Iodine-alumina catalyzed Aza- michael addition under solvent free conditions

Article abstract of DOI:10.2174/157017809790442961

An efficient aza-Michael addition of amines to a variety of activated olefins was carried out under solvent free conditions using iodine-alumina as a catalyst at room temperature or under microwave irradiation (in case of solid) in high yield. 2009 Bentham Science Publishers Ltd.

Full text of DOI:10.2174/157017809790442961

654
Letters in Organic Chemistry, 2009, 6, 654-658
Iodine-Alumina Catalyzed Aza- Michael Addition under Solvent Free
Conditions
Monmi Saikia, Dwipen Kakati, Maria Stalin Joseph and Jadab Chandra Sarma*
Natural Products Chemistry Division, North-East Institute of Science and Technology, Jorhat-785006, Assam, India
Received February 02, 2009: Revised August 27, 2009: Accepted September 16, 2009
Abstract: An efficient aza-Michael addition of amines to a variety of activated olefins was carried out under solvent free
conditions using iodine-alumina as a catalyst at room temperature or under microwave irradiation (in case of solid) in high
yield.
Keywords: Iodine, alumina, aza-michael, amine, olefin, microwave.
INTRODUCTION
synthetic methodologies and consequently a detailed re-
examination of the most important synthetic processes is also
needed [23]. Recently, Ranu et al. [7] have reported a
solvent free, catalyst free procedure for aza-Michael addition
of amines but only four amines were tested with minimum
cross checking of the substrates. Because of our continued
interest in the use of molecular iodine as a catalyst in organic
transformations [24] and also observing the wide spread
application of molecular iodine in various reactions of
synthetic organic chemistry including Michael reaction of
indoles and pyrrols with different olefins [25], we studied its
application as a catalyst for aza-Michael addition reaction.
We found it to efficiently catalyze the aza-Michael addition
at room temperature in solvent less condition when
supported over alumina within a very short reaction period.
In solvent less reactions elimination of the use of organic
solvents minimize the generation of waste, which is one of
the requirements of sustainable chemistry.
The modified form of Michael reaction for conjugate
addition of amines to electron deficient alkene is an
important class of carbon-nitrogen bond forming reaction in
organic synthesis and is usually known as aza-Michael
addition [1]. It has been demonstrated to be a powerful tool
in organic synthesis owing to its applicability in the
synthesis of ꢀ-amino ketones, esters, nitriles or amides. ꢀ-
Amino carbonyl compounds are widely used intermediates
for the synthesis of a variety of bioactive natural products,
antibiotics and heterocyclic compounds [2]. The
development of catalysts and novel methodologies for the
synthesis of these compounds is becoming an attractive area
of focus in recent years [3-7]. Though conventional method
of preparation of ꢀ-amino carbonyl compounds is via
Mannich reaction, yet its utility is restricted due to several
shortcomings like low yield, harsh reaction condition, long
reaction time etc. Widely used method for this reaction is
therefore the aza-Michael addition with a suitable catalyst.
In a set of preliminary experiments diethanol amine was
treated with methyl acrylate in equimolar amount at room
temperature with different catalysts like I2, Al2O3 (neutral),
Al2O3 (acidic), Al2O3 (basic), I2-Al2O3 (neutral), I2-Al2O3
(acidic), I2-Al2O3 (basic) and without any catalyst to get
products as plotted in Fig. (1) below. After 10 minutes the
reaction with I2-acidic alumina [1:2 w/w (alkene : catalyst)]
gives 76% product with 20% recovery of the starting amine
without any byproduct.
RESULTS AND DISCUSSION
Several research groups have reported many different
catalysts for this aza-Michael addition. But most of these
catalysts are transition metal salts or other metal salts like
InCl3 [8], CeCl3.7H2O-NaI [9], Yb(OTf)3 [10], Bi(NO3)3
[11], Cu-salts [12], LiClO4 [13], SmI2 [14], FeCl3.7H2O [15],
CrCl3.6H2O [15], SnCl4 [15], Cerium(IV) ammonium nitrate
[16] etc. which are not recommendable in green chemistry
protocol. Therefore development of efficient processes using
metal-free catalysts has been drawing much attention in
recent decades [17]. Various reports are coming on the use of
catalysts like clay [18], silica gel [19], boric acid [20],
cellulose supported Cu(0) [21], basic ionic liquid [22],
bromodimethylsulfonium bromide [4] etc for this reaction.
O
O
(EtOH)2NH +
conditions
(EtOH)2N
OMe
OMe
Scheme 1. Aza-Michael addition of diethanolamine to methyl
acrylate.
As emerges from the Fig. (1) below, catalysis with iodine
impregnated alumina allowed the isolation of the product in
reasonable yields while the reaction without any catalyst
turned out to be very slow.
Due to growing environmental regulations, the chemical
industry needs the development of more eco compatible
Therefore, the optimum condition for this transformation
is established as I2-Al2O3 (acidic) catalyst under solvent free
condition. We varied the amount of catalyst loading in the
reaction and there was no any improvement in yield with
decrease or increase of loading.
*Address correspondence to this author at the Natural Products Chemistry
Division, North-East Institute of Science and Technology, Jorhat-785006,
Assam, India; Fax: 913762370011; E-mail: sarmajc@rrljorhat.res.in
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Iodine-Alumina Catalyzed Aza- Michael Addition
Letters in Organic Chemistry, 2009, Vol. 6, No. 8
655
Fig. (1). Effect of variation in catalyst.
Table 1. I2-Al2O3 Catalyzed Aza-Michael Addition of Amines to Activated Alkenes
EWG
EWG
I2-Al2O3
R.T.
RNH2
+
RNH
Time
(min)
rt/mw
Yieldb
(%)
rt/mw
Ratio
(A:B)
Entry
Amines (A)
Alkenes (B)
Producta
Ref
O
O
HOCH2CH2NH2
3:1
3.1
1
2
15/NAc
15/NA
82
86
HOCH2CH2NH
OMe
CN
OMe
CN
[26]
[5]
HOCH2CH2NH
O
O
NH2
3:1
3
30/NA
81
NH
OMe
OMe
CN
NH
CN
3:1
3:1
3:1
4
5
6
30/NA
30/NA
15/NA
94
87
88
[6]
NH2
NH
OMe
O
O
OMe
NH
CN
CN
O
O
OMe
O
MeO
MeO
NH2CH2CH2NH2
1:4
7
15/NA
71/70
[27]
NCH2CH2N
OMe
OMe
O
O

