Tandem bis-aza-Michael addition reaction of amines in aqueous medium promoted by polystyrenesulfonic acid

Article abstract of DOI:10.1016/j.tetlet.2007.10.008

An efficient and environmentally benign tandem bis-aza-Michael addition of amines catalyzed by polystyrenesulfonic acid (PSSA) is described. This operationally simple high yielding microwave assisted synthetic protocol proceeded in water in the absence of any organic solvent.

Full text of DOI:10.1016/j.tetlet.2007.10.008

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8735–8738
Tandem bis-aza-Michael addition reaction of amines in aqueous
medium promoted by polystyrenesulfonic acid
Vivek Polshettiwar and Rajender S. Varma*
Sustainable Technology Division, National Risk Management Research Laboratory,
US Environmental Protection Agency, 26 W. Martin Luther King Dr., MS 443, Cincinnati, OH 45268, USA
Received 17 September 2007; revised 1 October 2007; accepted 2 October 2007
Available online 6 October 2007
Abstract—An efficient and environmentally benign tandem bis-aza-Michael addition of amines catalyzed by polystyrenesulfonic
acid (PSSA) is described. This operationally simple high yielding microwave assisted synthetic protocol proceeded in water in
the absence of any organic solvent.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
sive and toxic catalyst, and harsh reaction conditions.
Recently, Ranu and Banerjee have developed an aque-
ous protocol for the aza-Michael reaction without using
any catalyst.9 However, the protocol was restricted to
only aliphatic amines as aromatic amines do not under-
go reaction under those conditions.
The development of new methodologies aimed at
improving synthetic efficiency is an important goal in
contemporary organic synthesis. A domino process,
which involves several bond-forming reactions in a sin-
gle manipulation, represents an attractive strategy in
the facile assembly of molecular architecture. These
operationally simple processes are atom economic, and
minimize the generation of chemical waste and the use
of energy.1 In this context, aza-Michael addition is an
important class of carbon–nitrogen bond-forming reac-
tions, and has been intensively explored and demon-
strated to be a powerful tool in organic synthesis.
Several methods have been developed for Michael addi-
tion using a variety of reagents such as various Lewis
acids, Cu(acac)2/ionic liquid, and boric acid.2 While
most of the aza-Michael additions are performed in
organic solvents, increasingly the focus is shifting to
reactions in aqueous medium wherein b-cyclodextrin,3
ytterbium triflate,4 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU),5 pyrrolidine–thiourea,6 and surfactant-type
asymmetric organocatalyst (STAO) type catalyst7 have
been used. Although today’s environmental concerns
encourage the development of such greener synthetic
methodology in an aqueous medium,8 many of these
methods suffer from limitations such as the use of expen-
2. Results and discussion
In view of the emerging application of microwave (MW)
chemistry in aqueous reaction medium,10 and in keeping
with our ongoing program on the development of clea-
ner pathways,11 we tried to develop greener conditions
for these reactions. Our recent success in the application
of polystyrenesulfonic acid (PSSA) for various synthetic
protocols in aqueous medium using microwaves11a–c
prompted us to explore the aza-Michael (Scheme 1)
O
O
R2
R1
R2
O
N
H
O
R1 NH2
PSSA/H2O
80 ºC, MW
R1
CN
N
H
CN
R1 - Ph, Cy, 4-ClPh, PhCH2,
Bu, Et
Keywords: Aza-Michael reaction; Polystyrenesulfonic acid (PSSA);
Aqueous medium; Microwave irradiation.
R2 - Me, n-Bu
*
Corresponding author. Tel.: +1 513 487 2701; fax: +1 513 569
7677; e-mail: varma.rajender@epa.gov
Scheme 1. PSSA-catalyzed aza-Michael addition reaction of amines.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.008

