aza-Machael reactions catalyzed by
the functionalized ionic liquid have not yet been reported.
Herein, we have discovered that the functionalized ionic
liquid effectively promoted aza-Machael reactions of aro-
matic amines to conjugate a,b-unsaturated compounds un-
der relatively mild conditions (Scheme I).
Table 1. Effect of the [DDPA][HSO4]/solvent on the aza-
Machael reactiona
Entry
Catalyst/solvent
Yield (%)b
1
2
3
4
[DDPA][HSO4]/H2O
[DDPA][HSO4]/C2H5OH
[DDPA][HSO4]/CH3CN
[DDPA][HSO4]/CH2Cl2
90
87
90
79
a Reaction conditions: aniline (10 mmol), acrylonitrile (12 mmol),
r.t., 4 h
b Isolated yield
Table 2. Effect of amount of [DDPA][HSO4] on the reactiona
Entry
Catalyst (mmol)
Yield (%)b
1
2
3
4
5
0
0.5
1
trace
80
Aza-Michael addition of aromatic amines
to a,b-unsaturated compounds in the pres-
ence of [DDPA][HSO4]
Scheme I
90
2
90
4
88
a Reaction conditions: aniline (10 mmol), acrylonitrile (12 mmol),
r.t., 4 h
b Isolated yield
is important to carry out aza-Michael reaction in water
(entry 1) for the environmental and economic reasons.
Subsequently, the same reaction of aniline and acry-
lonitrile was employed as the model reaction to screen the
effect of the catalytic amount of [DDPA][HSO4] on the
aza-Michael reaction. The results showed that only trace of
desirable product could be detected when the reaction pro-
ceeded at room temperature for 4 h without any catalyst
(entry 1), which indicated that the catalyst should be abso-
lutely necessary for the reaction. With the amount of
RESULTS AND DISCUSSION
In the initial catalytic activity experiments, different
solvents were screened for aza-Michael reactions. Herein
the reaction of aniline and acrylonitrile was selected as
model (Scheme II). The results are summarized in Table 1.
It was shown that aza-Michael reactions could proceed ef-
fectively in polar organic solvents, for example enthanol
and acetonitrile (entries 2, 3). The chemical industry is un-
der considerable pressure to replace many of the volatile
organic compounds (VOCs) that are currently used as sol-
vents in organic synthesis. As a clean and cheap solvent, it
Aza-Michael addition of aniline to acry-
lonitrile in the presence of [DDPA][HSO4]
Scheme II
Fig. 1. Reusability of [DDPA] [HSO4].

Ionic Liquid Promoted Aza-Michael Reaction
J. Chin. Chem. Soc., Vol. 57, No. 6, 2010 1223

1224 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Liu et al.
[DDPA][HSO4] increased, a ramp in the yield was clearly
observed. The optimum amount of [DDPA][HSO4] was 1
mmol (10 mol% based on aniline) (entry 3), and increasing
the amount of catalyst beyond this led to no substantial
improvement in the yield.
amined aryl amines underwent addition with a,b-unsatu-
rated compounds successfully to give the corresponding
products in moderate to excellent yields. Anilines with
both electron donating groups like CH3, OCH3 and electron
withdrawing groups like Cl, Br reacted smoothly under the
present conditions providing high yields of desired adduct.
Even 3-nitroaniline, which has a strong electron withdraw-
ing group, still afforded the expected compound in moder-
ate yield (entry 14). Ortho, meta and para substituents on
aniline were also well tolerated. Meanwhile, the addition of
secondary amine such as N-methylaniline gived high yield
(entry 15). Furthermore, the reaction using sterically chal-
lenging a-naphthyl amine as nucleophile also proceeded
smoothly (entry 16). Compared to the classical aza-Mi-
chael method, one additional important feature of the
present protocol is the ability to tolerate variation in all
components simultaneously.