656 Letters in Organic Chemistry, 2009, Vol. 6, No. 8
Saikia et al.
(Table 1). Contd…..
Yieldb
Time
(min)
rt/mw
Ratio
(A:B)
Entry
Amines (A)
Alkenes (B)
Producta
Ref
(%)
rt/mw
CN
NC
NC
CN
8
1:4
15/NA
83/ 82
[27]
NCH2CH2N
CN
O
O
(HOCH2CH2)2NH
1:1
1:1
1:1
1:1
1:1
1:1
9
15/NA
15/NA
15/NA
15/NA
89
92
86
96
(HOCH2CH2)2N
OMe
CN
OMe
CN
10
11
12
(HOCH2CH2)2N
O
O
(CH3CH2)2NH
[20]
[7]
(CH3CH2)2N
OMe
CN
OMe
CN
(CH3CH2)2N
O
O
13
14
(CH2=CHCH2)2NH
30/2.0
30/2.0
85/84
75/77
[26]
[26]
OMe
CN
OMe
CN
(CH2=CHCH2)2N
(CH2=CHCH2)2N
O
N
N
N
OMe
1:1
1:1
15
16
15/NA
15/NA
89
87
[13]
[28]
N
H
OMe
O
O
O
CN
1:1
1:1
17
18
15/NA
360/5
89
[13]
[5]
CN
N
N
N
O
O
80d/81e
N
H
OMe
OMe
N
O
81d/80e
80d/80e
[9]
[6]
N
19
20
1:1
1:1
420/4
300/5
O
N
N
CN
CN
O
O
O
N
O
1.2:1
21
30/NA
84
[4]
N
H
OMe
OMe

