Aza-michael addition of amines to α,β-unsaturated compounds using molecular iodine as catalyst

Article abstract of DOI:10.1080/00397910903320241

Aza-Michael adducts are obtained in very good yields by the conjugate addition of aliphatic amines to α,β-unsaturated compounds using molecular iodine as catalyst in dichloromethane at room temperature. Aromatic amines were found to be reactive under reflux in toluene.

Full text of DOI:10.1080/00397910903320241

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Aza-Michael Addition of Amines to α,β-
Unsaturated Compounds Using Molecular
Iodine as Catalyst
Kalyan Jyoti Borah a , Mridula Phukan a & Ruli Borah a
a Chemical Sciences Department , Tezpur University, Napaam ,
Tezpur, Assam, India
Published online: 25 Aug 2010.
To cite this article: Kalyan Jyoti Borah , Mridula Phukan & Ruli Borah (2010) Aza-Michael Addition of
Amines to α,β-Unsaturated Compounds Using Molecular Iodine as Catalyst, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:19, 2830-2836,
DOI: 10.1080/00397910903320241
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Synthetic Communications1, 40: 2830–2836, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903320241
AZA-MICHAEL ADDITION OF AMINES TO
a,b-UNSATURATED COMPOUNDS USING
MOLECULAR IODINE AS CATALYST
Kalyan Jyoti Borah, Mridula Phukan, and Ruli Borah
Chemical Sciences Department, Tezpur University, Napaam, Tezpur,
Assam, India
Aza-Michael adducts are obtained in very good yields by the conjugate addition of aliphatic
amines to a,b-unsaturated compounds using molecular iodine as catalyst in dichloromethane
at room temperature. Aromatic amines were found to be reactive under reflux in toluene.
Keywords: Amine; b-amino carbonyl compound; aza-Michael addition; iodine; a,b-unsaturated compounds
INTRODUCTION
The conjugate addition of a nitrogen nucleophile to a a,b-unsaturated carbonyl
compound leads to the formation of a b-amino carbonyl compound, which is known
as Aza-Michael addition.[1] b-Amino carbonyl compounds have been considered not
only as building units of biologically important natural products including b-lactam
but also versatile nitrogen-containing intermediates such as b-amino alcohol, b-amino
acids, b-lactam antibiotics, and 1,2-diamines.[2] Among the methods for generating b-
amino carbonyl compounds, the Mannich reaction is a classical method for the prep-
aration of these derivatives. The conjugate addition of nitrogen nucleophiles to an
unsaturated system requires either basic or acidic catalysts.[3] Lewis acids catalyst, such
as SnCl4, AlCl3, or TiCl4, have been employed to effect this addition, but their use in stoi-
chiometric amounts often poses severe environmental problems in waste streams. Several
groups have reported[4] substoichiometric use of some Lewis acids, such as InCl3, BiNO3,
Cu(OTf)2, Bi(OTf)2, LiClO4, and hydrated CeCl3-NaI supported on silica gel or clay,
over the past few years.
In continuation of our earlier studies on iodine,[5] we wanted to extend the
catalytic activity of iodine on the conjugate addition of nitrogen nucleophiles to
a,b-unsaturated carbonyl compounds.
RESULTS AND DISCUSSION
Initially, we studied the addition of aliphatic amines to an a,b-unsaturated
system in dichloromethane at room temperature in the presence of iodine as catalyst.
Received May 6, 2009.
Address correspondence to Dr. Ruli Borah, Department of Chemical Sciences, Tezpur University,
Napaam, Tezpur 784028, Assam, India. E-mail: ruli@tezu.ernet.in
2830