8736
V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 8735–8738
O
O
O
O
O
O
H
N
N
N
O
O
O
N
H
O
O
O
O
PSSA/H2O
O
NH2
H2N
80 ºC,MW
CN
N
H
N
NC
N
H
CN
NC
CN
N
NC
CN
Scheme 2. PSSA-catalyzed tandem bis-aza-Michael addition reaction of alkyl diamines.
and tandem bis-aza-Michael (Scheme 2) addition reac-
tions of amines with alkyl acrylate and acrylonitrile.
Table 1. PSSA-catalyzed aqueous aza-Michael addition of amines
with alkyl acrylate using microwaves
Entry
R1
R2
Product
Yielda (%)
95
During initial exploratory reactions, aqueous aza-Mi-
chael addition of aniline with methyl acrylate under
MW irradiation condition was studied. We found that
PSSA was the most efficient catalyst for this protocol
in water at 80 °C. Using these optimized reaction condi-
tions, the scope and efficiency of this aqueous approach
were explored for a wide variety of amines with Michael
acceptors, methyl- and butyl acrylate (Table 1), and with
acrylonitrile (Table 2).
O
O
O
O
1
Ph
Me
N
H
O
Me
2
3
4
5
6
Ph
Bu
Me
Bu
Me
Bu
92
93
92
92
92
N
H
O
Bu
Cy
Aromatic amines bearing various functional groups
gave excellent results in terms of yield and purity. These
reactions also get completed under conventional heating
conditions in an oil bath at 100 °C with comparable
yields but requires extended periods of time, 2–3 h. In
order to study the versatility of this protocol, few exam-
ples of aliphatic amines were also examined using simi-
lar reaction conditions as applied to aromatic amines
and excellent yields of Michael products were obtained.
N
H
O
Me
Cy
N
H
O
Bu
Cl
Cl
O
4-ClPh
4-ClPh
N
H
O
Me
O
Table 2. PSSA-catalyzed aqueous aza-Michael addition of amines
with acrylonitrile using microwaves
N
H
O
Bu
Entry
1
R1
Product
Yielda (%)
90
Me
O
7
8
PhCH2
PhCH2
Bu
Me
Bu
Me
Bu
Me
Bu
88
89
90
90
92
90
Ph
NC
N
H
NH
NH
O
Bu
O
2
3
Cy
88
90
NC
O
O
N
H
O
9
Me
Bu
Bu
N
Cl
H
4-ClPh
NC
NC
N
H
O
O
O
10
11
Bu
Bu
N
O
H
N
H
4
5
PhCH2
Bu
85
88
86
Et
Et
N
Me
Bu
NC
NC
O
O
N
H
H
H
N
12
Et
Et
N
6
Et
H
a GC yields.
a GC yields.

V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 8735–8738
8737
Table 3. PSSA-catalyzed aqueous tandem bis-aza-Michael addition of
alkyl diamine with methyl acrylate (A) and acrylonitrile (B) using
microwaves
It is noteworthy to mention that these reactions are
working well in an aqueous medium without using any
phase-transfer catalyst (PTC). This may be due to selec-
tive absorption of microwaves by diamines, alkyl acry-
lates, and a polar aqueous medium,12 which accelerate
the reaction even in the absence of PTC. Also, we
observed that the catalyst PSSA can be reused without
any change in the reactivity (not shown).
Entry Diamine
Moles of Product
Yield
(%)
(A) (B)
O
H
NH2
NH2
N
O
1
2
4
—
—
95
90
O
O
N
H
H2N
O
O
O
O
Substituted diamines are an important class of com-
pounds extensively used for preparation of hybrid mate-
rials13 and functional nano-structured materials.14
To further explore the feasibility of this catalytic system,
we studied the tandem bis-aza-Michael addition reaction
of alkyl diamine with methyl acrylate (A) and acryloni-
trile (B) (Scheme 2) and the results are summarised in
Table 3.
N
2
N
H2N
O
O
O
O
H
N
NH2
NH2
NC
NC
3
—
—
2
4
92
89
N
CN
H2N
H
CN
N
4
N
H2N
A variety of bis-aza-Michael addition products of di-
amine were obtained readily depending upon the relative
mole ratio of the reactants. One mole equivalent of di-
amine with two mole equivalents of Michael acceptor
afforded disubstituted diamines (entries 1, 3, 5, 7, 9
and 11), without any tri or tetrasubstituted products,
whereas using four equivalents of Michael acceptor gave
exclusively the tetrasubstituted diamine product (entries
2, 4, 6, 8, 10 and 12).
NC
CN
O
NH2
O
O
N
H
NH
5
2
4
—
—
94
90
NH2
O
O
O
O
O
O
NH2
N
O
6
In conclusion, we have demonstrated a sustainable and
operationally simple aza-Michael MW-assisted protocol
using PSSA, which proceeds efficiently in an aqueous
medium without the use of an organic solvent. Also
the use of polymer supported, relatively low toxic, and
inexpensive PSSA as a catalyst renders this method
greener and eco-friendly.
N
NH2
O
O
NH2
NC
NC
N
7
—
—
2
2
92
90
96
H
NH
NH2
NC
NC
N
3. Experimental
NH2
CN
8
4
All starting materials were used as obtained. TLC (silica
gel; 20% EtOAc/hexane) and GC were used to monitor
the reactions. The crude products were identified by
GC–MS qualitative analysis using a GC system with a
mass selective detector. The identities were further con-
N
NH2
CN
O
NH2
O
O
N
H
1
firmed by H and 13C NMR spectra that were recorded
NH
9
—
NH2
O
in chloroform-d (CDCl3) with TMS as internal reference
using a 300 MHz NMR spectrometer.
O
O
O
O
Typical experimental procedure using MW heating: The
amines (1 mmol) and alkyl acrylate, or acrylonitrile
(1.2 mmol) were placed in a 10 mL crimp-sealed thick-
walled glass tube equipped with a pressure sensor and a
magnetic stirrer. The contents were dissolved in 20%
PSSA solution in water (one time the weight of amines)
and the reaction tube was placed inside the cavity of a
CEM Discover focused microwave synthesis system,
80 + 5 °C (temperature monitored by a built-in infrared
sensor), power range 40–140 W and pressure 40–70 psi
for 10–15 min. After completion of the reaction, products
were extracted with ethyl acetate and washed with sodium
bicarbonate solution. After concentration in vacuum, the
crude product was subjected to flash column chromatog-
raphy for further purification.
O
O
NH2
N
O
O
10
4
—
90
NH2
N
NH2
NC
NC
N
11
—
—
2
4
93
90
H
NH
NH2
NC
NC
NH2
N
CN
12
N
NH2
CN