Iodine-Alumina Catalyzed Aza- Michael Addition
Letters in Organic Chemistry, 2009, Vol. 6, No. 8
657
(Table 1). Contd…..
Time
(min)
rt/mw
Yieldb
(%)
rt/mw
Ratio
(A:B)
Entry
22
Amines (A)
Alkenes (B)
Producta
Ref
O
O
N
O
1:1
1:1
18/NA
15/NA
91
93
[18]
[4]
CN
CN
23
O
N
N
65d/70e
[6]
1:1
24
480/4
N
H
O
N
O
N
aThe products were characterized from their spectral data (IR, 1H NMR, 13C NMR, Mass).
bIsolated pure yield.
cNot applicable.
dStarting recovered.
eMixture of byproducts obtained.
Based on the experience of the preliminary reactions and
having the excellent catalyst system in hand we studied the
aza-Michael addition of three primary, three secondary, two
cyclic and one aromatic amine on three electron deficient
olefins to establish the generality of this method. One
primary diamine was also studied to get excellent yield of
the tetra addition product (Table 1, entry 7 & 8). In case of
primary amines, addition to the ꢀ,ꢁ-unsaturated system gave
rise to both single addition and double addition products, of
which using more than two equivalents of primary amine
minimized the formation of the latter. In most cases
unreacted amines were recovered during purification by
column chromatography.
EXPERIMENTAL
All commercially available chemicals and reagents were
purchased from Aldrich and used without further
purification. IR spectra were recorded on a Perkin-Elmer
1640 FT-IR instrument. The H- and 13C-NMR spectrum
1
were recorded on a Bruker DPX-300 NMR machine. Unless
otherwise specified, CDCl3 was used as solvent. Mass
spectra were recorded with a Bruker Daltonic Data Analysis
2.0 spectrometer. The I2-Al2O3 catalyst was prepared by the
procedure reported in reference 24(b).
Representative Procedure
But when one or both the substrates were solid the
reaction proceeded very slowly at room temperature (entry
18-20 and 24 in Table 1). Therefore we decided to try the
reaction under microwave activation. Activation through
microwave irradiation changed the course of the reaction
dramatically and reduced the reaction time to only a few
minutes. But we faced the problem of getting undesired side
products which may be because of the rapid polymerization
of the olefin under microwave heating. Therefore we limited
the application of microwave only to those reactions that
takes more than 30 minutes for completion at room
temperature.
3-[Bis-(2-Hydroxyethyl)-amino]-propionic acid methyl
ester (Entry 9)
Diethanol amine (0.105 g, 1.0 mmol), methyl acrylate
(0.086 g, 1.0 mmol) and 200 mg 5% I2-Al2O3 was taken in a
10 mL flask and homogenized. The mixture was kept at
room temperature with occasional shaking. After completion
(TLC), EtOAc (10 mL) was added to the reaction mixture
and filtered through a general laboratory filter paper. The
separated catalyst was washed with EtOAc (10 mL). The
combined organic layer was washed with Na2S2O3 solution
(10 mL) followed by water (10 mL). Finally, the separated
organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure. Since there was only a
single product no purification was needed. Yield 0.17 g,
89%.
CONCLUSION
In conclusion, we have reported a new, effective and
environment friendly method for the aza-Michael addition of
a variety of amines with or without microwave irradiation in
solvent less condition. The attractiveness of the procedure
lies in its operational simplicity and very short reaction time.
Further omission of toxic solvents like acetonitrile or
dichloromethane makes this endeavor more advantageous
over the existing ones.
Oily Compound,
1H NMR (300 MHz, CDCl3): ꢃ 3.71 (s, 3H), 3.67-3.60
(overlapping signal, 4H), 2.85 (t, J = 6.3 Hz, 2H), 2.78-2.73
(br s, 2H), 2.68-2.65 (m, 4H), 2.52 (t, J = 6.3 Hz, 2H); 13C
NMR (75 MHz, CDCl3): 173.6, 59.2, 55.7, 51.6, 49.2, 32.3;
IR (CHCl3): ꢄ 3391, 2918, 1729, 1597, 1368, 1084 cm-1; MS
(ESI) m/z: 193.2 (M++2).