ADDITION OF AMINES TO a,b-UNSATURATED COMPOUNDS
2831
Scheme 1. Synthesis of methyl 3-(N,N-diethylamino)-propionate using I2 as catalyst.
In a typical procedure, treatment of 0.1 mmol of iodine with a mixture of diethyl
amine (3 mmol) and methyl acrylate (3.3 mmol) in dichloromethane (3 ml) at ambi-
ent temperature gave the corresponding b-aminocarbonyl compound in 93% yield
(Scheme 1) within 15 min. The same reaction was done at room temperature in
Table 1. I2-catalyzed aza-Michael addition of aliphatic amine in dichloromethane at ambient temperature
Entry
Amine
Olefin
Product
Time
Yielda,b (%)
1
2
Et2NH
Et2NH
A
B
15 min
15 min
93
92
3
4
5
6
7
8
Et2NH
Et2NH
C
E
A
B
A
B
25 min
48 h
89
N=A
86
N=A
n-BuNH2
n-BuNH2
(iPr)2NH
(iPr)2NH
3 h
3 h
85
40 min
20 min
82
90
9
(iPr)2NH
(iPr)2NH
C
30 min
48 h
87
10
D
N=A
N=A
11
12
13
A
B
C
20 min
15 min
30 min
85
90
91
14
15
A
B
15 min
15 min
89
90
16
C
25 min
91
(Continued )

2832
K. J. BORAH, M. PHUKAN, AND R. BORAH
Table 1. Continued
Entry
Amine
Olefin
Product
Time
Yielda,b (%)
17
18
PhCH2NH2
PhCH2NH2
A
B
2.5 h
2.5 h
75
70
aAll the products were characterized by 1H NMR, IR, and mass spectrometry.
bIsolated yields.
Table 2. I2-catalyzed aza-Michael addition of aromatic amine under reflux condition using toluene as
solvent
Entry
Amine
PhNH2
PhNH2
Olefin
Product
Time (h)
Yielda,b (%)
1
2
A
B
7
8
70
65
3
4
4-NO2C6H4NH2
2-NO2C6H4NH2
A
A
N=A
N=A
20
20
N=A
N=A
5
6
7
4-MeO C6H4NH2
4-MeO C6H4NH2
4-Cl C6H4NH2
A
B
7
8
9
85
65
60
A
8
9
A
B
9
50
48
10
10
C
12
49
aAll the products were characterized by 1HNMR, IR, and mass spectrometry.
bIsolated yields.

ADDITION OF AMINES TO a,b-UNSATURATED COMPOUNDS
2833
the absence of iodine, and after 5 h, 60% of b-aminocarbonyl compound was
isolated. Various acyclic and cyclic aliphatic amines showed excellent 1,4-addition
with a range of a,b-unsaturated compounds to yield the corresponding adducts
(Table 1). The reaction completed within 15–40 min for secondary aliphatic amines
in the presence of methyl acrylate, acrylonitrile, and methyl merthacrylate. However,
with the primary amine (entries 5, 6, 17, and 18), the reaction was sluggish and
took 3 hr.
To extend the scope of this methodology, we tested the catalytic activity of iod-
ine for aniline and methyl acrylate condensation. At room temperature, no conden-
sation occurred; however, in refluxing toluene, the reaction went satisfactorily. We
have summarized the results of other aromatic amines in Table 2.
EXPERIMENTAL
All reactions were monitored by thin-layer chromatography (TLC) using silica
1
gel (Merck, 60–120 mesh). HNMR spectra were recorded on a Varian 400-MHz
FT-NMR spectrometer using CdCl3 as solvent and tetramethylsilane (TMS) as
internal standard. Mass spectrometry data were obtained on a Perkin-Elmer Clarus
600C mass spectrometer. Infrared (IR) data were recorded on a Nicolet instruments
410 Fourier transform (FT)–IR spectrophotometer using KBr optics. All products
1
were characterized by comparison of their IR, H NMR, and mass spectra with
those of authentic samples.[4e,6] The starting chemicals were obtained from commer-
cial suppliers and used without further purification.
General Procedure for the Synthesis of b-Amino Carbonyl
Compound
Iodine-catalyzed aza-Michael addition of aliphatic amine. A mixture of
aliphatic amine (3 mmol), a,b-unsaturated compound (3.3 mmol), and I2 (0.1 mmol)
in dichloromethane (3 ml) was stirred at ambient temperature for a definite period.
The progress of the reaction was monitored by TLC. After completion, the reaction
mixture was diluted with 10 ml of distilled water and washed with an aqueous sol-
ution of sodium thiosulfate for removal of iodine. Then the mixture was extracted
with dichloromethane (3 ꢀ 10 ml). The dichloromethane extracts were dried over
anhydrous sodium sulfate and removed in a rotary evaporator under reduced press-
ure. The crude reaction mixture was further purified by silica-gel column chromato-
graphy with different ratios of n-hexane and ethyl acetate as solvent system. The
product was isolated in pure form.
Iodine-catalyzed aza-Michael addition of aromatic amine. A mixture of
aromatic amine (3 mmol), a,b-unsaturated compound (3.3 mmol), and I2 (0.1 mmol)
in toluene (3 ml) was refluxed at 110 ꢁC for a definite period. The progress of the
reaction was monitored by TLC. After completion, the reaction mixture was diluted
with 10 ml of distilled water and washed with an aqueous solution of sodium thiosul-
fate for removal of iodine. Then the mixture was extracted with ethyl acetate
(3 ꢀ 10 ml). The ethyl acetate extracts were dried over anhydrous sodium sulfate
and removed in a rotary evaporator under reduced pressure. The crude reaction