Compare with traditional solvents and catalysts, ionic
liquids are easily reused, which is superior to the conven-
tional solvents and catalysts. When optimizing the reaction
condition, the recycling performance of [DDPA][HSO4] in
the same model aza-Michael reaction was investigated. Af-
ter the reaction, the products were separated from the cata-
lytic system by extraction with ethyl acetate. The aqueous
layer (containing the catalyst) was reused in the next run
without further purification. As shown in Fig. 1, the cata-
lyst could be reused at least five times without significant
decrease in catalytic activity.
With optimize conditions in hand we decided to ex-
plore the scope of this method. The structurally diverse aro-
matic amines were chosen to react with a,b-unsaturated
compounds in the presence of 10 mol% [DDPA][HSO4] at
room temperature to give the corresponding b-amino com-
pounds and the results are summarized in Table 3. All ex-
In conclusion, we have described an efficient proto-
col for the aza-Michael addition of aromatic amines with
a,b-unsaturated compounds catalyzed by the function-
alized ionic liquid, [DDPA][HSO4] to produce b-amino
compounds. High yields of the products, short reaction

Ionic Liquid Promoted Aza-Michael Reaction
J. Chin. Chem. Soc., Vol. 57, No. 6, 2010 1225
3. Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117.
4. Juaristi, E. Enantioselective Synthesis of b-Amino Acids;
Wiley-VCH: New York, 1997.
times, mild reaction conditions and simple experimental
procedure make this protocol complementary to the exist-
ing methods. Further, the catalyst can be reused without
obvious loss of the catalytic activity.
5. Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983.
6. Hagiwara, E.; Fujii; A.; Sodeoka, M. J. J. Am. Chem. Soc.
1998, 120, 2474.
EXPERIMENTAL
7. Drury, W. J.; Ferraris, D.; Cox, C.; Yong, B.; Leckta, T. J.
Am. Chem. Soc. 1998, 120, 11006.
Materials and Methods
Melting points were determined on a Thomas Hoover
capillary apparatus and were uncorrected. The IR spectra
were recorded with a Bomem Michelson model 102 FTIR.
1H NMR spectra were recorded on Bruker DRX (500 MHz)
spectrometer. Elemental analyses were performed on a
Yanagimoto MT3CHN recorder. Mass spectra were ob-
tained with automated FININIGAN Trace Ultra-Trace
DSQ GC/MS spectrometer. All starting chemicals (AR
grade) were purchased from commercial suppliers and
used without further purification.
8. Surendra, K.; Srilakshmi, N. K.; Sridhar, R.; Rao, K. R. Tet-
rahedron Lett. 2006, 47, 2125.
9. Jung, M. E. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I.; Eds.; Pergamon: Oxford, 1991; Vol. 4, p 30.
10. Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
11. Luo, H.; Kang, Y.; Nie, H.; Yang, L. J. Chin. Chem. Soc.
2009, 56, 186.
12. Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
2000, 122, 8180.
13. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int.
Ed. 1998, 37, 1044.
14. Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Pergamon: New York, 1992; p 114.
The functionalized ionic liquid [DDPA][HSO4] was
prepared by the procedures given in Refs.45
15. Perez, M.; Pleixates, R. Tetrahedron 1995, 51, 8355.
16. Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.;
Gyoung, Y. S.; Yamamoto, Y. J. Org. Chem. 1997, 62, 6274.
17. Fadini, L.; Togni, A. Chem. Commun. 2003, 30.
18. Loh, T. P.; Wie, L. L. Synlett 1998, 975.
19. Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri,
L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052.
20. Matsubara, S.; Yashioka, M.; Utimoto, K. Chem. Lett. 1994,
827.