8738
V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 8735–8738
2. Khan, A. T.; Parvin, T.; Gazi, S.; Choudhury, L. H.
Tetrahedron Lett. 2007, 48, 3805, and references cited
therein.
3. Surendra, K.; Krishnaveni, N. S.; Sridhar, R.; Rao, R. K.
Tetrahedron Lett. 2006, 47, 2125.
4. Ding, R.; Katebzadeh, K.; Roman, L.; Bergquist, K.;
Lindstrom, U. M. J. Org. Chem. 2006, 71, 352.
5. Yeom, C.; Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63,
904.
6. Cao, Y.-J.; Lai, Y.-J.; Wang, X.; Li, Y.-J.; Xiao, W.-J.
Tetrahedron Lett. 2007, 48, 21.
7. Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem.
Commun. 2006, 3687.
8. Varma, R. S. Org. Chem. Highlights 2007, Clean Chemical
Synthesis in Water. http://www.organic-chemistry.org/
Highlights/2007/01February.shtm.
For bis-aza-Michael reaction of diamines, a similar pro-
cedure was followed with the following mole ratios: for
disubstituted diamine, diamine (1 mmol), alkyl acrylate
or acrylonitrile (2 mmol), 10–15 min reaction time; for
tetrasubstituted diamine, diamine (1 mmol), alkyl acry-
late or acrylonitrile (4 mmol), 30 min reaction time.
Typical experimental procedure under conventional heat-
ing: The amines (1 mmol) and alkyl acrylate or acryloni-
trile (1.2 mmol) were placed in a 10 mL glass tube,
followed by addition of catalyst PSSA (20%) (one time
the weight of amines). The capped tube was then heated
at 100 °C for 2–3 h. After completion of the reaction,
products were extracted with ethyl acetate and washed
with sodium bicarbonate solution. After concentration
in vacuum, the crude product was subjected to flash
column chromatography for further purification.
9. Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48,
141.
10. (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107,
2563; (b) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 5, 68.
11. (a) Polshettiwar, V.; Varma, R. S. J. Org. Chem. 2007, 72,
7420; (b) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett.
2007, 48, 5649; (c) Polshettiwar, V.; Varma, R. S.
Tetrahedron Lett. 2007, 48, 7343; (d) Ju, Y.; Kumar, D.;
Varma, R. S. J. Org. Chem. 2006, 71, 6697; (e) Ju, Y.;
Varma, R. S. J. Org. Chem. 2006, 71, 135; (f) Ju, Y.;
Varma, R. S. Org. Lett. 2005, 7, 2409; (g) Wei, W.; Keh,
C. C. K.; Li, C.-J.; Varma, R. S. Clean Tech. Environ.
Policy 2005, 7, 62; (h) Kumar, D.; Chandra Sekhar, K. V.
G.; Dhillon, H.; Rao, V. S.; Varma, R. S. Green Chem.
2004, 6, 156; (i) Kumar, D.; Reddy, V. B.; Mishra, B. G.;
Rana, R. K.; Nadagouda, M. N.; Varma, R. S. Tetra-
hedron 2007, 63, 3093; (j) Strauss, C. R.; Varma, R. S. Top.
Curr. Chem. 2006, 266, 199.
Acknowledgment
Vivek Polshettiwar was supported, in part, by the Post-
graduate Research Program at the National Risk Man-
agement Research Laboratory administered by the Oak
Ridge Institute for Science and Education through an
interagency agreement between the US Department of
Energy and the US EPA.
References and notes
1. (a) Varma, R. S. In Green Chemistry: Challenging
Perspectives; Tundo, P., Anastas, P. T., Eds.; Oxford
University Press: Oxford, 2000; pp 221–244; (b) Anastas,
P. T.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University Press: Oxford, 2000.
12. Loupy, A.; Varma, R. S. Chim. Oggi 2006, 24, 36.
13. Polshettiwar, V.; Molnar, A. Tetrahedron 2007, 63, 6949.
14. Polshettiwar, V.; Hesemann, P.; Moreau, J. J. E. Tetra-
hedron 2007, 63, 6784.