Aqueous aza-michael reaction of conjugated alkenes: Toward spermine

Article abstract of DOI:10.1080/00397910903320647

An aqueous aza-Michael reaction is efficiently achieved with excellent conversions without any additives. The method works very well on a molar scale with selectively for aliphatic amines. An intermediate for spermine is also made by this green process.

Full text of DOI:10.1080/00397910903320647

Synthetic Communications1, 40: 2857–2863, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903320647
AQUEOUS AZA-MICHAEL REACTION OF
CONJUGATED ALKENES: TOWARD SPERMINE
Jigar H. Joshi, Akeel S. Saiyed, and Ashutosh V. Bedekar
Department of Chemistry, Faculty of Science, Maharaja Sayajirao
University of Baroda, Vadodara, India
An aqueous aza-Michael reaction is efficiently achieved with excellent conversions without
any additives. The method works very well on a molar scale with selectively for aliphatic
amines. An intermediate for spermine is also made by this green process.
Keywords: Aqueous medium; aza-Michael reaction; green chemistry; spermine
INTRODUCTION
The Michael reaction of conjugated alkenes is an important process extensively
used in synthetic organic chemistry.[1] Its aza version, with an amine as the nucleo-
phile, is an important method for the preparation of several biologically useful mole-
cules such as b-amino alcohols or corresponding carbonyl compounds, b-lactam
antibiotics, and other nitrogen-bearing entities.[2]
Performing organic reactions in an environmentally friendly way using
so-called green chemistry has become a conscious goal for many research labora-
tories. Several guidelines have been put in place by chemists with this ideology. Elim-
inating use of hazardous solvents, elevated reaction temperatures, and unnecessary
additives along with synthetic planning of atom economy are the key steps of green
synthesis that do not compromise the basic requirements of chemical conversions.
The aza-Michael reaction has been accomplished with several additives to increase
its efficiency. Among them are variety of Lewis acids such as InCl3,[3] Bi(NO3)2
and Bi(OTf)2,[4] PdCl2(MeCN)2,[5] Yb(OTf)2,[6] LiClO4,[7] FeCl3,[8] SmI2,[9] ceric
ammonium nitrate,[10] stoichiometric amounts of AlCl3=TiCl4=SnCl4,[11] clay,[12] het-
erogeneous solid salts,[13] ionic liquids with Cu(acac)2 or quaternary ammonium
salts,[14] b-cyclodextrin,[15] polystyrenesulfonic acid,[16] 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU),[17] some organic promoters,[18] and sodium dodecylsulfate.[19]
The use of these additives and organic solvents along with much higher reaction tem-
peratures do not agree with the main principles of green synthesis. In this communi-
cation, we present the results of our study that totally eliminate use of any additive
Received June 15, 2009.
Address correspondence to Ashutosh V. Bedekar, Department of Chemistry, Faculty of Science,
Maharaja Sayajirao University of Baroda, Vadodara 390 002, India. E-mail: avbedekar@yahoo.co.in
2857

2858
J. H. JOSHI, A. S. SAIYED, AND A. V. BEDEKAR
Scheme 1. Aqueous aza-Michael reaction of conjugated alkenes.
or organic solvent for this key reaction and demonstrate that the conversion can be
efficiently carried out in pure water at room temperature (Scheme 1).
RESULTS AND DISCUSSION
The possibility of using pure water as solvent for organic reactions has become
a prime choice because it is environmentally safe and has almost unlimited avail-
ability (hence low cost) and because it has some of its unique features.[20] Mention
of the Michael reaction conducted in an aqueous medium in the literature is rela-
tively limited,[21] but some studies have used elevated reaction temperatures and pro-
moters. In the present efforts, we carried out reaction of aliphatic amines with
acrylonitrile or acrylates as Michael acceptors in water at ambient conditions. The
careful analysis of the reaction mixture revealed that the reaction was complete
within minutes, and simple reaction workup gave us samples of pure products in
most cases. The results are summarized in Table 1, where a series of compounds were
Table 1. Michael reaction of amines with acceptors in water at room temperature
No.
1
Amine
Alkene (eq.)
Product
Time (h) Yield (%)
A (1.1)
0.5
97
with b-cyclodextrin, H2O, rt[15]
6
3
84
82
with clay, EDC, 80 ꢀC[12]
2
A (1.1)
0.5
91
with LiClO4, neat, 60 ꢀC[7]
with CAN, H2O, rt[10b]
1
1
80
95
86
98
with b-cyclodextrin, H2O, rt[15]
with DBU (0.5 eq.), neat, rt[17]
6
24
3
A (3.0)
0.5
20
87
with CAN, H2O, rt[10b]
80 (monoþdi)
(Continued )