2834
K. J. BORAH, M. PHUKAN, AND R. BORAH
mixture was further purified by silica-gel column chromatography with different
ratios of n-hexane and ethyl acetate as solvent system. The product was isolated
in pure form.
Spectral Data for Selected Compounds
3-(N,N-Diethylamino)-propionitrile (Table 1, entry 2)[6d]. Oil, IR (neat)
cmꢂ1: 2978, 2916, 2244. 1H NMR (CdCl3): d 2.67 (t, J ¼ 7.0 Hz, 2H), 2.40 (q,
J ¼ 7.3 Hz, 4H), 2.30 (t, J ¼ 7.0 Hz, 2H), 0.92 (t, J ¼ 7.3 Hz, 6H). MS (EI, 70 eV):
m=z ¼ 127 (M þ 1).
3-Butylaminopropionitrile (Table 1, entry 6)[6a]. Oil, IR (neat) cmꢂ1: 3440,
1
2960, 2916, 2253. HNMR (CdCl3): d 2.92 (t, J ¼ 6.65 Hz, 2H), 2.59 (t, J ¼ 7.15 Hz,
2H), 2.5 (t, J ¼ 6.64 Hz, 2H), 1.43–1.47 (m, 2H), 1.33–1.37 (m, 2H), 0.92
(t, J ¼ 7.5 Hz, 3H). MS (EI, 70 eV): m=z ¼ 127 (M þ 1).
Methyl-3-piperidinyl-propionate (Table 1, entry 11)[6d]. Oil, IR (neat)
1
cmꢂ1: 2936, 2856, 1738. H NMR (CdCl3): d 3.63 (s, 3H), 2.62 (t, J ¼ 8.0 Hz, 2H),
2.45 (t, J ¼ 8.0 Hz, 2H), 2.32–2.34 (m, 4H), 1.55–1.34 (m, 6H). MS (EI, 70 eV): m=
z ¼ 172 (M þ 1).
(3-Piperidin-1-yl)propionitrile (Table 1, entry 12)[6a]. Oil, IR (neat) cmꢂ1
:
1
2934, 2857, 2806, 2244. H NMR (CdCl3): d 2.65–2.70 (m, 2H), 2.51 (m, 2H), 2.43
(m, 4H), 1.55–1.57 (m, 4H), 1.44 (m, 2H). MS (EI, 70 eV) m=z ¼ 139 (M þ 1).
Methyl-3-pyrrolidinyl-propionate (Table 1, entry 14)[6d]. Oil, IR (neat)
1
cmꢂ1: 3410, 2959, 2872, 1736. H NMR (CdCl3): d 3.67 (s, 3H), 2.88 (t, J ¼ 7.0 Hz,
Hz, 2H), 2.26–2.35 (m, 6H), 1.18 (m, 4H); MS (EI, 70 eV): m=z ¼ 158 (M þ 1).
Methyl (2-methyl-3-pyrrolidinyl)-propionate (Table 1, entry 16)[6d]. Oil,
1
IR (neat) cmꢂ1: 3405, 2966, 1738. H NMR (CdCl3): d 3.67 (s, 3H), 2.82–2.40 (m,
7H), 1.75 (m, 4H), 1.15 (d, J ¼ 8.5 Hz, 3H). MS (EI, 70 eV) m=z ¼ 173 (M þ 1).
Methyl-3-phenylaminopropionate (Table 2, entry 1)[6e]. Oil, IR (neat)