General experimental procedures
To a round-bottomed flask charged with aromatic
amine (10 mmol), a,b-unsaturated compound (12 mmol) in
10 mL of water was added [DDPA][HSO4] (1 mmol) under
stirring. The mixture was then stirred for a certain time at
room temperature. The progress of the reaction was moni-
tored by TLC. After completion of the reaction, the mixture
was extracted with ethyl acetate. The organic layer was
separated and washed with brine. The aqueous layer (con-
taining the catalyst) could be reused directly in the next run
without further purification. The organic phase was then
dried (Na2SO4), filtered, and the solvent was removed un-
der vacuum. The crude product was purified by passing
through a column of silica gel using ethyl acetate-n-hexane
as the eluent. All products were known compounds, which
21. Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002, 43,
3891.
22. Xu, L. W.; Xia, C. G. Tetrahedron Lett. 2004, 45, 4507.
23. Jenner, G. Tetrahedron Lett. 1995, 36, 233.
24. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
25. Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 720.
26. Azizi, N.; Saidi, M. R. Tetrahedron 2004, 60, 383.
27. Yang, L.; Xu, L. W.; Xia, C. G. Tetrahedron Lett. 2005, 46,
3279.
1
were characterized by IR and H NMR spectra data and
28. Lee, A.; Lin, M.; Lin, C.; Chang, Y. J. Chin. Chem. Soc.
2010, 57, 795.
their mps compared with literature reports.
29. Shaikh, N. S.; Deshpande, V. H.; Bedekar, A. V. Tetrahedron
2001, 57, 9045.
ACKNOWLEDGEMENTS
Financial support from National Basic Research Pro-
gram of China is gratefully acknowledged.
30. Mayur, J. B.; Nitin, S. N.; Sachin, R. J.; Bhange, B. M. Catal.
Comm. 2008, 9, 1189.
31. Ai, X.; Wang, X.; Liu, J.-M.; Ge, Z.-M.; Cheng, T.-M.; Li,
R.-T. Tetrahedron 2010, 66, 5373.
Received July 8, 2010.
32. Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.
Chem. Lett. 2003, 32, 988.
REFERENCES
33. Kantam, M. L.; Neeraja, V.; Kavita, B.; Neelima, B.;
Chaudhuri, M. K.; Hussain, S. Adv. Synth. Catal. 2005, 347,
763.
1. Surendra, K.; Srilakshmi, N. K.; Sridhar, R.; Rao, K. R. Tet-
rahedron Lett. 2006, 47, 2125.
2. Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603.

1226 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Liu et al.
34. Xu, L. W.; Li, J. W.; Zhou, S. L.; Xia, C. G. New. J. Chem.
2004, 28, 183.
40. Fang, D.; Luo, J.; Zhou, X.; Ye, Z.; Liu, Z. J. Mol Catal. A
2007, 274, 208.
35. Chaudhuri, M. K.; Hussain, S.; Kantam, M. L.; Neelima, B.
Tetrahedron Lett. 2005, 46, 8329.
41. Fang, D.; Liu, Z.; Zhou, X. Chin. Appl. Chem. 2007, 24, 85.
42. Fang, D.; Luo, J.; Zhou, X.; Ye, Z.; Liu, Z. Ind. Eng. Chem.
Res. 2006, 45, 7982.
36. Garcia, M. T.; Gathergood, N.; Scammells, P. J. Green Chem.
2005, 5, 9.
43. Fang, D.; Gong, K.; Shi, Q.; Liu, Z. Catal. Commun. 2007, 8,
1463.
37. Gathergood, N.; Garcia, M. T.; Scammells, P. J. Green Chem.
2004, 6, 166.
44. Fang, D.; Cheng, J.; Gong, K.; Shi, Q.; Liu, Z. Catal. Lett.
2008, 121, 255.
38. Wasserscheid, P.; Hal, R.; Bösmann, A. Green Chem. 2002,
4, 400.
45. Fang, D.; Fei, Z. G.; Liu, Z. Catal. Commun. 2009, 10, 1267.
39. Fang, D.; Luo, J.; Zhou, X.; Liu, Z. Catal Lett. 2007, 116, 76.