AZA-MICHAEL REACTION OF CONJUGATED ALKENES
2859
Table 1. Continued
No.
4
Amine
Alkene (eq.)
A (1.2)
Product
Time (h) Yield (%)
0.5
0.5
81
97
5
A (6.0)
with PSSA, H2O, MW[16]
0.25
0.5
89
83
6
7
A (3.0)
A (3.0)
0.5
0.5
91
85
8
9
B (1.1)
B (2.2)
0.5
91
Notes. A, with acrylonitrile; B, with tert-butyl acrylate.
prepared and show satisfactory spectroscopic data. One can compare our results
without any additive with the reported examples with different promoters.
A controlled experiment with an equimolar mixture of an aromatic amine, an
aliphatic amine, and excess of acrylonitrile under the present condition was run, and
products were carefully separated and analyzed. The aromatic amine remained
unaffected, whereas more nucleophilic aliphatic amine underwent the aza-Michael
reaction selectively (Scheme 2).
The main objective of the reinvestigations of organic transformations from
the point of view of green chemistry will be justifiable only if the reaction can be per-
formed on a large scale. To establish this, we have carried out one representative
conversion, compound 1, at a molar scale and found the consistency in the results
(Scheme 3).
Scheme 2. Selectivity of aliphatic amines in aza-Michael reaction.

2860
J. H. JOSHI, A. S. SAIYED, AND A. V. BEDEKAR
Scheme 3. Multigram experiment of aqueous aza-Michael reaction.
Scheme 4. Synthesis of spermine intermediate.
The group of compounds with more than one amino group, polyamines, is
useful because of their considerable biological activity; one such molecule is sperm-
ine.[22] Spermine is reportedly prepared from the dicyano compound 3 by catalytic
hydrogenation. In the present work, we prepare 3 from 1,4-diaminobutane with 2
equivalents of acrylonitrile (Scheme 4).
Thus, the compound 3, an intermediate of spermine, can be efficiently prepared
by this method.
EXPERIMENTAL
Standard Reaction Condition
For 3-morpholin-4-yl-propionitrile (Table 1, entry 1), a representative reaction,
a mixture of acrylonitrile (3.35 g, 0.063 mol) and morpholine (5.0 g, 0.058 mol) in
water (75 mL) was stirred at room temperature until the reaction was complete (as
monitored by thin-layer chromatography, TLC, at about 0.5 h). The mixture was
extracted with ethylacetate (3 ꢁ 50 mL), dried over anhydrous sodium sulfate, and
concentrated under vacuum to give an oil (7.8 g, 97%), which was identified by its
H NMR and infrared (IR) analysis.
H NMR (CDCl3, 400 MHz): d 2.49–2.53 (m, 6H), 2.66–2.70 (t, J ¼ 7.44 Hz, 2
H), 3.72 (t, J ¼ 4.72 Hz, 4 H). IR (neat) t 3585, 2956, 2855, 2248, 1456, 1274, 1143,
1070, 799, 764 cmꢂ1
.
Spectral Data of Compounds
3-Piperidine-1-yl-propionitrile (Table 1, entry 2). 1H NMR (CDCl3,
400 MHz) d 1.40–1.46 (m, 2H), 1.56–1.61 (m, 4H), 2.41–2.44 (t, J ¼ 10.32, 4H),
2.48–2.51 (m, 2H), 2.65–2.69 (m, 2H). IR (neat) t 2936, 2853, 2248, 1443, 1190,
1042, 754 cmꢂ1
.