658 Letters in Organic Chemistry, 2009, Vol. 6, No. 8
Saikia et al.
Procedure for Microwave Activation
(75 MHz, CDCl3): 135, 119, 118.15, 56.91, 48.38, 16.3; IR
(CHCl3): ꢁ 3079, 2919, 2249, 1643, 1419, 1358, 922, 772
cm-1. MS (ESI) m/z: 151.8 (M++1).
3-Imidazol-1yl-propionic Acid Methyl Ester (Entry 18)
Imidazole 0.1 gm (1.47 mmol), methyl acrylate 0.117 g
(1.47 mmol) and 5% I2-Al2O3 (0.3 g) was taken in a reaction
vessel and homogenized. The mixture was irradiated for 5
min at 200 watt in a Prolabo Microwave Reactor. To the
cooled reaction mixture 10 ml of EtOAc was added and
worked up as reported earlier. After purification by column
chromatography yield was found to be 0.181 g (81%).
ACKNOWLEDGEMENTS
Authors are thankful to the Director, NEIST for
providing the facilities and to Dr N C Barua for constant
encouragement.
Spectral data of compounds not reported in literature are
given below.
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Gummy Compound
1H NMR (300 MHz, CDCl3): ꢀ 7.45-7.27 (m, 5H), 3.66
(s, 3H), 2.90- (m, 4H), 2.82 (t, J = 5.7 Hz, 2H), 2.53 (t, J =
6.5 Hz, 2H), 1.99 (s, 1H); 13C NMR (75 MHz, CDCl3):
172.8, 139.5, 128.4, 128.2, 125.9, 125.6, 51.4, 50.7, 44.6,
35.9, 34.1; IR (CHCl3): ꢁ 3318, 3027, 2951, 1736, 1454,
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Oily Compound
1H NMR (300 MHz, CDCl3): ꢀ 7.30 (d, J = 7 Hz, 2H),
7.26 to 7.20 (overlapping signal 3 H), 2.91(overlapping
signal, 4H), 2.82 (overlapping signal, 2H), 2.51 (t, J = 6.5
Hz, 2H); 13C NMR (75 MHz, CDCl3): ꢀ 139.5, 128.8, 128.7,
128.6, 126.5, 126.4, 118.8, 50.4, 44.9, 36.2, 18.6; IR
(CHCl3): ꢁ 3311, 3027, 2929, 2849, 2247, 1664, 1496, 1454,
1127, 751 cm-1; MS (ESI) m/z: 175.8 (M++1).
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3-[Bis-(2-Hydroxyethyl)-amino]-propionitrile (Entry 10)
Oily Compound
1H NMR (300 MHz, CDCl3): ꢀ 3.65 (t, J = 5 Hz, 4H),
2.90 ( t, J = 6.5 Hz, 2H), 2.71 (t, J = 5 Hz, 4H), 2.54 (t, J =
6.5 Hz, 2H); 13C NMR(75 MHz, CDCl3): 119.5, 59.7, 56,
50.4, 17; IR(CHCl3): ꢁ 3391, 2952, 2249, 1460, 1364, 1046,
771 cm-1; MS (ESI) m/z: 159.6(M++1).
[25]
3-Diallylamino-Propionitrile (Entry 14)
[26]
[27]
[28]
Oily Compound
1H NMR (300 MHz, CDCl3): ꢀ 5.90-5.77 (m, 2H), 5.22
(d, J = 16 Hz, 2H), 5.16 (d, J = 9 Hz, 2H), 3.13(d, J = 6.5 Hz,
4H), 2.80(t, J = 7 Hz, 2H), 2.45(t, J = 7 Hz, 2H); 13C NMR