cmꢂ1: 3377, 2929, 2727, 1736.1H NMR (CdCl3): d 7.16–7.23 (m, 2H), 6.67 (m,
1H), 6.63 (d, J ¼ 7.7 Hz, 2H), 4.00 (br, 1H), 3.68 (s, 3H), 3.47 (t, J ¼ 6.5 Hz, 2H),
2.65 (t, J ¼ 6.5 Hz, 2H). MS (EI, 70 eV): m=z ¼ 180 (M þ 1).
3-Phenylaminopropionitrile (Table 2, entry 2)[6a]. Oil, IR (neat) cmꢂ1
:
3356, 2960, 2926, 2245. 1H NMR (CdCl3): d 7.18–7.25 (m, 2H), 6.75–6.77 (m,
1H), 6.67–6.63 (d, J ¼ 7.6 Hz, 2H), 4.00 (br, 1H), 3.47 (t, J ¼ 6.5 Hz, 2H), 2.61 (t,
J ¼ 6.5 Hz, 2H). MS (EI, 70 eV): m=z ¼ 147 (M þ 1).
3-(4-Methoxyphenylamino)propionitrile (Table 2, entry 6)[6a]. Oil, IR
1
(neat) cmꢂ1: 3357, 2959, 2828, 2243. H NMR (CdCl3): d 2.62 (t, J ¼ 6.5 Hz, 2H),
3.45 (t, J ¼ 6.5 Hz, 2H), 3.76 (s, 3H), 6.54 (d, J ¼ 8.8 Hz, 2H), 6.80 (d, J ¼ 8.8 Hz,
2H). MS (EI, 70 eV): m=z ¼ 177 (M þ 1).
Methyl-3-(imidazol-1-yl)propionate (Table 2, entry 8)[6f]. Oil, IR (neat)
1
cmꢂ1: 1732, 1509. H NMR (CdCl3): d 7.54 (s, 1H), 7.05 (s, 1H), 6.93 (s, 1H),

ADDITION OF AMINES TO a,b-UNSATURATED COMPOUNDS
2835
4.27 (t, J ¼ 6.6 Hz, 2H), 3.70 (s, 1H), 2.78 (t, J ¼ 6.6 Hz, 2H). MS (EI, 70 eV):
m=z ¼ 155 (M þ 1).
CONCLUSION
In conclusion, we have developed a mild and efficient Aza-Michael addition of
aliphatic and aromatic amines to a,b-unsaturated compounds in organic solvent
using molecular iodine as catalyst. The advantages of this method include excellent
yield, simple workup procedure, good product selectivity, inexpensive catalyst, short
reaction time for aliphatic amines, and most importantly reactivity toward aromatic
amine at higher temperatures.
ACKNOWLEDGMENTS
The authors are thankful to the Council of Scientific and Industrial Research,
New Delhi, India, for Research Project Grant No. 01(2067)=06=EMR-II to R. B.
and to Central Instrument Facility, Indian Institute of Technology, Guwahati, for
their cooperation in sample analysis.
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