AZA-MICHAEL REACTION OF CONJUGATED ALKENES
2861
3-[4-(2-Cyanoethyl)piperazine-1-yl]propionitrile (Table 1, entry 3). 1H
NMR (CDCl3, 400 MHz) d 2.48–2.54 (m, 12H), 2.68–2.71 (m, 4H). IR (KBr) t
3378, 2938, 2820, 2248, 1435, 1190, 1045, 866, 744 cmꢂ1
.
3-Diethylaminopropionitrile (Table 1, entry 4). 1H NMR (CDCl3,
400 MHz) d 1.02–1.06 (t, J ¼ 14.32 Hz, 6H), 2.42–2.46 (t, J ¼ 14.24 Hz, 2H),
2.53–2.58 (m, 4H), 2.78–2.82 (t, J ¼ 14.2 Hz, 2H). IR (KBr) t 3059, 2860, 2248,
1420, 1262, 1077, 744 cmꢂ1
.
3-[{2-[Bis-(2-cyanoethyl)amino]ethyl}-(2-cyanoethyl)amino]propionitrile
(Table 1, entry 5). 1H NMR (CDCl3, 400 MHz) d 2.53–2.56 (t, J ¼ 13.2 Hz, 8H),
2.77 (s, 4H), 2.93–2.96 (t, J ¼ 12.8 Hz, 8H). IR (KBr) t 2943, 2808, 2248, 1650,
1375, 1285, 1166, 1052, 901, 794 cmꢂ1
.
3-[Benzyl-(2-cyanoethyl)amino]propionitrile (Table 1, entry 6). 1H
NMR (CDCl3, 400 MHz) d 2.43–2.47 (t, J ¼ 13.72 Hz, 4H), 2.88–2.91 (t,
J ¼ 13.68 Hz, 4H), 3.57 (s, 2H), 7.28–7.35 (m, 5H). IR (KBr) t 3062, 2930, 2247,
1630, 1420, 1262, 1077, 970, 829, 736 cmꢂ1
.
3-[(2-Cyanoethyl)-(2-hydroxypropyl)amino]propionitrile (Table 1, entry
7). 1H NMR (CDCl3, 200 MHz) d 1.81 (s, 1H), 2.51–2.57 (t, J ¼ 13.2 Hz, 4H),
2.71–2.77 (t, J ¼ 11.2 Hz, 4H), 3.61–3.69 (m, 2H). IR (KBr) t 3500, 2852, 2248,
1634, 1463, 1417, 1060, 960 cmꢂ1
.
tert-Butyl(3-diethylamino)propionate (Table 1, entry 8). 1H NMR
(CDCl3, 400 MHz) d 1.02–1.04 (t, J ¼ 14.28 Hz, 6H), 1.46 (s, 9H), 2.33–2.37 (t,
J ¼ 15 Hz, 2H), 2.48–2.53 (m, 4H), 2.74–2.78 (t, J ¼ 15 Hz, 2H). IR (neat) 3405,
2912, 2833, 1727, 1460, 1415, 1362, 1315, 1265, 1150, 833, 746 cmꢂ1
.
3-[4-(2-tert-Butyloxycarbonylethyl)piperazin-1-yl]propionic acid tert-
butyl ester (Table 1, entry 9). 1H NMR (CDCl3, 400 MHz) d 1.46 (s, 18H),
2.77–2.86 (m, 12H), 2.55 (s, 4H). IR (KBr) t 2823, 1725, 1462, 1410, 1368, 1324,
1211, 1059, 796, 758 cmꢂ1
.
1
3-[4-(2-Cyanoethylamino)butylamino]propionitrile (Scheme 4). H NMR
(CDCl3, 400 MHz) d 1.52–1.56 (m, 4H), 1.59 (s, 2H), 2.51–2.54 (t, J ¼ 13.2 Hz, 4H),
2.63–2.68 (m, 4H), 2.91–2.94 (t, J ¼ 13.2 Hz, 4H). IR (neat) t 3095, 2980, 2248, 1468,
1425, 1362, 1120, 1050, 758 cmꢂ1
.
CONCLUSION
In this short communication, we report the aza-Michael reaction of amines
with conjugate alkenes in water without any additives at ambient conditions.
Furthermore, we have prepared an intermediate of spermine and showed that the
process can be scaled up to a molar scale with excellent conversion.

2862
J. H. JOSHI, A. S. SAIYED, AND A. V. BEDEKAR
ACKNOWLEDGMENTS
We are grateful to Gujarat Narmada Fertilizer Corporation (Bharuch) for the
financial support and to Prof. B. V. Kamath for his constant encouragement as well
as providing laboratory facilities.
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